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A Systematic Review of Subjects for PG Medical Entrance Examinations

A Systematic Review of Subjects for PG Medical Entrance Examinations

Pradip Kumar Das


MD (RD), PGT

IPGME&R and SSKM Hospital Kolkata, India

JAYPEE BROTHERS MEDICAL PUBLISHERS (P) LTD


Kolkata St Louis (USA) Panama City (Panama) New Delhi Ahmedabad Bengaluru Chennai Hyderabad Kochi Lucknow Mumbai Nagpur

Published by Jitendar P Vij Jaypee Brothers Medical Publishers (P) Ltd Corporate Office 4838/24 Ansari Road, Daryaganj, New Delhi - 110002, India Phone: +91-11-43574357, Fax: +91-11-43574314 Registered Office B-3 EMCA House, 23/23B Ansari Road, Daryaganj, New Delhi - 110 002, India Phones: +91-11-23272143, +91-11-23272703, +91-11-23282021 +91-11-23245672, Rel: +91-11-32558559, Fax: +91-11-23276490, +91-11-23245683 e-mail: jaypee@jaypeebrothers.com, Website: www.jaypeebrothers.com Offices in India Ahmedabad, Phone: Rel: +91-79-32988717 e-mail: ahmedabad@jaypeebrothers.com Bengaluru, Phone: Rel: +91-80-32714073 e-mail: bangalore@jaypeebrothers.com Chennai, Phone: Rel: +91-44-32972089 e-mail: chennai@jaypeebrothers.com Hyderabad, Phone: Rel:+91-40-32940929 e-mail: hyderabad@jaypeebrothers.com Kochi, Phone: +91-484-2395740, e-mail: kochi@jaypeebrothers.com Kolkata, Phone: +91-33-22276415, e-mail: kolkata@jaypeebrothers.com Lucknow, Phone: +91-522-3040554 e-mail: lucknow@jaypeebrothers.com Mumbai, Phone: Rel: +91-22-32926896 e-mail: mumbai@jaypeebrothers.com Nagpur, Phone: Rel: +91-712-3245220 e-mail: nagpur@jaypeebrothers.com Overseas Offices North America Office, USA, Ph: 001-636-6279734 e-mail: jaypee@jaypeebrothers.com, anjulav@jaypeebrothers.com Central America Office, Panama City, Panama, Ph: 001-507-317-0160 e-mail: cservice@jphmedical.com, Website: www.jphmedical.com A Systematic Review of Subjects for PG Medical Entrance Examinations 2010, Pradip Kumar Das All rights reserved. No part of this publication should be reproduced, stored in a retrieval system, or transmitted in any form or by any means: electronic, mechanical, photocopying, recording, or otherwise, without the prior written permission of the author and the publisher. This book has been published in good faith that the material provided by author is original. Every effort is made to ensure accuracy of material, but the publisher, printer and author will not be held responsible for any inadvertent error (s). In case of any dispute, all legal matters are to be settled under Delhi jurisdiction only. First Edition: 2010 ISBN 978-81-8448-865-4 Typeset at JPBMP typesetting unit Printed at

Charis ne dhare thak ente, Ore hobe tor joy! Andhokar jay bujhi kete, Ore ar nei bhoy (Dont give up; hold tight, you will win. The dark is fading away, fear nothing) Rabindranath Tagore Gitanjali, 109

To My parents Sri Mahadeb Das and Smt Gouri Das And to my family and friends

Foreword
I am very glad to know that the book A Systematic Review of Subjects for PG Medical Entrance Examinations by Dr Pradip Kumar Das is coming out. Dr Das is one of my postgraduate trainees. I have seen the manuscript and have gone through few chapters. I found the matter of the book is very comprehensive and especially the systematic approach is unique. I think that this approach covers maximum topics in minimum space and it also saves one from unnecessary repetition of the same matter again and again. I am sure that this book will be very helpful for students preparing for various postgraduate medical entrance examinations both at the national and state levels. I wish Dr Das all the success. Prof (Dr) PK Deb Vice-Chancellor West Bengal University of Health Sciences Kolkata, India

Preface
Advances in medical knowledge have made the medical science changing everyday. It demands hard toil and constant vigilance to be at par with these advances. Preparation for PG medical entrance examinations require a firm grip on both the existing information and the new information coming in. While preparing for PG medical entrances, my friends and I felt the need for a book that will contain the already existing information, as relevant to our preparation as much as possible. We started our preparation with the good old technique of solving MCQs and underlining the textbooks. At the end of this basic work, we found that many valuable months have passed by. Why this book A Systematic Review of Subjects for PG Medical Entrance Examinations aims to contain as many information as possible, asked in previous exams or relevant to our preparation within the bounds of two covers. This is the result of the basic work of solving MCQs and scrutinizing the information again and again. The information contained herein has been gathered over several years from various sources, some of which are mentioned at the appendix. I have meticulously tried to verify every information and put in only those that have been asked or likely to be asked in various PG medical entrances. Information from major textbooks is contained in this book. The purpose of the book is to save time and energy for the basic work of building up a minimum level of knowledge base for PG entrances, to act as a readyreference for any topic and for rapid review before the exams. This book is a complement to and not a substitute for the textbooks; but I assure, this will save a lot of your valuable time and effort. It is not possible to mention references of all the information. But I have tried to believe on only those written in any textbook as much as possible. I realize, there may be statements that appear unlikely and their verification has been left to the user. As for me,

x A Systematic Review of Subjects for PGMEE I can say that I have tried to keep such disputable information as low as possible. How to use this book Of the many possible ways of organizing such a book, I have selected the systematic approach that is to take a system at a time and discuss topics from all the subjects, as relevant, starting from anatomy to medicine and surgery. The benefit of this approach is that, you do not have to read the same information again and again. As can be appreciated, it is not possible to cover all the subjects in one volume; this book certainly contains all the major information. You can start with a standard question bank and this book; take up a topic and solve the questions from the book. At the end, I am sure that you will find that you have covered up a great deal of information. I sincerely hope that A Systematic Review of Subjects for PG Medical Entrance Examinations will serve you in your preparation the way it helped me and many of my friends. Any kind of suggestion, correction and criticism is cordially welcome. Pradip Kumar Das e-mail: dr_pradipkdas@yahoo.co.in

Acknowledgments
No word of thanks can express my gratitude to my family members (Mahadeb Das, Gouri Das, Purabi Roy, Karabi Sarkar, Sudeb Das, Rajen Roy, Dipak Sarkar, Sweta and Deepro) who have always been a support to me in all my endeavors. They have been a constant source of inspiration for me. Mr Sudeb Das helped me in all stages of preparing the book; I convey my thanks and love to him. Dr Debasish Dey was instrumental in initiation of the process; I thank him for his support. I am thankful to many of my friends who have read my notes and encouraged me to bring it out as a book. I would like to mention the names of Dr Nimai Biswas, Dr Chinmay Nandi, Dr Susanta Bhanja, Dr Atanu Biswas, Dr Saroj Kumar Halder, Dr Soumya Mondal, Dr Santanu Suba, Dr Pramit Ghosh and all my friends at Calcutta Medical College and Dr Somnath Sarkar, Dr Bhaskar Mukherjee of NRS Medical College. I express my gratitude to my friends Mr Rana Das and Mr Surajit Ghosh for their support and company. A special word of thanks goes to Miss Malabika Das. I am grateful to my teacher Prof (Dr) PK Deb for forwarding this book. I am also thankful to my teachers (Prof Dr Utpalendu Das, Dr Sohini Sengupta, Dr Samiran Samanta, Prof Dr AK Bhadra, Dr T Dhibar) and friends at the Department of Radiology, IPGME&R and BINP , SSKM Hospital. Finally, I would thank all the staff of Jaypee Brothers Medical Publishers (P) Ltd. for their effort in publishing this book.

Contents
1. General Discussion ................................... 1 2. Gastrointestinal System .......................... 88 3. Respiratory System ............................... 164 4. Cardiovascular System .......................... 212 5. Immune System .................................... 259 6. Renal System ........................................ 309 7. Neurological Disorders .......................... 347 8. Endocrinology and Metabolism ............. 393 9. Infectious Diseases ............................... 472 10. Hematology .......................................... 637 11. Oncology .............................................. 705 12. Dermatology ......................................... 816 13. Genetics ............................................... 841 14. Nutrition ............................................... 871 15. General Pathology ................................. 901 Supplement ........................................... 930 Appendices ........................................... 957 Index .................................................... 961

1
PAIN PATHWAY

GENERAL DISCUSSION
PAIN
Peripheral receptors (naked nerve endings) Primary sensory afferents (A and C fibers) Dorsal root ganglia in the vertebral foramina Lateral spinothalamic tract (along with temperature sensation) Crosses mid-line Thalamus (opposite side) Somatic sensory area I in the post-central gyrus. II in the wall of Sylvian fissure.

Neurotransmitter For fast pain is Glutamate. For slow pain is substance P . PAIN PHYSIOLOGY Visceral Pain Viscera are relatively insensitive to noxious stimuli under normal circumstances. True visceral pain is produced by distension of a hollow viscus, spasmodic contraction, ischemia. Cutting does not induce visceral pain (also crushing or burning). Neuropathic Pain Pain produced by damage or dysfunction of the nervous system e.g. diabetic neuropathy.

2 A Systematic Review of Subjects for PGMEE Chronic Pain Syndrome Sympathetically maintained. i. Causalgia Severe burning pain produced by peripheral nerve injury in the region innervated by the nerve. ii. Reflex sympathetic osteodystrophy Most common cause is Colles fracture of forearm. Clinical feature: Pain, stiffness and swelling of hand. The overlying skin is tense and shiny. Treatment: Sympathetic (stellate ganglion) block. iii. Spontaneous pain is seen in thalamic syndrome due to damage of posterior thalamic nuclei caused by obstruction of posterior cerebral artery. Note: Indications of sympathectomy: i. Hyperhydrosis (NOT anhydrosis) ii. Causalgia iii. Reflex sympathetic osteodystrophy iv. Frost bite v. Raynauds disease vi. Thromboangiitis obliterans vii. Claudication not very effective, but indicated to relieve rest pain and ulceration (ischemic). Note: Allodynia means perception of nonpainful stimulus as painful. Referred Pain Pain from a viscus may be felt at some somatic structure which may be a considerable distance away. Such referral of pain is due to convergence of nerve fibers from the viscus and somatic structure at the spinal cord. For example, pain from diaphragm is referred to the tip of the shoulder because both are supplied by phrenic nerve. CHEST PAIN Anginal Pain Typically develops on exertion, after heavy meals or emotional stress, not affected by position, respiratory movement, etc. and resolves within 5 - 30 minutes. Site: Substernal region, anterior mid-thorax. Diagnosis: Pain is relieved more quickly (within 5 min) and more completely with sublingual nitroglycerine.

General Discussion

Myocardial infarction: Similar to angina but of more intensity and greater duration. Pain often radiates to left arm. Not relieved by rest or nitroglycerine. Accompanied by diaphoresis, nausea and hypotension. Pericarditis: Pericardium is pain insensitive. Pericardial pain is due to involvement of overlying pleura. Infectious pericarditis, nearly always involves the pleura and is always associated with pain. It is brought on by swallowing. Aggravated by cough and / or deep inspiration. Relieved in upright sitting position with body leaning forward. HEADACHE Pain sensitive structures in cranium are the scalp and aponeurotica, middle meningeal artery, dural sinuses, falx cerebri and large pial arteries. Lumbar Puncture Headache Occipitofrontal headache following lumbar puncture (usually within 48 hours). It is typically positional, increases on sitting and decreases on lying down. Last for 7 10 days. Cause Leakage of CSF. Prevention: Using small (25 G) bore needle. Treatment: IV caffeine sodium benzoate. Other types of headache See neurology section. BACK PAIN Disc Prolapse Site: Between L4 L5 in lumbar spine (most common), C5C6 in cervical spine. Tests: To detect nerve root compression i. Straight leg raising test. ii. Lasegue test. Defect: L4 root: Weakness of extensors of the knee. Knee jerk sluggish or absent. L5 root: Weakness of extensor hallucis longus normal and dorsi-flexors of foot. Ankle jerk normal. Investigation: MRI is the investigation of choice.

4 A Systematic Review of Subjects for PGMEE Treatment: 1. Surgery Microdiscectomy is done in a case of posterolateral prolapse of disc. 2. Chemonucleosis Injection of chymopapain into the disc. Note: Inverted Lasegue sign is seen in lesion of L3. Spinal Stenosis Compression of cauda equina. Pain radiating down the lower limbs induced by walking and relieved by rest (pseudoclaudication). Spinal Tumors Most common spinal tumors are secondaries from breast (most common), lung, prostrate, etc.
Primary tumors are usually benign

Extradural - Osteoid osteoma (most common spinal tumor) IntramedullaryEpendymoma

Intradural

Extramedullary Meningioma Neurofibroma

Multiple myeloma is the most common primary tumor of spine. Neurofibroma is the most common intradural tumor. Note: Extramedullary tumors produce pain, early involvement of corticospinal tract and loss of sacral sensations. CSF protein is raised. Sciatica Pain radiating down the back of thigh and calf. Cause: Degenerative arthritis, disc prolapse. SHOULDER PAIN Thoracic Outlet Syndrome Cause Cervical rib syndrome (7th cervical spine, usually unilateral, more commonly on right side).

General Discussion

Scalenus anterior syndrome. First thoracic rib syndrome. Costoclavicular syndrome. Structures compressed are: Nerve lower trunk of brachial plexus (4th first dorsal nerve, ulnar nerve). Artery subclavian artery. Clinical Feature Neurogenic: Shoulder pain radiating down the arm, decreased sensation on the palmar aspect of 4th and 5th digits, weakness of the intrinsic muscles of hand. Vascular: Pain in forearm which is induced by the use of the arm and relived by rest. It is due to ischemic changes in the muscles of the arm. Test Adsons test pain is accelerated if the arm is in raised position at the time of exercise. Costoclavicular compressive test. Hyperabduction test. Treatment Prompt extraperiosteal excision of the cervical rib. Brachial Plexus Disease Lower trunk is most commonly involved. Symptoms are as above. Cause 1. Squamous cell Ca of lung most common (Pancoast tumor). 2. Postradiation fibrosis (Breast Ca). Lower trunk disease may be associated with Horners syndrome (ptosis, miosis, anhydrosis, enophthalmos and loss of ciliospinal reflex) due to involvement of lower cervical sympathetic ganglion (Stellate ganglion). Note: Deformities in brachial plexus injury:

6 A Systematic Review of Subjects for PGMEE Erbs Palsy Cause Injury (e.g. birth trauma) to the upper trunk. Nerve roots involved mainly C5, partly C6. Deformity Arm: Adducted and medially rotated. Forearm: Extended and pronated. This is known as policemans tip hand or porters tip hand. Disability Movements lost are: Arm: Abduction and lateral rotation. Forearm: Flexion and supination. Klumpices Palsy Cause Injury to the lower trunk. Nerve roots involved mainly T1, partly C8. Deformity Claw hand hyperextension of the MCP joints and flexion of IP joints. Horners syndrome may be present. 1. Injury to nerve of Bell (long thoracic nerve C5, 6, 7) which supplies serratus anterior. Deformity: Winging of scapula. Disability: Loss of pushing and punching actions. Inability to abduct arm beyond 90o.

TEMPERATURE
PHYSIOLOGY Normal body temperature is 36.8oC 0.4oC (98.2oF 0.7oF).

General Discussion

Circadian rhythm: body temperature is maximum at 6 pm and minimum at 6 am (AM nadir and PM peak). Measurement: the following temperatures reflect the core temperature. i. Rectal most accurate, 0.5 1oF higher than oral temperature. ii. Lower esophageal. iii. Freshly passed urine. Regulation: By preoptic anterior (heat) and posterior (cold) hypothalamus. Heat acclimatization: Increase sweating to dissipate heat and conservation of fluid otherwise (decrease renal blood flow, increase aldosterone secretion which leads to Na+ retention and low urinary Na). FEVER AND HYPERTHERMIA Fever AM temperature > 98.9oF or PM temperature > 99.9oF. Pyrogen: Endotoxins (lipopolysaccharides), cytokines IL1, IL1, TNF, IFN, IL. Hyperpyrexia Temperature > 106oF. Causes: Malaria, septicemia, encephalitis, pontine hemorrhage, lobar pneumonia, heat stroke, datura poisoning. Malignant hyperthermia: Neuroleptic malignant syndrome. Types of Fever 1. Intermittent Fever present only for several hours and always touches the baseline. Causes: a. Quotidian occurs daily. E.g. Double infection with P. vivax. b. Tertian Fever occurs on first and third days (48 hours apart). E.g. Benign tertian malaria (P . vivax), malignant tertian malaria (P. falciparum). c. Quartan Fever on first and fourth days (72 hours apart). E.g. Quartan malaria (P. malariae).

8 A Systematic Review of Subjects for PGMEE 2. Continued/Sustained Fluctuation <1 o C and temperature never touches baseline. E.g. Lobar pneumonia, second week of typhoid fever, Meningococcal meningitis. 3. Remittent Daily fluctuation > 2oC but never touches baseline. E.g. Tuberculosis, viral infections and amebic liver abscess. 4. Relapsing fever Borrelia burgdorferi. 5. PelEbstein fever fever lasting 3 10 days followed by afebrile periods of 310 days. Classically seen in Hodgkins lymphoma. 6. Fever of cyclic neutropenia fever occurs every 21 days and accompany the neutropenia. Pulse-Temperature Ratio With every 1oF rise in temperature there is increase in pulse by 10 beats/min. Relative bradycardia is seen in typhoid fever, brucellosis, leptospirosis, acute rheumatic fever. Relative tachycardia seen in TB, diphtheritic myocarditis, PAN. Pulse-respiration Ratio With every 1oF rise in temperature there is increase in respiratory rate by 23 / min. Normal 4:1 (72:18) Increase 12:1 (72:6) seen in narcotic poisoning. Decrease 2:1 (72:36) seen in acute lobar pneumonia. Drug Induced Hyperthermia Seen in MAO inhibitors, TCAs, Amphetamines. Malignant Hyperthermia Inherited abnormality of skeletal muscles. Pathology: Increased intracellular Ca++ level due to release from sarcoplasmic reticulum leads to muscle contraction. Precipitated by: Halothane, Succinylcholine.

General Discussion

Features: Increased temperature, muscle contraction rigidity, rhabdomyolysis, acidosis. Treatment: External cooling. O2 inhalation, bicarbonate infusion, IV dantrolene. Investigation: Increased serum CPK. Neuroleptic Malignant Syndrome Caused by: Chlorpromazine, Haloperidol. Characterized by: Hyperthermia, muscle rigidity, tremor, semi-consciousness, fluctuating BP and heart rate. Treatment: IV dantrolene, bromocriptine. Heatstroke Complications: DIC, shock, hyperkalemia, hypocalcemia, cerebellar degeneration. HYPOTHERMIA Core temperature 35oC Risk factors: Extremes of age, ethanol use, Malnutrition, Hypothyroidism. Effects: Hypotension, bradycardia. Early tachypnea followed by hypoventilation. ECG QT prolongation, Osborn (J) wave, Lactic acidosis, hypoactivity, hyperglycemia. Complications: Atrial arrhythmias. Treatment: Re-warming Which should not be prompt. Methods Extracorporeal blood warming by hemodialysis or cardiopulmonary bypass best method. IV warmed NS. Neonatal Hypothermia Signs: Bradycardia, sclerema, metabolic acidosis. Treatment: Convection warmed incubators.

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A Systematic Review of Subjects for PGMEE

NERVOUS SYSTEM DYSFUNCTION


SYNCOPE Causes 1. Decreased cerebral blood flow: i. Vasovagal. ii. Postural or orthostatic. iii. Carotid sinus syncope. 2. Decreased venous return: i. Valsalva maneuver. ii. Cough. iii. Micturition. 3. Decreased cardiac output: i. Cardiac tamponade. ii. Aortic stenosis. 4. Arrhythmias: Second and third degree AV block with Stokes - Adams syndrome. 5. Congenital heart disease: Tetralogy of Fallot. Treatment 1. Vasovagal syncope with normal LV systolic functions -blockers, Disopyramide, Theophylline, Scopolamine and ephedrine. 2. Postural syncope: Postganglionic type: Salt loading, Fludrocortisone. Preganglionic type: Tyramine, MAO inhibitors. 3. Carotid sinus syncope Atropine or ephedrine. VERTIGO The most common cause of pathologic vertigo is vestibular dysfunction. Mnires Disease It is the most common cause of otogenic vertigo. Pathology: Hydrops or distension of the endolymphatic system. Clinical feature: Age group affected - 3050 years. Unilateral symptoms.

General Discussion

11

Episodic attacks of: Rotatory vertigo, fluctuating deafness (sensorineural), tinnitus, fullness in ear. Investigation: Audiometry Sensorineural deafness more in lower frequency (Cochlear). Recruitment tests - +ve on the affected side. Treatment: 1. Nicotinic acid (Vasodilator) increases endolymphatic reabsorption. 2. Surgery Cody tack operation.

WEAKNESS
PHYSIOLOGY OF MOTOR SYSTEM Higher Center The following parts of brain are involved in motor activities: 1. Cerebral cortex highest center. Motor cortex in the precentral gyrus (Brodmann area 4). Premotor cortex posterior ends of inferior, middle and superior frontal gyri (Brodmann area 6 and 8). Supplementary motor area on medial surface of brain. Note: In motor cortex, various parts of the body are represented in an inverted manner. Only the facial area is represented bilaterally. All other areas are unilateral, controlling movements of the opposite side. Spinocerebellum (medial) smoothens and coordinates movements. 2. Cerebellum Neocerebellum (lateral) planning and organizing voluntary movements. 3. Basal ganglia Planning and programming of movements. Descending Tracts A. PYRAMIDAL TRACTS: They arise from cerebral cortex and end either on motor neurons in spinal cord or cranial nerve nuclei in brainstem.

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A Systematic Review of Subjects for PGMEE

1. Corticospinal tract: a. Lateral corticospinal tract produces an elevation (pyramid) in midbrain. They comprise about 80 percent fibers of pyramidal system. They descend through the internal capsule, cross midline at cervicomedullary junction and end on lateral neurons in the ventral horn of spinal cord (on opposite side). Action concerned with distal limb muscle and with skilled movements (of opposite side). b. Ventral corticospinal tract 20 percent fibers that do not cross the midline until at the level where they synapse with motor neurons. They end primarily on interneurons (on the same side) which cross the midline and end on medial neurons in the ventral horn of spinal cord. Action control axial and proximal limb muscles. 2. Corticobulbar tract: From cerebral cortex to cranial nerve nuclei in the brainstem (usually on the opposite side). Some fibers end bilaterally e.g. those for muscles of mastication and upper half of face. Note: Locations of cranial nerve nuclei Midbrain 3 and 4. Pons 5, 6, 7 and 8. Medulla 9, 10, 11 and 12. B. EXTRAPYRAMIDAL (BULBOSPINAL TRACTS): 1. Ventromedial bulbospinal tracts: a. Tectospinal originate from tectum in midbrain. b. Vestibulospinal from the lateral and medial vestibular nuclei. c. Reticulospinal from the reticular formation. Action Influence axial and proximal muscles and are involved in maintenance of posture and integrated movements of limbs and trunk. 2. Ventrolateral bulbospinal tract: Rubrospinal from magnocellular portion of red nucleus. Action facilitate distal limb muscles. UMN vs LMN Upper motor neuron (UMN) neurons that contribute to pyramidal tract (Corticospinal + Corticobulbar).

General Discussion

13

Lower motor neuron (LMN) Anterior horn cells and related cranial motor nuclei and their axons. Difference between UMN lesion and LMN lesions
Sign 1. 2. 3. 4. 5. Atrophy Fasciculation Tone Tendon reflexes Babinskis sign UMN lesion Spastic Hyperactive + LMN lesion + + Flaccid Hypoactive/absent

Note: In Friedrichs ataxia, Babinskis sign is +ve (UMN lesion) but deep tendon reflexes are absent (LMN type). PATHOLOGY OF MOTOR SYSTEM Hypertonia Causes 1. UMN lesion (clasp knife spasticity) 2. Extrapyramidal lesion except chorea (lead pipe or cogwheel rigidity) e.g. Parkinsonism. 3. Tetanus. 4. Tetany hypocalcemia. 5. Strychnine poisoning. Types Spasticity in pyramidal (UMN) lesion. Rigidity in extrapyramidal lesion. Paratonia or Gegenhatten in frontal lobe lesion. Hypotonia (Flaccidity) Causes 1. 2. 3. 4. 5. 6. 7. LMN lesion. Tabes dorsalis (Posterior column lesion) Chorea Cerebellar lesion. Myopathy. Hypokalemia or hypercalcemia. Others Downs syndrome, Rickets.

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A Systematic Review of Subjects for PGMEE

CLINICAL Hemiplegia Due to UMN lesion above the midcervical spinal cord. Most common cause Thrombosis of lenticulostriate branch of middle cerebral artery. Investigation: CT scan, MRI. Crossed Hemiplegia Due to brainstem lesion. E.g. Webers syndrome Ipsilateral third nerve palsy (LMN type) with contralateral hemiplegia, due to midbrain (mesencephalon) lesion. Paraplegia Due to intraspinal lesions at or below the upper thoracic spinal cord level. Cause A. Spastic paraplegia (UMN type): 1. Cord compression most commonly due to carries spine. 2. Motor neuron disease. 3. Multiple sclerosis. 4. Acute transverse myelitis. 5. Friedrichs ataxia. 6. Syringomyelia. 7. Lathyrism. 8. Cervical spondylosis. B. Flaccid paraplegia (LMN type): 1. Poliomyelitis. 2. GB syndrome. 3. Progressive muscular atrophy. 4. Myasthenia gravis. 5. Myopathy. Traumatic Paraplegia Most common cause of paraplegia is trauma. Site: Most common site of spinal injury is dorsolumbar spine.

General Discussion

15

Note: Lesion above C5 is fatal due to respiratory failure. Lesion at C5-C6 level produces quadriplegia. Clinical feature: Flaccid paraplegia in spinal shock stage. Spastic paraplegia later on. Often with bladder involvement. Investigation: MRI is the method of choice. Complications: Negative nitrogen balance, decubitus ulcer, hypercalcemia leads to calcium stones. UTI most common complication. Treatment 1. High dose corticosteroid as early as possible. 2. Bladder care Intermittent catheterization is best. Monoplegia Todds paralysis in epilepsy. Note: Descending motor paralysis is caused by Diphtheria, botulinum toxin and polio. MOVEMENT DISORDERS Tremor Rest tremor Parkinsonism. Postural tremor Hyperthyroidism. Intention tremor Cerebellar disease. Flapping tremor/Asterixis Hepatic failure (precoma), uremia, respiratory failure, CO2 narcosis, renal failure. Hemiballismus Sudden flinging movement of limbs. Cause: Infarction of the contralateral subthalamic nucleus of basal ganglia. Chorea Rapid, jerky, irregular quasipurposive movement of basal ganglia. Cause: Lesion in caudate nucleus. Sydenhams chorea Rheumatic fever. Huntingtons Chorea most common type. Levodopa toxicity most common cause of chorea.

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A Systematic Review of Subjects for PGMEE

Features: Hypotonia, pronator sign, milking sign, spooning sign, hung up reflex, lizard tongue. Athetosis Lesion in Lentiform nucleus (Globus pallidus). Note: Basal ganglia lesions produce Hyperkinetic movements - chorea, athetosis and ballism. Hypokinetic movements Akinesia and bradykinesia. Myoclonus Cause: Lipid storage disease, Encephalitis (SSPE), Creutzfeldt-Jakob disease, Metabolic encephalopathies. Electrolyte imbalance.

BALANCE AND GAIT


Control a. Head position in space Controlled by inner ear. The utricle and saccule sense static head position and acceleration (linear). The semicircular canals sense rotatory motions (angular acceleration). Impulses pass though vestibular nerve to the vestibular nuclei in the lower pons and upper medulla. b. Head position relative to body: Receptors for joint position, joint movement and muscle stretch. Impulses are transmitted via posterior column and medial lemniscal pathways to the cerebrum and the spinocerebellar pathways to the cerebellum. Ataxia It is defined as clumsiness of movement without sensory or motor disturbance. Types: a. Cerebellar ataxia. b. Sensory ataxia due to involvement of: i. Peripheral sensory nerves, e.g. peripheral neuropathy. ii. Posterior nerve root Tabes dorsalis.

General Discussion

17

iii. Posterior column Multiple sclerosis, syringomyelia. iv. Diseases of parietal lobe. Test Positive Romberg sing. c. Vestibular ataxia often with vertigo. Note: Fenkels exercise is done in a case of ataxia (e.g. Tabes dorsalis). Abnormal Gait 1. Hemiparetic gait in cerebral stroke. 2. Paraparetic or scissoring gait in spinal cord disease 3. Stamping gait in sensory ataxia, classically in Tabes dorsalis. 4. Steppage or Equine gait in common peroneal nerve palsy (with foot drop). (Anterior tibial nerve injury). 5. Festinant gait Parkinsonism. 6. Waddling gait Myopathy. 7. Drunker or ataxic gait Cerebellar ataxia or acute alcohol intoxication. 8. Apraxic gait in bilateral frontal lobe disease. 9. Astasia abasia hysterical gait disorders. Signs of Cerebellar Disease 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. Hypotonia. Scanning speech. Intention tremor. Pendular knee jerk. Dysmetria. Ataxia. Decomposition of movements. Dysdiadochokinesia. Rebound phenomenon. Drunken or ataxic gait. Titubation.

EPISODIC DISORDERS
Abnormal Facial Movements 1. Hemifacial spasm Often involves the muscles around eyes and caused by paroxysmal facial nerve activity.

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A Systematic Review of Subjects for PGMEE

2. Facial tics Gilles de la Tourette syndrome. 3. Synkinesis, e.g. jaw winking in Bells palsy (after recovery). 4. Tic douloureux trigeminal neuralgia. Abnormal Limb Movements 1. Fasciculation in motor neuron disease. 2. Akathisia Parkinsonism. 3. Restless leg syndrome uremia and other neuropathies (in middle aged females). 4. Startle syndrome or hyper-reflexias result from mutations in glycine receptors. Muscle Disorders 1. Myotonia Myotonic dystrophy. Myotonia congenita AD or AR inheritance. Due to defective Cl- channel. 2. Paramyalgia Rheumatic Clinical feature: Stiffness and pain in shoulder and hip in patients over age 50. Muscle biopsy shows: muscle atrophy, CPK level is normal. Treatment: NSAIDs and prednisolone. Episodic Weakness Causes: 1. Hype/hyperkalemia. 2. Hypo/hypercalcemia. 3. Hyponatremia. 4. Hypophosphatemia. 5. Hypomagnesemia. 6. Myasthenia gravis and LambertEaton syndrome.

SPEECH
PHYSIOLOGY Language is a function of the dominant or categorical hemisphere that is the left hemisphere in right handed persons (Perisylvian region).

General Discussion

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Areas: 1. Wernickes area (Area 22) Location posterior third of superior temporal gyrus. Action Comprehension of auditory and visual information. 2. Brocas area (Area 44) Location Posterior part of inferior frontal gyrus. Function Speech production. The above two areas are connected by arcuate fasciculus. Blood supply by middle cerebral artery. APHASIA Wernickes Aphasia (Sensory Aphasia) Comprehension is impaired but fluency is normal or increased. There is paraphasia, neologism Jargon speech. Cause: occlusion of inferior division of middle cerebral artery. Brocas Aphasia (Motor Aphasia) Comprehension is preserved but fluency is decreased. Others: Word finding pause (telegraphic speech). Cause: Occlusion of superior division of the middle cerebral artery. Global Aphasia Involvement of both Wernickes and Brocas areas. Cause: Occlusion of entire middle cerebral artery (cerebral stroke). Prognosis: Worst. Crossed aphasia: right hemispherical lesion in right handed person. Conduction Aphasia Comprehension and fluency are preserved, but repetition and naming are impaired.

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A Systematic Review of Subjects for PGMEE

Cause Lesion in arcuate fasciculus. Lesions of auditory cortex (area 40, 41, 42). Anomic Aphasia Only naming is impaired. There is difficulty in understating written language. Cause: Lesions in angular gyrus. Characteristically seen in head trauma, metabolic encephalopathy, Alzheimers disease. Pure Word Deafness Cause: Bilateral or left sided superior temporal gyrus lesion. Alexia Cause: Occlusion of posterior cerebral artery. Note: Scanning speech is seen in disseminated sclerosis. APRAXIA It is a disorder of initiating and planning movement. Cause: Right sided apraxia is caused by lesion of left frontal lobe, or the left temporoparietal region (especially the supramarginal gyrus). Type: Ideomotor apraxia most common type. Gerstmanns Syndrome Acalculia, dysgraphia, finger anomia and right-left confusion. Cause: Damage of inferior parietal lobe (angular gyrus) of left hemisphere. Balints Syndrome Spatial disorientation caused by Oculomotor apraxia, optic ataxia and simultanagnosia. Cause: bilateral lesion in parietal lobe. Dressing Apraxia Cause: Bilateral or right sided (non-dominant) dorsal parietal lobe lesion (also construction apraxia).

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Prosopagnosia Inability to recognize face. Cause: Bilateral lesion in fusiform and lingual gyri of occipitotemporal cortex.

SENSORY SYSTEM
PHYSIOLOGY Receptors 1. Naked nerve endings. 2. Expanded nerve endings i. Merkels discs Slow adapting ii. Ruffini endings touch receptors 3. Encapsulated endings Mechanoi. Pacinian corpuscles receptors ii. Meissners corpuscles Rapidly adapting iii. Krauses end bulbs touch receptors

Pathways Fibers: A (large myelinated) fine touch and pressure. A (small myelinated) Temperature and pain. C (small unmyelinated) Pain and temperature. Tracts: Touch Ventral spinothalamic tract. Pain and temperature Lateral spinothalamic tract. Touch and proprioception Dorsal column / Lemniscal system. Spinothalamic tracts:
Afferents from peripheral nerves enter the spinal cord through dorsal horn Crosses the midline and ascends as ventral or lateral spinothalamic tracts Project to ventral posterolateral nucleus (VPL) of thalamus Ultimately project to the postcentral gyrus of parietal cortex

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A Systematic Review of Subjects for PGMEE

Lemniscal system:
Fibers from dorsal horn ascend in the posterior column of the same side First synapse in the gracile and cuneate nuclei of medulla Second order neurons cross midline and lie medial to medulla (medial lemniscus) Synapse at VPL of thalamus Third order neurons project to parietal cortex

Higher Centers Somatic sensory area I Post-central gyrus in parietal cortex (Brodmann area 1, 2, 3). Somatic sensory area II in the wall of the Sylvian fissure in parietal cortex. Cortical Sensations 1. 2. 3. 4. Two-point discrimination. Touch localization. Graphesthesia. Stereognosis lost in parietal cortex lesion.

Lost in ablation of SI

PATHOLOGY Sensory Neuropathies Causes: 1. Diabetes. 2. Beriberi. 3. Leprosy. 4. Alcohol. 5. Vitamin B12 deficiency. Dissociated Sensory Loss Pain and temperature sensations are lost but touch is spared. Cause: Syringomyelia. Note: Balaclave helmet type of sensory loss over face is seen in syringomyelia.

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ALERTNESS, CONFUSION AND COMA


PHYSIOLOGY Reticular Activating System Wakefulness alertness is maintained my RAS. Location Midventral portion of the medulla and midbrain (reticular formation) + thalamus. Brainstem RAS neurons project to thalamic relay nuclei which in turn projects to neocortex. Note: The reticular formation contains motor, sensory, autonomic, all types of fibers. Brainstem Reflexes 1. 2. 3. 4. 5. Papillary reaction to light. Spontaneous eye movement. Oculocephalic reflex or Dolls eye Oculovestibular reflex. Corneal reflex.

Note: Normal cerebral blood flow (CBF) is 75 ml/100 g/ min in gray matter and 30 ml/100 g/min in white matter (mean 55 ml/100 g/min). CBF < 10 ml /100g/min produce irreversible brain damage. Normal O2 consumption of brain 3.5 ml/100 g/min. PATHOLOGY Three major groups of lesions produce confusion and coma: 1. Supratentorial mass e.g. cerebral hemorrhage or cerebral tumor. 2. Infratentorial lesion. 3. Metabolic disorders like hypoxia, hypercapnia, hyponatremia, hyperosmolarity, hypercalcemia, hypoglycemia and metabolic encephalopathies (hepatic, renal, respiratory failures). Supratentorial lesions produce secondary compression of brainstem due to transtentorial herniation.

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A Systematic Review of Subjects for PGMEE

CLINICAL Signs of Brain Death Three essential elements: 1. Widespread cortical destruction shown by deep coma Isoelectric EEG. 2. Brainstem damage absent pupillary light reaction, oculovestibular and corneal reflexes. 3. Medullary destruction Complete apnea. Others: 1. No Gag reflex. 2. No motor response. 3. Pulse invariant and unresponsive to atropine. Note: If respiration is maintained artificially heart, kidneys and liver may continue to function normally. But after brainstem death has occurred, cardiac arrest will follow within 2 weeks. Diagnosis: 1. Blood Ethanol level > 200 mg/dl causes confusion and impaired mental activity. Level > 300 mg/dl causes stupor. 2. CT scan and MRI 3. EEG Alpha coma (widespread 812 Hz activity)Caused by high pontine diffuse cortical damage and associated with a poor prognosis. Beta coma (Fast activity) Sedatives. Delta coma (High voltage slow waves in frontal region) Metabolic encephalopathy. 4. CSF study. Differential diagnosis: 1. Pontine hemorrhage Fever, pin point pupils, ocular bobbing (diagnostic), hyperventilation, sweating, pseudocoma. 2. Cerebellar hemorrhage Occipital headache, vomiting, gaze paresis, inability to stand. 3. Metabolic encephalopathy Asterixis or flapping tremor, most characteristic sign.

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MEMORY
PHYSIOLOGY 1. Short-term memory: a. Recent memory concerned with hippocampus and perihippocampal portion of medial temporal cortex. b. Immediate memory Perisylvian cortex, frontal lobe. 2. Long-term memory Association cortex. AMNESIA Types 1. Retrograde amnesia Inability to recall events preceding the amnesic state (recent memory loss). Long-term memory is intact. Causes Cerebral concussion, Electroconvulsive therapy. 2. Anterograde amnesia Inability to store, retain and recall new knowledge. Cause Bilateral medial temporal lobe lesion. Other causes of short-term memory loss: 1. Brain tumor. 2. Brain infarction. 3. HS encephalitis. 4. Chronic alcoholism. 5. Degenerative dementias Alzheimers disease and Picks disease. Frontal Lobe Syndrome 1. Abulia Due to damage to dorsolateral prefrontal cortex. E.g. tumor. 2. Disinhibition damage to medial prefrontal or orbitofrontal cortex. 3. Confabulation Lesion of ventromedial portion of frontal lobe. Note: Personality change is seen in frontal lobe lesion. Glabellar or palmomental reflexes are represented at frontal lobe.

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A Systematic Review of Subjects for PGMEE

DEMENTIA Loss of cognitive function (mainly memory) with clear conscience. Most important risk factor is increasing age. Causes a. Cortical dementia: 1. Alzheimers disease. 2. Picks disease. b. Subcortical dementia: 1. Huntingtons chorea. 2. Parkinsonism. 3. Wilsons disease. c. Vitamin deficiencies: 1. Thiamine (B1): (Wernickes encephalopathy) most commonly due to chronic alcoholism. 2. Vitamin B12 (pernicious anemia). 3. Nicotinic acid (B3) Pellagra. d. Endocrinal Hypothyroidism, Hypo/Hyperparathyroidism. e. Pseudodementia Depression. f. Head trauma Punch drunk syndrome or dementia puglistica in Parkinsonism. Normal pressure hydrocephalous. g. InfectionsPrion (Creutzfeldt-Jakob disease) HIV (AIDS dementia complex) h. Toxic Dialysis dementia due to aluminium. Features Lesion in Frontal Lobe Personality change, impaired memory, anosmia, urinary incontinence, antisocial behavior. Parietal Lobe a. Dominant lobe: Aphasia, acalculia (Gerstmanns syndrome), ideomotor apraxia, agnosia. b. Nondominant lobe: Construction and dressing apraxia, spatial disorientation, neglect of non-dominant side. c. Bilateral: Balints syndrome, homonymous hemianopia.

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Temporal Lobe Poor memory, complex hallucinations, homonymous hemianopia. Others Aphasia, dyslexia, loss of musical skill. Occipital Lobe Prosopagnosia, visual agnosia, visual hallucinations, homonymous hemianopia, hemianopic scotoma.

EYE AND VISION


PHYSIOLOGY Retina Macula lutea: Yellowish pigmented spot near the posterior pole, contains the pigment xanthophyll. Responsible for central 10o vision. Fovea centralis It the small pit in the center of macula. It contains only cones. Area of maximum visual acuity. Optic disc Lies 3 mm medial to posterior pole. Optic nerve leaves the eye and blood vessels enter at this point. Contains no visual pigment blind spot. Visual Pigments 1. Rods: Operative under dim light (scotopic vision). Contain The pigment rhodopsin which is made up of protein called opsin and an aldehyde called 11 cis retinal (vitamin A). On exposure to light 11cis retinal is converted to alltrans retinal and vice versa. There are 100 million roads in human retina. 2. Cones: Operative under bright light (photopic vision). Also responsible for color vision. Cones contain pigments (idopsin) which respond maximally to wavelengths 450, 535 and 565 nm (red, green and blue vision). There are 5 million cones in retina, maximum in macula.

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A Systematic Review of Subjects for PGMEE

Ocular Reflexes 1. Light reflex: Constriction of pupil on exposure to light (direct and consensual). This is mediated by constrictor muscle of iris (sphincter pupillae) which is supplied by parasympathetic nerve via oculomotor nerve. Pathway See later. 2. Accommodation reflex: Increase in curvature (of the anterior surface) of lens on looking at a near object. It is due to contraction of ciliary muscles and relaxation of lens ligaments. 3. Near reflex: Constriction of pupil on looking at a near object. It is mainly initiated by medial rectus muscle which converges eyeballs on looking at a near object. Note: Near response: consists of: i. Accommodation. ii. Convergence of visual axes. iii. Pupillary constriction. iv. Corneal reflex: Absent in CP angle tumors, mediated by trigeminal nerve. PATHWAYS Visual Pathway Pigment epithelium in retina Bipolar cell with its axons (1st order neuron) Ganglion cells (2nd order neuron) Optic nerve Crosses midline at optic chiasma (only nasal fibers) (Optic tract) Lateral geniculate body (Optic radiation) Visual cortex (Brodmann area 17) in Occipital cortex around calcarine sulcus. Note: Visual cortex is supplied by posterior and middle cerebral arteries. Light Reflex Same as visual pathway up to optic chiasma pre-tectal nuclei in midbrain EW nuclei on both sides parasympathetic output via oculomotor nerve through ciliary ganglion sphincter of the iris. Note: No LGB in light reflex pathway.

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PUPILLARY DEFECTS Hippus Alternate dilatation and contraction of pupil. Seen in multiple sclerosis. Argyll Robertson Pupil (ARP) Features: i. Absence of light reaction ii. Presence of accommodation reflex. iii. Miosis, irregular pupil iv. Normal VA and optic disc v. No response to mydriatics. (Mnemonic: ARP accommodation reflex present). Cause: Lesion between pretectal nuclei and EW nuclei (Internuncial neurons). i. Neurosyphilis ii. Obstructive hydrocephalus iii. Pineal region tumors iv. Others Diabetes, syringomyelia, multiple sclerosis, chronic alcoholism. Marcus-Gunn Pupil Or relative afferent pupillary defect (RAPD). Feature: Direct light response is less than consensual light reflex. Test: Swinging flash light test. Cause: Retrobulbar optic neuritis (most common). Adies Tonic Pupil Unilateral dilated pupil with poor light reaction and slow redilatation after removal of near object. Cause: Idiopathic (most common). Diagnosis: 0.125 percent pilocarpine test tonic pupil constricts rapidly.

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A Systematic Review of Subjects for PGMEE

Miosis Horners syndrome: 1. Miosis. 2. Pseudoptosis (due to paralysis of Mllers muscle supplied by cervical sympathetic nerve). 3. Enophthalmos. 4. Anhydrosis. Cause: 1. Idiopathic most common. 2. Squamous cell Ca of lung. 3. Brainstem stroke. 4. Carotid dissection. Mydriasis 1. Oculomotor nerve palsy. 2. Injury to ciliary ganglion due to infections, trauma, diabetes, temporal arteritis. 3. Hutchinsons pupil fixed dilated pupil in subdural hemorrhage. Note: In optic disc glioma Direct reflex is absent but consensual reflex is present (in any optic nerve lesion). In cortical blindness (bilateral occipital lobe lesion) both direct and consensual reflexes are present in both eyes. COLOR VISION Red, green and blue are primary colors. Theories of Color Vision The Young-Helmholtz theory postulates the presence of 3 different types of cones for 3 primary colors. Color Blindness Congenital Nomenclature: Anomaly = weakness Anopia = blindness Prot = Red Deuter = Green Tri = Blue

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Cause: Gene for blue cone is located on chromosome 7. Genes for red and green are located on the long arm of X chromosome. Mutations of these genes produce congenital color blindness. Mutation of blue cone gene is extremely rare. Hence, most of the cases are transmitted as X-linked recessive and manifest in males. Type: Most common type is deuteranopia. Diagnosis: Ishiharas chart for red-green vision. Negels anamaloscope. Secondary Causes: 1. Optic neuritis/macular disease. 2. Bilateral occipital lobe lesion (area V8) Cerebral achromatopsia color blindness, decrease VA, nystagmus, prosopagnosia. 3. Lesion in dominant occipital lobe color anomia. 4. Drugs Ethambutol, Sildenafil (Viagra). VISUAL FIELD Normal visual field It is 60o above and nasally (minimum) 70-75o below and 100-110o temporal (maximum) to fixation point (fovea). Test Perimetry. VISUAL FIELD DEFECTS (SCOTOMA) Glaucoma Selectively destroys the arcuate fibers. i. Isopter contraction first change. ii. Isolated paracentral scotoma earliest field defect. iii. Seidels scotoma iv. Arcuate (Bjerrums) scotoma - most characteristic

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Also seen in Optic neuritis, ischemic optic neuropathy, optic disc drusen and BRAO. When both superior and inferior arcuate fibers are involved it produces a ring around macula, called ring scotoma. v. Roennes nasal step vi. Double arcuate scotoma last field defect, produces tubular vision. Altitudinal Hemianopia Due to damage to entire upper or lower pole of optic disc. Causes: 1. Anterior ischemic optic neuropathy (AION) - most common cause. Due to occlusion of short posterior ciliary arteries, most commonly due to atherosclerosis. Produces sudden visual loss with inferior hemianopia. 2. Retinal vascular occlusion 3. Advanced glaucoma 4. Optic neuritis. Ceco-central Scotoma Due to damage to papillomacular fibers produces temporal pallor. Cause: 1. Optic neuritis most common cause 2. Nutritional optic neuropathy due to deficiency of thiamine (Vitamin B1) in heavy drinkers and pipesmokers. 3. Toxic amblyopic due to methyl alcohol, may produce total optic atrophy. Also by Ethambutol. 4. Lebers hereditary optic neuropathy. Scintillating Scotoma Seen in migraine. Ring Scotoma Retinitis pigmentosa.

General Discussion

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Damage to Visual Pathways a. Tumors anterior to optic chiasm Junctional scotoma. Cause Meningioma of tuberculum sella. b. Compression of optic chiasm Bitemporal hemianopia. Cause Pituitary adenoma, meningioma, craniopharyngioma, glioma, aneurysms. c. Injury to post-chiasmal pathway, i.e. optic tract, LGB, optic radiation and occipital cortex produces homonymous hemianopia. d. Damage to optic radiation in temporal lobe (Meyers loop) Superior quadrantopia. e. Damage to optic radiation in parietal lobe inferior quadrantopia. f. Lesion in occipital lobe due to occlusion of posterior cerebral artery produces homonymous hemianopia with macular sparing because tip of macula is supplied by middle cerebral artery. SYMPTOMATOLOGY Painful Red Eye 1. 2. 3. 4. 5. 6. Conjunctivitis most common cause Blepharitis Keratitis Uveitis Acute angle-closure glaucoma Endophthalmitis.

Sudden Visual Loss 1. Transient or amaurosis fugax Central retinal artery occlusion most commonly due to emboli (cholesterol emboli called Hollenhorst plaque) from atherosclerotic plaque in carotid artery. Also seen in papilledema. 2. Branch or central retinal vein occlusion. 3. Anterior ischemic optic neuropathy (AION). 4. Optic neuritis painful. 5. Lebers optic atrophy. 6. Toxic amblyopia. 7. Optic disc drusen. 8. Vitreous degeneration/hemorrhage/opacity.

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9. Retinal detachment. 10. Classic migraine. 11. Hypertensive retinopathy. Chronic Loss of Vision 1. 2. 3. 4. 5. 6. 7. Cataract. Glaucoma. Age-related macular degeneration. Central serous retinopathy. Diabetic retinopathy. Retinitis pigmentosa. Melanoma of choroid.

Proptosis Measured by Hertel exophthalmometer. 1. Graves ophthalmoplegia most commonly involves the medial and inferior recti. 2. Orbital pseudotumor. 3. Tumors of orbit most commonly hemangioma. 4. Carotid cavernous fistula pulsating proptosis. Ptosis a. Myogenic: Lid-lag on ptosis side on down gaze. 1. Myasthenia gravis fluctuating ptosis that worsens late in day. 2. Kearns-Sayre syndrome ptosis, retinitis pigmentosa and heart block. b. Neurogenic: 1. Horners syndrome (pseudoptosis) due to paralysis of Mllers muscle pupils are miotic. 2. Oculomotor nerve palsy pupils are larger or normal. Test: Tensilon test Treatment: 1. FasanellaServat operation for Horners syndrome. 2. Blaskowics levator resection. Nystagmus 1. Optokinetic or jerk nystagmus physiological nystagmus.

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2 Congenital nystagmus Pendular or sinusoidal due to blindness from anterior visual pathway disease early in life. 3. Gaze evoked most common type of jerk nystagmus. Exaggerated by myasthenia, brainstem lesion, cerebellar lesion. 4. Vestibular nystagmus Mnires disease. 5. Downbeat nystagmus Lesions near craniocervical junction (e.g. Chiari malformation, posterior fossa tumor). 6. Upbeat nystagmus Phenytoin toxicity, stroke, posterior fossa tumors. 7. See-saw nystagmus Chiasmal lesion (e.g. craniopharyngioma). 8. Ataxic (gaze-paretic) nystagmus also called internuclear ophthalmoplegia due to damage of medical longitudinal fasciculus. 9. Opsoclonus bursts of consecutive saccades (saccadonia) seen in viral hepatitis. 10. Ocular flutter seen in neuroblastoma. 11. Rotatory nystagmus seen in miners.

SMELL
PHYSIOLOGY Olfactory receptor cells: Bipolar cells located in the olfactory neuroepithelium in the superior 1/3rd of nasal mucosa. Each bipolar cell has a short, thick dendrite with an expanded end called an olfactory rod. It bears 6-8 cilia which contain the odorant receptors. Two characteristic of olfactory cells are that: i. They are regularly replaced by new cells. ii. They regenerate after injury. Other cells in olfactory neuroepithelium are microvillar cells, sustentacular cells and basal cells. Olfactory Pathways Olfactory receptor cells axons pierce cribriform plate Olfactory glomeruli in olfactory bulb Mitral and tufted cells (2nd order neurons) Olfactory cortex. Note: Olfactory sensation is not relayed by thalamus.

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Olfactory Cortex i. ii. iii. iv. Piriform cortex Orbitofrontal gyri in frontal lobe Amygdala (emotional response to smell). Entorhinal cortex (olfactory memory).

PATHOLOGY Anosmia Causes: 1. Head trauma most common cause in children and young adults. 2. Viral infections most common cause in older adults. 3. Congenital anomaly Kallmanns syndrome Anosmia and hypogonadotrophic hypogonadism. 4. Neoplasm Meningioma of frontal lobe (most common). 5. Nutritional deficiencies of a. Vitamin A b. Vitamin B12 c. Zn Note: Hallucination of bad smell Temporal lobe lesion Parosmia Perception of bad smell.

TASTE
PHYSIOLOGY Taste Buds Are test receptor cells. Types with locations: i. Fungiform papillae On the dorsum of tongue, most numerous at the tip. ii. Foliate papillae along the lateral margins. iii. Vallate papillae back of tongue. Other locations: Palate, epiglottis, larynx and esophagus.

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Taste Pathways Fibers carrying taste sensation: i. From anterior 2/3 of tongue: Chorda tympani nerve. ii. From posterior 1/3 including vallate papillae: Glossopharyngeal nerve. iii. Vagus nerve from other sites. They synapse on NTS in medulla 2nd order neurons cross midline and project to the thalamus along with fibers in medial lemniscus 3rd order neurons project to taste projection area in the cerebral cortex at the foot of the postcentral gyrus. Taste Modalities Sweet Organic substances Salt Due to Na+ Sour due to H+ Bitter Due to cations. Taste buds for above modalities are located in the tongue from anterior to posterior (tip to base) in the above order, i.e. sweet at the tip and bitter at the base. PATHOLOGY Hypogeusia Diminished taste sensation is cause by captopril. i. ii. iii. iv.

HEARING
ANATOMY AND PHYSIOLOGY Inner Ear It consists of two parts: 1. Cochlea involved in hearing. 2. Semicircular canal involved in equilibrium (see above). Structurally, it has two parts the bony labyrinth outside and membranous labyrinth inside separated by perilymph.

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A Systematic Review of Subjects for PGMEE

Cochlea It has 2 and turns. It has 3 parts on cross-section: 1. Scala vestibuli above Reissners membrane, filled with perilymph and connects laterally with the oval window. 2. Scala tympani below basilar membrane, filled with perilymph and connects to the round window. The above two are connected through helicotrema. 3. Scala media part between the above two, filled with endolymph, and contains the organ of Corti. This is also called the cochlear duct. Organ of Corti Located on the basilar membrane in the cochlear duct. Contains hair cells which are the auditory receptors. Afferent neurons innervate the inner hair cells and efferent neurons the outer hair cells. Axons of afferent neurons form the cochlear division of the VIII cranial nerve. Fluids 1. Perilymph occupies the area between bony and membranous labyrinth (perilymphatic space) and scala vestibuli and scala tympani. It contains high levels of Na+ and low K+. 2. Endolymph occupies the membranous labyrinth (scala media) and contains high K+ and low Na+. Auditory Pathway
Hair cells in the organ of Corti cochlear division of VIII nerve Cochlear nuclei in medulla oblongata cross midline Trapezoid body Lateral lemniscus Inferior colliculus Medial geniculate body in the thalamus Auditory cortex

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Auditory cortex situated in the superior part of temporal cortex in the Sylvian fissure (Brodmann area 41). TESTS OF HEARING Rinnes Test Using a 256 Hz tuning fork. It compares air conduction (AC) with bone conduction (BC). In normal ear, AC > BC positive Rinne. In conductive deafness, BC > AC negative Rinne. False negative Rinne is seen in severe unilateral sensorineural deafness. This is confirmed by Weber test. Weber Test Bone conduction test. In conductive deafness sound lateralized to the deaf ear. In sensorineural deafness sound lateralized to the better ear. Absolute Bone Conduction Test In conductive deafness ABC is normal. In sensorineural deafness ABC is shortened (Diagnostic). Gelles Test Bone conduction test. Note: AC signifies conduction through ossicular pathway. BC signifies conduction through sensory neural pathway. AUDIOMETRY a. Subjective i. Pure tone audiometry ii. Speech audiometry iii. ABLB or Fowlers test iv. Tests for adaptation Bekesy audiometry, Tone-Decay test.

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A Systematic Review of Subjects for PGMEE

b. Objective i. Tympanometry ii. Brainstem evoked response audiometry (BERA or ABR). Pure Tone Audiometry Most common type. Frequencies used from 250-8000 Hz. Response are measured in decibels (a logarithmic unit). Interpretations: i. Conductive deafness air-bone gap (threshold elevation for BC > AC). ii. Sensorineural deafness greater threshold at higher frequencies, except in acoustic trauma (noise-induced deafness) where there is a sudden dip at 4000 Hz. iii. Otosclerosis conductive deafness (AB gap) with a dip at 2000 Hz (Carharts notch). Speech Audiometry Response is speech discrimination at phonetically balanced words. i. Conductive deafness 95-100 percent speech discrimination. ii. In cochlear deafness 50-80 percent speech discrimination. iii. In retro-cochlear deafness 0-50 percent speech discrimination. ABLB or Fowlers Test Test of recruitment. The graph is called the laddergram. In conductive deafness and in normal ear negative. In sensorineural deafness (e.g. presbyacusis) positive. In cochlear lesion (e.g. Mnires disease) positive. Tone-Decay Test A decay > 30 dB is diagnostic of retrocochlear lesion (acoustic neuroma).

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Tympanometry Or impendence audiometry. Test of impendence of middle ear to sound. Graph is called the tympanogram. Interpretations: Type A normal. Type B (flat or dome shaped curve) secretory otitis media. Type C Eustachian tube blockade. Type D ossicular disruption. Stapedial Reflex This is due to contraction of middle ear muscles (tensor tympani and stapedius). This is absent in otosclerosis. This is a protective reflex against loud sound. Brainstem Evoked Response Audiometry (BERA) Most useful test for localization of lesion in sensorineural deafness. DEAFNESS Definition Hearing loss more than 90 dB in the better ear or total hearing loss. Etiology a. Conductive deafness i. Chronic suppurative otitis media most common cause. ii. Secretory otitis media most common nonsuppurative cause in children. iii. Otosclerosis most common cause in adults. b. Sensorineural deafness 1. Childhood deafness i. Hereditary autosomal recessive, e.g. Pendred syndrome, trisomy 18, familial sensorineural deafness. ii. Meningitis most common cause of sensorineural deafness in children. iii. Congenital infections TORCH.

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iv. Others unconjugated hyperbilirubinemia, asphyxia. 2. Presbyacusis or senile deafness most common cause. Note: other causes of congenital deafness: i. Alports syndrome ii. Ushers syndrome iii. Pendred syndrome iv. Treacher-Collin syndrome
Tests at a glance Normal Pure tone audiometry Normal Cochlear lesion Sensorineural deafness 50-80% Positive > 70% < 25 dB Normal Normal Retrocochlear lesion Sensorineural deafness 0-50% Negative 0-20% > 25 dB Abnormal V wave delayed or absent

Speech discrimination Recruitment (ABLB) SISI (short increment sensitivity index) Tone decay Stapedial reflex BERA

90-100% Absent 0-15% 0-15 dB Normal Normal interval between I and V

ORAL CAVITY
ORAL MUCOSA Pigmented Lesions 1. Heavy metal poisoning (lead, mercury) blue-black line along the gingival margin. 2. Black hairy tongue elongation of filiform papillae due to tobacco, chromogenic agents. 3. Fordyces spot ectopic sebaceous gland, situated on the lips. 4. Forchheimers spot (palatal petechiae) rubella, infectious mononucleosis, scarlet fever.

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White Lesion Hairy leukoplakia HIV infection. TONGUE Macroglossia Etiology i. ii. iii. iv. v. vi. Downs syndrome Pierre-Robin syndrome Hurlers syndrome Primary amyloidosis Acromegaly, cretinism Actinomycosis, tertiary syphilis.

Geographic Tongue Benign migratory glossitis. Asymptomatic and require no treatment. Strawberry/Raspberry Tongue Scarlet fever. Bald Tongue Xerostomia, pernicious anemia, iron deficiency anemia, pellagra, syphilis.

PULMONARY FUNCTION
REGULATION OF RESPIRATION Higher Center Respiratory center is situated in the medulla. Pre-Bottzinger complex in medulla is the respiratory pacemaker. Note: Expiration is passive during quiet breathing. If brainstem is transected at the inferior border of pons, spontaneous respiration continues but becomes irregular and gasping.

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CHEMICAL CONTROL OF BREATHING Chemoreceptor i. Carotid body situated near carotid bifurcation on each side. Note: blood flow to each carotid body = 2000 ml/100 gm/minute. ii. Aortic body near the arch of aorta. Stimulus: i. Increased H+ ion concentration in arterial blood acidosis. ii. Decreased PO2 hypoxia. Both lead to hyperventilation. Medullary chemoreceptor: These mediate responses produced by increased arterial PCO2 via CSF and brain interstitial H+ concentration. Note: CO2 is most permeable to BBB. Effect of CO 2 : A rise of arterial PCO 2 produces hyperventilation which washes out excess CO2. However, when the CO2 concentration of inspired gas exceeds 7%, there is rise of PCO2 despite hyperventilation. The resultant hypercarbia depresses central nervous system including the respiratory center and produces headache, confusion and coma (CO2 narcosis). NON-CHEMICAL CONTROL OF BREATHING Airway and lung receptors mediated by vagus nerve.
Non-chemical control of breathing Receptors Location Stimulus Lung inflation Response Hering-Breur reflex increased duration of expiration Hyperpnoea, cough, bronchoconstriction, mucus secretion Slow adapting Airway (myelinated) smooth muscle Rapidly adapting (myelinated) Airway epithelial cells

Unmyelinated C fibers J receptors

Lung hyperinflation, exogenous/ endogenous substances (histamine, PG) Alveolar Lung hyperApnea followed interstitium inflation by rapid breathing, (juxtabradycardia and capillary) hypotension (pulmonary chemoreflex)

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Effects of Exercise i. Increased pulmonary blood flow. ii. Increased alveolar-capillary PO2 gradient (PO2 of pulmonary blood falls from 40 to 25 mmHg) more O2 enter the circulation. iii. Respiration Initially abrupt increase due to impulses from propioceptors in muscles, joints, tendons. Followed after a brief pause by more gradual increase due to humoral responses. Mechanism increase in body temperature, increase in plasma K+ induced by exercise. Note: arterial pH, PCO2 and PO2 remains normal in moderate exercise. CLINICS Types of Breathing a. Vesicular breathing: Produced by air passage through tracheobronchial tree up to alveoli. Variations: i. Diminished vesicular pleural effusion, pneumothorax, empyema. ii. Prolonged expiration bronchial asthma, COPD. iii. Absent pneumonia, massive effusion, collapse with obstructed bronchus. b. Bronchial breathing: Air passage through tracheobronchial tree and a patent bronchus (not in alveoli). Variations: i. Tubular consolidation. ii. Cavernous cavity lung (e.g. TB) iii. Amphoric bronchopleural fistula (open pneumothorax). Cheyne-Stokes Breathing Alternate phases of apnea and hyperapnea, each phase lasting for 30 seconds and whole cycle completed in 2 minutes.

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Seen in: i. Cardiac failure ii. Uremia iii. Narcotic poisoning iv. Increased ICT v. Normal in infants and adults during sleep. Kussmauls Breathing Deep respiration at a rapid rate. Seen in: i. Diabetic ketoacidosis ii. Uremia iii. Cerebral tumor iv. Hepatic coma. PERCUSSION Normal resonant. Dull stony dull in pleural effusion and woody dull in consolidation. Tympanic pneumothorax. Hyperresonant emphysema. Impaired thickened pleura. PULMONARY EDEMA Development Two stages: 1. Interstitial edema characterized by tachypnea, decreased gas exchange and Kerley B lines on chest X-ray, is due to increased pulmonary vascular pressure, increased lymphatic flow and a net gain of water in extravascular space. 2. Alveolar edema characterized by full blown symptoms with bilateral rales and ronchi and diffuse haziness of lung fields on chest X-ray. This is due to disruption of alveolar capillary membrane. Clinical feature: Pink (blood-stained) frothy sputum. Etiology a. Increased PCWP i. Cardiogenic mitral stenosis, left heart failure. ii. Non-cardiogenic severe liver disease, nephrotic syndrome, protein losing enteropathy.

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b. Normal PCWP i. High altitude ii. Narcotic overdose most commonly with heroin. iii. Pulmonary embolism iv. Cardiopulmonary bypass. c. Others radiation pneumonitis. Unilateral pulmonary edema is seen in: i. Lymphoma, ii. Aspiration iii. Post-pleural tap aspiration. Note: Bat wing appearance in CXR is seen in cardiogenic pulmonary edema. PULMONARY HYPERTENSION Normal pulmonary arterial pressure is 25/10 mmHg. Pulmonary hypertension means pressure > 35/15 mmHg. Etiology: i. Left heart failure MS, MR, AS, AR. ii. Congenital heart diseases ASD, VSD, PDA. iii. Pulmonary thromboembolism iv. SLE, PAN v. Sickle cell anemia vi. Progressive systemic sclerosis vii. Toxic oil (rape seed) syndrome. Treatment General diuretics, anticoagulant. Specific calcium channel blocker, endothelin receptor antagonist (Bostenan), phophodiesterase 5 inhibitor (sildenafil), prostacyclins (Iloprost). COUGH Staccato paroxysm of cough whooping cough, chlamydia infection. Barking or brassy cough laryngotracheobronchitis. Hawking cough post-nasal drip. Honking cough psychotic. Bovine cough laryngeal paralysis. STRIDOR Laryngomalacia most common cause of stridor (present at birth), intermittent in nature, increased by crying and relieved on lying down.

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Laryngotracheobronchitis presents at 1-5 years of age. Acute epiglottitis Subglottic hemangioma presents at 3-6 months of age, increases on crying, managed by tracheostomy, steroid and CO2 laser. HEMOPTYSIS Source of bleeding bronchial arteries. Most common site of bleeding tracheobronchial tree. Etiology: i. Bronchitis ii. Bronchogenic Ca Produces iii. Bronchiectasis iv. Tuberculosis most common cause. massive hemoptysis. v. Aspergilloma vi. Foreign body. CYANOSIS Produced by: Reduced Hb > 5 gm/dl. Sulphemoglobin > 0.5 gm/dl. Methemoglobin > 1.5 gm/dl. Etiology: a. Central cyanosis: 1. Congenital heart diseases tetralogy of Fallot (most common), Eisenmengers complex (ASD, VSD or PDA with reversal of shunt due to pulmonary hypertension). 2. Acute pulmonary edema (due to LVF) most common cardiac cause. b. Peripheral cyanosis: 1. Exposure to cold most common cause. 2. CCF . c. Differential cyanosis: 1. Hands blue and feet red coarctation of aorta with transposition of great vessels. 2. Hands red and feet blue PDA with reversal of shunt. CLUBBING AND HYPERTROPHIC OSTEOARTHROPATHY Degrees First degree increased fluctuation of nail bed (earliest change) with loss of onychodermal angle (normal 120o).

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Second degree first degree + increased diameter of nail. Third degree second degree + increased pulp tissue. Fourth degree third degree + swelling of wrist and ankle due to HOA. Etiology: a. Cardiac: i. Congenital cyanotic heart diseases. ii. Infective endocarditis. iii. Aortic aneurysm. iv. Atrial myxoma. b. Lung: i. Neoplasms bronchogenic Ca (most common cause), mesothelioma. ii. Infections empyema, lung abscess, bronchiectasis. iii. Pulmonary fibrosis interstitial lung disease. iv. Cystic fibrosis. c. Ulcerative colitis and Crohns disease. d. Biliary cirrhosis e. Idiopathic f. Neoplasms g. Genetic autosomal dominant. h. Hyperthyroidism. Hypertrophic Osteoarthropathy (HOA) It is subperiosteal new bone formation in the proximal and distal diaphyses of tibia, fibula, radius and ulna. Bone involvement is bilateral and symmetrical. Diagnosis: Bone X-ray. Note: HOA is most commonly seen in bronchogenic Ca.

EDEMA
Total Body Water Water constitutes 60 percent of body weight. 2/3rd of TBW is intracellular and remaining 1/3rd is extracellular. ECF is distributed in interstitial fluid (75%) and plasma (25%).

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TBW is measured by D2O method. Edema is an increase in fluid volume in the interstitial space. Pathogenesis Two primary forces acting in vascular system regulates fluid movement are: i. Hydrostatic pressure which tries to drive out water and ii. Oncotic pressure (primarily contributed by plasma proteins, mainly albumin) which tries to retain water. Etiology a. Increased hydrostatic pressure CCF most common cause. b. Decreased oncotic pressure (fall in plasma protein > 85%) i. Nephrotic syndrome ii. Cirrhosis iii. Protein losing enteropathy. c. Lymphatic obstruction i. Inflammatory edema, e.g. filariasis. ii. Neoplastic, e.g. breast Ca. Note: In acute heart failure, there is a fall in hydrostatic pressure in systemic capillaries due to peripheral vasodilatation edema does not develop. Clinical Types Pitting edema, e.g. in CCF . Non-pitting edema, e.g. in myxedema, filariasis and angioneuritic edema. Differential Diagnosis CCF starts with edema in the dependant parts (legs). Nephrotic syndrome starts with facial edema. Cirrhosis starts with ascites. Hypoproteinemia periorbital edema.

Facial edema: Seen in nephrotic syndrome (hypoproteinemia), trichinosis, allergic reactions, myxedema.

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Idiopathic edema: Periodic episodes of edema seen in women which is unrelated to the menstrual cycle. Cause: Orthostatic retention of Na+ and water (not estrogen mediated). Differential diagnosis: Cyclical or premenstrual edema in which Na+ and water retention occurs secondary to high estrogen. Treatment: ACE inhibitors may be helpful.

SHOCK
Types 1. Hypovolemic shock most common clinical type. Stages of hypovolemia: i. Covert compensated most common type. ii. Overt compensated iii. Decompensated 2. Cardiogenic shock Most common cause is myocardial infarction (> 40% of LV). Features: SBP < 80 mmHg. Cardiac index < 1.8 L/min/mt2. LV filling pressure > 18 mmHg. Pulmonary edema. 3. Distribution shock due to peripheral vasodilatation, e.g. septic shock, anaphylactic shock. Pathophysiology
Diagnosis Hypovolemic shock Cardiogenic shock Septic shock PCWP Decreased Increased Decrease/ normal Cardiac output Decreased Decreased Increase/ normal Peripheral vasculature Constriction Constriction Dilatation

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Clinical Feature Hypotension, tachycardia, tachypnea, oliguria, metabolic acidosis, cold and clammy skin (in septic shock, skin may be flushed and hot due to vasodilatation). Grading of hypovolemia: Mild (< 20%) cold extremities, anxiety. Moderate (20-40%) same + tachycardia, tachypnea, decreased urine output. Severe (> 40%) decreased BP , marked tachycardia. Management a. Hypovolemic shock Fluid infusion is the main treatment. Initial choice of fluid is crystalloids (according to Harrison) and colloids (according to Bailey and Love). In severe hypovolemia ionotropics (dopamine) may be used. b. Cardiogenic shock Intra-aortic balloon pump, ionotropic drugs dopamine, dobutamine (drug of choice in pump failure), amrinone, milrinone. Monitoring Urine output most useful method. It should be > 0.5 ml/kg/hr. PCWP and CVP are not very helpful in determining left ventricular function (tissue perfusion) in shock. CARDIAC ARREST AND SUDDEN CARDIAC DEATH Cardiac arrest is the most common cause of sudden death. Etiology 1. Electrical disturbance ventricular fibrillation is the most common cause of cardiac arrest. Others are ventricular tachycardia and asystole. 2. Decreased cardiac output acute pulmonary emboli, ruptured aortic aneurysm, cardiac rupture after myocardial infarction.

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Structural Defect Atherosclerotic heart disease most common cause. Cardiomyopathy. Conducting system disease. Predisposing Factors i. Hypoxia most common cause. ii. Electrolyte disturbance Hypokalemia, hypocalcemia (heart stops at diastole). Management Heimlich maneuver for dislodging an aspirated foreign body. Cardiopulmonary resuscitation has two components i. Chest compression (cardiac massage) over the lower sternum, at the rate of 80-100/minute, force to depress sternum 3-5 cm (1.5-2 inches). ii. Ventilation 10-12 times/minute, i.e. compression: Ventilation ratio = 5:1 (2 in succession every 15 compression when one person is performing). Note: Maximum cardiac index attained by external compression is 40 percent (normal is 2.6-4.2 L/min/mt2). Advanced life support: i. Endotracheal intubation ii. Defibrillation/cardioversion and/pacing adrenaline is given if defibrillation fails. If not controlled completely, lignocaine/procainamide/bretylium is given. iii. IV fluid. iv. IV NaHCO3 in acidotic patients. v. IV calcium gluconate in hyperkalemia, hypocalcemia, CCB therapy. Prognosis Those with VT carry best prognosis. Asystole carries the worst prognosis.

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GI FUNCTIONS
Dysphagia a. Type of food: To solids mechanical obstruction, e.g. malignancy. To both solids and liquid achalasia, diffuse esophageal spasm. Scleroderma Dysphagia to solid unrelated to posture and dysphagia to liquid in recumbent but not in upright posture. b. Duration : Progressive dysphagia malignancy. Episodic dysphagia lower esophageal ring. c. Odynophagia (painful swallowing: fungal or herpetic esophagitis or pill-induced esophagitis. Vomiting Mechanism: a. Vomiting center in dorsal portion of lateral reticular formation in medulla. b. CTZ in area prostema of the floor of fourth ventricle. Peripheral muscles: 1. Abdominal musculature provides the main ejection force. 2. Diaphragm. 3. Intercostal muscles. Clinical feature: a. Type: Projectile vomiting in increased ICT. b. Time: Early morning nausea early pregnancy, uremia, alcoholic gastritis. Shortly after taking food peptic ulcer. 4-6 hours after taking food gastric retention. c. Character: Increased acid content gastric outlet obstruction duet to Z-E syndrome. Absent free HCl gastric carcinoma. Bile obstruction below ampulla of Vater. Complications: i. Metabolic hypochloremic, hypokalemic, metabolic alkalosis. ii. Rupture of esophagus Boerhauves syndrome.

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iii. Hematemesis Mallory-Weiss tear. iv. Aspiration pneumonia in comatose patients. Differential diagnosis: a. Hiccups seen in uremia, acidosis, anoxia, systemic infections. Cause is gastric distension. b. Rumination seen in bulimia nervosa. DIARRHEA Acute a. Watery diarrhea enteric viruses (rotavirus most common), EPEC, cholera, protozoa, helminths. b. Watery then bloody diarrhea campylobactor, shigella, V. parahemolyticus. c. Bloody diarrhea salmonella, shigella, EIEC, yersinia, entamoeba. Note: Most common cause of diarrhea in neonates E. coli. Most common cause of diarrhea in infants/children rotavirus. Most common cause of diarrhea in AIDS patients Cryptosporidium. Preformed toxins are produced by Bacillus cereus, Staphylococcus aureus and Clostridium perfringens (mnemonic BSC). Chronic a. Inflammatory ulcerative colitis, Crohns disease, radiation, eosinophilic gastroenteritis. b. Osmotic lactose intolerance (milk allergy), pancreatic cholera, tropical sprue, Whipples disease, celiac sprue, short bowel syndrome, abetalipoproteinemia. c. Secretory (watery) Z-E syndrome, villous adenoma, carcinoid syndrome, medullary Ca of thyroid, cholerrheic diarrhea, and diabetes mellitus type I due to altered motility. Note: Intestinal lymphangiectasia causes selective protein loss with steatorrhea with preserved carbohydrate absorption.

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Diagnosis a. Inflammatory diarrhea hallmark is the presence of blood and leukocytes in stool. Blood is detected by Benedicts reaction. Leukocytes are detected by Wrights or methylene blue stain. b. Malabsorption i. Stool fat increased in pancreatic insufficiency. ii. Carbohydrate d-xylose absorption test in celiac/ tropical sprue. iii. Intestinal biopsy definitive test for malabsorption. Diagnostic in Whipples disease, abetalipoproteinemia, agammaglobulinemia. iv. 1-antitrypsin assay best test for protein-losing enteropathy. v. Schillings test for vitamin B12 assay, done in pernicious anemia, pancreatic insufficiency. vi. Bacterial growth 14C-xylose breath test. vii. Fecal osmolality to differentiate osmotic from secretory diarrhea. Fecal osmotic gap > 50 mosmol/ kg H2O suggests osmotic diarrhea. Treatment a. Travelers diarrhea (ETEC) bismuth subsalicylate, diphenoxylate + atropine, loperamide. b. Oral rehydration for mild (5-7% of body weight) or moderate (7.5-10% body weight) dehydration. WHO ORS: Principle: Glucose promotes absorption of Na+. Composition:
Ingredient (in gram) NaCl NaHCO3 KCl Glucose Potable water Or Trisodium citrate dehydrate in place of NaHCO3 3.5 2.5 1.5 20 1 lit. 2.9 Quantity (in mmol/L) Na + K+ ClCitrate Glucose 90 20 80 10 110

Total 310

Dose 75 ml/kg in the first 4 hours then 10-20 ml/ kg for each liquid stool.

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Drawback when used in non-choleric diarrhea, it produces periorbital edema due to excess Na+ absorption (hypernatremic dehydration causes irritability). New formula ORS: For cholera and non-cholera diarrhea. It has low Na+ (NaCl 2.6 gm, Na+ 75 mmol/lit) and low glucose (glucose 13.5 gm, 75 mmol/lit). Super ORS: ORS that in addition to rehydration increases intestinal absorption and decreases stool formation. For example, alanine, glycine added ORS, boiled rice best for developing countries. c. IV rehydration for severe dehydration. Indication: Fluid loss > 10 percent of body weight. i. Dhaka fluid contains 5 gm of NaCl, 1 gm of KCl and 4 gm of NaHCO3 dissolved in 1 liter of water or 5 percent dextrose. ii. Ringers lactate recommended by WHO. It provides Na+ - 130 mmol/l K+ - 4 mmol/l Cl- - 109 mmol/l Lactate 28 mmol/l Total 271 mmol/l. Dose: 30 ml/kg in the first hour and 70 ml/kg in the next 5 hours for infants < 1 year. In older children same dose should be given in hour and 2 hours, respectively. d. Other drugs Sulfasalazine in IBD. Octreotide in carcinoid syndrome. Clonidine in opiate withdrawal and diabetic diarrhea. Indomethacin - in medullary Ca of thyroid and villous adenoma. Cholestyramine drug of choice in bile salt malabsorption. Metronidazole/vancomycin in pseudomembranous colitis. WEIGHT Weight gain Hypothyroidism Myxedema Cushings syndrome Craniopharyngioma Insulinoma Weight loss Hyperthyroidism Pheochromocytoma Diabetes mellitus

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GI BLEEDING Hematemesis is vomiting of blood produced by pathology proximal to the ligament of Treitz. At least 60 ml of blood is required to produce a single black stool and blood should remain for at least 8 hours in the gut. Etiology Upper GI bleeding: 1. Erosive hemorrhagic gastropathy (NSAID induced) 2. Duodenal ulcer most common cause. 3. Gastric ulcer. 4. Mallory-Weiss tear. 5. Esophageal varices. 6. AV malformation. 7. Gastric tumors least common cause. Most common gastric tumor to bleed is leiomyoma. All the above conditions can produce both hematemesis and melena. Note: Most common cause of upper GI bleeding in children is from esophageal varices due to portal hypertension. Lower GI bleeding: Age < 55 years Hemorrhoids most common cause Colitis (IBD, infections) Age > 55 years Hemorrhoids, fissure scant bleeding. Diverticulosis most common cause of massive bleeding. Diverticulosis Angiodysplasia. They usually produce hematochezia. Note: Most common cause of bleeding per rectum in children is rectal polyp. Investigation Occult blood by card test for Hb peroxidase. False negative test may be due to chronic ingestion of vitamin C.

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Most sensitive method to detect GI bleeding is radiolabelled erythrocyte screening which can detect blood as small as 0.01-0.05 ml/min. Angiography may detect bleeding as small as 0.5 ml/min.

JAUNDICE
BILIRUBIN METABOLISM Bilirubin is produced by catabolism of heme (the iron porphyrin in Hb). Heme Synthesis It is essentially the incorporation of ferrous ion into protoporphyrin III the parent porphyrin in heme. Heme synthesis occurs in mitochondria in most mammalian cells except the RBC which does not contain mitochondria. The rate limiting enzyme is ALA synthetase in liver (dependant on pyridoxal phosphate). Note: Lead poisoning causes increased protoporphyrin in RBC and increased ALA and coproporphyrin in urine. Bilirubin Heme is catabolized to bilirubin in the RE cells of peripheral tissues through the following steps: Hb (red) hemin (blue-purple) biliverdin (green) bilirubin (yellow). Note: The color change in a bruise or hematoma is due to the above reason. 1 gm Hb yields 35 mg of bilirubin. Daily production in human = 250-350 mg.

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Types
Bilirubin Unconjugated Water solubility Renal excretion Albumin binding Van den Bergh reaction No No +++ Indirect Conjugated Yes Yes + Direct

Note: Unconjugated bilirubin = total bilirubin conjugated bilirubin (in VDB test). Metabolism It consists of the following steps: 1. Uptake of unconjugated bilirubin bound to albumin by liver. 2. Conjugation with glucoronide by UDP-glucuronyl transferase. Conjugation makes it water soluble. 3. Secretion into bile and into GI tract. 4. Intestinal circulation conjugated bilirubin is not absorbed by intestine. In terminal ileum and colon, it is converted to urobilinogen which is excreted in the feces. Some urobilinogen is absorbed, taken up by the portal vein and re-excreted by the liver (enterohepatic circulation). In unconjugated hyperbilirubinemia, some urobilinogen is also excreted in urine (as in hemolysis) due to excess production of bile pigments (acholuric jaundice). In obstructive jaundice, conjugated bilirubin may be present in urine without urobilinogen (choleric jaundice). (See below) JAUNDICE Normal serum bilirubin level Total = 0.3 to 1.0 mg/dl Conjugated (direct) = 0.1 to 0.3 mg/dl. Unconjugated (indirect) = 0.2 to 0.7 mg/dl. Hyperbilirubinemia is bilirubin > 1.0 mg/dl. Latent jaundice is bilirubin 1.0 2.5 mg/dl. Clinical jaundice is bilirubin > 2.5 mg/dl. Most common site for detecting jaundice is upper bulbar conjunctiva. Scleral tissue has high level of elastin which has high affinity for bilirubin.

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Classification A. Unconjugated hyperbilirubinemia (indirect): 1. Overproduction hemolysis. i. Rh incompatibility most common cause in newborn. ii. ABO incompatibility. iii. Thalassemia. iv. Vitamin K. 2. Decreased bilirubin conjugation (decreased hepatic glucuronyl transferase activity). i. Gilbert syndrome (mild deficiency). ii. Crigler -Najjar type II (moderate deficiency) AD. iii. Crigler-Najjar type I (absent enzyme) AR. iv. Physiological jaundice of neonates. v. Breast milk jaundice. vi. Septicemia. B. Conjugated (Direct) hyperbilirubinemia: Direct bilirubin > 15 percent of total bilirubin. 1. Impaired hepatic excretion (intrahepatic defect) i. Dubin-Johnson syndrome. ii. Rotor syndrome. iii. Hepatocellular disease hepatitis, cirrhosis. iv. Alcoholic liver disease. 2. Extrahepatic biliary obstruction i. CBD stones Most common cause of benign surgical jaundice. ii. Biliary atresia Most common cause in newborn. iii. Others choledochal cyst, Pancreatic Ca. Evaluation of Jaundice
Condition Serum bilirubin D + I Increased I (indirect) Increased D + I Urine Fecal urobilinogen

Normal Hemolysis Hepatitis

Obstruction Increased D (direct)

Urobilinogen Bilirubin Mild + Absent Increased Absent (acholuric) Decreased + (in micro(in microobstruction) obstruction) Absent Present (choleric)

Present Increased Decreased

Note: Bilirubin in urine is detected by Ehrlichs test.

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LFT: a. Unconjugated no enzymatic disturbance (e.g. hemolysis) b. Conjugated i. Hepatitis increased ALT and AST. ii. Obstruction increased alkaline phosphatase, 5 nucleotidase and/or GGT. NEONATAL JAUNDICE Classification A. Early jaundice (<10 days) unconjugated. a. First 24 hours Rh incompatibility (Most common cause), ABO incompatibility, others G-6PD deficiency, Vitamin K. b. After 24 hours - Physiological jaundice, Cephalhematoma, Congenital hemolytic anemia Gilbert syndrome and Crigler-Najjar syndrome, Galactosemia. B. Prolonged jaundice (> 10 days): a. Unconjugated Breast milk jaundice, Septicemia. b. Conjugated Congenital infections (TORCH, etc), Dubin-Johnson, Rotor syndrome, Hypothyroidism, Extrahepatic biliary atresia, Intrahepatic dilatation of bile duct Carolis disease. Choledochal cyst. Idiopathic infantile hepatitis most common cause. EARLY JAUNDICE Hemolytic Disease of Newborn Due to isoimmunization (Erythroblastosis fetalis) Rh incompatibility: Most common cause. Mechanism: AntiD antibody (IgG) in a sensitized mother (Rh ve) may cross the placenta and produce hemolysis in Rh +ve fetus (not in first pregnancy). Mechanism of sensitization APH, PPH, PIH, CS, post-dated pregnancy. Note: Immunization occurs when > 0.1 ml of fetal blood enters maternal circulation.

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Associated ABO incompatibility reduces the chance of Rhimmunization. Manifestations: a. Hydrops fetalis Most serious form. Diagnosis: USG Edema of scalp, skin and pleural / pericardial effusion, ascites (large abdomen). X-ray Buddha position of head. Placenta large due to hyperplasia. b. Neonatal jaundice develops within 24 hours after birth. c. Congenital anemia of newborn red cell destruction continues for up to 6 weeks. Diagnosis: a. Mother Quantitative assay Maternal serum anti-D antibody level < 4 IU/ml low risk 4-10 IU/ml moderate risk. > 10 IU/ml severe risk.
IgG antibody detection by indirect Coombs test Genotype of the husband If homozygous, 100 percent chance of affection If heterozygous, 50 percent chance of affection Amniocentesis

b. Amniocentesis: To assess disease progression. Time: i. No previous history at 30-32 weeks. ii. Positive previous history at least 10 weeks prior to previous stillbirth (usually before 20 weeks). Inference: Spectophotometric analysis of amniotic fluid shows optical density difference at 450 nm with deviation bulge in Rh hemolytic disease. The deviation bulge is plotted in Lileys chart. If it falls in the i. Low zone (zone I) continue pregnancy. ii. Mid zone (zone II) may require termination after 34 weeks.

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iii. High zone (zone III) severely affected child, if > 34 weeks termination, if < 34 weeks intrauterine fetal transfusion. c. Baby: Sensitized baby show positive direct Coombs test. Prevention: Administration of Rh anti-D immunoglobulin to unsensitized (Coombs negative) mother within 72 hours following childbirth (300 g), abortion (100 g) and ectopic pregnancy (50 g), amniocentesis, external cephalic version. Management: See below. ABO incompatibility: Occurs when the mother is group O and the baby is either group A or B. First baby may be affected (c.f. Rh incompatibility). Non-immune hemolysis: G6PD deficiency, vitamin K. Note: Causes of non-immune hydrops (fetal edema) i. Downs syndrome ii. Congenital cardiac anomaly iii. Beta thalassemia, G6PD deficiency iv. Infection parvovirus, toxoplasma, rubella, syphilis. Physiological Jaundice of Newborn Incidence: 65 percent Features: Appears after 30 hours (on third day). Peak level of bilirubin maximum 12 mg/dl on day 4 or 5. Rate of increase in bilirubin concentration < 5 mg /day. Disappears by 7 14 days. Aggravating factors: Prematurity, hypoglycemia, hypoxia, dehydration, intestinal stasis. Kernicterus Cause: Unconjugated hyperbilirubinemia > 20 mg/dl or serum bilirubin:protein ratio > 3:5. Pathology: Damage to basal ganglia (most common), hippocampus and subthalamic nuclei. Note: Cerebral cortex is spared. Risk factors: Prematurity, hypoglycemia, hypoxia, hypothermia, ketoacidosis. Drugs Sulfamethoxazole, Gentamicin, Novobiocin.

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Management of Early Jaundice 1. Phototherapy: Indications Serum bilirubin > 18 mg/dl at term. a. Hemolytic (ABO) bilirubin level 10 at < 12 hours. 12 14 at < 18 hours. 15 at > 24 hours. b. Non-hemolytic bilirubin level 15 at < 2 days. 18 at 2-3 days. 20 at 3-4 days. Mechanism: Photoisomerization of bilirubin (E isomerism), toxic 4Z-15Z bilirubin is converted to 4Z-15E bilirubin. Blue light is most sensitive. Complication: i. Dehydration due to insensible water loss most common. ii. Diarrhea most common cause in newborn. iii. Bronzing of skin. iv. Retinal damage. 2. Exchange transfusion: Indication: a. Term baby i. Unconjugated bilirubin > 25-28 mg/dl in nonhemolytic cases and > 18-20 mg/dl in hemolytic cases. ii. Serum bilirubin: Protein ratio > 3.5. b. Erythroblastosis i. Maternal antibody titer > 1:64 ii. Baby direct Coombs positive with body weight < 2.5 kg. iii. Cord Hb < 10 gm/dl and cord bilirubin > 5 mg/ dl. iv. Previous history of affected child. Method: Rh-negative whole blood from unsensitized donors with same ABO blood group. Complication: i. Hypovolemia shock (usually hypervolemia occurs). ii. Citrate tetany. iii. Cardiac arrest. iv. Hypercalcemia.

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PROLONGED JAUNDICE Breast Milk Jaundice Gradual onset (after 10 days). Peak bilirubin level 25 mg/dl on 2nd or 3rd week. Settles in 6 hours, may continue up to 4 months. Cause pregnanediol interferes with bilirubin conjugation.

Neonatal Cholestatic Jaundice Etiology: i. Idiopathic neonatal hepatitis most common cause (50-60%). ii. Extrahepatic biliary atresia 20 percent. iii. 1-antitrypsin deficiency 15 percent. Investigation: Hepatobiliary imaging to differentiate between intrahepatic and extrahepatic obstruction. Liver biopsy giant hepatocytes with many nuclei. Most specific investigation peroperative cholangiography. Blood increased alkaline phosphatase, increased 5 nucleosidase, increased GGT (normal 5-40 IU/lit). GGT is increased > 10 times in atresia and > 3 times in neonatal hepatitis.

ASCITES
Ascitic Fluid
Differential diagnosis Exudate Protein Serum-ascites albumin gradient (SAG) Specific gravity > 2.5 gm/dl < 1.1 gm/dl > 1.016 Transudate < 2.5 gm/dl > 1.1 gm/dl < 1.016

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Etiology a. Exudate i. Pyogenic peritonitis ii. Tubercular peritonitis iii. Pancreatic ascites iv. Malignancy. b. Transudate i. Cirrhosis of liver ii. CCF iii. Nephrotic syndrome iv. Protein-losing enteropathy. Diagnosis Signs Fluid thrill at least 2 liter of fluid should be accumulated. Shifting dullness -1 liter of fluid should be accumulated. Puddle sign can detect fluid as little as 120 ml. USG best to detect minimal fluid. Diagnostic paracentesis 50-100 ml of fluid is aspirated. Differential Diagnosis 1. Tuberculosis: Straw colored or hemorrhagic fluid, exudative in nature, contains cells > 1000/mm3 (70% of them are lymphocytes), confirmation of diagnosis is by peritoneal biopsy. 2. Chylous ascites: Turbid, milky fluid with TG > 1000 mg/dl. Cause: Lymphatic obstruction from trauma, tumor, TB, filariasis, lymphoma, nephrotic syndrome. 3. Pancreatic ascites: Cause: A leaking pseudocyst. Exudate with increased amylase level in ascitic fluid. 4. Mucinous ascites: Pseudomyxoma peritonii due to mucinous cystic tumors of ovary and appendix. Colloid Ca of stomach or colon with peritoneal implant. 5. Meigs syndrome Ascites (Transudate) + hydrothorax in a case of fibroma of ovary. PseudoMeigs syndrome Brenners tumor of ovary.

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RENAL FUNCTIONS
HEMATURIA It means presence of intact RBC in urine. Etiology a. Surgical usually painless. i. TB of kidney most common cause of hematuria. ii. Renal cell carcinoma. iii. Bladder stone terminal hematuria. iv. Bladder Ca painless hematuria is the earliest and most common symptom. v. Renal trauma hematuria is the cardinal feature. vi. Urethral rupture initial hematuria. b. Medical causes i. Acute glomerulonephritis most common medical cause. ii. Isolated hematuria IgA nephropathy, H-S purpura. iii. HUS. Diagnosis Benzidine test. Investigation All cases of hematuria should be investigated. Differential Diagnosis of Red Urine Hemoglobinuria, myoglobinuria, Ingestion of beet root, phenolphthalein, Acute intermittent porphyria, Drugs phenindione, clofazimine, rifampicin.

PROTEINURIA Normal adults excrete 30-150 mg of protein per day of which only 30 mg is albumin and remainder secreted proteins by renal tubules (e.g. Tamm-Horsfall protein). Proteinuria is mild (200-500 mg/day), moderate (500 mg/day to 2 gm/day) or massive (> 2 gm/day). When it exceeds 3.5 gm/day, it is called nephrotic range.

General Discussion

69

Nephrotic range proteinuria is seen in nephrotic syndrome (with edema) or multiple myeloma (without edema). Diagnosis: Albumin is detected by dipstick method. URINARY CAST 1. RBC cast (with hematuria, subnephrotic proteinuria and dysmorphic RBC) acute glomerulonephritis. They are produced as RBC enters the tubules and become trapped in cylindrical mold of Tamm-Horsfall protein. 2. Hyaline cast usually normal, but also seen in prerenal azotemia. They are formed in concentrated urine from the normal constituents principally Tamm-Horsfall proteins. 3. Granular or tubular cast seen in acute renal failure. They are pathognomonic of renal disease. 4. Waxy cast (degenerated cellular cast) seen in chronic glomerulonephritis. 5. Broad cast seen in chronic renal failure. 6. White cell cast (with bacteruria) seen in pyelonephritis. Note: Tamm-Horsfall protein is a normal protein secreted by the epithelial cells of the loop of Henle. URINE OUTPUT Oliguria urine output < 400 ml in 24 hours. Polyuria urine output > 3 liters in 24 hours.

MEDICAL DISORDERS DURING PREGNANCY


PHYSIOLOGY Weight Gain Total weight gain during pregnancy = 11 kg. In this, 50 percent (~ 6 kg) is reproductive weight gain and 50 percent (~ 6 kg) is net maternal weight gain.

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Hematological Changes 1. Blood volume: Increased to maximum 40 percent at 3032 wks. Plasma volume: Increased to maximum 50 percent (Net 1.25 liters). RBC volume: Increased to 20 30 percent - increased O2 carrying capacity). Due to disproportionate increase in plasma and RBC volume, there is a state of hemodilution during pregnancy. (Apparent in Hb concentration by 2% and blood viscosity). 2. Protein: Total protein increased. But due to hemodilution, plasma protein concentration falls from 7 to 6 percent. Albumin decreased and Globulin increased. Normal A: G ration of 1.7: 1 is decreased to 1:1. 3. Coagulation factors: Fibrinogen level increased by 50 percent. ESR increased (4 fold increase). All procoagulants are increased. Decreased antithrombin III. Increased activity of factors 2, 7, 8, 9 and 10. Note: For above reasons, there is increased risk of thromboembolism in pregnancy. Decreased XI and XIII, increased plasminogen activity. CVS 4. Cardiac output: Increased to maximum 40 percent at 2430 wks. Clinical Feature: Murmurs in pregnancy i. Systolic murmur over apical/pulmonary area. ii. Continuous hissing murmur over tricuspid area mammary murmur. 3rd heart sound. 5. Blood pressure: Mid pregnancy drop to 100/70 mmHg due to decreased peripheral resistance in pregnancy. 6. Regional circulation: To uterus is increased from 50 ml (non-pregnant) to 750 ml near term. Supine hypotension syndrome postural hypotension during late pregnancy.

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Metabolism 7. Protein: Positive nitrogen balance. 8. Carbohydrate: Maternal fasting hypoglycemia and post-prandial hyperglycemia and hyperinsulinemia. Glycosuria is normal in pregnancy. 9. Fat: increased FFA, triglycerides and ketone bodies. Increased cholesterol and phospholipids. 10. Iron: Total iron requirement in pregnancy = 1000 mg. Maximum: Requirement in 2nd half (67 mg/day). 11. Calcium: Daily requirement in pregnancy = 1 to 1.5 gm. 12. Kilocalories: Daily requirement 2500 (+300 from non-pregnant state). Renal GFR is increased by 50 percent due to increased renal plasma flow. Respiratory System VC unaltered, TV increased (+40%), RV decreased (-20%) Respiratory alkalosis compensated by mild acidosis. Remember: All are increased in pregnancy except Hb and plasma protein (apparent fall), albumin and A:G ratio and BP , antithrombin III. HYPERTENSION IN PREGNANCY Pregnancy Induced Hypertension Pre-eclampsia Definition: BP > 140/90 mmHg Edema and/or proteinuria Pregnancy beyond 20 weeks. Pathology: Characterized by widespread fibrin deposit due to abnormality in endothelial integrity. There is decreased synthesis of PGI2 (antiaggregatory and vasodilator) from endothelium and increased sensitivity

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to angiotensin II vasoconstriction, increased BP and platelet aggregation. Kidney: Fibrin deposit in basement membrane of glomeruli. Liver: Periportal hemorrhagic necrosis. Blood: Hemolytic anemia, elevated LDH and low platelets (HELLP syndrome). Note: Physiological edema in pregnancy: Due to increased venous pressure of the legs by gravid uterus pressing on common iliac vein. Usually unilateral (more on night leg) and disappears on rest. Risk factors: i. Primigravidae ii. Family history iii. Other medical disorders hypertension, hepatitis. iv. Pregnancy complication like H. mole, multiple pregnancy, hydramnios, Rh-incompatibility. Clinical feature: Swelling over ankles in the morning. Earliest sign: Rapid weight gain > 5 lb a month or 1 lb a week. Alarming symptoms Headache, epigastric pain, blurring of vision due to retinal detachment. Diagnosis: Urine Proteinuria > 0.3 gm/lit in 24 hours. Blood increased uric acid> 4.5 mg/dl (marker of pre-eclampsia), increased BUN and increased creatinine. Increased serum LDH. BP SBP > 30 mmHg or increased DBP > 15 mm Hg. Mean arterial pressure (DBP + 1/3 PP) > 90 mmHg. If DBP>110, it is called severe PIH. Prevention: Low dose aspirin throughout pregnancy in high-risk patients. Screening test: Roll over test (at 28-32 wks). Management: Antihypertensive Drugs used in pregnancy

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- blockers. - methyl dopa - drug of choice. Hydralazine Labetolol Drug contraindicated ACE inhibitors. Termination Beyond 37 weeks. Induction of labor by ARM - preferred method. During labor IV ergotamine following delivering of anterior shoulder is withheld. Eclampsia Definition Pre-eclampsia complicated with convulsion and/or coma. Convulsion is generalized tonic-clonic in nature. Cause: Cerebral anoxia. Complication: Pulmonary edema (most common). Types: Antepartum (most common), intrapartum, postpartum within 48 hours of delivery. Prognosis: Bad prognostic features are: SBP > 200 mm Hg. Oliguria and proteinuria > 5 mg/day. Antepartum eclampsia. Management : a. Anticonvulsants i. Lytic cocktail regime (of Menon) - modern regime. Contains Chlorpromazine, Promethazine and Pethidine. ii. Magnesium sulphate regime (of Pritchard) Therapeutic Mg level 4-7 mEq/l. Monitoring is done by knee jerks, urine output and respiratory rate. Advantage: Least effect on neonates. Single most effective drug. iii. Diazepam (Lean) iv. Phenytoin. In status epilepticus Thiopentone sodium. b. Obstetric: Termination to be done by ARM.

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Gestational Hypertension BP> 140/90 mmHg beyond 20 wks. No features of pre-eclampsia. Absence of any underlying cause. BP returns to normal within 10 days following delivery.

CARDIAC DISEASE Criteria for Diagnosis of Heart Disease in Pregnancy i. Diastolic murmur ii. Loud systolic murmur with thrill. Types Rheumatic MS is the most common heart disease in pregnancy. Congenital ASD is the most common congenital disease in pregnancy. CCF in pregnancy occurs around 30 weeks. Mitral Stenosis Overall most common. Treatment Closed mitral valvulotomy (balloon valvuloplasty) may be performed between 14-18 wks (Best time of surgery). Open heart surgery is contraindicated. Mitral Regurgitation Well tolerated during pregnancy. Aortic Stenosis Worst heart disease in pregnancy. It is a contraindication to pregnancy. Maternal mortality of 15 percent with critical AS. Pulmonary Hypertension Contraindication to pregnancy. Very high maternal mortality.

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Eisenmenger Syndrome High maternal and fetal mortality (maximum - 50%). Treatment: S and E (absolute indication of abortion). Pulmonary Stenosis Well tolerated during pregnancy. Coarctation of Aorta Treatment: Elective CS. Note: Contraindications to pregnancy 1. Critical AS 2. Pulmonary hypertension and Eisenmenger syndrome. 3. Marfans syndrome. 4. Chronic dilated cardiomyopathy with heart failure. Management of Labour in Heart Disease 1. Prophylactic antibiotic. 2. Second stage: Forceps or ventouse at station O. IV ergotamine is withheld. 3. Third stage: Oxytocin drip, IV frusemide. Note: There is no indication of CS for heart disease. It is done for obstetric indications, except Coarctation of aorta. Note: Contraindications to prophylactic ergotamine: 1. Severe pre-eclampsia and eclampsia 2. Organic heart diseases 3. Suspected pleural pregnancy 4. Rh-negative mother. DVT AND PULMONARY EMBOLISM Causes of Increased Risk of Thromboembolism in Pregnancy 1. Increased level of all coagulation factors (except XI and XIII) 2. Decreased antithrombin III level 3. Decreased fibrinolytic activity. Time DVT is more common in postpartum (puerperium) period.

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Management During pregnancy IV Heparin. [Note: Heparin does not cross the placenta. Warfarin is contraindicated in pregnancy due to increased fetal abnormalities (skeletal and facial anomalies)] During puerperium IV heparin for 7 to 10 days followed by warfarin for 36 months. Note: Patient on oral anticoagulant should switch over to heparin at 36 wks. Phlegmasia Alba Dolens (Milk leg/White leg): Due to iliofemoral vein thrombophlebitis in pregnancy. Anticoagulant in pregnancy: Up to 12 weeks heparin, 1236 weeks warfarin, 36 weeks7 days postpartum heparin, Lactation warfarin. DIABETES MELLITUS Pregnancy is diabetogenic because of: i. Insulin resistance. ii. Increased absorption of glucose from gut. iii. Decreased peripheral utilization. Glycosuria (due to decreased renal threshold) may be normal in pregnancy. Gestational Diabetes This is pregnancy induced glucose intolerance. Diagnosis: Screening Between 2428 weeks. Method: Fasting blood sugar levels after 50 gm oral glucose load. if 1 hr glucose level > 140 mg/dl. 100 gm oral glucose tolerance test is done after overnight fasting. A diagnosis of gestational diabetes is made if plasma glucose level is > 190 mg percent at 1 hour. > 165 mg percent at 2 hours.

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> 145 mg percent at 3 hour (any 2 of above 3 values). Potential candidates for screening: Previous birth to a large baby Recurrent fetal loss Tendency to polyhydramnios. Treatment: Diet and later insulin. Overt Diabetes This is pregnancy in a diabetic woman. Complications: Maternal Polyhydramnios Pre-eclampsia Preterm labour During labour - shoulder dystocia. Fetal 1. Macrosomia. 2. Hairy pinna. 3. Congenital anomalies i. Neural tube defects (anencephaly- most common and microcephaly). ii. Cardiac asymmetric VSD, transposition of great vessels most common cardiac anomaly. iii. Caudal regression - sacral agenesis most characteristic. Neonatal 1. Hypoglycemia - Due to hyperplasia and hypertrophy of fetal islet cells increased fetal insulin. 2. Hypocalcemia 3. Polycythemia 4. Respiratory distress syndrome. 5. Hyperbilirubinemia Long-term 1. Obesity 2. Diabetes 3. Mental retardation 4. Blindness. Investigation: For early detection of fetal anomalies 1. Glycosylated HbA (HBA1C) estimation before 14 weeks of gestation. A value > 9.5 percent suggests increased risk.

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2. Maternal serum -FP at 16 weeks. To detect neural tube defects. (-FP level is increased). 3. USG at 20 weeks to detect cardiac anomalies investigation of choice. Treatment: Target PP blood glucose level < 140 mg/dl. Agent Soluble insulin is the agent of choice because it does not cross placenta and insulin demand is increased in pregnancy. Note: Oral hypoglycemic agents are contraindicated in pregnancy. Termination of pregnancy after 37 weeks (because chance of IUFD is increased beyond that period) by CS. - agonists should be avoided as tocolytics in diabetes. Contraception: Barrier method is ideal. Progesterone only pill. Glycosuria in Pregnancy Diagnosis: Second fasting morning specimen of urine is tested for glucose. Glycosuria on 1 occasion before 20th week and on 2 or more occasions thereafter is an indication for oral GTT. Diabetes Insipidus in Pregnancy Associated with: 1. Pre-eclampsia 2. Oligohydramnios 3. Hepatic dysfunction. ANEMIA IN PREGNANCY Definition (WHO) Hb 11 gm percent, In India, the value is 10 gm percent. Type: Most common type of anemia in India is Dimorphic type due to combined deficiencies of iron, folic acid and/ or vitamin B12. Characterized by anisocytosis (micro + macrocytosis) and hypo/normochromia.

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Iron Deficiency Anemia Total iron requirement during pregnancy is 1000 mg. This is mostly needed in second half of pregnancy when daily requirement of iron is 67 mg. Anemia: Microcytic hypochromic. Diagnosis: MCHC < 30 percent MCV < 75 m3 MCH < 25 pg Decreased serum iron, decreased ferritin, increased TIBC. Complications: 1. Pre-eclampsia. 2. Intercurrent infection 3. Heart failure 4. Postpartum hemorrhage. Prophylaxis: 200 mg FeSO4 (60 mg elemental iron) + 0.5 mg (500 g) folic acid daily. Treatment: Tab. Fersolate (FeSO4) 200 mg (60 mg elemental iron) - 1 tab 3 times daily with or after meals. Megaloblastic Anemia Folate deficiency is the main cause. Daily requirement during pregnancy 300 g (normal 50 g) Prophylaxis: 400 g daily Treatment: 5 mg oral daily with supplementary iron with or without IM vitamin B12 100 g/day. Thalassemia Prenatal diagnosis: 1. Amniocentesis (between 1416 weeks) by amniotic fluid fibroblasts. 2. Chorion-villus biopsy (between 1012 weeks) by trophoblasts. 3. Cordocentesis (after 18 weeks) by fetal blood.

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JAUNDICE IN PREGNANCY Cause 1. Viral hepatitis most common (most commonly due to Hepatitis B). 2. Intrahepatic cholestasis. 3. Acute fatty liver of pregnancy. Viral Hepatitis Hepatitis B Most common cause. (Others HDV and HCV in association with HIV). Risk of transmission to fetus 10 percent in first trimester, 90 percent in third trimester. Chance of transmission is more in HBsAg +ve mother who are also HBeAg +ve. Mode of transmission During the time of delivery. Hepatitis E Associated with high internal mortality during pregnancy. Intrahepatic Cholestasis Second most common cause. Clinical feature: Usually appear in last trimester. Generalized pruritus is the main symptom. Diagnosis: Bilirubin < 5 mg percent Markedly increased alkaline phosphatase level. Increased AST and ALT (not more than 60 U). Prognosis: Tends to recur in subsequent pregnancies. Acute Fatty Liver Microvesicular. Diagnosis: Bilirubin > 10 mg/dl. Increased ALT and AST, Increased PT.

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THYROTOXICOSIS IN PREGNANCY Management: a. Medical Propylthiouracil is the drug of choice. b. Surgery thyroidectomy may be done. I131 is absolutely contraindicated. GI TRACT There is increased chance of cholesterol gallstones in multiparae. Pregnancy may cause a flare up of symptoms of inflammatory bowel diseases. Acute appendicitis Laparotomy should be done at the earliest opportunity. RENAL DISEASES Asymptomatic Bacteriuria Definition: Bacterial count > 105/ml in midstream specimen of urine on two occasions without symptoms of infection. Incidence: 210 percent Cause: E. coli is the most common organism. Risk factor: Urinary tract abnormality. Treatment: Ampicillin 500 mg QID. Prognosis: Risk of developing chronic renal lesion in later life. Acute Pyelonephritis Predisposing factors: i. Asymptomatic bacteriuria ii. Abnormality in renal tract. iii. Stasis of urine. Causative organism: E. coli (most common). Note: Renal disorders associated with worst pregnancy outcome are PAN and scleroderma.

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INFECTIONS Bacterial 1. UTI: Most common infection during pregnancy. Most common causative organism is E. coli. 2. Syphilis: Transplacental transmission can occur at any stage of pregnancy, but more common in early stages. 3. Gonorrhea: Ophthalmia neonatorum occurs as a result of infection of the fetus during delivery. 4. Gr. B streptococcus: Most common cause of postpartum bacteremia. 5. Streptococcus pyogenes: Most common cause of epidemic puerperal sepsis. Viral 1. CMV most common cause of congenital viral infection. 2. Rubella most serious viral infection in pregnancy, produces maximum congenital abnormalities. Most serious and maximum transmission occurs in first trimester (Maximum in first 5-6 weeks). Rubella vaccine is contraindicated in pregnancy. 3. HSV Mainly HSV II. Transmission occurs during delivery. Active HSV infection is an indication of elective CS. Drug Acyclovir (Indications Disseminated herpes, Chickenpox in 1st trimester, prophylaxis in recurrent herpes.) Neonatal infection may be Disseminated (fatal) or Localized (involvement of CNS, eye, mucosa) 4. HIV Rate of transmission from mother to fetus or infant is 30 percent. Routes i. Transplacental transfer ii. Contaminated secretion and blood during delivery. iii. Colostrum and breast milk. Antibody testing is of limited value in infants. 5. Hepatitis B See above.

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6. Chickenpox Highest risk in case of delivery within 1 week before or after the onset of maternal varicella. Varicella zoster causes cicatrical skin lesions, limb hypoplasia, and rudimentary digits. Protozoal 1. Toxoplasmosis: 1st trimester lowest chance of infection but maximum risk of fetal abnormalities. 3rd trimester highest chance of transmission but asymptomatic in children. The fetus is at risk only if the mother is sero-negative 2. Malaria : Treatment: Chloroquine is the drug of choice. Fungal 1. Candida albicans: Vulvovaginal candidiasis is more common during pregnancy than non-pregnant state. Note: Infections transmitted during delivery 1. Gonorrhea 2. HSV 3. Hepatitis B. VACCINES Contraindicated in Pregnancy Live attenuated vaccines - Rubella, Measles, Mumps and Varicella, Meningococcal vaccine, Typhoral. Safe in Pregnancy Toxoids (TT and DT), Polio, Yellow fever and inactivated vaccines HBV, Influenza, and Pneumococcal vaccines. Breastfeeding Is not a contraindication to any vaccine. SLE a. Effect of pregnancy on SLE: May flare-up. b. Effect of SLE on pregnancy: First trimester abortion, lupus nephritis, recurrent DVT. PIH, prematurity, IUGR, stillbirth.

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c. Effect on neonate Hemolytic anemia, leukopenia, thrombocytopenia isolated congenital heart block. EPILEPSY Frequency may be increased in 45 percent cases, mostly in 1st trimester. Treatment Drugs contraindicated in pregnancy are: 1. Phenytoin Produces cleft lip and /or palate, microcephaly, mental retardation, cardiac anomalies, limb defects hypoplasia of the terminal phalanges. 2. Valproate Produces neural tube defect. 3. Carbamazepine Increased incidence of neural tube defect. Note: Drug safe in pregnancy is phenobarbitone. Effect of Epilepsy on Pregnancy More chance of stillbirth.

PUBERTY AND ADOLESCENCE


Time Period Puberty 1016 years. Adolescence 1021 years. PUBERTY Changes during Puberty In 1. 2. 3. 4. females Thelarche (Development of breast) 10 years. Puberche (Development of hair) 11 years. Adolescent growth spurt Menarche (First menstruation) - 13 years.

Note: Ability to be pregnant develops 12-24 months after menarche. Maximum growth spurt in girls is seen at menarche. Peak height = Stage III thelarche/puberche. Peak weight = Stage IV thelarche/puberche.

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In

males Growth in testicular volume- 11 years. Pubic hair 12 years. Axillary hair Beard 16 years.

Sexuality Homosexual experimentation is normal during adolescence. Precocious Puberty For girls who show thelarche < 8 years or menarche < 10 years of age (for boys puberty <9 years). Cause: 1. Constitutional most common cause. 2. Hypothyroidism 3. Intracranial tumor, trauma, hypothalamic hamartomas. 4. Gynaecological Granulosa cell tumor, estrogen or androgen intake. 5. McCune Albright syndrome 6. Congenital adrenal hyperplasia in males. Delayed Puberty For girls who does not have breast development and/or pubic hair by 13 years or menarche by 16 years. Causes: 1. Hypopituitarism 2. Hypothyroidism 3. Anorexia nervosa. McCune Albright Syndrome Precocious puberty, polyostotic fibrous dysplasia, cystic degeneration of long bones, caf au lait spots. Adolescent Mortality and Morbidity Most common cause of mortality is violence (especially accidents). Most common cause of morbidity is substance abuse.

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Medico Legal Aspects 1. Criminal responsibility : Age < 7 years no responsibility <12 years cannot give valid consent >18 years can give valid consent 2. Rape Section 375, IPC. < 15 years even if she is his own wife, <16 years even with her consent, 3. Employment The Factories Act, 1948 < 14 yrs Cannot be employed 1518 yrs- termed as adolescent. 4. Attainment of majority 18 years (can cast vote). 5. Marriage 18 years in females. 21 years in males. Juvenile Delinquency Offense by a juvenile defined as: A boy < 16 years or a girl < 18 years. No juvenile can be imprisoned or sentenced to death. They are sent to juvenile homes. Brostal for boys over 16 years.

GERIATRIC MEDICINE
Geriatric deals with people over 65 years. Biology of Aging Theories 1. Pleotrophic antagonism. 2. Random damage (by free radicals). 3. Telomer shortening. 4. Wear-and-tear theory. Changes in Old Age All are decreased with age except ADH secretion, body fat, autoantibodies, chondroitin sulphate in cartilages, residual volume, SBP , pulse pressure increased Not changed with age Hematocrit.

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Diseases of Old Age Most common problem in old age is visual impairment. There is increased incidences of Bone and joint disorders, Cardiovascular disorders, Neurological disorders, Respiratory disorders, Malignancy. Progeria or Accelerated Aging Seen in Werner syndrome, Cockayne syndrome, Ataxia telangiectasia, cutis laxa. Epidemiology Population over 65 years in India 3.8 percent. Note: Life expectancy at birth in India Male 62.8 years. Female 63.8 years.

GASTROINTESTINAL SYSTEM
ESOPHAGUS

ANATOMY Length of the esophagus is approximately 25 cm (10 inches). It extends from the lower border of the cricoid cartilage, opposite the sixth cervical vertebra to the cardiac orifice of the stomach, opposite the eleventh thoracic vertebra (C6-T11). Constrictions Blood supply
Constrictions of esophagus Site 1. 2. 3. 4. Cricopharyngeal sphincter Crossing of arch of aorta Crossing of the left bronchus Cardiac end Level C6 T4 T5 T10 Distance from upper incisor (cm) 15 25 27 40

Cricopharyngeus sphincter is the narrowest point of the gastrointestinal tract in adults; whereas subcricoid region is the narrowest part in children. i. Inferior thyroid arteries cervical part. ii. Esophageal branches of aorta thoracic part. iii. Esophageal branches of left gastric artery abdominal part. iv. Others inferior phrenic artery, bronchial artery. CONGENITAL ANOMALIES Tracheoesophageal Fistula Incidence: 1 in 4000 live births. Etiology: Failure of caudal growth of tracheoesophageal septum.

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Types: 5 types1. Upper end is blind (proximal esophageal atresia) and lower end of esophagus communicates with trachea (distal TE fistula) - most common variety (85%). 2. Both ends open into the trachea - least common. Clinical features: 1. Continuous drooling of saliva - the sign. 2. Choking and cyanosis. Esophageal atresia may occur as a part of the VATER or VACTERL group of anomalies. V = Vertebral body segmentation defects A = Anal atresia C = Cardiovascular anomaly (PDA, ASD) TE = Tracheoesophageal fistula R = Unilateral renal agenesis L = Radial ray hypoplasia. Diagnosis: Antenatal absent stomach bubble in USG. Postnatal air bubble in stomach in X-ray. Diagnosis is confirmed by passing a semi-rigid nasogastric tube followed by X-ray that shows obstruction if TE atresia is present as well as the level of the obstruction. Dysphagia Lusoria Dysphagia produced by compression of the esophagus by vascular anomalies. Etiology: 1. Vascular rings, such as double aortic arch- most common cause. 2. Aberrant right subclavian artery. ESOPHAGEAL RUPTURE Etiology 1. Iatrogenic- due to instrumentation- most common cause. Instrumental perforation is most common at the pharyngoesophageal junction. 2. Boerhaaves syndrome- spontaneous rupture due to increased intraesophageal pressure associated with forceful vomiting or retching. 3. Esophageal diseases- corrosive poisoning, ulcer, neoplasm.

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Mallory-Weiss syndrome Etiology: Vigorous vomiting (common in alcoholics, pregnant females). Pathology: Vertical tear which involves the gastric mucosa just below the squamocolumnar junction at the cardia. Clinical feature: A history of emesis followed by either melena or hematemesis (which is usually not severe). INFLAMMATORY DISORDERS Gastro-esophageal Reflux Disease (GERD) Factors preventing gastro-esophageal reflux: 1. Esophago-gastric angle 2. Pinchcock action of the right crus of diaphragm 3. Rosette like folds of mucous membrane at the cardia. Etiology: Incompetence of the lower esophageal sphincter (LES) causing gastro-esophageal reflux. Clinical features: 1. Retrosternal burning pain (heartburn) and epigastric pain which is aggravated by fatty foods (fatty dyspepsia)most common. 2. Dysphagia (due to peptic stricture) and odynophagia (painful swalloing). 3. Recurrent pulmonary aspiration may cause aspiration pneumonia. Diagnosis: 1. Endoscopy may show reflux esophagitis, peptic stricture or Barretts esophagus. 2. Manometry to exclude achlasia. 3. 24 hours pH recording gold standard. 4. Barium swallow Xray. 5. Bernstein test acid infusion test. Treatment: a. Medical- includes antiemetics (metoclopramide), PPIs (omeprazole). b. Surgery- total (described by Nissen) or partial fundoplication (laparoscopic). Pill-Induced Gastritis Cause: Antibiotics such as doxycycline, tetracycline and clindamycin.

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Barretts Esophagus Pathology: Replacement of normal squamous epithelium of esophagus by columnar epithelium. Etiology: Reflux esophagitis. Complication: 1. Columnar epithelium represents a type of intestinal metaplasia which predisposes to adenocarcinoma of the lower 1/3 rd of esophagus in 2-5 percent cases. 2. Peptic ulcer and stricture. Infectious Esophagitis
Causes of infectious esophagitis In immunocompetent persons HSV 1 Varicella-zoster virus Candida In immunocompromised patients HSV 1or 2 Varicella-zoster virus Candida CMV only in immunocompromised patients

MOTILITY DISORDERS Achalasia Definition: A motor disorder of esophageal muscle in which the LES does not relax properly with swallowing. Pathology: Cause - destruction of Auerbachs (myenteric) plexus in proximal dilated segment. Abnormalities i. Incomplete or absent relaxation of LES ii. Absent peristalsis of the body of esophagus the proximal esophagus becomes dilated (megaesophagus) and tortuous. Clinical features: Affects both sexes at all ages (commonly between third and fifth decades). 1. Dysphagia To both liquid and solid (more to liquid) 2. Regurgitation Aspiration pneumonia. Diagnosis: 1. Chest X-ray shows widening of mediastinum and a posterior mediastinal air-fluid level.

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2. Barium swallow Shows dilated esophagus with a tapering end at distal esophagus birds beak deformity. 3. Manometry Most diagnostic. Mecholyl test: Administration of cholinergic muscarinic agonist mecholyl causes a marked increase in baseline esophageal pressure. (Normal LES pressure is 10-25 mm Hg.) Findings on manometry: i. Hypertensive LES that does not relax completely on swallowing. ii. Aperistlasis of the esophageal body. iii. Increased pressure of esophagus. Treatment: 1. Botulinum toxin maximum chance of recurrence. 2. Drugs nifedipine or nitroglycerine. 3. Balloon dilation. 4. Hellers myotomy (esophagomyotomy). Prognosis: May lead to malignancy. Diffuse Esophageal Spasm Diffuse esophageal spasm is characterized by nonperistaltic contractions, usually of large amplitude and long duration which on Barium swallow X-ray shows Corkscrew esophagus (multiple sacculations and pseudodiverticulae in the wall). Clinical feature: intermittent chest pain, non-progressive dysphagia to both solids and liquids. Diagnosis: Manometry is diagnostic. An esophageal motility pattern showing hypertensive but peristaltic contractions has been called nutcracker esophagus. Scleroderma of Esophagus Pathology: Weakness of lower 2/3rd of esophagus and incompetence of the LES. Clinical features: i. Dysphagia to liquids. ii. Heartburn and regurgitation due to reflux esophagitis.

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Diagnosis: Barium swallow X-ray dilated esophagus with loss of peristaltic movement in the middle and distal portion of the esophagus. OTHER DISORDERS Zenkers Diverticulum Pathology: It is a pseudodiverticulum due to protrusion through the natural weak point between the oblique and horizontal fibers of inferior constrictor muscle (pulsion diverticulum). Clinical features: 1. Halitosis and regurgitation of food particles consumed several days earlier. 2. Dysphagia and complete obstruction due to impaction of food. 3. Lung abscess most common complication. Treatment: Cricopharyngeal myotomy with or without diverticulectomy. Plummer-Vinson (Paterson-Brown Kelly) Syndrome Components: Hypopharyngeal webs, Iron deficiency anemia, Angular stomatitis, Glossitis and Koilonychia. Clinical features: Common in middle aged women. Dysphagia (more to solids): main symptom. Treatment: Large doses of iron and vitamins. Prognosis: Pre-cancerous lesion (malignancy in post-cricoid region). Hiatus Hernia Sliding hernia: The gastro-oesophageal junction and fundus of the stomach slide upwards during increased intraabdominal tension most common type. Paraesophageal (rolling) hernia: The gastro-oesophageal junction remains in its normal position, but the pouch of stomach rolls into the chest through esophageal opening. Clinical feature:Chest pain with respiratory distress. X-ray: A gas bubble, often with a fluid level behind the heart.

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Complications: Volvulus, perforation and gangrene. Diagnosis: Barium swallow is the best investigation. Treatment: Always surgical. ESOPHAGEAL TUMORS Please see the chapter of oncology.

PHYSIOLOGY OF GI TRACT
DIGESTION Digestive Enzymes
Source Saliva pH = 7 Stomach pH = 1.5 Enzyme Substrate Products

Exocrine pancreas pH = 8 Vol.=1.5

Small intestine

-Amylase Starch Dextrins, maltose, (rich in K +) maltotriose Pepsinogen(activated Protein and Cleaves peptide by HCl to pepsin) polypeptides bond adjacent by chief cells to aromatic amino acid ( 1-4) trypsin Lipase Triglycerides Fatty acid + glycerol Proteins and Basic amino acids Trypsinogen enteropeptidase polypeptides (arginine and lysine) trypsin lit Chymotrypsinogen Do Aromatic amino acids chymotrypsin Lipase Triglycerides Monoglycerides + fatty acids A number of Polypeptides Amino acids peptidases Maltase Maltose Glucose Lactase Lactose Glucose + galactose Sucrase Sucrose Fructose + glucose

Parietal cells (oxyntic cells) secrete HCl and intrinsic factor. Rennin (chymosin) is present in the stomach and it coagulates milk. Endopeptidases are pepsin, trypsin, chymotrypsin and elastase. They break peptide bonds within a protein. Serine proteases are trypsin, chymotrypsin, elastase. (Note - 1 antitrypsin is a serine protease inhibitor).

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Site of Digestion
Food Carbohydrate Protein Fat Site of digestion Mouth and small intestine Stomach, small intestine Stomach (mostly by lingual lipase), duodenum (mostly by pancreatic lipase)

ABSORPTION 1. Carbohydrate: Site: Small intestine, mainly as hexoses. Glucose is co-transported with Na+ by a symport called sodium-dependant glucose transporter (SGLT). This is a type of secondary active transport. Glucose is also transported by facilitated diffusion by GLUT 2 (this occurs in renal epithelium, too) 2. Proteins: Site: mainly duodenum and jejunum (also ileum) 3. Fat: Site: long chain fatty acids are mainly absorbed from jejunum (also in ileum). Short chain fatty acids are absorbed from colon. 4. Vitamins: All vitamins are absorbed mainly from jejunum except Vit B12 which is absorbed from terminal ileum. 5. Water and electrolytes: i. Fluid (7000 ml secreted per day) 98 percent reabsorbed. ii. Na+ - upper and lower intestine, colon. iii. Ca++ - upper intestine. iv. Fe++ - upper intestine. 6. Bile salts: Site: terminal ileum. Sites of Absorption
Sites of absorption Upper intestine (jejunum) All vitamins, long chain fatty acids and electrolytes, iron, calcium Mid intestine Sugars, aminoacids Terminal intestine Bile salts, Vit B12, Na + Colon Na + (water), short chain fatty acids K+ and HCO3- are secreted in colon (K+ content 30 mEq/lit.)

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REGULATION OF GI FUNCTION The Enteric Nervous System Consists of: 1. Myenteric (Auerbachs) plexus in between outer longitudinal and inner circular muscle layer. 2. Submucous (Meissners) plexus between circular muscle and the mucosa. Extrinsic Innervation 1. Parasympathetic cholinergic system - intestinal smooth muscle tone and relaxation of sphincter emptying. 2. Sympathetic system - smooth muscle tone with contraction of sphincters retention. Basic Electrical Rhythm (BER) Pacemaking of G.I. tract, produced by interstitial cell of Cajal (mainly at the fundus). Migrating Motor Complex (MMC) Cyclic motor activity that migrates from stomach to distal ileum during fasting. Peristalsis Rate 2 to 25 cm/sec. Regulation of Peristalsis: By Myenteric plexus
antero grade cholinergic fibers
retrograde substance cholinergic fibres

P and ACh

contraction behind the stimulus.

NO, VIP and ATP relaxation ahead of stimulus GASTROINTESTINAL HORMONES Gastrin Gastrin occurs in 3 forms viz. G17, G14 and G34. G17 is the principal form that mediates gastric acid secretion.

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Source: 1. G cells in the gastric antrum. 2. Pancreatic islets in fetal life. 3. Anterior and intermediate lobes of the pituitary gland. Action: 1. Stimulation of gastric acid and pepsin secretion. 2. Stimulation of the growth of mucosa of the stomach and intestine (trophic action). 3. Stimulation of gastric motility. (Note: Normal acid level in stomach 15-20 mEq) Regulation:
Secretion increased by 1. Gastric content peptides and amino acids 2. Gastric distension 3. Neural - vagal discharge GRP 4. Blood-borne Ca++, Epinephrine Secretion decreased by 1. Luminal acid, somatostatin 2. Blood-borne secretin, glucagon, VIP , GIP

Cholecystokinin Pancreazymin (CCK) Source: 1. J cells in the mucosa of upper intestine (jejunum). 2. Nerves in the distal ileum and colon. Action: 1. Contraction of gallbladder. 2. Secretion of pancreatic juice rich in enzymes 3. Augmentation of action of secretin to produce alkaline pancreatic juice. 4. Inhibition of gastric emptying. Regulation: Secretion increased by: 1. Peptides and amino acids best stimulant. 2. Fatty acids containing more than 10 C atoms. Secretin First hormone to be discovered by Bayliss and Starling. Source: S cells located deep in the glands of the mucosa of the upper small intestine (duodenum). Action: 1. Increases secretion of HCO3 watery alkaline pancreatic juice low in enzymes.

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2. Augments the action of CCK. 3. Decreases gastric acid secretion and may cause contraction of pyloric sphincter. Regulation: Secretion increased by products of protein digestion and by acid bathing the gastric mucosa (acid chime). Somatostatin Action: Decreases gastrin and gastric acid secretion. REGULATION OF GASTRIC SECRETION 1. Cephalic phase: Mediated by vagus nerve gastrin by GRP ACh acid and pepsin So this phase is mostly affected by vagotomy. 2. Gastric phase: Mediated by i. Local neuronal reflex responses ii. Gastrin 3. Intestinal phase: Mediated by neuronal and hormonal mechanisms. Control fats, carbohydrates and acid in duodenum inhibit gastric acid and pepsin secretion and decrease gastric motility. REGULATION OF GASTRIC MOTILITY AND EMPTYING 1. Type of food: Fatty foods decrease gastric motility. 2. Osmolality: Hyperosmolality in duodenum decreases gastric emptying. 3. Enterogastric reflex: Action: Decreases gastric motility. Initiated by: i. Products of protein digestion and H+ ii. Distension of duodenum 4. Gastroileal reflex: When food leaves the stomach, caecum relaxes and passage through ileocaecal valve is increased. It is associated with mass peristalsis. 5. Gastrocolic reflex: Distension of stomach by food initiates contraction of rectum and a desire to defecate.

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STOMACH AND INTESTINE


ANATOMY Size Mean capacity of stomach at birth is one ounce (30 ml). In adults 1 2 lit. Stomach bed It is formed by i. The diaphragm ii. Left suprarenal gland iii. Splenic artery iv. Left kidney v. Pancreas vi. Splenic flexure of colon vii. Transverse mesocolon (Mnemonic: Dr Sunil Sen Kills Patients Cruelly and Mercillessly). Duodenum First part: Posterior relations are portal vein, bile duct (right) and hepatic artery (left). Third part: 10 cm long. Anterior relations are superior mesenteric artery, root of mesentery. Posterior relations are IVC and aorta. Arterial supply: Part above the opening of CBD by superior pancreaticoduodenal artery. Part below that by inferior pancreaticoduodenal artery. First part of duodenum is also supplied by right gastric artery, supraduodenal artery and retroduodenal branches of gastro-duodenal artery. Duodenal fossa Paraduodenal fossa Lodges the inferior mesenteric vein. PEPTIC ULCER Duodenal Ulcer Site: more than 95 percent of duodenal ulcers occur in the first part of the duodenum.

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Etiology: rare before the age of 16 years. 1. H. pylori infection. 2. Blood group O. 3. Cigarette smoking. 4. NSAIDs. Pathology: Kissing ulcer the situation in which there is both a posterior and an anterior duodenal ulcer. Anteriorly placed ulcers tend to perforate. Posteriorly placed ulcers tend to bleed due to erosion of vessels like the gastroduodenal artery. Diagnosis: 1. Barium meal X-ray discrete craters in proximal duodenum Trifoliate deformity. 2. Upper GI endoscopy most accurate 3. Investigations for detection of acid production i. Pentagastrin test best method. ii. Kays augmented histamine test size of oxyntic cell mass. iii. Hollanders insulin test. Treatment: Primary aim is to prevent complication. 1. For H. pylori infection A. Standard triple therapy contains Bismuth salicylate, Tetracycline and Metronidazole for 2 weeks. B. Triple therapy with acid reduction Omeprazole, Clarithromycin and Metronidazole or Amoxicillin for 1 week. 2. Prostaglandins Misoprostol is used for analgesic induced gastritis. Side effects causes uterine contraction, so contraindicated in women of childbearing age. Gastric Ulcer Site: more common on the lesser curvature, especially at the incisura angularis. Malignancy: gastric ulcers can turn malignant ulcer cancer (cf. cancer ulcer or ulcerative cancer). Diagnosis: by four quadrant biopsy (if all the quadrants show malignancy then it is a cancer ulcer).

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Hour glass stomach: Due to cicatrical contraction of a saddle-shaped ulcer at the lesser curvature. Surgery for Peptic Ulcer Rational for surgery: Aim is to exclude the damaging effects of acid on duodenum. This has been achieved by 1. Diversion of acid away from duodenum Billroth I and II operations. 2. Reducing the secretory potential of stomach vagotomy. 3. Both. Types: 1. Billroth I - gastric resection with gastroduodenal anastomosis. 2. Billroth II- gastric resection with gastrojejunal anastomosis. Complication leakage from duodenal stump occurs on 6th day (duodenal blow out due to avascular necrosis of stump). 3. Gastrojejunostomy It is the most commonly performed operation. It causes a clean contaminated wound. It has the maximum chance of recurrence. 4. Truncal vagotomy and drainage (of Dragstedt). Drainage pyloroplasty. 5. Highly selective vagotomy - only the parietal cell mass is denerveted. No drainage operation is needed. Most satisfactory operation for duodenal ulcer. It has the least mortality rate. Nerves of Laterjet supplying the antrum are preserved. Complication recurrent ulcer. 6. Truncal vagotomy and antrectomy least chance of recurrence. Maximum reduction of acidity. Useful in recurrent ulcer. ( Note: Completeness of vagotomy is tested by Hollanders test). Complications of Surgery 1. Gastrojejunal and gastrocolic fistula: patient suffers from diarrhea which is severe and follows every meal following gastrojejunostomy.

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2. Afferent loop syndrome: Cause: Billroth II operation Clinical feature: abdominal bloating and pain 20 minutes to 1 hour after eating followed by nausea and vomiting containing bile, which relieves the discomfort. 3. Dumping syndrome (Post cibal syndrome): Cause: gastrectomy or vagotomy and drainage. Early dumping: abdominal and vasomotor symptoms (like palpitation, tachycardia, light headedness) following 30 minutes after meal. Etiology: rapid emptying of hyperosmolar gastric contents into proximal small intestine. Late dumping: occurs 90 minutes to 3 hours after eating meals rich in carbohydrates. Treatment: i. Dietary measures limitation of sugar containing foods and liquids. ii. Frequent small meals. iii. Somatostatin analogue octreotide. 4. Postvagotomy diarrhea. 5. Anemia: Iron deficiency: most often with Billroth II. Vitamin B12 deficiency: most common after total gastrectomy. (Note:Fat laden cells are seen in post-gastrectomy). 6. Anastomotic hemorrhage: after truncal vagotomy and gastrojejunostomy. 7. Gallstone: after truncal vagotomy. Complications of Peptic Ulcer 1. Peptic perforation: Most common site anterior aspect of duodenum. Chest X-ray shows gas under diaphragm. Prognosis depends on age, duration of history, peritonitis. 2. Hematemesis and Melena: Most common cause of death in peptic ulcer. 3. Gastric Outlet Obstruction: Cause i. Pyloric stenosis secondary to peptic ulceration. ii. Gastric cancer most common cause.

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Most common site: first part of duodenum. Clinical feature: vomiting which is devoid of bile. Metabolic changes: Hypochloremic, hypokalemic (hyponatremic) metabolic alkalosis with paradoxical acidic urine. Management: Rehydration with IV NS and K + supplementation. Surgery: Truncal vagotomy with gastrojejunostomy. GASTRITIS Chronic Gastritis (Atrophic) Stages: 1. Superficial gastritis 2. Atrophic gastritis 3. Gastric atrophy Type A (Autoimmune Gastritis) Cause: Autoantibodies against parietal cells. Site: Fundus and body of stomach. Pathology:
Atrophy of parietal cell mass production of IF Pernicious anemia Hypochlorhydria and achlorhydria High level of gastrin from antral G cells (hypergastrinemia) Hypertrophy of ECL cells of stomach Carcinoid tumors

Diagnosis: Pentagastrin fast achlorhydria seen in pernicious anemia. Type B Gastritis Cause: H. pylori infection. Site: Antrum of stomach. But in developed countries, pangastritis is more common more prone to malignancy.

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Mntriers Disease Characterized by large, tortuous gastric mucosal folds due to massive foveolar hyperplasia increased mucus production and hypochlorhydria. Clinical feature: Protein losing gastropathy hypoproteinemia Anemia It is a premalignant lesion. NON-GASTRITIS EPITHELIAL CELL INJURY Erosive Gastropathy Stress Related Mucosal Injury Features: Multiple, mostly in fundus. Causes: i. Mechanical ventilation ii. Coagulopathy iii. Sepsis and multiorgan failure iv. Curlings ulcer Cause: Massive injury, burn Clinical feature: Painless GI hemorrhage Diagnosis: Upper GI endoscopy shows superficial erosions on gastric mucosa. v. Cushings ulcer Cause: Intracranial injury, Increased intracranial tension (brain tumor, subdural hematoma) Clinical feature: Hemorrhage and perforation. Sites: Esophagus, stomach and proximal duodenum. Other Erosive Conditions 1. NSAIDs (particularly aspirin) produce hemorrhagic erosive gastropathy most common cause. 2. Alcohol. PEDIATRIC DISODERS Hypertrophic Pyloric Stenosis Pathology: Hypertrophy of the circular musculature of the pylorus and adjacent antrum.

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Clinical features: First-born male child is most commonly affected. Seen within 4 weeks after birth. Symptoms: Vomiting which is forcible and projectile without bile. Weight loss. Sign: Visible peristalsis in upper abdomen. Palpable hypertrophied pylorus: most important clinical feature. Metabolic effects: like GOO. Diagnosis: USG investigation of choice; pyloric canal appears > 14 mm. Treatment: 1. Rehydration with DextroseNS with K+ supplementation. 2. Ramstedts operation pyloromyotomy. Note: Treatment of adult pyloric stenosis is pyloroplasty. Duodenal Atresia Most common cause of acute intestinal obstruction of the newborn. Duodenum is the most common site of atresia in the GI tract. Clinical features: Vomiting from birth; is bile-stained. Sign Distension usually not present Visible peristalsis. Associated with: Downs syndrome in 30 percent cases. Diagnosis: Radiology Double stomach appearance due to gross distension of stomach. Two air-fluid levels. Gastric aspiration >20ml at birth. Treatment: duodenoduodenostomy. Ileal Atresia The child is born with abdominal distension.

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DISORDERS OF ABSORPTION Tests for Malabsorption 1. Stool fat: Increased in steatorrhea. Diagnostic in pancreatic insufficiency. 2. Xylose absorption: Most commonly employed test for carbohydrate absorption. Abnormal result is found in diseases affecting the mucosa of the proximal small intestine such as celiac sprue and tropical sprue. 3. Schilling test: For vitamin B12 absorption. Used in pernicious anemia and pancreatic insufficiency. 4. Intestinal biopsy: Diagnostic in: 1. Whipples disease. 2. Abetalipoproteinemia. 3. Agammaglobulinemia. May be diagnostic in: 1. Intestinal lymphangiectasia. 2. Giardiasis. Not diagnostic in: 1. Celiac sprue. 2. Tropical sprue. Causes of Malabsorption Endocrine 1. Diabetes mellitus. 2. Hypoparathyroidism. 3. Hyperthyroidism. Short Bowel Syndrome Causes: 1. Massive intestinal resection following a vascular insult to small intestine. 2. Regional enteritis (Crohns disease). 3. Jejunal bypass for morbid obesity. 4. Most common cause is mesenteric infarction. Effect: Resection of 40-50 percent of bowel is well tolerated provided the proximal duodenum, distal ileum and ileocecal valves are preserved. Treatment: Diet containing at least 2500 C and consist primarily of carbohydrate and protein with fat restricted less than 40 gm/day.

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(Note: - All are seen in massive resection of small bowel hypergastrinemia, Vit B12 deficiency, malabsorption, oxalate renal stone, cholesterol gallstone, hypocalcemia, hyperuricemia, arthritis, fatty infiltration of the liver). Tropical Sprue Caused by E.coli. Features: Impaired absorption of fat, Xylose and Vitamin B12 (at least 2 for the diagnosis). Biopsy: Not diagnostic but characteristic. Shows villous atrophy (also seen in Giardiasis and Celiac sprue). Treatment: Vitamin B12, folate and antibiotics (tetracycline). Celiac Sprue (Non-tropical Sprue) Pathogenesis: It is a non-infectious process. It is due to intolerance to Gluten which is found in wheat and wheat products, hence known as Gluten induced enteropathy. Gluten contains gliadin. Pathology: Impaired digestion of fat and protein (due to decreased CCK) and consequent malabsorption. Association: HLA DQ2 and DQ8. Clinical features: Diarrhea with other features of malabsorption. Vitamin B12 deficiency does not occur. Anti-gliadin and anti-endomysial antibodies are increased in serum. There is increased chance of intestinal lymphoma. Biopsy: Blunting and flattening of the mucosal surface with either absent or broad and short villi. Treatment: Gluten free diet (rice and maize). Lactase Deficiency Produces lactose or milk intolerance. Features: Symptoms abdominal cramps, bloating or distension and diarrhea after ingestion of milk (not in primary variety). Others: Stool is acidic due to production of lactic acid.

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Types: 1. Primary hereditary. Diagnosis Measurement of breath H2 after ingestion of 50 gm lactose. 2. Acquired due to i. Celiac and topical sprue. ii. Regional enteritis, ulcerative colitis. iii. Infections Giardiasis, Shigella, Entamoeba, Yersinia. iv. Abetalipoproteinemia. Whipples Disease Causative agent: Tropheryma whippelli which is a gramnegative actinomycetee. Features: Usually in middle aged male. Abdominal pain, diarrhea, malabsorption. Arthralgia. Memory loss or dementia most common CNS manifestation. Uveitis, nystagmus, ophthalmoplegia. Hypotension. Lymphadenopathy. Diagnosis: Biopsy: Presence in the mucosa of macrophages containing large cytoplasmic granules that stain brilliant magenta with the PAS reagent. Treatment: Cotrimoxazole. Intestinal Lymphangiectasia Characterized by enteric loss of protein, hypoproteinemia, edema, lymphocytopenia, malabsorption and abnormal dilated lacteal.
Biopsy features Whipple disease Lamina propria infiltrated with macrophages containing PASpositive glycogen Tropical sprue Same as celiac sprue Celiac sprue Blunting and flattening of mucosal surface Villi absent or markedly atrophied Crypts hypertrophied Mononuclear cell infiltration in lamina propia. Changes are more marked in proximal small gut.

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Protein Losing Enteropathy Any of the above diseases can produce protein-losing enteropathy. Blind Loop Syndrome Pathology: Stasis produces abnormal bacterial flora which prevents breakdown of foods. Effect: High loops (upper intestine) Steatorrhea Low loops (lower intestine) Vitamin B12 deficiency anemia. Treatment: Antibiotics, Surgical extirpation. TUMORS OF STOMACH AND DUODENUM Please see the chapter of oncology. OTHER CONDITIONS Trichobezoar Hairy balls in stomach. Complications ulceration, GI bleeding, perforation and obstruction. Acute Gastric Dilatation Associated with some form of ileus. Stomach is atonic and dilated enormously. Clinical feature: Patient is dehydrated with electrolyte disturbance, Sudden massive vomiting with aspiration into the lungs. Treatment: Nasogastric suction. Fluid replacement Treatment of underlying condition. Diverticulum of Stomach Diverticulum is least common in stomach in the GI tract.

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Usually located in the posterior surface at the cardiac end. Mostly asymptomatic, may produce hemorrhage.

SMALL AND LARGE INTESTIENE


ANATOMY Ileum contains Peyers patches at the ante-mesenteric border. Villi leaf-like in jejunum and finger-like in ileum. Jejunum and ileum are supplied by superior mesenteric artery. Appendices epiploicae are present in large intestine except the appendix, caecum and rectum. MEGACOLON Hirschsprungs Disease Also called the congenital megacolon. Pathology: Heterogeneous genetic disorders (some are autosomal dominant, some recessive). Etiology: Absence of the ganglion cells in the neural plexus of the intestinal wall (both myenteric and Auerbachs plexuses) give rise to a contracted nonperistaltic segment with a dilated hypertrophied segment of normal colon above it. Site: Rectum and lower sigmoid colon are the most common sites. Clinical features: More common in males. Symptom: Delayed passage of meconium (usually within the first 4 days of life) together with mild abdominal distension in neonates. May also present in childhood. Chronic constipation within first few weeks of life. Severe constipation without soiling in otherwise healthy children and adults. Diagnosis: Rectal biopsy confirmation of diagnosis depends upon histology (aganglionosis).

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Barium enema shows a transition zone between proximal dilated and distal constricted segments; reversal of rectosigmoid ratio (sigmoid colon more dilated than rectum). Treatment: 1. Rectal saline washout. 2. Surgery temporary colostomy and definitive surgery when the child is 10 kg. Duhamel operation excision of the aganglionic segment. Swensons operation. Soaves operation. INFLAMMATORY BOWEL DISEASE Ulcerative Colitis Etiology: 1. Heredity 2. Milk allergy 3. Smoking is protective. Pathology: Usually starts in the rectum and spreads proximally up to 30 cm of the ileum from ileocecal junction. It is a nonspecific inflammatory disease primarily affecting the mucosa and superficial submucosa produce minute ulcers. Chronic inflammation may lead to pseudopolyps. Features suggestive of chronicity are Distortion of crypt architecture (cryptitis) and mononuclear infiltrate in lamina propria (crypt abscess). Clinical feature: First symptom is watery or bloody diarrhea. Complications: 1. Toxic megacolon in severe fulminant colitis a section of colon, especially transverse colon, may become actually dilated and the intestinal wall becomes extremely thin. 2. Perforation Grave complication. 3. Severe hemorrhage. 4. Precancerous change more chance than Crohns disease. Increased chance in young patients. Investigations: 1. Barium enema shows loss of haustrations, pseudopolyps.

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2. Sigmoidoscopy essential for diagnosis. 3. Colonoscopy and biopsy. Extraintestinal manifestations: 1. Arthritis migratory, most commonly at knee; ankylosing spondylitis. 2. Skin lesions erythema nodosum, pyoderma gangrenosum, and apthous ulcer. 3. Eye Iritis. 4. Liver Sclerosing cholangitis. Management: A. Medical Acute steroids, if unsuccessful cyclosporin. Chronic sulfasalazine steroids azathioprine/6mercaptopurine. B. Surgery Proctocolectomy and ileostomy treatment of choice. In emergency (e.g. perforation) total colectomy and ileostomy. Colectomy does not reduce the risk of sclerosing cholangitis. Ulcerative colitis in pregnancy: Pregnancy causes flare up of symptoms of ulcerative colitis especially during first trimester and in postpartum period. Crohns Disease It can affect any part of the GI tract from lips to anal margin, but terminal ileum and colon are the most common sites. Pathology: In 60 percent cases, there are noncaseating giant cell granulomatous ulcers. Earliest mucosal lesions are Apthous ulcer. All the layers are involved, leading to fibrotic thickening of the intestinal wall. Edema of the mucosa between the ulcers gives rise to Cobble stone appearance. Segments of bowel are involved with intervening normal bowel skip lesions. Etiology: Multiple pathogens ( Salmonella, Shigella, Clostridium difficile, Campylobacter) may initiate IBD. Complications: Transmural inflammation leads to 1. Adhesions. 2. Crypt abscess.

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3. 4. 5. 6.

Inflammatory masses with mesenteric abscess. Fistula enteroenteric, enterovesical, entero-cutaneous. Have malignant potential. Bleeding, perforation.

Diagnosis: Barium enema String sign of Kantor. Ulcerative Tuberculosis Cause: Secondary to pulmonary tuberculosis due to swallowing of infected sputum. Hyperplastic Tuberculosis A form of secondary TB. Site: Ileocecal region is most common. Clinical feature: Abdominal pain and diarrhea, right iliac fossa mass. Radiology: Barium follow through or small bowel enema show a long narrow filling defect in terminal ileum. Caecum is pulled up (cephalad retraction of caecum). Treatment: Chemotherapy Surgery ileocaecal resection when obstruction is present. Tuberculous Ulcer Involves the Payers patches of terminal ileum. Ulcers are transverse with fibrosis stenosis is common. Typhoid Ulcer Most common site Payers patches of terminal ileum. Morphology: Gross Ulcers are along the long axis of gut. No significant fibrosis so stenosis is uncommon. Microscopy Erythrophagocytosis with mononuclear cell infiltrates. Clinical feature: Most common presentation is intestinal bleeding. Complications: 1. Paralytic ileus most common 2. Perforation occurs during 3rd week, less common in children below 5 years. 3. Hemorrhage.

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Amoebic Ulcer Site: Colon, mostly sigmoid colon. Ulcers: Typically flask-shaped with narrow neck and broad base. Choleric Ulcer The mucosa remains intact. Pseudomembranous Colitis Etiology: It is associated with antibiotic use particularly clindamycin, lincomycin (also ampicillin, tetracycline and chloramphenicol). Organisms: Clostridium difficile. Pathology: Production of enterotoxin A and B as well as cytotoxin. Endoscopy: punctate yellow exudates in colon. Histology: small ulceration with slough. Treatment: Vancomycin is the drug of choice (Also used is Metronidazole). DIVERTICULAR DISEASE Meckels Diverticulum Development: From Vitelo-intestinal duct. Rule of 2: Present in 2 percent of population (most common congenital anomaly of GI tract). Length 2 inches Site 2 feet (60 cm) away from ileo-caecal valve in the antimesenteric border of ileum. Pathology: It is a true diverticulum, as it possesses all the 3 layers of intestine and has separate blood supply. It contains ectopic mucosa, mainly gastric, also pancreatic and colonic. Complications: 1. Severe hemorrhage caused by peptic ulceration of ectopic gastric mucosa. Ulceration may also produce pain in periumbilical region and nausea after taking food.

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2. Intussusception. 3. Diverticulitis. 4. Obstruction is rare due to board base. It is usually due to band. 5. Litters hernia- Meckels diverticulum in an inguinal or a femoral hernia. Diagnosis:
99mTc

scan.

Colonic Diverticulum Site: Sigmoid colon is most commonly affected. Rectum is never affected. Saints triad: Colonic diverticulosis, gallstone and hiatus hernia. Epidemiology: Diverticular disease is rare in people taking diet containing natural fibers. Complications: 1. Perforation. 2. Intestinal obstruction. 3. Hemorrhage important cause of hematochezia in patients over 60 years of age. It usually produces massive hemorrhage. Most common site of bleeding is ascending colon (i.e. from the superior mesenteric aretery). 4. Fistula Vesicocolic is most common. Diverticulitis is not a precancerous lesion. Diagnosis: 1. CT scan is diagnostic in acute phase. 2. Barium enema Saw toothed appearance. 3. Sigmoidoscopy i. In acute phase painful to perform. ii. Mucosa inflamed. iii. Necks of diverticula can be seen. 4. Mesenteric angiography is both diagnostic (in localizing bleeding site) and therapeutic in patients with severe hemorrhage. It can detect bleeding as minimum as 0.5 ml/min. Management: Diverticulosis by high-residue diet. Diverticulitis i. Medical in acute cases. Rest and IV Cefuroxime + Metronidazole.

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ii. Surgery in case of obstruction Hartmanns operartion. VASCULAR ANOMALIES Angiodysplasia Pathology: Angiodysplasia is a vascular malformation associated with aging. The malformation consists of dilated tortuous submucosal veins. Site: Ascending colon and caecum most common. Clinical feature: Age over 60 years. Bleeding per rectum usually chronic and intermittent. There is an association with aortic stenosis. Investigation: i. Barium enema is unhelpful and should be avoided. ii. Angiography iii. 99mTc labelled RBC confirmatory. Treatment: Colonoscopic diathermy. Ischemic Colitis Most common in the splenic flexure. X-ray Thumb printing appearance. MESENTERIC DISORDERS Mesenteric Adenitis Cause: Specific Tuberculosis Non-specific (idiopathic) much more common. Some cases are associated with yersinia infection. Mesenteric Cyst Types: 1. Chylolymphatic most common type. Arises in congenitally misplaced lymphatics. 2. Enterogenous Arises from a sequestrated diverticulum from the mesenteric border of intestine.

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Clinical feature: A painless fluctuating swelling around umbilicus which moves freely in a plane at right angles to the attachment of mesentery. Treatment: Chylolymphatic cyst Enucleation. Enterogenous cyst Resection of a segment of gut along with the cyst followed by intestinal anastomosis. Acute Mesenteric Ischemia Etiology: Occlusive arterial thrombi or embolus. Most commonly in patients with atrial fibrillation or atherosclerosis. Clinical features: Persistent vomiting and defecation. Severe abdominal pain, often colicky. On examination tenderness and distension of abdomen. Bowel sounds are often normal. Investigations: Occult blood in stool. Blood polymorphonuclear leukocytosis. X-ray absence of gas in the thickened small gut. Gas bubbles in mesenteric vein (thumb printing) is pathognomonic. RETROPERITONEAL SPACE Retroperitoneal Fibrosis Etiology: 1. Idiopathic (Ormonds disease). 2. Extravasation of urine. 3. Retroperitoneal irritation by leakage of blood or intestinal contents. 4. Trauma. 5. Drugs chemotherapeutic agents, Methysergide, -blockers. Idiopathic Retroperitoneal Fibrosis It is a type of fibromatoses (others being Dupuytrens contracture and Peyronies disease). Extensive collagen deposits surround the ureters first retroperitoneal structure to be affected.

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INTESTINAL OBSTRUCTION Types: A. Dynamic Intraluminal : Foreign body, gallstone Intramural : Strictures. Extramural : Bands and adhesions (most common cause of intestinal obstruction), hernias, volvulus, intussusception. B. Adynamic Paralytic ileus, Mesenteric vascular occlusion, Pseudoobstruction. Site: 1. High small bowel vomiting is early, distension is minimum with little fluid levels on abdominal radiograph, causes maximum water loss (dehydration). 2. Low small bowel pain is predominant with central distension. Vomiting is delayed. Multiple fluid levels are seen on radiographs. 3. Large bowel distension is early, pain is minimum and vomiting and dehydration are late. Acute obstruction usually affects small bowel first symptom is pain. Chronic obstruction usually affects large bowel symptoms are constipation and distension. Pathology: The distension proximal to an obstruction is produced by two factors 1. Gas appears early. 70-80 percent of intestinal gas consists of swallowed air. Rest by aerobic and anaerobic digestion. 2. Fluid appears late. Source various digestive juices. Strangulation There is direct interference to blood flow, threatening the viability of the bowel. Causes: 1. External compression hernias, adhesions and bands. 2. Interruption of mesenteric blood flow by volvulus, intussusception.

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3. Mesenteric infarction. 4. Closed loop obstruction. Diagnosis: Coffee bean sign. Large Bowel Obstruction Most common cause is malignancy. Surgery should be considered early because of the chance of gangrene and perforation (most commonly at the caecum). Adhesions and Bands Most common cause of intestinal obstruction. Cause: Iatrogenic most common. Treatment: Initial management is based on IV rehydration (with Hartmanns solution or NS) and nosogastric suction. Enteric Strictures Cause: TB, Crohns disease, lymphoma, radiation. Treatment: Resection and anastomosis. Gallstones Classically there is impaction about 60 cm proximal to the ileo-caecal valve. Acute Intussusception Etiology: 1. Idiopathic most common in children (most common cause between 3 month 6 years of age). Lead point Meckels diverticulum, HS purpura. 2. Adult polyp, lipoma or tumor. Pathology: It is believed that hyperplasia of Peyers patches in the terminal ileum may be the initiating event. Parts: Intussusceptum (the entering or inner tube) Intussuscipiens (the outer tube)

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Clinical feature: Most common in children between 3-9 months. Site Ileocolic type is most common. Least common is the multiple type. Symptoms: Pain is the first and most common symptom. Stool blood and mucus are evacuated at a later stage the red current jelly stool. Sign No distension. Lump may be felt. Emptiness in the right iliac fossa- the sign of Dance. X-ray: The Claw sign. Treatment: Barium enema. Superior Mesenteric Syndrome Cause: Compression of third part of duodenum by the superior mesenteric artery. Clinical feature: Most commonly seen in young females. Features of obstruction vomiting, distension. Weight loss, postprandial epigastric pain. Risk factor: Weight loss (asthenic built), immobilization, scoliosis, body cast. Diagnosis: Barium follow through upper GI tract or hypotonic duodenography. Treatment: Initially conservative. Definitive surgery is duodenojejunostomy. Meconium Ileus It is the neonatal manifestation of cystic fibrosis. Inheritance: Autosomal recessive. Pathology: Meconium is normally kept fluid by the action of pancreatic enzymes (trypsin). The viscid meconium and mucus fill the terminal ileum and cause neonatal obstruction. Diagnosis: 1. Abdominal radiograph may reveal a distended small intestine, with mottling. Fluid levels are generally not seen.

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2. Absence of trypsin from stool or bile. 3. Sweat chloride > 80 mmol/lit. Treatment: The Bishop-Koop operation. Necrotizing Enterocolitis Neonatal necrotizing enterocolitis develops 1-2 days after birth. Clinical feature: First change is non-specific bowel dilatation. Others - Bradycardia, blood in stool, decreased bowel sounds. X-ray: X-ray abdomen shows pneumatosis intestinalis or free intraperitoneal air. Prevention: Probiotics. Paralytic Ileus Varieties: 1. Postoperative for first 24-72 hours. 2. Intra-abdominal sepsis. 3. Fracture of the spine or rib, retroperitoneal hemorrhage reflex ileus. 4. Metabolic uremia and hypokalemia. TUMORS OF THE SMALL INTESTINE Types Benign: 1. Adenomas most common benign tumor of the small gut. Brunners gland adenoma it is not a true neoplasm, but represents a hypertrophy or hyperplasia of submucosal glands. They secrete highly viscous alkaline mucus. 2. Polyps Peutz-Jeghers syndrome. 3. Lipomas most common at the distal ileum and the ileo-cecal valve; radiolucent; intramural and asymptomatic. Malignant: 1. Adenocarcinoma most common primary cancer of the small gut. Most common site is the distal duodenum.

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Diagnosis by endoscopic biopsy. Treatment surgical resection. 2. Lymphomas Most common at ileum. Mainly diffuse large cell (T cell) non-Hodgkins lymphoma. Immunoproliferative small intestinal disease (IPSID) Or IgA lymphoma shows IgA with shortened alpha heavy chain and absent light chains. Lymphoepithelial lesions are seen. 3. Carcinoid tumors Arise from argentaffin cells of the crypts of Liberkhn, predominantly in the distal ileum. Usually asymptomatic. Peutz-Jeghers Syndrome 1. Peutz-Jeghers polyp-hamartomatous polyp affects jejunum. 2. Melanosis of the oral mucous membrane and the lips. TUMORS OF THE LARGE INTESTINE Please see the chapter of oncology. Genetics in Colorectal Carcinoma Knudsons hypothesis of adenoma-carcinoma sequence: Loss of APC gene earliest and most common (80%) event in sporadic Ca. It leads to increased beta catenin and activation of MYC and cyclin D1 leading to increased cell proliferation. Mutation of K-RAS gene. 18q21 deletion (DCC gene) in 60 - 70 percent cases. Loss of TP53 in 7080 percent cases. DNA mismatch repair genes: Are involved in 10 15 percent of sporadic cases. Inherited mutations in one of five DNA mismatch repair genes (most commonly MLH1) leads to hereditary nonpolyposis colon carcinoma (HNPCC). OTHER DISORDERS Traumatic Rupture Cause: Blunt trauma.

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Note: in penetrating trauma, small intestine is most commonly affected. Site: Least chance of rupture at ileo-caecal junction. Sigmoid colon is ruptured most commonly during colonoscopy. Treatment: 1. In small intestine and sterile wounds simple closure of the perforation. 2. In lacerated mesentery and non-viable bowel resection. 3. In large bowel (often in gun shot injury) temporary colostomy followed by secondary closure of wound. Pneumatosis Cystoides Intestinalis Gas filled cysts in the sub-serosa and sub-mucosa of small intestine and colon. Cause: COPD Necrotizing enterocolitis Diverticulitis Clinical feature: Often symptom less. May cause intestinal obstruction and rectal bleeding, diarrhea. Rupture of cyst may cause tension pneumoperitoneum. Diagnosis: Sigmoidoscopy, barium enema. Treatment: Conservative. Drug Metronidazole. Spontaneous regression may occur. Enterocutaneous Fistula Most common cause is previous surgery. Colostomy Temporary: Indications are 1. After an anterior resection.

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2. Following traumatic injury to the rectum or colon. 3. To facilitate the operative treatment of a high fistula in ano.

APPENDIX
Anatomy Position: Retro-caecal is the most common type. Least common type is preileal. Arterial supply: Appendicular artery, a branch of lower division of ileo-colic artery. Development: The appendix is developed from the primitive mid-gut. Acute Appendicitis Pathology: 1. Mechanism of perforation is usually due to tension gangrene due to accumulation of secretions. 2. A mucocele of the appendix is a retention cyst. 3. Diffuse peritonitis following acute appendicitis is usually seen when appendicular perforation occurs early (within 24 hours). Clinical feature: 1. Pain is the earliest symptom. 2. Pain is referred to umbilicus (T10). 3. Murphys triad pain, anorexia, nausea and vomiting. Anorexia is a constant feature. 4. Pyrexia is mild temperature over 38.3C (101F) suggests perforation. 5. Signs i. Pointing index sign ii. Rovsings sign palpation of the left iliac fossa produces pain in the right iliac fossa. iii. Psoas sign iv. Obturator sign. Investigations: Diagnosis of acute appendicitis is best done by physical examination. Abdominal USG is useful. Blood leukocytosis > 20,000 cells/ L suggests perforation.

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D/D of acute appendicitis: In children H-S purpura, lobar pneumonia. In adults tabes dorsalis, porphyria, diabetes. Management: A. Medical i. IV fluid ii. Antibiotics iii. Antipyretics. B. Surgery Incisions 1. Grid-Iron most commonly employed. It is made at right angles to a line joining the anterior superior iliac spine to the umbilicus, its centre being along the line at McBurneys point. Complication inguinal hernia. It has got least complications. 2. Transverse or long (skin crease) incision. 3. Rutherford-Morrison- it is an oblique muscle cutting incision with its lower end at McBurneys point and extending obliquely upwards and laterally. A Grid-Iron incision can be converted to a RutherfordMorrison incision by cutting the internal oblique and transversus abdominis muscles in the line of incision. Special circumstances: 1. When the base of the appendix is inflamed, it should not be crushed but ligated close to the caecal wall the stump is invaginated. 2. If the base is gangrenous neither crushing nor ligation should be attempted. 3. In case of Crohns disease appendicectomy is not done. Postoperative complications: 1. Wound infection most common. 2. Ileus. 3. Respiratory infection. 4. Intestinal obstruction. 5. Nerve injury to iliohypogastric nerve. 6. Portal pyemia postoperative jaundice. Management of appendicular mass (lump): Conservative Ochsner-Sherren regimen.

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Carcinoid Tumor of the Appendix Appendix is the most common site of carcinoid tumor. Carcinoid tumors arise in Argentaffin cells. Site most commonly the distal third. Unlike carcinoid tumors arising in other parts of the intestinal tract, carcinoid tumor of appendix rarely gives rise to metastasis less chance of carcinoid syndrome. ( Note: Least malignant carcinoid tumor is that of bronchus). Treatment: i. Appendicectomy if the tumor size is < 2 cm ii. Right hemicolectomy when tumor size is > 2 cm, caecal wall is involved or lymph nodes are involved. Pathology: On transection, carcinoid tumors appear as solid, yellow-tan due to lipochrome deposition.

LIVER
ANATOMY Ligamentum venosum: It is a remnant of Ductus venosus. Falciform ligament: Contains Ligamentum teres. Kupffers cells: Kupffers cells are derived from bone marrow and found in liver. Spaces of Disse: Found in liver. Ito cells: i. Located in Spaces of Disse. ii. Secrete collagenous matrix responsible for development of cirrhosis. iii. Store the fat soluble Vitamin A. Liver acinus of Rappaport: It is the structural and metabolic unit of liver. It has 3 zonesi. Inner zone (Zone 1) around the vascular back-bone and is well oxygenated. ii. Intermediate zone (Zone 2) moderately oxygenated. iii. Outer zone (Zone 3) close to central vein and is least oxygenated most susceptible to anoxic injury.

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Nutrition of liver: from 2 sources i. Portal vein (66-75%) ii. Hepatic artery (25-34%) Hepatic blood flow = 30 percent of cardiac output. Hepatic veins: Drain into IVC. Calots triangle: It is bounded Above and laterally, by under surface of liver. Below and laterally, by cystic duct. Medially by the common hepatic duct. Development: 1. Portal vein from infra hepatic part of right and left vitelline veins. 2. Hepatic vein from supra hepatic part of right vitelline vein. Line of surgical division of liver: Gallbladder bed to IVC. Segments of liver: Caudate lobe Right lobe Left lobe PHYSIOLOGY Bile 1. Daily production 500 ml (20 ml/hours). 2. 90-95 percent of the bile salts are absorbed from the small intestine (mostly ileum) and undergo enterohepatic circulation. 3. Cholagogues are substances that cause contraction of gallbladder. E.g. fatty acids and amino acids, CCK. 4. Choleretics are substances that increase the secretion of bile, e.g. bile salts (most potent). Note gallbladder concentrates bile 510 times. LIVER FUNCTION TESTS Serum Bilirubin: Normal value 0.21.0 mg/dl Conjugated 0.20.6 mg/dl Unconjugated 0.20.4 mg/dl. Serum albumin: Normal 4 6 gm/dl. Serum alkaline phosphatase: Normal value 313 KAU (King Armstrong Unit). Described by Couinaud. Segment I Segments V-VIII Segments II-IV

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Very high values are obtained in post-hepatic obstruction. Serum transaminases: i. ALT (Alanine Amino Transferase) or SGPT Normal value 515 IU/L. ALT is more sensitive indicator of parenchymal liver disease. ii. AST (aspartate transaminase) or SGOT. Normal value-5-20 IU/L. Lactate dehydrogenase (LDH): Normal value 80-150 IU/L. Value increased in infective hepatitis. Obstructive jaundice. Ca liver. Gamma glutamyl transpeptidase (GGT): Normal value- <30 U/L. Increased in obstructive jaundice and alcoholic hepatitis (most sensitive marker).

-FP: Increased in hepatocellular carcinoma.


PT time: Is a prognostic marker of acute and chronic hepatocellular injury (e.g. hepatitis). HYPERBILIRUBINEMIA Unconjugated: (Due to deficiency of Glucuronyl transferase) 1. Gilbert syndrome autosomal dominant. i. Mild, persistent, unconjugated hyperbilirubinemia. ii. LFTs are normal. iii. Liver cells appear normal on L/M. 2. Crigler-Najjar syndromeConjugated: 1. Dubin- Johnson syndrome- Liver is darkly pigmented. 2. Rotor syndrome. Recurrent Jaundice of Pregnancy i. Serum bilirubin levels are < 6 mg/dl. ii. The serum alkaline phosphatase and cholesterol levels are markedly increased. iii. Other LFTs are only mildly deranged. See the chapter of general discussion for more of jaundice.

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ACUTE VIRAL HEPATITIS All the hepatitis viruses are RNA viruses except hepatitis B virus which is a DNA virus. Type A Hepatitis Picorna viridae. Incubation period: 15-45 days. Transmission: By fecal-oral route. Cases are the only source of infection. No carrier state. Most common sporadic cases in children. More severe infection in adults. Clinical feature: Transient jaundice, spiking fever. Recovery is slow over a period of 4-6 weeks. Diagnosis: Demonstration of IgM antibody in serum. Type B Hepatitis Hepadnaviridae. Incubation period: 6 weeks to 6 months. Transmission: Sexual transmission - Most common in heterosexuals. Blood borne. Genetic structure: S gene codes for envelop protein HBsAg. C gene codes for nucleocapside proteins. 1. HBcAg core protein. 2. HBeAg nucleocapsid protein. P gene codes for DNA polymerase which activates DNA dependant DNA polymerase and RNA polymerase (reverse transcriptase). X gene HBxAg (transactivation protein). Immune response: 1. HBsAg The first virological marker to appear after infection (appears before the onset of symptoms). It is a specific marker of infection.

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HBsAg is a serological marker of disease prevalence. Anti-HBs antibody is protective and associated with resistance to infection. 2. HBcAg Does not appear in serum. Anti-HBc antibody appears in pre-icteric phase and persists for months. It is the evidence of current or recent infection during window period (between the disappearance of HBsAg and appearance of anti-HBs). 3. HBeAg Related to infectivity and viral replication. HBsAg +ve serum containing HBeAg is more likely to be highly infectious. 90 percent of HBeAg +ve mothers but only 10-15 percent of anti-HBeAg +ve mothers transmit HBV infection to their child. Associations of HBV infection: Serum sickness, glomerulonephritis and PAN. Diagnosis: Acute infection HBsAg, IgM anti-HBc. Chronic infection HBsAg, IgG anti-HBc. HBsAg is found in saliva, tears, CSF , seminal fluid, synovial fluid, breast milk, urine. Liver function tests: Serum AST and ALT show a variable increase during the prodromal phase of acute infection. But, the acute level of these enzymes does not correlate well with the degree of liver damage. HBV-DNA by PCR. More sensitive marker of viral replication than HBeAg. Use to determine the course of the disease and need for antiviral therapy. Special cases: 1. Carrier state: Persistence of HBsAg after acute illness; also persistence of HBeAg for > 3 months. i. Super carriers have HBeAg in their blood and is highly infectious. ii. Simple carriers more common. No HBeAg and a low level of HBsAg in blood. (Persistent carriers presence of HBsAg in blood for > 9 months.) HBsAg carrier state is associated with Downs syndrome, leprosy, leukemia, lymphoma, PAN and chronic renal failure on hemodialysis.

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2. Immunization After immunization with Hepatitis B vaccine (which contains only HBsAg), anti-HBs antibody is the only marker to appear in blood. Pathology: Carrier state HBV Ground glass hepatocytes, sanded nuclei. Acute hepatitis Ballooning degeneration. Bridging necrosis. Hepatocyte damage is due to damage of the virusinfected cells by CD8+ cytotoxic T cells. Treatment: Acute self-limited; no treatment required. Chronic lamivudine is the first line drug; interferon alpha (combination is not advantageous). Prevention: For perinatal exposure of infants born to HBsAg +ve mothers A single dose of HBIG 0.5 ml IM in the thigh immediately after birth PLUS complete course of 3 injections of hep B vaccines to be started within 12 hours of birth. (Note: Hepatitis B is not transmitted by pasteurized albumin.) Course: May lead to hepatocellular carcinoma most common cause in India. Type C Hepatitis Flavivirus. It is the most common cause of post-transfusion hepatitis. High risk of chronic liver disease and hepatocellular carcinoma most common cause in western countries. Associations of HCV infection: Cryoglobulinemia, MPGN, lichen planus, autoimmune thyroiditis. Diabetes mellitus type II is more common in hepatitis C infection. Diagnosis: Detection of anti-HCV during acute period is not possible but diagnostic after that; not protective. In early infection HCV RNA or RIBA for anti HCV. It cannot be cultured.

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Treatment: Acute interferon. Chronic combination of lamivudine and interferon; ribavarin. Type D Hepatitis The delta hepatitis agent requires the helper function of HBV for its replication and expression. Type E Hepatitis HEV is an Alphavirus, resembles calcivirus. They may cause epidemics. Transmission by water-borne. It is highly infective and fatal during pregnancy especially in the last trimester. In India, HEV is responsible for most of the epidemics and sporadic hepatitis in adults. Type G Hepatitis Flavivirus. Transmission by percutaneous route. It causes chronic viremia lasting at least 10 years. Coinfection with HIV improves survival. CHRONIC HEPATITIS Etiology: 1. Viral most common cause (HBV HCV, HDV). 2. Wilsons disease. 3. 1 antitrypsin deficiency. 4. Chronic alcoholism. 5. Drugs -methyldopa (aldomet), methotrexate, isoniazid. 6. Autoimmune. Classification: Etiological viral, autoimmune, drug-induced, etc. Grading based on the degree of necrosis and inflammation. Staging based on the degree of fibrosis. Types: 1. Chronic active hepatitis. 2. Chronic persistent hepatitis.

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They are differentiated on histological ground. Investigation: Liver biopsy and serum transaminase elevation. Treatment: Chronic replicative hep B and hep C interferon . Interferon is not effective in chronic HCV when there is long-term hepatic cirrhosis. Autoimmune hepatitis: Type I ANA and/or Sm antibody. Type II Anti-LKM 1 (same as chronic hepatitis C). Type III Anti SLA/LP (soluble liver antigen).
LKM antibodies (Liver Kidney Microsomes antibody) Anti-LKM 1 Type II autoimmune hepatitis Chronic hepatitis Anti-LKM 2 Drug induced hepatitis Anti-LKM 3 Chronic hepatitis D

Granulomatous hepatitis: Cause halothane, candidiasis, sarcoidosis. Liver reaction to extrahepatic neoplasm (but not hepatic metastases). Morphology of Hepatitis Acute: Parenchymal change Ballooning degeneration of hepatocytes. Hepatocytic necrosis focal or centrizonal; if severe, bridging necrosis. Acidophilic degeneration of hepatocytes Councilman bodies. Inflammation predominantly mononuclear infiltrates. Regeneration Fatty changes in HCV. Chronic: Fibrosis and necrosis bridging/periportal/piece meal. Ground glass appearance in chronic HBV. CIRRHOSIS OF LIVER Definition: Three characteristics 1. Bridging fibrous septa.

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2. Parenchymal nodule. 3. Disruption of architecture of the entire liver. Etiology: Micronodular (<0.3 cm): 1. Alcoholic liver disease most common cause. 2. Biliary cirrhosis. 3. Hereditary hemochromatosis. 4. Wilson disease. 5. 1 antitrypsin deficiency causes cirrhosis in childhood. Macronodular (>0.3 cm): 1. Viral hepatitis. 2. Hepatotoxins CCl4, mushroom poisoning. 3. Drugs Acetaminophen, -methyldopa. 2. Alcohol. Others cystic fibrosis. Childs Classification of Hepatocellular Function in Cirrhosis
Childs classification A Bilirubin Albumin Ascites Neurologic symptoms Nutrition < 2 > 3.5 Excellent B 2 3 3 3.5 + + Good C > 3 < 3 + ++ Wasting

Alcoholic Liver Disease Pathology: 1. Hepatic steatosis (fatty liver) reversible. 2. Acute hepatitis i. Hepatic swelling (ballooning) and necrosis. ii. Mallory bodies Hepatocytes containing intermediate filaments. They are highly suggestive, but not specific of alcoholic liver disease. Also found in Primary biliary cirrhosis, Indian childhood cirrhosis, Wilsons disease, Chronic cholestasis, Hepatic tumor, Uncontrolled diabetes, Morbid obesity, Jejunal bypass operation. iii. Netrophilic infiltration. iv. Fibrosis

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Sinusoidal and perivenular (central hyaline sclerosis). Periportal fibrosis may occur in repeated bouts of heavy alcohol intake. 3. Micronodular cirrhosis (Laennecs cirrhosis) Liver becomes brown and shrunken Hobnail appearance. Clinical feature: Jaundice Palmer erythema, spider angioma Parotid and lacrimal gland swelling Clubbing of the fingers Liver enlarged, normal or decreased in size Splenomegaly Portal hypertension ascites, variceal bleeding In men, decreased body hair and testicular atrophy In women, virilization and menstrual irregularities Dupuytrens contracture Hepatic encephalopathy and coma Peripheral neuropathy. Laboratory findings: Varying elevations of serum alkaline phosphatase. AST is disproportionately elevated relative to ALT (c.f. viral hepatitis) and serum AST:ALT >2 is suggestive and > 3 is highly suggestive of alcoholic liver disease. PT is increased. Decreased albumin and globulin in serum. Increased MCV (macrocytosis). Increased GGT. Increased CDT (carbohydrate deficient transferin). Biliary Cirrhosis Primary Etiology: Autoimmune. Clinical feature: Pruritus is the earliest and most common symptom; xanthomas, osteoporosis. Diagnosis: i. Increased serum alkaline phosphatase. ii. Increased cholesterol iii. An abnormal lipoprotein in RBC called Lipoprotein X. iv. Increased IgM (antimitochondrial antibody).

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Secondary Due to extra-hepatic bile duct obstruction most commonly due to stricture. Budd-Chiari Syndrome Etiology: Occlusion of the hepatic veins (most common) or IVC mainly by thrombosis or venous web. Predisposing factors: Polycythemia vera (most common) and other myeloproliferative disorders Pregnancy and postpartum OCP Paroxysmal nocturnal hemoglobinuria Hepatocellular carcinoma Hyperprothrombinemia (factor II) Activated protein C resistance (factor V Leiden mutation) Protein C and S. Clinical feature: Liver is grossly enlarged and tender. Severe intractable ascites. Weight gain and abdominal pain. Diagnosis: Duplex Doppler USG. Carolis Disease Congenital dilatation of the intrahepatic biliary tree with presence of intrahepatic stone formation. Non-cirrhotic Hepatic Fibrosis Cause: 1. Idiopathic portal hypertension. 2. Schistosomiasis. 3. Congenital hepatic fibrosis. Non-cirrhotic Portal Fibrosis Clinical feature: Age 3rd or 4th decade of life. GI hemorrhage massive hematemesis.

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Massive splenomegaly but no hepatomegaly. Mild ascites. Cause: Chronic arsenic poisoning. Portal Vein Thrombosis Clinical feature: Massive hematemesis due to esophageal varices (portal hypertension). Moderate splenomegaly. Normal liver functions. Etiology: Infarct of Zahn is produced by intrahepatic thrombosis of portal vein radicles. Banti syndrome is subclinical thrombosis of portal vein from neonatal omphalitis or umbilical vein catheterization. Veno-occlusive Disease Most commonly seen in post-bone marrow transplant patients. Produces centrilobular necrosis. MAJOR COMPLICATIONS OF CIRRHOSIS Portal Hypertension Normal portal pressure 8-12 mm Hg (10-15 cm saline). Portal hypertension > 30 cm saline. Causes of portal hypertension: Presinusoidal portal vein thrombosis, schistosomiasis. Sinusoidal cirrhosis of liver (most common cause). Postsinusoidal Budd-Chiari syndrome, IVC thrombosis, venoocclusive disease. Clinical feature: Hemorrhage most common manifestation; usually variceal bleeding. It is usually precipitated by minor febrile illness. NSAIDs may accentuate it. Splenomegaly (with hypersplenism). Ascites. Acute and chronic encephalopathy. Dilatation of collaterals piles, caput medusae, etc.

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Management of variceal bleeding: 1. Initial management i. Vigorous replacement of blood loss. Only when the patient is hemodynamically stable should specific diagnostic studies (endoscopy) be undertaken. ii. Vitamin K. iii. Balloon tamponade is done by Sengstken Blakemore tube (3 lumen) or Minnesota tube (4 lumen) for emergency temporary hemostasis. Pressure applied is about 40 mmHg. 2. Medical measures i. Vasopressin (Terlipressin) acts on V1 receptors, causes vasoconstriction. ii. Nitroglycerin. iii. Octreotide long acting somatostatin analogue. 3. Endoscopic sclerotherapy with 5 percent ethanolamine oleate. Other sclerosing agents Polydochyl, cynoacrylate, alcohol, ethanolamine oleate. 4. Transjugular intrahepatic portosystemic stent shunt (TIPSS) for emergency control of variceal bleeding when drugs and sclerotherapy fail to control bleeding. 5. Esophageal stapled transection. 6. Patients with splenic or portal vein thrombosis splenectomy and gastroesophageal devascularization. 7. Porto-caval shunt for Childs group A cirrhosis. (Note Most common cause of hematemesis in children is portal hypertension. Most common cause of portal hypertension in children is extrahepatic obstruction.) Ascites Etiology: 1. Portal hypertension. 2. Hypoalbuminemia and decreased plasma oncotic pressure. 3. Renal secondary hyperaldosteronism. Clinical feature: Physical examination (shifting dullness) are positive only when fluid accumulates > 500 ml. Investigation: Minimal ascites can be detected by USG.

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Treatment: Of refractory ascites a side-to-side portacaval shunt. See the chapter of general discussion for more of ascites. Spontaneous Bacterial Peritonitis Clinical feature: Abrupt onset of fever, chill and generalised abdominal tenderness. On examination: Ascitic fluid low concentration of albumin. Blood high white cell count. Hepatorenal Syndrome Characterized by Worsening azotemia with avid sodium retention and oliguria in the absence of identifiable specific causes of renal dysfunction. On examination: Renal biopsy NAD. Urine Na+ < 5 mmol/L Sediment nil. Hepatic Encephalopathy (Portasystemic Encephalopathy) Predisposing factors: 1. GI bleeding. 2. Hypokalemia, hyponatremia, hypoxia, alkalosis. 3. Diuretics. 4. Intercurrent infection. 3. Dietary protein. 4. Azotemia. 5. Constipation. 6. Drugs CNS depressants. Clinical feature: Disturbance of sleep and reversal of sleep-wake pattern earliest symptom. Asterixis most characteristic symptom. Diagnosis: EEG is characteristic. Treatment: Restriction of dietary protein.

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Neomycin, tetracycline, ampicillin or metronidazole. Lactulose. INFILTRATIVE AND METABOLIC DISEASES Fatty Liver A. Macrovesicular B. Microvesicular 1. Alcoholic liver disease. 1. Reyes syndrome. 2. Diabetes mellitus. 2. Pregnancy. 3. Obesity. 3. Drugs tetracycline. 4. Protein-energy malnutrition. Liver Necrosis 1. Centrilobular necrosis i. Chronic venous congestion most common cause. ii. Hemorrhagic shock iii. Drugs CCl 4 , halothane, acetaminophen, rifampicin. 2. Peripheral phosphorus poisoning. 3. Mid-zonal yellow fever, eclampsia. Reyes Syndrome Characterized by fatty liver and encephalopathy. Clinical feature: Age < 15 years. Symptom vomiting, progressive CNS damage, hypoglycemia, tachypnea. Onset follows an URTI especially influenza and chickenpox. Jaundice is characteristically minimal or absent. Etiology: Viral Influenza, varicella, adenovirus, RSV. Drug Salicylates. Pathology: Liver is enlarged. Characteristic microvesicular steatosis in liver and renal tubules. Glycogen depletion in hepatocytes. Laboratory findings: Metabolic acidosis with respiratory alkalosis. Increased serum transaminase. Increased PT.

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Treatment: i. IV glucose. ii. FFP . iii. IV mannitol to reduce cerebral edema. Wilson Disease (Hepatolenticular Degeneration) Pathology: There is increased intestinal absorption and decreased biliary excretion of copper. There is abnormal accumulation of copper in hepatocytes and other tissues. Accumulation in RBCs result in hemolysis. PCTs are affected resulting in Fanconis syndrome. In cornea, produces K-F rings (deposition of copper in Descemets membrane in the limbus of cornea). Genetics: Autosomal recessive. It is due to mutation of chromosome 13 (ATP7B gene). Clinical feature: Age 6-15 years. 1. Hepatic dysfunction acute onset of jaundice and hepatomegaly; micronodular cirrhosis. Course may mimic chronic active hepatitis. 2. Neuropsychiatric symptoms Basal ganglia (especially putamen) damage leads to chorea, tremors (rest or intentional), rigidity, difficulty in speech, abnormal posture, and dysphagia. Note: It is a combination of features of cerebellar ataxia and Parkinsonism. Sensory changes never occur. Psychosis. 3. Coombs ve hemolytic anemia. 4. Eye sunflower cataract. K-F rings do not produce any visual impairment. Diagnosis: 1. K-F ring in cornea On slit-lamp examination appears brownish or gray green in descemets membrane. 2. Serum ceruloplasmin < 20 mg/dl. 3. Serum copper < 20 g/dl. 4. Increased Cu excretion in urine > 100 g/24 hour. 5. Increased Cu in liver biopsy > 250 g/gm dry weight.

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Note: stains: Rhodanine for copper, Orcein for cuassociated protein. Treatment: Oral d-Penicillamine drug of choice. Others trientine, oral Zn acetate. LIVER INFECTIONS Ascending Cholangitis Cause: Biliary tract obstruction. Bile duct stones are common predisposing factor. Clinical feature: Jaundice, rigors and tender hepatomegaly. Organ failure may occur secondary to septicemia. Pyogenic Liver Abscess Cause: 1. Ascending cholangitis most common cause. 2. Hematogenous spread of bacteria. 3. Local spread from contiguous structures. Organisms: Streptococci milleri. E.coli. Amoebic Liver Abscess May rupture into pleural space. Management conservative. Hydatid Cyst Treatment Indicated to prevent progressive enlargement and rupture of the cyst. LIVER TRAUMA Liver is one of the most common organs to be injured by penetrating injury. (Other organs affected in penetrating injury are chest and pericardium). (Note: Blunt injury causes damage to spleen and kidneys.)

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LIVER TUMORS Please see the chapter of oncology. LIVER TRANSPLANTATION Indications 1. Biliary atresia (in children). 2. Cirrhosis (alcoholic). 3. Primary sclerosing cholangitis. 4. Chronic viral hepatitis. 5. Primary hepatocellular malignancy. Note: See also the chapter of organ transplantation.

THE GALLBLADDER
ANATOMY The GB fossa separates the right and quadrate lobes of liver. Capacity of GB about 30-50 ml. Fundus of GB projects in the angle between the lateral border of the right rectus abdominis and 9th costal cartilage at transpyloric plane. The CBD is 8 cm long and 6 mm in diameter. The ampulla of Vater is situated 810 cm distal to the pylorus. The supraduodenal part of CBD lies in the free margin of lesser omentum and has following relations i. Anteriorly liver. ii. Posteriorly portal vein and epiploic foramen. iii. To the left hepatic artery. The retroduodenal part has IVC in its posterior relation. Blood supply cystic artery a branch of right hepatic artery. CONGENITAL ANOMALIES Biliary Atresia Clinical feature: Jaundice which is present at birth or appear within 1 week of life. Stools are pale. Urine dark.

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Prolonged steatorrhea give rise to osteomalacia (biliary rickets). Increased serum cholesterol. Investigation: i. HIDA scan. ii. Liver biopsy. Choledochal Cyst It is the extrahepatic dilatation of the common bile duct. Note: Intrahepatic dilatation of bile canaliculi is known as Carolis disease. Etiology: Specific weakness in a part of or the whole of the wall of CBD. Clinical feature: Patient may present at any age. Progressive Obstructive jaundice. Cholangitis pain. Abdominal swelling. Investigation: USG and MRI. Treatment: Radical excision of the cyst with reconstruction of the biliary tract using a Roux-en-Y loop of jejunum (hepatojejunostomy). Gallstones Types: 1. Cholesterol stones often solitary. 2. Mixed stones most common type. Made up of cholesterol and calcium salts (usually calcium-phosphate and calcium-carbonate). Often multiple. 3. Pigment stones of calcium bilirubinate. Predisposing Factors Cholesterol and Mixed Stones Pathology Cholesterol stones are formed when the concentration of cholesterol is more than bile salts and phospholipids in bile lithogenic or supersaturated bile. Factors

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A. Increased bile cholesterol OCP , clofibrate, obesity. B. Decreased bile salts i. Estrogens. ii. Ileal disease or resection or bypass. iii. Cholestyramine therapy. iv. Primary biliary cirrhosis. v. Truncal vagotomy. Pigment Stones They are formed in patients with hemolysis with excess production of bilirubin. E.g. hemolytic anemias. Cholecystitis Mediator: Lysolecithin. Investigation: 1. Oral Cholecystography: Procedure One X-ray is taken on previous day and a tablet (containing iapanoic acid) is given on the night before. Next day X-rays are taken before and after a fatty meal (at least 3 pictures). Interpretation It signifies that: i. The tablet is absorbed properly. ii. Liver is functioning. iii. Concentrating power of gallbladder is normal. iv. There is no obstruction in cystic duct. v. Gallbladder contraction is normal after fatty meal. Drawback It is not diagnostic of gallstone disease. 2. USG: It is the investigation of choice. It shows i. Presence of stones inside the gallbladder. ii. Edema around the gallbladder wall. iii. Impaction of stone in the infundibulum. 3. MRCP best investigation for gallstones. 4. HIDA scan: Best for visualizing biliary tree. Management of gallstones: 1. Medical UDCA and CDCA inhibits cholesterol synthesis. Indications Functioning gallbladder with radiolucent stones < 15 mm in diameter. 2. Surgical Laparoscopic cholecystectomy is the gold standard of management of gallstone disease.

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Indications i. Palpable duct stones ii. Jaundice or h/o jaundice or cholangitis. iii. CBD is dilated. iv. Abnormal LFT especially alkaline phosphatase level is increased. [Note after choledochotomy, a T-tube is placed in-situ. It can be clamped after 10 days. Na-ditrazoite is injected down the tube to obtain a cholangiogram after 10-14 days to see any left over stone in the CBD. The tube can be removed after 4 weeks]. Management of bile-duct obstruction: If the symptoms particularly jaundice persist after cholecystectomyi. Immediate USG. ii. If there is obstruction-immediate ERCP and removal of stone, if present by endoscopic sphincterotomy. iii. If there is leakage - Drain placed in the subhepatic space and stent placed in the bile duct. Emphysema Cholecystitis Organisms: Gas producing anaerobes viz. Clostridium welchii and Clostridium perfringens. Patient profile: Elderly male, diabetic patients. X-ray: Gas within gallbladder lumen. Prognosis: Bad. Gallstone Ileus Entrance of stone into the duodenum is through a cholecystoenteric fistula. Impaction proximal to the ileo-cecal valve. Treatment: Laparotomy and removal of stone from intestine as well as from gallbladder. Porcelain Gallbladder Calcium salts are deposited within the wall of a chronically inflamed gallbladder. Risk Chance of malignancy. Treatment Cholecystectomy.

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Cholesterosis/Strawberry Gallbladder Submucous deposition of cholesterol crystals and cholesterol esters in the wall of the gallbladder. Mucocele of Gallbladder Distension of the gallbladder by accumulating mucus due to obstruction of neck by gallstones. Treatment cholecystectomy. Complications empyema of the gallbladder, perforation and gangrene. STONES IN CBD Cholangitis Organism: E. coli. Symptoms of cholangitis: Charcots triad Pain, jaundice and fever with chill. Reynolds pentad Charcots triad + shock and mental obtundation. Commonly associated with non-alcoholic acute pancreatitis. Sign: Courvoisiers law A dilated gallbladder is usually associated with obstruction other than that caused by CBD stones (e.g. carcinoma head of pancreas). Diagnosis: By cholangiography either preoperatively by ERCP or intraoperatively at the time of operation. Blood leukocytosis. Treatment: i. Preoperative ERCP with endoscopic papillotomy and stone extraction (by Dormia busket) is preferred method for single stone < 1.5 cm. ii. Supraduodenal choledochotomy. Note indications of transduodenal sphincterotomy 1. Stone impacted near the ampulla of Vater. 2. CBD dilated with multiple stones and biliary sludge. 3. Papilla is fibrosed and stenosed. Note best suture for bile duct is non-synthetic, absorbable.

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OTHER CONDITIONS CBD Strictures Most common cause is postoperative. Hemobilia Cause: Traumatic or operative injury to the liver or bile ducts. Clinical features: Triad of biliary colic, obstructive jaundice and melena/occult blood in stool. Treatment: Hepatic artery ligation. Hepatic Artery Ligation Indication 1. Hepatoma and liver secondaries used preoperatively but can not cure the malignancy. 2. Hemobilia best result. Primary Sclerosing Cholangitis Etiology: Unknown. Affects: The extrahepatic and intrahepatic bile ducts, may involve gallbladder and/or pancreas. Association: With ulcerative colitis. Clinical feature: Jaundice, pruritus, right upper quadrant abdominal pain or acute cholangitis. Risk: Increased chance of cholangiocarcinoma. MALIGNANCY Please see the chapter of oncology.

PANCREAS
ANATOMY The posterior surface of pancreas is in relation to i. The aorta and SMA. ii. Left crus of the diaphragm. iii. Left suprarenal gland.

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iv. Left renal vessels. v. Splenic vein (but NOT splenic artery). Tail of the pancreas: Lies in the lienorenal ligament. Comes in contact with the lower part of the gastric surface of spleen. The endocrine part consists of only 10-20% of total pancreatic mass. Islets of langerhans are most numerous in the tail. Main pancreatic duct = Wirsungs duct. Accessory pancreatic duct = Santorinis duct. CONGENITAL ANOMALIES Annular Pancreas Associated with Downs syndrome. Treatment Duodenojejunostomy or duodenoduodenostomy. PANCREATITIS Acute Pancreatitis Etiology: 1. Alcoholism. 2. Gallstones most common cause. 3. Blunt abdominal trauma (most common cause in children). 4. Hypercalcemia (hyperparathyroidism), hyperlipidemia. 5. Mumps. 6. Drugs- Thiazide diuretics, valproic acid, L- asparginase, steroids, diadinosine. 7. Pregnancy. Clinical feature: Abdominal pain is the major symptom. Pain radiates to back and is relieved by sitting upright. Others fever, vomiting. Cullens sign Faint blue discoloration around the umbilicus. Grey-Turners sign Bluish discoloration of the flanks. Investigation: 1. Screening tests Serum amylase and lipase, trypsin. The latter two are more diagnostic.

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Serum amylase value>3 times the normal value is highly specific. Amylase level is elevated within 24 hours and returns to normal in about 4872 hours. Serum amylase is also elevated in i. Pancreatic pseudocyst. ii. Mumps. iii. Perforated peptic ulcer. iv. Ruptured ectopic pregnancy. v. Ca pancreas. vi. Intestinal obstruction. vii. Peritonitis. 2. CT scan Investigation of choice to evaluate the complications. 3. X-ray abdomen Generalized or local ileus (sentinel loop), Colon cut-off sign, Renal halo sign, Pleural effusion in 20 percent cases, Gasless abdomen. Prognosis: Depends on: Ranson Criteria a. On admission: i. Age > 55 years ii. WBC count > 16,000/ l iii. Blood glucose > 200 mg/dl (11 mmol/lit) iv. LDH > 350 U/liter. v. SGOT > 250 U/liter. b. During first 48 hours: i. Hematocrit fall > 10 percent ii. Serum calcium < 2.0 mmol/lit (8 mg%) - worst prognostic factor iii. Hypoxemia (PaO2) iv. Fluid deficit > 4 liter. Others: Hypotension (BP < 90 mm Hg) Note serum amylase level is not included. Other prognostic criteria: CECT grade of the severity index. APACHE (Acute Physiology and Chronic Health Evaluation) II system. Balthazar grade of acute pancreatitis.

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Complications: 1. Purtschers retinopathy loss of vision. 2. Pancreatic pseudocyst: Most common complication of acute pancreatitis. Pseudocyst because not lined by epithelium. Cause: i. Acute pancreatitis 90 percent ii. Trauma 10 percent Site: Body or tail of the pancreas. Investigation: 1. Serum amylase is increased in 75 percent of patients. 2. USG is confirmatory. 3. CT scan is complementary to USG. Course: Spontaneous healing may occur within 6 weeks. Treatment: For those > 5 cm in diameter and persist for > 6 weeks drainage operation (cystogastrostomy or cystojejunostomy). Excision of the cyst. Complications: i. Infection is the most common complication. ii. Rupture. iii. Hemorrhage. iv. Abscess. Chronic Pancreatitis Clinical feature: Recurrent abdominal pain may be the only symptom. Endocrine dysfunction diabetes mellitus. Exocrine dysfunction steatorrhea Investigation: CT scan/MRI Investigation of choice shows intraductal and intraparenchymal calcification. ERCP Chain of lakes appearance. Treatment: Surgery Indications Mass in the head of pancreas. Operation Resection of the head either by a pancreatoduodenectomy or a Beger procedure.

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CARCINOMA OF PANCREAS Please see the chapter of oncology.

SPLEEN
ANATOMY Position: Spleen rests on 9th to 11th ribs on the left side. Axis: It is directed obliquely along the 10th rib. Splenic notch: On superior border. Ligaments: 1. Lieno-phrenic suspends the spleen from above suspensory ligament of spleen. 2. Phrenico-colic supports the spleen from below sustentaculum lienis. Arterial supply: Only by splenic artery, branch of celiac trunk. This is the largest branch of celiac trunk. Hence in celiac trunk obstruction, spleen is mainly affected. Spleen contains about 2 percent of total blood volume. Nerve supply: Sympathetic fibers are derived from the celiac plexus. Development: From dorsal mesogastrium. Function: removal of senescent RBC from the circulation is called culling. Portal Vein Formation: Splenic vein joins the superior mesenteric vein behind the neck of the pancreas to form the portal vein. Relations: In front and to the right bile duct. In front and to the left hepatic artery. Porto-systemic shunts: 1. At lower end of esophagus Left gastric vein (portal) + hemi-azygos vein. 2. At rectum Superior rectal vein (portal) + middle and inferior rectal veins. 3. At umbilicus The paraumbilical vein (portal) + epigastric vein.

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CONGENITAL ANOMALIES Splenunculi (Accessory Spleen) Sites: i. Hilum of the spleen most common site. ii. Greater omentum. iii. Tail of the pancreas. RUPTURE OF SPLEEN Cause: Blunt trauma. Clinical feature: Kehrs sign pain referred to left shoulder. Investigation: USG. X-ray features of splenic rupture: 1. Obliteration of splenic outline most important. 2. Obliteration of psoas shadow. 3. Indentation of the left side of gastric bubble. 4. Fracture of the ribs on left side. 5. Elevation of the left hemidiaphragm. 6. Free fluid between gas-filled intestinal coils. Treatment: In stable young patients and especially in children splenectomy is not done. Compression in vicryl mesh bag is the treatment of choice. Others splenectomy. Spontaneous Rupture of Spleen Causes: 1. Malaria most common cause worldwide. 2. Infectious mononucleosis most common cause in USA. SPLENOMEGALY Causes: a. Blood 1. Chronic leukemias (CML, CLL) and hairy cell leukemia.

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2. Hereditary spherocytosis. 3. Autoimmune hemolytic anemia. 4. Thalassemia. 5. Sickle cell anemia at early stages. 6. ITP . b. Neoplastic Primary fibrosarcoma, Hodgkins lymphoma. c. Infections 1. Malaria. 2. Kala-azar. Hypersplenism Includes 1. Splenic enlargement. 2. Anemia, leucopenia or thrombocytopenia. 3. Compensatory bone marrow hyperplasia. 4. Improvement after splenectomy. Feltys Syndrome 1. Chronic rheumatoid arthritis. 2. Leucopenia, especially neutropenia. 3. Splenomegaly. Neoplasm Benign most common is hemangioma. Malignant most common is lymphoma (most commonly small lymphocytic lymphoma). Splenic Infarction Causes: 1. Infective endocarditis. 2. Sickle cell anemia. 3. Hodgkins lymphoma. 4. CML. 5. PAN. Splenic Abscess Multiple abscesses are seen in immunosuppressive therapy. SPLENECTOMY Indication: 1. Trauma most common indication.

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2. Hereditary spherocytosis at 3-4 years of age. 3. ITP . 4. Autoimmune hemolytic anemia not absolutely indicated. 5. Thalassemia. 6. Sickle cell anemia. 7. Primary fibrosarcoma. 8. Splenic abscess. 9. Splenic vein thrombosis. Postoperative complication: 1. Pulmonary complications most common is left basal atelectasis. 2. Septicemia Organism Streptococcus pneumoniae. More chance in patients i. Receiving chemotherapy/radiation. ii. With thalassemia, sickle cell disease, autoimmune anemia or thrombocytopenia. Prevention Pneumococcal antitoxin should be given 10 days preoperatively. All children with splenectomy should receive penicillin till the age of 18 years. Note after splenectomy blood shows: Howell-Joly bodies, neutrophilia, target cells, aniso and poikilocytosis, basophil stippling.

RECTUM
Prolapse Partial: Only the mucosa and submucosa are prolapsed. Treatment i. In infants Digital reposition. ii. In adults Excision of prolapsed mucosa. Complete: All the layers of rectal wall are prolapsed. Treatment: Abdominal approach (best) Wells operation (surgery of choice), rectopexy, Ripsteins operation. Perineal approach in old, very young and injured or ill patients Dolormes operation.

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Solitary Rectal Ulcer Situated in the anterior wall of rectum. May cause anterior rectal wall prolapse. Rectal Stricture Lymphogranuloma venorum is the most common cause of inflammatory rectal stricture. NEOPLASMS Please see the chapter of oncology.

ANAL CANAL
ANATOMY Length 4 cm. Dentate/Pectinate Line It represents the muco-cutaneous junction of anal canal and corresponds with the position of the anal valves.
Part above the pectinate line Histology Development Arterial supply Lymphatic drainage Nerve supply Simple columnar epithelium From endodermal cloaca Superior rectal artery Internal iliac nodes Autonomic nerve Insensitive to modalities of cutaneous sensation Distended and varicose veins are called internal hemorrhoids Portal system via superior rectal vein Part below the pectinate line Stratified squamous epithelium From ectodermal proctodeum Inferior rectal artery Superficial inguinal nodes Inferior rectal nerve branch of pudendal nerve External hemorrhoids

Applied

Venous drainage

Systemic vein via inferior rectal vein.

Anorectal Ring Made up of puborectalis part of levator ani muscle. This is responsible for anal continence.

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CONGENITAL ANOMALY Imperforate Anus Radiology: Invertogram taken after 6 hours of birth. ANAL FISSURE Location: Mid-line posteriorly most common site. Diagnosis: History and superficial clinical examination. Sentinel Pile It is a tag of edematous skin guarding (hence Sentinel) a chronic anal fissure at the lower end. Note there is a hypertrophied papilla at the upper end of the fissure. Clinical feature: Pain most common symptom, Bleeding, Discharge. Treatment: Approach Conservative (preferred) if fails, dilatation under GA if fails, surgery. 1. Conservative with G.T.N. ointment preferred. 2. Surgery Dilatation under GA. Acute stage Lateral sphincterotomy. Chronic/recurrent dorsal fissurectomy and sphincterotomy. Note digital examination is very painful and should not be done. HEMORRHOIDS It means dilated veins. External Hemorrhoids 5 day self-subsiding painful lesion is a thrombosed external pile (perianal hematoma). Management: Conservative. Internal Hemorrhoids First-degree: Hemorrhoids that bleed but do not prolapse outside the anal-canal. Second-degree: Hemorrhoids that prolapse on defection but return to normal or keep in position if replaced.

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Third-degree: Hemorrhoids that are permanently prolapsed. Clinical feature: Painless bleeding P/R most common cause of rectal bleeding in young adults. On examination: Internal hemorrhoids cannot be felt on digital examination. Investigation proctoscopy. Treatment: 1. First-degree injection sclerotherapy. 2. Second-degree banding. 3. Surgery hemorrhoidectomy. Indications of surgeryi. 3rd degree hemorrhoids. ii. Failure of non-operative treatments in 2nd degree hemorrhoids. iii. Fibrosed hemorrhoids. iv. Interoexternal hemorrhoids. Complications of surgeryi. Acute urinary retention most common. ii. Hemorrhage. ANAL FISTULA It is a tract lined by granulation tissue which connects deeply in the anal canal or rectum and superficially on the skin around anus. Types: 1. Low level below the ano-rectal ring. 2. High level above the ano-rectal ring. Intersphincteric is the most common type. Treatment: Low level fistulas can be laid open without fear of permanent incontinence. Surgery of choice is fistulotomy. In AIDS patients seton is used. ANO-RECTAL ABSCESS Most common is the perineal type.

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MALIGNANCY Please see the chapter of oncology.

HERNIAS
ANATOMY Inguinal Canal Length: 3.75 cm. Formation: Oblique canal. Anterior wall External oblique aponeurosis. Lateral 1/3rd reinforced by internal oblique. Posterior wall Fascia transversalis. In the medial half Conjoint tendon which is formed by internal oblique and transversus abdominis muscles. Roof Arched fibers of internal oblique and transversus abdominis. Floor Groove of inguinal ligament. Medially by lacunar ligament. Inlet: Deep inguinal ring an oval gap in fascia transversalis above mid-inguinal point. Triangle of Hasselbach Bounded: Laterally by inferior epigastric artery. Medially by lateral border of rectus abdominis. Below by inguinal ligament. Contents: 1. Spermatic cord in male. Round ligament of uterus in female. 2. Ilio-inguinal nerve- leaves the canal through superficial ring. Applied: 1. Indirect/oblique hernia: most common of all types. Enters the canal through deep ring. Coverings of a complete (which descends through superficial ring) hernia (from outside inwards) are i. Skin. ii. Dartos muscle (in scrotum).

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iii. External spermatic fascia. iv. Cremasteric muscle and fascia. v. Internal spermatic fascia. vii. Extra-peritoneal fat. viii. Peritoneum. 2. Direct: Through Hasselbachs triangle. INGUINAL HERNIA Indirect Inguinal Hernia More common in young males. More common on right side. Direct Inguinal Hernia More common in older people. Strangulated Inguinal Hernia Type: Indirect hernias more often strangulate. Direct hernias do not often strangulate due to wide mouth of the sac. Constricting agent: Neck of the sac most common. External inguinal ring in children. Contents: Small intestine (more common), omentum. Treatment: 1. Surgery Emergency. Fundus is delivered first. 2. Resuscitation with IV fluids, nasogastric suction and antibiotics. Surgery for inguinal hernia: Inguinal herniotomy basic operation for all other procedures. It is sufficient in infants, children and young adults. Complications injury to the ilio-inguinal nerve. Note the most important step in hernia repair is narrowing of the internal ring. Sliding Hernia Posterior wall of the sac is formed by peritoneum and sigmoid colon and mesentery on the left side; caecum on the right (indirect); bladder (direct).

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Clinical feature: More common on left side. Treatment: A sliding hernia is impossible to control with struss. So surgery is always indicated. SPECIAL TYPES Littres Hernia: When the content of the hernia is Meckels diverticulum. Pantaloon Hernia: When both direct and indirect inguinal hernias occur simultaneously. Gibbons Hernia: Hernia with hydrocele. Bergers hernia: Hernia into the pouch of Douglas. FEMORAL HERNIA Anatomy Femoral Canal Length 1.25 cm. Position It occupies the most medial compartment of femoral sheath. Extent femoral ring above to saphenous opening below. Base is directed upwards. Femoral Ring Boundary Anteriorly by inguinal ligament. Posteriorly by pectineus muscle and fascia. Medially by base of lacunar ligament. Laterally by femoral vein. Saphenous Opening Situation 3 cm below and lateral to the pubic tubercle. Covering Cribriform fascia. Pierced by i. Great saphenous vein. ii. Superficial epigastric and superficial external pudendal arteries.

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iii. Few branches of medial femoral cutaneous nerve. iv. Few lymph vessels. Features Sex more common in females. Side more common on right side. Most common hernia to be strangulated because of the narrowness of the neck and its rigid surroundings. Richters Hernia Content only a portion of the circumference of the intestine. More commonly complicates the femoral hernia. ABDOMINAL WALL HERNIAS Umbilical Hernia (Exomphalos/Omphalocele) Etiology: Failure of all or part of the mid gut to return to the coelom during early fetal life. Covering: amniotic membrane and peritoneum. Content: 1. Defect < 4 cm (herniation of the umbilical cord) a single loop of intestine. 2. Large defect > 4 cm any abdominal viscus. Feature: The intestine remain freely mobile within the hernia sac without any signs of adhesions or inflammation least chance of obstruction. Surgery: surgery is done soon after birth for small defects. Paraumbilical Hernia It is a protrusion through linea alba just above or sometimes below the umbilicus. Size: These may become very large. Content: Usually greater omentum accompanied by small intestine. Sometimes a portion of transverse colon.

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Clinical feature: More common in aged females. Symptom dragging pain, gastrointestinal symptoms. Treatment: 1. Epigastric herniorrhaphy for small defects (described by Mayo). 2. Paraumbilical hernioplasty for larger defects. Complication: Strangulation is a frequent complication. Treatment of complication Paul-Mikulicz method for gangrenous transverse colon. Epigastric Hernia Protrusion through linea alba. Site: Anywhere between the xiphoid process and the umbilicus, usually midway between the two. Origin: Thought to be due to protrusion of extraperitoneal fat at the site where small vessels pierce the linea alba. Content: Extra-peritoneal fat, peritoneum in true hernia. Clinical feature: Often symptomless. Referred pain pain suggestive of a peptic ulcer. Spigelian Hernia Interparietal hernia occurring at the level of the arcuate line lateral to the rectus muscle and below the umbilicus (infraumbilical). Recurrent Hernia Causes: Absorbable suture, Sliding hernia, Missed sac, Infection.

RESPIRATORY SYSTEM
ANATOMY

BRONCHOPULMONARY SEGMENTS Pyramidal in shape Each segment is aereted by a tertiary or segmental bronchus and has its own separate artery, but does not have own vein. Segments:
Bronchopulmonary segments Rt. lung Upper lobe: i. Apical ii. Anterior Middle lobe: i. Medial ii. Lateral Lower lobe: i. Superior ii. Anterior basal iii. Posterior basal iv. Lateral basal Lt. lung Upper lobe: i. Apico-posterior ii. Anterior Lingular lobe: i. Superior ii. Inferior Lower lobe: i. Antero-medial basal ii. Posterior basal iii. Lateral basal

Arterial supply of lung Bronchial tree upto respiratory bronchiole: bronchial artery and pulmonary artery. Part distal to respiratory bronchiole: pulmonary artery alone.

PHYSIOLOGY
RESPIRATORY FUNCTION Definitions
Different respiratory volumes Definition Value Tidal volume (TD) The amount of air that moves into the lungs with each inspiration 0.5 L

Contd...

Respiratory System
Contd... Definition Value

165

Inspiratory reserve The air inspired with 3.3 L volume (IRV) maximum effort in excess of TV Expiratory reserve The volume of air 1 L volume (ERV) expelled by an active expiratory effort after passive expiration Residual volume The air left in lungs after 1.2 L (RV) a maximum expiratory effort Vital capacity The largest amount of air 0.5+3.3+1.0 (VC) that can be expired after = 4.8 L a maximal inspiratory effort. VC= TV+IRV+ERV Total lung TLC= VC+RV 4.8+1.2 capacity (TLC) = 6.0 L Timed vital The rate at which air can FEV 1 = 80% capacity/forced be expelled from the lungs - of VC expiratory volume FEV1 = at 1 second; FEV 3 = 97% FEV3 = at 3 seconds of VC The maximal Forced expiratory flow midexpiratory flow (FEF) between 25 and rate (MMFR) 75% of the VC, or FEF25-75% Maximum voluntary 125-170 L mm ventilation Functional residual The volume of gas in 1.0+1.2= 2.2 L capacity (FRC) the lungs at the end of a normal exhalation FRC= ERV+RV Relaxation volume Lung volume at which It is equal intrapulmonary pressure to FRC= 2.2 L is 0.

Compliance: Change in lung volume per unit change in airway pressure. (V/P). TLC depends upon lung compliance. Compliance is decreased by pulmonary congestion and interstitial lung fibrosis. It is increased in emphysema. Diffusing capacity: The ability of gas to diffuse across the alveolar-capillary membrane is ordinarily assessed by the diffusing capacity of the lung for carbon monoxide (DLco). DLco is decreased in interstitial lung disease, emphysema, primary pulmonary hypertension, and recurrent pulmonary emboli.

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DLco is increased in CCF , alveolar hemorrhage (e.g. Good Pastures disease). Closing volume: This is the volume at which the small airways tend to collapse. It determines small airway resistance. Measurement 1. Spirometer: Measures IRV, ERV, VC, TV but not RV, FRC or TLC. 2. Vitalograph: measures VC and FEV. 3. N2 wash out measures RV. 4. Diffusion of CO (DLco): Diffusing capacity. 5. Helium dilution and body plethysmography - measure RV, FRC and TLC. Body plethysmography is particularly useful in patients with emphysematous bullae not connected to bronchial tree. Alterations in Ventilatory Function
Alterations in ventilatory function TLC Obstructive lung disease Restrictive lung disease N or RV VC FEV/FVC N or

PULMONARY CIRCULATION The pulmonary circulation is a distensible low-pressure system. In an upright position, pulmonary arterial pressure (PAP) is lowest at the apex of the lung and highest at the lung base. As a result, in the upright position, perfusion is least at the apex and greatest at the base. Pulmonary arterial pressure = 24/9 mmHg with mean pressure of 15 mmHg, i.e. 1/7th of systemic arterial pressure. Pulmonary veins are distended at the lower portion of the lungs. Systemic hypoxia causes pulmonary arterioles to constrict increased pulmonary arterial pressure. Measurement PVR = 80(PAPPCWP)/CO Where PVR = Pulmonary vascular resistance.

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PAP = Pulmonary arterial pressure. PCWP = Pulmonary capillary wedge pressure. It corresponds to left atrial pressure. CO = Cardiac output. Swan-Ganz catheter measures PAP and PCWP . CO can be obtained by the thermodilution method. Intraventricular pressure measurement by pulmonary artery catheter is done at the end of expiration. GAS EXCHANGE Dead Space 1. Anatomical dead space: A portion (approximately 30%) of the fresh air inspired with each breath does not reach the alveoli but remains in the conducting airways of the lung. This component of each breath, which is not generally available for gas exchange, is called the anatomic dead space component = 150 ml. 2. Physiological dead space: In a normal individual both are equal. In certain diseases, some alveoli are ventilated but not perfused, so that some ventilation in addition to the anatomic dead space component is wasted. In these conditions, physiological as well as total dead space is increased. The total or physiological dead space can be measured by Bohrs equation using Pco2 of expired air (PAco2) Pco2 of arterial blood (Paco2) and Tidal volume. Ventilation and Perfusion Ventilation barrier: The ventilation barrier is constituted by alveolocapillary membrane made up of the pulmonary epithelium, the capillary endothelium and their fused basement membranes with scant pericapillary interstitial tissue. Values In normal individual V/Q =1. Ventilation per unit volume and blood flow (perfusion) are both greater at the lung bases than at the apices; but V/Q ratios are greater at the lung apices than at the bases.

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Gases Alveolar air O2 concentration (PAo2) = 100 mmHg. Alveolar air CO2 concentration (PAco2) =40 mmHg. PAo2 Pao2 is usually <15 mmHg for subjects <30 years old and increases by ~3 mmHg per decade after age 30. Hypoxemia It is defined as Pao2 <80 mmHg. Causes: 1. V/Q mismatch- most common cause; it is due to airway diseases (asthma, COPD), interstitial lung disease, alveolar disease, pulmonary vascular disease. 2. Decrease in inspired air, e.g. due to high altitude. 3. Hypoventilation- it is due to decreased respiratory drive or neuromuscular diseases. 4. Shunting, e.g. atelectasis, intra-alveolar filling (pneumonia, pulmonary edema), intracardiac shunts, vascular shunts within lungs. Diagnosis
Respiratory failure Type I Pao2 Paco 2 PA-aO2 Mechanism Causes (<60 mmHg) or ( 49 mmHg) Defective oxygenation V/Q mismatch, Decrease in inspired air, Shunting Type II (<60 mmHg) (> 49 mmHg) Normal Hypoventilation Depressed respiratory center (e.g. brain injury), Respiratory muscle weakness, Polio, Kyphoscoliosis

Note: Hypoxemia due to V/Q mismatch and hypoventilation are correctable by 100% oxygen. Hypoxia Hypoxia means deficient oxygen supply to the tissues. Hypoxic hypoxia Most common type. The arterial PO2 is decreased leading to stimulation of chemoreceptors and hyperventilation.

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Causes 1. Ventilation-perfusion mismatch- most common cause, 2. Ascend to high altitude. Changes at high altitude: Rapid in PAO 2 hyperventilation PACO2 Respiratory alkalosis. Acclimatization Increased erythropoietin secretion Increased cortisol secretion Reticulocytosis Increased RBC in blood. Increased 2,3 DPG decreased O2 affinity. CSF - Increased H+ and decreased HCO3 (acidosis) hyperventilation. 3. Shunt- congenital cyanotic heart diseases. 4. Atelectasis or collapse of the lung. (Note: N2 prevents atelectasis). 5. Asthma, emphysema- COPD. i. ii. iii. iv. v. Anemic hypoxia Pathology: Decreased O2 carrying of blood due to decreased Hb. PO2 remains normal, and respiratory center is not stimulated. CO poisoning - produces anemic hypoxia. CO binds to Hb to form carboxyHb (cherry-red color). Treatment: Hyperbaric oxygenation. Stagnant hypoxia Due to slow circulation (hypotension). Hypoxia affects kidney and heart in shock and liver and brain in CHF. Histotoxic hypoxia Due to cyanide poisoning inhibition of cytochrome oxidase and inhibition of tissue oxidative process. Hyperbaric O2 therapy Exposure to 100% O2 at 2-3 atmospheric pressure for 5 hours. Indications: 1. Carbon monoxide poisoning 2. Radiation injury 3. Gas gangrene

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4. Diabetic leg ulcer 5. Decompression sickness 6. Air-embolism. Hypoventilation Cause 1. Bulbar poliomyelitis 2. Kyphoscoliosis 3. COPD 4. Metabolic alkalosis 5. G-B syndrome Pathophysiology: in alveolar Pco2 (PAco2) in arterial in plasma. Pco2 (Paco2) respiratory acidosis HCO3 Pickwickian syndrome: Obesity hypoventilation hypercapnia, hypoxemia polycythemia, pulmonary hypertension, right ventricular failure and day time somnolence. Primary Pulmonary Hypoventilation Etiology: Impaired ventilatory response to chemical stimuli. Clinical features: Common in males aged 20-50 years Chronic hypoxemia, hypercapnia. Diagnosis: Respiratory acidosis. Hyperventilation Causes: 1. High altitude 2. Pneumonia 3. CCF 4. Metabolic acidosis 5. Drugs- aspirin, -blockers Clinical features: 1. Dyspnea- most common symptom. 2. Respiratory alkalosis - dizziness, visual impairment, syncope, paresthesia, tetany (due to decreased Ca++), muscle weakness (due to decreased PO42).

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CO2 Narcosis When PAco 2> 7%, arterial CO 2 increases despite hyperventilation produces CNS depression (respiratory center is also depressed) and produces headache, confusion and coma; fall in pH of CSF; and papilledema. GAS TRANSPORT O2 Transport O2-Hb dissociation curve: Each gram of Hb contains 1.34 ml of O2. 1 Hb molecule reacts with 4 molecules of O2 to form Hb4O8. Iron in Heme is in Fe++ state, and it stays in this state in Hb4O8, so the reaction is oxygenation, not oxidation. The curve has a sigmoid shape. Note: PO2 of 100 mmHg in arterial blood corresponds to 97.5% saturation of Hb or 0.3 ml/dl of dissolved O2. Regulation 1. Any shift to right decreases affinity and vice versa. 2. The curve shifts to right by: i. Increase in temperature. ii. Fall in pH. iii. Increased 2, 3-DPG concentration. 3. The curve shifts to right in shock, RDS and CCF. pH: Decrease in O2 affinity of Hb when pH is decreased is called Bohr effect. It is because; deoxygenated Hb binds H+ more actively than does oxyHb. 2, 3-DPG It is formed from 3-phosphoglyceraldehyde in E-M pathway. 2, 3-DPG concentration is increased ini. Exercise ii. Ascent to high altitude iii. Anemia iv. Chronic hypoxia Consequently all these conditions decrease O2 affinity. 2, 3-DPG concentration is decreased ini. Stored blood ii. Fall in pH iii. Fetal Hb (HbF)

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Myoglobin Binds only 1 molecule of O2 per mole. Its dissociation curve has a rectangular hyperbolic shape. CO2 Transport The solubility of CO2 in blood is about 20 times that of O2. Fate in plasma: 1. Formation of carbamino compound with plasma proteins. 2. HydrationCO2 + H2O

CA

H2CO3

H+ + HCO3

remains as such H+ is buffered primarily by Hb, HCO3 . and CO2 is transported in blood as HCO3

Fate in RBC 1. Formation of carbamino-Hb. enters the plasma. 2. Hydration, H+ buffered, 70% HCO3 in RBC is transported to plasma 3. The excess HCO3 in exchange of Cl - by Band 3, a process called chloride shift. Amount of CO2 transported to lungs and excreted = 200 ml/min at rest = 288 L/day. Venous blood vs. arterial blood: Venous blood contains i. More Clii. More hematocrit by 3%. DIAGNOSTIC PROCEDURES Chest X-ray Hilar shadow: is composed of: i. Pulmonary arteries. ii. Upper lobe pulmonary veins. iii. Major bronchi. iv. Lymph nodes. Kerley lines: Types i. Kerley A lines- radiate from hila.

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ii. Kerley B lines Extend from pleural surface. Perpendicular to pleural surface. Best seen in costophrenic angle. iii. Kerley C lines- spider web appearance. Cause Thickening or widening of interlobular septa. Distension of interlobular lymphatics. Seen in 1. Pulmonary venous hypertension i. LVF ii. MS 2. Lymphatic obstruction i. Pneumoconiosis ii. Lymphangiitis carcinomatosa iii. Sarcoidosis 3. Interstitial pneumonitis. Pulmonary nodule: A nodule defined as solitary circumscribed density <6 cm in diameter. Causes of solitary pulmonary nodule i. Congenital- hamartoma (popcorn calcification). ii. Neoplastic- adenoma, neurofibroma. iii. Infection- tuberculosis, hydatid cyst, lung abscess. CT Scans Uses: 1. Assessment of hilar and mediastinal disease. 2. Identifying and characterizing diseases close to chest wall or spine (including pleural disease). 3. Identifying areas of fat density or calcification in pulmonary nodules. 4. Important tool for staging of lung cancer. Bronchoalveolar Lavage BAL is particularly helpful in recovery of organisms such as Pneumocystis carinii in patients with HIV infection. BAL is also useful in the evaluation of interstitial lung diseases shows increased neutrophil count.

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DISEASES OF RESPIRATORY SYSTEM


Obstructive lung disease 1. Asthma 2. Chronic obstructive pulmonary diseases (COPD) i. Chronic bronchitis ii. Emphysema 3. Bronchiectasis 4. Cystic fibrosis 5. Bronchiolitis Restrictive lung disease A. Parenchymal 1. Idiopathic pulmonary fibrosis 2. Sarcoidosis 3. Hypersensitivity pneumonitis 4. Diffuse alveolar hemorrhage syndrome 5. Pulmonary angitis and granulomatosis 6. Lung in collagen vascular diseases B. Extraparenchymal 1. Neuromuscular a. Diaphragmatic paralysis b. Myasthenia gravis c. G-B syndrome d. Muscular dystrophies e. Cervical spine injury 2. Chest wall a. Kyphoscoliosis b. Obesity c. Ankylosing spondylitis

OBSTRUCTIVE LUNG DISEASES


ASTHMA Pathogenesis Constriction of terminal bronchioles hyperventilation decreased PCO2. Mediators: Histamine, bradykinin, the leukotrienes C, D and E; PAF and PGE2, PGF2 and PGD2. Drugs inducing asthma: Aspirin, coloring agents (e.g. Tartrazine), - -blockers. Aspirin sensitive respiratory syndrome - associated with nasal polyps. Incidence - 1 to 2%. Environmental factors: Games like ice hockey, ice-skating provoke asthma. Indoor swimming in heated pool is relatively safe.

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Clinical Features Severe Acute Asthma: Symptoms- triad of dyspnea, cough and wheezing (sinequa-non). SignsExpiration is prolonged. Tachypnea, tachycardia. Mild systolic hypertension. Ronchi- may be absent in very severe asthma- silent chest. Accessory muscles become visibly active. Pulsus paradoxus (the last two signs indicate severity of obstruction) Sweating. Cyanosis- a late sign. The end of an episode is marked by a productive cough. The produce takes the cast of the distal airways (Curschmann spirals). Under microscope they show numerous eosinophils and Charcot-Leyden crystals. Chronic asthma: May produce Pigeon chest deformity. Cough variant asthma: Patient presents with persistent cough with no (or episodic) wheezing and dyspnea. Treatment Severe Acute Asthma (Status asthmaticus): 1. O2. 2. 2-agonists- nebulization with O2. Drugs - sulbutamol or terbutaline. (salmeterol- not recommended for acute episodes). 3. Systemic steroids - IV hydrocortisone or oral prednisolone. (Inhaled steroids have no role in acute asthma). 4. Ipratropium bromide. Chronic Asthma: Drug therapy 1. 2-agonists - salbutamol, terbutaline, salmeterol. 2. Methyl xanthines - theophylline, aminophylline. 3. Anticholinergics - atropine sulfate, ipratropium bromide. 4. Glucocorticoids - inhalation route preferred. Side-effects of inhalation steroids Thrush, dyspnea, adrenal suppression, cataract formation, decreased growth in children, purpura.

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5. Mast cell stabilizers- sodium cromoglycate (not used in acute asthma). They are most effective in atopic patients who have either seasonal disease or perennial airway stimulation. 6. Leukotriene Modifiers: Zileuton (5-lipoxygenase synthesis inhibitor) provides protection against exerciseinduced asthma, and diminishes nocturnal symptoms, but it has limited effectiveness against allergens. The LTD 4 receptor antagonists (Zafirlukast and Montelukast) - longer acting. Monitoring: The course of the illness and the effectiveness of therapy can be followed by measuring peak expiratory flow rates (PEFRs) at home and/or the FEV1 in the laboratory. CHRONIC OBSTRUCTIVE PULMONARY DISEASES (COPD) Definition Chronic bronchitis: Productive cough on most days of at least 3 consecutive months for more than 2 successive years. Emphysema: Permanent dilatation of air spaces distal to terminal bronchioles with destruction of pulmonary septa. COPD: Chronic obstructive pulmonary disease (COPD) is the name of a group of chronic and slowly progressive respiratory disorders characterized by reduced maximal expiratory flow during forced exhalation. COPD comprises of emphysema and chronic bronchitis. Airflow obstruction is characterized by FEV1 <80% of predicted and FEV1/FVC ratio <70%. Risk Factors 1. 2. 3. 4. Cigarette smoking - most important risk factor. Air pollution - especially SO2 and NO2. Infection - rhinovirus, mycoplasmas. 1 antitrypsin deficiency - it is a serine proteinase inhibitor; hence its deficiency leads to increased protease activity. The disorder is transmitted as an

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autosomal recessive trait. It is associated with premature development of severe emphysema, chronic bronchitis, or bronchiectasis and hepatic cirrhosis. Pathology Chronic bronchitis: Hypertrophy of mucus-producing glands; bilateral involvement. Reid index: Ratio of thickness of submucosal glands to that of bronchial wall. Normal value- 0.44 0.09 With H/O bronchitis - 0.52 0.08 Emphysema Types1. Centriacinar (centrilobular) most common type. Involves respiratory bronchioles but spares distal alveoli. Most commonly associated with cigarette smoking. 2. Panacinar (panlobular) acini uniformly involved from respiratory bronchiole to distal alveoli. Most commonly associated with 1 antitrypsin deficiency. 3. Distal acinar (paraseptal) more striking adjacent to pleura. Forms multiple cyst-like air spaces adjacent to pleura. Probably cause spontaneous pneumothorax in young adults. Clinical Features
Differentiating features Features Dyspnea Hyperventilation Predominant emphysema Severe +ve (So they have adequate oxygenation of Hb- Pink puffers) (35-40 mmHg) Predominant bronchitis Mild ve (So they retain CO2. become hypoxic and cyanotic- blue bloters) (50-60 mmHg)

Chronic Paco2 (Normal 40 mmHg) Chronic Pao2 (65-75 mmHg) (Normal 100 mmHg) Respiratory Uncommon infection Cor pulmonale Rare (Pul HPT+ RVF)

(45-60 mmHg)

Common Common

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Chest X-ray Emphysema is manifested by an increased lucency of the lungs. In smokers, these changes are more prominent in the upper lobes, while in 1 antitrypsin deficiency, they are more likely in basal zones. In emphysema, CXR shows wide intercostals spaces. Complications 1. Pulmonary hypertension. 2. Pneumothorax in severe long standing emphysema. 3. ECG changes most commonly supraventricular tachycardia. 4. Acute respiratory failure indicated by a drop in Pao2 10-15 mmHg. Management 1. Smoking cessation - most important part. 2. Bronchodilators like 2 -adrenergic agonists, anticholinergics, and theophylline derivatives. 3. Glucocorticoids. 4. Management of exacerbations in similar way to that of acute asthma. BRONCHIECTASIS Definition Bronchiectasis is the abnormal permanent dilatation of bronchi and bronchioles caused by destruction of muscle and elastic supporting tissue, resulting from or associated with chronic necrotizing infections. Pathology The bronchial dilatation of bronchiectasis is associated with destructive and inflammatory changes in the walls of medium-sized airways, often at the level of segmental or subsegmental bronchi. The normal structural components of the wall, including cartilage, muscle, and elastic tissue, are destroyed and may be replaced by fibrous tissue. The dilated airways frequently contain pools of thick, purulent material, while more peripheral airways are often occluded by secretions or obliterated and replaced by fibrous tissue.

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Types In cylindrical bronchiectasis the bronchi appear as uniformly dilated tubes that end abruptly at the point that smaller airways are obstructed by secretions. In varicose bronchiectasis the affected bronchi have an irregular or beaded pattern of dilatation resembling varicose veins. In saccular (cystic) bronchiectasis the bronchi have a ballooned appearance at the periphery, ending in blind sacs without recognizable bronchial structures distal to the sacs. Etiology Congenital 1. Primary ciliary dyskinesia - structural abnormality of the dyenin arms, radial spokes and microtubules; autosomal recessive disorder. Kartageners syndrome (immotile cilia syndrome): Bronchiectasis (due to primary ciliar dysfunction), sinusitis, transposition of viscera and male infertility. 2. Cystic fibrosis. 3. Panhypogammaglobulinemia is associated with recurrent infection and bronchiectasis, patients often also have a history of sinus or skin infections. Acquired In children - usually due to pneumonia following whooping cough or measles. In adults - organisms commonly responsible are Adenovirus and influenza virus, Staphylococcus aureus, Klebsiella, and anaerobes, Pseudomonas aeruginosa, Hemophilus influenza - most common infection. Pulmonary tuberculosis. Clinical Features Site: most common in left lower lobe. Symptoms: Recurrent cough with purulent sputum, hemoptysis. Sign: Course crepitations over the affected area; finger clubbing.

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Complication 1. 2. 3. 4. Amyloidosis. Lung abscess. Abscess at distant sites e.g. brain. Arthropathy. Note: Bronchiectasis has no malignant potential.

Investigations 1. Sputum examination. 2. High resolution CT scan - most sensitive and also the investigation of choice. The classic appearance of a cross-section of a thick-walled dilated bronchus next to the accompanying pulmonary artery is the Signet ring sign. 3. Chest X-ray - it may be normal; or may show nonspecific changes or characteristically show tram track appearance in longitudinal view and ring shadow in cross-sectional view. 4. Bronchography has now been replaced by CT scans. CYSTIC FIBROSIS Genetics CF is an autosomal recessive disorder. The CF gene is located on chromosome 7 and codes for a protein called the cystic fibrosis transmembrane regulator protein (CFTR) which acts as an ATP responsive chloride channel and regulates other ion channels especially sodium. Pathophysiology Sweat glands - sweat has high concentrations of both sodium and chloride. Respiratory tract - The diagnostic biophysical hallmark of CF is the raised transepithelial electric potential difference (PD) detected in airway epithelia. This also leads to local impairment of antibacterial defenses and subsequent bacterial colonization and recurrent respiratory tract infection, bronchiectasis. Pancreas - malabsorption and progressive destruction of the pancreas with cyst formation (fibrocystic disease of pancreas). The islet cells too are progressively destroyed leading to insulin deficiency and diabetes.

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Biliary tract biliary cirrhosis and associated extrahepatic biliary stenosis. Gut meconium ileus in neonates and the distal intestinal obstruction syndrome in adults. Reproductive system male infertility due to azoospermia because of congenital bilateral absence of the vas deferens (CABVD). Microbiology Respiratory infection is a chronic and serious occurrence in CF. Staphylococcus aureus is the most common organism in childhood whereas Pseudomonas aeruginosa is the commonest colonizing organism after the age of 10 years. Others are Haemophilus influenzae, Burkholderia cepacia, Aspergillus fumigatus. Diagnosis It is based on a combination of clinical criteria and analyses of sweat Cl- values. To diagnose cystic fibrosis in a child, the sweat chloride concentration should be greater than 60 mmol/l, and the sweat sodium concentration less than that of chloride. In adults Sweat Cl concentration is typically >70 mmol/l. Na concentration is also increased. Nasal electrical potential difference is raised. BRONCHIOLITIS Organism: Respiratory syncytial virus (RSV). Course: There is relationship of acute bronchiolitis and bronchial asthma in latter life. Clinical Features Common age is 6 months, artificial feeding predisposes to it. Tachypnea, respiratory distress (retraction of IC spaces and suprasternal notch), cyanosis, rales and ronchi. Treatment Humid atmosphere.

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O2 is the mainstay of treatment. Antibiotics have no role though antiviral ribavirin is used.

RESTRICTIVE OR INTERSTITIAL LUNG DISEASES


Classification
Major categories of alveolar and interstitial inflammatory lung disease Lung response: Lung response: Alveolitis, Granulomatous interstitial inflammation, and fibrosis Known cause Hypersensitivity Asbestos, Fumes, gases pneumonitis (organic Drugs (antibiotics, amiodarone, dusts) gold) and chemotherapy drugs Inorganic dusts: Radiation beryllium,silica Aspiration pneumonia Unknown cause Idiopathic interstitial (lymphocytic interstitial pneumonias pneumonitis associated Idiopathic pulmonary fibrosis with connective tissue most common cause. disease) Desquamative interstitial Eosinophilic pneumonias pneumonia Lymphangio Respiratory bronchiolitisleiomyomatosis associated interstitial lung Amyloidosis disease Inherited diseases Acute interstitial pneumonia (Tuberous sclerosis, (diffuse alveolar damage) neurofibromatosis, Nien, Cryptogenic organizing ann-Pickdisease, pneumonia (bronchiolitis Gauchers disease, obliterans with organizing Hermanskypneumonia) Pudlaksyndrome) Nonspecific interstitial Gastrointestinal or liver pneumonia diseases (Crohns disease, Connective tissue diseases primary biliary cirrhosis, (Systemic lupus erythematosus, chronic active rheumatoid arthritis, ankylosing hepatitis,ulcerative colitis) spondylitis, systemic sclerosis, Graft-vs.-host disease Sjgrens syndrome, (bone marrow polymyositis-dermatomyositis) transplantation;solid organ Pulmonary hemorrhage transplantation) syndromes(Good pastures syndrome, idiopathic pulmonary Sarcoidosis hemosiderosis, isolated Langerhans cell pulmonary capillaritis) granulomatosis Pulmonary alveolar proteinosis (eosinophilic granuloma Lymphocytic infiltrative disorders of the lung) Contd...

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Contd... Granulomatous vasculitides Bronchocentric (Wegeners granulomatosis, granulomatosis allergic granulomtosis of Churg- Lymphomatoid Strauss) granulomatosis

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Pathology There is diffuse thickening of pericapillary interstitium and alveolar wall by inflammatory cells and exudates (e.g. ARDS), granulomas (e.g. - sarcoidosis), hemorrhage (e.g. - Goodpasteurs syndrome) and/or fibrosis (e.g. - fibrosing alveolitis). Clinical Features Symptoms - shortness of breath on exertion. Sign - digital clubbing, end-inspiratory crepitations Investigation Bronchoalveolar lavage (BAL). HRCT Investigation of choice. IDIOPATHIC PULMONARY FIBROSIS/ CRYPTOGENIC FIBROSING ALVEOLITIS Clinical Features Exertional dyspnea, a nonproductive cough, with or without digital clubbing. Bilateral end-inspiratory crepitations - over the lower zones posteriorly. Diagnosis A surgical biopsy showing the usual interstitial pneumonia pattern of pathology and Major criteria 1. Exclusion of other known causes of diffuse lung disease such as certain drug toxicities, environmental exposures, and rheumatological diseases; 2. Abnormal pulmonary function studies that include evidence of restriction (reduced VC often with an increased FEV1/FVC ratio) and impaired gas exchange (increased P(A-a)O2 at rest or on exercise or decreased DLco);

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3. Bibasilar reticular abnormalities with honeycombing and minimal or no ground glass opacities on high resolution computed tomography scans; 4. Transbronchial lung biopsy or bronchoalveolar lavage showing no features to support an alternate diagnosis, such as granulomas on biopsy or an excess of lymphocytes on bronchoalveolar lavage. Minor criteria1. Age more than 50 years; 2. Insidious onset of otherwise unexplained dyspnea on exertion; 3. Duration of illness more than 3 to 6 months; 4. Bibasilar, inspiratory crackles on chest auscultation. The presence of all of the following major diagnostic criteria as well as at least three of the four minor criteria increases the likelihood of a correct clinical diagnosis of cryptogenic fibrosing alveolitis. SARCOIDOSIS Multisystem disorder characterized by: 1. Non-caseating granuloma in lungs. 2. Bilateral hilar and paratracheal lymphadenopathypotato nodes on chest X-ray. 3. Involvement of almost any organ in the body except adrenals. Diagnosis: Kveims test. HYPERSENSITIVITY PNEUMONITIS/EXTRINSIC ALLERGIC ALVEOLITIS These are a group of disorders caused by hypersensitivity to organic dusts. For deposition of the dust to occur predominantly in the gas exchanging tissues, particle size must be largely confined to the range 0.5 to 5 m. This is a combination of type III and type IV hypersensitivity reactions.
Examples of hypersensitivity pneumonitis Disease Bagassosis Bird fanciers, breeders, or Antigen Thermophilic actinomycetesa Parakeet, pigeon, chicken, turkey Source of Antigen Moldy bagasse (sugar cane) Avian droppings or feathers Contd...

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Contd... Disease handlers lung Chemical workers lungb Farmers lungb
b

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Antigen proteins isocyanates

Source of Antigen

Polyurethane foam, varnishes,lacquer Thermophilic Moldy hay, grain, actinomycetesa silage Humidifier or Aureobasidium pullulans Contaminated water air-conditioner or other microorganisms in humidification or lung (ventilation forced-air airpneumonitis) conditioning systems Woodworkers Wood dust, Alternaria Oak, cedar, pine, and lung mahogany dusts
a

Thermophilic actinomycetes species include Micropolyspora faeni Thermoactinomyces vulgaris, T. saccharrii, T. viridis, and T. candidus. Most common causes of hypersensitivity pneumonitis in the United States.

Farmers Lung Hypersensitivity to mouldy hay containing thermophilic actinomycetes, particularly Micropolyspora faeni (now known as Saccharopolyspora rectivirgula) and Thermoactinomyces vulgaris; also non-thermophilic aspergillus species. Bagassosis Hypersensitivity to sugar cane dust. Bagasse control - spraying bagasse dust with 2% propionic acid. Diagnosis After acute exposure to antigen, neutrophilia and lymphopenia are frequently present. Eosinophilia is not a feature (cf. pulmonary infiltrates with eosinophilia). Elevations in erythrocyte sedimentation rate, C-reactive protein, rheumatoid factor, and serum immunoglobulins. Precipitin test - presence of serum precipitins against suspected antigens.

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PNEUMOCONIOSIS Asbestosis Asbestosis is pulmonary fibrosis caused by exposure to fibres of asbestos. Type of fibers: Chrysolite, amosite, anthophyllite, and crocidolite (most common). Epidemiology: The disease does not usually appear until after 5-10 years of exposure. But once established, it is progressive even after removal of the worker from contact. Pathology: The characteristic lung lesions are: Macroscopic appearance - grey fibrosis more marked peripherally and in the lower zones. In severe cases the fibrosis appears like a honeycomb. Parietal pleural plaques implies exposure and not disease. These are often calcified. Microscopically there is diffuse alveolar wall fibrosis; larger asbestos fibers may be seen coated with a protein complex (the asbestos or ferruginous bodies). Benign pleural effusions may occur. Clinical feature: Asbestosis produces a restrictive type of lung defect. Diagnosis: Chests X-ray shows predominantly basal and peripheral irregular linear shadowing progressing to honeycombing, ground glass appearance in some cases. Sputum may show the presence of asbestos bodies (sheek kebab appearance). Complication: There is increased risk of developing malignancies like Lung cancer most commonly squamous cell carcinoma and adenocarcinoma. Mesothelioma of pleura and peritoneum. Colonic carcinoma. Laryngeal carcinoma. Silicosis Silicosis is a fibrotic disease of the lungs due to inhalation of crystalline silicon dioxide, usually in the form of quartz.

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Pathology: Progressive massive fibrosis of lung which is characteristically apical and nodular. Hilar lymphadenopathy and calcification of hilar nodes. Epidemiology: Most dangerous are the particles of size 0.5-3 m. Classic disease appears after 15-20 years of exposure. Chest X-ray: In acute disease diffuse military infiltration or consolidation. In long-term disease rounded opacities in upper lobe (snow-storm appearance). Egg shell pattern of calcified hilar nodes. Complication: There is increased chance of acquiring tuberculosis infection. Coal Workers Pneumoconiosis (Anthracosis) This occurs due to exposure to coal dust, especially in anthracite miners after more than 20 years of exposure. Pathology: Nodular fibrosis in early stages progressing to nodule size > 1 cm involving the upper lobe or the whole lung, known as progressive nodular fibrosis (less chance than silicosis). It is additive to cigarette smoking in developing COPD. Caplans syndrome - seropositive rheumatoid arthritis with characteristic PMF. Berylliosis It has some genetic predisposition. Pathology: The disease is identical with that of sarcoidosis, with non-caseating granulomas and varying amounts of interstitial fibrosis; with bilateral hilar lymphadenopathy being less common, It is Kveims test negative. Clinical feature: In acute phases it causes acute pneumonitis and tracheobronchitis. Chronic berylliosis is characterized by a restrictive lung defect.

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DIFFUSE ALVEOLAR HEMORRHAGE SYNDROME Goodpastuers Syndrome Pathology Diffuse pulmonary hemorrhage and cresentic, rapidly progressive glomerulonephritis with linear deposition of antibody (90 per cent of which are directed against the -3 chain of type IV collagen) along the glomerular basement membrane. Clinical feature: 1. Renal- hematuria, nephritic urinary sediment and subnephrotic proteinuria (that of RPGN). 2. Pulmonary- hemoptysis which may be massive and fatal. It precedes hematuria. Diagnosis: Serological testing (for anti-GBM antibodies) and kidney biopsy. Treatment: Steroids, cyclophosphamide and plasmapheresis. COLLAGEN VASCULAR DISEASE
Lung involvement in collagen vascular disease Disease Progressive systemic sclerosis (PSS) Polymyositis/dermatomyositis Rheumatoid arthritis Respiratory manifestations

Fibrosing alveolitis Pulmonary vascular disease Diffuse lung disease Fibrosing alveolitis Organizing pneumonia Bronchiolitis obliterans Bronchiectasis Pulmonary rheumatoid nodules (Caplans syndrome) Pleurisy with or without effusion Sjgrens syndrome Diffuse lung disease Systemic lupus erythematous Pleuritis with or without effusion (SLE) (most common) Diffuse lung disease Extrapulmonary restriction (shrinking lung syndrome) Diffuse alveolar hemorrhage Pulmonary hypertension

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PULMONARY INFECTIONS
PNEUMONIA Pneumonia is an acute or chronic infection involving the pulmonary parenchyma. Etiology
Microbial pathogens that cause pneumonia Community-acquired Hospital-acquired HIV infectionassociated Pneumocystis carinii M. tuberculosis S. pneumoniae H. influenzae

Streptococcus Enteric aerobic gram pneumoniae (MC) negative bacilli (MC) Haemophilus influenzae Pseudomonas Mycoplasma pneumoniae aeruginosa Chlamydia pneumoniae S. aureus Legionella pneumophilia Oral anaerobes Oral anaerobes Moraxella catarrhalis Staphylococcus aureus Nocardia spp. Virusesa Fungib Mycobacterium tuberculosis Hlarnydia psittaci
a

Influenza virus, cytomegalovirus, respiratory syncytial virus, measles virus, varicella-zoster virus, and hantavirus. b Histoplasma, Coccidioides, and Blastomyces spp.

Pathology The pneumonic process may involve primarily the interstitium or the alveoli. Involvement of an entire lobe is called lobar pneumonia. When the process is restricted to alveoli contiguous to bronchi, it is called bronchopneumonia. Cavities develop when necrotic lung tissue is discharged into communicating airways, resulting in either necrotizing pneumonia (multiple small cavities, each <2 cm in diameter, In one or more bronchopulmonary segments or lobes) or lung abscess (one or more cavities >2 cm in diameter). Classification of illness for infants aged 2 months to 5 years 1. Very severe disease- convulsions, stridor, malnutrition. 2. Severe pneumonia- chest indrawing, grunting, cyanosis.

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3. Pneumonia- fast breathing (>50/mm for 2 month to 1 year and >40/mm for 1-5 years). 4. No pneumonia - only cough and cold. Streptococcal Pneumonia Streptococcus pneumoniae is the most common cause of community-acquired pneumonia. Pathology Stages: 1. Congestion. 2. Red hepatization- alveolar spaces packed with neutrophils, red cells and fibrin. 3. Gray hepatization- red cells get lysed but the fibrinous exudate persists. 4. Resolution. Clinical features: Symptoms - sudden onset of cough productive of blood, fever and chest pain. Sign - tachypnea, tachycardia. Signs of pulmonary consolidation (dullness, increased fremitus, egophony, bronchial breath sounds, and rales) may be found. Chest X-ray: CXR invariably shows an infiltrate, and lobar consolidation specifically suggests this diagnosis. A pleural effusion is present in about 25 percent of patients. Treatment: Streptococcus pneumoniae shows escalating rates of resistance to penicillin, other -lactams, macrolides, cotrimoxazole (TMP-SMX), clindamycin, and tetracycline. The only drug that is virtually always active is vancomycin. Fluoroquinolones with enhanced activity against S. pneumoniae include levofloxacin, trovafloxacin, and gatifloxacin. Atypical Pneumonia Organisms: Mycoplasma pneumoniae - most common. Chlamydia pneumoniae. Legionella pneumophila. Pneumocystis carinii in HIV infected patients. Certain viruses.

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Pathology: Interstitial inflammation; the inflammatory reaction is largely confined within the walls of alveoli. They are usually mononuclear cell infiltrates. Clinical features: The atypical presentation is characterized by a more gradual onset, a dry cough, shortness of breath, a prominence of extrapulmonary symptoms (such as headache, myalgias, fatigue, sore throat, nausea, vomiting, and diarrhea), and abnormalities on chest radiographs despite minimal signs of pulmonary involvement (other than rales) on physical examination. Chest X-ray: Hilar lymphadenopathy occasionally seen in M. pneumoniae infection. Patchy of lobar consolidation Diagnosis: Sputum - often NAD. Mycoplasma pneumoniae - Polymerase chain reaction (PCR); cold agglutinins may be found in blood. Treatment: The usual therapeutic agents are macrolides (such as erythromycin, clarithromycin or azithromycin) or doxycycline; fluoroquinolones are also active. Staphylococcal Pneumonia Pathology: Pneumatocele - pathognomonic of Staphylococcal pneumonia. Clinical features: Grunting respiration. Complication: 1. Empyema- in a child <2 years is almost always due to staphylococcus. 2. Along with staph. endocarditis, it is a serious complication of IV drug users. Chest X-ray: Lung cavities often found (also in pneumococcus type 3 infection). Treatment: Antistaphylococcal penicillin (flucloxacillin, oxacillin, or nafcillin) or a first-generation cephalosporin (cefazolin), or vancomycin (for methicillin-resistant strains and for patients with severe penicillin allergy).

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Klebsiella pneumonia The classic presentation of Friedlanders pneumonia was a serious pneumonia in an alcoholic patient with a chest radiograph that showed upper lobe involvement and the bulging fissure sign (indicating abscess formation) and sputum that resembled currant jelly. Pneumocystis pneumonia It is a fungus causing lung diseases in immunocompromised patients. Risk factors: 1. In HIV-infected individuals, those at greatest risk have CD4+ T lymphocyte counts less than 200 cells/ l. 2. In non-HIV immunosuppressed individuals, glucocorticoid administration is an independent risk factor. 3. Children with primary immunodeficiency diseases. Pathology: Within the lung, P. carinii infection is characterized by an eosinophilic, foamy intra-alveolar exudate, associated with a mild plasma cell interstitial pneumonitis. Morphologically, two forms of P. carinii may be identified: thick-walled cysts (6-7 m diameter) which lie freely within the alveolar exudate are demonstrated by Grocotts methenamine silver, toluidine blue O, or cresyl violet stains. The exudate consists largely of thin-walled, irregularly shaped, singlenucleated trophozoites (2-5 m diameter) which are shown by Geimsa stain but lack distinctive features. Extrapulmonary dissemination is rare. Most important risk factor is pentamidine prophylaxis. The most common sites of extrapulmonary involvement are the lymph nodes, spleen, liver, and bone marrow. Clinical feature: Symptom - dyspnea, fever, and nonproductive cough; retrosternal pain. Sign - tachypnea, tachycardia, and cyanosis, but lung auscultation reveals few abnormalities. Diagnosis: Chest X-ray: the changes are non-specific.

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In early cases, CXR may be normal. Classical finding - bilateral diffuse infiltrates beginning in the perihilar regions; these may progress to diffuse bilateral alveolar (air space) consolidation that mimics pulmonary edema. Atypical findings - intrapulmonary nodules, cavitary lesions, lobar consolidation, pneumatoceles, or hilar/ mediastinal lymphadenopathy. Predominantly apical change may be seen in patients who have received prophylaxis with nebulized pentamidine. Induced sputum may demonstrate cyst or trophozoite with appropriate staining. Bronchoscopy - Fibreoptic bronchoscopy with BAL has a sensitivity of more than 90 percent for detection of P. carinii. Immunofluorescence staining increases the diagnostic yield compared to conventional histochemical staining. Molecular diagnostic tests - Detection of P. cariniispecific DNA by the polymerase chain reaction (PCR) on BAL fluid and induced sputum has the greatest sensitivity. Transbronchial biopsy and open lung biopsy - rarely used. Oxygen desaturation with exercise is a relatively sensitive and specific test. Gallium-67 and indium-111 lung scans are highly sensitive indicators of Pneumocystis carinii pneumonia. Treatment: Co-trimoxazole is the drug of choice. Alternative regimens: For mild to moderate cases: TMP plus dapsone, clindamycin plus primaquine, or atovaquone alone. Moderate to severe forms of pneumocystosis: pentamidine IV or trimetrexate plus folinic acid. Prophylaxis: Indications for primary prophylaxis - those who have CD4+ cell counts of <200/ L, unexplained fever [>37.8C (100 F)] for 2 weeks, or a history of oropharyngeal candidiasis. Co-trimoxazole is again the drug of choice for primary prophylaxis. Alternative drugs are dapsone either alone or in combination with pyrimethamine, pentamidine or atovaquone.

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PULMONARY INFILTRATES WITH EOSINOPHILIA


Pulmonary infiltrates with eosinophilia Etiology known Allergic bronchopulmonary mycoses Parasitic infestations Drug reactions Eosinophilia-myalgia syndrome Idiopathic Loefflers syndrome Acute eosinophilic pneumonia Chronic eosinophilic pneumonia Allergic granulomatosis of Churg and Strauss Hypereosinophilic syndrome

Allergic Bronchopulmonary Mycosis Etiology: A. fumigatus is the most common cause of ABPA (allergic bronchopulmonary aspergillosis). Pathology: The disorder is caused by a combination of type I and type II hypersensitivity reactions. The bronchial asthma of ABPA likely involves an IgE-mediated hypersensitivity, whereas the bronchiectasis associated with this disorder is thought to result from a deposition of immune complexes in proximal airways. It may complicate existing cystic fibrosis. Clinical features: It is a fungal hypersensitivity developing in atopic subjects with asthma, additional manifestations may occur in the lung. These include eosinophilic pneumonia, mucoid impaction, bronchiectasis and pulmonary fibrosis. Earliest feature is breathlessness. When bronchiectasis develops productive cough, intermittent hemoptysis may occur. Investigation: Chest X-ray - the classic radiographic feature is fleeting pulmonary infiltrates. High-resolution CT is a sensitive, noninvasive technique for the recognition of proximal bronchiectasis, Diagnosis: Diagnostic features of allergic bronchopulmonary aspergillosis (ABPA) Main diagnostic criteria Bronchial asthma

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Pulmonary infiltrates Peripheral eosinophilia (>1000/mL) Immediate wheal-and-flare response to A. fumigatus Serum precipitins to A. fumigatus Elevated serum IgE Central bronchiectasis Other diagnostic features History of brownish plugs in sputum Culture of A. fumigatus from sputum Elevated IgE (and IgG) class antibodies specific for A. fumigatus Treatment: Long-term use of systemic glucocorticoids. Aspergilloma: Fungus ball-occurs in preexisting pulmonary cavities. Lofflers syndrome (acute eosinophilic pneumonia, simple pulmonary eosinophilia) It is characterized by transient, benign syndrome of migratory pulmonary infiltrates and peripheral blood eosinophilia. Etiology: Blood borne parasites migrating through the lung, particularly larvae of Ascaris lumbricoides. Drugs - p-amino salicylic acid, aspirin, sulphonamides (including the antimalarial combination sulphadiazine and pyrimethamine or Fansidar), penicillin, and imipramine; also nitrofurantoin. Chest X-ray: The pulmonary shadows reflect fan-shaped areas of consolidation, often peripheral and sometimes rather nodular. Tropical Eosinophilia This is caused by migrating larvae of the filarial worms Wuchereria bancrofti and Brugia malayi. Churg-Strauss syndrome (Allergic angiitis and granulomatosis) Pathology: Vasculitis of small arteries and veins with necrotizing extravascular granulomas.

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It commonly involves lungs, gut, peripheral nerves, skin, and kidneys. Clinical feature: It frequently develops in persons with asthma. It is characterized typically by asthma, eosinophilic pneumonia, and very high numbers of circulating eosinophils (>5 10 9 /l) but the pulmonary manifestations may additionally include localized hemorrhage and hemoptysis. Diagnosis: Biopsy tissue is needed to confirm the diagnosis. Treatment: Immunosuppressive therapy including steroids, azathioprine and cyclophosphamide. Hypereosinophilic syndrome Pathology: The eosinophils appear mature, and infiltrate a number of organs including the bone marrow (most important), lungs, liver, spleen, skin, and nervous system. Clincal features: Eosinophilic pneumonia may be extensive and associated with pleural effusion. The heart may be involved with tricuspid valve abnormalities or endomyocardial fibrosis and a restrictive, biventricular cardiomyopathy. Weight loss, muscle weakness, enlargement of spleen and lymph nodes, gut and renal dysfunction, and venous thromboembolism. Treatment: Treatment consists of glucocorticoids and/or hydroxyurea. Lung Abscess Etiology: 1. Aspiration of infected material- most common cause. 2. As a complication of necrotizing bacterial pneumonia, particularly those caused by Staph. aureus. 3. In children- Staph. aureus (most common), Klebsiella, E. histolytica. 4. Bronchiectasis. 5. Lung cancer.

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Site: Posterior segment of right upper lobe - most common site. Apical segment of right lower lobe. INFECTIONS OF THE LARYNX Infectious Croup (Laryngitis and laryngotracheobronchitis) Etiology: Parainfluenza type I (most common), influenza or respiratory syncytial virus, rhinovirus, adenovirus. Pathology: It causes marked subglottic edema. Clinical feature: It mainly affects 2- and 3-year-old children and usually follows the onset of upper respiratory tract infection by 1 to 2 days. Symptoms include fever, hoarseness, a seals bark cough, and inspiratory stridor. Treatment: 1. Humidified O2. 2. Adequate hydration -IV fluid. 3. Antibiotics - ampicillin. 4. Sedatives should not be used. Epiglottitis Etiology H. influenzae type b was the most common pathogen before the introduction of Hib vaccine. The disease is rare now. Clinical feature: The typical young child with epiglottitis has a several-hour history of fever, irritability, dysphonia, and dysphagia and presents sitting forward and drooling. Diagnosis: Lateral neck films may show an enlarged epiglottis (the thumb sign). Treatment: Intravenous cefuroxime, ceftriaxone, ampicillin/ sulbactam, or trimethoprim-sulfamethoxazole.

VASCULAR DISORDERS
Pulmonary Thromboembolism Source: Deep vein thrombosis of leg (most common - 70 to 80%) and pelvis (10-15%). Isolated calf vein thrombi are the most common source of paradoxical embolism.

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Pathophysiology: Massive emboli become lodged in the proximal pulmonary arteries and chambers of the right heart patient develops right heart failure. They present with systemic arterial hypotension. Small and medium sized emboli become lodged in segmental arteries causing pulmonary infarction. Infarcts are typically hemorrhagic and adjacent to pleura, often covered by fibrinous exudates. They have normal right heart function and normal systemic arterial pressure. Precipitating factors: Stressors that may precipitate pulmonary thromboembolism Surgery, trauma Obesity Oral contraceptives, pregnancy, postpartum, postmenopausal hormone replacement Cancer (sometimes occult) or cancer chemotherapy Immobilization (stroke or intensive care unit patients) Indwelling central venous catheter Factor V Leiden defect. Clinical features: Dyspnea is the most common symptom. Tachypnea is the most common sign. Massive emboli - Patients usually present several days after a major operation with central chest pain, acute dyspnea and apprehension. Others features are cyanosis, syncope, hypotension due to right ventricular failure. Small or medium sized emboli Pleuritic chest pain, cough and hemoptysis. Investigations: 1. Arterial blood gas analysis- shows hypoxemia. 2. Estimation of D-dimer - it has high negative predictive value. 3. Chest X-ray- a normal or near normal CXR in a dyspneic patient suggests PTE. Well- established abnormalities include focal oligemia (Westermarks sign), a peripheral wedged- shaped density above the diaphragm (Hamptons hump), or an enlarged right descending pulmonary artery (Pallas sign). 4. ECG - sinus tachycardia, right ventricular strain.

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5. Ventilation-perfusion scan - investigation of choice. 6. Pulmonary angiography - is most diagnostic; gold standard investigation. 7. Spiral CT scan. Treatment: Primary therapy Indication- right ventricular dysfunction as diagnosed by echocardiography Therapy 1. Thrombolysis with recombinant tissue plasminogen activator. 2. Embolectomy. Secondary therapy1. Anticoagulants (LMWH, warfarin) are mainstay of treatment in recurrent PTE. They have no role in acute attack. 2. Inferior vena caval filters- The Birds nest filter infrarenally or, if necessary, a Greenfield filter suprarenally are recommended to prevent recurrent embolism in those with contraindication to anticoagulant therapy. Primary Pulmonary Hypertension (PPH) By definition pulmonary hypertension is defined as a mean pulmonary artery pressure in excess of 25 mmHg at rest. More importantly, during exercise there is a rapid rise in pulmonary artery pressure as the pulmonary blood flow increases with cardiac output. Clinical feature: Typical patient is female aged 20-40 years. Symptoms - unexplained breathlessness at the onset followed by symptoms of right ventricular failure, including syncope, angina-like chest pain, and peripheral edema. General malaise and cachexia of cardiac failure are end stage symptoms. Sign - loud second heart sound. Diagnosis: The ECG shows right ventricular strain and RBBB pattern. Chest radiography shows large pulmonary arteries. The screening test is transthoracic echocardiography with Doppler estimation of the tricuspid valve regurgitant flow velocity.

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Ventilation and perfusion lung scintigraphy followed by a diagnostic right heart catheter. Treatment: Anticoagulation therapy. Vasodilators like nifedipine and diltiazem. Prostacyclin.

DISORDERS OF PLEURA
PLEURAL EFFUSION The normal volume of pleural fluid is 20-30 ml.
Differential diagnoses of pleural effusions
Features Pleural fluid protein Pleural fluid protein: Serum protein Pleural fluid LDH: Serum LDH Fluid LDH concentration Causes Transudative < 30 gm/L <0.5 Exudative > 30 gm/I >0.5

<0.6 <200 IU

>0.6 >200 IU

1. Congestive heart failure 2. Cirrhosis 3. Pulmonary embolization 4. Nephrotic syndrome 5. Peritoneal dialysis 6. Superior vena cava obstruction 7. Myxedema

1. Neoplastic diseases a. Metastatic disease b. Mesothelioma 2. Infectious diseases a. Bacterial infections b. Tuberculosis 3. Gastrointestinal disease a. Esophageal perforation b. Pancreatic disease 4. Collagen-vascular diseases 5. Others - Sarcoidosis, Uremia, Meigs syndrome, Drug-induced pleural disease, Chylothorax

Pleural Fluid Examination Macroscopic appearance: Transudates are clear, straw-colored fluids that do not clot on standing. Exudates may be turbid due to presence of cells; bloodstained fluid is seen in malignancy (mesothelioma) and acute pancreatitis.

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Biochemistry: The glucose concentration in the pleural fluid is < 16 mmol/l in rheumatoid arthritis, tuberculosis, empyema, malignancy, and lupus. Increased pleural fluid amylase is seen in acute pancreatitis, pancreatic pseudocyst, or esophageal rupture. Presence of cholesterol crystals in pleural fluid may be seen in tuberculosis, rheumatoid arthritis and myxedema. In tubercular effusion there may be TB markers in the pleural fluid (adenosine deaminase > 45 IU/L, gamma interferon> 140 pg/mL). Microscopic and cytological examination: Most transudates have cell counts of less than 1000/mm 3 , with the cells being a mixture of lymphocytes, polymorphs, and mesothelial cells; exudates tend to have higher white cell counts. A polymorphonuclear leucocytosis is indicative of a bacterial infection, pulmonary infarction or pancreatitis. Predominant lymphocytosis may be seen in tuberculosis, malignancy including lymphoma and after by-pass surgery. Chest X-ray At least 200 ml of fluid is required to produce a change in CXR (blunting of the costophrenic angle). Best CXR view for minimal pleural fluid to be visualized is lateral decubitus view. Best view for CXR to detect interlobular effusion is reverse lordotic. Drainage In patients with a large pleural effusion or a pneumothorax, the most usual site is in the axilla, in a triangle bounded by the anterior axillary line, the lateral margin of the pectoralis major, and a horizontal line at the level of the nipple (usually through 7th IC space in mid-axillary line). An alternative site for an apical pneumothorax is in the second intercostal space in the midclavicular line.

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PNEUMOTHORAX Pneumothorax is the presence of gas in the pleural space. A spontaneous pneumothorax is one that occurs without antecedent trauma to the thorax. A primary spontaneous pneumothorax occurs in the absence of underlying lung disease, while a secondary spontaneous pneumothorax occurs in its presence. A traumatic pneumothorax results from penetrating or nonpenetrating chest injuries. A tension pneumothorax is a pneumothorax in which the pressure in the pleural space is positive throughout the respiratory cycle. Primary Spontaneous Pneumothorax Cause: Rupture of apical pleural blebs. It occurs almost exclusively in smokers. Recurrence is common after treatment. Clinical feature: Symptom - sudden onset of chest pain and breathlessness. Sign reduced breath sounds. Treatment: i. Initial therapy - simple aspiration. ii. Recurrent disease Pleurodesis by doxycycline or talc. Pleuredectomy with stapling- definitive treatment. Note: agents used for pleurodesis are tetracycline, talc, c. parvum, mustine HCl. Secondary Spontaneous Pneumothorax Cause: COPD (open type). Treatment: Tube thoracostomy and the instillation of a sclerosing agent such as doxycycline or talc. Thoracoscopy with bleb resection and pleural abrasion for patients with persistent air leak or recurrent disease.

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Traumatic Pneumothorax Cause: Penetrating or non-penetrating chest injuries; may be iatrogenic. Treatment: Tube thoracostomy (intercostal drainage) through the 2nd intercostal space. Tension Pneumothorax Cause: It occurs during mechanical ventilation and resuscitative efforts. Feature: Pressure in the pleural space is positive throughout the respiratory cycle resulting in decreased venous return to heart. Treatment: It is a medical emergency; a large bore needle is inserted through the 2nd intercostal space. Definitive treatment is tube thoracostomy. EMPYEMA Etiology: Most common cause is postpneumonia (Staph. aureus is the causative agent under 2 years of age). Diagnosis: Fever persisting even after treatment of pneumonia likely to be empyema. Treatment: Acute- water seal drainage.

MEDIASTINAL DISORDERS
MEDIASTINAL MASSES
Mediastinum and its masses Anterior mediastinum Contents Remnant of the thymus gland, Branches of the internal mammary artery, veins, and associated lymph nodes. Middle mediastinum The pericardium, Ascending aorta and aortic arch, The vena cavae, The brachiocephalic vessels, and the pulmonary arteries and veins, The trachea and Posterior mediastinum The descending thoracic aorta, Esophagus, Azygos veins, Thoracic duct, lymph nodes, and Autonomic nerves. Contd...

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Contd... Anterior mediastinum Middle mediastinum Posterior mediastinum

Masses

major bronchi with their associated lymph nodes, The phrenic nerves and the vagus nerve. Thymoma (most Vascular masses Neurogenic common), (e.g. aortic tumors Lymphoma, aneurysm) - most (neurilemmoma Teratoma, common, most Thyroid masses Meningoceles, common, Lymph node neurofibroma), enlargement, Gastroenteric Mediastinal cysts cysts, (pericardial and Esophageal bronchogenic cysts) diverticula.

Thymoma Most common mediastinal mass. Site: The superior portion of the anterior mediastinum. Pathology: Composed of two types of cells i.e. epithelial cells and variable infiltrate of lymphocytes X-ray: The sail sign, the wave sign, the notch sign. Associated with: Myasthenia gravis is the commonest (incidence 5-15%), Graves disease, hypogammaglobulinemia (immunodeficiency), aplastic anemia, pure red cell aplasia, thrombocytopenia, systemic lupus erythematosus, and polymyositis. Bronchogenic Cyst Site: Most common site is the middle mediastinum behind carina or mainstem bronchi; also occurs in lungs. Feature: They are lined by respiratory epithelium and may contain inspissated mucus. They are not premalignant. Complication: Chance of recurrent infection. Chest X-ray: CXR shows air-fluid level which differentiates them with pericardial cysts. Treatment: Surgical excision.

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MEDIASTINITIS Causes Acute: 1. Esophageal perforation - most common cause. 2. Medial sternotomy for cardiac surgery. Chronic: 1. Granulomatous inflammation of lymph nodes - most common cause is tuberculosis or histoplasma; other causes are sarcoidosis, silicosis, and other fungal diseases. 2. Fibrosing mediastinitis. Note: Most common cause of mediastinal fibrosis is histoplasma. PNEUMOMEDIASTINUM Cause: 1. Alveolar rupture, 2. Perforation or rupture of esophagus. Clinical feature: Hammans sign - a crunching or clicking noise synchronous with the heartbeat and best heard in the left lateral decubitus position. DIAPHRAGM Diaphragmatic Paralysis
Diaphragmatic paralysis Bilateral Less common. Commonly due to high spinal nerve injury. May produce hypercapnic respiratory failure Unilateral More common. Most commonly due to nerve invasion by bronchogenic carcinoma. Usually asymptomatic. Diagnosis: Sniff test- when a patient is observed with fluoroscopy while sniffing, the paralyzed diaphragm moves paradoxically upward (paradoxical breathing).

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Congenital Diaphragmatic Hernia Openings: 1. Through the foramen of Morgagni - anteriorly Cause - defect in the sternal origin of diaphragm. 2. Through the foramen of Bochdalek - posteriorly, behind the lateral arcuate ligamentmost common type. Cause - persistence of pleuroperitoneal canal. Clinical features: It is seen more often on the left side. Triad of i. Respiratory distress (slow, gasping respiration), ii. Apparent dextrocardia (due to mediastinal shift to the right) and iii. Scaphoid (flat) abdomen. . Pathology: It may produce hypoplasia of the lung. Diagnosis: Chest X-ray shows - multiple air-containing lesions (intestine) in chest. Treatment: Urgent nasogastric suction followed by surgery.

MISCELLANEOUS DISORDERS
Sleep Apnea Syndrome It is defined as temporary pause in breathing during sleep lasting at least 10 seconds. Types: 1. Obstructive sleep apnea is due to occlusion of the upper airway usually at the level of the oropharynx. Cause In infants - pre-maturity. In adults - alcohol, obesity. 2. Central sleep apnea is due to transient abolition of central drive to the ventilatory muscles. Clinical features: Recurrent episodes of nocturnal asphyxia and arousal from sleep. Tachyarrhythmias. Pulmonary hypertension, mild to moderate systemic hypertension. Diagnosis: Polysomnography.

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Acute Respiratory Distress Syndrome Also known as-shock lung or diffuse alveolar damage. Etiology:
Conditions that may lead to the acute respiratory distress syndrome Direct injury to alveolar epithelium Aspiration of gastric contents Diffuse pulmonary infection Near drowning Pulmonary contusion Toxic inhalation Indirect lung injury Sepsis syndrome Severe nonthoracic trauma Hypertransfusion Pancreatitis Cardiopulmonary bypass

Pathophysiology: Increased vascular permeability to proteins leading to transudation of albumin in alveoli and terminal bronchioles. Pathology: Lungs are heavy, edematous, atelectic - stiff lung. Formation of hyaline membrane composed of fibrin. Clinical features: Earliest sign - increase in respiratory frequency followed shortly by dyspnea (acute onset), Arterial blood gas - decreased PO2 and decreased PCO2 LV function is normal, It is the most common cause of non-cardiogenic pulmonary edema with normal PCWP . Chest X-ray: Fields are either clear or show only minimal and scattered interstitial infiltrates in early stage; diffuse infiltrates in late stage. Differential diagnosis:
Recommended criteria for acute lung injury (ALI) and acute respiratory distress syndrome (ARDS)
Timing Oxygenation ALI Criteria Chest radiograph Pulmonary arterial occlusion pressure

Acute PaO2/FIO2 Bilateral infiltrates onset 300 mmHg seen on frontal (regardless of chest radiograph PEEP level) Acute Pao2/FIO2

ARDS

l8 mmHg when measured or no clinical evidence of left atrial hypertension Bilateral infiltrates l8 mmHg when

Contd...

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Contd...
Timing Oxygenation Criteria onset Chest radiograph Pulmonary arterial occlusion pressure measured or no clinical evidence of left atrial hypertension

200 mmHg seen on frontal (regardless chest radiograph of PEEP level)

NOTE: PaO2, arterial oxygen tension; FIO2, inspiratory O2 fraction; PEEP , positive end expiratory pressure.

Treatment: Once the X-ray shows diffuse, extensive, bilateral interstitial and alveolar infiltrates, hypoxemia cannot be corrected by increasing O2 concentration of inspired gas and mechanical ventilation is needed. O2 concentration used to treat is 50-100 mmHg PEDIATRIC DISORDERS Hyaline Membrane Disease: (Respiratory Distress Syndrome) It occurs most commonly in pre-mature infants. Risk factors: Maternal diabetes, Asphyxia, Acidosis, Hypothermia, Delivery by caesarean section, Breech delivery. Pathology: Deficiency of pulmonary surfactant. Pathophysiology: Same as ARDS. Pre-natal assessment of lung maturity: Lecithin: Sphingomyelin ratio >2.0 indicates maturity of lungs; Presence of phosphatidyl glycerol; Shake or Bubble test - +ve test indicates lung maturity. Clinical feature: Respiratory distress which occurs within 6 hours of birth with respiratory rate> 60/min. Chest X-ray: Ground glass appearance (also seen in pneumonia, obstructive TAPVC);

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Reticulonodular pattern in mild disease and white out lungs in severe disease. Treatment: O2 therapy (usually 90%). Transient Tachypnea of Newborn It is seen in term infants due to delayed clearance of lung fluid as in caesarean section. Clinical feature: Tachypnea starts few hours after birth and rarely lasts beyond 48 hours; no or minimum respiratory distress. Chest X-ray: CXR shows increased vascular markings. Treatment: Treatment is symptomatic. Prognosis: Prognosis is good. Meconium Aspiration Syndrome It is the most common cause of respiratory distress in mature newborn. It is common in post-dated and smallfor-date babies. Clinical feature: Respiratory distress within 24 hours of birth. Chest X-ray: CXR shows bilateral pneumonia; may cause air-leak (pneumomediastinum). Treatment: IV fluids, oxygen and IPPV, if needed. Bronchopulmonary Dysplasia It occurs in premature infants. Diagnosis: Oxygen requirement beyond 36 weeks postconceptional age or beyond 28 days of life. Cause: Barotraumas and oxygen toxicity. Chest X-ray: Pulmonary edema due to capillary damage. Treatment: Frusemide, salbutamol, steroids. Hypoxemic-ischemic Encephalopathy Etiology: Perinatal asphyxia.

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Clinical features: Cerebral cortical damage hypertension infants assume extensor posture. Surfactant Composition: A mixture of dipalmitoyl phophatidyl choline (DPPC), other lipids and proteins. Site: Lining the alveolar membrane. Source: Secreted by type II alveolar epithelial cells. Surfactant production starts at 20 weeks of intranatal life and peaks at 35 weeks. Action: Lowers the surface tension and prevents alveolar collapse. Control: Maturation of surfactant in lungs is accelerated by glucocorticoids. Surfactant level is decreased in smoking. MECHANICAL VENTILATION Indications a. Hypoxemic respiratory failure: 1. Severe pneumonia 2. Pulmonary edema 3. Respiratory distress syndrome causing V/Q mismatch and shunt b. Hypercarbic respiratory failure: 1. Asthma and COPD 2. Restrictive lung disease 3. Neuromuscular diseases Ventilator Modes
Characteristics of different ventilatory modes
Ventilator mode Independent variables (Set by user) FIO2 Tidal volume Ventilator rate Level of PEEP Inspiratory flow Dependent variables (Monitored by user) Advantages Disadvantages Initial settings

ACMVa

Peak airway Timer backup Not useful pressure, Patient-vent for weaning PaO2, PaCO2 synchrony Potential for Mean airway Patient dangerous pressure controls respiratory

FIO2=1.0b Vt = 10 -15 mL / Kga f = 12 15 /min PEEP

Contd...

Respiratory System
Contd...
Ventilator mode Independent variables (Set by user) Dependent variables (Monitored by user) Advantages

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Disadvantages Initial settings

SIMVa

CPAP

PCVa

PSV

= 0-5 cm H2 O Inspiratory flow = 60 L/min Same as for Same as for Timer backup Potential Same as ACMV ACMV useful for dysynchrony for weaning ACMVa FIO2 Tidal volume Allows No backup FIO2 = 0.5 Level of CPAP Rate, flow assessment of 1.0b CPAP pattern spontaneous = 5 15 cm Airway function H2 O pressure Helps prevent PaO2, atelectasis PaCO2, I/E ratio FIO2 Tidal volume System Requires FIO2 =1.0b Inspiratory Flow rate, pressure heavy PC = 20 -40 pressure level pattern regulated sedation cm H2O Ventilator rate Minute Useful for Not useful PEEP = 5Level of PEEP ventilation barotraumas for weaning 10 cm H2O pressure limit PaO2, treatment f = 12 -15 / I /E ratio PaCO2 Timer backup min I /E = 0.7 / 1 -4 / 1 FIO2 Same as for Assure No timer FIO2=0.5Inspiratory PCV + I /E synchrony backup 1.0b pressure level ratio Good for PS = 10 PEEP pressure weaning 30 cm H2O limit 5 cm H2O usually the level used PEEP = 0-5 cm H2 O

pattern, Peak I/E ratio inspiratory flow Pressure limit

minute ventilation

alkalosis

open lung ventilation (OLV) involves the use of any of these specific types of tidal volumes (or applied pressure) to achieve 5-6 ml/kg, and positive end expiratory pressures achieve maximal alveolar recruitment. FIO2 is usually set to 1.0 initially, unless there is a specific indication to minimize FIO2 such as history of chemotherapy with bleomycin. Once adequate oxygenation is documented by blood gas analysis, FIO2 should be decreased in decrements of 0.1-0.2 as tolerated, until the lowest FIO2 required for an SaO2 > 90 percent is achieved.

Abbreviations - f, frequency; l/E, inspiration/expiration. ACMV Assist control mode ventilation SIMV Synchronized intermittent mandatory ventilation CPAP Continuous positive airway pressure PCV Pressure control ventilation PSV Pressure support ventilation

4
PULSE
Type

CARDIOVASCULAR SYSTEM

Arterial Pulse
Special types of arterial pulse Seen in Mitral regurgitation, ventricular septal defect, arteriovenous fistula Aortic regurgitation, hypertrophic cardiomyopathy Aortic stenosis Dilated cardiomyopathy Left ventricular failure Pericardial tamponade, airway obstruction, SVC obstruction

Bounding pulse

Pulsus bisferiens Anacrotic pulse Dicrotic pulse Pulsus alternans (varying pulse pressure with normal rhythm) Pulsus paradoxus (decreased SBP in inspiration)

Note: Bisferiens and alternans pulses are more prominent in peripheral artery (e.g. radial artery).

Jugular Venous Pulse

a x v y c

wave produced by right atrial contraction descent produced by atrial relaxation wave produced by ventricular systole descent produced by ventricular filling wave produced by bulging of TV during isovolemetric contraction of RV

Cardiovascular System
Variants of jugular venous pulse Variant Giant a wave Seen in

213

Cannon a wave

Absent a wave Accentuated x descent Prominent v wave Deep y descent Kussmauls sign (increase in CVP during inspiration)

Tricuspid stenosis, pulmonary hypertension, pulmonary stenosis (all cause increased resistance to atrial contraction) Junctional rhythm, AV dissociation (ventricular tachycardia, complete heart block) Atrial fibrillation Constrictive pericarditis, cardiac tamponade Tricuspid regurgitation, constrictive pericarditis Severe TR, constrictive pericarditis Right ventricular failure, constrictive pericarditis

HEART SOUND First Heart Sound (S1) It is produced by closure of AV valves at ventricular systole. Louder S1 is seen in tachycardia, increased cardiac output, mitral stenosis, short PR interval. Soft S1 is seen in mitral regurgitation, rigidity and calcification of mitral valve leaflets. Reverse splitting of S1 is seen in left bundle brunch block. Second Heart Sound (S2) It is produced by closure of aortic and pulmonary valves at ventricular diastole. Loud P2 is seen in pulmonary hypertension. Fixed splitting is seen in ASD. Variable splitting is seen in VSD. Paradoxical splitting is seen in congenital aortic stenosis, LBBB, hypertension, coarctation of aorta. Wide splitting is seen in ASD, VSD. Reverse splitting is seen in LBBB, right ventricular ectopic beat, systolic hypertension, ischemic heart disease.

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Third Heart Sound (S3) It is produced by termination of rapid filling after A2. It is related to myocardial contraction. Physiological S3 is seen in children and young adults, athletes, pregnancy, fever. Pathological S3 in persons over age 40 years indicates impairment of ventricular function, AV valve regurgitation, constrictive pericarditis (pericardial knock) or heart failure. Fourth Heart Sound (S4) It is a presystolic sound produced during ventricular filling. It is associated with an effective atrial contraction. Pathology: decreased Ventricular compliance and increased resistance to ventricular filling. It is seen in systemic hypertension, aortic stenosis, hypertrophic cardiomyopathy, mitral regurgitation, acute myocardial infarction. Abnormal Heart Sounds

Adventitious heart sounds Type Ejection click Pitch High Time Early systolic Cause Aortic stenosis, pulmonary stenosis, hypertension Mitral stenosis, tricuspid stenosis

Opening snap High

Pericardial knock (S3) Tumor plop Non-ejection click

High Low

Early diastolic (corresponds to dicrotic notch in carotid pulse) Early diastolic Early/mid diastolic Systole

Constrictive pericarditis Atrial myxoma Mitral valve prolapse

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MURMUR Systolic Murmur Early Systolic Acute severe mitral regurgitation (due to papillary muscle/chordae tympani rupture). Ventricular septal defect (small muscular). Tricuspid regurgitation with normal pulmonary artery pressure. Mid/ejection Systolic Semilunar valve stenosis (aortic, pulmonary). Increased flow and hyperkinetic states (e.g. - Stills murmur in children and young adults normal). Hypertrophic cardiomyopathy. Late Systolic Mitral valve prolapse (non-ejection click). Holo/pansystolic AV valve regurgitation (mitral and tricuspid Carvallos murmur). Ventricular septal defect. Diastolic Murmur Early Diastolic Semilunar valve incompetence (aortic and tricuspid regurgitation Graham Steell murmur). Mid Diastolic AV valve stenosis (mitral and tricuspid). Carey Coombs murmur in acute rheumatic fever. Austin Flint murmur in severe/chronic aortic regurgitation. Left atrial myxoma. Atrial septal defect.

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Continuous Murmur Patent ductus arteriosus. Coronary arteriovenous fistula. Atrial septal defect. Ruptured aneurysm of sinus of Valsalva. Coarctation of aorta. Note: Regurgitation murmurs tend to be early where as stenotic murmurs tend to be mid/ejection. ECG PR interval = 0.12 to 0.2 seconds. QRS complex = 0.08 to 0.10 seconds. QRS axis = - 30 to +100. PR = Atrial depolarization + conduction through AV valve. QRS = Ventricular depolarization + atrial repolarization. QT = Ventricular depolarization + ventricular repolarization. ST = Ventricular repolarization. Cardiac Hypertrophy LVH = SV1+(RV5 or RV6) 35 mm. Bundle Branch Block LBBB - wide, predominantly negative QS complexes in V1 and entirely positive R complexes in lead V6. Myocardial Ischemia Transmural- ST elevation, hyper acute T wave. Subendocardial - ST depression (elevation in aVR). Metabolic Changes Hyperkalemia K+ > 7 mEq/L = starts with tall T wave (Tenting of T wave), prolong PR and QRS. K+ > 8.5 mEq/L = absent P wave, broad QRS complex, sine- wave pattern, ventricular fibrillation or asystole.

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Hypokalemia K+ prolongs ventricular repolarization (QT prolongation) with prominent U wave actually there is QU prolongation. Flattening or inversion of T wave, ST depression, prolongation of PR, decreased voltage and widening of QRS.
Causes of QT change QT prolongation QT shortening

1. Hypokalemia 1. Hypercalcemia 2. Intracranial bleeding 2. Digitalis toxicity particularly subarachnoid (scooping of the ST-T hemorrhage wave complex) 3. Hypothermia (Osborn wave)-J wave 4. Hypocalcemia (ST prolongation)

Causes of Electrical Alternans Cardiac tamponade, often in pericardial effusion. DISORDERS OF RHYTHM Bradycardia = <60 beats/min; Tachycardia = >100 beats/ min. Sinus Bradycardia Causes Hypothyroidism - myxedema Advanced liver disease Hypothermia Typhoid fever Brucellosis Athletes

Treatment: Permanent pacemakers are the mainstay of therapy for patients with symptomatic sinus node dysfunction. AV Conduction Disturbances Etiology Levs disease: Calcification and sclerosis of fibrous cardiac skeleton.

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Lenegres disease: Sclerosis of conducting system without involvement of the myocardium or fibrous skeleton. Heart Block First-degree block prolongation of AV conduction (PR interval >0.25 seconds). Mobitz second-degree block Type I (Wenckebach phenomenon) progressive PR interval prolongation prior to block of an atrial impulse. Type II disease of His-Perkinje system. QRS prolongation (conduction fails without prior PR changes). Type III (third degree or complete block) may produce syncope (Stokes - Adams syndrome). The ventricle beats at a low rate independent of atria known as idioventricular rhythm. Idioventricular rate: In AV nodal block = 45 beats/min. In infranodal block = 35 beats/min. Treatment: Pacing. Indication of permanent pacing: 1. AV block in adults- complete heart block. 2. After myocardial infarction - with partial or complete AV block bundle brunch block. 3. Sinus node dysfunction - Sick sinus syndrome. 4. Hypertensive carotid sinus and neovascular syndromes. TACHYARRHYTHMIAS Atrial Premature Complexes APCs can be found on 24-hour Holter monitoring in over 60 percent of normal adults. Ventricular Premature Complexes (Ventricular Ectopics) They are followed by a compensatory pause and SA node discharges normally. APC and VPCs are not strong enough to produce a pulse at the wrist.

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Diagnosis: 24 hour Holter monitoring. ECG: Wide (>0. 14s), bizarre QRS complexes not preceded by P waves and a fully compensatory pause. Treatment: Indications More than 5 beats/minute, occurring in pairs, R-on-T phenomenon in ECG. -blockers are the drug of choice. Atrial Fibrillation Causes: Normal individual Acute alcohol intoxication Rheumatic heart disease Hypertension Atrial septal defect Constrictive pericarditis Mitral valve diseases (e.g. MS) Myocardial infarction Clinical feature: Pulse 350-600 beats/min. ventricular rate 80-160/min. ECG Atrial activity - wavy irregular baseline with no discrete P waves. Ventricular activity - irregularly irregular (variable RR). Treatment:
No severe cardiovascular complication Severe cardiovascular complication

Slowing of ventricular rate by -blockers/CCBs/Digitalis Successful Conversion to sinus rhythm by quinidine/flecainide

DC cardioversion t/t of choice Fails in 24 hrs

Amiodarone is used in resistant AF and to prevent recurrence. When presented late (>48 hrs) anticoagulants (aspirin) should be started to prevent embolization.

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Atrial Flutter Clinical Feature: Atrial rate 250-350 beats/min. Ventricular rate 1/2 of that, i.e. about 150 beats/min. ECG: Saw tooth like flutter waves with variable AV block. Treatment: DC cardioversion t/t of choice. Atrial pacing - in patient with open heart surgery or acute myocardial infarction. Drugs to reduce ventricular rate (as above) and to restore sinus rhythm. Digitalis is least effective and occasionally converts atrial flutter to fibrillation. Paroxymal Supraventricular Tachycardia (PSVT) In PSVT impulses arise from SA node, atria and AV node. AV nodal re-entry (circus movement) Most common cause of paroxysmal arrhythmia. Tachycardia @ 120-250 beats/min. ECG: Tachycardia with narrow QRS. Treatment:
No Mild hypertension hypertension Carotid sinus massage IV phenylephrine Valsalva maneuver Ocular pressure If fails Adenosine drug of choice Atrial or ventricular pacing via a temporary Severe ischemia and/or hypertension DC cardioversion

pacemaker.

-blockers and verapamil are second line drugs. WPW syndrome (pre-excitation syndrome) There is an additional muscular nodal tissue (Bundle of Kent) between atria and ventricles. ECG: Short PR interval (< 0.12s) and broad QRS (> 0.12s but < 0.14s) with a slurred upstroke of the QRS complexes- delta wave. Treatment: For symptomatic patients only: Drugs to reduce conduction flecainide, amiodarone (digitalis and verapamil should be used cautiously as they may reduce ERP of the aberrant pathway).

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With AF DC cardioversion or procainamide (drug of choice)/lignocaine. Permanent cure radiofrequency catheter ablation of the aberrant tract treatment of choice. Ventricular Tachycardia Clinical feature: Intermittent cannon a wave and varying S1 suggests AV dissociation and is diagnostic of VT. Pulse rate 160-240 beats/mean. ECG: Characteristic 12 lead ECG shows i. AV dissociation ii. Capture/fusion beats iii. QRS > 0.14s iv. Extreme left axis deviation v. Concordance of QRS complexes in all precordial leads. Treatment: For symptomatic patients only With organic heart disease -blockers, verapamil, procainamide, flecainide, amiodarone. Without organic heart disease: Presence of ischemia/CHF/CNS hypoperfusion DC cardioversion. Well tolerated IV lignocaine is the drug of choice. Torsades de Pointes ECG:VT characterized by polymorphic QRS complex with QT prolongation. Precipitating factors: i. Hypokalemia ii. Amiodarone iii. Chlorpromazine iv. TCAs (Mnemonic - CATcH) v. Quinidine. Treatment: -blockers. Prolonged QT Syndrome Congenital (Romanoward syndrome). Treatment: -blockers. Acquired caused by drugs, hypokalemia. Treatment: Atrial or ventricular overriding pacing and magnesium.

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Ventricular Fibrillation (Cardiac Arrest) Cause: In patients with severe hypoxia or ischemia. It is the most common cause of cardiac arrest and sudden cardiac death. Management: Immediate defibrillation - asynchronous DC cardioversion (use CPR before arrangements are ready) fails 2 or more DC shock + CPR fails IV adrenaline Defibrillation within 30-60 sec fails Other drugs like procainamide, lignocaine, bretyllium, mag sulph, NaHCO3 can be tried. HEART FAILURE Etiology In infants: i. Congenital heart diseases. Note: Most common cause in first week of life is hypoplastic right/left ventricle. Patent ductus arteriosus is the most common congenital heart disease to produce CCF. ii. Myocarditis iii. PSVT In children: Most common cause is rheumatic heart disease. Clinical Feature Left heart failure - it is indicated by PCWP > 20 mmHg. In infants manifested by tachypnea and tachycardia. In adults manifested by pulmonary congestion (cough, wheezing, rales). Right heart failure: In infants manifested as hepatomegaly, facial edema. Pedal edema appears late. In adults manifested as facial and pedal edema, congestive hepatomegaly, systemic venous distension, and oliguria.

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Framingham criteria: Major 1. Paroxysmal nocturnal dyspnea 2. Neck vein distension 3. Rales 4. Cardiomegaly 5. Acute pulmonary edema 6. S3 gallop 7. Positive hepatojugular reflex Pathology Heart failure cells: alveolar macrophages filled with hemosiderin due to phagocytosis of RBCs. Chest X-ray Kerley B line (when left atrial pressure > 20 mmHg). Pleural effusions with interlobular effusion. Chamber enlargement. Prominent pulmonary and apical veins (NOT lower lobe veins).

Treatment Diuretics are the most effective drugs for symptomatic relief in cases of moderate to severe CHF. Combination of diuretics and ACE inhibitors is used for initial therapy. Digitalis is not used in primary therapy. It is used in persistently symptomatic patients and cases associated with atrial fibrillation. Digitalis reduces morbidity due to CHF but does not increase life expectancy. Drugs that reverse the disease progression and improve survival are - ACE inhibitors, AT1 antagonists, blockers - metoprolol, bisoprolol and carvedilol; aldosterone antagonists spironolactone. Digitalis Mechanism of action: Inhibition of Na+-K+ ATPase. Glycosides prolong the effective refractory period of the AV node as a result of vagal effect. This explains the slowing of ventricular rate produced by digitalis in AF or Afl.

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Use in HF: Digitalis is particularly useful in patients with HF accompanied by atrial flutter and atrial fibrillation and a rapid ventricular rate. Poor response in high output failure (anemia). Digitalis Toxicity Occurs when plasma concentration is>2.4 ng/ml. Risk factors: Old age, Hypothermia, Hypokalemia (most common cause), Acute MI, Hypoxemia, Renal insufficiency, Hypocalcemia. Symptoms: Anorexia, nausea, vomiting - earliest symptoms. Headache, Visual disturbance. ECG: Ventricular premature beats (most frequent finding). VT, VF, AV block bradycardia. Non-paroxysmal atrial tachycardia with variable AV block is characteristic. PR interval widening to 1/2 times the initial PR interval. Treatment: withdrawal of the drug. For tachyarrhythmias - infusion KCl. For VF/VT Lignocaine. For PSVT propanolol. For AV block- atropine. Fab fragments - digitalis antibodies. Diuretics and hemodialysis are not very effective. Acute Pulmonary Edema Treatment: Morphine 100 percent O2 in sitting position. Positive pressure ventilation. IV frusemide. IV Na-nitroprusside.

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Dopamine/Dobutamine. Rotating tourniquets in extremities. EXTRACARDIAC ASSOCIATIONS


Extracardiac associations Syndrome Noonan syndrome Cardiac manifestation Extracardiac manifestation

Osler-RenduWeber syndrome Williams syndrome

Ehlers-Danlos syndrome Marfans syndrome

Homocystinuria Cri-du-chat syndrome

Downs syndrome

Turners syndrome

Congenital rubella

Lithium

Pulmonary stenosis, Antimongoloid slant, cardiomyopathy short stature, webbed (usually hypertrophic) neck, pectus excavatum, cryptorchidism (mnemonic ASNEC) AV fistula Multiple telangiectasias high output failure Supravalvular aortic Elfin facies, idiopathic stenosis hypercalcemia, mental retardation Arterial dilatation Hyperextensible joints, and rupture, hyperplastic and mitral regurgitation friable skin Aortic dilatation, Arachnodactyly with aortic and mitral hyperextensibility, incompetence lens subluxation Intravascular Lens subluxation, thrombosis osteoporosis Ventricular septal Moon face, broad chest, defect cat like cry, microcephaly, antimongoloid slant Atrial septal defect Mental retardation of endocardial and other features cushion type Coarctation Short stature, primary of aorta amenorrhea, shield chest and other anomalies Patent ductus Sensorineural deafness, arteriosus, VSD, cataract, glaucoma pulmonary stenosis and other features Ebsteins anomaly Hypothyroidism

CONGENITAL HEART DISEASES Classification I. Acyanotic with left to right shunt: 1. Atrial septal defect 2. Ventricular septal defect 3. Patent ductus arteriosus

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II. Acyanotic without shunt (obstructive) 1. Congenital aortic stenosis 2. Coarctation of aorta 3. Pulmonary stenosis III. Cyanotic with right to left shunt: A. With pulmonary stenosis (decreased pulmonary blood flow): 1. Fallots tetralogy 2. Tricuspid atresia 3. Ebstein s anomaly B. With pulmonary hypertension: Eisenmenger syndrome C. With increased pulmonary blood flow: 1. Complete transposition of great vessels 2. Total anomalous pulmonary venous connection Causation Multifactorial. Strongest genetic influence is seen in Holt-Oram syndrome. Strongest environmental influence is high altitude increased chance of PDA and ASD. ACYANOTIC WITH LEFT TO RIGHT SHUNT Atrial Septal Defect Ostium primum - lies immediately adjacent to the AV valves, either of which can be deformed. Ostium secundum most common type, defect involving fossa ovalis. Pathology: Right atrial and ventricular hypertrophy with normal left atrium. Clinical features: Most cases are asymptomatic. More common in patients with Downs syndrome. S2 - widely split and fixed. Murmurs - no shunt murmur, only flow murmurs. Delayed diastolic murmur (TV), ejection systolic murmur (PV). Parasternal impulse.

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Chest X-ray: Pulmonary plethora is characteristic because pulmonary flow > systemic flow.
Associations of ASD Lutembacher syndrome Holt-Oram syndrome Ellis Van Crevald syndrome Osteum secondum defect ASD with bony defect ASD with single atrium

ECG: Ostium primum - RBBB with left axis deviation beyond 30. Ostium secundum - right axis deviation with right ventricular hypertrophy. Fluoroscopy: Hilar dance sign. Complications: CCF and infective endocarditis are very rare with ASD. Treatment: Operation between the ages of 2-5 years for all patients with uncomplicated atrial septal defect. Contraindication - small defect and trivial left to right shunt, severe pulmonary vascular disease (pulmonary hypertension with increased pulmonary vascular resistance) without significant left to right shunt. Ventricular Septal Defect Most common congenital defect. 90 percent situated in the membranous part. Maladie de Roger = small VSD. Clinical feature: Highest frequency in Downs patients. Pansystolic murmur at left sternal border. S2 widely split and variable. Course: 70-80 percent cases undergo spontaneous closure. Patient may develop pulmonary stenosis. Complications: VSD is the most common cause of infective endocarditis, may also develop CCF.

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Chest X-ray: Increased cardiac silhouette of LV type, pulmonary plethora.


Complications of CHD Infective endocarditis Most common cause Least common cause Ventricular septal defect Atrial septal defect Congestive cardiac failure Patent ductus arteriosus Tetralogy of Fallot

Patent Ductus Arteriosus Ductus arteriosus: Bifurcation of pulmonary artery to the aorta just distal to left subclavian artery. Closure - physiologically it closes soon after birth (by bradykinin). Anatomically it closes in 1-3 months. It forms ligamentum arteriosum. It is kept patent by PGE2 and PGI2. Pathology: Blood flows from aorta to pulmonary artery (aorto-pulmonary window) Clinical feature: Continuous murmur. Diffirential cyanosis - in reversal of shunt. Complications: Most common congenital disease to produce CCF , pure LVF may occur. Bacterial endocarditis. Treatment: Indomethacin may help in closure if treated within 2 weeks after birth. It is kept patent by Alprostadil (PGE1) before surgery is undertaken. Surgery: Complication - recurrent laryngeal nerve injury. Contraindication - reversal of shunt. ACYANOTIC WITHOUT SHUNT Congenital Aortic Stenosis Clinical feature: Paradoxically split S2. May cause sudden death in children.

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Coarctation of Aorta Site: Most common distal to the origin of the left subclavian artery. Coarctation syndrome: Coarctation of aorta is associated with other cardiac anomalies, most commonly a bicuspid aortic valve. Others are PDA, VSD, tubular hypoplasia of aortic isthmus. It is seen in patients with Turners syndrome. Clinical feature: Mostly asymptomatic. Symptoms - intermittent claudication, dyspnea on running, headache, epistaxis, cold extremities. Sign- hypertension in the upper extremities. Absence, marked diminution or delayed pulsation in the femoral artery. Enlarged and pulsatile collateral in intercostals spaces, axillae and interscapular area may be palpated. Supex and thorax may be more developed than infex. X-ray: characteristic E sign or 3 sign. Ribs - notching at the lower border due to erosion by dilated collateral vessels. Typically involves 4th-8th ribs bilaterally. Double bulging. Heart size remains normal but LVH may be present.
Causes of rib notching Superior notching Marfans syndrome Rheumatoid arthritis Systemic lupus erythematous Systemic sclerosis Neurofibromatosis Inferior notching Coarctation of aorta Tetralogy of Fallot Takayasus arteritis Superior/inferior venacaval obstruction Arteriovenous fistula Hyperparathyroidism Atheroma

Complications: Rupture of aneurysm in circle of Willis, rupture of aorta, left ventricular failure, infective endocarditis. Treatment: Surgical. Surgery may not cure hypertension.

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Pulmonary Stenosis Association with Noonans syndrome. Site: Supravalvular (uncommon), valvular (most common) and subvalvular. Most common associated cardiac anomaly is atrial septal defect. CYANOTIC WITH RIGHT TO LEFT SHUNT Tetralogy of Fallot Most common congenital cyanotic heart disease. Components: 1. Ventricular septal defect. 2. Pulmonary stenosis (outflow obstruction). 3. Overriding or dextroposed aorta. 4. Right ventricular hypertrophy (without enlargement). Clinical feature: Commonest symptoms are dyspnea on exertion, syncope (most common congenital heart disease to produce syncope). Patient assumes squatting position. Sign - central cyanosis with clubbing. X-ray: Boot shaped heart (Coeur en sabot). But heart size is normal. ECG: Right axis deviation with right ventricular hypertrophy. Complications: CCF never occurs. No chance of recurrent respiratory tract infection. Treatment: Shunts used in treatment of Fallots tetralogy are 1. Ballock Taussig shunt - between subclavian and pulmonary artery. 2. Potts shunt - between descending aorta and pulmonary artery. 3. Waterson shunt - between ascending aorta and right pulmonary artery. Tricuspid Atresia Pathology: Hypoplasia of right ventricle, patent foramen ovale or ASD. Clinical feature: Central cyanosis since birth.

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X-ray: Lungs are oligemic. ECG: Left axial deviation, left ventricular hypertrophy, right atrial enlargement. Ebsteins Anomaly Pathology: Downward displacement of tricuspid valve into the right ventricle. Due to anomalous attachment of tricuspid leaflets called atrialization of ventricle. Clinical feature: Progressive cyanosis. X-ray: Marked cardiomegaly. Diagnosis: Intracardiac ECG with pressure recording. Echocardiography. Eisenmengers Syndrome VSD with pulmonary hypertension - right to left shunt. Mechanism: Left to right shunt RV hypertrophy pulmonary hypertension right to left shunt. Transposition of Great Vessels Pathology: Aorta arises from right ventricle and pulmonary artery from left ventricle. Mitral valve is continuous with pulmonary valve. Pulmonary O2 saturation always > systemic arterial saturation. Clinical feature: Central cyanosis with systolic murmur. Chest X-ray: Cardiomegaly, plethoric lung fields and features of pulmonary hypertension. Egg-on-side appearance. Treatment: Confirmation of diagnosis is done by cardiac catheterization and angiocardiography. Prostaglandin E Balloon atrial septostomy (Rashkind) Atrial switch procedure (Mustard) or Jantenes switch procedure - treatment of choice.

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Total Anomalous Pulmonary Venous Connection Pathology: All the pulmonary veins join anomalously to result in all the venous blood ultimately reaching the right atrium. Type: Infracardiac type is always obstructive. Hemodynamics: The O2 saturation of blood in the pulmonary artery that in aorta. Chest X-ray: Non-obstructive type-Snowman heart or figure of 8 heart Obstructive type- ground glass appearance. Anomalous Origin of Left Coronary Artery from Pulmonary Artery Clinical feature: Presents with CCF within first few months of life. Recurrent attacks of abdominal pain, restlessness, irritability, diaphoresis on feeding. Non-specific murmur. X-ray: Cardiac enlargement. Risk: Development of myocardial infarction and fibrosis. RHEUMATIC HEART DISEASE Etiopathogenesis Causative organism - group A -hemolytic streptococcus (Streptococcus pyogenes). Preceding event - URTI (sore throat). Incidence 3 percent. Time interval - 10 days to few weeks. Pathology Fibrosis is common in cardiac tissue in rheumatic fever. Aschoff body: It is the hallmark of acute rheumatic carditis. It may occur in any layer of heart but most common in subendocardial region and myocardial interstitium. It contains Fibrinoid material surrounded by histiocytes Aschoff giant cells Lymphocytes

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Plasma cells Fibroblasts Collagen Anitschkow cells.

Carditis: It is characteristically pancarditis. Pericardium- fibrinous pericarditis with serous or serosanguinous pericardial effusion - bread and butter pericarditis. Endocardium- foci of fibrinoid necrosis. Mitral valve is involved in 100 percent cases. Small wart like vegetations at valve cusp margins. Least commonly involved is pulmonary valve. McCallums plaque: subendocardial lesion in left atrium. It is the hallmark of chronic rheumatic carditis. Clinical Feature Major criteria: 1. Carditis: Pancarditis, early manifestation (within 2 weeks of onset of fever). Myocarditis - Carey Coombs murmur (diastolic). Endocarditis - pansystolic murmur of MR (most common valvular abnormality). Pericarditis - pericardial friction rub. Others - sinus tachycardia, cardiomegaly (most common cause of in children). Note: Rheumatic carditis is aggravated by pregnancy. 2. Migratory polyarthritis: Risk increases with age, no residual damage. 3. Sydenham s chorea: Late manifestation (after 3 months of fever), self-limiting. 4. Erythema marginatum and 5. Subcutaneous nodules: Painless, over extensor surface of joints; appear 4 weeks after onset of fever. Rarely occurs unless active carditis is present. Note: The last 2 features are more common in children. Minor criteria: Clinical- fever and arthralgia Laboratory- increased acute phase reactants (increased polymorphonuclear leucocytes, ESR and C-reactive protein). ECG - prolonged PR interval.

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Diagnosis Jones criteria: 2 major or 1 major and 2 minor criteria are required plus essential criteria as below Evidence of recent streptococcal infection indicated by increased ASO titer, positive throat culture, or recent history of scarlet fever. Chest X-ray: Cardiomegaly (most common cause in children). Complication Mitral stenosis (fish mouth or button hole stenosis) with or without AF - may lead to cerebral embolism. Treatment Aspirin. Steroids - in severe carditis with CCF. Chronic Rheumatic Carditis Characterized by fibrosis. Mitral stenosis is more common than mitral regurgitation (c.f. acute carditis). McCallums patch in left atrium due to chronic valvular involvement is characteristic.
Vegetations Rheumatic fever Small, firm, warty, friable Non-bacterial thrombotic Small, friable Libman Sacks Infective endocarditis endocarditis Large, bulky, irregular On upper surface

Medium size, flat, verrucous, irregular Along the line Along the line On surface, of valve of valve closure both sides of closure cusps; mainly undersurface Sterile Sterile Sterile No destruction Non destructive Destructive of underlying structures Rheumatic Hypercoagulable SLE fever state

Infected Ulceration and perforation Infective endocarditis

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VALVULAR HEART DISEASE Mitral Stenosis Pathology: Normal area of mitral orifice in adults = 4-6 cm2. Left ventricular diastolic pressure is normal in isolated MS. LVH is due to presence of MR, aortic valve disease or systemic hypertension. There is a gradient between PCWP (left atrial pressure) and left ventricular diastolic pressure. Such gradient is also seen in atrial myxoma (see later). Clinical feature: Symptom - hemoptysis. On examination - Accentuated S1. Opening snap- audible in expiration. OS corresponds to dicrotic notch in carotid pulse. Murmur - low-pitched, mid-diastolic, rumbling murmur best heard at the apex and left lateral recumbent position. Graham Steell murmur of PR. Severity of MS: It is assessed by A2-OS gap (inverse relation) and the length of the diastolic murmur. ECG: Right ventricular hypertrophy. Chest X-ray: Straightening of left heart border. Prominence of main pulmonary arteries. Dilatation of upper lobe pulmonary veins. Kerley B line. Echocardiography: most useful. Differential diagnosis: Left atrial myxoma. Mitral Regurgitation Most common valvular defect in rheumatic carditis. Clinical feature: systolic murmur that is most prominent at the apex and radiates into the axilla. Severity of MR: is assessed by presence of pulmonary hypertension, wide split S2, diastolic murmur and S3 gallop.

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Mitral Valve Prolapse (Barlows syndrome/Floppy valve syndrome/Billowing mitral valve) Autosomal dominant trait. Pathology: Myxomatous degeneration of the valve. Clinical feature: More common in females. Mostly asymptomatic. Symptoms- chest pain that is difficult to evaluate. Arrhythmias- palpitation. Auscultation- mid/late systolic click (non-ejection). Late systolic crescendo-decrescendo murmur. Factors regulating murmur: Increased by standing and Valsalva maneuver. Decreased by squatting and exercise (c.f. - HOCM). ECG: Normal. Echocardiography: Investigation of choice. Complication: Transient ischemic attacks Mitral regurgitation Sudden death Infective endocarditis. Aortic Stenosis Etiology: May be due to degenerative calcification of the valve. Pathology: Aortic orifice <0.5 cm2/m2 of body surface area is considered critical to maintain left ventricular outflow. There develops gradient between aortic and left ventricular systolic pressure (also occurs in hypertrophic cardiomyopathy). Clinical feature: Exertional dyspnea, angina pectoris and syncope - 3 cardinal features. Sudden death is common. Poorest symptom is dyspnea. Ejection systolic murmur, sustained systolic thrust (characteristic of severe AS). ECG: LVH. Severity of AS: is assessed by: Symptomatic patients Presence of S3, S4 or systolic thrill

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Delayed peak of systolic murmur Narrow pulse pressure ST and T changes in ECG Cardiac enlargement Note: Exercise tolerance test is absolutely contraindicated in aortic stenosis.

Aortic Regurgitation Etiology: 1. Rheumatic fever- most common cause. 2. Infective endocarditis. 3. Syphilis and ankylosing spondylitis. 4. Marfans syndrome Clinical feature: Water hammer pulse. Widening of aortic pulse pressure to 75-90 mmHg in severe AR. Corrigans pulse at the carotids. Quinckes pulse - alternative flushing and paling of the skin at the root of the nail while pressure is applied. Traubes sign - pistol shot sound over femoral arteries. Palpation- apex beat is heaving. Auscultation - high pitch, blowing, decrescendo, early diastolic murmur. Austin Flints murmur mid diastolic (often mistaken for MS). ECG: LVH. Tricuspid Regurgitation Usually functional and most commonly due to dilatation of right ventricle. COR PULMONALE Etiology: Acute- most common cause is pulmonary embolism. Chronic- most common cause is chronic obstructive pulmonary disease (COPD). Others- obesity, kyphoscoliosis. Chest X-ray: Pulmonary trunk and hilar vessels are enlarged, widening of the descending right pulmonary artery shadow.

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Complication: COPD leads to pulmonary hypertension due to: i. Pulmonary vasoconstriction. ii. Increased cardiac output. iii. Increased blood viscosity caused by polycythemia. CARDIOMYOPATHY AND MYOCARDITIS Dilated Cardiomyopathy Most common type of cardiomyopathy in India. Most common myocardial disease in children. Secondary causes of DCM: 1. Infective myocarditis (all types by virus, bacteria, protozoa, etc.). 2. Metabolic. 3. Connective tissue disorder. 4. Alcohol. 5. Peripartum heart disease. Pathology: Progressive cardiac hypertrophy, dilatation and contractile (systolic) dysfunction. Treatment: Cardiac transplantation (most common indication of cardiac transplantation in children). Alcoholic cardiomyopathy: Without heart failure- consists of recurrent ventricular tachyarrhythmia and follows an episode of binge drinking - Holiday heart syndrome. Note: Most common alcoholic cardiotoxicity is atrial fibrillation. Hypertrophic Cardiomyopathy Also called asymmetric septal hypertrophy or idiopathic hypertrophic subaortic stenosis. Characterized by: 1. Left ventricular hypertrophy with asymmetric septal hypertrophy (ASH). 2. Dynamic left ventricular outflow obstruction due to subaortic stenosis. 3. Abnormal diastolic filling. 4. Systolic anterior motion (SAM) of the mitral valve. Pathology: Atrial dilatation occurs but ventricular dilatation is uncommon.

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Clinical feature: Symptoms most common complaint is dyspnea. Graying out spells- cyanosis On examination- Double or triple apical precordial impulse. Late systolic murmur- best heard at the lower left sternal border.
Factors regulating murmur of HOCM Factors worsening obstruction and increasing murmur Increased myocardial contractility i. Exercise ii. Digitalis iii. Isoprotenanol Decreased ventricular volume (preload) i. Valsalva maneuver ii. Standing iii. Nitroglycerine Factors decreasing obstruction and murmur Increased arterial pressure i. Phenylephrine ii. Squatting iii. Sustained hand grip Increased venous return i. Passive leg rising ii. High blood volume

Treatment: -blockers (propanolol), amiodarone, disopyramide, verapamil and diltiazem. Digitalis is avoided. Restrictive Cardiomyopathy Pathology: Myocardial fibrosis. Characterized by- defective diastolic filling decreased cardiac output and increased filling pressure symmetrical thickening of ventricular walls. Secondary causes: Beriberi Amyloidosis Hemochromatosis Glycogen deposition (Pompes disease) Fabrys disease Sarcoidosis Eosinophilia (eosinophilic endomyocardial fibrosis or Loefflers endocarditis). Friedreichs ataxia

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Muscular dystrophy Cystic fibrosis Tapioca (endomyocardial fibrosis). Myocarditis Cause: Most common cause is Coxsackie B virus infection. Others- rubella, diphtheria, measles, trichinella. Cardiac Hypertrophy Concentric: Due to pressure overload - apex not shifted. Caused by hypertension, aortic stenosis, coarctation of aorta. Eccentric: Due to volume overload - apex is shifted. Caused by Aortic regurgitation. Mitral regurgitation. Anemia. Thyrotoxicosis. Ventricular septal defect. Patent ductus arteriosus. PERICARDIUM Pericarditis Etiology: I. InfectiveViral- Coxsackie virus A and B. Pyogenic (empyema). Tuberculosis. II. Non-infective- uremia. Clinical feature: Friction rub is the most important sign of acute pericarditis. ECG: Widespread (in all leads) elevation of the ST segment in acute pericarditis except in aVR which shows ST depression. PR depression but T wave remains normal until late in the disease (c.f. AMI).

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Pericardial Effusion Pericardial effusion is the most common presentation of radiation carditis. Clinical feature: Heart sounds become faint. Ewarts sign- a patch of dullness beneath the angle of scapula. Signs are obvious when fluid accumulates > 500 ml. Chronic constrictive pericarditis may produce proteinuria. Diagnosis: X-ray - Water bottle configuration. ECG - Electrical alternans (pathognomonic). Two-dimensional transthoracic echocardiography- most sensitive method. Causes of bloody effusion: Tuberculosis. Tumor. Rheumatic fever. Uremic pericarditis. Cardiac Tamponade Etiology: 1. Neoplastic diseases. 2. Idiopathic pericarditis. 3. Uremia. 4. Bleeding into pericardial sac following cardiac operations and trauma (hemopericardium). Clinical feature: Hepatic engorgement. Jugular venous hypertension. Hypotension. Narrow pulse pressure. Pulsus paradoxus- hallmark of tamponade. ECG: Electrical alternans. Diagnosis: 2-D echocardiography - shows right atrial and ventricular diastolic collapse. Treatment: Emergency pericardiocentesis.

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Differential diagnosis

Features Pulsus paradoxus Prominent y descent Kussmauls sign Electrical alternans Pericardial knock Prominent x descent

Cardiac tamponade + ve ve ve May be + ve ve + ve

Constrictive pericarditis ve (only in 1/3rd cases) + ve + ve ve + ve Usually + ve

Chronic Constrictive Pericarditis Etiology: Tuberculosis - most common. Pyogenic - empyema thoracis. Uremia. Clinical feature: Kussmauls sign - venous pressure fails to decline during inspiration. Distended neck veins- Square root sign - in ventricular pressure pulse. Apical impulse- decreased in intensity. Splenomegaly, hepatic engorgement. Ascites. Diagnosis: ECG - low voltage QRS in all leads. No ST change. Echocardiography. CT scan and MRI - most sensitive to detect thickened pericardium. Causes of hemorrhagic pericarditis: 1. Tuberculosis. 2. Malignant involvement of pericardial sac. 3. Bleeding diasthesis. 4. Post-myocardial infarction. 5. Uremia. 6. Cardiac surgery. 7. Dissecting aortic aneurysm. CARDIAC TUMORS Metastatic tumors are more common than primary.

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Metastatic Tumors Source: Carcinoma lung (most common) and breast. Malignant melanoma (high incidence). Lymphomas and leukemias. Primary Tumors Atrial Myxoma Sporadic: Most common primary tumor of heart. Site: Left atrium (most common). Pathology: Usually solitary. Microscopy- composed of mucopolysaccharide rich stroma. Clinical feature: More common in older age group (30-70 years) with female preponderance. May present with peripheral or pulmonary emboli. Clubbing, rash. Raynauds phenomenon. Prolonged fever. ESR increased. Mid-diastolic low pitched sound - tumor plop (c.f. mitral stenosis). Diagnosis: 2-D echocardiography. Treatment: Recurrence is uncommon. Familial: Occurs in younger are group. Usually multiple. Recurrence more common. Associations: NAME syndrome. LAMB syndrome. Rhabdomyoma Most common cardiac tumor in infancy and childhood. In 90 percent cases associated with tuberous sclerosis.

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VASCULAR DISEASES
ATHEROSCLEROSIS Pathology The key processes in atherosclerosis are intimal thickening and lipid accumulation in smooth muscles known as atheroma. Fatty streaks are lipid-filled foam cells. They are the initial lesions in atherosclerosis and may evolve into precursors of atheromatous plaque. Histology: Parts of an atheroma are: i. Fibrous cap - consisting of smooth muscle cells, macrophages and dense collagen. ii. Necrotic centre - consisting of cell debris, cholesterol crystals and foam cells. iii. Tunica media of vessel wall. Risk factors: Hypercholesterolemia. High LDL level - atherogenic fatty acid and low HDL level. High lipoprotein A level. Hyperhomocysteinemia. Obesity, diabetes, hypertension. Pathogenesis: The response to injury hypothesis - ATH is a chronic inflammatory response of the arterial wall initiated by injury to the endothelium. Monckeberg medial calcific sclerosis: Characterized by calcific deposits in muscular arteries. ACUTE MYOCARDIAL INFARCTION Pathology
Pathology of AMI Artery involved Left coronary artery (LCA) anterior descending branch Right coronary artery Site of heart involved Anterior and apical left ventricle, anterior 2/3rd of interventricular septum Posterior wall of left ventricle, posterior 2/3rd of interventricular septum Lateral wall of left ventricle

Left circumflex coronary artery

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Sequence of changes: Earliest irreversible changes in electron microscopy occurs after 1-2 hours.
Sequence of changes Time interval Gross changes 4-12 hours 24-72 hours 4-7 days 7-8 days 10 days 7-8 weeks Microscopic changes

None Early coagulation necrosis Pallor Heavy neutrophilic infiltration Central pallor with Macrophages appear hyperemic border Ingrowth of granulation tissue Yellow shrunken Phagocytes, organization of granulation tissue Gray Fibrosis (healed)

Diagnosis A. ECG: Transmural - Q waves (may be ST elevationhallmark of MI). Non-transmural - absence of Q waves, only ST segment (ST depression) and T wave (T wave inversion) changes. B. Serum cardiac markers: 1. Creatine phosphokinase: Earliest enzyme to appear after MI. CKl or CK-BB - brain and lungs. CK2 or CK-MB - myocardium. CK3 or CK-MM - skeletal muscle and heart.
CK enzymes Appearance Total CK CK-MB 2-4 hours 2-4 hours Peak 24 hours 18 hours Disappearance 48-72 hours 48 hours

CK-MB2 : CK-MB 1 ratio > 1.5 is highly sensitive. However CK is not specific as it is elevated in other conditions like i. Muscular diseases- including muscular dystrophy, myopathy and polymyositis. ii. Skeletal muscle injury. iii. Cardioversion. iv. Clofibrate therapy. 2. Troponins: Cardiac troponin T (cTnT) - heart. Troponin I (cTnI) - skeletal muscle. cTnT is more specific than CK-MB.

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3. 4. C.

Appearance Disappearance cTnT 2-4 hrs 10-14 days Hence TnT is of little value in case of reinfarction. Lactate dehydrogenase: appears last in MI (after 24 hours). AST. Imaging: Two-dimensional echocardiography. Myocardial perfusion scanning with thallium 201 or Tc99m sestamibi - shows cold spots. With Tc99m strontium pyrophosphate shows hot spots.

Management 1. Morphine- to relieve pain. 2. Aspirin, infusion of nitroglycerine , infusion of unfractionated heparin or SC administration of lowmolecular weight heparin, -blockers. 3. Thrombolysis: Indications: MI with ST elevation. Agents: tissue plasminogen activator (tPA), streptokinase, tenecteplase (TNK), and reteplase (rPA). Time: within 1-3 hours (golden hours) of onset of pain is most effective (should be started before 12 hours). Contraindications: i. H/O cerebrovascular hemorrhage at any time. ii. H/O nonhemorrhagic stroke or other cerebrovascular event within past 1 year. iii. Marked hypertension (> 180/110 mmHg). iv. Aortic dissection/internal hemorrhage. v. Relative contraindications recent (< 2 weeks) surgery, current use of anticoagulants, prolonged cardiopulmonary resuscitation, known bleeding diasthesis, pregnancy, a hemorrhagic ophthalmic condition (e. g. hemorrhagic diabetic retinopathy), active peptic ulcer and a history of severe hypertension that is recently adequately controlled. Complications: Hemorrhage- most common. 4. Antithrombotics: i. Antiplatelet agents. ii. Antithrombin . 5. Treatment of complications.

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Complications 1. Cardiac arrhythmias: most common complication of AMI More with subendocardial infarct. Ventricular fibrillation is most common and vast majority of deaths due to ventricular fibrillation occur within 24 hours (>50% occurs within 1 hour) of onset of symptoms. Treatment: Lignocaine is the drug of choice. For ventricular ectopic after MI drug of choice is -blocker. 2. Left ventricular failure with pulmonary edema: Treatment of choice - intra-aortic balloon pump. 3. Cardiogenic shock: Treatment- dopamine, intra-aortic balloon pump. 4. Right ventricular infarction: Occurs in 1/3rd cases of inferior wall MI. Features: Increased JVP , Kussmauls sign, hepatomegaly, cardiomegaly and arrhythmia. Treatment: IV fluid. 5. Mitral regurgitation: Occurs in 10-50 percent cases. Most common valvular defect after MI. It is due to papillary muscle rupture. 6. Dresslers syndrome (post-myocardial infarction syndrome): Characterized by- fever and pleuropericardial chest pain. Cause- autoimmune pericarditis Time- develops from a few days to 6 weeks after infarction. Treatment- responds promptly to salicylates. 7. Thromboembolism: Arterial emboli occur most commonly in anterior MI. Both arterial and pulmonary embolisms occur in septal MI. 8. Ventricular aneurysm: ECG shows persistent ST elevation. 9. Myocardial rupture: Occurs in first week. Characterized by sudden loss of pulse and drop in BP; electromechanical dissociation in ECG. ISCHEMIC HEART DISEASE Etiology: Atherosclerosis most common cause. Critical narrowing - >80 percent of the lumen of coronary artery.

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Angina Pectoris Stable angina: Clinical feature: Pain lasts for 1-5 minutes. ECG: ST segment depression (plateau or square wave). Unstable angina: i. Patients with new onset (<2 months) angina that is severe and frequent (3 episodes/day). ii. Patients with accelerating angina. iii. Angina at rest. Prinzmetals variant: It represents transmural ischemia. Ischemic pain occurring at rest, often in sleep. ECG: Multilead ST-elevation during pain, normal without pain. Treatment: Calcium antagonists (diltiazem - DOC). -blockers are contraindicated in Prinzmetals variant. Coronary Revascularization Indications: a. PTCA (Percutaneous transthoracic coronary Angiography) indicated in i. Angina pectoris- most common. ii. To dilate stenosis in native coronary arteries and in grafts following coronary artery bypass surgery. PTCA is contraindicated in LCA stenosis. b. Coronary artery bypass grafting (CABG) - is indicated in multivessel disease (3 vessel CAD) and LCA (Left Coronary Artery) stenosis. Grafts used for CABG are Long saphenous vein, internal mammary artery (best). HYPERTENSIVE VASCULAR DISEASE Morphology Vascular changes in hypertension are most prominent in kidneys. These include: 1. Hyaline arteriosclerosis - in benign hypertension. 2. Hyperplastic arteriosclerosis - in malignant hypertension. Characterized by onion-skin like concentric

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thickening of vessel wall with fibrinoid necrosis (nectrotizing arteriolitis). Seen in - kidneys, small gut, gallbladder, peripancreatic and periadrenal fat. Heart- left ventricular hypertrophy (concentric type). Diagnosis a. Pheochromocytoma - measurement of catecholamine or their metabolites in a 24 hour urine sample. b. Cushings syndrome - 24 hour urine test for cortisol or dexamethasone suppression test (a +ve test rules out the diagnosis). c. Renovascular (Gold Blatt hypertension) most common cause is renal artery stenosis. Renal artery stenosis causes increased renin activity. Tests for renovascular hypertension: ScreeningCaptropril enhanced radionuclide scan (best). Duplex Doppler flow study. Magnetic resonance imaging. Spiral CT scan - most sensitive and specific. Diagnostic Renal angiogram and renal vein renin determination. Malignant Hypertension BP >200/140 mmHg, Papilledema, Retinal hemorrhage and exudates, Renal failure, Microangiopathic hemolytic anemia.

Wagner-Barker Classification of Hypertensive Retinopathy Normal A:V (diameter of artery to vein) ratio= 3:4. Grade I: Mild arteriolar narrowing (A:V= 1:2) Grade II: A:V ratio 1:3. Focal spasm 2:3 (area of spasm: proximal arteriole). Arteriolar light reflex - Copper wire.

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A V crossing defect - Nicking, depression or humping of veins. Grade III: A:V ratio 1:4. Focal spasm 1:3. Hemorrhage +, Exudates +. Cotton wool spots. Arteriolar light reflex - Silver wire. AV crossing defects - right angle deviation, tapering and disappearance of vein under artery. Grade IV: Arteriole - Cord like. Obliteration of distal flow. Hemorrhage/Exudates +. Papilledema +. ARTERIAL DISORDERS Aortic Aneurysm Arteries involved: 1. Abdominal aorta - most common site. Least common site is the arch and root of aorta. 2. Splenic artery - next common site. 3. Peripheral aneurysm - most commonly involves the popliteal artery. 4. Superficial temporal artery - involved in cirsoid aneurysm.
Causes and sites of aneurysm Cause Atherosclerosis Cystic medial necrosis Syphilis Marfans syndrome Takayasus arteritis Site Abdominal aorta distal to renal artery Proximal aorta and the sinus of Valsalva Ascending and arch of aorta Ascending aorta Arch of aorta, subclavian artery

Abdominal Aortic Aneurysm Abdominal aorta is the most common site of atherosclerotic aneurysm, commonly involves below the renal arteries. Clinical feature: Most cases are asymptomatic. Sudden severe symptoms may appear when they expand and rupture (e.g. severe back pain indicates enlargement of sac).

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Complications: Rupture- posterior rupture is most common; produces retroperitoneal hematoma. Diagnosis: Plain X-ray - may reveal calcified outline of the aneurysm. USG. CT scan and MRI - best (MRI is the investigation of choice). Differential diagnosis: With other pulsating tumors viz.: 1. Bone sarcoma. 2. Osteoclastoma. 3. Secondaries from hypernephroma. Treatment: For symptomatic patients - excision with replacement with graft. Asymptomatic - surgery is indicated if size > 6.5 cm. Prognosis: Depends on size. Without surgery 80 percent of symptomatic patients die within 1 year. An elective surgery carries 2-5 percent mortality. Popliteal Aneurysm Most common peripheral aneurysm. Often bilateral and associated with aortic aneurysm. Iliac Aneurysm Occurs in conjunction with aortic aneurysm. Clinical feature: GI bleeding. Diagnosis: P/R examination. Cystic Medial Necrosis Produces fusiform aneurysm of proximal aorta and sinus of Valsalva. Associated with: Marfans syndrome, Ehlers-Danlos syndrome, pregnancy, hypertension. Treatment: Long term -blocker therapy.

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Syphilitic (Leutic) Aneurysm Pathology: It is an endarteritis obliterans in tertiary syphilis. Site: Involves the vasa vesorum of arch of aorta medial necrosis and scarring the proximal aorta and arch become dilated aneurysm. Abdominal aorta is not involved. X-ray: Tree- barking like calcification. Mycotic Aneurysm Not caused by fungus, but by bacteria viz. Staphylococcus, Streptococcus and Salmonella. Pseudoaneurysm Produces pulsating tumor. Cause: 1. Atherosclerosis - most common cause. 2. Post MI rupture. 3. Leak at the junction of a vascular graft with a natural artery. Aortic Dissection It is a transverse tear of the intima. Cause: Hypertension - most common. Marfans syndrome. Iatrogenic. Cystic medial necrosis - produces spontaneous dissection. Site: Along the right lateral wall of ascending aorta. Type: Proximal: Involves the ascending aorta - more common and more dangerous - peripheral pulses may be abnormal. Distal: Peripheral pulses normal. Clinical feature: Severe pain in chest which radiates downwards and to back. Pleural effusion may develop.

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Complication: Rupture (most common cause of death). Investigation: Transesophageal echocardiography - initial investigation of choice. MRI-best. DSA. Treatment: Antihypertensive and surgery (definitive). VASCULAR DISEASES OF EXTREMITIES Atherosclerosis Risk factors: Diabetes, hypercholesterolemia, smoking. Clinical feature: Intermittent claudication: Occurs during exercise and relieved by rest. Site- distal to the site of occlusion. Calf claudication in femora-popliteal disease. Symptoms may appear at night. Lerich svndrome: Buttock, hip and thigh discomfort in patients with aortoiliac obstruction. In bilateral obstruction there is male infertility. Fibromuscular Dysplasia Hyperplastic disorder of arteries. Renal artery involvement may cause stenosis and hypertension. Angiography shows string of beads appearance. Thromboangiitis Obliterans (Buergers Disease) Pathology: Inflammation of small and medium sized arteries and veins in the distal upper and lower extremities. Most commonly involves the tibial artery. Epidemiology: Does not occur in women and non-smokers. Clinical feature: Triad of: 1. Claudication. 2. Raynauds phenomenon. 3. Migratory superficial vein thrombophlebitis. Normal brachial and popliteal pulses but reduced or absent radial, ulnar and/or tibial pulses.

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Death occurs most commonly due to myocardial infarction. Diagnosis: Arteriography - may show corrugation of the femoral arteries. Treatment: Sympathectomy may relieve rest pain and venous leg ulcers. But it is not much effective in pain of claudication. Raynauds Phenomenon Characterized by: Sequential development of digital blanching, dusky cyanosis and rubor of the fingers and toes on exposure to cold and subsequent rewarming. Types: 1. Idiopathic or Raynauds disease More common in females. Upper extremities commonly affected. Peripheral pulses are normal. 2. Secondary Due to collagen vascular diseases particularly scleroderma and SLE Atherosclerosis of extremities. Thromboangiitis obliterans. Treatment: Calcium channel blockers- nifedipine. Adrenergic blockers- reserpine. Sympathectomy. VENOUS DISORDERS Varicose Veins Pathology: Normal blood flow in extremities is from superficial to deep veins. This is regulated by valves. In varicose vein, the valves are defective and blood flows from deep to superficial veins resulting in dilatation of superficial veins. There are four valves in the leg, and one at the lower thigh. Site: Long saphenous vein is the most commonly affected. Most common site of reflux are - saphenofemoral junction (SFJ) and saphenopopliteal junction (SPJ).

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Cause: Incompetence of the valves. Note: Pulsatile varicose vein is seen in AV fistula, KlippelTrenaunay syndrome. Klippel Trenaunay syndrome: Congenital AV fistula. Cutaneous hemangiomas. Varicose veins. Hypertrophy of involved extremity. Absence of deep venous system. Test: Trendelenburgs test to detect perforator incompetence. Complications: Venous ulcers - usually located just proximal to the lateral or medial malleolus. Management: First management of ruptured varicose vein is compression and elevation of limb. Injection sclerotherapy using Ethanolamine oleate for varicosity <3 mm. Surgery: Indication - varicosity >3 mm in size. Contraindication - deep vein thrombosis. Procedure Trendelenburgs procedure - ligation of SFJ and SPJ and removal of varicose vein. Cocket and Dodds procedure- subfascial ligation Complications - bleeding and discomfort. Recurrence rate after surgery 10 percent. Deep Vein Thrombosis Causes: 1. SurgeryOrthopedic operations on the lower limbs (hip and knee replacement) are at increased risk. Also abdominal operations. 2. Paraneoplastic syndromeAdenocarcinoma of pancreas, stomach, colon or lung may produce migratory thrombophlebitis - Trousseaus sign. 3. High estrogen therapy. 4. Thrombocytosis. 5. PNH. 6. Endocrinal - Nephrotic syndrome, Cushings syndrome. 7. Thrombophilia - congenital deficiency of antithrombin III, protein C and S.

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Risk factors: Old age Obesity Pregnancy and puerperium Immobilization (for >4 days) Varicose vein Lupus anticoagulant Behcets syndrome Homocystinemia Site: Calf veins (popliteal and posterior tibial) most common. Clinical feature: Swelling, pain, calf tenderness. Dilated superficial veins. Fever (low grade). Pain in calf on dorsiflexion (Homans sign). Complications: Pulmonary embolism (most common source is from femoral veins). Investigations: Duplex ultrasound- method of choice. Enhanced helical CT- for pulmonary embolism. Treatment: IV heparin + warfarin at the same time (for at least 5-7 days). Heparin dose should be 2.5 to 3.5 times the normal INR (international normalized ratio). Phlegmasia alba dolens (milk leg): Ilio-femoral vein thrombosis in pregnancy. Superficial Vein Thrombosis Cause: Most common cause is canulation of vein for IV infusion. Site: Most commonly involves great saphenous vein. Treatment: Symptomatic with analgesic and antiinflammatory drugs. Axillary Vein Thrombosis Cause: As a complication of thoracic outlet syndrome associated occasionally with cervical rib. May also occur following vigorous exercise.

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Clinical feature: Swollen arm with dilated superficial veins. Treatment: Anticoagulants- early. Fibrinolytics (streptokinase or tPA) - in severe cases. Arteriovenous Fistula Causes: 1. Congenital. 2. Traumatic - most common cause. Effects: a. Structural - veins become dilated, tortuous and thick (arterialization of veins). b. Physiological- increased venous return leads to increased pulse rate and cardiac output. Increased pulse pressure. LVH and failure. Local gigantism. Clinical feature: Pulsatile swelling, dilated veins, thrill and bruit. Pressure on artery proximal to fistula causes decrease in size of swelling, decrease in thrill and bruit, decrease in pulse rate. Pulse pressure returns to normal. This is known as Nicoladonis or Branhams sign. Diagnosis: Arteriography (confirmatory). Treatment: Embolisation, excision. Ligation of artery and vein both above and below the lesion (quadruple ligation). LYMPHATIC DISORDERS Acute Lymphangitis Organism: Streptococcus pyogenes or Staphylococcus aureus. Treatment: IV penicillin. Lymphedema Types: Congenital - onset before 1 year of age. i. Sporadic ii. Familial - Milroys disease.

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Precox - onset between 1-35 years of age. i. Sporadic ii. Familial - Meige s disease. Tarda - onset after 35 years of age. Causes: PrimaryCongenital (Milroys disease) SecondaryFilariasis (most common cause), lymphatic malignancy, radiation. Complication: Chronic lymphedema predisposes to 1. Lymphangiosarcoma. 2. Recurrent infections. 3. Thickening of skin. Milroys Disease Onset: At or within one year of birth (present at birth or noticed shortly thereafter). Clinical feature: More common in males. Often bilateral. Involves the whole leg. Lymphedema Precox Occurs in post-menarche females with involvement of single leg only. Lymphangiogram shows: Hypoplasia of the lymphatics (absent or reduced distal superficial lymphatics). Lymphangiosarcoma Most common cause - post-mastectomy. Occurs after several years of operation.

5
ANTIGEN

IMMUNE SYSTEM
ANTIGEN AND ANTIBODY

Antigens are substances which, when introduced parenterally into the body, stimulate production of an antibody with which it reacts specifically and in an observable manner. Smallest unit of antigenicity is antigen determinant or epitope (the site on antigen which is recognized by antibody). Isospecificity Isoantigens are antigens found in some but not all members of a species e.g. blood group antigens and histocompatibility antigens. Haptens Are substances which do not induce antibody production but can react specifically with antibodies. They become immunogenic on combining with a carrier. ANTIBODY The combining area of antibody corresponding to epitope is paratope. Character: On the basis of electrophoretic mobility, they fall into the group of gamma-globulins. All antibodies are immunoglobulins (Ig), but all immunoglobulins are not antibodies because proteins in multiple myeloma, cryoglobulinemia, etc. are also immunoglobulins. Structure: An Ig is lysed by papain into: i. An insoluble fraction called Fc (crystallizable) it is composed of the carboxyterminal of the H chain.

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ii. A soluble fragment called Fab (antigen binding) composed of the aminoterminal of H chain and L chains. Igs are glycoproteins, each molecule consists of 2 pairs of polypeptides called light chain (molecular weight 25000) and heavy chain (molecular weight 50000). The H chains are structurallty and antigenically distinct for each class. The L chains are similar in all classes of Igs, and are either kappa () or lambda () chains. The aminoterminals act as antigen binding sites (hypervariable region). The carboxy terminals determine the biological properties of Ig molecule like complement fixation, placental transfer, etc. Types IgG It is the most abundant Ig (80% of the total). IgG1 is the most abundant subtype. It is the only maternal antibody to cross placenta. It is a late antibody and appears after IgM. Examples antiRA antibody, antiRh antibody. It is more powerful than IgM in complement fixation. IgA It is present in colostrums, saliva and tears. It is secreted by mucosal or glandular epithelial cells. It has a dimeric structure with a J or joining piece. It has a secretory piece which is responsible for its presence in secretions. It has important role in local immunity against respiratory and intestinal pathogens. It is the only Ig to fix complement via alternate pathway. IgM Molecular weight 1000000 millionaire molecule. It is a pentamer. Effective valency is 5 (due to steric hindrance). It is the earliest Ig to appear in the fetus (at 20 weeks). Presence of IgM in fetal or newborn blood indicates intrauterine infection (e.g. syphilis, rubella, HIV, toxoplasmosis). It is short lived, so presence of IgM indicates recent infection.

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It is responsible for the primary response. It is more effective than IgG in opsonization. IgM deficiency is often associated with septicemia. Treatment with 0.12M 2-mercaptoethanol selectively destroys IgM and is a method for differential estimation of IgG and IgM.

IgE It is the atopic reagin antibody responsible for type I hypersensitivity. It is heat labile. Its levels are increased in asthma, hay fever, intestinal parasitism. It has the shortest half-life. It has affinity for the surface of tissue cells (particularly mast cells) of the same species (homocytotropism). It mediates the Prausnitz-Kstner reaction. Abnormal Igs Bence Jones protein they are the light chains of Ig, either or , but never both, found in multiple myeloma. It is detected in urine it agglutinates at 50oC but redissolves at 70oC. Cryoglobulins form a gel or precipitate on cooling which redissolves on heating. They are IgG or IgM, found in myelomas, macroglobulinemias, SLE, etc. ANTIGEN-ANTIBODY REACTION Forces: Forces that act to bind antigen to antibody are: i. Van der Waals forces ii. Ionic bonds iii. Hydrogen bonds. Detection of Antibody and Antigens Precipitation Test i. ii. Occurs with soluble antigens. Exhibits Zone phenomenon: Prozone or antibody excess Postzone or antigen excess

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Mechanism lattice hypothesis. Examples: 1. Ring test Lancefield grouping of streptococci and Ascolis thermoprecipitation test. 2. Slide test VDRL test for syphilis. 3. Tube test Kahn test for syphilis. 4. Immunodiffusion (precipitation in gel) Erek gel precipitation test for toxigenicity of diphtheria bacilli. 5. Electroimmunodiffusion counterimmunoelectrophoresis for fetoprotein in serum, specific antigens of cryptococcus and meningococcus in CSF . Agglutination Test Occurs with particulate antigens. More sensitive and convenient than precipitation test. Examples: 1. Slide agglutination for blood grouping and crossmatching. 2. Tube agglutination Widal test for typhoid, Weil-Felix reaction for typhus fever, Paul-Bunnel test for infectious mononucleosis, cold agglutination test for atypical pneumonia. 3. Coombs test for detection of incomplete antibodies. a. Direct Coombs test sensitization of RBC occurs in vivo, e.g. hemolytic disease in newborn due to Rh incompatibility. b. Indirect Coombs test sensitization occurs in vitro, e.g. in brucellosis. 4. Passive agglutination test a precipitation test can be converted to an agglutination test by attaching a soluble antigen to the surface of a carrier particle (like RBC, latex particles or bentonite). Examples include Rose-Waller test for RA factor, latex agglutination is used to detect hepatitis B, ASO, CRP , RA factor, hCG, etc. Complement Fixation Test Reagents: a. Complement system antigen, antibody (patients serum) and complement.

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b. Hemolytic system sheep RBC, amboceptor (rabbit antibody to sheep RBC). Result Lysis of sheep RBC negative CFT. No lysis of sheep RBC positive CFT. Example Wassermann test for syphilis. Opsonization This helps in phagocytosis. IgM is more effective in opsonization than IgG. Other opsonins are Fc portion of IgG, C3b and collectins. Immunofluorescence Direct for detection of rabies antigens. Indirect FTA test for syphilis. Radioimmunoassay Most sensitive method of antigen detection. Hormones are assayed by this method. ELISA Enzyme Linked Immunosorbent Assay. Example detection of rotavirus antigen in feces, detection of anti-HIV antibody. THE COMPLEMENT SYSTEM Complement Activation Two pathways: 1. Classical pathway in this pathway, C3 is activated by C42 (classical C3 convertase). First step in this pathway is binding of C1 to the antigenantibody complex (bound IgG or IgM). At the end, all the component levels are decreased. 2. Alternative pathway (Properdin system) Activator is zymosan. In vivo activators are bacterial endotoxin, IgA and IgD, cobra venom and the nephritic factor.

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Alternate pathway C3 convertase is C3b,Bb. Properdin stabilizes this enzyme. C1,2,4 are not involved, hence their levels remain normal at the end. Functions C3a and C5a (anaphylatoxin) cause increased histamine release from mast cells leading to increased vascular permeability and vasodilatation. C5a chemotaxis. C3b opsonization. Dysfunction 1. Hereditary angioneurotic edema: Cause: Deficiency of C1 inhibitor leads to autocatalytic activation of C1 and unrestrained breakdown of C4 and C2. Consequently levels of C1 remain normal but that of C4 and C2 are depleted. Clinical feature: Episodic laryngeal edema with respiratory distress. 2. Deficiency of C1,2,4 is associated with SLE and other collagen vascular diseases. 3. Deficiency of C5 to C8 is associated with bacteremia, mainly with gram-negative diplococci (e.g. meningococci). STRUCTURE AND FUNCTION OF THE IMMUNE SYSTEM Types 1. Humoral or antibody mediated immunity (AMI) mediated by immunoglobulins. 2. Cell mediated immunity (CMI) mediated by sensitized lymphocytes. Cells Lymphocytes T cells (thymus derived) produce lymphokines and mediate CMI. It constitutes 70-80 percent of normal peripheral blood lymphocytes.

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B cells (bursa or bone marrow derived) produce plasma cells which synthesize Igs and mediate AMI. B cell precursors, pro B cells, develop in the fetal liver during embryonic life and in the bone marrow afterwards. Plasma cells are antibody secreting cells. They have a cartwheel appearance. Differentiation:
Differentiation of T and B cells Property Binding to sheep RBC T cells B cells

Forms rosettes No by CD2 antigen EAC rosette (C3 receptor) No Yes Blast transformation with phytohemagglutinin Yes No Surface immunoglobulins Negative Positive Markers CD1 to CD8 CD10, CD19 except CD6. to CD23 CD1 Langerhans cells CD2 Receptor cells CD3 Pan T cell marker CD4 Helper T cells CD8 Cytotoxic T cells

Null Cells Also known as the large granular lymphocytes, they lack the features of either T or B cells. They constitute 5-10 percent of lymphocytes and are present in peripheral blood. Most important member of the group is the natural killer (NK) cells. IL-2 acts as a growth factor for NK cells (lymphokine activated killer LAK cells). Properties: 1. Their activity is natural or nonimmune. 2. Their cytotoxicity is not antibody dependant or MHC restricted. 3. They cause direct cell lysis without prior sensitization. Function: Immune surveillance and natural defence against virus infected and malignant mutant cells. Markers: CD16 (Fc portion of IgG), CD56.

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Antigen Presenting Cells 1. Macrophages In blood they are called monocytes. In tissues called histiocytes (e.g. alveolar macrophages in lungs), Kupffer cells in liver, microglia in the brain. Activated macrophages secrete tumor necrosis factor alpha (TNF ), colony stimulating factor (CSF), IL-1 and IL-8. Function MHC II positive and central APC to CD4+ helper T cells. Involved in CMI (delayed hypersensitivity). They also give rise to multinucleated giant cells in granulomatous inflammation. Markers CD13 to CD15 and CD33. 2. Dendritic cells: These are nonphagocytic cells that express high levels of MHC class II. Also express CD83. They are present in lymphoid tissue (interdigitating dendritic cells) and in epidermis of skin (called the Langerhans cells). They are the most potent APCs to T cells. Follicular dendritic cells are found in the germinal centers of lymphoid follicles in spleen and lymph nodes. They express Fc portion of IgG. They facilitate the maintenance of immunological memory. 3. B lymphocytes. MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) MHC I proteins determine histocompatibility and the acceptance or rejection of allografts. MHC II proteins regulate the immune system MHC III proteins some are components of complement system; govern the susceptibility to autoimmune diseases. Human Leukocyte Antigen (HLA) HLA gene is located on the short arm of chromosome 6. HLA system is highly polymorphic, i.e. multiallelic.

Immune System
Human leukocyte antigen HLA I Loci 3 loci A, B and C HLA II HLA III

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1 loci D with 3 sub faces DR, DQ and DP Location Present on all Expressed on antigen nucleated cells presenting cells and platelets (macrophages, dendritic cells and B cells) Function Presentation of Presentation of Components of antigen by APCs antigen to complement to CD8+ cells CD4+ cells system (C2 and C4), properdin, factor B, TNF alpha and beta

HLA typing: Typing is done serologically by microcytotoxicity. Serological typing is not possible for HLAD and HLA-DP antigens, which are detected by the mixed leukocytic reaction (MLR) and primed lymphocyte typing (PLT), respectively. This is used primarily for testing compatibility between recipients and potential donors before tissue transplantation (mainly HLA-D). It has application also in disputed paternity. Disease association:
HLA type and disease association HLA B27 Ankylosing spondylitis HLA DR2 SLE Reiters syndrome Goodpastures syndrome Reactive arthritis IgA nephropathy Psoriatic arthritis Multiple sclerosis Juvenile rheumatoid arthritis Narcolepsy almost Acute anterior uveitis 100 percent association HLA DR3 SLE HLA DR4 Type I diabetes Gluten sensitive Rheumatoid arthritis enteropathy (DQ2) Chronic active hepatitis Type I diabetes Myasthenia gravis HLA B5 Ulcerative colitis Behcets disease HLA A3 Primary hemochromatosis

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IMMUNE RESPONSE Primary Response It is short, slow with long lag phase and low titre of antibodies. Predominant antibody is IgM. Secondary Response It is prompt, powerful and prolonged with short lag phase and higher levels of antibodies. Predominant antibody is IgG. CYTOKINES They are peptide in nature.
Cytokines Types Interleukins IL-1 ( and ) Source Macrophages and other APCs, somatic cells Activated TH1 cells, TC cells, NK cells T cells TH2 cells, mast cells Effects Proliferation and differentiation of T, B and other cells; endogenous pyrogen; induce acute phase proteins Proliferation of cytotoxic T cells and NK cells Induce hematopoiesis B cell proliferation, IgE expression and MHC II expression Acute phase proteins

IL-2 IL-3 IL-4

IL-6 IL-7 IL-8 IL-12

Activated TH2 cells, APCs Spleen and bone marrow stromal cells Activated CXC () chemokine, macrophages chemotactic for neutrophils Cell mediated immunity

Tumor necrosis factor TNF Activated macrophages TNF Activated TH cells (lymphotoxin) Interferons IFN Leukocytes (B lymphocytes), macrophages Fibroblasts TH1 cells, NK cells

IL-1 like effects; vascular thrombosis and tumor necrosis, cachexia Do

IFN IFN

Antiviral activity CMI, activation of macrophages

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Note: TH1 cells secrete IL-2 and IFN which help direct CMI responses including macrophage and NK cell activation. TH2 CD4+ cells secrete IL-4, IL-5 and IL-10 that promote humoral immunity (B cell proliferation) and type I hypersensitivity (synthesis of IgE). CHEMOKINES 1. CXC or -chemokine IL-8 (chemotactic for neutrophils). 2. CC/ chemokine monocytes, macrophage (MCP-1, MIP1); RANTES chemotactic for CD4+ T cells Eotaxin chemotactic for eosinophils. Note CXCR4 and CCR5 act as coreceptors for binding of HIV to lymphocytes.

HYPERSENSITIVITY
Coombs and Gell Classification a. Immediate (B cell or antibody mediated) Type I Anaphylactic/atopic (IgE mediated) Type II Cytolytic and cytotoxic Type III immune complex disease Arthus reaction and serum sickness. b. Delayed (T cell mediated) TYPE I REACTION: ANAPHYLAXIS It is the immediate (most rapid) hypersensitivity reaction to an antigen when introduced in a sensitized host. The first dose is called the sensitizing dose and a second dose is called the shocking dose (most effective with a gap of 2-3 weeks). Anaphylaxis has been extensively studied in guinea pig. Mediators a. Immunological IgE. b. Chemical i. Primary histamine (most important mediator), serotonin, chemotactic factor (eosinophilic and neutrophil), heparin.

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ii. Secondary formed by the action of primary mediators prostaglandins and leukotriens (also called the slow reacting substance of anaphylaxis or SRS-A). iii. Anaphylatoxins C5a and C3a. Mechanism: Allergen stimulates TH2 cells IL 4 and IL 5 increased IgE from B cells. Example: Theobald Smith phenomenon Casonis test for hydatid disease. Atopy This refers to naturally occurring familial hypersensitivities in human beings. Mediated by IgE (also called the reagin antibody). Characteristics of IgE: 1. It cannot be demonstrated by conventional serological methods such as the precipitation or complement fixation tests. IgE is detected by ELISA, passive agglutination and radioallergosorbent test (RAST). 2. It is homocytotropic, i.e. species specific. This is the basis of Prausnitz-Kustner (PK) reaction for detection of atopic antibody. 3. It is heat sensitive. Example: i. Asthma ii. Hay fever iii. Atopic dermatitis or eczema iv. Urticaria. Management: Specific desensitization a. Serial small dose injection of the antigen causes exhaustion of the intracellular store of histamine in mast cells. b. Depot therapy or injection of the allergen in an oil adjuvant produces blocking (IgG) antibodies. TYPE II REACTION: CYTOLYTIC AND CYTOTOXIC Combination of IgG or IgM antibodies with the antigenic determinants on the surface of cells produces cell lysis and cell death. Mediators complement, NK cells.

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Examples: i. Autoimmune hemolytic anemia, thrombocytopenia and agranulocytosis ii. Blood transfusion reaction iii. Transplant rejection (acute) iv. Diabetes v. Goodpastures disease vi. Graves disease vii. Myasthenia gravis viii. Pernicious anemia ix. Rheumatic fever x. Pemphigus vulgaris xi. Erythroblastosis fetalis xii. Drug reactions e.g. penicillin induced hemolysis. TYPE III REACTION: IMMUNE COMPLEX DISEASE Antigen-antibody complex mediated. Arthus Reaction Localized manifestation of a generalized disease Occurs with repeated doses of antigens. Latent period of 4-12 hours after subsequent dose. Serum Sickness Systemic disease Occurs with single massive dose of antigen. Latent period of 7-12 days. Examples: i. PAN ii. Post-streptococcal glomerulonephritis iii. Rheumatoid arthritis iv. Acute viral hepatitis v. Penicillamine toxicity vi. SLE. TYPE IV REACTION: DELAYED HYPERSENSITIVITY Occurs after several hours of introduction of an antigen in a sensitized host. Mediators: Cellular T4 lymphocytes and macrophages Chemical IL 2 and IL 12, interferon gamma (most important) and tumor necrosis factor.

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Example: i. Tuberculosis (tuberculin test) ii. Lepromin test iii. Sarcoidosis iv. Contact dermatitis Note: Granulomatous inflammations are special type of delayed hypersensitivity. TYPE V REACTION: It is also antibody mediated (like type II), but instead of killing cells, antibodies stimulate their target. For example, Graves disease mediated by LATS.

ORGAN TRANSPLANTATION
Types of Transplants a. According to source Between same species Genetically identical (twin) isograft. Genetically different allograft. Between different species heterograft or xenograft b. According to site Orthotropic when placed in normal anatomical position, e.g. skin graft. Heterotropic when placed in anatomically abnormal sites, e.g. thyroid placed in subcutaneous tissue, kidney placed in iliac fossa. c. According to purpose Vital grafts those living grafts which function physiologically, e.g. kidney or heart. Static/structural graft nonliving, provide only a scaffolding on which new tissues are laid, e.g. bone/ artery. GRAFT REJECTION Transplantation immunity is predominantly cell mediated (T cell) but antibodies do play some role mainly in hyperacute rejection. Hyperacute Rejection Occurs within minutes to hours. Due to preformed antibodies against HLA class I antigen of donor.

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Pathology intravascular thrombosis and fibrinoid necrosis of arterial walls. Such graft is called white graft. Most commonly seen after renal transplantation. It is avoidable by prior antibody detection and cross matching. Acute Rejection Occurs within 6 months. It is predominantly T cell mediated. Pathology mononuclear cell infiltration. It is reversible by immunosuppressant therapy.

Chronic Rejection Occurs after 6 months. Due to both cell mediated and antibody mediated effector mechanisms. Risk factor most important risk factor for chronic rejection is acute rejection. Pathology vascular changes in the form of arterial myointimal proliferation resulting in ischemia and fibrosis. It is non-reversible. Note: Liver is remarkably resistant to all types of graft rejection. Pretransplant Testing 1. Blood grouping (only ABO) and cross matching. Rh groups need not to be tested. 2. HLA typing and matching most important factor of allograft survival is HLA compatibility. HLA typing is done by microcytotoxicity test. HLA groups important in transplant immunology are HLA-DR > HLA-B > HLA-A. HLA matching is not necessary before liver transplantation. Organ Donation Most of the organs used for transplantation are obtained from brainstem dead, heart-beating cadaveric donors. Commonly used preservatives are university of Wisconsin solution and Eurocollins solution.

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Kidney Transplantation Please see Renal System. Pancreas Transplantation For treatment of diabetes mellitus, isolated pancreatic islets are transplanted into recipient liver by injection into portal vein. Liver Transplantation First attempted by Starzl in 1963. Indications i. Chronic cirrhosis or chronic liver failure most common. ii. Acute fulminant liver failure iii. Metabolic liver diseases iv. Primary hepatic malignancy. Heart Transplantation First performed by Christian Barnard in 1967. First heart-lung transplantation was performed by Bruce Reitz in 1981. Indication NYHA class III or IV disease in patients < 65 years of age. Contraindication carboxyhemoglobin level > 20 percent, prior myocardial infarction and prolonged cardiac arrest. GRAFT-VERSUS-HOST DISEASE (GVHD) It is the opposite of graft rejection. In GVHD, graft mounts an immune reaction against the host antigens. This occurs when immunologically competent cells are introduced into recipients who are immunocompromised. Occurs most commonly in allogenic bone marrow transplantation. Pathology: Acute GVHD causes epithelial cell necrosis in three primary target organs liver, skin and gut. Runt disease is an example of GVHD.

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PRIMARY IMMUNODEFICIENCIES
DISORDERS OF SPECIFIC IMMUNITY Classification A. Humoral immunodeficiencies (B cell defects) 1. X linked agammaglobulinemia 2. Common variable immunodeficiency 3. Hyper IgM syndrome B. Cellular immunodeficiency 1. Thymic hypoplasia (DiGeorges syndrome) 2. Chronic mucocutaneous candidiasis C. Combined immunodeficiencies (B and T cell defects) 1. Nezelof syndrome 2. Ataxia telangiectasia 3. Wiskott-Aldrich syndrome 4. Severe combined immunodeficiency 5. Immunodeficiency with thymoma. X-Linked Agammaglobulinemia (Bruton Disease) Cause: Mutation in tyrosine kinase. Inheritance: X-linked recessive. Clinical feature: Recurrent bacterial infection in childhood, chronic giardiasis. Diagnosis: Absent or decreased B cells, absent plasma cells, decreased Ig in serum. Treatment: IV gammaglobulin. Common Variable Immunodeficiency Defective humoral immunity due to lack of differentiation of B cells. Clinical feature: Same as Bruton disease, onset is late, chronic giardiasis. Diagnosis: Normal B cells but absent plasma cells. Others: Increased chance of autoimmune diseases (hemolytic anemia, pernicious anemia) and lymphoid tumors.

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Isolated IgA Deficiency Most common of all the primary immunodeficiencies. Clinical feature: Usually asymptomatic, chronic sinopulmonary infection and diarrhea. Hyper-IgM Syndrome Cause: Mutations in CD40L or CD40, resulting in defective isotype switching. Inheritance: Usually X-linked. Diagnosis: Normal or increased IgM but lack of IgG, IgA or IgE isotypes. Severe Combined Immunodeficiency Defects in both humoral and cell-mediated immunity. Cause: X-linked cytokine (IL-7) receptor mutation Autosomal recessive adenosine deaminase deficiencythe most common enzyme deficiency. Clinical feature: Recurrent infection. Treatment: Bone marrow transplantation. Wiskott-Aldrich Syndrome There is loss of cellular as well as humoral immunity. Clinical feature: Characterized by thrombocytopenia, eczema and recurrent infection. Inheritance: X-linked. Diagnosis: Decreased T cell and defective cellular immunity, Defective antibody formation to polysaccharide (encapsulated organisms), Decreased IgM but IgG, IgA are normal or increased, IgE is also increased, Decreased ratio of CD4:CD8 cells, Small platelets in peripheral smear. Treatment: Bone marrow transplantation.

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Thymic Hypoplasia (DiGeorges Syndrome) Cause: Deletion of chromosome 22q11. Clinical feature: Thymic hypoplasia leads to deficient T cell maturation increased viral, fungal and protozoal infection. Parathyroid hypoplasia hypocalcemic tetany. It is associated with Fallots tetralogy and other congenital anomalies and a characteristic facial appearance. Nezelof Syndrome Depressed cell mediated immunity is associated with selectively elevated, decreased or normal levels of immunoglobulin. Immunodeficiency with Thymoma Spindle cell thymoma is associated with hypogammaglobulinemia, impaired cell mediated immunity and aplastic anemia. INHERITED DISORDERS OF PHAGOCYTIC FUNCTION Classification a. Defective adhesion leukocyte adhesion deficiency b. Defective chemotaxis Jobs syndrome, Lazy leukocyte syndrome, Shwachmans disease. c. Defective microbicidal activity myeloperoxidase deficiency, Chediac-Higashi syndrome, chronic granulomatous disease. Leukocyte Adhesion Deficiency Defect: Type 1 defective synthesis of CD18 -subunit of leukocyte integrins LFA-1 and Mac-1. Type 2 absence of Sialyl-Lewis X (selectin receptor on endothelium). Clinical feature: Type 1 delayed separation of umbilical cord, recurrent infection.

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Type 2 severe mental retardation, short stature, Bombay blood group, recurrent infection. Hyper IgE-recurrent Infection (HIE) or Jobs Syndrome Clinical feature: Eczema, cold abscess, recurrent staphylococcal pneumonia, coarse facies, bony abnormalities, serum IgE > 2000 IU/ml. Myeloperoxidase Deficiency Most common neutrophil defect. Usually asymptomatic. Chediac-Higashi Syndrome Defect: Reduced chemotaxis and phagolysosome fusion. Clinical feature: Recurrent pyogenic infections specially with Staphylococcus aureus. Oculocutaneous albinism, nystagmus, peripheral neuropathy, mental retardation. Diagnosis: Giant primary granules in neutrophils. Chronic Granulomatous Disease 60 percent X-linked, 40 percent autosomal recessive. Defect: Lack of one of four NADPH oxidase subunit absent respiratory burst decreased production of H2O2. Clinical feature: Recurrent infection with catalase positive pyogenic organisms like Staphylococcus aureus. Lymph node suppuration, granuloma formation which may obstruct GI tract or genitourinary tract. Diagnosis: NBT test (screening test) Absent superoxide and H2O2 production by neutrophils. Shwachmans Disease Decreased neutrophil mobility, pancreatic malfunction, bone abnormalities.

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HIV AND ACQUIRED IMMUNODEFICIENCY


HIV VIRUS Formerly known as the HTLV III. Two subtypes: HIV 1 is the prevalent form worldwide; and HIV 2 was isolated from West Africa. HIV 2 differs in envelope glycoprotein. Infection with HIV 2 is mostly asymptomatic. Structure: Spherical enveloped virus. Genome contains diploid DNA. In association with the viral RNA is the enzyme reverse transcriptase (RT) or RNA directed DNA polymerase. RT allows formation of a dsDNA form a ssRNA. DNA in turn forms mRNA as otherwise. Genome contains three structural genes gag, pol and env. The gag gene determines the core. The major core antigen is p24 which is the earliest to appear in HIV infection. Env gene shows greatest variability. Pathogenesis HIV virus attacks CD4+ cells such as the TH cells, monocytes and the macrophages and also the B lymphocytes. Macrophages act as reservoir for the virus. Immunological abnormalities after HIV infection i. Reduction in number of T4 (CD 4) cells (normal 950/ l. ii. Inversion of T4:T8 ratio (normally CD4 is expressed in 60% T cells and CD8 in 30% T cells, so that normal CD4:CD8 ratio is 2:1). iii. Decreased delayed hypersensitivity. iv. Hypergammaglobulinemia: Predominantly IgG and IgA. Chemokine receptors: CCR5 and CXCR4 are important for HIV import. Persons with CCR5 deletions are less likely to be infected with HIV.

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Transmission 1. Sexual most common in homosexual males (receptive anal intercourse). But in developing countries, maximum transmission occurs in heterosexuals. 2. Blood transfusion least common mode (1 in 1 million). Products that transmit HIV are whole blood, packed red cell, platelets, leukocytes and plasma. Products that do not transmit HIV are hyperimmune gammaglobulin, hepatitis B immunoglobulin, plasmaderived hepatitis B vaccine, Rh immunoglobulin. 3. Vertical transmission maximum transmission in the perinatal period. Prophylaxis with antiretroviral drugs reduce the chance of transmission (see below). Postnatal transmission through colostrum and breast milk. 4. IV drug abusers chance of transmission is 1.5 percent. 5. Needle prick in occupational set up chance of transmission is 0.3 percent (c.f. similar chance of hepatitis B transmission is 6-30%). Clinical Feature 1. Acute HIV infection after 3-6 weeks of primary infection. Symptoms low grade fever, malaise, headache, spontaneous resolution occurs. Diagnosis detection of p24 antigen. 2. Asymptomatic stage HIV replication continues even during clinical latency period. 3. Persistent generalized lymphadenopathy. 4. Early symptomatic disease: i. Generalized lymphadenopathy ii. Oral thrush iii. Reactivation of herpes zoster iv. Thrombocytopenia. Neurological diseases i. Aseptic meningitis ii. AIDS dementia complex or HIV encephalopathy. most common CNS manifestation of AIDS. iii. Lymphoma

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iv. Seizures most commonly due to toxoplasmosis; next is due to cryptococcal meningitis. v. GB syndrome vi. Progressive multifocal leukoencephalopathy (PML) due to JC virus; occurs years after infection. MRI scan shows multiple white matter lesions in T2. AIDS Definition: 1. Infections or malignancies that rarely occur in absence of immunodeficiency (e.g. P . carinii, CNS lymphoma etc.). 2. Positive HIV serology with some infection/malignancies that are more common in HIV patients (e.g. pulmonary TB, invasive cervical Ca). 3. Positive HIV serology with nonspecific conditions, e.g. dementia and wasting. 4. CD4 count < 200// l. Findings that are specific for and indicative of HIV: 1. Hairy leucoplakia of tongue 2. Disseminated Kaposis sarcoma 3. Cutaneous bacillary angiomatosis. Mean time interval to develop AIDS is 10 years from the initial infection. Opportunistic Infection Protozoa 1. Pneumocystis carinii most common opportunistic infection worldwide. Clinical feature: Fever, dyspnea, non-productive cough, tachypnea, tachycardia, cyanosis. Recurrent pneumonia due to P. carinii is the most common manifestation of childhood AIDS. Diagnosis: Chest X-ray shows bilateral pulmonary infiltrates (diffuse or perihilar). Upper lobe cavitary lesion in patients with pentamidine prophylaxis. Lobar infiltration, pleural effusion.

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Demonstration of trophozoite or cyst in samples obtained by induced sputum, BAL or transthoracic biopsy. Stain used is silver nitrate. Wright-Giemsa stain of induced sputum if negative, go for BAL. Treatment Co-trimoxazole is the drug of choice. Prophylaxis with aerolized pentamidine or systemic therapy with co-trimoxazole (best). Note: Extrapulmonary (most commonly to lymph nodes) involvement may occur. Pentamidine prophylaxis is a risk factor for that. 2. Toxoplasmosis It is the most common cause of secondary CNS infection. It is the most common cause of mass lesion in CNS. It is the most common cause of seizure in AIDS patients. 3. Cryptosporidiosis 4. Systemic strongyloidosis Bacteria 1. Tuberculosis most common opportunistic infection in India. It is one of the totally curable conditions in HIV infected persons. Organism in developing countries M. tuberculosis. In developed countries atypical mycobacteria (M. avium intracellulare). Mycobacterium avium complex infection in AIDS It occurs in patients with CD4 count < 100 l (late complication) Often the patient has < 10/ l CD4 count at the time of presentation. Clinical feature Fever, weight loss and night sweats, diarrhea, lymphadenopathy, liver involvement is common with increase in alkaline phosphatase level. Chest X-ray shows bilateral lower lobe infiltrates. Diagnosis demonstration of AFB in biopsy from bone marrow/lymph node or liver and stool specimen.

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Treatment clarithromycin (or azithromycin) + ethambutol rifabutin. 2. Others salmonella, campylobacter, nocardia, legionella. Fungal 1. Candidiasis most common fungal infection. 2. Cryptococcus neoformans most common cause of meningitis in AIDS. Treatment - amphotericin B. 3. Histoplasmosis 4. Aspergillosis 5. Coccidioidomycosis Viral 1. CMV most common viral infection. 2. Herpes simplex 3. E-B virus oral hairy leucoplakia. Infections according to CD4 count CD4 count Infection < 500/ l M. tuberculosis, candida, herpes zoster < 200/ l P. carinii, histoplasma, Cryptococcus, toxoplasma < 50/ l M. avium intracellulare (now 10/ l at the time of presentation), CMV Note: CD4 count provides information about the immunological status of the patient. Neoplasms 1. Kaposis sarcoma It is the most common malignancy in AIDS. It is not specific of AIDS as it is also seen after renal transplantation. It is not seen in childhood AIDS. More common in homosexual males and in women with bisexual partners. Origin Endothelial cells. They are multicentric, consisting of multiple vascular nodules appearing in the skin, mucous membrane and viscera (GI tract and lungs), lymph nodes.

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They are either indolent or aggressive but rarely invasive. Commonly seen in the lower limbs. Cause Herpes virus KSHV or HHV 8. Skin manifestation Nodular, reddish-purple. Site Sun-exposed skin most commonly on the tip of the nose. Propensity to occur on areas of trauma Koebner phenomenon. May be disabling when involves the lower extremities. Diagnosis Biopsy. Lymph node involvement occurs early and is of little significance. Treatment Localized irradiation Interferon and chemotherapy in disseminated disease. 2. Lymphoma 1. Grade III or IV immunoblastic lymphoma. 2. Burkitts lymphoma (B cell non-Hodgkins lymphoma) 3. Primary CNS lymphoma (non-Hodgkins ) second most common cause of SOL in brain in AIDS. 3. Intraepithelial dysplasia and neoplasia of the cervix or anus Malignancies common in childhood AIDS are nonHodgkins lymphoma, leiomyosarcoma. Others Gynecological: Vaginal candidiasis, PID, CIN. Ophthalmic manifestation: 1. Cotton wool spots most common fundoscopic finding due to ischemia of nerve fiber layer (cystoid bodies) 2. CMV retinitis most common opportunistic infection of eye in AIDS. Clinical feature - permanent painless, progressive loss of vision. Fundoscopy perivascular hemorrhage and exudates. Treatment - IV ganciclovir, foscarnet, cidofovir.

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CNC Perivascular giant cells (macrophages) are seen in frontal and temporal lobes, may produce infarction. Diffuse and focal spongiform changes. Microglial nodules most characteristic. Vacuolar myelopathy. Kidney: Focal segmental glomerulosclerosis (collapsing glomerulopathy) most common. Skin: Ichthyosis, seborrheic dermatosis. Immunology: Drug allergies, anaphylaxis is extremely rare. Diagnosis 1. Antigen detection: p24 (marker of active replication). Earliest test to be positive (after 2 weeks). 2. Antibody detection: IgG antibodies appear 4-8 weeks after infection (seroconversion). The time period between primary infection and detection of antibodies is called window period. a. ELISA test sensitivity > 99.5 percent. It is more sensitive but less specific than Western blot test. It is 50 percent positive after 22 days and 95 percent positive in 6 weeks. False positive ELISA is seen in recurrent influenza vaccination, connective tissue disorders. b. Karpas test c. Western blot test confirmatory and most specific. Specificity when combined with ELISA is >99.99 percent. 3. HIV RNA detection: It is the best predictor of disease progression, i.e. prognostic indicator. PCR is useful for at-risk infants gold standard investigation. Indication positive or intermediate ELISA and intermediate Western blot test results. Note: Antibody detection is unreliable in neonatal HIV (hence ELISA and Western blot). DNA-PCR is the preferred method in neonates.

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Treatment Antiretroviral therapy: Classification of antiretroviral drugs: a. Nucleoside reverse transcriptase inhibitors - purine (thymidine) analogue Zidovudine, lamivudine, stavudine, didanosine and zalcitabine. b. Nonnucleoside reverse transcriptase inhibitors Nevirapine, efavirenz and delavirdine. c. Protease inhibitors Ritonavir, indinavir, saquinavir, nelfinavir. Mechanism of action they act at a late stage; inhibit aspartate protease. Side effects 1. Zidovudine anemia and neutropenia (most common); headache and myalgia. 2. Peripheral neuropathy occurs with stavudine, zalcitabine and didanosine. 3. Pancreatitis didanosine (most common), zalcitabine. 4. Lamivudine relatively safe. 5. Protease inhibitors cause gastric intolerance, crystaluria by indinavir. Drug interactions Rifampicin induces metabolism of NNRTI and PIs. (rifabutin should be given in place of rifampicin). Ritonavir is contraindicated with both. Indication for therapy 1. All cases of symptomatic HIV disease. 2. Asymptomatic with CD 4 count <500/ l. 3. Asymptomatic with CD 4 count > 200/ l. with i. CD 4 count declines at the rate of 100 cell/ l. or ii. HIV-RNA > 20000 copies/ml. Regimens Initial case 2NRTI + 1 PI/ 2NRTI + 1 NNRTI/ 3 NRTI. Late case NRTI + NNRTI + PI/ Boosted PI (PI + low dose ritonavir) + 1 NNRTI. Antiretroviral therapy in pregnancy 1. Short-term/truncated regimen Zidovudine to mother during last few weeks of pregnancy or during labour and delivery and to infant for a week reduces the chance of transmission by 50 percent.

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2. Perinatal regimen Beginning in the second trimester plus during labour and delivery plus to infant for 6 weeks reduces the chance of transmission by 67-68 percent. Post-exposure prophylaxis: Combination of zidovudine, lamivudine and indinavir started as soon as possible after the injury for at least 4 weeks.

AMYLOIDOSIS
Amyloid is an amorphous, eosinophilic, hyaline, extracellular deposition. Structure 95 percent of any amyloid deposition consists of fibril protein. Remaining 5 percent consists of P component or other glycoproteins. Fibril proteins: In X-ray crystallography and infrared spectroscopy have pleated sheet structure. Light microscopy amorphous, eosinophilic, extracellular hyaline. Electron microscopy non-branching fibril of 7.5-10 nm width. Types with Etiology 1. AL amyloid protein in primary amyloidosis: i. They are immunoglobulins (light chains) derived from plasma cells. ii. Classically seen in multiple myeloma. iii. Macroglossia is a characteristic feature. 2. AA amyloid protein in secondary or reactive amyloidosis: i. They are non-immunoglobulin proteins derived from liver from serum amyloid associated protein. ii. Found in tuberculosis, leprosy, Hodgkins lymphoma, chronic osteomyelitis, bronchiectasis, rheumatoid arthritis (most common), ankylosing spondylitis, inflammatory bowel diseases and renal cell carcinoma.

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3. A amyloid protein: Found in cerebral lesions in Alzheimers disease and is derived from amyloid precursor protein. 4. 2 microglobulin: Deposited in the carpal ligaments of wrist joint (causing carpal tunnel syndrome) and in knee joints in patients on chronic hemodialysis. 5. AE proteins: Found in medullary carcinoma of thyroid. 6. Heredofamilial amyloidosis: i. Familial Mediterranean fever AA protein. ii. Familial amyloidotic neuropathies ATTR (mutant transthyretin) protein. 7. Amyloidosis of aging: Normal transthyretin is deposited in the heart. Clinical Presentation 1. Kidney: It is the most common and most serious involvement. It causes severe proteinuria (nephrotic syndrome), azotemia but no hypertension (only in 20-25% cases hypertension is seen). Grossly, the kidneys may appear normal. Renal failure is the most common cause of death in secondary amyloidosis. 2. Nervous system: Peripheral neuropathy especially in heredofamilial amyloidosis. 3. GI tract: Macroglossia is a characteristic feature in primary amyloidosis. 4. Spleen: When involves the splenic follicles (focal involvement) sago spleen. When involves the sinusoids in red pulp (diffuse involvement) lardoceous spleen. 5. Heart: Gray-pink dewdrop like subendocardial elevations are seen. Heart is most commonly involved in senile amyloidosis. Restrictive cardiomyopathy is the most common cause of death in primary amyloidosis. Diagnosis Biopsy Site rectum, gingival or intestine. Dye Congo red Shows bright pink under light microscopy and green birefringence under polarizing light.

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Note: Most common organ involvement in primary amyloidosis is heart. Most common organ involvement in secondary amyloidosis is kidney. Most common organ involvement in localized (nodular/ tumor forming) amyloidosis is lung.

IMMUNOLOGICALLY MEDIATED SKIN DISEASE


Please see the chapter of Dermatology. SYSTEMIC LUPUS ERYTHEMATOSUS This is an autoimmune disorder probably mediated by CD 4+ helper T cells, more common in females (in the child bearing age) and blacks. Pathogenesis Genes involved are MHC class II and complement system. T cell involved are the CD 4+ T cells. There is production of IgG autoantibodies. LE bodies or hematoxylin bodies are seen. Criteria 1. Malar rash erythematous maculopapular (butterfly rash). 2. Discoid rash 3. Photosensitivity 4. Oral ulcers 5. Arthritis nonerosive polyarthritis involving peripheral joints. 6. Serositis pleuritis and pericarditis. 7. Renal disorders: proteinuria > 0.5 gm/dL or > 3+ or cellular cast. 8. Neurologic disorders. 9. Hematologic disorders.

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10. Immunological disorders 11. Positive antinuclear antibody (ANA). Any 4 of the above 11 criteria are required for the diagnosis. Renal Disorder Class I Normal Class II Mesangial lupus glomerulonephritis mildest form. Class III Focal glomerulonephritis Class IV Diffuse proliferative glomerulonephritis most common and most serious renal lesion. When extensive, they produce wire loop appearance on light microscopy. Should be treated with aggressive immunosuppressant. Class V Membranous glomerulonephritis. Renal lesion in SLE is due to immune-complex disease. Features proteinuria, hematuria and RBC cast. Spleen Onion skin lesion. Neurological Disorders Seizures, psychosis and pseudotumor cerebri. Investigation EEG is abnormal in 70 percent cases. CSF shows elevated protein in 50 percent cases. Neurological symptoms improve with immunosuppressants. Hematological Disorders This is present in 100 percent patients with SLE. Anemia, usually normocytic normochromic but occasionally hemolytic. Leucopenia or lymphopenia Thrombocytopenia should be treated with glucosteroids. Immunologic Disorders Anti dsDNA antibody specific and diagnostic. Anti Sm antibody specific and diagnostic. Anti-phospholipid antibodies

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Antinuclear Antibody (ANA) Very sensitive but not specific best screening test. Cardiac Lesions Pericarditis, myocarditis, Libman-Sacks endocarditis non-infective verrucous endocarditis involving both sides of valve leaflets. Valvular incompetence. Other Features 1. 2. 3. 4. Thrombosis Hair loss non-scarring (lupus hair) Hypocomplementenemia LE cells are neutrophils or macrophages.

Antiphospholipid Antibodies Lupus anticoagulant (LA) and anti-cardiolipin (aCL) in blood produce Thrombocytopenia, Recurrent venous/arterial clotting Pulmonary embolism, hypertension Recurrent fetal loss Hypoprothrombinemia leading to bleeding False positive VDRL test. Effect on pregnancy Pregnancy induced hypertension, IUGR and abruptio placentae. Spontaneous abortion and stillbirths are frequent. In children Heart block is seen in babies born to SLE mothers due to anti Ro antibody. Arthritits and skin rash are common presenting symptoms in children. CNS and renal involvement are more common than adults. Treatment Indications of steroids in SLE i. Neuropsychiatric lupus ii. Nephrotic syndrome iii. Pericarditis, myocarditis (but not endocarditis) iv. Thrombocytopenia, hemolytic anemia

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Drug Induced SLE Drugs causing SLE are hydralazine, isoniazid, phenytoin and procainamide. Renal and CNS diseases are rare. Anti dsDNA antibody is absent. Anti-histone antibody is characteristic. RHEUMATOID ARTHRITIS Pathology Initially, the synovium becomes swollen or edematous. Microvascular injury and increase in the number of synovial lining cells appear to be the earliest lesion in RA. Pannus formation. May lead to fibrosis and calcification with permanent ankylosis. Note: Possible causative agents Mycoplasma, EBV, CMV. Pathogenesis Association with HLA DR 4 and/or HLA DR 1. Stages 1. Soft tissue proliferation 2. Early cartilage erosion. On X-ray there is reduction in joint space. 3. Bony changes X-ray shows para-articular erosion, subchondral cyst, juxta-articular rarefaction. Clinical Feature Age of onset 20-50 years. Sex women are affected three times more commonly than men. Note: Autoimmune disorders are more common in females. Articular 1. Morning stiffness 2. Bilateral symmetrical polyarthritis involving large and small joints.

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Joints involved are metacarpo-phalangeal and proximal interphalangeal joints (MP and PIP) of fingers (but not the distal interphalangeal joint). Axial involvement only the cervical spine. Deformities Swan-neck deformity, Z deformity. 3. Pain and swelling behind the knee due to extension of inflamed synovium into popliteal space (Bakers cyst). Extra-articular manifestations 1. Rheumatoid nodule Non-tender, up to 2 cm in size. Sites olecrenon bursa (most common), dorsal surface of forearm, tendo-Achilles. 2. Rheumatoid vasculitis Raynauds phenomenon, chronic leg ulcers. Peripheral neuritis (mononeuritis multiplex, treated by steroids). 3. Pleuropulmonary manifestations Pulmonary nodule, when associated with pneumoconiosis in diffuse nodular fibrosis, it is called Caplans syndrome. 4. Cardiac manifestation Asymptomatic pericarditis (serofibrinous) is found in 50 percent cases at autopsy. 5. Eye uveoparotitis (also seen in sarcoidosis). 6. Others i. Normocytic normochromic anemia ii. Feltys syndrome rheumatoid arthritis + splenomegaly + neutropenia and occasionally anemia and thrombocytopenia. iii. Anserine bursitis iv. Splenic infarcts. Laboratory Findings 1. Blood decreased Hb level and increased ESR (c.f. in osteoarthritis, these are not seen). 2. Rheumatoid factor is present in 80 percent of cases. It is an autoantibody (IgM type) reactive with the Fc portion of IgG. This is not specific for RA because RF is also found in tuberculosis, infectious mononucleosis and syphilis. It is associated with a bad prognosis.

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Tests for RF latex fixation test (most sensitive) and Rose-Waaler test. Treatment a. Disease modifying antirheumatic drugs gold, d-penicillamine, chloroquine and sulfasalazine. b. Surgery Preventive synovectomy Reconstructive c. Physiotherapy muscle-building exercise to gain strength. JUVENILE RHEUMATOID ARTHRITIS Onset before 16 years of age. Pauciarticular Involves 4 joints. 1. Iridocyclitis is observed in 25 percent cases. Other eye signs are complicated cataract, band shaped keratopathy. 2. Large joints of lower extremities usually the hip girdle is commonly affected. 3. A family history of ankylosing spondylitis may be present. 4. Associated with HLA B27. 5. X-ray shows epiphyseal enlargement. 6. Positive ANA, negative RF. Systemic (Previously Called the Stills Disease) Common in boys. Clinical features i. Intermittent fever ii. Evanescent maculopapular rash with central clearing most characteristic of Stills disease. iii. Hepatosplenomegaly iv. Lymphadenopathy v. Leukocytosis. vi. ANA may be present my RF is absent. Treatment naproxen, ibuprofen, pyroxicam (note aspirin was the previous drug of choice; but it is not used now because of the risk of Reyes syndrome).

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Polyarticular Involves 5 joints. ANA positive, may be RF positive. Uveitis may be present. SYSTEMIC SCLEROSIS/SCLERODERMA It is a multisystem disease of unknown etiology characterized by fibrosis of skin (most common, hence the name scleroderma), blood vessels and visceral organs (GI tract, lungs, heart and kidneys). Pathologic hallmark: Fibroblast activation and excessive fibrosis. Types 1. Diffuse: Characterized by rapid development of symmetric skin thickening of proximal and distal extremities, face and trunk. Greater chance of organ involvement. 2. Limited: Skin thickening limited to distal extremities and face. It is also known as the CREST syndrome for calcinosis, Raynauds phenomenon, esophageal dysmotility, sclerodactyly and telangiectasia. Clinical Feature 1. 2. 3. 4. Raynauds phenomenon Skin thickening, subcutaneous calcification. Arthritis GI tract esophageal dysmotility (rubber-hose like), dysphagia, pneumatosis intestinalis, malabsorption. 5. Pulmonary pulmonary fibrosis, pulmonary hypertension and aspiration pneumonia. 6. Congestive cardiac failure due to myocardial fibrosis. 7. Renal failure malignant hypertension. Diagnosis Autoantibodies Antitropoisomerase 1 specific for diffuse scleroderma. Anticentromere specific for limited scleroderma. ANA may be positive.

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Radiology: Diffuse periosteal reaction, esophageal dysmotility, erosion of the tip of the phalanges. Prognosis Patients with diffuse disease develop renal and other visceral disease early and have a worse prognosis. POLYMYOSITIS AND DERMATOMYOSITIS Clinical Feature 1. Gradual onset, symmetrical involvement 2. Weakness of the proximal limb muscles, especially the hip and thigh (Inability to rise from squatting position, climbing stairs, combing, etc.). 3. Patient may present with weakness of the large muscles of trunk, neck (flexion) and limbs (deltoid). 4. Ocular muscles are not involved. 5. May cause dysphagia, respiratory impairment. 6. In dermatomyositis erythematous maculopapular rash (Lilac colored or heliotrope rash) on eyelids. Laboratory Findings Elevated levels of enzymes creatine kinase, aldolase and lactate dehydrogenase. Anti-Jo antibodies (against tRNA synthetase) are common in polymyositis. Diagnosis Typical clinical picture, typical EEG, elevation of serum CK. Muscle biopsy diagnostic. Perivascular inflammatory cell infiltration is the hallmark of polymyositis. SJGRENS SYNDROME Primary form is idiopathic and is known as Sicca syndrome. Secondary form is associated with i. Rheumatoid arthritis (most commonly) ii. SLE iii. Polymyositis iv. Scleroderma v. Chronic active hepatitis

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vi. Sarcoidosis vii. Thyroiditis. Clinical Feature Dry mouth (xerostomia), dry eye (keratoconjunctivitis sicca) and bilateral enlargement of parotids. Other features synovitis, pulmonary fibrosis, peripheral neuropathy, increased risk of MALT lymphomas (pseudolymphoma). Differential Diagnosis Bilateral parotid gland enlargement 1. Mumps, EBV, influenza 2. Sarcoidosis 3. Sjgren syndrome 4. Diabetes mellitus 5. Chronic pancreatitis. 6. Amyloidosis 7. Cirrhosis 8. Acromegaly Diagnosis ANA and RF may be present. Anti RNP antibodies [SS-A (Ro) and SS-B (La)]. ANKYLOSING SPONDYLITIS Pathology Sacroiliac joint is the first joint to be involved. Earliest lesion is subchondral granulation tissue. Least affected is the elbow joint. Clinical Feature Common in males during early adulthood (15-30 years). Earliest symptom is low back pain. Peripheral involvement asymmetric polyarthritis. Others Acute anterior uveitis (most common extra-articular manifestation). Aortic insufficiency, cardiomegaly, pericarditis, conduction defect.

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Examination Schober test for measuring flexion of the lumbar vertebrae. Gaenlsens test for sacroiliac joint involvement. Fleches test for cervical spine involvement. Chest expansion < 5 cm. Investigation 1. X-ray lumbar spine shows i. Squaring of the vertebrae. ii. Loss of lumbar lordosis iii. Bamboo-spine appearance. Others Haziness of the sacroiliac joint is the first change on X-ray. Subchondral erosion. Enthesopathy calcification of tendons, ligaments and muscle attachments. Bony ankylosis. 2. Genetic marker HLA B 27 is present in > 85 percent cases. 3. Mild anemia. REACTIVE ARTHRITIS Acute non-purulent arthritis complicating an infection elsewhere in the body. Reiters Syndrome Triad of i. Arthritis ii. Urethritis iii. Conjunctivitis With additional mucocutaneous lesions. Etiology: Most commonly associated with Shigella flexneri infection (diarrhea) and chlamydia. Associated with HLA B27. Others Yersina, Campylobacter, Salmonella, ureaplasma urealyticum and Mycoplasma genitalium.

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Skin lesion: Characteristic skin lesion is called keratoderma blenorrhagica. On glans penis produce circinate balanitis. Treatment: Indomethacin is the drug of choice. BEHETS SYNDROME It is a multisystem disorder presenting with recurrent oral and genital ulceration with ocular involvement. Epidemiology Worldwide distribution. Affects mainly young adults. Males having more serious disease than females. Associated with HLA B5.

Clinical Feature Recurrent apthous ulceration sine-qua-non for diagnosis. Eye hypopyon uveitis. Arthritis, superficial and deep vein thrombosis, Pulmonary emboli. Diagnosis Pathergy test a non-specific skin inflammatory reactivity to any scratches or intradermal saline injection. Treatment Symptomatic; steroids.

VASCULITIS SYNDROMES
POLYARTERITIS NODOSA (PAN) This is a necrotizing vasculitis of small to medium size arteries of any organ except the lungs. Pathology Characterized by segmental transmural necrotizing inflammation of medium to small size arteries.

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Acute stage polymorphonuclear cell infiltration with fibrinoid necrosis. Chronic stage fibrous thickening may produce nodules. Segmental erosion with weakening of arterial wall may cause aneurysmal dilatation and rupture. Clinical Feature PAN is often preceded by a history of bronchial asthma. Kidney renal involvement is most common with hypertension but no glomerulonephritis. GI tract abdominal pain and melena. Muscular pain. Peripheral neuritis (motor). Skin palpable purpura, livedo reticularis, cutaneous infarcts (digital gangrene). Diagnosis 1. Renal biopsy 2. p-ANCA positive in < 20 percent cases. Classical PAN is ANCA negative. 3. Hepatitis B antigenemia. Treatment Cyclophosphamide, steroids. CHURG-STRAUSS DISEASE Allergic angitis and granulomatosis characterized by granulomatous vasculitis of multiple organ systems, particularly the lungs (c.f. PAN, where lungs are not involved). Vasculitis may involve vessels of any size or type (vein or arteries). Association with asthma or peripheral eosinophilia. WEGENERS GRANULOMATOSIS Pathology Necrotizing vasculitis of small arteries and veins together with granuloma formation typically involving the respiratory tract.

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Lung involvement multiple bilateral nodular cavitary lesions. Clinical Feature Persistent pneumonitis is the most common presentation. Typically presents with paranasal sinus pain and purulent or bloody nasal discharge. Serous otitis media conductive deafness. Renal involvement proteinuria, hematuria (cresenteric glomerulonephritis). Lower respiratory tract infection cough, hemoptysis, dyspnea. Skin palpable purpura. Investigation c-ANCA positive, increased ESR, increased IgA level, may be RF positive. But complement levels remain normal. Treatment Treatment of choice is cyclophosphamide. MICROSCOPIC POLYANGIITIS Necrotizing vasculitis affecting arteries, capillaries and venules. More commonly involves the lungs (causing hemoptysis) and kidneys (90%) causing glomerulonephritis. p-ANCA is positive in over 80 percent cases.
Vasculitis causing necrotizing inflammation 1. Polyarteritis nodosa 2. Churg-Strauss disease 3. Microscopic polyangiitis Vasculitis causing granuloma 1. 2. 3. 4. Giant cell arteritis Takayasus arteritis Wegners granulomatosis Churg-Strauss disease

MONONEURITIS MULTIPLEX Causes: 1. PAN the most common cause. 2. Hypersensitivity vasculitis.

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3. Leprosy most common cause in India. 4. Rheumatoid arthritis. Treatment: Steroids. TEMPORAL ARTERITIS (GIANT CELL ARTERITIS) It is a granulomatous inflammation characteristically involving one or more branches of the carotid artery, particularly the temporal artery. Vertebral and ophthalmic arteries are also involved. Clinical Feature Age of onset about 70 years, female preponderance. Symptoms: Headache is predominant symptom (most commonly temporal headache). It is unilateral but may be bilateral, dull and boring with episodic lancinating pain, worse at night and aggravated by exposure to cold. May cause ischemic optic neuritis which leads to sudden blindness. Claudication of tongue, jaw, scalp pain. Sign Tender thickened or nodular artery, which may be pulsatile. Polymyalgia rheumatica stiffness and pain in muscles of neck, back and thigh. Fever, anemia and weight loss. Diagnosis Increased ESR. Liver function increased alkaline phosphatase. Temporal artery biopsy is confirmatory. Treatment NSAIDs, glucosteroids. TAKAYASUS ARTERITIS It is characterized by fibrous thickening of aorta and its branches (most commonly the subclavian artery).

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Pathology Intimal proliferation and fibrosis Vascularization of the media Degeneration of the elastic lamina. Clinical Feature Common in younger females (< 40 years). Ocular symptoms blindness. Absent pulses in the upper extremities (pulseless disease). Asymmetric radial pulse. Renal artery stenosis may cause hypertension.

KAWASAKIS DISEASE Also known as mucocutaneous lymph node syndrome. Characterized by 1. 2. 3. 4. Nonspecific cervical lymphadenopathy. Congested conjunctiva (conjunctivitis). Erythema of the oral cavity, lips and palms. Desquamation of the skin of the fingertips.

Others Occurs in children with prolonged fever (for > 5 days) that is unresponsive to antibiotics. Associated with coronary artery aneurysm, myocarditis and even myocardial infarction. Blood thrombocytosis and increased ESR. Treatment High dose IV gamma globulin. Note: Best result occurs with IV gammaglobulin in Kawasakis disease.

SARCOIDOSIS
Pathology It is characterized by non-caseating epitheloid granuloma. Granulomas contain Langerhans or foreign body type of giant cells. These cells contain 3 types of inclusion

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bodiesSchaumann body, asteroid body and residual body. Clinical Feature Lungs Involved in 90 percent cases. It is an interstitial lung disease. Pleural effusion (unilateral) is seen in 1-5 percent cases. Lymphadenopathy Bilateral hilar lymphadenopathy Paratracheal nodes. Skin: Erythema nodosum, lupus pernio. Eye Most common involvement after the lungs. Anterior uveitis (causing blurred vision) and keratoconjunctivitis sicca. Kidney: Rarely involved. May cause hypercalciuria with or without hypercalcemia. Renal stones, if chronic. Nervous system: Unilateral facial paralysis. Endocrine: Diabetes insipidus, Addisons syndrome. Exocrine: Bilateral parotid gland enlargement. Note: Uveoparotitis is seen in rheumatoid arthritis and sarcoidosis. Laboratory Findings Chest X-ray Bilateral hilar lymphadenopathy is the hallmark of sarcoidosis. Other features eggshell calcification, military shadow. Cavitation is rare. Blood: False positive RF and ANA. Increased ACE level (60% cases). Skin: Kveim-Siltzbach skin test. Biopsy Most commonly from the lungs shows non-caseating granuloma.

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Bronchoalveolar lavage shows Increased lymphocytes, increased CD4:CD8 ratio. Gallium 67 lung scan, CECT chest. Treatment Prednisolone. 50 percent cases resolve spontaneously. Prognosis Most common cause of death is due to respiratory failure due to interstitial lung disease.

DISEASES OF JOINTS
OSTEOARTHRITIS This is a degenerative condition. Predisposing Factors 1. 2. 3. 4. 5. 6. Congenital malformation of a joint. Irregularity of the joint surface from previous trauma. Damaged articular surface. Internal derangement of the knee such as a loose body. Mal-alignment (bow legs). Obesity and excessive weight. Osteoarthritis occurs at an early age in Ehler-Danlos syndrome.

Pathology First change is an increase in water content and depletion of the proteoglycans from the cartilage matrix. Fibrillation, osteophyte formation. Clinical Feature Knee is the most common involvement. Hand DIP and PIP joint are the most commonly involved with sparing the wrist and MCP and CMC joints except at the base of thumb. DIP Heberdens node, PIP Bouchards node.

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Radiology 1. 2. 3. 4. 5. Narrowing of joint space Subchondral sclerosis Osteophyte formation Loose bodies in joint Subchondral cyst.

Treatment: Glucosamine and chondroitin sulphate. Total joint replacement. PSEUDOGOUT Deposition of CPPD (calcium pyrophosphate dehydrate) crystals in articular cartilage, synovium, periarticular ligaments and tendons. Clinical Feature Knee is most commonly involved. Meniscal calcification (chondrocalcinosis). Investigation: Polarizing microscopy rhomboid crystals with weak positive birefringence in the extracellular fluid and in neutrophils. Treatment Joint aspiration, NSAIDs and intra-articular glucocorticoid injection. INFECTIVE ARTHRITIS Organism Staphylococcus aureus is the most common cause of nongonococcal arthritis. Pathology Exudation of fluid within the joint space. It is the most common cause of ankylosis. Clinical Feature Monoarticular arthritis. Knee is the most commonly involved joint. Note: Most common cause of infective polyarticular arthritis is gonococcus. Diagnosis Joint aspiration best method.

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PSORIATIC ARTHRITIS Asymmetric polyarthritis involving the distal joints of hand and foot. PIP and DIP are the most commonly involved with sausage-shaped digits (dactylitis). Onychodystrophy onycholysis, ridging and pitting of nails. This helps it to be distinguished from rheumatoid arthritis. Sacroilitis. X-ray Pencil-in-cup appearance, opera glass deformity. Laboratory Findings RF may be positive. Uric acid levels may be increased. ARTHRITIS IN INFLAMMATORY BOWEL DISEASES Symmetric, migratory polyarthritis affecting mainly the large joints of the lower extremities most commonly the knee joint.
Joint involvement in arthritis Rheumatoid arthritis Osteoarthritis MP and PIP joints of hand Spares the DIP PIP and DIP of hand but spares the MCP and CMC (wrist) joints except at the base of the thumb i.e. the first CMC joint is also involved. PIP , DIP , MCP with or without the wrist joint.

Psoriatic arthropathy

SERONEGATIVE ARTHRITIS Causes 1. 2. 3. 4. 5. Ankylosing spondylitis Reiters arthritis Psoriatic arthritis Enteropathic arthritis (IBD) Reactive arthritis

Clinical Feature Involvement of the sacroiliac joint. Absence of rheumatoid factor (hence called seronegative). Association with HLA B 27.

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ARTHRITIDES Neuropathic Joint Disease (Charcots Joint) Causes 1. Diabetes mellitus affects the tarsal and tarsometatarsal joints of foot. 2. Tabes dorsalis knees, hips and ankles are most commonly involved. 3. Syringomyelia shoulder, elbow. 4. Amyloidosis 5. Leprosy. Clinical feature: Progressive, painless swelling of joints with articular destruction. Tietzes Syndrome Painful swelling of costochondral joint, most commonly the second and third costochondral joints. HEMOPHILIC ARTHROPATHY Hemophilia is the most common cause of acute or chronic hemarthrosis. Most commonly involved joints are the knees. X-ray feature i. Juxta-articular osteopenia, marginal sclerosis and subchondral cyst. ii. Osteoporosis. iii. Widening of the femoral intercondylar notch. iv. Enlargement of the proximal radius. v. Squaring of the distal end of patella. Note: Bleeding may occur into the joint space. Blood remains liquid because of the absence of intrinsic clotting factors. Most common muscle into which bleeding may occur is iliopsoas. ALKAPTONURIC ARTHRITIS Seen in alkaptonuria (a defect of metabolism of phenylalanine). Spine and shoulders are most commonly involved. X-ray shows characteristic disc space calcification (ocronosis).

6
Nephrons

RENAL SYSTEM

PHYSIOLOGY

Types: 1. Cortical nephron- 85 percent. 2. Juxtamedullary nephron-15 percent. They have long loops. Renal tubule: 1. Proximal convoluted tubule- 15 mm long, lined by columnar epithelium. 2. Descending loop of Henle- lined by flattened epithelium. 3. Ascending loop of Henle- lined by cubical epithelium. 4. Distal convoluted tubule- 5 mm long, lined by cuboidal epithelium. Note: Urothelium or Transitional cell lining is present in bladder, ureter and urethra. Juxtaglomerular apparatus: Formed by juxtaglomerular of JG cells (which secret renin), the macula densa and the lacis cells. JG cells are smooth muscular cells (epitheloid cells) in the afferent arterioles of glomerulus. Renal medulla: Is made up of loop of Henle, vasa rectae and renal pyramids. Renal cortex: Is made up of superficial and juxtamedullary glomerulus, arcuate artery and vein, interlobular artery and capillary bed. Renal Blood Flow Measurement: By infusing p-aminohippuric acid (PAH) and measuring its concentration in urine and plasma. Value: The value obtained by above method is called Effective Renal Plasma Flow (ERPF). In humans, ERPF= 625 ml/min.

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Renal blood flow accounts for 20 percent of cardiac output. Regulation of renal blood flow: 1. Norepinephrine- constricts renal vessels (afferent). 2. Dopamine- dilates renal vessels. 3. Angiotensin II constricts efferent vessels. 4. Acetylcholine- dilates renal vessels. Regional blood flow and O2 consumption: Arteriovenous O2 difference for whole kidney is 14 ml/L of blood.
Blood flow (ml/gm/min) 1. 2. 3. Cortex Outer medulla Inner medulla 5 2.5 0.6 O2 consumption (ml/gm/min) 7 3.5 0.084

Glomerular Filtration Rate Measurement: Substances used are 1. Creatine clearance- good measure (normal plasma creatinine= 0.6-1.2 mg/dl) 2. Inulin best. 3. 51Cr-EDTA 4. Tc99DTPA Value: 125 ml/min Filtration fraction: The ratio of GFR and the renal plasma flow. Filtration barrier: It is made up of 1. Podocytes, 2. Basement membrane, 3. Capillary endothelium. Tubular Function Na+ - excreted amount 150 mEq/24hr. Na+ Absorbed from PCT (maximum), DCT, CD except thin portion of loop of Henle. Glucose, amino acids and HCO3 - absorbed along with Na+ in the early portion of PCT. PAH - secretion is a linear function of plasma level (hence, PAH is used to measure ERPF). Urea clearance - 88 ml/min. K+ - reabsorbed only in PCT and secreted in DCT.

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Water Clearance Water loss as sweat - 600-800 ml/day. 60-70 percent of filtered water (GFR) is reabsorbed in PCT. Water is reabsorbed from PCT, DCT, descending loop of Henle, CD. Acidification of Urine HCO3 reabsorption is associated with H+ secretion and occurs maximally in PCT. H+ secreted by renal tubular cells reacts with NH3 (also secreted) to produce NH4+ which is responsible for acidification of urine. Minimum pH that can be attained in urine is 4.8. Bladder Function Emptying of bladder: The first urge to void is felt at bladder volume of 150 ml. Marked sense of fullness at about 400 ml. Regulation of Renin Secretion Stimulatory: 1. Increased sympathetic activity. 2. Increased circulatory catecholamines. 3. PGs. Inhibitory: 1. Increased Na+ and Cl reabsorption across macula densa (at DCT). 2. Increased afferent arteriolar pressure. 3. Angiotensin II. 4. Vasopressin. ACUTE RENAL FAILURE Definition: ARF is a syndrome characterized by rapid decline in GFR (hours to weeks), retention of nitrogenous waste products (azotemia) and disturbance in ECF volume and acid-base homeostasis. Oliguria (<400 ml urine in 24 hours) is the major symptom of ARF.

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Types with etiology: I. Pre-renal azotemia: diseases that cause renal hypoperfusion. Causes1. Hypovolemia. 2. Low cardiac output. 3. Altered renal-systemic vascular resistance ratio. Note: Most common cause of post-operative renal failure is decreased renal perfusion due to hypovolemia. II. Renal azotemia: Causes1. Acute tubular necrosis (ATN)- most common cause of ARF (hence the terms ARF and ATN are often used synonymously). 2. Glomerular disease. 3. Interstitial nephritis. III. Post-renal azotemia: Due to urinary tract obstruction. Pre-renal Azotemia Hepatorenal syndrome- reversible. Urine-NAD. Renal Azotemia Causes1. Ischemic ARF 2. Nephrotoxic ARF Ischemic ARF Etiology: 1. Hypovolemia and shock. 2. Trauma. 3. Acute pancreatitis. 4. Septicemia. 5. Hemolytic crisis. Pathology: 3 phases 1. Initiation phase- GFR declines rapidly. 2. Maintenance phase- GFR stabilizes at its nadir (typically 5-10 ml/min), urine output is lowest and uremic complications arise. 3. Recovery or diuretic phase- gradual improvement of GFR marked diuresis.

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Nephrotoxic ARF Etiology: 1. Heavy metals- mercury, Pb, As (produce PCT necrosis). 2. Organic solvents- carbon tetrachloride. 3. Radiographic contrast agents. 4. Aminoglycoside toxicity- non-oliguric renal failure. 5. Rhabdomyolysis and hemolysis. 6. Multiple myeloma- Tamm-Horsfall protein. Renal Failure Indices Helps in distinguishing prerenal and renal azotemia. 1. Fractional excretion of sodium (FeNa)- most useful 2. Urine Na+ concentration (UNa) 3. Urine creatinine to plasma creatinine ratio 4. Urine specific gravity (SG) 5. Urine osmolality (UO)
Index 1. 2. 3. 4. 5. FeNa (%) UNa (mmol/L) UCr : P Cr Specific gravity Urine osmolality (mosmol/kg H2O) 6. Serum urea: Creatinine 7. Renal failure index Pre-renal azotemia Renal azotemia <1 <10 >40 >1.018 > 500 >20 < 1 >1 >20 >20 <1.015 <300 <10 > 1

Complications of ARF General: 1. Intravascular volume overload. 2. Electrolyte disturbance- hyponatremia, hypocalcaemia, hyperkalemia, hyperphosphatemia, and hypermagnesemia (decreased Na+ and Ca++; increased K+, PO4, Mg++). 3. Metabolic acidosis with increased anion gap. 4. Anemia. Rhabdomyolysis: Hyperkalemia, hyperphosphatemia, hypercalcemia and increased serum uric acid and increased CK (Creatine kinase). Recovery phase: Vigorous diuresis leads to intravascular volume depletion, hypernatremia and decreased K+, Mg++, PO4, Ca++.

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CHRONIC RENAL FAILURE Definition: Progressive and irreversible destruction of nephron mass. Etiology: 1. Diabetes mellitus 2. Hypertension 3. Glomerulonephritis Stages: GFR 35-50 percent of normal- no symptoms. GFR 20-35 percent of normal- azotemia appears. GFR 20 percent or less of normal- overt renal failure. Effects of Uremia 1. Fluid and electrolytes: Hyper/hyponatremia Hyper/hypokalemia Hypocalcaemia Hyperphosphatemia Metabolic acidosis 2. Endocrine-metabolic: Secondary hyperparathyroidism Aluminium induced osteomalacia- due to dialysis Vitamin D-deficient osteomalacia Hyperuricemia Infertility and sexual dysfunction 3. Neuromuscular: Peripheral neuropathy, myelopathy Dialysis dementia- Al+3 may be the cause 4. Cardiovascular: Congestive heart failure and/or pulmonary edema Pericarditis Uremic lung 5. Dermatology: Pruritus 6. Hematological: Normocytic normochromic anemia Note: All the complications are improved by dialysis except sexual dysfunction and pruritus. Renal Osteodystrophy Radiological examination of uremic patients before dialysis reveals 3 types of lesions:

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1. Renal rickets 2. Osteitis fibrosa cystica- due to secondary hyperparathyroidism; characterized by osteoclastic bone resorption and subperiosteal erosion, especially in terminal phalanges. 3. Osteosclerosis- enhanced bone density in the upper and lower margins of vertebrae, producing so-called rugger jersey spine. (Note: Difference with osteomalacia- in osteomalacia, serum Ca++ decreased and PO43 decreased. In renal osteodystrophy Ca++ decreased but PO43 either normal or increased). DIALYSIS Principle: Diffusion across a semipermiable membrane. Indications: 1. Plasma urea>30 mmol/L and creatinine >600 mol/L 2. Hyperkalemia 3. Fluid overload 4. Uremic pericarditis 5. Convulsion 6. Metabolic acidosis (pH < 7.2) 7. Encephalopathy 8. Coagulopathy. Note: Dialysis should be started when GFR = 10 ml/ min or serum creatinine is 8 mg/dl. Hemodialysis Types: 1. Conventional hemodialysis 2. Slow continuous ultrafiltration 3. Continuous arteriovenous hemodialysis (CAVHD) 4. Continuous venovenous hemodialysis (CVVHD) Complications: 1. Infection- most common organism is Staph. aureus 2. Hypotension 3. Dementia- long-term 4. Microcytic anemia secondary to5. Aluminium toxicity 6. Mechanical- blood leak

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7. Cardiovascular disease 8. Malnutrition Peritoneal Dialysis Types: 1. Intermittent peritoneal dialysis (PID) 2. Continuous ambulatory peritoneal dialysis (CAPD) 3. Continuous cyclic peritoneal dialysis (CCPD). Advantage: 1. Avoidance of heparization and vascular surgery 2. Slower clearance (helpful in cardiovascular patients) 3. Self-amenable. Disadvantage/complications: 1. Peritonitis- most common 2. Protein loss- malnutrition 3. Hypercholesterolemia and hypertriglyceridemia- obesity Contraindications: 1. Pulmonary disease 2. Extensive abdominal adhesion 3. Scleroderma, vasculitis 4. Malignant hypertension. RENAL TRANSPLANT Indications: Advanced CRF. The transplant: Usually the left kidney of a cadaver is selected because it has a longer artery than right side. Immunosuppression: Drugs used are 1. Azathioprine- most commonly used 2. Mycophenolate mofetic 3. Cyclosporin 4. Tacrolimus 5. Sirolimus 6. Glucocorticoids. Complications: 1. Pulmonary infection- most commonly by Pneumocystis carinii Treatment- cotrimoxazole 2. Malignancy- most common is cancer of the skin and lips.

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Transplant Rejection a. Hyperacute rejection: Occurring immediately- most common type. Cause- preformed antibodies against HLA class I antigens expressed by the donor. Pathology due to intravascular thrombosis. The graft in hyperacute rejection is called the white graft. It is avoidable by prior immunosuppression. b. Acute rejection: Mediated by T-lymphocytes, occurring within 6 months. Pathology characterized by mononuclear cell infiltration. It can be reversed by immuno suppressive therapy. c. Chronic rejection: It is due to antibody and cell mediated effector mechanism. Most important risk factor for chronic rejection is acute rejection. Diagnosis: Most sensitive and specific indicator of rejection is creatinine clearance. Best investigation to detect early graft rejection is Doppler ultrasound. Radionuclid study is also used. Prognosis: Recovery of renal function after renal transplant takes about 1 month. Diseases that can recur after renal transplantation are diabetes mellitus, membrano-proliferative GN, and focal segmental glomerulosclerosis. Disease that never recur after renal transplantation is Alports syndrome. GLOMERULOPATHIES Acute Nephritic Syndrome Onset: very acute (over days to weeks). Characterized by1. Acute renal failure and oliguria

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2. Macroscopic hematuria- with dysmorphic red cells and RBC cast in urine. 3. Extracellular fluid retention, edema and hypertension. Pathology with Types There are 3 basic pathologies involved in acute nephritic syndromeI. Immune-complex glomerulonephritis: (>70%) Characterized by Hypocomplementemia Normal ANCA and anti-GBM antibody Granular deposition of Ig along GBM. Types: 1. Idiopathic Proliferative GN Crescentic GN Mesangioproliferative GN 2. Post-streptococcal GN- Most important 3. Systemic diseases Lupus nephritis H-S purpura Cryoglobulinemia Bacterial endocarditis Basic pathology: Proliferation- due to infiltration of glomerular tuft by neutrophils and monocytes and subsequently to proliferation of resident endothelial and mesangial cells (endocapillary proliferation). II. Anti-GBM disease: (Very rare <1%) - mainly crescentic. Characterized by Anti-GBM antibody in blood No ANCA and normal C3 Linear deposition of Ig along GBM Types: 1. Idiopathic 2. Goodpastures syndrome III. Pauci-Immune GN: (<30%) - Mainly crescentic. Characterized by ANCA in blood No anti-GBM antibody and normal C3

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Types: 1. Wegeners granulomatosis 2. Microscopic PAN 3. Idiopathic


ANCA positive glomerulonephritis pANCA Microscopic polyangiitis Goodpastures disease Churg Strauss disease Cresentic glomerulonephritis cANCA Wegeners granulomatosis Active glomerulonephritis

Note: PAN does not cause glomerulonephritis.

Rapidly Progressive/Crescentic GN (RPGN) Onset- weeks to months. Features: Nephritic urinary cast (RBC cast, dysmorphic RBC) and subnephrotic proteinuria (<3.5 gm/24 hours). Oliguria, hypertension, edema and hypervolemia are variable features. Pathology: Whatever may be the cause, RPGN in characterized by presence of crescents in most of the glomeruli. Crescents are made up by proliferation of parietal cells and migration of monocytes with multinucleated giant cells. Etiology: 1. Type I CrGN (Anti-GBM)-very rare <10 percent i. Idiopathic ii. Goodpastures syndrome 2. Type II CrGN (Immune complex) - 45 percent i. SLE ii. Postinfections iii. H-S purpura 3. Type III CrGN (Pauci-immune) - 45 percent. Treatment of RPGN: 1. IV pulse methylprednisolone 2. Plasmapheresis 3. Combination of prednisolone, cyclophosphamide and anticoagulants. Prognosis: Depends upon the number of crescents.

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Diagnosis of ANS and RPGN: 1. Renal biopsy- gold standard 2. Immunofluorescence microscopy 3. Serology- for C3, anti-GBM antibody and ANCA (antinuclear cytoplasmic antibody). Post-streptococcal GN It is the prototype of acute proliferative immune-complex disease. Epidemiology: Age- 2-6 years. Cause: Streptococcal infection (group A -hemolytic). Predisposing illness: i. Sore-throat (pharyngitis) - by strain 4 and 12, develops after 10 days; common in winter, may cause epidemic. ii. Skin (impetigo) - by strain 49; common in summer. Note: Early treatment of throat/skin infection does not eliminate the risk of glomerulonephritis. Clinical features: Puffiness around eyes and edema of the feet Hypertension. Complications: 1. Convulsions- due to hypertensive encephalopathy 2. LVF 3. ARF (CRF is very rare in PSGN). Diagnosis: 1. Urine: Smoky due to gross hematuria, RBC cast, dysmorphic RBC. 2. Serology: Increased ASO, increased anti-DNAse B, antistreptokinase, antihyaluronidase- indicates recent streptococcal infection. Decreased C3 and Ig. 3. Immunofluorescence: Deposition of IgG and C3 along GBM- Starry sky appearance. 4. Renal biopsy: Mostly proliferative (subepithelial humps) changes. May show crescents. Goodpastures Disease It is the prototype of Anti-GBM disease. Etiology: Autoantibody directed against type IV collagen.

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Clinical features: 1. Renal- hematuria, nephritic urinary sediment and subnephrotic proteinuria (that of RPGN). 2. Pulmonary- hemoptysis-precedes hematuria Hypertension is unusual. Pathology: Anti-GBM disease mainly presents as crescentic GN (RPGN). Diagnosis: Renal biopsy. Treatment: As in RPGN Plasmapheresis is the treatment of choice. Pauci-immune GN Mainly presents as RPGN. There is overlapping between proliferative and crescentic GN. Treatment steroids with or without cyclophosphamide/ azathioprine. NEPHROTIC SYNDROME Features: 1. Massive proteinuria (>3.5 gm/24 hours) 2. Hypoalbuminemia (<3 gm/dl) 3. Edema- most obvious sign. 4. Hyperlipidemia and lipiduria 5. Hypercoagulability: Pathology: 1. Proteinuria: Altered permeability of the glomerular filtration barrier to protein. 2. Hypoalbuminemia: Due to i. Proteinuria ii. Increased renal catabolism iii. Inadequate hepatic production. 3. Edema: Underfilling hypothesis Hypoalbuminemia decreased plasma oncotic pressure leakage of ECF from blood to interstitium activation of renin-angiotensin-aldosteron system and release of ADH with suppression of ANP salt and water retention more leakage of fluid into the interstitium.

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4. Hyperlipidemia- increased hepatic production of lipoprotein. 5. Hypercoagulability: Increased fibrinogen Decreased antithrombin III, protein C and S. Classification: a. In children most cases are idiopathic. Minimal change disease is the most common type. Significant lesions include mesangial proliferative (most commonly), FSGS, MPGN (in children over 8 years). b. In adults Idiopathic membranous GN is the most common type. Secondary due to various causes. Complications: 1. Protein malnutrition 2. Microcytic hypochromic anemia 3. Hypocalcemia and secondary hyperparathyroidism 4. Infections- due to low IgG. 5. Pulmonary embolism, DVT 6. ARF . Minimal Change Disease (Nil Disease or Lipoid Nephrosis) This is the most common cause of nephrotic syndrome in children between 3-8 years of age. Pathology: On light microscopy no change is seen. Only pathological change on EM is- loss of foot processes of the podocytes of visceral epithelial cells. Glomerular function is lost due to loss of poly charge on both sides of glomerular foot process. Pathogenesis: Mutations in the nephrin gene give rise to congenital nephrotic syndrome (Finnish type) with minimal change morphology. Nephrin (NPHS1) is located on chromosome 19q13. Podocin (NPHS2) is associated with an autosomal recessive form of FSGS.

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Clinical features: Selective proteinuria. Diagnosis: Hyaline or granular cast in urine Renal biopsy- not required. Treatment: Prednisolone most effective among the nephrotic lesions. Prognosis: Excellent. May progress to FSGS. Focal and Segmental Glomerulosclerosis with Hyalinosis (FSCG) Characterized by sclerosis with hyalinosis involving portions (segmental) of <50 percent (focal) glomeruli. Variants: i. Collapsing worst prognosis. Characterized by proliferation and hypertrophy of glomerular visceral epithelial cells. ii. Cellular tip lesion best prognosis. Etiology: i. HIV infection Collapsing FSG. ii. Reflux nephropathy iii. SLE iv. Heroin use. Clinical feature: Presents as nephrotic (in 2/3rd cases) or nephritic (in 1/3rd cases) syndrome. Membranous Glomerulopathy Most common cause of idiopathic nephrotic syndrome in adults. Pathology: Diffuse thickening of GBM, most apparent on staining with PAS. It is the Most common cause of renal vein thrombosis. Subepithelial deposits (spike and dome pattern) are seen. Etiology: 1. Infection- Hepatitis B and C, malaria, syphilis, leprosy, filariasis, schistosomiasis. 2. SLE

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3. Ca breast and lung 4. Drugs- gold and penicillamine 5. Miscellaneous- Fanconis syndrome Membrano (Mesangio) Proliferative GN (MPGN) Pathology: Thickening of GBM, and proliferative changes on LM. This is caused by Splitting of the GBM. Type I MPGN (2/3)- subepithelial or mesangial deposits of IgG or IgM and C3. Type II MPGN (1/3)- dense deposit disease. Deposition of only C3 in the GBM and mesangium. (presence of autoantibody C3 nephritic factor); tram track appearance. Treatment: These patients are not responsive to steroid therapy. Isolated Hematuria - IgA Nephropathy (Buergers Disease) Pathology: Immune-complex disease with normal C3 level in blood. Deposition of IgA in the mesangium (hence, a type of MPGN) proceeds from diffuse proliferative to focal and segmental involvement. IgA complex contains IgA, C3, properdin and IgG or IgM (in 50% cases). Clinical features: Age- commonly affects children and young adults. Patients present with gross hematuria often 24-48 hours after a pharyngeal or gastrointestinal infection. (c.f. HS purpura presents 10-12 days after infection). May present with microscopic hematuria at routine examination with or without proteinuria. Hypertension is unusual presentation. Etiology: 1. H-S purpura 2. Idiopathic interstitial pneumonitis 3. Crohns disease 4. Leprosy 5. Ankylosing spondylitis 6. Sjgrens syndrome

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Treatment: Corticosteroids. Note: Subepithelial deposits are seen in PSGN, membranous GN and RPGN. Subendothelial deposits are seen in MPGN and SLE. GLOMERULOPATHIES IN SYSTEMIC DISEASES Diabetic Nephropathy Changes in kidneys associated with diabetes are: Gross: Kidneys are normal or increased in size. Microscopic: 1. Capillary basement membrane thickening. 2. Diffuse glomerulosclerosis - most common lesion. 3. Nodular glomerulosclerosis - also called KimmelstielWilson lesion most characteristic. 4. Renal atherosclerosis and arteriosclerosis. 5. Pyelonephritis - including necrotizing papillitis. Clinical feature: Microalbuminuria (30-300 mg/dl). Wegeners Granulomatosis Type III CrGN (pauci-immune) Treatment: Glucocorticoids and cyclophosphamide. Hemolytic-Uremic Syndrome Pathology: Hyaline thrombi only in the afferent arterioles and glomerular capillaries in kidney. Pathogen: In India, Shigella dysenteriae type 1 Others - E. coli (EHEC O157:H7) Toxin - verotoxin Clinical features: Microangiopathic hemolytic anemia- pallor (Coombs ve) Thrombocytopenia- purpura Acute renal failure- oliguria Fever Onset is preceded by an acute diarrheal or dysenteric illness

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Hyperkalemia, hyponatremia, hypoglycemia, hypertension CNS involvement seizures, altered sensorium Diagnosis: Blood- broken and distorted RBC (schistocytes) Increased urea and creatinine Hypofibrinogenemia Feces - verotoxin Urine - hematuria, cylinduria Prognosis: Has improved than past. Diarrhea negative HUS: Microangiopathic lesions affect interlobular arteries and result in severe hypertension and progressive renal insufficiency. Amyloidosis Most common involvement is kidney. Features: Massive proteinuria Acute/chronic renal failure- azotemia No hypertension Kidney size - usually normal. HEREDITARY DISEASES Alports Syndrome Usually X-linked dominant. Clinical features: Males are commonly affected Renal- microscopic hematuria Extra-renal- sensorineural deafness Bilateral anterior lenticonus. Pathogenesis: Mutation of the gene coding for collagen type IV Morphology foam cells, basket weave appearance. Diagnosis: Renal biopsy and EM examination characteristic. Treatment: Many patients progress to ESRD (End stage renal Disease) and are suitable candidates for dialysis and transplantation. This does not recur after renal transplantation.

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Systemic Lupus Erythematosus (SLE) Pathology: Diffuse proliferative glomerulonephritis- most common renal lesion Focal segmental glomerulosclerosis When extensive, Wire loop appearance on LM. Clinical features: Persistent proteinuria Cellular cast- RBC cast Treatment: Should be treated with aggressive immunosuppressants. Lipodystrophy MPGN II (dense deposit disease) is the most common glomerular lesion. Denys-Drash Syndrome Nephrotic syndrome in the first 3 months of life Male pseudohermaphroditism Increased risk of Wilms tumor. TUBULOINTERSTITIAL DISEASE Inflammatory conditions that primarily involve interstitium and tubules. Often involves the renal pelvis- hence called pyelonephritis (infections). Interstitial nephritis- is the term reserved for noninfectious causes of TIN such as drugs. Etiology: 1. Bacterial: Most common - acute and chronic pyelonephritis 2. Interstitial nephritis: a. Toxinsi. Drugs- methicillin ii. Analgesic nephropathy iii. Lead nephropathy b. Metabolici. Gouty nephropathy ii. Hypercalcemic nephropathy iii. Hypokalemic nephropathy c. Radiation injury

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Pathology: PCT dysfunction leads to selective reabsorption defecthypokalemia, aminoaciduria, glycosuria, phosphaturia, uricosuria or bicarbonaturia (proximal or type II RTA)Fanconi syndrome. DCT- impaired absorption of Na + (Salt wasting nephropathy). Hyperchloremic acidosis- due to reduced capacity to generate and excrete NH4+. Papillary Necrosis Necrosis of renal pelvis. Causes: 1. Diabetes 2. Sickle cell disease 3. Analgesic nephropathy 4. Chronic alcoholism 5. Chronic interstitial nephritis 6. Renal vascular thrombosis. Diagnosis: Ring shadow on pyelography. Acute Pyelonephritis Organism: E. coli is the most common organism. Pathology: Necrotising papillitis or papillary necrosis. Diagnosis: Urine- may show pyuria, bacteriuria and pus cell cast. Chronic Pyelonephritis Salt-wasting nephropathy. Morphology: Gross - kidneys are unevenly contracted Microscopic - periglomerular fibrosis Thyroidisation- colloid casts in dilated renal tubules. Xanthogranulomatous Pyelonephritis Occurs in middle aged poorly functioning kidneys (as in diabetics).

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Features: More common in females Diffuse disease is more common Lipid laden foam cell (fat density lesion on USG) Renal stones. Hypercalcemic Nephropathy Pathology: Inability to concentrate urine maximally resulting in polyuria and nocturia. Radiation Nephritis Clinical features: Rapidly progressive azotemia, moderate to malignant hypertension, anemia and proteinuria. INFECTIONS OF KIDNEY Pyonephrosis Etiology: 1. Renal calculi- most common cause 2. Infection of a hydronephrosis 3. Acute pyelonephritis. Clinical features: Usually unilateral Triad of symptoms- anemia, fever and a swelling in the loin. Treatment: It is a surgical emergency. Procedure1. Percutaneous nephrostomy- to aspirate the pus 2. Subcapsular nephrectomy- in long standing cases. Renal Tuberculosis Route: Hematogenous infection from a distant focus. Clinical features: 1. Urinary frequency- earliest symptom. 2. Acidic, Sterile pyuria- most consistent finding. 3. Painless hematuria- most common cause of hematuria. Diagnosis: X-ray - shows areas of calcification (pseudocalculi).

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Tuberculous granulomas may be visible in the bladder wall. IVU - earliest investigation needed and also the best. Cystoscopy golf hole ureteric orifice. Urine culture of 3 morning specimens. Schistosomiasis Caused by schistosoma hematobium. Features: Calcified granulomas (sandy patches) on bladder wall fetal head appearance on X-ray. Bladder contracted, risk of developing squamous cell carcinoma. VASCULAR INJURY TO THE KIDNEY Renal Artery Stenosis Etiology: 1. In middle-aged and elderly- atheromatous plaque. 2. In young women- fibromuscular dysplasia (in western countries); aorto-aortitis (in India). Clinical features: Age >50 or <30 years Hypertension Epigastric bruit Diagnosis: DSA. Fibromuscular Dysplasia Non-atherosclerotic and non-inflammatory irregularity of medium and small arteries. Usually affects women in 3050 years. Vessels involved are renal (most common), carotid and common iliac. Clinical feature: Renovascular hypertension, renal insufficiency, TIA, claudicaiton, intracranial aneurysms are present in 50 percent patients with carotid artery involvement. Diagnosis: Angiography shows string of beads pattern.

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Renal Vein Thrombosis Associated with Nephrotic syndrome Renal cell Ca OCP use In children, dehydration. Clinical feature: Proteinuria, hematuria, lumbar tenderness with enlarged kidney, hypovolemic shock. Benign Nephrosclerosis It is the renal change in benign hypertension. Morphology: Gross- symmetrically bilateral contracted kidney (c.f.chronic pyelonephritis). Microscopic- hyaline arteriosclerosis, interstitial fibrosis, fibrinous thickening of media (vessels). Malignant Nephrosclerosis Occurs in malignant hypertension. Morphology: Gross flea-beaten appearance. Microscopic fibrinoid necrosis, necrotizing arteriolitis, hyperplastic arteriolitis (onion-skin lesion).
Bilateral contracted kidney Symmetrical Benign nephrosclerosis Chronic glomerulonephritis Assymetrical Chronic Pyelonephritis Flea beaten kidney Malignant hypertension Infective endocarditis Polyarteritis nodosa

HEREDITARY TUBULAR DISORDERS Polycystic Kidney (Adult) Inheritance: Autosomal dominant. Gene- PKD1 (90%)- on short arm of chromosome 16 which codes for polycystin 1. PKD2 (10%)- on chromosome 4 which codes for pol. 2. Pathology: Often associated with cysts of liver (5070%), pancreas, spleen, ovaries and lungs; Berry aneurysm of circle of Willis.

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Other associations- colonic diverticula, MVP . Morphology cylindrical dilatation of renal tubule. Clinical features: Onset - 3rd/4th decade. Almost always bilateral. Features 1. Massive renal swelling 2. Flank pain most common symptom. 3. Hypertension 4. Urinary infection 5. Intermittent hematuria 6. Intracranial/subarachnoid hemorrhage 7. End-stage renal disease (ESRD) Diagnosis: Excretory urography - Spider leg appearance. USG investigation of choice. Treatment: Surgery Uncap the cyst (Rovsings operation). Surgery does not restore normal renal function. Ultimate treatment of choice is renal transplantation when renal failure develops. Autosomal Recessive Polycystic Kidney Clinical feature: Age of onset first year of life. Bilateral abdominal mass. Complication: Hypertension, renal insufficiency and end stage renal disease. Death is due to pulmonary hypoplasia. Diagnosis: by USG. Screening: By perinatal USG in at risk females. Medullary Sponge Kidney (MSK) Clinical features: Age of onset 3rd or 4th decade. UTI. Recurrent hematuria. Hypercalciuria- renal stone formation. Investigation: IVU.

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Juvenile Nephronophthisis Pathology: Autosomal recessive. Cysts throughout renal medulla, cortex and pelvis. Clinical feature: Age of onset childhood. Polyuria, anemia, renal failure, growth retardation. Diagnosis: USG/CT scan shows bilateral small kidneys, loss of corticomedullary differentiation and renal cyst. Biopsy is confirmatory. Medullary Cystic Disease All are same as juvenile nephronophthisis except: i. Autosomal dominant. ii. Age of onset in 3rd or 4th decade. iii. No growth retardation. iv. Hypertension may be seen. von Hippel-Lindau Syndrome Renal cysts + angioma of retina + hemangioma of cerebellum. Bartters Syndrome 1. 2. 3. 4. Hypokalemia - polyuria, polydypsia and weakness, Metabolic alkalosis, Normal to low BP , Growth retardation.

RENAL TUBULAR ACIDOSIS Characterized by: Hyperchloremic metabolic acidosis with normal anion gap. Pathology: i. Defective bicarbonate reabsorption in the PCT. ii. Suppressed renal amoniagenesis. iii. Inadequate distal tubule proton (H+) secretion. All these abnormalities lead to acidosis.

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Types Type 1 (Distal) RTA Pathology: i. Excessive back-diffusion of H+ from lumen to blood ii. Inadequate transport of H+ alkaline urine. a. Chronic acidosis decreased Ca++ reabsorption renal hypercalciuria and secondary hyperparathyroidism. b. Decreased urinary concentration and decreased K+ conservation polyuria and hypokalemia. c. Decreased citrate reabsorption. All these lead to mobilization of Ca++ from bones (rickets and osteomalacia) calcium phosphate stones and nephrocalcinosis. Diagnosis: Oral NH4Cl loading test- no fall in urinary pH Metabolic acidosis with alkaline urine (pH >5.5) Rickets, osteomalacia, calcium phosphate stones or nephrocalcinosis support diagnosis Differential diagnosis: GI bicarbonate loss where urine anion gap is ve. Type 2 (Proximal) RTA Pathology: HCO3 reabsorption in the PCT is defective leading to bicarbonaturia. Absorption of glucose, amino acid, phosphate are also decreased- Fanconis syndrome. Diagnosis: Hyperchloremic acidosis with bicarbonaturia. Urinary pH <5.5. Ca-stones are unusual. Type 4 RTA (Hyperkalemic Distal RTA) Pathology: Distal tubule secretion of both K+ and H+ are abnormal- hyperchloremic acidosis with hyperkalemia.

Renal System
RTA at a glance Findings RTA 1 RTA 2 RTA 4 <5.5 Low +Ve Ve

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1. Minimum urinary pH >5.5 2. Serum K+ Low (hypokalemia) 3. Fanconis syndrome Ve 4. Renal stone +Ve

<5.5 High (hyperkalemia) Ve Ve

Fanconis Syndrome Idiopathic variety is inherited as autosomal dominant/ recessive or X-linked recessive. Features: Generalised defect in PCT transport involving amino acids (amino aciduria), glucose (glycosuria), uric acid (hypouricemia), Na+, K+ (hypokalemia), PO42 (hypophosphatemia) and also polyuria. NEPHROLITHIASIS Kidney Stones Etiology: 1. Idiopathic hypercalciuria 2. Hyperuricosuria 3. Primary hyperparathyroidism 4. Distal RTA 5. Interstitial hyperoxaluria 6. Hereditary hyperoxaluria 7. Gout 8. Medullary sponge kidney 9. Randalls plaque and Carrs microlith. Types of Stone 1. Calcium stones: Calcium oxalate or calcium phosphatemost common. Causesi. Primary hyperparathyroidism, ii. Distal RTA (type I). Clinical features: Oxalate stones are most painful. Diagnosis: X-ray. 2. Uric acid stones: Radiolucent - so not visible on X-ray.

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3. Cystine stones: Appears in acid urine- so UTI (E. coli) favours cystine stones. Radioopaque. 4. Struvite (MgNH4PO4) stones: Common in females. Predisposing factors: i. Bladder catheterization, ii. UTI with urea-splitting organism Proteus that produces alkaline urine. Pathology: These stones tend to grow in size and fill the whole renal collecting system- Stag horn calculus. Diagnosis: 1. X-ray KUB region: 90 percent stones are radiopaque (except urate stones) Bowels must be evacuated before taking X-ray. Features of renal stones on X-ray i. Keeps a constant position relative to urinary tract during respiration, ii. Uniform opacity (Gallstones are usually ring shaped with a radiolucent center). iii. Lateral X-ray- renal stones superimpose on the bodies of vertebrae. So if the opacity is in front of the vertebrae it is probably a calcified mesenteric node or opacity within the alimentary canal. D/D of renal stone opacity: i. Calcified mesenteric lymph node ii. Gallstone iii. Phleboliths iv. Calcified tip of the 12th rib v. Foreign body 2. IVU - most diagnostic. 3. CT scan investigation of choice. Treatment: 1. Conservative: Stones smaller than 0.5 cm are likely to pass spontaneously unless they are impacted. 2. Surgery - Percutaneous nephrolithotomy 3. ESWL- Contraindications are i. Uncontrolled bleeding disorder ii. Pregnancy iii. Ureteric stricture iv. UTI v. Cardiac pacemaker

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Ureteric Stones Ureteric stones almost always arise in kidney and passes down to the ureter. Usually small and single. Clinical features: Ureteric colic passes from loin to groin and not associated with fever. Colic is caused by hyperperistalsis of ureter and spasm of smooth muscle to overcome the obstruction. Location of pain depends on the site of stone in the ureter.
Stone at Pelvi-ureteric jn. (upper ureter) Mid-ureter Pelvic brim Intramural ureter Pain referred to Testicles McBurneys point on right side and iliac fossa on left side Inner side of thigh via genitofemoral nerve Tip of penis (strangury)

Management: i. Proximal stone: <2.5 cm ESWL. >2.5 cm Percutaneous nephrolithotomy. ii. Distal stone (lower third of ureter): Small stone Dormia busket. Ureteroscopic removal. iii. Midureteric stone: Can be pushed back to renal pelvis by flushing through cartheter (Push bang) and then removed. Urinary Bladder Stone a. Primary stone: Develops in sterile urine often in the kidneys and drops down to bladder. Rare in western countries especially among children. E.g. oxalate stone (Jack stone), uric acid stone. b. Secondary stone: Develops in the bladder in presence of urea splitting organism proteus, e.g. triple phosphate stone. c. Mixed stone: Most common. Incidence: Common in Indian children. Secondary stones are more common than primary.

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Clinical features: More common in males. Frequency is the earliest symptom. Pain (strangury) maximum with speculated oxalate stones. Occurs at the end of micturition and referred to the tip of penis. Terminal hematuria (at the end of micturition). Interruption of urinary stream. Investigation: Most stones are visible on X-ray. IVU radiolucent stones appear as filling defect. Cystoscopy confirmatory. Treatment: Transurethral litholapaxy for large and hard stones. Endoscopic lithotripsy. Contraindications to litholapaxyi. Very large stone, ii. Contracted bladder, iii. Urethral stricture, iv. Patients age < 10 years. Nephrocalcinosis 1. Herditary distal RTA. 2. Medullary sponge kidney. 3. Hypercalcemic states, hyperparathyroidism, vitamin D toxicity. X-ray: Shows multiple papillary calcifications. CONGENITAL ANOMALIES Development of Kidney From two sources: 1. The excretory tubules (nephrons) from metanephros. 2. The collecting part from ureteric bud. Note: Full number of nephrons is present by 36 weeks of gestation. GFR begins between 9 and 12 weeks initiating urine formation. Adult concentrating ability is achieved at 1 year of age.

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Renal Ectopia Incidence: 1 in 1000 people. Site: near the pelvic brim usually on left side. Ectopic Ureter Always opens above the external sphincter. Most commn site of opening is prostatic urethra. May produce continuous incontinence (paradoxical incontinence). Renal Agenesis Unilateral increased chance in single umbilical artery. Bilateral Potters disease. Non-ascent of Kidney This is due to fault in the peritoneal fold containing umbilical arteries. Horseshoe Kidney Complications: Urinary stasis leading to infection and nephrolithiasis. Diagnosis: Usually radiological, usually calyces of lower poles are directed towards midline. Rarely all the calyces are reversed. On IVU - Ureters have flower vase like curves. Aberrant Renal Vessels Most commonly on the left side Aberrant vessels probably do not cause hydronephrosis, although a hydronephrotic renal pelvis may bulge between renal vessels. Duplication of Renal Pelvis Most common congenital abnormality of upper renal tract. Ureterocele Cause: Cystic dilatation of the intramural part of ureter due to congenital atresia of the ureteric orifice.

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Clinical features: Present from childhood. Common in women. Mostly asymptomatic. May cause hydronephrosis or pyonephrosis. Diagnosis: Excretory urography- Adder head appearance. Cystoscopy- diagnostic. Treatment: Endoscopic diathermy incision. Congenital PUJ Obstruction May be bilateral. Associated with renal agenesis, most often results from intrinsic disease. Often asymptomatic. Prenatal diagnosis with USG. Diagnosis - Whittaker test. Treatment - dismembered pyeloplasty or endoscopic pyelotomy. Vesicoureteric Reflux Risk factors for: Urinary tract infection most common cause in neonates. Acute pyelonephritis. Reflux nephropathy. Renal dysplasia. Incidence: Most common in newborn females. 3035 percent cases are familial. Diagnosis: Radiocontrast MCU most commonly used method. Isotope radionuclide cystography more sensitive, used for screening. Grading: I to V depending on anatomical change of kidneys and ureters.

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Management: a. Medical: Continuous antibiotic prophylaxis with cotrimoxazole (drug of choice) to prevent UTI. b. Surgery: Indications Bilateral III/IV grade reflux in 610 years of age group. Bilateral grade V reflux in children over 1 year of age. Otherwise antibiotic prophylaxis is indicated. Reflux Nephropathy Characterized by renal cortical scarring (in the poles). Results in hypertension, ESRD in children. NEOPLASMS OF KIDNEY Wilms Tumor Site: Usually unilateral (in one or other pole of one kidney). Multicentric in origin. Associated features: Malformations associated with Wilms tumor are: 1. Aniridia 2. Hemihypertrophy 3. Genitourinary i. Cryptorchidism ii. Hypospadias iii. Gonadal dysgenesis iv. Pseudohermaphroditism v. Horseshoe kidney 4. Beckwith-Wiedeman syndrome 5. Drash syndrome gonadal dysgenesis, renal anomalies. 6. WAGR syndrome Wilms tumor Aniridia Ambiguous genitalia Mental retardation Chromosomal anomaly: WT2 gene on 11p15 is associated with BeckwithWiedeman syndrome.

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Deletion of WT1 gene on 11p13 is associated with Drashs syndrome and WAGR syndrome. Clinical features: Age of onset- during first 4 years of life. Symptoms- triad of Painless abdominal mass (earliest symptom). Fever Hematuria often with pain not always present. Denotes extension to renal pelvis and poor prognosis. Diagnosis: USG- hypoechoic shadow. Biopsy nephrogenic rests are precursor of Wilms tumor. Patients with these may have Wilms tumor in contralateral kidney. Metastasis: Via bloodstream to lungs (most common). Sarcoma type metastasizes to bones. Rhabdoid type metastasizes to brain. Treatment: Nephrectomy- as early as possibly followed by radiotherapy with or without chemotherapy. Chemotherapeutic agent actinomycin D and vincristine. Prognosis: Related to age. Age <1-year carries 80 percent survival rate. Differential diagnosis: Neuroblastoma Note: D/D of abdominal mass Neonatal period an asymptomatic abdominal mass is due to multicystic renal dysplasia. 1-3 years Wilms tumor, HUS, RTA. 3-6 years minimal change disease, acute PSGN. 6-14 years acute PSGN, non-minimal nephrotic syndrome. Renal Cell Carcinoma (Hypernephroma) Type: Adenocarcinoma.

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Origin: From renal tubular cells. Pre-existing adenomas may be present. Predisposing factors: 1. Smoking 2. Obesity 3. Polycystic kidney (acquired) following chronic dialysis 4. Tuberous sclerosis 5. von-Hipple-Lindau syndrome 6. Exposure to cadmium. Pathology: Site- usually upper pole of the kidney. Grossly Cut section is yellowish or dull white with areas of hemorrhage and necrosis. Microscopici. Clear cell Ca (most common) defect in chromosome 3 (loss of VHL gene). Solid areas of polyhedral or cubical clear cells with deeply stained small rounded nuclei and abundant cytoplasm and scanty stroma. ii. Papillary Ca characteristically invades the renal vein. Associated with trisomy 7 (gain of MET gene). iii. Chromophobe Ca - Tumor cells are large tan-brown with prominent nuclei surrounded by halo. Metastasis: 1. To IVC via renal vein (most common)- pulsatile metastasis, then to lungs. 2. To bones. 3. To para-aortic lymph nodes. Clinical features: Sex- male: female= 2:1 Symptoms Painless hematuria (most common) Rapidly developing varicocele PUO Hypertension Paraneoplastic syndrome Polycythemia Hypercalcemia Other hormones like renin and calcitonin are also produced.

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Diagnosis: MRI is the most sensitive in detecting IVC invasion. Next sensitive is Doppler ultrasound. CXR- cannon ball shadow. Treatment: Nephrectomy with a transabdominal approach. Renal collar is put around renal vein to prevent metastasis. Adenocarcinoma of kidney does not respond well to radio/chemotherapy. Prognosis: Poor prognosis depends on 1. Macroscopic involvement of renal vein, 2. Tumor invasion beyond the capsule, 3. Lymph node involvement, 4. Sarcomatoid type worst type, 5. Pulmonary secondaries worst prognosis. Tumors of Renal Pelvis Transitional cell Ca most common type. Squamous cell (epidermoid) Ca associated with renal stones. Benign Tumors of Kidney Angiomyolipoma associated with tuberous sclerosis. RENAL INJURIES Injury to Kidney Clinical feature: 1. Hematuria the cardnal sign. 2. Meteorism abdominal distension 24-48 hours after injury due to retroperitoneal hematoma. Investigation: After initial resuscitation an urgent IVU should be obtained to assess the damage. Management: 1. Conservative - > 90 percent cases with fluid resuscitation, analgesics, antibiotics and daily urine examination. 2. Surgery indicated in < 10 percent cases with massive hemorrhage.

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Nephrectomy is done if the kidney is completely avulsed. Route of operation transperitoneal. Complications: i. Bladder outflow obstruction by clot, ii. Pararenal pseudohydronephrosis, iii. Hypertension, iv. Renal artery aneurysm and subsequent rupture least chance (occurrence < 1%). Injury to Bladder and Urethra Rupture of urethra: a. Bulbar urethra most common; due to fall astride on object (like manhole injury). b. Membranous urethra due to violent injury like pelvic fracture (road traffic accidents). Rupture of bladder: a. Intraperitoneal duet to fall on a full bladder. b. Extraperitoneal most common; due to pelvic fracture. Extravasation of urine: a. Bulbar rupture superficial extravasation. Urine collects in the scrotum and penis and beneath the deep layer of superficial fascia (of Scarpa) in the abdominal wall. b. Membranous urethra and extraperitoneal bladder rupture deep extravasation. Urine extravasates in the layers of the pelvic fascia and retroperitoneal tissue. Note: Membranous urethra is a content of deep perineal space bounded above and below by superior and inferior fascia of urogenital diaphragm, respectively. c. Intraperitoneal bladder rupture urine extravasates into the peritoneal cavity may cause peritonitis. Clinical feature: Triad of signs in rupture of bulbar urethra Retention of urine, perineal hematoma and bleeding from urinary meatus. Investigation: For intraperitoneal bladder rupture retrograde cystrography most reliable. Intravenous urography.

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Management: a. Bulbar rupture Analgesics and antibiotics. If the bladder is full percutaneous suprapubic catheterization. Patient should be discouraged to pass urine. b. Membranous rupture and extraperitoneal bladder rupture usually associated with serious pelvis fracture. So initial attention should be given towards that. A suprapubic catheter may be inserted for shortterm. c. Intraperitoneal bladder rupture urgent laparotomy with repair of bladder. Complication: i. Urethral stricture most common complication of urethral rupture. ii. Peritonitis in intraperitoneal bladder rupture. MISCELLANEOUS Radiological Appearance Rim/crescent sign hydronephrosis. Flower vase pattern horse shoe kidney. Cobra (adder) head ureterocele. Thimble bladder TB bladder. Spider leg appearance polycystic kidney. Soap bubble appearance hydronephrosis.

NEUROLOGICAL DISORDERS

NEUROIMAGING CT scan: CT scan is helpful in imaging osseous structures of the spine, skull base and temporal bones. CT is more sensitive and specific than MRI in detecting acute parenchymal and subarachnoid hemorrhage. MRI: This utilizes hydrogen ions (protons). Contrast material most commonly used is gadolinium. CSF (and other watery media like edema fluid) appears low (hypointense) on T1 and high (hyperintense) on T2 weighted MRI. Contraindications: Pacemaker, metallic foreign body, hemostatic clips in CNS, clostrophobia, cochlear implants, prosthetic valves, insulin pump. Myelography: Contrast material iodinated compound myodil. Complication i. Headache, nausea and vomiting most common. ii. Postural headache due to CSF leak. This is aggravated on standing and relieved on lying down. iii. Allergic reaction most serious complication. iv. Puncture of the spinal cord. Angiography: Route through the femoral artery. Lumbar puncture: Contraindication i. Increased ICT due to chance of cerebellar or tentorial herniation. ii. Brain abscess. iii. Mass lesion in brain. CSF albumino-cytological dissociation is seen in infective polyneuritis (G-B syndrome) and spinal cord tumors. Normal CSF pressure in sitting posture is 2-12 mmHg.

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CONGENITAL ANOMALIES OF CNS Classification a. Neural tube defects 1. Anencephaly most common CNS malformation. 2. Encephalocele 3. Spinal anomalies i. Spina bifida or spinal dysraphism ii. Meningocele iii. Meningomyelocele. iv. Tethered cord v. Syringomyelia vi. Diastematomyelia. b. Disorders of neural migration forebrain abnormalities 1. Lissencephaly 2. Schizencephaly 3. Porencephaly 4. Holoporencephaly 5. Corpus callosum agenesis. c. Posterior fossa abnormalities 1. Arnold Chiari malformation (Chiari type II). 2. Dandy-Walker malformation. Anencephaly This is the most common and most severe CNS malformation. Risk i. ii. iii. factors: Low socioeconomic status. Maternal age over 40 years. Dietary folate deficiency during pregnancy.

Associations: i. Polyhydramnios. ii. Increased gestational age. Complications in pregnancy: i. Malpresentation face (most common), breech. ii. Postmaturity. iii. Shoulder dystocia. Clinical feature: More common in females. Baby dies in utero or soon after birth. Diminution of size of adrenal glands.

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Antenatal diagnosis: i. Amniocentesis at 10-12 weeks, shows increased alpha fetoprotein and ACE levels in amniotic fluid. ii. USG at 14-16 weeks, investigation of choice. Management of pregnancy: Before 20 weeks termination of pregnancy. Late presentation induction of labour with PGE2 vaginal gel. Shoulder dystocia cleidotomy. Prevention: Folic acid supplementation beginning 1 month before conception to about 12 weeks of pregnancy. Spina Bifida Spina bifida occulta: Most common type. Mildest form. Site most common in lumbosacral spine (S1). Clinical feature asymptomatic, telltale sign in the form of a dimple in skin, lipoma, dermal sinus or a tuft of hair. Investigation MRI. Spinal bifida aperta: Most common site dorso-lumbar spine. Types myelocele (most common), meningocele, meningomyelocele, syringomyelocele. Note: Lacunar skull is associated with meningocele. Hydrocephalus CSF production: Amount 50 ml in infant, 150 ml in adults. Rate 500 ml/day or 20 ml/hour. Source choroid plexus mainly in the lateral ventricle (also third and fourth ventricles). Pathways
Lateral ventricle foramina of Monro Third ventricle aqueduct of Sylvius Fourth ventricle foramina of Luschka and Magendie Basal cisterns (subarachnoid space) Absorbed in subarachnoid villi.

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Hydrocephalus resulting from obstruction in ventricular system is called obstructive or non-communicating and from obliteration of subarachnoid cisterns or malformation of arachnoid villi is called non-obstructive or communicating hydrocephalus. Note: CSF pressure is mainly regulated by rate of absorption. Etiology: a. Obstructive Aqueductal stenosis (most common), Chiari malformation (type II), Dandy-Walker syndrome, posterior fossa tumors. b. Non-obstructive Subarachnoid hemorrhage (most common) usually as a result of intraventricular hemorrhage in premature infant. Meningitis Pneumococcal and tuberculous. Clinical features: In infants Head is enlarged most prominent sign, anterior fontanel wide open and bulging. In late cases Spasticity, brisk tendon reflexes, Babinski sign. In older children (whose sutures have closed) symptoms of increase ICT like headache, vomiting, etc. Signs Sunset sign in eyes, cracked-pot or Macewen sign. Investigation: Xray skull beatensilver appearance, CT scan/MRI and USG. Treatment: Conservative Acetazolamide, Furosemide. Most cases require Ventriculoperitoneal shunt. Hydrocephalus ex vacuo: Compensatory enlargement of ventricles and increase in CSF volume secondary to loss of brain parenchyma. Seen in Alzheimers disease, Picks disease. Chiari Malformation Chiari Type I Presents during adolescence or adult life and usually not associated with hydrocephalus. There is protrusion of cerebellar tonsils through the foramen magnum into the cervical canal. Most common associated finding is syringomyelia.

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Chiari Type II: Arnold Chiari Malformation Characterized by hydrocephalus and myelomeningocele. Pathology: Small posterior fossa, malformed midline cerebellum, extension of vermis through foramen magnum. Other changes caudal displacement of brainstem, tectal beaking, aqueductal stenosis, hydromyelia. Clinical feature: Hydrocephalus may develop at anytime in life, with foreshortened occiput. May present with ataxia, spasticity, incoordination. Dandy-Walker Malformation Consists of cystic dilatation of 4th ventricle and posterior fossa expansion. (Due to obstruction of foramen of Lushcka and Magendie). There may be hypoplasia or aplasia of cerebellar vermis and corpus callosum. Clinical feature: Hydrocephalus with prominent occiput (Bendas sign), cerebellar ataxia. Syringomyelia It is a cyst like cavity within the spinal cord (in the central canal) with progressive destruction of gray and white matter. It may communicate with CSF pathways (associated with Chiari type I) or may remain localized and noncommunicating. Clinical feature: Most common site involved is cervical spine. Disruption of lateral spinothalamic tract produces dissociated sensory loss (loss of pain and temperature sensation in supex with preservation of touch). Corticospinal tract and anterior horn cell involvement leads to muscle wasting of hands, absent deep tendon reflexes in supex, UMN paralysis of infex. Investigation: MRI is the study of choice.

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Diastematomyelia It is division of spinal cord into two halves by a fibrocartilaginous or bony septum. It is a disorder of neural tube fusion. Most commonly involves lumbar vertebrae (L1 L3). There may be associated bony deformities like hemivertebra, kyphoscoliosis, etc. Clinical feature: Cutaneous hemangioma (tell tale sign) over midline skin. Unilateral foot abnormalities TEV, claw toes, atrophy of gastrocnemius, loss of pain and temperature. Forebrain Abnormalities Lissencephaly or agyria: Decrease in number of gyri to total absence, leaving a smoothsurfaced brain. Schizencephaly: Presence of uni / bilateral clefts within cerebral hemisphere. Porencephaly: Presence of cysts or cavities within the brain. It is seen in vascular malformation. Leads to cerebral infarction. Holoporencephaly: Incomplete separation of cerebral hemisphere across the midline. Agenesis of corpus callosum: Radiology shows misshapen lateral ventricles (bat-wing deformity). Cranio-facial Malformations Treacher-Collins Syndrome Autosomal dominant. Features: Hypoplasia of malar bones. Anti-mongoloid (downward) slant of palpebral fissure. Colobomas in outer third of lower eyelid. Blind fistula between angle of mouth and ear. Deafness. Dental malocclusion, high arched / cleft palate. Craniosynostosis Premature closure of cranial sutures. Normally, metopic suture (between two frontal bones) closes before 2 years of age and coronal, sagittal and lambdoid sutures close after age 13 years.

Neurological Disorders
Name Scaphocephaly (most common) or dolicocephaly (long head) Brachycephaly Trigonocephaly

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Premature closure of Sagittal suture Coronal suture Metopic suture

Associations Crouzon syndrome: AD. Brachycephaly, ocular proptosis, hypoplasia of maxilla and orbital hypertelorism. Apert syndrome: Above plus syndactyly and high arched palate. Carpentar syndrome: AR. Kleeblattschadel skull deformity, soft-tissue syndactyly of hand and feet, mental retardation. HEADACHE Migraine Clinical feature: Headache is characterized by pulsating headache usually restricted to one hemisphere (frontotemporal), lasts for 4-48 hours and often associated with nausea (most commonly), vomiting, visual disturbances (scintillating scotoma, photopsia, fortification spectrum, visual hallucinations), paresthesia, seizures, vertigo, etc. Headache starts after awakening, and quelled by sleep. Incidence: Occurs in all ages, but more common in children and young adults. More common in females. Types: Migraine with aura classical type. Symptoms are better with increasing age. Migraine without aura common type. Theories: Vascular theory headache is due to extracranial vasodilatation. Neurogenic theory. Treatment: Severe migraine ergot alkaloids/sumatriptan (drug of choice) + antiemetics. Early treatment aborts an attack.

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Prophylaxis propanolol, amitriptyline, flunarizine, methysergide/cyproheptadine. Note: Triptans are selective serotonin activators and act on serotonin receptor 5HT IB/ID. Ophthalmoplegic Migraine Headache followed by partial paralysis of the III cranial nerve on the same side (most common nerve involvement in migraine). Cluster Headache Clinical feature: Peak age 30-50 years, with male preponderance. Headache periodic, nocturnal, periorbital or temporal in location, strictly unilateral. Headache is provoked by alcohol ingestion. Associated with ipsilateral lacrimation, reddening of the eyes, nasal stuffiness and nausea. Treatment For chronic disorder lithium (drug of choice for prevention). EPILEPSY Neonatal Seizure Etiology: 1. Perinatal anoxia most common cause. 2. Intracranial birth injuries. 3. Intraventricular and subarachnoid hemorrhage. 4. Metabolic hypoglycemia, hypocalcemia. 5. Others homocystinuria, phenylketonuria. Type: Subtle seizures are most common. Prognosis: Poor prognosis birth injury and anoxia. Best prognosis hypocalcemic seizure. Treatment: IV phenobarbitone is the drug of choice. Preventive in intraventricular hemorrhage phenobarbitone, vitamin K. Febrile Convulsion Most common cause of seizure in early childhood (6 months to 5 years).

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Characteristics: Convulsions occur during fever (within 24 hours of onset of fever). This is not related to the height of temperature, but usually seen when temperature rises above 38oC. Frequently seen if temperature rises abruptly. Recurrent in nature in 30-40 percent cases. Does not last for > 10 minutes. Generalized convulsion. No post-ictal neurological deficit. EEG done a few days after the seizure is normal. Family history among siblings may be present. Treatment: Acute attack antipyretics (aspirin not given), IV diazepam/phenobarbitone. Intermittent prophylaxis antipyretics and diazepam. Continuous prophylaxis sodium valproate/ phenobarbitone. Prognosis: Prognosis is good. Only 1-5 percent cases progress to epilepsy. Breath Holding Spells This occurs between 6 months and 5 years of age. Clinical feature: Breath is held in expiration for few seconds. Child becomes cyanosed and limp. If persists for 10-15 seconds, convulsions may occur. Treatment: The attack could be aborted by strong stimulus like pinch at the beginning of the spell. Iron supplementation. Atropine sometimes used. Antiepileptics are not used. Kindness and understanding attitude towards the infant. Overanxiety of the parents is harmful. GENERALIZED SEIZURES Generalized Tonic-clonic Seizure Most common type. GTC seizures tend not to occur in the first month of life.

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Phases: 1. Aura 2. Tonic phase 3. Clonic phase 4. Postictal phase. Investigation: EEG when abnormal, it is diagnostic of epilepsy. Treatment: First year of life phenobarbitone is the drug of choice. Beyond first year phenytoin or valproic acid. Status Epilepticus Treatment: IV lorazepam (drug of choice)/diazepam, Phenobarbitone/phenytoin/paraldehyde. Generalized Absence Seizure (Petit-mal) Characteristic: Common between ages 4-5 years. Abrupt onset of unawareness or loss of consciousness usually for short duration. No aura, no post-ictal confusion. No loss of motor functions hence called absence seizure. Hyperventilation often precipitates an attack. EEG: Shows characteristic 3 per second spike and slowwave pattern. Treatment: Ethosuximide drug of choice. Others valproate, clonazepam. Myoclonic Seizure Sudden shock-like momentary contraction of muscles of a limb or the whole body. Juvenile Myoclonic Seizures (Janz Syndrome) Age of onset 12-16 years. Clinical feature: Myoclonic jerks on awakening in the morning. Some patients can present with GTC seizures. About onethird patients present with absence seizures.

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Salaam seizures sudden flexion of body at waist. EEG: 4-6 Hz irregular spike. Treatment: Valproate for whole life. Infantile Spasms (West Syndrome) EEG: Hypsarrhythmic pattern. Treatment: Corticosteroids or ACTH given for 8-12 weeks in gradually decreasing doses drug of choice. Sodium valproate, clonazepam. PARTIAL SEIZURES Simple Partial Seizure Convulsion limited to localized group of muscles, without loss of consciousness. Complex Partial Seizure (Temporal Lobe Epilepsy) Bizarre or confused behavior and purposeless movements, emotional changes lasting for 1-2 minutes along with impairment of consciousness. An aura often precedes. The seizure focus is located in the temporal lobe. Treatment: Carbamazepine is the drug of choice. Mesial Temporal Lobe Epilepsy Positive family history. Aura common. Temporal spikes on EEG. Small hippocampus with increased signal on T2 weighted MRI. Surgery extremely helpful. Note: Drugs of choice in epilepsy GTC valproate/phenytoin. Partial seizure carbamazepine. Absence seizure ethosuximide. Atonic seizure valproate. Myoclonic seizure valproate. Status epilepticus IV lorazepam.

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CEREBROVASCULAR DISEASES Classification a. Cerebral ischemia-infarction: i. Atherosclerosis with thromboembolism most common cause. ii. Embolic obstruction (cardiogenic) most commonly non-rheumatic atrial fibrillation. b. Intracranial hemorrhage: i. Intracerebral hemorrhage most common type. Hypertension is the most common cause. ii. Subarachnoid hemorrhage most common cause is trauma, next is rupture of sacular aneurysm. iii. Subdural and epidural hemorrhage traumatic. Cerebral Ischemia Infarction Major cause of cerebral ischemia infarction is atherosclerosis which commonly affects the origin of the internal carotid artery in the neck and the origins of the major and minor arterial branches inside the head. Clinical feature: Transient ischemic attack (TIA) is a feature of ischemic stroke. So, history of TIA excludes the possibility of hemorrhage. Clinical feature depends upon the level of obstruction by the atherosclerotic plaque.
Levels and symptoms of obstruction Internal carotid artery Hemiplegia with decreased vision in contralateral side.

Middle cerebral artery Entire MCA Contralateral hemiplegia, hemianaesthesia, homonymous hemianopia, global aphasia (if involves the dominant hemisphere). Superior division of MCA Sensory weakness, motor weakness, motor aphasia (dominant hemisphere) Inferior division of MCA Wernickes aphasia. Anterior cerebral artery Proximal ACA (A1) No symptoms due to rich collaterals. Post-communal (A2) Contralateral motor and sensory loss branch over foot and leg, abulia, bilateral pyramidal signs with paresis, urinary incontinence if both A2 branches are blocked.

(Contd...)

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Penetrating branch (Heubners artery) Frontal ataxia (contralateral), apraxia, ideomotor dyspraxia.

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Posterior cerebral artery Peripheral territory Bilateral homonymous hemianopia with cortical blindness (with macular sparing due to collaterals from MCA); memory defect due to hippocampal lesion Central territory Thalamic syndrome sensory loss, spontaneous pain (hyperpathia). Webers syndrome lesion in mid-brain produces third nerve palsy with contralateral hemiplegia. Antero-inferior cereContralateral spinothalamic tract is bellar artery affected causing loss of pain and temperature sensation over the opposite half of the body. Vertebro-basilar artery Midbrain Webers syndrome (see above) Claudes syndrome crossed cerebellar ataxia. Pons Millard Gublar syndrome ipsilateral VII nerve palsy with contralateral hemiplegia.

Medullary Syndromes Medial Medullary Syndrome Etiology: Occlusion of vertebral or lower basilar artery. Features: Ipsilateral 12th nerve involvement paralysis and atrophy of half of the tongue. Contralateral Pyramidal tract involvement paralysis of arm and leg sparing the face. Medial lemniscus involvement impaired tactile and propioceptive senses. Lateral Medullary Syndrome (Wallenbergs Syndrome) Etiology: Block of vertebral, postero-inferior cerebellar artery and superior, middle or inferior branches of medullary arteries. Features: Ipsilateral 5th nerve involvement pain, numbness and sensory loss over half of the face.

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Vestibular nucleus involvement nystagmus, diplopia. Sympathetic tract involvement Horners syndrome. 9th and 10th nerves involvement dysphagia, hoarseness of voice, palatal paralysis. Cerebellar tracts ataxia. Contralateral Spinothalamic tract involvement loss of pain and temperature sensation. Intracerebral Hemorrhage This is the most common type of intracranial hemorrhage. Most common cause is hypertension. This is most commonly due to rupture of lenticulostriate branch of MCA. Most common sites are putamen of basal ganglia, thalamus. Clinical feature: Putamen eyes deviated to healthy side. Thalamus eyes deviated downwards with pupil 23 mm dilated and minimally reactive. Pons pin-point pupil (1 mm) reactive to light, loss of consciousness, hyperpyrexia. Cerebellum eyes deviated laterally. Investigation: CT scan can detect hemorrhage 1 cm in diameter. MRI more sensitive for posterior fossa lesions. Lumbar puncture contraindicated. Management: Surgical drainage for hematomas more than 3 cm in size. Mannitol to decrease ICT. Prognosis: Depends on the size and location of hemorrhage. Subarachnoid Hemorrhage Subarachnoid space: Ends at S2 and contains CSF. Etiology: Most common cause of subarachnoid hemorrhage is trauma.

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Most common cause of spontaneous hemorrhage is the rupture of sacular aneurysm. Site: i. Junction of the anterior communicating and anterior cerebral arteries most common site. ii. Junction of the posterior communicating and internal carotid artery. iii. Bifurcation of the MCA. iv. Vertebral artery least common site. Clinical feature: Sudden, severe headache in the absence of focal neurological symptoms. 3rd and 6th nerve palsies (intracranial aneurysms most commonly compress the 3rd nerve). Delayed neurological deficits Cause rerupture, hydrocephalus, vasospasm (most common cause), hyponatremia. Diagnosis: Lumbar puncture: Hallmark of aneurysmal rupture is blood in the CSF. CT scan: Investigation of choice. If done within 72 hours, sensitivity is 80 percent. Cerebral angiography: Best to determine the cause of hemorrhage. AV Malformation They are hamartomas most common vascular malformation of nervous system. Presentation intracerebral (subarachnoid) hemorrhage with headache. Investigation: MRI. Treatment: Surgery (stereotactic radiosurgery). Embolotherapy using heat contrast. PRIMARY DEMENTIAS Alzheimers Disease Most common cause of dementia in people over 65 years of age.

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factors: Age over 65 years Female sex Head trauma Lower educational attainment Downs syndrome Family history of dementia.

Pathology: Pathological hallmarks in Alzheimers disease are i. Neurofibrillary tangles. ii. Senile plaques. iii. A amyloid deposition. iv. Biondi ring tangles in choroid plexus (also seen in elderly). Most common sites for pathological changes are hippocampus (degeneration), temporal lobes and nucleus basalis of Meynert. Clinical feature: Progressive dementia without neurological sign. Released reflexes in dementia due to frontal lobe pathology. They are grasp reflex, palmo-mental reflex and glabellar tap reflex. Biochemistry: There is decrease in acetylcholine concentration in brain. Choline acetyltransferase (CAT) and nicotinic cholinergic receptors are also reduced. CT scan of brain: Shows diffuse atrophy of cerebral cortex with enlargement of ventricles. Treatment: Anticholinesterases tacrine, rivastigmine, donepezil and galantamine. Normal Pressure Hydrocephalus This i. ii. iii. is characterized by the triad of: Dementia, Abnormal gait (ataxia or apraxia), Urinary incontinence.

Investigation MRI shows enlarged lateral ventricles (hydrocephalus) with little or no cortical atrophy. CSF pressure high normal.

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Huntingtons Disease Genetics: Autosomal dominant. Disorder of trinucleotide repeat sequence. Clinical feature: Chorea, behavioral abnormalities and dementia. Memory is frequently not impaired until late in the disease. Adult HD onset in 4th/5th decade. Duration is typically 15 years. Juvenile HD onset before 20 years of age. Associated with rigidity, ataxia and cognitive decline. More rapid disease progression. Pathology: Most commonly affects the striatum. There is atrophy of the caudate nucleus. Biochemically, there is loss of intrastriatal GABA-ergic and cholinergic pathways. Progressive Supranuclear Palsy (SteeleRichardson-Olszewski Syndrome) This is characterized by Vertical supranuclear gaze palsy (difficulty with down gaze), Axial rigidity frequent falls, Subcortical dementia, Convulsions. Picks Disease Reveals characteristic inclusions known as Picks bodies composed of Tau protein. Note: Lewy bodies contain synuclein. EXTRAPYRAMIDAL DISORDERS Parkinsons Disease Pathology: Degeneration of the nigrostriatal dopeminergic system. Eosinophilic intranuclear inclusion granules called the Lewy bodies are present in the basal ganglia.

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Clinical feature: Tremor at rest 4-6 Hz in frequency, decrease on movement. Rigidity (lead pipe or cog wheel). Bradykinesia or akinesia. Mask like facies. Festinant gait. Others micrographia, flexed attitude of the body, slurred speech, normal intelligence. Plantar response flexion. Shy-Drager Syndrome Parkinsonism, impaired autonomic function (postural hypotension, sweating, abnormal bowel and bladder control, impotence and gastroparesis) and widespread neurological involvement (pyramidal, cerebellar or lower motor neuron). Treatment: 1. Anticholinergics trihexyphenidyl (Benzhexol), benztropine, procyclidine and orphenadrine. 2. Dopamine facilitator amantadine. 3. Dopamine precursor levodopa. 4. Dopamine agonist bromocriptine. 5. Neuroprotective to prevent neuronal degeneration, MAO-B inhibitor selegiline and vitamin E (tocopherol). Drug Induced Parkinsonism Cause: 1. Antipsychotics phenothiazines (maximum with trifluoperazine and haloperidol, least with thioridazone). 2. Metoclopramide. 3. Reserpine. Rabbit syndrome or perioral tremors late onset (years after) drug induced EPS. Treatment: i. Discontinution of the offending drug. ii. Anticholinergics trihexyphenidyl. iii. Levodopa is not used.

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ATAXIAS Classification: Autosomal dominant spinocerebellar ataxia. Autosomal recessive Friedriechs ataxia, telangiectasia, Cockayne syndrome, xeroderma pigmentosa. Infective chickenpox. Friedreichs Ataxia Cause: Inherited disorder (autosomal recessive). Associated with vitamin E deficiency. Pathology: This involves the pyramidal tract, dorsal column and spinocerebellar tracts. Clinical feature: Symptoms Progressive staggering gait (lower limbs are commonly affected), frequent falling, dysarthria, sensory loss. Signs Extensor plantar response with absent deep tendon reflexes. Cardiomegaly Increased incidence of diabetes, skeletal abnormalities, optic atrophy. MOTOR NEURON DISEASES Classification: UMN primary lateral sclerosis. LMN progressive muscular atrophy or progressive bulbar palsy. UMN + LMN amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis (Lou Gehrig Disease) It is a degenerative disorder involving the upper motor neurons (UMN) and lower motor neurons (LMN). Note: UMN includes the anterior horn cells in spinal cord and LMN includes the corticospinal tract. Feature: Progressive muscle weakness, atrophy (amyotrophy) and spasticity. Earlier asymmetric weakness, gradually progresses to symmetrical involvement.

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Sensory, bowel and bladder and cognitive functions are preserved. Extraocular muscles are not involved. Reflexes hyperactive (UMN) or hypoactive (LMN). Fasciculation is characteristic of MND. Spinal Mascular Atrophy Genetically linked. Infantile SMA most rapidly fatal. CRANIAL NERVES Trigeminal (5th Nerve) Palsy Features: i. Loss of corneal reflexes. ii. Loss of sensation of face. iii. Deviation of jaw on opening of mouth to the affected side. iv. Bilateral UMN lesion above pons causes exaggerated jaw jerk. Trigeminal Neuralgia (Tic Doulourux) Characterized by excruciating paroxysms of pain in the lips, gums, cheek or chin. Initiation of pain by stimulation of certain areas of face (trigger zone). Treatment: Carbamazepine is the drug of choice. Facial Nerve Palsy Important causes of facial nerve palsy a. Central pontine gliomas, polio, multiple sclerosis. b. Intracranial (CP angle) acoustic neuroma, meningioma. c. Intratemporal i. Idiopathic Bells palsy (most common cause), Melkerssons syndrome. ii. Infections iii. Trauma Note: Facial nerve palsy in temporal bone fracture is most common with transverse fractures. iv. Mastoidectomy v. Malignancy glomus jugulare tumor

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d. Extracranial parotid gland surgery. e. Systemic causes diabetes, hypothyroidism, uremia, PAN, Wegeners granulomatosis, sarcoidosis. Features: UMN palsy produces contralateral involvement of lower face (upper face escapes because of bilateral innervation). LMN palsy produces ipsilateral involvement of both upper and lower face. Complete paralysis causes: 1. Deviation of corners of mouth to the opposite side. 2. Loss of wrinkling on forehead. 3. Eyelids are difficult to close on forced closure of the lids, the eye on the paralyzed side is seen to roll upwards (Bells phenomenon). 4. Drooling of saliva from the angle of mouth. In case of incomplete recovery: Attempts to move one group of facial muscles result in contraction of all the muscle groups synkinesis or associated movement. Anomalous regeneration causes: Tearing while eating food (crocodile tear). Jaw opening causes closure of the eyelids on the side of palsy (jaw-winking). Other effects of facial nerve palsy: At the lateral geniculate body loss of lacrimation. At sternomastoid canal loss of ipsilateral corneal reflex. Bells Palsy It is idiopathic LMN type of facial nerve palsy. Ramsay Hunt Syndrome Unilateral facial nerve palsy. Bilateral Facial Nerve Palsy G-B syndrome or infective polyneuritis. Heerfordt syndrome a variant of sarcoidosis. Also known as uveoparotid fever. Melkersson-Rosenthal syndrome Characterized by the triad of recurrent facial nerve palsy, facial (particularly labial) edema, plication of the tongue.

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Oculomotor (3rd Nerve) Palsy Features: i. Severe ptosis ii. Dilated pupil iii. Divergent squint iv. Crossed diplopia Note: 3rd nerve palsy with crossed hemiplegia Webers syndrome. Isolated 3rd nerve palsy occurs in diabetes. SPINAL CORD Hemisection (Brown-Sequard Syndrome) Characterized by: Ipsilateral weakness (pyramidal tract involvement), loss of joint position and vibration senses (lemniscal system involvement). Contralateral loss of pain and deep temperature senses (spinothalamic tract involvement). Complete Transection (Spinal Shock) Stages: 1. Stage of spinal shock all reflexes are decreased, lasts for a minimum of two weeks. 2. Return of reflexes with hyperactivity first reflex to return is a slight contraction of the leg flexors and adductors in response to noxious stimulus. Complication: i. Negative nitrogen balance. ii. Decubitus ulcer. iii. Hypercalcemia and hypercalciuria predispose to renal stone formation. iv. UTI most common complication. Treatment: i. Acute administration of high dose of glucocorticoids as early as possible. ii. Neurotrophins.

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Spinal Cord Compression Epidural Masses 1. Metastasis from the breast (most common), lungs, prostate, kidneys, lymphoma and plasma cell dyscrasias (multiple myeloma). 2. Thoracic cord is most commonly involved. 3. Prostate and ovarian carcinomas involve the sacral and lumbar vertebrae due to spread through Bartons plexus of veins in the epidural space. 4. Investigation of choice MRI. Epidural Abscess Causative organism: Most commonly due to Staphylococcus aureus. Clinical feature: Triad of pain, fever and rapidly progressive weakness. Risk factors: i. Impaired immune status (diabetes mellitus, renal failure, alcoholism, malignancy). ii. IV drug abuse. iii. Infections of the skin and other tissues hematogenous spread (most common route). Intradural Masses 1. Meningioma. 2. Neurofibromas most common. Intramedullary Masses Ependymoma. Spinal Cord Trauma Causes: 1. Atlantoaxial dislocation is seen in i. Rheumatoid arthritis ii. Hydrocephalus iii. Retropharyngeal abscess iv. Downs syndrome 2. Jeffersons fracture is a ring fracture of atlas.

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3. Hangmans fracture is a fracture through the pedicle of C2. 4. Teardrop fracture is crushing of vertebral body. Diagnosis: Investigation of choice for traumatic paralysis is MRI. Spinal Cord Infarction Blockade of anterior spinal artery causes paraplegia or quadriplegia and dissociated sensory loss affecting pain and temperature sensations but sparing vibration and position senses. Transverse Myelitis Initial symptom is focal neck or back pain. Most commonly involves the thoracic and lumbar vertebrae. Often begins during recovery from a viral infection. Clinical feature: Paresthesia, sensory loss, motor weakness, sphincter disturbance. Treatment: Steroids. CHRONIC MYELOPATHIES Syringomyelia Clinical feature: Dissociated sensory loss loss of only pain and temperature sensations with sparing of vibration and position senses. Areflexic weakness in the upper limbs. Balaclava helmet type of sensory loss over face. Chiari Malformations and Dandy-Walker Syndrome Please see the chapter of Congenital CNS Anomalies. Subacute Combined Degeneration Etiology: Vitamin B12 deficiency. Pathology: Involvement of the pyramidal tract and the posterior and lateral tracts.

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Clinical feature: Paresthesia in the hands and feet. Early loss of vibration and position senses. Progressive spastic and ataxic weakness. Corticospinal tract involvement causes increased tendon reflexes, clonus, extensor plantar response. Note: Neurological symptoms may occur in the absence of anemia. Diagnosis: Schilling test. Treatment: Vitamin B 12 for life. Folate may cause deterioration of symptoms. Tabes Dorsalis Pathology Involvement of dorsal column loss of position and vibration senses. Dorsal root ganglia and nerve roots. Clinical feature: Fleeting and repetitive, lancinating pain, occur mostly in the legs. Bladder disturbance. Cardinal signs impaired position and vibration senses, loss of reflexes in the legs, Rombergs sign, bilateral Argyll Robertson pupil, ataxia (due to loss of position sense), ptosis, miosis, flexor plantar response. Note: Frenkels exercise is done in tabes dorsalis. TRAUMATIC INJURY Acute Subdural Hemorrhage This is hemorrhage beneath the dura (between dura and arachnoid matter). Subdural hemorrhage is the most common type of traumatic hemorrhage in brain. Cause: Contusions of head most common cause. Acceleration forces such as whiplash injury. Most commonly due to disruption of the bridging veins. Clinical feature: Most patients are comatosed from the onset (though a lucid interval is found in 1/3 cases). Unilateral headache. Dilated pupil on the side of injury.

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Diagnosis: CT scan shows crescentic (concavo-convex) hyperdense lesion located mainly in the frontotemporal region. Management: In acutely deteriorating patients with impaired alertness and pupillary dilatation burr holes or emergency craniotomy may be performed even before obtaining a CT scan. Acute Epidural (Extradural) Hemorrhage This is hemorrhage between the dura and the skull. Etiology: Most commonly associated with fracture of the squamous portion of the temporal bone. Most commonly due to middle meningeal artery rupture. Clinical feature: Characterized by a lucid interval before the onset of coma. Pupils dilated. CT scan: Shows lenticular (biconvex) hyperdense lesion. Treatment: Require urgent evacuation by burr hole. Chronic Subdural Hemorrhage Clinical feature: Symptoms appear after a period of weeks, or even months, following a trivial injury. Symptoms headache which is fluctuating and often positional; confusion, personality changes, seizures. CT scan shows hypodense lesion. Note: Acute bleeding appears hyperdense in CT scan, whereas old bleeding appears hypodense. Most common type of hemorrhage in boxers ear bleed. Glasgow Coma Scale
Eye opening Spontaneous4 To loud voice3 To pain2 Nil1 Motor response Obeys command6 Localizes pain5 Withdraws limbs4 Abnormal flexion3 Extension2 Nil1 Verbal response Oriented5 Confused4 Inappropriate word3 Incomprehensible sounds2 Nil-1

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Note: Maximum Glasgow score = 15 and minimum score = 3. Score of 3-4 85 percent chance of dying. Score > 11 85 percent chance of surviving. BRAIN TUMORS Primary Brain Tumors Most common solid tumor in children. In children mostly infratentorial. In adults mostly supratentorial. Gliomas Astrocytoma: Tumors arising from astrocytes are the most common intracranial neoplasm. Classification: a. High grade (infiltrating) fibrillary astrocytoma Grade I includes juvenile pilocytic astrocytoma excellent prognosis after surgical excision. Grade II astrocytoma (well differentiated). Grade III anaplastic astrocytoma (moderately differentiated). Grade IV glioblastoma multiforme most aggressive, worst prognosis. b. Low grade astrocytoma. Low-grade astrocytoma More common in children, benign in nature. Pilocytic astrocytoma Arises from the cerebellum. Shows characteristic spindle-shaped cells. Management : 1. Surgical excision in symptomatic children. 2. Radiotherapy usually reserved for tumor recurrence. 3. In undissectable tumor partial excision or biopsy with external beam irradiation. Prognosis: Excellent (best prognosis in children).

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High-grade astrocytoma Features of aggressiveness: i. Hypercellularity ii. Miotic activity correlation with clinical course. iii. Cellular atypia iv. Endothelial Most common predictors of proliferation aggressiveness v. Necrosis Common in adults, supratentorial. Metastasis via CSF to spine. Management: Steroids, surgery, post-op radiation, chemotherapy (nitrosoureas). Prognosis usually fatal. Oligodendrogliomas Benign, supratentorial, occurs in adults. Pathology: Usually show a mixture of astrocytes and oligodendrocytes. 70-90% are calcified. Some show satellitosis. Management: Surgery. Prognosis: Good. Ependymomas Site: In children, they occur within the ventricles, most commonly the 4th ventricle causing increased ICT and hydrocephalus. In adults, they are located mainly in spinal canal, usually the lumbosacral region. Metastasis: Via CSF (brain tumor metastases that spread to the spinal cord by this means are called drop metastases). Management: Total surgical excision. Prognosis: Excellent. Medulloblastoma This is the most common malignant brain tumor in children.

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Origin: From the primitive neuroepithelial cells (others such tumors are neuroblastoma, Ewings sarcoma). Site: Most common in the midline posterior fossa (cerebellum). Pathology: Homer Wright rosettes. Metastasis: It is the most common tumor to metastasize through CSF . Metastasis outside the CNS occurs. Clinical feature: Obstruction of fourth ventricle may produce hydrocephalus, gait abnormalities. Treatment: Surgical excision. Radiation in children less than 3 years. Primary CNS Lymphoma They are most common in immunocompromised patients. But incidences among immunocompetent and immunocompromised patients are equally increasing. Nature: B-cell origin (like non-Hodgkins lymphoma). Intermediate to high grade. Multicentric in origin. Characteristically shows angiocentric growth. Etiology: Most commonly associated with E-B virus. Treatment: Radiotherapy is the mainstay of treatment. Prognosis: Poor. Meningiomas They are derived from the cells of arachnoid granulations (arachnoid cap cells). They are associated with the loss of NF2 tumor suppressor gene due to deletion of chromosome 22. Histology: Psammoma bodies (also seen in ovarian cystadenoma and papillary ca of thyroid). Nature: Benign. Management: Surgery.

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Schwannomas Origin: They arise from the schwann cells of nerve roots most commonly the 8th cranial nerve (acoustic schwannoma). May arise from any cranial nerve except olfactory and optic nerves. Association: Neurofibromatosis type II strongly predisposes to acoustic neuroma. Treatment: Surgery. Craniopharyngioma Origin: From the remnants of Rathkes pouch. Site: Supra-sellar. Clinical feature: 1. Growth failure in children. 2. Endocrine abnormalities such as diabetes insipidus and delayed puberty in adults. 3. Bitemporal homonymous hemianopia in either age groups; sea-saw nystagmus. 4. Increased ICT headache, vomiting, papilledema most common in young adults. X-ray: 80 percent tumors show suprasellar calcification. Treatment: Trans-sphenoidal resection + postoperative radiotherapy. BRAIN TUMORS AT A GLANCE 1. Astrocytomas are the most common brain tumors. 2. Medulloblastomas are the most common malignant brain tumors in children. 3. Astrocytomas (gliomas) are the most common posterior fossa tumors. 4. Medulloblastomas are the most common midline cerebellar tumors. 5. CSF metastases are seen in high-grade astrocytoma, ependymoma, medulloblastoma (most common). 6. All tumors are treated by surgery except primary CNS lymphoma where radiotherapy is the treatment of choice (also unresectable low-grade astrocytoma).

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7. Medulloblastomas are the most radiosensitive tumors. 8. Intracranial calcification is seen in craniopharyngioma (most common), oligodendrogliomas. 9. Investigation for brain tumors: Contrast enhanced CT scan. MRI scan with gadolinium contrast. Lumbar puncture is contraindicated as it may produce brain herniation in patients with mass lesions. 10. Most common supratentorial tumor in children is craniopharyngioma. 11. Most tumors in children are infratentorial. Metastatic Tumors of Brain Route: Hematogenous. Source: i. Leukemias and lymphomas most common source. ii. Lungs most common solid tumor. iii. Breast iv. Melanoma v. GI tract. Clinical feature: Focal neurological deficits most common sign. NEUROCUTANEOUS SYNDROMES Neurofibromatosis Type 1 (von Recklinghausens Disease) This is characterized by: 1. Neurofibromas (2 or more) these are benign tumors of peripheral nerve or 1 plexiform neurofibroma pathognomonic for NF1. 2. Caf au lait spots at least 6 spots measuring > 1.5 cm in diameter. 3. Lisch nodules (2 or more) hamartomas of the iris, causes no clinical problem. Others: Hydrocephalus, pseudoarthrosis, dysplasia of the greater sphenoid wing, scoliosis, and limb hypertrophy (elephant man).

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Genetics: Autosomal dominant. Mutation of NF1 tumor suppressor gene on chromosome 17 that codes for neurofibromin. Prognosis: Increase risk of developing nervous system neoplasms including plexiform neurofibromas, optic gliomas (most common), pheochromocytoma, ependymoma, meningiomas and astrocytomas. May undergo sarcomatous changes in 5-10 percent cases (fibrosarcoma). Note: Plexiform neurofibromatosis (elephant man) involves most commonly the orbital division of the 5th cranial nerve. Neurofibromatosis Type 2 Characterized by bilateral acoustic schwannomas and increased risk of meningiomas, ependymomas and schwannomas of other cranial and spinal nerves. Genetics: Autosomal dominant. Deletion of chromosome 22q is noted in 90 percent cases. It encodes for merlin.
Difference between neurofibromas and schwannomas Neurofibroma Origin Capsule Cleavage plane Schwann cells and fibroblasts Not encapsulated None nerve always removed with tumor Schwannoma Schwann cells Encapsulated Cleavage plane between tumor and nervetumor can be excised without involving the nerve.

Tuberous Sclerosis (Bourneville Disease) Autosomal dominant and spontaneous mutation of chromosome 9, 11. Characterized by: 1. Cutaneous lesions including i. Adenoma sebaceum (facial angiofibromas), ii. Ash-leaf shaped hypopigmented spots (best seen under UV light with Woods lamp), iii. Shagreen patches, iv. Depigmented nevi.

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2. Seizures. 3. Mental retardation. Note: Also called EPILOIA for epilepsy, low IQ and adenoma sebaceum. Others: Intracranial hamartomas (cortical tubers and subependymal nodules, subependymal astrocytoma most commonly at foramen of munro, rhabdomyomas of myocardium, angiomyolipomas of kidney. von Hippel-Lindau Syndrome 1. Retinal angiomas (hemangioblastoma). 2. Cerebellar hemangioblastomas may produce increased erythropoietin leading to polycythemia. 3. Others renal cell carcinoma, pheochromocytoma and cysts of the kidneys, pancreas, epididymis and liver. INTRACRANIAL INFECTIONS Acute Bacterial Meningitis Etiology: a. First 2 months of life i. Group B and D streptococci (streptococcus agalactiae most common cause). ii. E. coli iii. Listeria monocytogenes b. 2 months to 12 years i. Streptococcus pneumoniae most common cause ii. N. meningitides iii. H. influenzae type b c. 12 years to 20 years N. meningitides d. Above 20 years Streptococcus pneumoniae. Others Fungal Cryptococcus, candida, coccidioides, sporothrix Note: Cause of recurrent meningitis CSOM. Complications: i. SIADH hyponatremia ii. Mental retardation iii. Hydrocephalus iv. Brain abscess.

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H. Influenzae Meningitis Complication: i. Subdural effusion ii. Residual auditory deficit auditory evaluation (BERA) should be done before discharge. Treatment: Ampicillin is the drug of choice for susceptible isolates. Third generation cephalosporins for beta lactamase producing strains. CSF study: See below. Tubercular Meningitis Involves the basal brain (basal exudates), subarachnoid space (subarachnoiditis), leptomeninges (pia and arachnoid matters, dura is spared). Complication: Arachnoid fibrosis which may lead to communicating hydrocephalus and endarteritis obliterans. May also cause arterial end occlusion and cerebral infarction. CSF study: See below. Aseptic Meningitis Etiology: i. Enteroviruses (polio, coxsackie A) most common cause ii. Arbovirus iii. HIV iv. HSV-2 v. Others mumps. CSF study: See below.
CSF study at a glance
Protein Glucose Chloride ion Cell count (20-50 md/dl) (40-70 mg/dl) (116-122 mEq) (< 5/microlit) Bacterial meningitis TB meningitis Markedly increased (> 220) Increased (> 50) Decreased (< 34) Decreased (<40) Decreased Increased neutrophils Increased lymphocytes and neutrophils Increased lymphocytes

Decreased

Aseptic meningitis

Increased

Normal

Normal

Neurological Disorders

381

Brain Abscess Etiology: Mixed infections are most common. Most common organisms are streptococcus, Staphylococcus aureus, gram-negative bacilli (E.coli) etc. Most common anaerobic organisms are bacteroides. Source: Most common source is from otitis media. Site: Most common sites are frontal lobes temporal lobes. Clinical feature: Headache is the most common symptom. Triad of fever, headache and focal neurological deficits. Investigation: CT scan most useful. MRI. LP is contraindicated. Treatment: Antibiotics PnG is the drug of choice + chloramphenicol/cefotaxime/metronidazole. Total excision of the abscess. Steroids. Subdural Empyema Causative organism: Streptococcus most common. Pathogenesis: Infection spreads from the paranasal sinuses (most commonly the frontal sinus). Osteomyelitis of the skull. CSOM most common cause. Clinical feature: Headache, fever, stiff neck. Increased ICT vomiting. Focal deficits hemiparesis and hemiplegia. Meningismus. Diagnosis: CECT and MRI. LP is contraindicated.

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Treatment: Emergency surgery. Viral Encephalitis Etiology: i. Arbovirus (Japanese B encephalitis) most common cause of epidemic viral encephalitis. ii. Enteroviruses. iii. HSV-1 most common cause of sporadic viral encephalitis. iv. Mumps virus. v. Less common CMV, EBV, HIV, measles, nipah virus (paramyxovirus). Investigation: 1. PCR amplification of viral nucleic acid diagnostic for many types. 2. Serology. 3. Brain biopsy. 4. MRI hyperintense areas in brain are seen in HSV encephalitis. Morphology: i. Perivascular mononuclear cell infiltration. ii. Microglial nodules. iii. Inclusion bodies, e.g. rabies and CMV. iv. Neuronophagia. Clinical feature: Features of meningitis and altered consciousness. General fever, altered sensorium, headache. Focal neurological signs especially in HSV encephalitis. Treatment: Acyclovir for HSV encephalitis. Progressive Multifocal Leukoencephalopathy Etiology: JC virus. Almost all patients have immunosuppressive disorder. Clinical feature: Visual defects homonymous hemianopia. Mental impairment.

Neurological Disorders

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Diagnosis: MRI periventricular lesion, PCR amplification of JC virus from CSF is diagnostic. Subacute Sclerosing Panencephalitis (SSPE) Etiology: Measles virus. Clinical feature: Age 5-15 years. Progressive intellectual deterioration, seizures, myoclonus, ataxia, visual disturbance. EEG periodic patterns. Prion Diseases These are degenerative disorders of the CNS caused by infectious proteins called the prions. Features of prion diseases: Long incubation periods. Amyloid plaques in brain. No inflammation. Always fatal. Etiology: Prion proteins are formed due to misfolding of proteins. Note: Secondary structure of prion proteins is -sheets. Types: i. Kuru ii. Creutzfeldt-Jakob disease iii. GSS syndrome iv. Fatal familial insomnia v. Scrapie in sheep. Creutzfeldt-Jacob Disease Pathology: Spongiform degeneration of the brain mostly in the cortex and basal ganglia. This is equivalent to mad cow disease in cattle. Diagnosis: Brain biopsy is specific. Clinical feature: Age of onset 50-75 years. Rapidly progressive dementia.

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Prominent associated myoclonus (in 90% cases). EEG is characteristic. Gerstmann (GSS) Syndrome Spinocerebellar degeneration. NUTRITIONAL AND METABOLIC DISEASES OF CNS Anoxic-ischemic Encephalopathy Pathology: Diffuse cortical necrosis almost invariably involving the hippocampus. MITOCHONDRIAL DISORDERS Kearns-Sayre Syndrome Triad of retinitis pigmentosa, external ophthalmoplegia and heart block. Others sensorineural deafness, dementia, diabetes, hypothyroidism. Lebers Optic Atrophy Due to inherited point mutation in mitochondrial DNA. Clinical feature: Bilateral, subacute, painless loss of vision with central scotomas and abnormal color vision. MERRF Syndrome Myoclonic epilepsy and ragged red fibers due to mtDNA point mutation. PERIPHERAL NEUROPATHY Clinical feature: 1. Sensory loss - glove and stocking pattern. 2. Areflexia. 3. Motor weakness more in extensor muscles than the flexor groups. 4. Muscle atrophy. Diagnosis: Nerve conduction study decreased velocity is most important finding. Nerve biopsy from the sural nerve.

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Etiology: a. Pure motor neuropathy i. Amyotrophic lateral sclerosis ii. Poliomyelitis iii. Lead poisoning chronic iv. Porphyria - acute v. Diphtheria - acute vi. Others dapsone, L-E syndrome, M. gravis, tick paralysis. b. Pure sensory neuropathy i. Diabetes mellitus chronic ii. Beriberi iii. Leprosy iv. Alcohol v. Vitamin B12 deficiency c. Mixed neuropathy i. G-B syndrome ii. Uremia iii. Nitrofurantoin iv. Arsenic poisoning POLYNEUROPATHY Guillain-Barr Syndrome (Acute Demyelinating Polyneuropathy) Features: Areflexia. Muscle paralysis ascending, legs are more commonly affected, may lead to respiratory failure. Sensory loss Facial nerve is involved in 50 percent cases. Lower cranial nerves are also involved. Deep tendon reflexes disappear within a few days of onset. Bladder function is spared. CSF study acellular rise of total protein. Treatment: IV immunoglobulin. Plasmapheresis. Steroids have no role. Ventilatory assistance may be needed in case of respiratory failure.

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Prognosis: Good. About 85 percent of patients make a complete recovery. Chronic Relapsing Polyneuropathy Causes: Diabetes, Djerine Sotta syndrome. NEUROMUSCULAR JUNCTION Myasthenia Gravis Pathology: Decrease in available ACh receptors at the N-M junctions due to an antibody mediated immune attck. Associated with HLA-B8, DR3. Other associations thymoma (most common association), hyperthyroidism. Clinical feature: Women are most commonly affected. Diplopia and ptosis most common initial symptoms. Difficulty in swallowing. Limb weakness often proximal and asymmetric. Deep tendon reflexes preserved. Muscle weakness worsens by exercise. Diagnosis: Edrophonium chloride (tensilon) injection highly probable diagnosis if unequivocally positive. Repeated nerve stimulation detrimental response. Treatment: 1. Anticholinesterases oral pyridostigmine. 2. Immunosuppressants. 3. Thymectomy should be carried out in all patients with generalized myasthenia gravis between the ages of puberty and at least 55 years. 4. Plasmapheresis. 5. IV immunoglobulin. Prognosis: Spontaneous remission may occur. Stage with best prognosis is stage 1, active.

Neurological Disorders

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Lambert-Eaton (L-E) Syndrome It is a presynaptic disorder of the N-M junction due to antibody against calcium channels. Association small cell carcinoma of lungs. Clinical feature: Proximal muscles of lower limbs are most commonly affected. Diplopia and ptosis may be present. Reflexes decreased or absent. Autonomic changes such as dry mouth and impotency. Diagnosis: Repeated nerve stimulation causes an incremental response (c.f. myasthenia gravis). Treatment: Guanidine and pyridostigmine. Plasmapheresis. IV immunoglobulin. DISEASES OF MUSCLE Hereditary Myopathies Duchenne Muscular Dystrophy (Pseudohypertrophic Muscular Dystrophy) Inheritance: X-linked. Features: Onset before 5 year of age. Progressive muscle weakness Gowers sign. Usually involves the proximal and neck flexors. (Pseudo)hypertrophy of calf muscles. CVS cardiomegaly, RVF. Mental retardation. Scoliosis impaired pulmonary function. Pathology: Defect in the gene that codes for the sarcolemmal protein dystrophin. There is marked variation in size of muscle fibers as well as small groups of necrotic and regenerative fibers (heterogenicity).

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A Systematic Review of Subjects for PGMEE

Diagnosis: Serum CK level increased this is positive before clinical features are evident. Muscle biopsy diagnostic, shows heterogenicity. EMG. Prognosis: Death is due to respiratory failure in second or third decade. Becker Dystrophy Onset in childhood (5-25 years). Death in the fourth decade. No mental retardation. Rest same as Duchenne dystrophy.

Myotonic Dystrophy This is the most common muscular dystrophy in adults. Genetics: Autosomal dominant, involves the gene at chromosome 19q13.3. Features: Onset in the second decade of life. Involves the distal muscles (whereas all other myopathies involve proximal muscles). Hatched-faced appearance. Congenital variety is characterized by neonatal respiratory insufficiency appearing before the age of 5 years. Others cardiac defects, mental retardation, cataract, gonadal atrophy. Diagnosis: Muscle biopsy shows selective atrophy of type I muscle fibers. Congenital Myopathies Types: i. Central core disease ii. Nemaline myopathy iii. Centronuclear (myotubular) myopathy. Serum normal CK level. Notes: Most common dystrophy in old age (5th-6th decade) is oculopharyngeal dystrophy.

Neurological Disorders

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Heart is not involved in facioscapulohumeral and oculopharyngeal dystrophies. Floppy Baby Syndrome Causes: i. Downs syndrome ii. Werding Hoffman spinal muscular dystrophy iii. Central core disease iv. Mitochondrial myopathies v. E-D syndrome vi. Infant botulism Clinical feature: Hypotonia, frog-like posture, delay in motor milestones. Spinal Muscular Atrophy Normal IQ. Tongue fasciculation. Plus above mentioned features. Toxic Myopathies Most common cause is injection of narcotic analgesics (pentazocine), meperidine and heroin. Periodic Paralysis Etiology: i. Hypokalemic periodic paralysis due to calcium channel defect. ii. Hyperkalemic periodic paralysis due to sodium channel defect. iii. Paramyotonia congenita. iv. Thyrotoxic periodic paralysis. v. Hypophosphatemia. Note: High carbohydrate diet can provoke hypokalemic paralysis. Drug of choice for an acute attack of familial periodic paralysis is KCl. Neurological Channelopathies Calcium channelopathies: i. Episodic ataxia type 2 ii. Spinocerebellar ataxia type 6 iii. Familial hemiplegic migraine

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A Systematic Review of Subjects for PGMEE

iv. Malignant hyperthermia v. Hypokalemic periodic paralysis Sodium channelopathies: i. Paramyotonia congenitax ii. Hyperkalemic periodic paralysis iii. Normokalemic periodic paralysis Chloride channelopathies: i. Generalized myotonia ii. Myotonia congenitax Potassium channelopathy: i. Episodic ataxia type 1 Note: All are autosomal dominant, except myotonia congenita which is autosomal recessive plus dominant. MULTIPLE SCLEROSIS It is characterized by chronic inflammation, demyelination and gliosis (scarring). Clinical feature: Relapsing and remitting course. Symptoms Weakness of limbs pyramidal involvement. Optic neuritis. Sensory disturbance paresthesia, hypesthesia. Diplopia. Ataxia duet to cerebellar involvement. Impotency. Extrapyramidal symptoms are not seen. Diagnosis: CSF mononuclear cell pleocytosis, elevation of total Ig, presence of oligoclonal Ig. Others visual evoked response test slowing. MRI diagnostic, shows white matter involvement. ERG is normal. Treatment: Interferon 1. AUTONOMIC NERVOUS SYSTEM Postural Hypotension Defined as a postural fall from supine to standing position of at least 20 mmHg in SBP or 10 mmHg in DBP sustained for at least 3 minutes.

Neurological Disorders

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Etiology: i. Diabetes ii. Tabes dorsalis iii. Antihypertensive drugs iv. Posterior fossa tumors v. Syringomyelia vi. G-B syndrome vii. Amyloidosis Test: Valsalva response. Symptoms of autonomic dysfunction: Impotence, bladder dysfunction, constipation (sometimes diarrhea), anhidrosis, orthostatic hypotension, hypertension, resting tachycardia, silent MI. Mononeuropathy Multiplex Pathology: Involvement of multiple noncontiguous nerves simultaneously. It is a vasculitis affecting the vasa nervosum. Cause: Polyarteritis nodosa most common cause. Hypersensitivity vasculitis. Rheumatoid arthritis. SLE. Leprosy, sarcoidosis, amyloidosis. Treatment: Steroids. MONONEUROPATHY Carpal Tunnel Syndrome Pathology: Compression of the median nerve as it passes below the flexor retinaculum. Etiology: i. Idiopathic most common cause. ii. Pregnancy. iii. Tenosynovitis with arthritis involving the wrist. iv. Hormonal acromegaly, hypothyroidism, diabetes. v. Rheumatoid arthritis. vi. Metabolic gout, amyloidosis. vii. Trauma Colles fracture.

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Clinical feature: Affects middle aged female. Tingling and numbness of the thumb, index and middle fingers which is worse at night. Diagnosis: Phallens test is positive. Nerve conduction velocity along the median nerve is slowed. Treatment: Surgical decompression. Tarsal Tunnel Syndrome Due to involvement of the posterior tibial nerve.

ENDOCRINOLOGY AND METABOLISM


PHYSIOLOGY

Respiratory Quotient It is the ratio of volume of CO2 produced and the volume of O2 consumed per unit time in steady state equilibrium. RQ values: Carbohydrate 1.00 Fat 0.70 Protein 0.82 Basal Metabolic Rate It is the minimum energy required at rest in a room at a comfortable temperature in the thermoneutral zone 1214 hours after the last meal. BMR falls by about 10 percent during sleep and up to 40 percent during starvation. It best correlates with body surface area. Determinants: 1. Age BMR is high in children. 2. Sex BMR is high in males. 3. Mental state anxiety and tension increase the BMR. 4. Hormones BMR is increased by catecholamine and thyroid hormones.

PITUITARY GLAND
Hormones from the Anterior Lobe of Pituitary
The pituitary hormones Hormones ACTH Prolactin Growth hormone TSH LH and FSH Nature Polypeptide Polypeptide Polypeptide Glycoprotein Glycoprotein Secreted by cell type Basophilic Acidophilic Acidophilic Basophilic Basophilic

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A Systematic Review of Subjects for PGMEE

Hormones from the Posterior Pituitary Vasopressin and oxytocin are secreted from the cell bodies of the magnocellular neurons in supraoptic and paraventricular nuclei of hypothalamus. Vasopressin mainly from the suproptic nucleus and oxytocin mainly from the paraventricular nucleus. Oxytocin Action: i. It increases the force and frequency of uterine contractions (uterine stimulant or oxytocic). ii. Oxytocin contracts the myoepithelium of mammary alveoli and causes milk ejection reflex. T1/2 of oxytocin is 6 minutes. Vasopressin or ADH ADH circulates in free form in plasma. Receptors: V1 receptors all vasopressin receptors except those on renal CD cells and some blood vessels. V2 receptors located primarily on the collecting duct cells in the kidney regulate their water permeability through cAMP production. Actions: Kidney ADH acts on the collecting duct cells to increase their water permeability. They promote exocytosis of aquaporin-2 water channel through the apical membrane of the principal cells. GROWTH HORMONE Actions: 1. Increased gluconeogenesis 2. Increased ketogenesis 3. Increased protein synthesis (anabolic) 4. Increased phosphate in blood 5. Decreased blood urea and nitrogen. GH is diabetogenic because it increases hepatic glucose output and exerts its anti-insulin effect in muscle. It is also ketogenic.

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DISORDERS OF GH SECRETION GH Excess (Acromegaly and Gigantism) Cause: Pituitary adenomas, 70 percent being macroadenomas. Associated with mutation in GNAS1 gene on chromosome 20q13. TRH (thyroxin releasing hormone) increases secretion of GH in acromegaly. Prolactin secretion is also increased. Clinical feature: Tall stature (hands and feet are large acral means parts). Coarse facial features, protrusion of the jaw (prognathism). Thick skin and subcutaneous tissue. Increased body hair. CVS hypertension and cardiomegaly. Gynecological amenorrhea, galactorrhea and hirsutism. Laboratory findings: 1. Insulin resistance is seen in 80 percent of cases, although abnormal glucose tolerance and clinical diabetes are less common. 2. Increased serum phosphate, hypercalciuria. Diagnosis: 1. Measurement of glucose-suppressed GH secretion. 2. Measurement of IGF-1 concentration (somatomedin C). 3. Increased TRH in 80 percent cases. 4. X-ray shows Enlargement of the paranasal sinuses. Increased heel pad thickness. Arrow headed finger. Treatment: Surgery transsphenoidal surgery. Radiation. Drugs bromocriptine, octreotide. Growth Hormone Deficiency (Hypopituitarism) Most commonly due to chromophobe adenomas of the pituitary.

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A Systematic Review of Subjects for PGMEE

Infants with GH deficiency are born normal. They develop features of growth impairment within a few months after birth. But a clinical diagnosis is made at 1-2 years of age. Clinical feature: Short stature (dwarfism) with normal body proportions. Premature fusion of epiphysis the height is less than skeletal age (bone age is less than chronological age by 2 years). The development of teeth is delayed. Macroglossia. Normal mental state. Associated hormone deficiencies: ACTH hypoglycemia and convulsions in neonates. Gonadotrophins delay in sexual development. Diagnosis: Insulin provocative test. Note: Bone age < chronological age in hypopituitarism, hypothyroidism, constitutional delay and malnutrition. Bone age > chronological age in Downs syndrome, Turners syndrome and intrauterine infections. PROLACTIN Prolactin is under the control of TRH which also controls TSH. Action: Prolactin causes proliferation of ductal and acinar cells in the breast and induces synthesis of milk proteins and lactose. Regulation: Prolactin synthesis is decreased by prolactin inhibitory hormone (PRIH) from hypothalamus. PRIH is dopamine which acts on pituitary lactotrope D2 receptors. Prolactin synthesis is decreased by dopaminergic agonists like bromocriptine, apomorphine. Prolactin secretion is increased by dopaminergic antagonists like chlorpromazine, haloperidol, metoclopramide and dopamine depleters like reserpine and methyldopa may cause hyperprolactinemia.

Endocrinology and Metabolism

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Hyperprolactinemia Etiology: i. Pituitary adenomas, mainly microadenomas (prolactinomas) most common cause. ii. Drugs mentioned above. iii. Pituitary stalk lesion due to loss of normal inhibitory influence of hypothalamus. Clinical feature: In females galactorrhea, amenorrhea and infertility. In males gynecomastia, impotence and infertility. Visual defects most common pressure symptom and most distressing symptom of prolactinomas. Diagnosis: 1. TRH response test no rise in prolactin level (paradoxical effect see the normal effect). 2. MRI for detection of prolactinomas. 3. Serum prolactin level > 300 g/liter (normal 15-20 g/liter). Note: Non-functioning pituitary adenomas may present with features of hyperprolactinemia due to stalk compression and mass effect but prolactin level is only slightly increased. Treatment: Bromocriptine a dopamine agonist. CRANIOPHARYNGIOMA Origin: From the remnants of Rathkes pouch. Site: Most of these are suprasellar tumors. Histology: Cysts lined by stratified squamous epithelium. Clinical feature: Features of increased intracranial pressure due to hydrocephalus headache, vomiting and papilledema. Visual abnormalities loss of vision and field of vision. Diagnosis: X-ray shows suprasellar calcification. It is the most common calcifying tumor of brain in children. Empty Sella Syndrome Clinical feature: Middle aged obese female presents with headache and hypertension.

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A Systematic Review of Subjects for PGMEE

CT scan the sella is symmetrically ballooned without bony erosion. Pituitary volume is normal. Cause: Cavernous venous thrombosis. ANTIDIURETIC HORMONE Physiology: See above. Diabetes Insipidus Cause: Deficiency of ADH. a. Primary or idiopathic autosomal dominant. b. Secondary due to head injury, pituitary tumors, infections, metastasis, histiocytosis, pregnancy, Sheenans syndrome and SLE. Clinical feature: Polyuria, excessive thirst and polydipsia. Diagnosis: Urinary concentration < 300 mmol/kg and specific gravity < 1.010. Plasma osmolality not changed or slightly increased. Mild hypernatremia. Water deprivation test there is very little increase in urine osmolality with increase in plasma osmolality. Hickey-Hare test. Treatment: i. Desmopressin is the drug of choice. ii. Chlorpropamide. iii. Hydrochlorothiazide. Differential diagnosis: a. Psychogenic polydipsia both urine and plasma are hypo-osmolar. b. Dilutional hyponatremia (e.g. Adrenal insufficiency) orthostatic hypotension, tachycardia and increased BUN. c. Pseudohyponatremia due to increased glucose/ protein/triglycerides in blood. d. Sick-cell syndrome low set hypothalamic osmoreceptors. Note: Nephrogenic diabetes insipidus Is due to inability of the kidneys to respond to vasopressin.

Endocrinology and Metabolism

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Congenital - due to congenital defects in the V2 receptors (X-linked). Drugs lithium, amphotericin B, aminoglycosides, cisplatin. Amyloidosis, pregnancy. Treatment: Thiazide effective both in central and in nephrogenic diabetes insipidus. Amiloride drug of choice in lithium induced nephrogenic DI. Syndrome of Inappropriate ADH Secretion (SIADH) Etiology: 1. Small cell carcinoma of lungs 2. Lung abscess, COPD 3. Skull fracture 4. Acute encephalitis 5. Drugs vincristine, vinblastine, cyclophosphamide 6. Hypothyroidism 7. Acute intermittent porphyria. Pathology: There is water retention and sodium excretion. Excretion of concentrated urine (osmolality > 300 mmol/kg) despite a subnormal plasma osmolality (< 280 mmol/kg) and low serum sodium concentration hyponatremia and increased total body water, but edema and hypertension do not develop. Hypouricemia. Urinary sodium > 20 mEq/lit. Diagnosis:Water load test- normal values. Treatment: 1. Fluid restriction to 800-1000 ml daily. 2. IV infusion of 3-5 percent (hypertonic) NaCl solution. 3. IV frusemide. 4. Treatment of the underlying cause. 5. In chronic SIADH, demeclocycline or fludrocortisone.

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A Systematic Review of Subjects for PGMEE

THYROID GLAND
ANATOMY Position: The thyroid gland lies against C5-T1 vertebrae. Isthmus is situated on the 2nd and 3rd rings of trachea. Capsule: True capsule False capsule it is derived from the pretracheal layer of the deep cervical fascia. Apex of the gland: Apex is limited superiorly by the attachment of the sternothyroid muscle which prevents upward enlargement of the gland. Arterial supply: 1. Superior thyroid artery branch of external carotid artery. 2. Inferior thyroid artery branch of thyrocervical trunk. 3. Arteria thyroidea ima branch of brachiocephalic trunk. 4. Accessory thyroid arteries. Development: From the thyroglossal duct. Parafollicular cells are derived from the caudal pharyngeal complex or the ultimo-branchial body. PHYSIOLOGY Thyroid hormones a. Follicular cells secrete thyroxine (T4) and triiodothyronine (T3). b. Parafollicular C cells secrete calcitonin. Synthesis: Tyrosine 2 molecules condense to form thyroxine iodination produce T3 and T4. Steps: 1. Iodine uptake. 2. Oxidation and iodination 3. Coupling 4. Storage as thyroxine 5. Peripheral conversion of T4 to T3.

Endocrinology and Metabolism

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Transport: T4 is the main transport form. It binds to 3 plasma proteins thyroxine binding globulin (TBG), prealbumin (transthyretin) and albumin. TBG level: Increased in pregnancy, estrogen therapy. Decreased by glucocorticoids, L-asparaginase, androgens. Note: Thyroglobulin is the storage form. T4 is the transport form. T3 is the active hormone. Daily secretion T4 80 g T3-4 g ECTOPIC THYROID AND ANOMALIES OF THYROGLOSSAL TRACT Lateral Aberrant Thyroid Due to metastasis in a cervical lymph node from an occult thyroid carcinoma, almost invariably papillary Ca. Thyroglossal Cyst Site: In the midline, below the hyoid bone (most common). Clinical feature: The swelling moves upwards on protrusion of the tongue as well as swallowing. Thyroglossal Fistula Cause: Never congenital; it is due to infection or inadequate removal of a thyroglossal cyst. Histology: Lined by columnar epithelium, discharges mucus. Treatment: Sistrunks operation. HYPOTHYROIDISM Etiology 1. Endemic cretinism often goitrous and due to iodine deficiency.

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A Systematic Review of Subjects for PGMEE

2. Autoimmune thyroiditis (chronic lymphocytic thyroiditis). Non-goitrous primary myxedema. Goitrous Hashimotos disease. 3. Iatrogenic after thyroidectomy, after radioiodine therapy. Drug therapy antithyroid drugs, amiodarone, lithium, PAS and iodides. 4. Dyshormonogenetic goiter congenital biosynthetic defect. 5. Goitrogens cabbage. 6. Secondary to pituitary or hypothalamic diseases. Cretinism (Congenital Hypothyroidism) Most common cause of cretinism is thyroid dysgenesis. Features: Not present at birth. Infants: Delayed closure of fontanelles earliest sign. It is also seen in Downs syndrome, osteogenesis imperfecta. Persistent physiological jaundice, absent social smile. Dwarfism short stature, head size is normal but the extremities aer short (disproportionate body proportions). Bone dentition and skeletal maturity are delayed (bone age to height age ratio is deceased). Mental retardation. Others coarse features, large protruding tongue, umbilical hernia, hypothermia, loss of eyebrows. Note: In neonatal screening programme for detection of congenital hypothyroidism, blood is collected from cord on first day or from the heel pad on the fourth day. Adult Hypothyroidism Features: Lethargy, constipation, cold intolerance. Carpal tunnel syndrome. Menorrhagia and galactorrhea. Dementia. Decreased appetite, weight gain. Hair is dry and fall-out. Skin is dry. Hoarseness of voice.

Endocrinology and Metabolism

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Myxedema: This is due to accumulation of mucopolysaccharides in the ground substance of dermis. Dull expressionless face. Periorbital edema. Malar flush and yellow tinge of skin. Pericardial effusion. Increased plasma cholesterol may lead to atherosclerosis. Skin cool, dry with doughy consistency. Hung-up reflex the relaxation phase of the deep tendon reflexes is characteristically prolonged. Mild diastolic hypertension. (Note: BP is increased in both hypo and hyperthyroidism). Laboratory diagnosis: i. Increased serum TSH most useful (but not in case due to pituitary dysfunction). ii. Decreased serum T4 and T3. iii. ECG bradycardia. X-ray: Bone punctate epiphyseal dysgenesis. Skull wormian bones. Chest cardiomegaly (water bottle configuration). Treatment: Levothyroxin (l-troxin) dose 0.1 to 0.2 mg/day. Dose is best determined by clinical criteria and measurement of TSH by an ultrasensitive assay. In myxedema coma supplemented by IV liothyronine (T3). Others IV fluids, hydrocortisone, gradual warming. GOITER It is a generalized swelling of the thyroid gland. Classification 1. Simple goiter (euthyroid) i. Diffuse hyperplastic ii. Multinodular 2. Toxic i. Graves disease ii. Toxic adenoma iii. Neoplasms (benign and malignant)

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A Systematic Review of Subjects for PGMEE

3. Inflammatory i. Autoimmune chronic lymphocytic thyroiditis, Hashimotos thyroiditis. ii. Granulomatous sub-acute thyroiditis. iii. Fibrosing Riedels thyroiditis. Simple Goiter Etiology: Iodine deficiency endemic cretinism. Characterized by deaf-mutism, squint, mental retardation and rigidity (spastic diplegia). Stature normal (c.f. congenital cretinism). Investigation: Euthyroid normal serum T4 and T3 levels. Radioactive iodine uptake studies usually normal but may be increased in the presence of iodine deficiency (endemic goiter). Epidemiology: Endemic goiter is said to be present when the prevalence of goiter in a defined population is > 10 percent. Treatment: Levothyroxin which often causes the goiter to shrink. Pendreds Syndrome Goiter with congenital deafness. Diffuse Hyperplastic Goiter The goiter appears in childhood in endemic areas. In sporadic cases, it occurs at puberty, so called the puberty goiter. Retrosternal Goiter It arises from the lower pole of a nodular goiter. Clinical feature: Dyspnea, dysphagia, engorgement of neck veins. Treatment: Resection from the neck.

Endocrinology and Metabolism

405

Graves Disease Characterized by hyperthyroidism with diffuse goiter, ophthalmopathy and dermopathy. It causes primary hyperthyroidism characterized by goiter appearing at the same time as hyperthyroidism. Cause: Abnormal thyroid stimulating antibodies. Strongly associated with HLA DR3. Eye signs of primary hyperthyroidism: Most commonly involved ocular muscle is the inferior rectus muscle. Lid retraction Dalrymples sign. Lid lag Von Grafes sign. Infrequent blinking Stellwags sign. Poor forehead wrinkling Joffroys sign. Weakness of convergence Mobius sign. Proptosis or exophthalmos (may be unilateral). Treatment: For lid retraction guanethidine eye drop. For malignant exophthalmos lateral tarsorrhaphy, orbital decompression, sleeping propped-up. CVS: Hyperkinetic circulatory state characterized by Tachycardia which is present at sleep. Wide pulse pressure, atrial fibrillation (irregularly irregular pulse). Ejection systolic murmur. Pericardial friction rub (Means-Lerman scratch). Apex beat hyperdynamic but in normal position. Skin: Localized or pretibial myxedema. Thyrotoxicosis Anxiety, tremor, increased sweating, heat intolerance, weight loss, dancing carotid, diarrhea, amenorrhea. Warm and moist hands differentiate with anxiety state. Proximal myopathy. Note: Proptosis, ophthalmoplegia and pretibial myxedema are not due to thyrotoxicosis per se and occurs only in primary hyperthyroidism.

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Diagnosis: Undetectable TSH, increased T4 and T3 levels, increased RAIU values. Treatment: Propanolol alleviates sweating, tremor and tachycardia. Age < 45 years surgery for large goiter (subtotal thyroidectomy), antithyroid drugs for small goiter. Age > 45 years radioiodine (complication thyroid insufficiency). Toxic Nodular Goiter Causes secondary thyrotoxicosis characterized by absent eye signs. It is a consequence of long-standing simple goiter. So it occurs in elderly. Features of hyperthyroidism present long after the appearance of goiter. It may present with cardiac failure or atrial fibrillation. Treatment: Surgery or radioactive iodine (131I). Surgery for Thyrotoxicosis Subtotal thyroidectomy. Pre-operative preparation: Carbimazole is the drug of choice. Iodides given with carbimazole and not alone. Propanolol continued for 7 days after surgery. Postoperative complications: 1. Hemorrhage: Management of postoperative hemorrhage opening of the wound to remove tension by removing the sutures. 2. Respiratory distress due to laryngeal edema which is most commonly due to tension hematoma. 3. Hypocalcaemia manifests 2-5 days after surgery with tetany. Management IV calcium gluconate or oral calcium. 4. Thyrotoxic crisis (storm) Clinical feature extreme irritability, delirium or coma, fever, tachycardia, hypotension, vomiting and diarrhea. Cause inadequate control of thyroid status before operation (most common), stressful illness, radioiodine therapy for thyrotoxicosis.

Endocrinology and Metabolism

407

Management IV hydrocortisone, carbimazole, Lugols iodine, propanolol. 5. Recurrent laryngeal nerve palsy. Note: Hypocalcemia is not a complication of hemithyroidectomy. NEOPLASM Benign Adenomas Follicular adenomas present as solitary thyroid nodules. Scintiscan: Follicular adenomas take up the dye and are called hot nodules. Eighty percent of solitary thyroid nodules are cold nodules, but only 15 percent of them are malignant. Diagnosis: FNAC is the investigation of choice for solitary nodules. Indication of surgery: Malignancy, pressure symptoms, cosmetic. Surgery for solitary nodule: Hemithyroidectomy.
Choice of treatment Graves diasease Toxic nodular goiter Toxic nodules Age < 45 years 131I Age > 45 years subtotal thyroidectomy Subtotal thyroidectomy Age < 45 years hemithyroidectomy Age > 45 years 131I.

Malignant Usually euthyroid and appear as cold nodules on thyroid scan. Papillary Carcinoma The most common type, also least malignant type. Etiology: Papillary Ca develops often due to exposure to radiation in childhood (latent period about 30 years). Features: Bimodal frequency, unencapsulated and multicentric. Spread: Through the thyroid capsule to structures surrounding the neck, especially the regional lymph nodes may

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present as occult primary with cervical lymphadenopathy. Blood-borne metastasis is rare. Pathology: Papillary Ca shows psammoma bodies and orphan-Annie eyed cells. Treatment: Surgery near total thyroidectomy for tumors > 2 cm in size. Regional lymph nodes should be explored and removed if there is evidence of involvement, but radical neck dissection is not justified. For tumors < 2 cm in size lobectomy and isthmusectomy (hemithyroidectomy). 131I for residual cancer or neck glands detected after surgery. Prognosis: Good. Follicular Carcinoma Etiology: They arise in long standing cases of goiter. Features: Encapsulated, capsular and/or vascular invasion is common. Spread: Hematogenous spread to lungs, bone (osteolytic secondaries) and brain. Hurthle-cell tumor: It is a variant of follicular Ca. It metastasizes frequently to bones. Diagnosis: FNAC is often unhelpful as it fails to demonstrate capsular and/or vascular invasion which differentiates it from follicular adenoma. Prognosis: Worse. Medullary Carcinoma Origin: From the parafollicular C cells of the thyroid. Features: High levels of calcitonin are produced may lead to hypocalcemia. Diarrhea most common symptom. It is associated with adrenal pheochromocytoma and hyperparathyroidism (MEN IIa). Associated with stimulation of RET proto-oncogene.

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Metastasis: Involvement of cervical lymph nodes (most common) occurs early. Blood borne metastasis is also early. Pathology: Medullary Ca shows amyloid deposition. Serum calcitonin screening measurement of serum calcitonin is useful when the diagnosis of medullary ca is suspected. Treatment: Surgery total thyroidectomy and resection of involved lymph nodes with either a radical or modified neck dissection. Other Carcinomas Anaplastic Ca: Worst prognosis. Treatment is radiotherapy. Lymphoma: Treatment by radiotherapy plus chemotherapy. THYROIDITIS Riedels Thyroiditis Chronic fibrosing thyroiditis, It is always hypothyroid and never hyperthyroid (compare the later two). Subacute Thyroiditis Also called the de Quervains thyroiditis or granulomatous thyroiditis. Cause Viral infection. Clinical feature: Onset often follows an upper respiratory tract infection. Pain in neck, fever, enlargement of thyroid. Investigation: Increased ESR, leukocytosis. Decreased RAIU. Early, serum T3 and T4 levels are high and TSH level is low (hyperthyroidism). Later, serum T3 and T4 levels are low and TSH level is high (hypothyroidism). Course: Subsides spontaneously and return to normal in few months.

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Chronic Lymphocytic Thyroiditis (Hashimotos Thyroiditis) It is the most common type of thyroiditis. Characterized by increased titer of thyroid antibody, lymphocyte infiltration of the gland (Hurthle cells). Cause: Antithyroid peroxidase antibody. Most commonly against thyroid receptors. Clinical feature: Hypothyroidism, transient hyperthyroidism occurs early. Occurs in women at menopause. Treatment: Thyroxin.

ADRENALS
ANATOMY Anterior relations of adrenal glands: Right gland liver, inferior venal cava and right suprarenal vein. Left gland spleen, stomach, splenic artery, pancreas and left suprarenal vein. Medial border related to inferior phrenic artery. Arterial supply: 1. Superior suprarenal artery branch of the inferior phrenic artery. 2. Middle suprarenal artery branch of the abdominal aorta. 3. Inferior suprarenal artery branch of the renal artery. Venous drainage: The right suprarenal vein drains into the inferior vena cava. The left suprarenal vein drains into the left renal vein. Note: During fetal life the human adrenals are large.

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ADRENAL CORTICAL HORMONES


PHYSIOLOGY Source: Zona glomerulosa aldosterone. Zona fasciculata cortisol. Zona reticularis androgens (dehydroepiandrosterone and androstenedione). Structure: All contain a CPP ring in their structures. Aldosterone and cortisol are C 21 steroids. Androgens are C 19 steroids they contain a keto group at position 17, hence called the 17 ketosteroids. Adrenals are the major source of 17 ketosteroids in urine. Glucocorticoids Action: 1. Metabolic effects i. Carbohydrate decreased insulin synthesis and decreased peripheral uptake of glucose lead to increased hepatic glycogenesis and gluconeogenesis hyperglycemia. Also increases the activity of glucose6-phophatase. ii. Protein increased protein catabolism. iii. Fat increased lipogenesis and ketosis in diabetics. iv. Calcium decreased intestinal absorption and increased renal excretion leads to hypocalcemia and decreased formation and increased resorption of osteoid. 2. Permissive actions i. For glucagon and catecholamine to exert their calorigenic action. ii. For catecholamine to exert their lipolytic action. iii. For catecholamine to produce pressor response and bronchodilatation. 3. Inflammation Glucocorticoids reduce inflammation by reduction of capillary permeability, limitation of recruitment of inflammatory cells at the site and inhibition of phospholipase A leading to decreased production of PG, LT and PAF.

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Test for glucocorticoids reserve: Within minutes after administration of ACTH, cortisol level increases in venous blood. Mineralocorticoid Aldosterone increases sodium reabsorption from urine, sweat, saliva, gastric contents and expands the CSF. Increased loss of K+ and H+ in urine and increased urinary acidity. In kidneys, they act on the principal (P) cells of the collecting duct. Regulation: Aldosterone secretion is increased by high K+ intake and hemorrhage. HYPERFUNCTION OF ADRENAL CORTEX Cushings Syndrome Due to increased production of cortisol from the adrenals. Etiology: 1. Bilateral adrenal hyperplasia most common endogenous cause. This may be due to i. Secondary to pituitary ACTH over production due to pituitary ACTH-producing adenomas (usually microadenomas) Cushings disease or due to pituitary-hypothalamus dysfunction. ii. Ectopic ACTH or CRH production by small cell Ca of lungs, carcinoid of thymus, medullary Ca of thyroid and pancreatic Ca. 2. Adrenal neoplasia 3. Iatrogenic exogenous steroid administration is the most common cause of Cushings syndrome. Pathology and features: 1. Mobilization of peripheral supportive tissue causes muscle weakness, fatiguability, osteoporosis, cutaneous striae and easy bruisability. 2. Increased gluconeogenesis and insulin resistance cause impaired glucose tolerane (hyperglycemia). 3. Redistribution of body fat in the face (moon face), the interscapular area (buffalo hump) and the mesenteric bed (truncal obesity).

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4. Hypertension (both systolic and diastolic BP are increased). 5. Emotional changes to frank psychosis. 6. Due to increased androgen production acne, hirsutism, amenorrhea in women. Occasionally, hypokalemia, hypocalcemia and metabolic alkalosis particularly common in ectopic ACTH producing tumors (differentiate ectopic ACTH production from Cushings disease). 7. Others weight gain, poor wound healing, polycythemia, impotence and atrophy of testis in men, pathological fracture. Diagnosis:
Loss of circadian rhythm (plasma cortisol level does not fall at midnight) earliest manifestation. 24 hour urinary free cortisol (> 275 nmol/day) Low dose (1 mg) dexamethasone suppression test High dose (2 mg) dexamethasone suppression test Suppression No suppression - Adrenal hyperplasia Adrenal hyperplasia due secondary to pituitary to ectopic ACTH production ACTH overproduction or adrenal neoplasia Increased ACTH Decreased ACTH (Adrenal hyperplasia) (Adrenal neoplasia) Pituitary imaging Abdominal CT, urinary 17 keto Petrosal sinus sampling Steroids or DHEA sulphate level for ACTH Pituitary adenoma or Abdominal No mass ectopic tumor mass 17 KS/DHEA Normal Adrenal Ca. Adrenal adenoma

Treatment: 1. Adrenal neoplasm adrenal exploration and excision of the tumor. 2. Adrenal hyperplasia i. Surgery for pituitary microadenoma. ii. Radiation. iii. Bilateral adrenalectomy iv. Medical adrenalectomy by aminoglutathimide, metyrapone which decreases 11 beta hydroxylase.

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Nelsons Syndrome Pituitary adenomas that secrete ACTH in patients after surgical removal of adrenal glands for the treatment of Cushings syndrome. Clinical feature: Mass effect (e.g. visual disturbance), hyperpigmentation due to increased MSH (melanocyte secreting hormone). Aldosteronism Etiology: Primary due to aldosterone secreting adrenal adenoma (Conns syndrome). May also be due to bilateral cortical nodular hyperplasia. Adrenal adenomas: They are usually 1-2 cm in size and most are found incidentally (incidentallomas). Size > 4-6 cm suggests carcinoma. Clinical feature: 1. Due to Na+ retention diastolic hypertension without edema. 2. Due to K+ depletion hypokalemia (muscle weakness) and metabolic alkalosis. 3. Polyuria and polydipsia. Diagnosis: 1. Plasma renin activity In primary aldosteronism, plasma renin is decreased. In secondary aldosteronism due to renin producing tumors it is increased with accelerated hypertension. 2. Failure of suppression of aldosterone secretion by dexamethasone. 3. Adrenal carcinoma abdominal CT scan. 4. Postural decrease in plasma aldosterone and increased plasma 18-hydroxycorticosterone levels differentiate from bilateral adrenal hyperplasia. Management: Adenoma surgical removal of the tumor. Bilateral hyperplasia bilateral adrenalectomy. Drugs spironolactone, glucosteroids.

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Liddles Syndrome It mimics hyperaldosteronism with hypokalemia and hypertension. Androgen Excess Please see later. HYPOFUNCTION OF ADRENAL CORTEX Addisons Disease Etiology: Destruction of more than 90 percent gland due to 1. Idiopathic autoimmune, most common cause. 2. Infection tuberculosis (most common cause in India). 3. Secondary to exogenous glucocorticoids administration. Clinical feature: 1. Pigmentation of skin and mucous membrane. 2. Weight loss. 3. Hypotension. 4. Asthenia. 5. Hypoglycemia. Laboratory finding: Decreased levels of Na+, Cl- and HCO3- in blood. Increased levels of K+ and Ca++. Diagnosis: ACTH stimulation test in primary case, fails to increase aldosterone. Low or absent 24 hour urine cortisol. Polyglandular Syndrome Associated with Autoimmune adrenalitis Hashimotos thyroiditis Pernicious anemia Type I diabetes mellitus Idiopathic hypoparathyroidism. Type I autosomal recessive; associated with AIRE gene on chromosome 21q. Type II associated with HLA B8, HLA DR3 and HLA DQ5.

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ADRENAL MEDULLA
Catecholamines They are norepinephrine, epinephrine and dopamine. Synthesis:
Phenylalanine Phenylalanine hydroxylase Tyrosine Tyrosine hydroxylase DOPA DOPA decarboxylase Dopamine Beta hydroxylase Norepinephrine PNMT Epinephrine

Tyrosine hydroxylase is the rate limiting enzyme. Metabolism: Most of the circulating catecholamines are sulfate conjugates and inactive. They are methoxylated and then oxidized to vanillylmandelic acid (VMA). 50 percent of secreted catecholamines appear in urine as free or conjugated metanephrine and normetanephrine (major excreted products); and 35 percent are excreted as VMA. Regulation: 1. Level of NE is increased by 50-100 percent on standing. 2. Level of E (also NE) are decreased during sleep. 3. Catecholamine levels are increased by sympathetic discharge. 4. Hypoglycemia is a potent stimulus for catecholamine secretion. 5. Adrenalectomy plasma NE remains normal, but free E level falls to essentially zero. Pheochromocytoma They are composed of chromaffin cells and arise from the adrenal medulla. Extra-adrenal sites: 1. Organ of Zuckerkandl at the aortic bifurcation most common extra-adrenal site.

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2. Chromaffin cells in or about sympathetic ganglia (paragangliomas). 3. Chemodectomas derived from carotid body. 4. Ganglioneuromas derived from postganglionic sympathetic neurons. 5. Others urinary bladder, chest and neck. Note: Extra-adrenal tumors are more malignant. Rule of 10 1. 10 percent of pheochromocytomas arise in association with one of the several familial syndromes MEN2A and 2B, Type I neurofibromatosis (von Recklinghausen disease), von Hippel-Lindau syndrome and SturgeWeber syndrome autosomal dominant trait. 2. 10 percent are extra-adrenal in origin. 3. 10 percent are bilateral. 4. 10 percent are malignant. Pathology: They secrete NE and E. The percentage of NE is greater than in the normal adrenal. Microscopically, characteristic nests of cells (zeuballen) are seen. Both capsular and vascular invasion are seen in benign tumors. The diagnosis of malignancy is therefore based exclusively on the presence of metastasis. Malignant tumors produce increased amounts of dopamine and homovanillic acid which is uncommon in benign tumors. Clinical feature: 1. Hypertension most common sign. 2. Headache most common symptom. 3. Profuse sweating and/or palpitation. 4. Mild to moderate weight loss. 5. Orthostatic hypotension. 6. Carbohydrate intolerance hyperglycemia. 7. Hypercalcemia. 8. Increased hematocrit values. 9. Ventricular arrhythmia sudden cardiac death may occur. Diagnosis: 1. Urine increased free catecholamines or their metabolites mainly metanephrine, normetanephrine (marker of choice) and VMA.

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2. Pharmacological test i. Phentolamine test reduction of BP of at least 35/25 mmHg that peaks after 2 minutes and persists for 10-15 minutes. ii. Glucagon provocative test. Investigation: CT scan and MRI for adrenal tumors. Radionuclide scanning with radiopharmaceutical 131I metaiodobenzylguanidine (MIBG) for extra-adrenal sites. Treatment: a. Surgery Preoperative management i. -blocker phenoxybenzamine. ii. Nitroprusside, calcium channel blockers and ACE inhibitors to reduce BP . This should be continued till the day of operation. b. For non-operable cases Metyrosine inhibits tyrosine hydroxylase.

PANCREAS
PHYSIOLOGY Cells of pancreas: cells secrete glucagon. cells insulin is secreted from the cells of the islets of Langerhans in the pancreas. In human, there are 1-2 million islets in the pancreas. cells secrete somatostatin. F cells secrete pancreatic polypeptide. Insulin Insulin is a polypeptide containing 51 amino acids. It is formed from a precursor protein called proinsulin. T1/2 of human insulin in plasma is 5-9 minutes. Pig insulin contains alanine in its B chain 30 position (human insulin contains threonine).

Regulation: Glucose is the main regulator of insulin secretion. Glucose increases insulin secretion by increasing ATP/ADP ratio

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inhibition of ATP-sensitive K+ efflux channels depolarization of B cells and activation of voltage-gated Ca++ channels the calcium influx results in insulin secretion. Catecholamines decrease insulin secretion by 2 action (predominant) and increase secretion by 2 action. Overall action is decrease in insulin secretion. Insulin secretion is also decreased by somatostatin, diazoxide and aloxan. Note: In animals, diabetes can be produced by administration of aloxan. Action: Insulin acts primarily on liver, muscle and adipose tissue. 1. Increased glucose entry in muscle and adipose tissue (direct action). 2. Increased hepatic glycolysis (by augmenting the actions of glucokinase, phosphofructokinase and pyruvate kinase). In diabetes, glucokinase is deficient. 3. Increased lipogenesis (by providing the glycerol involved in TG synthesis). Mechanism increases acetyl-CoA carboxylase activity, activates pyruvate dehydrogenase and decreases intracellular cAMP level. 4. Increased protein synthesis. 5. Increased glycogen synthesis. 6. Increased uptake of amino acids, ketones and K+. Glucose transporters
Glucose transporters Transporters Location Function

Facilitated diffusion GLUT 1 GLUT 2 GLUT 3 GLUT 4 GLUT 5 Brain, kidney, colon, placenta, erythrocyte Liver, pancreatic B cells, small intestine, kidney Brain, kidney, placenta Heart and skeletal muscle, adipose tissue Small intestine Uptake of glucose Uptake and release of glucose Uptake of glucose Insulin-stimulated uptake of glucose Absorption of glucose

Sodium dependant transporter SGLT 1 Small intestine and kidney Active uptake of glucose from intestine and reabsorption of glucose in PCT of kidney against a concentration gradient

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Note: Direct entry of glucose by insulin occurs in muscle and adipose tissue (by GLUT 4). Indirect entry of glucose occurs in liver by inducing glucokinase. Insulin receptor: It is a tetramer (22 glycoprotein). The beta subunit has tyrosine kinase activity. The number of insulin receptor per cell is increased in starvation and decreased in obesity and acromegaly. DIABETES MELLITUS Glucose Tolerance Impaired glucose tolerance in diabetes is in part due to decreased peripheral utilization of glucose. Oral glucose tolerance test: 1. Fasting (overnight) venous plasma glucose 140 mg/ dl on at least 2 separate occasions. 2. Following ingestion of 75 gm of glucose, venous plasma glucose 200 mg/dl at 2 hour and on at least one other occasion during the 2 hour period. HbA1c: It gives an estimate of glucose level in plasma in the preceding 3 months. For good control, it should be < 7 percent. Classification with cause Primary: 1. Autoimmune (type 1) DM insulin dependant DM (IDDM) or juvenile onset DM. 95 percent cases express HLA DR3 or HLA DR4. It causes degeneration of B cells. Destruction of at least 80 percent of B cells produce hyperglycemia. Association of IDDM: SLE, Addisons disease, Hashimotos thyroiditis. 2. Non-autoimmune (type 2) DM non-insulin dependant DM (NIDDM) or maturity onset DM. This is due to insulin resistance. Secondary: 1. Chronic pancreatitis in alcoholics.

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2. Hormonal pheochromocytoma, acromegaly, Cushings syndrome. 3. Genetic myotonic dystrophy, ataxia telangiectasia. 4. Total pancreatectomy. Epidemiology: Prevalence of diabetes in India is 2-5 percent (3.8%). Features
Features of diabetes Characteristic Genetic locus IDDM NIDDM Unknown more common familial, autosomal dominant trait > 40 years Obese Normal or increased Increased, resistant Increased Hyperosmolar coma Responsive to resistant Responsive

Chromosome 6; association with HLA DR3 or HLA DR4 Age of onset < 40 years Body Normal to wasted Plasma insulin Decreased or absent Plasma glucagon Increased, suppressible Plasma triglyceride Normal Acute complication Ketoacidosis Insulin therapy Responsive Oral hypoglycemics Unresponsive

ACUTE COMPLICATIONS OF DIABETES Hypoglycemia More common with IDDM. Somogyi phenomenon: Rebound hyperglycemia following an episode of hypoglycemia due to counter regulatory hormone release. Dawn phenomenon: Early morning hyperglycemia requiring increased amount of insulin to maintain normal glucose level. Diabetic Ketoacidosis Occurs in IDDM. Cause: Insulin deficiency with a relative or absolute increase in glucagon concentration. It is precipitated by cessation of insulin intake, stress either physical (infection, surgery) or emotional.

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Pathogenesis: The hormonal changes have two critical effects 1. Induce gluconeogenesis and impair peripheral utilization of glucose causing severe hyperglycemia induce an osmotic diuresis that leads to the volume depletion that characterizes ketoacidotic state. 2. Increased ketogenesis and metabolic acidosis (mostly beta hydroxybutyrate). Clinical feature: Symptoms i. Anorexia, nausea, vomiting. ii. Polyuria and abdominal pain. iii. Coma. Sign i. Kussmaul respiration or air hunger rapid, deep respiration with a low volume rapid pulse. ii. Dehydration. iii. Body temperature normal or decreased. Fever indicates infection. iv. Leukocytosis is a feature of diabetic ketoacidosis and may not indicate infection. v. Electrolytes- metabolic acidosis with high anion gap, decreased K+ and Na+, hypertriglyceridemia. Diagnosis: Urine for glucose and ketone bodies. Treatment: 1. Insulin therapy 25-50 U initial dose IV followed by an infusion of 15-25 U an hour until ketoacidosis is reversed. 2. IV fluid total fluid loss in ketoacidosis is about 35 liters. 1-2 liters of normal saline or Ringers lactate solution rapid IV. When plasma glucose falls to 300 mg/dl, 5 percent dextrose should be added to provide free water and prevent later cerebral edema. 3. K+ supplementation. 4. Bicarbonate therapy in severe acidosis. Prognosis: Acidosis is the most common cause of early death in clinical diabetes.

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Hyperosmolar Non-ketotic Coma (HONC) Occurs in NIDDM. Cause: Sustained diuresis under conditions when patient is unable to drink enough water. Phenytoin therapy precipitates HONC. Clinical feature: Severe hyperglycemia (plasma glucose level > 1000 mg/dl or 55 mmol/liter). Profound dehydration (fluid loss 10-11 liters). Hyperosmolarity of urine. CNS clouded consciousness to coma. Complications: Infection particularly gram negative pneumonia and sepsis indicates grave prognosis. Treatment: HONC can be corrected by large amount of fluid alone. Protocol as described in diabetic ketoacidosis. Insulin, K+ and HCO3- are also given. LATE COMPLICATIONS Diabetic Retinopathy It is more common in IDDM. Maculopathy is more common in NIDDM. Predictor: The best predictor of diabetic retinopathy is the duration of diabetes. Pathogenesis: Increased vascular permeability as evidenced by leakage of dye into vitreous after fluorescein injection. Stages: 1. Background diabetic retinopathy Features: i. Microaneurysms. ii. Dot and blot shaped hemorrhages. iii. Superficial flame-shaped hemorrhage. iv. Hard exudates. 2. Diabetic maculopathy Most common cause of visual impairment in diabetic retinopathy.

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Feature: Macular edema. 3. Pre-proliferative diabetic retinopathy Features: i. Cotton wool spots (soft exudates). ii. Intraretinal microvascular abnormalities (IRMA). 4. Proliferative diabetic retinopathy Features: i. Neovascularization most characteristic. ii. Vitreous hemorrhage. iii. Retinal detachment. Treatment: Argon laser photocoagulation. Diabetic Nephropathy Occurs both in IDDM and NIDDM. a. Glomerulus Diffuse glomerulosclerosis (most common renal lesion). Nodular glomerulosclerosis (Kimmelstiel-Wilson lesion). b. Renal vasculature hyaline arteriosclerosis. c. Pyelonephritis with necrotizing papillitis. Clinical feature: Stages i. Asymptomatic for 10-15 years. ii. Microalbuminuria excretion of 30-300 mg/day of albumin. iii. Macroproteinuria excretion of > 500 mg/day of albumin. Treatment: ACE inhibitors prevent progression of nephropathy, hence they are the drug of choice in hypertension with diabetes. Diabetic Neuropathy Peripheral polyneuropathy most common manifestation. Charcot joints, particularly in the feet (tarsal joints). Treatment: Topical application of capsaicin for burning pain and hyperesthesia. Others tricyclics (amitriptyline), phenytoin.

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Diabetic Foot Ulcer This is secondary to diabetic neuropathy. Others 1. 2. 3. 4. Hypertriglyceridemia. Skin lesions necrobiosis lipoidica. Hyperviscosity. Infections Malignant otitis externa due to Pseudomonas aeruginosa. Rhinocerebral mucormycosis. Emphysematous cholecystitis/pyelonephritis in diabetic men.

Reversibility of Changes Meticulous control of diabetes with insulin infusion pumps has been reported to 1. Decrease microalbuminuria. 2. Improve motor nerve conduction velocity. 3. Decrease plasma lipoproteins. 4. Decrease capillary leakage of fluorescein in the retina. HYPOGLYCEMIA Recognizable symptoms occur when blood glucose falls below 45 mg/dl. Causes of Hypoglycemia 1. Hormonal hypopituitarism, Addisons disease, catecholamine and glucagon deficiency. 2. Enzyme G-6-PD deficiency. 3. Liver disease hepatic congestion, severe hepatitis, cirrhosis of liver. 4. Others hypothermia. 5. Tumors causing hypoglycemia insulinoma, soft tissue sarcoma, heptocellular carcinoma. Neonatal Hypoglycemia Plasma glucose level < 40 mg/dl or blood glucose < 35 mg/dl.

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Hypoglycemic Unawareness This occurs in meticulously controlled DM due to lower symptomatic threshold. Patient shows neuroglycopenic symptoms before autonomic symptoms are initiated.

TESTIS
ANATOMY Coverings of testis: From outside inwards skin, dartos muscle, external spermatic fascia, cremasteric muscle and fascia, internal spermatic fascia, tunica vaginalis (parietal layer). Mnemonic: Some Decent English Call It Testis. Venous drainage: Pampiniform plexus 15-20 in number at the origin; 4 in the inguinal canal. Testicular veins: Right vein drains into the IVC. Left vein drains into the left renal vein. Lymphatic drainage: Lymphatics from the testis drain into pre-aortic and para-aortic lymph nodes. Development Primordial germ cells are developed in the wall of the yolk sac. Descent of testis: Testis passes through inguinal canal at 7th month of intrauterine life. Normally reaches the scrotum by 8th month. Appendix of testis: It is a remnant of the paramesonephric duct. Appendix of epididymis: It represents the cranial end of mesonephric duct. PHYSIOLOGY Sertoli Cells They have FSH receptors on them. Spermatogenesis occurs in them.

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They are glycogen containing cells and have a cartwheel appearance. Function: 1. They secrete. i. Androgen binding protein. ii. Inhibin inhibits FSH secretion. iii. MIS causes regression of Mllerian ducts in males during fetal life. 2. The tight junctions between the Sertoli cells form the blood-testis barrier. 3. They provide nutrition to the germ cells. 4. They contain aromatase which converts androgens to estrogen. Leydig Cells They are acted upon by LH. They secrete gonadal androgens. Spermatogenesis Stages:
Spermatogonia (primitive germ cells) Primary spermatocytes Secondary spermatocytes Spermatids (contain 23 chromosomes) Spermatozoa

Pathway: Seminiferous tubules straight tubules rete testes efferent tubule epididymis. Spermatozoa acquire motility during their passage through the epididymis. Note: Viability of sperms in female genital tract 48 hours. Total period of spermatogenesis 61 days. Time for capacitation 2-6 hours. Length of spermatozoa 50 micron. Spermatogenesis occurs at a temperature lower than core body temperature (at about 32C).

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Semen Contents: Sperm normally about 100 million/ml; at least 20 million/ml. Secretions from the seminal vesicles, prostate and Cowpers gland. Prostaglandins are high in semen and comes from the seminal vesicles. Fructose is produced by the seminal vesicles and is the main nutritional supply for the spermatozoa. Note: Human sperms move at a rate of 3 mm/min. Volume of ejaculate 2-6 ml. 60 percent of the sperms should be motile and of normal morphology. Secretions from Testis 1. Androgens: Synthesis: Cholesterol pregnenolone androstenedione testosterone dihydrotestosterone. Dihydrotestosterone is the most potent androgen. Testosterone to dihydrotestosterone conversion occurs by the enzyme 5- reductase. Action: Increased protein synthesis and decreased protein breakdown (anabolic action), electrolyte (e.g. calcium) retention. 2. Estrogen: 80 percent of estradiol and 95 percent of estrone in plasma of adult male is formed by aromatization of circulating testosterone and dihydrotestosterone. The rest comes from the testes. 3. Inhibin. Note: Androgen receptor is coded in long arm of X chromosome. Half of men who have been vasectomized develop antibody against spermatozoa.

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Sexual Precocity 1. Virilizing syndrome (hypothalamopituitary activity is normal for age). Causes: Leydig cell tumors, adrenal tumors, congenital adrenal hyperplasia (mainly 21-hydroxylase and 11 beta hydroxylase deficiency). Diagnosis: Increased 17 ketosteroids in blood and urine. 2. Premature activation of hypothalamopituitary system idiopathic or due to CNS abnormality. Treatment: For Leydig cell hyperplasia MDPA. For idiopathic and inoperable CNS lesions LHRH analogue.

OVARIES AND FEMALE GENITAL TRACT


ANATOMY Ovarian fossa: It is bounded i. Anteriorly, by the obliterated umbilical artery. ii. Posteriorly, by the ureter and the internal iliac artery. The ovaries are connected to the posterior layer of the broad ligament by a short fold of peritoneum called the meso-ovarium. The suspensory ligament of ovary: It extends from the infundibulum of the uterine tube to the external iliac vessels (infundibulopelvic ligament). It contains the ovarian vessels and nerves. Ovarian artery: Arises from the abdominal aorta. Ovarian vein: Right vein drain into the IVC. Left vein drains into the left renal vein. Lymphatic drainage: Lymphatics from the ovaries drain into the pre-aortic and para-aortic lymph nodes. Fallopian tubes: They are lined by ciliated columnar epithelium.

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PHYSIOLOGY Ovarian Hormones Five steroidal hormones are secreted from the ovaries namely i. Estrogen. ii. Progesteron. iii. Androgens. iv. Inhibin secreted from the granulosa cells of ovarian follicles. They inhibit FSH secretion. v. Relaxin secreted from the preovulatory follicle and corpus luteum. Estrogen Estrogen is a C18 steroid, i.e. they lack angular methyl group at C10 position. Synthesis : Sites Granulosa cells (most common site), Theca cells and ovarian stroma, Corpus luteum, The placenta. Pathways

Metabolism: Three types of estrogen are secreted estradiol (most potent) estrone and estriol. In the liver, they are converted to glucuronide sulfate conjugates. All these compounds along with their metabolites are excreted in urine. In postmenopausal women, estradiol is metabolized to estrone (see later).

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Actions: Mechanism by binding to nuclear receptor. 1. Uterus increases vascularity and hyperplasia. Withdrawal of estrogen causes bleeding (withdrawal bleeding) and menstruation. 2. Secondary sex character feminizing, except axillary and pubic hairs which are under the control of adrenal androgens. 3. Metabolic decreases LDL cholesterol and increases HDL cholesterol and TG. It has a cardioprotective effect. It increases blood glucose. 4. Hormonal it decreases FSH secretion and increases LH secretion. 5. Skeletal maturation and epiphyseal closure in both sexes. 6. Others increases blood coagulability due to increased synthesis of clotting factors, increases lithogenicity of bile. Progesterone Secretion: Sites i. Theca cells and granulosa cells of corpus luteum during the luteal phase main source. ii. Both the cells of follicles and ovarian stroma. iii. Placenta. Pathway: Cholesterol pregnenolone progesterone. Metabolism: It is metabolized in the liver to sodiumpregnanediol glucoronide and excreted in urine. Actions: See below. MENSTRUAL CYCLE Normal age of menarche is around 13 years. Normal Cycle Interval 28 days. Duration 5 days. Amount 20-80 ml (mean 50 ml).

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Oogenesis A mature ovum (oocyte) is the largest cell in the body and measures 130 microns in diameter. Oocytes are developed from the primitive germ cells which are developed from the yolk sac in fetal life.
Germ cells (yolk sac) mitosis Oogonia (Reaches maximum number at 20th week of intrauterine life, about 7 million) Some enter the prophase of first meiotic division and are called the primary oocytes (46 XX) and do not complete the meiotic division until puberty Completes the first meiotic division and forms secondary oocytes (23 X) and first polar body (23 X). Ovulation occurs soon after the formation of secondary oocyte. Secondary oocyte completes the second meiotic division only after fertilization by the sperm in the fallopian tube (if not fertilized, it undergoes degeneration within 24 hours).

Hormonal Changes Gonadotrophins (LH and FSH) are glycoproteins secreted by basophilic cells of the anterior pituitary under the control of LHRH (which control both) of hypothalamus. FSH (in association with minimal LH) causes maturation of primary follicles which secrete 17-beta estradiol from the granulosa cells of ovary. Estradiol causes three changes i. Produces proliferative changes in the endometrium. ii. Decreases FSH secretion from anterior pituitary and iii. Increases LH secretion from anterior pituitary. LH in turn causes final maturation of graffian follicles and rupture of follicles at ovulation and to form a corpus luteum. Note: Peak estrogen level occurs 48 hours before ovulation whereas peak LH (LH surge) level occurs 24-36 hours before ovulation. Corpus luteum secretes progesterone which causes a. Uterus i. Myohyperplasia. ii. Decreased frequency of uterine contraction.

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iii. Increased tone of circular muscles of uterus. iv. Secretory changes in the endometrium. v. Thick and viscid cervical mucosa and vi. Sodium and water retention. b. Raises basal body temperature by 0.5oF just after the ovulation. In the absence of pregnancy, both estrogen and progesterone levels decline gradually and brings about the menstruation. Note: Pulsatile release of GnRH is under control of glutamate (excitatory) and GABA (inhibitory). Before puberty levels of glutamate are low and that of GABA are high. Points to be noted: Selection of dominant follicle: The one with highest antral estrogen concentration and lowest androgen:estrogen ratio and whose granulosa cell contain the maximum receptors for FSH, becomes the dominant follicle. Cause of rupture of follicle: Necrobiosis of the overlying tissue due to passive stretching. Anovular menstruation: Menstruation is unrelated to ovulation and anovular menstruation occurs in adolescence, following childbirth and in women approaching menopause. Endometrium remains either in proliferative or hyperplastic state and menstruation occurs due to irregular shedding of endometrium (dysfunctional uterine bleeding). Endometrial Changes Endometrium has two zones i. Basal zone not under hormonal control and regeneration after menstruation occurs from this zone. ii. Functional zone under the influence of ovarian hormones estrogen and progesterone and produces the cyclical change seen in menstrual cycle. Stages: 1. Regeneration from basal zone, complete in 2-3 days. 2. Proliferative stage is due to ovarian estrogen and lasts up to ovulation. Ovulation occurs at the end of this stage.

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3. Secretory stage is due to progesterone secreted from corpus luteum after ovulation. The duration of secretory phase is constant and is 14 days. So ovulation occurs 14 days prior to the next menstruation (and not 14 days after menstruation). Changes earliest change (earliest evidence of ovulation) is subnuclear vaculation containing glycogen. 4. Menstruation occurs due to degeneration of endometrium as a result of vasospasm and ischemia. Note: The stages of regeneration and proliferation are collectively called the ovulatory phase, whereas secretory phase is also called the luteal phase. Changes in the Cervix Estrogen makes it thinner and more alkaline. Progesterone makes it thick, tenacious and cellular. Estrogen causes fer n-like pattern of mucosa of the cervix which is lost after ovulation. Elasticity or spinnbarkeit is increased by estrogen loss of elasticity occurs by progesterone after ovulation. Tests for Ovulation
Tests for ovulation Method BBT Endometrial biopsy Cervical mucus study Day of cycle Throughout cycle 21-23 12-14 and 21-23 Observation Biphasic pattern Secretory endometrium (best evidence) Mucosa turns to thick and viscid Elasticity is lost, fer n-pattern is lost after ovulation

Corpus Luteum It is the ruptured graafian follicle after ovulation. Life cycle: 1. Stage of proliferation 2. Stage of vascularization 3. Stage of maturation Maximum secretory activity is seen 7-8 days after ovulation (days 22-23 of menstrual cycle). 4. Regression transformed into corpus luteum.

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Function: It secretes progesterone and brings about the secretory changes in endometrium. Corpus luteum of pregnancy: If fertilization occurs, there is a surge of hyperplasia between 23-28 days due to HCG. The growth reaches peak at about 8 weeks. The corpus luteum of pregnancy is active up to 10-12 weeks of pregnancy. DISORDERS OF MENSTRUATION Definition Menorrhagia: Bleeding more than 80 ml or/and duration more than 5 days. Poly(epi)menorrhea: Menstrual cycle 21 days apart. Oligomenorrhea: Menstrual cycle > 35 days apart. Metrorrhagia: Acyclical and irregular bleeding superimposed on normal menstruation. Dysmenorrhea: Painful menstruation. Precarious menstruation: Menarche before the age of 13 years. Hypomenorrhea: Scanty bleeding lasting less than 2 days. Menorrhagia Causes: 1. Dysfunctional uterine bleeding. 2. Fibroid uterus/uterine polyp. 3. Adenomyosis. 4. Chronic tubo-ovarian mass. 5. Granulosa cell tumor of ovary. 6. General hypothyroidism, generalized TB. Metrorrhagia Causes: 1. DUB. 2. Submucous fibroid. 3. Uterine polyps. 4. Carcinoma cervix and endometrium.

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Poly(epi)menorrhea It usually occurs in adolescent girls and premenopausal women. Treatment: Cyclic hormone therapy (OCP for 3 cycles). Dysmenorrhea Types: 1. Primary or spasmodic most common type. No identifiable pelvic pathology. May be associated with submucous fibroid. Seen in affluent girls 2-3 years after menarche. Clinical feature: Pain starts few hours before or just after onset of menstruation and radiates to the back and thigh. Pain lasts for few hours. Systemic features like vomiting, headache, syncope may be present. Treatment: Often symptomatic. i. Prostaglandin synthetase inhibitors like mefenamic acid. ii. OCP . iii. Surgery dilatation of cervical canal, paracervical block, presacral neurectomy. 2. Secondary or congestive: Due to some underlying pelvic pathology like fibroids, adenomyosis, PID, endometriosis. Clinical feature: Pain starts 3-5 days before menstruation and relieves with the onset of bleeding. Pain does not radiate. Pain is not associated with systemic features. Unilateral dysmenorrhea: Causes 1. Ovarian dysmenorrhea 2. Bicornuate uterus 3. Unilateral pelvic endometriosis 4. Small fibroid near the cornu. Mittelschmerzs Syndrome Also called ovular pain. Pain appears in midmenstrual period (around ovulation) and is located in hypogastrium or one iliac fossa. Pain lasts for less than 12 hours. Treatment: Assurance and analgesics.

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Dysfunctional Uterine Bleeding It is abnormal bleeding without any clinically detectable pelvic pathology. Classification: Primary a. Anovular bleeding (80%) most common type. i. Puberty menorrhagia, ii. Metropathia hemorrhagica, iii. Premenstrual menorrhagia. b. Ovular bleeding i. Epimenorrhea, ii. Oligomenorrhea, iii. Functional menorrhagia due to irregular shedding of endometrium or irregular ripening of endometrium. Secondary Hematological disorders, e.g. ITP . Hypothyroidism. Iatrogenic IUCD or OCP . Pathology: The etiology is purely hormonal. There is increase titer of estrogen with absent progesterone. Endometrium becomes hyperplastic in 30 percent cases, remain normal in 60 percent cases. Puberty Menorrhagia Treatment: Progesterone and OCP . Premenopausal Menorrhagia Endometrial carcinoma must be excluded by fractional curettage. Metropathia Hemorrhagica or Cystic Glandular Hyperplasia (Schroeders Disease) Clinical feature: Most common in premenopausal women. Presents with heavy vaginal bleeding. Uterus symmetrically enlarged to size of about 810 weeks of pregnancy. Endometrium proliferative (no secretory change). Endometrium shows cystic glandular hyperplasia or Swiss cheese pattern. Treatment progesterone.

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Management of DUB a. General blood transfusion for severe anemia. b. Hormonal therapy method of choice. Drugs used are i. Norethisterone acetate. ii. Medroxyprogesterone acetate. iii. Estrogen. iv. OCP . v. Danazole. vi. Gestrinone. vii. Clomiphene citrate. viii.GnRH analogue. Note: Progesterone is most effective in anovular bleeding. Clomiphene citrate is the drug of choice in anovular DUB with infertility wanting pregnancy. c. Anti-fibrinolytic agents Tranexamic acid or EACA. Use in IUCD induced menorrhagia. d. Surgery i. Premenopausal dilatation and curettage. ii. Postmenopausal fractional curettage. Treatment of choice is hysterectomy. e. Recent methods i. Radiofrequency induced thermal endometrial ablation (RITEA) done soon after menses. ii. Balloon therapy the depth of endometrial destruction is 8 mm. MENOPAUSE It is the cessation of menstruation for more than consecutive 6 months. Premature menopause before the age of 40 years. Hormonal Changes In premenopausal period, estrogen output from ovary begins to decline. FSH level begins to increase before menses stop. Eventually, both FSH and LH increase by 10-20 folds (sustained elevation of FSH and LH is conclusive evidence of ovarian failure).

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Decreased serum androstenedione by 50 percent (majority being produced by adrenals). Increased testosterone from ovary. Estrone becomes the main estrogen and is derived from peripheral conversion of androstenedione in adipose tissue. Estradiol is produced by peripheral conversion of testosterone. DECREASED MENSTRUATION Cryptomenorrhea Causes: a. Congenital: i. Imperforate hymen most common cause. ii. Transverse vaginal septum. iii. Atresia of upper third of vaginal and cervix. b. Acquired: Stenosis of the cervix following amputation, deep cauterization and conisation. AMENORRHEA Types Primary: Menarche does not occur till 16 years of age. Causes: 1. Gonadal dysgenesis most common cause. 2. Mllerian agenesis. 3. Testicular feminization syndrome. 4. Hypogonadotrophic hypogonadism (Kallmann syndrome). 5. Dysfunction of adrenal and thyroid glands. 6. Infections TB. 7. Unresponsive endometrium. Secondary: Causes: 1. Polycystic ovarian disease (PCOD) most common cause worldwide. 2. Tubercular endometritis most common cause in India. 3. Premature ovarian failure. 4. Resistant ovary syndrome. 5. Uterine synechiae (Ashermans syndrome). 6. Pituitary prolactinomas, Sheehans syndrome. 7. Stress.

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8. Hypothyroidism. Remember most common cause of secondary amenorrhea is pregnancy. ANATOMIC FACTORS Mllerian Agenesis: (Mayer-Rokitansky-KusterHauser syndrome) Karyotype 46 XX, phenotype female. Feature: Primary amenorrhea, absent vagina, absent or rudimentary uterus. Diagnosis: Biphasic BBT curve characteristic of ovulation. Elevated levels of progesterone during luteal phase. Treatment: Surgery for vaginal agenesis is done prior to or soon after marriage vaginoplasty (McIndoe Williams). Androgen Insensitivity/Testicular Feminization Syndrome Inheritance: X-linked. Features: Phenotype female. Patient tends to be tall. Breasts normal (grade IV thelarche). Axillary and pubic hairs scanty (grade II puberche). External genitalia normal. Vagina short and blind. The upper third of vagina, uterus and tubes are absent. Gonads testes, are placed in labia or inguinal canal or intra-abdominal. Gonads secrete MIF (Mullerian inhibiting factor) by sertoli cells. Diagnosis: Patient presents with primary amenorrhea or infertility. Karyotype 46 XX (male). Confirmation by gonadal biopsy. Treatment: Pre-pubertal castration. Testicular Agenesis Karyotype 46 XY, phenotype female. Features : Sexual infantilism, absent uterus.

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Ashermans Syndrome Cause: Formation of adhesions following uterine curettage. Feature: Seconday amenorrhea. Treatment : Adhesiolysis with a uterine probe with IUCD insertion. OVARIAN FAILURE Gonadal Dysgenesis Causes hypergonadotropic (FSH > 40 MIU/ml) hypogonadism. This is the most common cause of primary amenorrhea. Turners Syndrome Karyotype 45 XO, phenotype female. Morphogenesis: Homebox gene defect (which is involved in vertical growth). Features: i. Primary amenorrhea. ii. Short stature with webbed neck and low hairline. iii. Shield chest with widely spaced nipples. iv. Short 4th metacarpals and metatarsals. v. Edema of hand and feet. vi. Cubitus vulgus deformity. vii. Associations coarctation of aorta, bicuspid aortic valves, horseshoe shaped kidney. viii. No mental retardation. Diagnosis: Gonads are streaks. Increased FSH and LH, decreased estrogen. Treatment: Gonadectomy. Noonan Syndrome Mental retardation. Pectus excavatum. Normal 4th metacarpals. Pulmonary stenosis. Others like Turners syndrome.

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Chromosomal Mosaicism Karyotype 45 XX/45 XO. Gonads streaks with few or absent follicles. There is increased chance of malignancy in mosaicism involving Y chromosome. Streak gonads are removed prophylactically if Y chromosome is present on karyotyping. Premature Ovarian Failure Menopause before the age of 40 years. Cause: Ovarian autoantibodies. Feature: May be associated with adrenal insufficiency, hypothyroidism and other autoimmune disorders. Increased FSH with ovarian failure. Resistant Ovary Syndrome Cause: Resistance to the action of FSH in the ovary. Chronic Anovulation with Estrogen Present Diagnosis: Withdrawal bleeding present after progesterone administration. Polycystic Ovarian Disease (PCOD) (Stein-Leventhal Syndrome) Features: Secondary amenorrhea, hirsutism, obesity and infertility. Hormone status: Excess production of androgens (androstenedione) leads to excess extragonadal production of estrogen (mainly estrone) positive feedback on LH secretion (increased LH secretion) and negative feedback on FSH secretion (decreased FSH secretion). i. Increased LH and decreased FSH and LH:FSH ratio > 2. ii. Decreased estrogen and increased estrone. iii. Mild increase in testosterone level and DHEA-S level. iv. There may also be increased prolactin level. Diagnosis: USG shows necklace appearance of ovary.

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Treatment: i. Clomiphene citrate drug of choice to induce ovulation. ii. HMG, LHRH analogues, purified FSH to induce ovulation. iii. OCP in patients not wanting pregnancy. iv. Surgery. Risk: Increased chance of endometrial carcinoma. Chronic Anovulation with Estrogen Absent Diagnosis no withdrawal bleeding after progesterone challenge test. Isolated Hypogonadotropic Hypogonadism Kallmann syndrome: Feature: Amenorrhea with defects of smell (anosmia), sexual infantilism, normal stature. Prolactinomas See above. Panhypopituitarism Cause: i. Surgery for prolactinomas. ii. Radiation. iii. Postpartum hemorrhage in the pituitary Sheehans syndrome. Sheehans syndrome: Pathology: Anterior pituitary necrosis due to postpartum hemorrhage into the pituitary. Feature: Failure to lactate or ovulate, loss of pubic and axillary hair, hypothyroidism, adrenal insufficiency, secondary amenorrhea, atrophy of breasts and genitalia. Treatment: Cortisone. DISORDERS OF SEXUAL DIFFERENTIATION Disorders of Chromosomal Sex Klinefelter Syndrome Karyotype 47 XXY, phenotype male.

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Features: Small, firm testes (testicular atrophy). Azoospermia and infertility. Gynecomastia. Decreased body hair. Tall stature with long legs, slim and underweight. Increased plasma gonadotrophins, decreased testosterone. Diagnosis: Barr bodies are seen in cells. Risk: Increased chance of breast malignancy in males. DISORDERS OF PHENOTYPIC SEX Female Pseudohermaphroditism Congenital Adrenal Hyperplasia Inheritance: Autosomal recessive trait. Pathways:
Cholesterol Pregnenolone 17 hydroxylase Androgen Progesterone 17 hydroxylase 21 hydroxylase Deoxycorticosterone 11 hydroxylase Corticosterone

21-hydroxylase Deficiency It is the most common type and most common cause of ambiguous genitalia in newborn. Characterized by decreased aldosterone and increased androgens. Features: Virilization in females and precocious masculinization in males. Female child is born with enlarged clitoris and fusion of labia (pseudohermaphroditism). Salt-losing form decreased sodium, increased potassium and dehydration. 11- Hydroxylase Deficiency Normal deoxycorticosterone, increased androgen.

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Hypertensive form. Virilization in females and precocious puberty in males, hypertension. 17- Hydroxylase Deficiency Characterized by decreased androgen and increased aldosterone. Feature: In girls sexual infantilism (amenorrhea). In boys male pseudohermaphroditism. In both hypokalemia, hypertension. Treatment: Steroids. Note: Causes of male pseudohermaphroditism i. Gonadal dysgenesis. ii. Testicular feminization. iii. Testicular agenesis.

MULTIPLE ENDOCRINE NEOPLASIA (MEN)


MEN1 (Wermers Syndrome) Associated with MEN1 tumor suppressor gene located on chromosome 11q13. Characterized by 3 Ps. 1. Parathyroid hyperplasia causing hyperparathyroidism. 2. Pancreas islets cell hyperplasia, endocrinal tumors, most commonly gastrinomas (Z-E syndrome). 3. Pituitary hyperplasia or adenoma (most commonly prolactin secreting microadenoma). Clinical feature: Peptic ulceration (due to pancreatic endocrine tumor) and renal stone (due to hyperparathyroidism). MEN2A (Sipple Syndrome) Associated with mutation of RET proto-oncogene on chromosome 10q11.2. 1. Thyroid medullary carcinoma of thyroid. 2. Adrenal medulla pheochromocytoma. 3. Parathyroid hyperplasia.

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MEN2B (Williams Syndrome) Same as MEN2A except: i. No hyperparathyroidism. ii. Mucosal and gastrointestinal neuromas. iii. Marfanoid features.

HEMOCHROMATOSIS
It is deposition of iron in parenchymal cells of the liver, pancreas, heart and pituitary (but not in testes). Cause: Increased absorption of iron from the intestine. Inheritance: Autosomal recessive. Associated with HLA-A3. Most common genetic defect is mutation of HFE gene on chromosome 6. Clinical feature: 1. Liver most common involvement. Causes hepatomegaly, cirrhosis, hepatocellular Ca. 2. Skin pigmentation (bronze color). 3. Diabetes mellitus. 4. Congestive cardiac failure. 5. Arthropathy most commonly involving the small joints of hand. 6. Hypogonadism due to hypopituitarism. Laboratory findings Increased values of serum iron, increased ferritin and increased transferrin saturation. Liver biopsy confirmatory. Treatment: 1. Phlebotomy weekly venesection for 2-3 years. 2. Deferoxamine when anemia or hypoproteinemia is severe enough to preclude phlebotomy.

PORPHYRIAS
Porphyrins are synthesized in the liver and bone marrow. Acute Intermittent Porphyria Autosomal dominant.

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Cause: Deficiency of the enzyme HMB synthase (uroporphyrinogen I synthase). Pathology: Increased activity of ALA synthase and increased gamma ALA level and increased urinary excretion of porphobilinogen. Precipitating factors: i. Endogenous and exogenous gonadal steroids. ii. Drugs barbiturates (phenobarbitone). iii. Alcohol ingestion. Note: Bromides are safe in AIP and were used to control seizures. Clinical feature: Seen in childhood. Abdominal pain most common symptom. Peripheral neuropathy due to axonal degeneration. Mental symptoms are characteristic. Fever and leukocytosis are usually absent or mild. No photosensitivity. Diagnosis: Watson-Swartz test to differentiate between porphobilinogen and urobilinogen. It detects porphobilinogen (also Hoesch test). Porphyria Cutanea Tarda Most common type of porphyria. Cause: Deficiency of urobilinogen decarboxylase. Clinical feature: Photosensitivity characterized by increased fragility of sun-exposed skin. Vesicles and bullae that rupture and heal slowly with crusting and purplish discoloration. Hypertrichosis. Hyperpigmentation. Increased chance of hepatocellular Ca. Treatment: Phlebotomy Low dose chloroquine. Note: Preservative used for urine to detect porphyrin is HCl.

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Congenital Erythropoietic Porphyria (Gunthers Disease) Cause: URO synthase III deficiency. Genetics: It is autosomal recessive while all other porphyrias are autosomal dominant. Clinical feature: Photosensitivity increased fragility of sun-exposed skin. Hemolytic anemia.

HYPERURICEMIA AND GOUT


Blood Level Mean blood level of uric acid is 6.8 mg/dl. Hyperuricemia means > 7 mg/dl of urate in serum. Causes 1. Urate overproduction Myeloproliferative diseases Polycythemia vera Psoriasis Pagets disease Lesch-Nyhan syndrome Lymphoma 2. Decreased urate excretion Hyperparathyroidism Renal failure Diuretic therapy 3. Combined mechanism Glucose-6-phosphatase deficiency (von-Gierkes disease) hyperuricemia from infancy and gout develops early in life. Lesch-Nyhan Syndrome It is due to complete deficiency of hypoxanthineguanine phosphoribosyl transferase (HGPRT) enzyme. Inherited as X-linked trait. Feature: Self-mutilation, choreoathetosis with gout, renal calculi.

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Kelly-Seegmiller Syndrome This is due to partial deficiency of HGPRT. Feature: Patient develops only gout and renal calculi. Clinical Feature Gouty Arthritis Acute monoarticular arthritis. Most common site is the metatarso-phalangeal joint of great toe. Pathology: There is deposition of sodium biurate crystals in soft tissues, viz. cartilage, tendon and bursa. Tophi deposition of monosodium urate monohydrate crystals in the skin, muscle and articular cartilage. Renal Disease Uric acid stones are seen in 30-40 percent cases. Diagnosis Biochemical marker urate crystals aspirated from joint fluid is confirmatory. Note: Transport media for stones in gout is alcohol. Treatment a. Acute gout colchicines, NSAIDs (most effective), intra-articular glucocorticoids. b. Chronic gout allopurinol, probenecid.

DISORDERS OF LIPOPROTEIN METABOLISM


LIPID TRANSPORT Lipids are insoluble in water. To make them water soluble, lipoproteins are formed. Structure of lipoproteins Central core contains hydrophobic non-polar lipids triglycerides and cholesterol esters.

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Surface contains amphipathic phospholipids and free (unesterified) cholesterol. Apolipoproteins present on the surface. Types of Lipoproteins 1. Chylomicrons transport lipid from intestine to tissues. Contains maximum TG. 2. VLDL transports lipid from liver to tissues. Mainly contains TG. 3. IDL also called VLDL-remnants, produced by metabolism of VLDL. 4. LDL contains maximum cholesterol. 5. HDL transports cholesterol from tissues to the liver (reverse cholesterol transport). Contains maximum phospholipids and least TG. Apolipoprotein The protein part of a lipoprotein is called apolipoprotein. VLDL contains Apo B100, Apo E and Apo C. IDL contains Apo B100 and Apo E. LDL contains Apo B100. HDL contains Apo A, Apo E and Apo C. Chylomicrons contain Apo B48, Apo A, Apo E and Apo C. Functions Apo A-1 helps in reverse cholesterol transport (by HDL). It activates LCAT (Lecithine:cholesterol acyltransferase). Apo B100 secretion of VLDL from the liver, ligand for LDL receptor. Apo B48 chylomicron secretion from intestine. Note: Apo B100 and Apo B48 are synthesized by the same gene and mRNA. It is an RNA-editing mechanism in intestine that forms Apo B48. Apo CII activation of lipoprotein lipase. Apo E mediates LDL uptake in liver (also of chylomicron remnants). Lipoprotein Lipase It is synthesized in adipose tissues and muscles and is present on the endothelial surface of capillary beds.

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Action: It hydrolyses TG of chylomicrons and VLDL to produce fatty acid and glycerol. Regulation: Insulin inhibits whereas epinephrine and norepinephrine stimulate it. Defective LPL is associated with hypertriglyceridemia. LDL (Apo B100, E) Receptor This is present on all cells (maximum in adrenals). Action: Uptake of cholesterol rich LDL by live as well as extrahepatic tissues. Regulation: Cholesterol delivered to cytoplasm by LDL receptor decreases the rate of cholesterol synthesis in the liver and also decreases the number of LDL-receptors in cell surface. Note: Increased LDL and Apo B100 in blood increase the risk of atherosclerosis (through a separate scavenger receptor pathway where LDL undergoes peroxidation). Probucol an antioxidant, inhibits LDL oxidation and lowers the risk of CHD. HYPERLIPOPROTEINEMIAS
Hyperlipoproteinemias
Type Disease I IIa Familial LPL deficiency Familial hypercholesterolemia Defect Serum Serum cholesterol TG Elevated lipoprotein Chylomicron LDL

IIb III

Familial mixed lipoproteinemia Familial Apo E dysbetalipoproteinemia

LPL Normal Increased deficiency LDL Increased Normal receptor defect Unknown Increased Increased Increased Increased

IV V

Familial triglyceridemia Familial combined hyperlipidemia

Unknown Normal Apo C Normal

Increased Increased

LDL and VLDL VLDL remnants and chylomicron remnants VLDL VLDL and chylomicrons

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Type I: Familial Lipoprotein Lipase Deficiency Characterized by hyperchylomicronemia. Clinical feature: Starts at infancy with pancreatitis, eruptive xanthomas, hepatosplenomegaly, foam cell infiltration of bone marrow, lipemia retinalis. Diagnosis: A layer of cream (chylomicrons) at the top of plasma. Treatment: Diet containing less fat and more complex carbohydrates. Type II: Familial Hypercholesterolemia Autosomal dominant. Clinical feature: Tendon xanthomas (most common in Achilles tendon). Tuberous xanthomas, xanthelasmas (corporis = deposition around eyelids). Increased risk of CHD. Note: All increase the risk of CHD except type I and type V. Wolmans Disease Cholesteryl ester storage disease due to deficiency of cholesteryl ester hydrolase with increased LDL. Secondary Causes of Hyperlipoproteinemias Hypercholesterolemia Nephrotic syndrome Primary biliary cirrhosis Hypertriglyceridemia diabetes mellitus. Others myxedema, chronic alcoholism, drugs (OCP , beta blockers, corticosteroids). Treatment a. In increased LDL-Chl. (Type II and V): 1. Bile acid sequestrants (resins) Mechanism of action increase excretion of bile and cholesterol in stool increase hepatic cholesterol synthesis and increase LDL receptor (due to increased HMG-CoA activity). Action decrease LDL-Chl. All others are normal.

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2. HMG-CoA reductase inhibitors (statins) first choice drug. Mechanism of action decrease cholesterol synthesis decrease LDL and VLDL compensatory increase in LDL receptors. b. In increased TG (Type III, IV, V): 1. Nicotinic acid highly effective. 2. Fibric acid derivatives (gemfibrozil is the drug of choice, clofibrate). They both increase HDL. HYPOLIPOPROTEINEMIA Abetalipoproteinemia Cause: Absent microsomal triglyceride transfer protein (MTP). Feature: Low cholesterol and no VLDL, IDL, LDL or chylomicron. Clinical feature: Malabsorption of fat, soluble vitamins A and E. acantholytic RBC, ataxia and retinitis pigmentosa, steatorrhea. Treatment: Vitamin E supplementation. Fish Eye Disease LCAT deficiency. Others Hematological malignancies, Gauchers disease, NiemannPick disease.

LYSOSOMAL STORAGE DISEASES


THE MUCOPOLYSACCHARIDOSIS (MPS) All are autosomal recessive except Hunters disease which is X-linked recessive. Cause: Defective metabolism of glycosaminoglycans (GAG) due to specific deficiencies of lysosomal hydrolases. Note: GAGs are heteropolysaccharides containing amino sugars (d-glucosamine or d-galactosamine) and uronic acid (d-glucuronate or d-iduronate).

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MPS I (Hurlers Disease) or Gargoylism Cause: -L-iduronidase deficiency. Features: Short stature, organomegaly (hepatosplenomegaly), corneal clouding, coarse features, mental retardation, joint stiffness, large tongue. CVS Valvular heart disease, no ECG changes (c.f. Pompes disease). Others kyphosis, umbilical hernia, hydrocephalus, profuse nasal discharge due to respiratory infection. Urinary metabolites dermatan sulfate, heparan sulfate, increased uronic acid in urine. MPS II (Hunters Disease) Cause: Iduronate sulfatase deficiency. Absence of corneal clouding and mild or absent mental retardation.

LIPID AND GLYCOGEN STORAGE DISEASES


All are autosomal recessive except Fabrys disease which is X-linked.
Storage Diseases Disease Gauchers disease Deficient enzyme Features

Fabrys disease NiemannPick disease

Lipid storage disease -glucocerebrosidase Type I: Hepatosplenoresults in accumulation megaly, cholestasis and of cerebrosides in cells. mental retardation in neonates; bone erosion, pancytopenia. No symptoms in adults. Type II: CNS symptoms, lethal. Biopsy wrinkle paper appearance of cells Treatment enzyme replacement therapy. -galactosidase Multiple angiokeratomas. Sphingomyelinase Foam cells in blood, childhood cholelithiasis.

(Contd...)

Endocrinology and Metabolism (Contd...)


Disease Tay-Sachs disease Sandroffs disease Krabbes disease Wolmans disease 1. VonGierkes disease 2. Pompes disease Deficient enzyme Features

455

GM2 Gangliosidosis Hexosaminidase A Cherry red spot in eye. Hexosaminidase A and B Cherry red spot in eye.

Leukodystrophies -galactosidase Deep white matter lesion with bilateral deep bright thalamus Adrenal calcification Glycogen Storage Diseases Glucose-6Hepatomegaly, phosphatase hypoglycemia, lactic acidosis, hyperuricemia, hyperlipidemia. 1,4 and 1,6 Hepatosplenomegaly, CVSglucosidase (acid high voltage QRS complex maltase) causes and a short PR interval, accumulation of cardiomegaly, HOCM, glycogen in lysosomes. CHF, hypotonia, macroglossia, coarse features. Debranching enzyme

3. Forbes disease 4. Andersons Branching enzyme disease 5. McArdles Muscle phosphorylase disease 6. Hers Liver phosphorylase disease

Note: Type 2, 3 and 5 of glycogen storage diseases involve muscles, hence muscle biopsy is helpful in their diagnosis.

INHERITED DISORDERS OF CONNECTIVE TISSUE


Osteogenesis Imperfecta Inheritance: Autosomal dominant in type 1 (most common type). Autosomal recessive in type 2 (lethal).

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Pathology: Abnormal development of type 1 collagen which is present in bones, skin, joints and sclerae. Features: Type 1 mildest form, characterized by Pathological fracture of bones (brittle bones) but fractures heal normally. Blue sclerae. Dental abnormalities (dentinogenesis imperfecta). Hearing loss due to otosclerosis. Positive family history. Joint laxity and permanent dislocations. Type 2 lethal in utero or shortly after birth. Ehler-Danlos Syndrome Inheritance: Autosomal dominant/recessive/X-linked. Characterized by: Hyperelasticity of the skin and hypermobility of joints. Complication: Rupture of colon and arteries (type IV) due to deficiency of collagen type III. Ocular rupture (type VI). Diaphragmatic hernia (type I). Achondroplasia Inheritance: Autosomal dominant. But a positive family history is present in only 20 percent cases. Remaining 80 percent cases arise from a fresh gene mutation. Pathology: Failure of normal ossification of bone leading to dwarfism. Clinical feature: Dwarfism, characterized by disproportionate shortening of proximal extremities. Bowing of legs, increased lumbar lordosis, short and stubby fingers (trident hand). Intelligence and sexual characters are normal.

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Marfans Syndrome Inheritance: Autosomal dominant. Associated with increased age of father. Pathology: Abnormality of fibrillin 1 which is a major component of microfibrils found in extracellular matrix. Fibrillin is coded by FBN1 gene on chromosome 15. Features: Stature tall, slender with long extremities. Fingers tall and have a spider-like appearance (arachnodactyly). Eyes dislocation or subluxation of lens (bilateral) ectopia lentis. Chest pectus excavatum (depression) or pectus carinatum (protrusion). Spine kyphoscoliosis. Joint mobility is normal but may be hypermobile. CVS aortic aneurysm involving the ascending aorta and aortic dissection, mitral valve prolapse and mitral regurgitation, floppy valve syndrome; death is due to aortic rupture. Others high arched palate and high pedal arches, spontaneous pneumothorax, inguinal and visceral hernias, cutis laxa (premature aged appearance). Alports Syndrome Inheritance: Most common type is X-linked dominant. Features: Hematuria, sensorineural deafness, lenticonus.

INHERITED DISORDERS OF AMINO ACID METABOLISM AND STORAGE


Phenylketonuria Cause: Deficiency of phenylalanine hydroxylase enzyme which converts phenylalanine to tyrosine.

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Alternative pathways convert phenylalanine to phenylpyruvate which undergoes incomplete oxidation to produce phenyketoacids (phenylacetate, phenyllactate) that are excreted in urine. Phenylketonuria type II is due to deficiency of dihydropteridine reductase. Clinical feature: Mental retardation, hyperactivity, seizures. Skin hypopigmentation and eczema, vulnerable to minor inflammatory lesions. Mousy odor of skin, hair and urine due to phenylacetate. Microcephaly at birth. Maternal phenylketonuria causes Microcephaly, mental retardation, growth retardation and congenital heart disease in their babies. Diagnosis: Increased plasma phenylalanine (usually after feeding provocative protein meal test). Increased urinary levels of phenylpyruvate, Normal plasma tyrosine. Screening tests: Guthrie bacterial inhibition assay. FeCl3 turns green in presence of phenylalanine in urine. 2-4 dinitrophenol hydrazine yellow precipitate. Treatment: Tyrosine becomes an essential amino acid in PKU. So treatment consists of diet low in phenylalanine and rich in tyrosine (but phenylalanine should not be completely eliminated from food). Diet should be started soon after birth and continued up to 6 years of age. Prevention: Neonatal screening test for PKU. Homocystinurias Pathogenesis: Defects in metabolism of methionine. Most common type is due to deficiency of cystathione -synthase that converts methionine to cystine.

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Result is increased concentration of sulfur-containing amino acids homocystine in blood and urine. Methionine Homocystine Cystine cystathione -synthase Clinical feature: Age of onset 3-4 years. Metal retardation, glaucoma, osteoporosis, ectopia lentis, mousy odor in urine, thrombosis. Diagnosis: Cyanide nitroprusside test for detection of sulfur containing compounds in urine. Treatment: Methionine-restricted, cystine-supplemented diet. Some types respond to vitamin B6. Tyrosinemia Type I: Tyrosinosis This causes hepatorenal symptoms cirrhosis, hepatocellular carcinoma. Others cabbage-like odor, respiratory tract infections, neuropathy. Without treatment death from liver failure occurs in 6-8 months. Diagnosis: Millons test. Type II: Tyrosine Transaminase Deficiency Oculo-cutaneous manifestations (but no cataract). Alkaptonuria Cause: Defect in tyrosine metabolism due to deficiency of the enzyme homogentisate oxidase. Clinical feature: Generalized pigmentation of connective tissues (ochronosis). Sites involved are ears, sclerae, articular cartilage, heart valves, larynx, skin and tympanic membrane (not nose). Arthritis, prostatic calculi. Diagnosis: Darkening of urine on exposure to air.

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Maple Syrup Urine Disease Cause: Deficiency of -keto acid decarboxylase enzyme. Pathology: Branched-chain amino acids leucine, isoleucine and valine and their alpha ketoacids are increased in plasma and urine. Clinical feature: Infants are difficult to feed. Vomiting, lethargy. Characteristic odor of maple syrup or burnt sugar in urine. Ataxia, convulsions, spasticity. Skin pigmentation. Metabolic acidosis and ketosis. Diagnosis: Guthries test. FeCl3 blue color. Isovaleric Acidemia Sweaty feet odor. DEFECTS OF MEMBRANE TRANSFER Cystinuria Characterized by impaired tubular reabsorption and excessive urinary exretion of cystine, ornithine, arginine and lysine (COLA). There is malaborption of the amino acids from intestine, too. Clinical feature: Recurrent urinary calculi. Hartnups Disease Cause: Defects in the intestinal and renal transport of neutral amino acids, including tryptophan (which is the precursor of niacin in body). Clinical feature: Pellagra-like features (due to niacin deficiency). Increased fecal excretion of indole derivatives. Cystinosis Due to defective carrier mediated transport of cystine.

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Clinical feature: Photophobia, blindness, delayed puberty, fancony syndrome, end-stage renal disease. Diagnosis: Cystine level in leukocytes and fibroblasts. Cystine crystals in cornea and conjunctiva.

DEFECTS IN CARBOHYDRATE METABOLISM


Galactosemia Cause: Most commonly due to deficiency of galactose-1phosphate uridyl transferase. Other enzymes involved are galactokinase, epimerase. Clinical feature: Symptoms start within few days after birth with onset of breastfeeding. Physiological jaundice is prolonged. Cataract, mental retardation, cirrhosis and liver failure. Diagnosis: Presence of non-glucose reducing sugar in urine. Management: Patient should avoid milk. Dietary management should be continued life-long. Hereditary Fructose Intolerance Cause: Deficiency of aldolase B present in liver. Feature: Fructose induced hypoglycemia, e.g. after ingestion of sugar cane juice. Prolonged intake leads to hepatomegaly, jaundice, PCT dysfunction and intellectual impairment. Treatment: Complete elimination of sucrose, fructose and sorbitol from diet.

CALCIUM, PHOSPHORUS AND BONE METABOLISM


VITAMIN D Vitamin D is a steroid prohormone.

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Synthesis and Metabolism


7-dehydrocholesterol cholecalciferol (vitamin D3) (In sun exposed skin) Vitamin D3 | Liver 25-hydroxylase (rate limiting) 25-hydroxycholecalciferol (25-hydroxy vitamin D3) | Renal, bone or placental 1- hydroxylase 1,25-Dihydroxycholecalciferol [1,25 (OH)2D] or Calcitriol

25-hydroxy vitamin D3 is the major form in circulation and major storage form in liver. Calcitriol is the most potent form. Action calcitriol stimulates intestinal absorption of calcium and phosphate. It acts on nuclear receptors. Effects of vitamin deficiency: Calcium decreased absorption from intestine feedback increase of PTH (secondary hyperparathyroidism) increased bone resorption liberation of calcium in blood calcium level remains normal in blood. Phosphate increased release of PTH causes decreased urinary reabsorption of phosphate hypophosphatemia. PARATHYROID HORMONE Source: Chief cells of parathyroid glands. Actions: 1. It increases calcium concentration in blood by i. Decreasing renal clearance of calcium (increases calcium reabsorption from the DCT). ii. Increased bone resorption. iii. Increased calcium absorption from intestine by promoting the synthesis of calcitriol. 2. Decreases phosphate concentration due to decreased renal reabsorption of phosphate. Note: Calcium is excreted by kidney and intestine. Calcitonin Source: Parafollicular C cells of thyroid.

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Action: It is a hypocalcemic hormone. It inhibits bone resorption by direct action on osteoclasts. Use: Pagets disease of bone, hypercalcemic states, osteoporosis. HYPERCALCEMIA Etiology a. Parathyroid related 1. Primary hyperparathyroidism 2. Lithium therapy 3. Familial hypocalciuric hypercalcemia asymptomatic, occurs in the first decade of life. b. Malignancy related 1. Solid tumors of breast 2. Squamous cell Ca of lung 3. Hematological multiple myeloma, lymphoma. c. Vitamin D related 1. Vitamin D intoxication 2. Increased calcitriol sarcoidosis. d. High bone turnover 1. Hyperthyroidism 2. Immobilization 3. Thiazide diuretics 4. Vitamin A intoxication. e. Renal failure 1. Secondary hyperparathyroidism 2. Aluminum toxicity 3. Milk-alkali syndrome due to excessive ingestion of calcium and absorbable antacids such as milk or calcium carbonate. Characterized by hypercalcemia, alkalosis and renal failure. Primary Hyperparathyroidism Cause: Solitary adenoma of the parathyroids most common cause. Most commonly involves the inferior parathyroid glands. MEN1 and MEN2A syndromes. Hyperplasia of all the four parathyroid glands. Result hypercalcemia and hypophosphatemia.

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Clinical feature: Half or more of patients are asymptomatic. Anorexia, nausea, vomiting. Constipation, depression, polyuria. Ectopic calcification. (painful bones, renal stones, abdominal groans and psychic moans). Renal stones. Bone osteitis fibrosa cystica. Subperiosteal resorption of phalanges most characteristic. Tiny punched-out lesions may cause the so called salt-and-pepper appearance of the skull. Loss of lamina dura of teeth. Giant multinucleated osteoclasts Brown tumor. Subcutaneous calcification. Triradiate pelvis. Others increased level of alkaline phosphatase, increased calcium and cAMP level in urine. Secondary Hyperparathyroidism Cause: i. Renal failure most common cause. ii. Osteomalacia. iii. Pseudohypoparathyroidism (deficient response of PTH at the level of receptors). Characterized by: Increased PTH, normal or decreased calcium and increased phosphate in blood. Clinical feature: Characteristic bone lesion in renal failure is called renal osteodystrophy. Tertiary Hyperparathyroidism Conversion of the parathyroids from a state of reversible hyperplasia to an irreversible growth defect and state of PTH hypersecretion no longer responsive to medical therapy. Management of Hypercalcemia 1. Hydration with saline. 2. Forced diuresis. 3. Oral/IV phosphate.

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4. Hypocalcemic agents bisphosphonates (etidronate, pamidronate), steroids, gallium nitrate, plicamycin, mithramycin, calcitonin. 5. Dialysis. Investigation for Localizing Parathyroid Adenoma: Thallium-Tc substraction scan. Treatment: Treatment of parathyroid adenoma removal of adenoma. Treatment of parathyroid hyperplasia removal of 31/ 2 glands. Autoimplantation: Indication tertiary hyperparathyroidism in patients on chronic renal dialysis, recurrent hyperparathyroidism. Site into the arm. Recurrent hyperparathyroidism can also be treated by USG guided alcohol injection into the mass. Role of steroids: Steroids increase urinary calcium excretion and decrease intestinal calcium absorption. In normal individuals and in primary hyperparathyroidism, steroids neither increase nor decrease calcium level in blood. In certain osteolytic tumors like multiple myeloma, leukemia, lymphoma, breast Cathey are helpful. They are also effective in vitamin D intoxication and sarcoidosis. HYPOCALCEMIA Etiology 1. 2. 3. 4. 5. 6. Chronic renal failure Hereditary and acquired hypoparathyroidism Vitamin D deficiency malabsorption Pseudohypoparathyroidism Hypomagnesemia Surgical removal of parathyroid glands most common cause in clinical practice. 7. Hyperventilation 8. Tumor lysis syndrome

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Clinical Feature Signs of hypocalcemia starts to appear when serum calcium level falls below 4 mg/dl. Muscle spasm carpopedal spasm, laryngospasm, circumoral tingling, hyperactive tendon reflexes. CNS increased ICT with papilledema, psychosis. ECG QT prolongation. Chvosteks or Trousseaus sign, Erbs sign. Electrolytes decreased calcium and increased phosphate levels. HEREDITARY/IDIOPATHIC HYPOPARATHYROIDISM DiGeorge Syndrome Defective development of both thymus and parathyroid glands due to deletion of chromosome 22q11. Autoimmune Polyglandular Deficiency Failure of adrenal, ovaries and parathyroids associated with recurrent mucocutaneous candidiasis, alopecia, vitiligo and pernicious anemia. PSEUDOHYPOPARATHYROIDISM Features: Usually affect females. Short stature, short metacarpals and metatarsals, flat nose, round face and multiple exostosis. Signs of hypoparathyroidism. Mechanism: Deficient end organ response to PTH hyperplasia of parathyroids increased PTH level. Albrights Hereditary Osteodystrophy Short stature, round face, brachydactyly and heterotopic calcification. Electrolytes increased PTH, decreased calcium and increased phosphate. Resistance to PTH action defective urinary cAMP response to PTH administration.

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METABOLIC BONE DISEASES


OSTEOPOROSIS It is the reduction of bone mass per unit volume of bone due to bone resorption more than bone formation. Etiology: a. Endocrinal i. Hyperparathyroidism ii. Hyperthyroidism iii. Cushings disease b. Others i. Chronic glucocorticoid administration ii. Rheumatoid arthritis iii. Alcoholism iv. Smoking v. Old age vi. Chronic heparin therapy vii. Cytotoxic drugs, e.g. methotrexate. Clinical feature: Pathological fracture most common site is the dorsolumbar spine. Pain in the back and deformity of the spine are the most common symptoms. Diagnosis: Normal levels of calcium, phosphate and alkaline phosphatase. X-ray shows decreased mineral density in bones. Cod-fish appearance of vertebra. Dual energy X-ray absorptiometry (DEXA) gold standard investigation for detection of bone density. Treatment: Estrogen to postmenopausal women. Drug of choice etidronate. RICKETS AND OSTEOMALACIA Rickets Defective mineralization of the organic matrix of the skeleton predominantly at growth plates (epiphysis).

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A Systematic Review of Subjects for PGMEE

Etiology: Type I 1. Deficiency of vitamin D dietary deficiency. 2. Defective hepatic and renal metabolism. Type II 1. Defective resorption of phosphates through renal tubules familial hypophosphatemic vitamin D resistant rickets X-linked dominant. 2. Fanconis syndrome 3. Renal tubular acidosis type I. Clinical feature: Age later half of first year or in second year (unusual before 3 months of age). Craniotabes earliest manifestation (it is also seen in hydrocephalus, congenital osteodystrophy). Bossing of the skull. Broadening of the ends of long bones. Delayed teeth eruption, growth retardation. Harrisons sulcus along the lower part of the chest. Pigeon chest elevation of the lower borders of ribs. Rachitic rosary costo-chondral junctions on the anterior chest wall become prominent. Mascular hypotonia (pot-belly). Lumbar lordosis. Deformities knock-knees or bow-legs, coxa vera. Wind-sweep deformity. Quants sign T shaped depression in the left occipital bone. Hypophosphatemic rickets hypophosphatemia, hypercalcemia and lower limb deformities. X-ray: i. Delayed appearance of epiphyses. ii. Widening of the epiphyseal plates. iii. Cupping of the metaphysis. iv. Splaying of the metaphysis. v. Fraying of the metaphysis. vi. Pseudofractures or Loosers zone. vii. Osteopenia. Laboratory Findings: Serum calcium and phosphate levels are decreased and serum alkaline phosphatase level is increased.

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Treatment:
600000 IU oral vitamin D single dose X-ray after 3-4 weeks If no improvement, repeat the same dose If no response if improves Vitamin D resistant rickets 400 IU/day

Osteomalacia Common in women. Clinical feature: Bone pains back ache. Muscle weakness. Spontaneous fracture of spine. Triradiate pelvis. Laboratory findings as above.
Summary of laboratory findings Disease Calcium (8.5-10.5 mg/dl) Normal Decreased Increased Decreased Normal Phosphate (3-4.5 mg/dl) Normal Decreased Decreased Normal or increased Normal Alkaline phosphatase (5-15 IU) Normal Increased Increased

Osteoporosis Rickets and osteomalacia Hyperparathyroidism Renal osteodystrophy Pagets disease of bone

Increased

MAGNESIUM METABOLISM Hypomagnesemia Etiology: 1. Infection giardiasis. 2. Endocrine hyperthyroidism, hypo/hyperparathyroidism. 3. Chronic alcoholism. 4. Thiazide, amphotericin B. 5. Massive blood transfusion. 6. Small bowel resection. Clinical feature: Hypomagnesemia coexists with hypokalemia. Associated hypocalcemia may produce Chvostek and Trousseaus signs. Athetoid tetany, convulsions.

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ECG QT prolongation. Note physical findings of hypomagnesemia is due to associated hypocalcemia and cardiac findings are due to associated hypokalemia. PAGETS DISEASE It is characterized by progressive tendency of one or more bones to bend, get thickened and spongy. Clinical feature: Tibia most commonly affected. Facial pain and headache. Backache in lumbar region. Hearing loss. Platybasia. X-ray: Multiple confluent lytic areas with interspersed new bone formation hair-on-end appearance. Bone scan shows increased uptake. Laboratory findings: Increased alkaline phosphatase with normal calcium and phosphate. Increased urinary excretion of hydroxyproline. Complications: i. Pathological fracture. ii. Urinary stones. iii. Malignant change sarcoma. iv. Deafness due to otosclerosis. Treatment: Calcitonin and bisphosphonates. MISCELLANEOUS BONE DISEASES Hyperostosis It is an increase in bone mass of bone per unit. Etiology: i. Primary hyperparathyroidism. ii. Hypothyroidism. iii. Radiation osteitis. iv. Vitamin A intoxication.

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Osteopetrosis Also called marble bone disease or Albers-Schonberg disease. Characterized by dense but brittle bones with a tendency to fracture. Clinical feature: Autosomal recessive. Most commonly affects infants with progressive anemia, hepatosplenomegaly and hydronephrosis. Others pancytopenia, jaw osteomyelitis and cranial nerve palsies. Treatment: Bone marrow transplantation. Hyperostosis Corticalis Generalisata (Von Buchems Disease) Characterized by osteosclerosis of skull, lower jaw, clavicle and ribs. Clinical feature: Blindness, deafness, facial nerve palsy. Laboratory finding: Increased alkaline phosphatase in serum. Fibrous Dysplasia (McCune-Albright Syndrome) Polyostotic fibrous dysplasia, precocious puberty and cutaneous pigmentation in girls. The lesions of dysplasia are focal and have a radiolucent appearance. Occurs equally in both sexes.

INFECTIOUS DISEASES

SEPSIS AND SEPTIC SHOCK Pathogenesis: Most cases of septic shock are caused by endotoxin producing gram-negative bacilli. Endotoxins are bacterial wall lipopolysaccharides (LPS) released when the cell walls are degraded.
LPS TNF IL-1 IL-6 / IL-8 NO, PAF and other mediators Low quantities Moderate quantities High quantities 1. Monocyte/ 1. BrainFever 1. Heart Increased macrophage/ 2. Liver Acute CO neutrophil phase reactants 2. Decreased activation 3. Bone peripheral 2. Endothelial cell leukocytes resistance activation Systemic effect 3. Blood vessel 3. C3a, C5a injury Local thrombosis, DIC inflammation 4. Lungs ARDA Septic shock

Note: Normal or increased cardiac output and decreased peripheral resistance is characteristic of septic shock and distinguishes it from other types of shock. Systemic Inflammatory Response Syndrome (SIRS) This is the systemic inflammatory response to a variety of severe clinical insults viz infections, burn, trauma, pancreatitis, etc.

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Manifested by 2 or more of the following conditions 1. Temperature > 38C or < 36C 2. Heart rate > 90 beats/min 3. Respiration rate > 20 breaths/min or PaCO2 < 32 torr 4. WBC count > 12000/ l or < 4000/ l or > 10 percent immature (band) cells. Most important mediators are TNF, IL-1 and IL 6 (all secreted by macrophages). Sepsis: Same as SIRS but with a documented microbial origin. Severe sepsis: Sepsis associated with organ dysfunction, hypotension or hypoperfusion (lactic acidosis, oliguria, altered mental state). Septic shock: Sepsis associated with hypotension despite adequate fluid resuscitation, along with the presence of perfusion anomalies listed above or organ dysfunction. Clinical Feature Fever or hypothermia, tachypnea and tachycardia often herald the onset of sepsis. Hyperventilation is an early sign. Disorientation, confusion also develop early. Hypotension and DIC predispose to acrocyanosis and ischemic necrosis of peripheral tissue, most commonly the digits. Skin lesions N. meningitidis Sepsis with cutaneous petechiae of purpura. Ecthyoma gangrenosum Seen exclusively in neutropenic patients, caused by Ps. aeruginosa. Toxic shock syndrome Generalized erythema caused by Staphylococcus aureus or Streptococcus pyogenes. Complications 1. Adult respiratory distress syndrome. 2. Myocardial dysfunction, systemic vasodilatation leading to hypotension. 3. Renal failure due to acute tubular necrosis. 4. Activation of coagulation cascade leading to DIC.

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5. Electrolytes Early, respiratory alkalosis due to hyperventilation. Late, metabolic (lactic) acidosis. Diagnosis Blood: Leukocytosis or leukopenia. Thrombocytopenia. Hyperbilirubinemia. Neutrophils may contain toxic granules, Dohle bodies or cytoplasmic vacuoles. Urine proteinuria. Treatment Pneumatic antishock garment improves cardiac filling. Also used in aortic aneurysm rupture. IV fluids + inotropic agent (e.g. dopamine). Neonatal Septicemia Cause: Through nursery personnel. Diagnosis: Neutropenia, >20 percent immature neutrophils, increased CRP , increased ESR. Predisposing factors: Preterm and LBW baby, PRM, late breastfeeding. C/Organism: E coli, Streptococcus agalactiae. Clinical feature: Lethargy. FEVER OF UNKNOWN ORIGIN Definition It consists of 1. Temperature > 38.3o C (101oF) on several occasions. 2. A duration of fever > 3 weeks. 3. Failure to reach a diagnosis despite 1 week of inpatient investigation. Classification: 1. Classic FUO Fever without elucidation of a cause by 3 outpatients visits or 3 days in hospital or 1 week of intelligent and invasive ambulatory investigation.

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2. Nosocomial FUO Fever acquired after admission to a hospital. Three days of investigation, including 2 days incubation of cultures, is the minimum requirement for diagnosis. 3. Neutropenic FUO Fever in patients whose neutrophil count is <500/l or is expected to fall to that level in 1 or 2 days. Diagnosis: As above. 4. HIVassociated FUO. Cause I. Infections: 1. Extrapulmonary TB most common cause. 2. Intra-abdominal abscess. 3. UTI. 4. Osteomyelitis. 5. Bacterial endocarditis. 6. Malaria. 7. Fungal histoplasma, cryptococcus. 8. Viral EBV, CMV, HIV. II. Neoplasm: 1. Hodgkins and nonHodgkins lymphoma. 2. Leukemia. 3. Renal cell Ca. 4. Hepatoma. 5. Atrial myxoma. III. Collagen vascular diseases: 1. Stills disease. 2. Rheumatoid arthritis. 3. PAN, SLE. IV. Granulomatous disease: 1. Sarcoidosis. 2. Crohns disease. Stills Disease Characterized by: Increased ESR, leukocytosis and anemia. Arthralgia (Rheumatoid arthritis). Polyserositis (pleuritis, pericarditis). Lymphadenopathy. Splenomegaly. Rash maculopapular.

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But no Rhfactor is found. [C.f. Feltys syndrome arthritis, splenomegaly, neutropenia and +Rh factor]. INFECTIVE ENDOCARDITIS It involves the cardiac valves or mural surface of the endocardium and characterized by formation of vegetations. Etiology and Classification A. According to onset and course: 1. Acute: Microorganism Staphylococcus aureus (overall most common). Occurs on normal valves, rapidly destructive, produces metastatic foci and if untreated fatal in less than 6 weeks. Most common in drug addicts. 2. Subacute: Microorganism Streptococcus viridans. Occurs on damaged valves. B. According to predisposing factors: 1. Native valve endocarditis: Organism Streptococcus viridans (Streptococcus sanguis) most common source is dental infections. Staphylococcus aureus (most common). Enterococci. HACEK (Haemophilus, Actinobacillus, Cardiobacterium, Eikenella, Kingella) 2. Prosthetic valve endocarditis: Organism Staphylococcus epidermidis. In early onset disease (< 2 months)- Streptococcus epidermidis. Late onset Streptococcus viridans. 3. IV drug abusers: Organism Staphylococcus aureus, Candida Epidemiology Native valve endocarditis common in males > 50 years. Predisposing factors: 1. Rheumatic valvular disease 2. Congenital heart disease

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VSD (most common), PDA, TOF , coarctation of aorta, MVP , aortic regurgitation. Low risk in MVP without MR, ASD (Least risk). 3. Calcific aortic stenosis IV drug abusers Common in young males. Skin is the most common source of infection. Pathology Left heart (mitral valve most common) is involved in most cases except in IV drug abusers in whom right heart [tricuspid valve (also in septic abortion) most common] involvement is more common. Pathologic hallmark of bacterial endocarditis are vegetations which are composed of platelets and fibrin with superadded infection.
Acute BE vegetations are small and solitary

Systemic embolisation is common

Enlarge progressively and become bulky and friable

Abscesses can develop at the site of emboli

Extension of infection to adjacent myocardium my produce ring abscess May produce septal perforation

Subacute bacterial endocarditis: Firm and multiple vegetations, presence of granulation tissue at their bases. Systemic emboli may occur but the resultant infarcts are less likely to undergo suppuration. Systemic embolisation: Occurs in heart, brain, kidney, spleen, liver, extremities; may produce splenic and renal infarcts, also myocardial infarction. Pulmonary embolisation occurs in right sided endocarditis (large warty vegetations). Mycotic aneurysm may develop in cerebral arteries. Clinical Feature 1. Fever Minimum criteria for diagnosis is unexplained fever of 7-10 days duration in patients with known heart disease.

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2. Changing cardiac murmur except in patients with early acute endocarditis and in IV drug abusers with tricuspid valve infection. 3. Splenomegaly. 4. Splinter hemorrhage subungual linear, darkred streaks result from trauma especially in fingers. 5. Roths spot oval retinal hemorrhage (also occurs in connective tissue disorder). 6. Oslers node small tender nodules usually on the finger or toe pads. 7. Janeway lesions small hemorrhage on the palms and soles. 8. Clubbing. 9. Arthralgia, myalgia. 10. Glomerulonephritis-Microscopic hematuria. 11. Normocytic normochromic anemia. Note: Features 3-10 are due to immunologically mediated vasculitis. Complications 1. Pulmonary embolism in right heart endocarditis. 2. Thromboembolism most common complication. 3. Brain abscess less common, occurs with Staphylococcus aureus. 4. Neurological cerebral infarct, encephalopathy, meningitis. 5. Myocardial abscess most common in acute endocarditis (Staphylococcus aureus). 6. Mycotic aneurysm. 7. Renal Focal/Diffuse glomerulonephritis. Diagnosis 1. Blood culture repeated cultures are often needed to establish a diagnosis. 2. All suspected cases should undergo baseline transthoracic echocardiography (TTE). Transesophageal echo (TEE) is more sensitive than TTE in detecting small vegetations. Prophylaxis Amoxycillin or erythromycin.

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Indications: 1. Valvular of congenital hear t disease (except uncomplicated ASD). 2. Intracardiac prostheses. 3. Asymmetric septal hypertrophy. 4. Previous endocarditis. Patients who do not require prophylaxis: 1. Coronary artery bypass grafts. 2. Transvenous pacemakers. 3. Patients undergoing cardiac catheterization. Note: Anticoagulants should not be used to prevent embolisation. INTRA-ABDOMINAL INFECTIONS AND ABSCESS PERITONITIS Primary Peritonitis It is the infection, often monobacterial, of the peritoneal fluid without any intra-abdominal cause. It is seen in 2 settings: 1. In children most commonly caused by Streptococcus pneumoniae; occurs in the setting of nephritic syndrome or SLE. Often follows an ear or URT infection. In females genital tract infection. More common due to spread of infection through open abdominal osteum of fallopian tube. 2. In adults often occurs with alcoholic cirrhosis and ascites. Spontaneous Bacterial Peritonitis Infection of ascitic fluid most commonly following alcoholic cirrhosis. Route: Hematogenous. Organism: E. coli (most commonly) monobacterial. Clinical feature: Fever is most common manifestation ascites, abdominal pain. Diagnosis: Ascitic fluid PMN count >300 / l. Ascitic fluid culture.

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Treatment: IV antibiotic Ampicillin + Gentamicin or 3rd generation Cephalosporin. Secondary Peritonitis Most common form of peritonitis. Peritoneal infection from intra-abdominal source. Most common from rupture of hollow viscus. Clinical feature: Abdominal pain (most common). C/Organism: Usually mixed infection. Aerobes E. Coli (most common), Anaerobes B. fragilis. Treatment: Second or third generation cephalosporin + metronidazole. Surgery is often life saving. Peritoneal Dialysis Associated Peritonitis Occurs with CAPD. Source of infection skin flora. C/Organism: Monobacterial; Staphylococcus aureus (most common), Staphylococcus epidermidis, E.coli, Candida. Treatment: Intraperitoneal Vancomycin + Gentamicin. Tertiary Peritonitis Persistent diffuse peritonitis following the initial treatment of secondary peritonitis. It represents both a failure of host response and super infection. Sclerosing Peritonitis Fibrinous peritonitis caused by Practolol ( blocker) Note: Meconium peritonitis: Intra-abdominal calcification (in X-ray) Note: Least irritant fluid to peritoneum is blood. INTRA-ABDOMINAL ABSCESS Pelvic Abscess It is the most common intra-peritoneal abscess.

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Definition: It is the collection of pus in rectovesical or rectouterine pouch (pouch of Douglas). Cause: Appendicitis. C/Organism: B. fragilis, E. coli. Diagnosis: USG. Treatment: Antibiotics; Per rectal drainage of pus under GA. In females, posterior colpotomy is the definitive surgery. Subphrenic Abscess Subphrenic spaces: A. Intraperitoneal spaces: 1. Right anterior 2. Right posterior (Rutherford Morisons kidney pouch) (Rt. subhepatic) most common site of subphrenic abscess. Most common site of intra-abdominal abscess following laparotomy. 3. Left anterior 4. Left posterior B. Extraperitoneal spaces: 1. Right perinephric space 2. Left perinephric space 3. Midline bare area of liver. Etiology: Right-sided abscess Cholecystitis, appendicitis. Left anterior space - Surgery of stomach (most common). Left posterior space - pancreatic pseudocyst. Right and left perinephric abscess TB. Midline abscess ruptured amoebic liver abscess or pyogenic abscess of the liver. Clinical feature: Signs of toxemia. C/Organism: E. coli, Klebsiella, Streptococci, Anaerobes. Treatment: Antibiotics, Percutaneous drainage US guided, Open drainage indicated in only 10 20 percent of cases.

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A Systematic Review of Subjects for PGMEE

Visceral Abscesses Liver Abscess (Pyogenic) Most common visceral abscess. Source: Ascending cholangitis (most common), hematogenous. C/Organism: Biliary tract E. Coli and enterococci, Hematogenous Staphylococcus aureus, Streptococcus milleri. Clinical feature: Fever most common sign. May present as PUO, hepatomegaly, and jaundice - present in only 50 percent cases. Diagnosis: LFT most reliable finding is increased alkaline phosphatase. Imaging USG, CT scan Investigation of choice. Treatment: Drainage, Interventional radiology (CT or USG guided aspiration) is the treatment of choice. Splenic Abscess Most commonly associated with bacterial endocarditis. Route Hematogenous. C/Organism: Streptococcus most common, Staphylococcus aureus. Perinephric and Renal Abscess Most commonly associated with renal stone. Source: Ascending infection from bladder (UTI). C/Organism: E. coli, Proteus, Klebsiella. Clinical feature: Flank pain and abdominal pain. Diagnosis: USG and abdominal CT scan.

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INFECTIOUS DIARRHEA AND FOOD POISONING Diarrhea Watery Diarrhea Produced by enterotoxins. 1. Cholera Cholera toxin has one A and 5 B subunits. B subunit binds CT to enterocyte surface receptor, the ganglioside GM1. A subunit activates adenylate cyclase. Increased production of CAMP Increased water secretion and decreased absorption Loss of fluid in stool Rice water stool 2. Enterotoxigenic E. coli produces 2 toxins i. Heat labile toxin (LT) acts similar to CT. ii. Heat stable toxin (ST) acts by activation of guanylate cyclase increased cGMP Note: most common cause of diarrhea is neonates is E. coli 3. Clostridium perfringens 4. B. cereus Produce pre-formed toxin 5. Staphylococcus aureus 6. Rotavirus diarrhea most common cause of diarrhea in infant and children. 7. Other viral diarrheas - Norwalk virus, Adenovirus, Astrovirus, Corona virus, Calcivirus. 8. Giardia 9. Cryptosporidium important cause of diarrhea in AIDS patients. Inflammatory Diarrhea 1. Shigella dysentriae 2. Salmonella typhimurium 3. Enterohemorrhagic E. coli (most common serotype O157:H7) produce shiga-like toxin. 4. Enteroinvasive E. coli 5. V. parahemolyticus 6. Clostridium difficile 7. Campylobacter jejuni 8. Yersinia enterocolitica 9. Entamoeba histolytica

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Travelers Diarrhea

Most common cause is Enterotoxigenic E. Coli Treatment: Bismuth Salicylate (also used for prophylaxis). Loperamide, Diphenoxylate + Atropine. Food Poisoning
Incubation period 1-6 hours 816 hours >16 hours Organism Staphylococcus aureus B. cereus Cl. perfringens B. Cereus Vibrio cholerae ETEC Salmonella, Shigella V. parahemolyticus Source Poultry, egg, salad, milk Fried rice Beef, poultry Meats Shellfish Salads Dairy products Mollusks

Staphylococcus aureus and B. cereus produce neurotoxins which act on central nervous system to produce vomiting by vagal stimulation. B. cereus produces 2 types of syndromes 1. Emetic form with 1- 6 hours of incubation period, occurs following eating fried rice and mediated by enterotoxins. 2. Diarrheal form with long (8 16 hours) incubation period, mediate a by E. coli LT type of enterotoxin. There is diarrhea and abdominal cramps but no vomiting. Both types of illness are mild and self-limited requiring no specific treatment.

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SEXUALLY TRANSMITTED DISEASES Etiology


Disease Organism Bacterial 1. Gonorrhea 2. Nongonococcal urethritis 3. Syphilis 4. Lymphogranuloma venorum 5. Chancroid 6. Granuloma inguinale (Donovanosis) 7. Bacterial vaginosis 8. Genital chlamydiasis N. gonorrhoeae most common STD Chlamydia trachomatis most common, Ureaplasma urealyticum T. pallidum Chlamydia trachomatis (L serotype) Hemophilus ducreyi Calymmatobacterium granulomatosis Gardenella vaginalis (Hemophyllus vaginalis) Most common STD worldwide Viral 1. AIDS 2. Genital herpes 3. Condyloma acuminata (genital warts) 4. Molluscum contagiosum 5. Viral hepatitis 6. Cervical intraepithelial neoplasia (CIN) HIV1 and HIV2 HSV2 HPV 6 and 11 Pox virus Hepatitis B HPV 16, 18 and 31 Protozoal 1. Trichomonas vaginitis 2. Proctocolitis 3. Enteritis T. vaginalis-most common trophozoite infection Entamoeba histolytica Giardia lamblia Fungal 1. Monilial vaginitis Candida albicans Ectoparasites 1. Scabies 2. Pediculosis pubis Sarcoptes scabie Phthirus pubis

Gonorrhea Affects sexually active adults. It has affinity for columnar and transitional epithelium. The disease involves a. In men urethra, prostrate, seminal vesicles and epididymis (but not the testes).

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b. In female urethra, Skenes gland, Bartholins gland and the cervix. In adults, vaginitis does not occur because squamous epithelium is resistant to it. Most common manifestation is acute urethritis with profuse mucopurulent discharge. Involvement of endocervix may be asymptomatic. Gonococcal salpingitis causes fimbrial block. Urethritis Etiology: 1. N. gonorrhea most common cause. 2. Chlamydia trachomatis most common cause of nongonococcal urethritis. 3. Ureaplasma urealyticum. Genital Ulcers Genital Herpes Most common cause of genital ulcer in developed countries. Now most common cause in developing countries (India), too. Features: Typical pastules or vesicles or a cluster of painful ulcers that were preceded by vesicopapular lesions. May predispose to Ca cervix. C/Organism: HSV2. Chancroid Or soft-sore. It was the most common cause of genital ulcer in developing countries. Incubation period 4 to 7 days. C/Organism: H. ducreyi. Other Herpes hominis virus. Ulcer: Painful with inguinal lymphadenopathy (bubo), which is non-indurated (hence called softsore) with fluctuance or overlying erythema. Ulcers may suppurate and discharge on skin. Diagnosis: Itos test. Treatment: Cotrimoxazole/Erythromycin/Cephalosporin.

Infectious Diseases

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Syphilis Second most common cause world-wide. Ulcer: Known as chancre, single, painless papule that rapidly becomes eroded and indurated (hard-sore). Inguinal lymphadenopathy firm, non-tender and nonsuppurative. Lymphogranuloma venorum (LGV) C/Organism: Chlamydia trachomatis (L2 serotype most common). Ulcer Small, painless vesicle or papule often asymptomatic and remain unnoticed; painful inguinal lymphadenopathy which may suppurate leading to multiple discharging sinuses; sign of groove; may produce esthiomene (elephantiasis of the female genitalia); may cause rectal stricture, multiple fistulae. Diagnosis: Freis test (Skin test). Now-a-days cell culture is commonly used for diagnosis; or antibody detection by CFT or micro IF. Elementary bodies called Miyagawas granulocorpuscles. Granuloma inguinale (Donovanosis) C/Organism: Calymmatobacterium granulomatis. Ulcer: Painless papule with no lymphadenopathy (hence called pseudo-bubo). Satellite lesions. Diagnosis: By demonstrating Donovan bodies which have safety pin appearance. Mikulicz cells. Treatment: Tetracycline/Erythromycin, Doxycycline drug of choice. Genital Ulcers at a Glance
Disease Ulcer Lymphadenopathy - ve Tender (bubo), non-indurated (soft), may suppurate Non-tender, indurated - ve (pseudo-bubo) Painful, may suppurate 1. Herpes genitalis Painful vesicles or pustules 2. Chancroid Painful (soft-sore) 3. Syphilis 4. Donovanosis 5. LGV Painless papule Painless papule Painless vesicles (often unnoticed)

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Acute Arthritis Most common forms of acute arthritis in sexually active young adults are 1. Gonococcal arthritis-dermatitis syndrome. 2. Reiters syndrome. Chlamydial Infection C/Organism: Chlamydia trachomatis (D-K serotype). Pathology: Chlamydia affects the columnar and transitional epithelium of lower genital tract. There is no deep penetration. Clinical feature: It affects Urethra (urethritis), Bartholins gland, cervix (cervicitis), fallopian tubes (salpingitis); may produce infertility. Diagnosis: Ligase chain reaction and PCR most sensitive. Other ELISA, cell culture, direct IFA technique. Treatment: Azithromycin is the drug of choice. Also used doxycycline. The sexual partner should also be treated with the same regimen. Bacterial Vaginosis Or bacterial vaginitis. C/organism: Gardenella vaginalis (hemophyllus vaginalis). Diagnosis: Clue cells; fishy odor when mixed with 10 percent KOH. Number of lactobacillus and leukocytes are decreased. Feature: White milky non-viscous discharge adherent to vaginal wall. pH > 4.5, minimal vulval irritation. Treatment: Metronidazole.

Infectious Diseases

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Trichomonas vaginitis Most common congenital infection in females. C/organism: Trichomonas vaginalis (a parasite). Clinical feature: Profuse and offensive vaginal discharge which is greenish yellow in color. Irritation and itching. Diagnosis: Punctate hemorrhagic spots and strawberry appearance of the cervix on speculum examination. Treatment: Metronidazole; husband should also be treated. Monilial vaginitis C/organism: Candida albicans. Predisposing factors: Diabetes, pregnancy, OCP use, broad-spectrum antibiotic therapy. Note: Candida infection is favored by a low pH (<4) [c.f. above two which are favored at relatively high (> 4.5 5) pH]. Clinical feature: Pruritus which is out of proportion to the discharge. Discharge thick, curdy white and in flakes (cottage cheese discharge). Treatment: Miconazole is the drug of choice. Nystatin applied through a pessary. Husband should also be treated with local nystatin ointment. But treatment of partner is not routinely indicated. Condyloma acuminata (Genital Warts) C/organism: HPV 6 and 11. D/D: Verrucous Ca. Treatment: Cryotherapy, 20 percent podophyllin resin in liquid paraffin produces systemic toxicity, so not used now-a-days.

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A Systematic Review of Subjects for PGMEE

PELVIC INFLAMMATORY DISEASE PID implies infection of the upper genital tract (which includes endometrium, tubes and ovaries). Route: Ascending infection most common route. Hematogenous as in tuberculosis. Etiology: 1. Sexually transmitted diseases most common cause. i. Gonococcal 30 percent. ii. Chlamydia 30 percent. 2. Others Mycoplasma hominis (10%), tuberculosis, E. coli, anaerobes. 3. Rare causes include leprosy, syphilis and schistosomiasis. Risk factors: 1. Menstruating teenagers. 2. Sexual promiscuity (multiple sex partners). 3. Operative procedures like D and C, hCG. 4. Contraception IUCD insertion. 5. Previous history of PID. 6. Septic abortion and puerperal sepsis. Protective: 1. Contraception barrier methods especially condom; OCP . 2. Pregnancy. 3. Menopause. 4. Azoospermia of husband. Clinical feature: Temperature > 38oC. Lower abdominal pain most common symptom. Tenderness on movement of the cervix. Adnexal mass. Supportive diagnostic aids Blood leukocytosis > 10000/cu.mm. ESR > 15/hr. Laparoscopic evidence of tubal affection. Culdocentesis with purulent fluid having WBC count > 30000/ml. Note: Most common feature of cervicitis is profuse watery discharge.

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Treatment: All patients should receive orally 7-14 days course of any one of the followings Tetracycline/doxycycline/erythromycin/clindamycin. Chronic PID Failure to resolve the acute PID results in chronic tuboovarian masses. These include 1. Hydrosalpings. 2. Chronic pyosalpings. 3. Chronic interstitial salpingitis. 4. Tubo-ovarian cyst. 5. Tuberculous form. Clinical feature: Abdominal pain, low back pain, dysmenorrhea. Fixed solid mass in pelvis frozen pelvis. C/organism: Staphylococcus, E.coli, gonococcus, chlamydia. Pathology: The tubes assume retort shape; often bilateral. Management: a. In young women conservative surgery - salpingectomy or salpingo-oophorectomy. b. In multiparous and older women abdominal hysterectomy with bilateral salpingo-oophorectomy. c. Tuboplasty to treat infertility. Best result is obtained in tubo-tubo (isthmo-isthmic) anastomosis. TUBERCULOSIS OF GENITAL TRACT Pathogenesis: Genital TB is almost always secondary to primary infection elsewhere in the body. Route: Most common route is hematogenous spread. Pathology Most common site of infection is the fallopian tubes. Both the tubes are affected simultaneously. The initial site of infection is in the submucosal layer (interstitial salpingitis) of the ampullary part of the tube.

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The muscular layer gets replaced by fibrous tissue. The walls get thickened, become calcified or even ossified. The abdominal osteum remains patent. The tubes get elongated and distal part distended, giving the appearance of tobacco- pouch. Uterus the endometrium is infected from the tubes either by lymphatics or by direct spread through continuity (retrograde spread). Clinical feature: Most common in the age group 20-30 years. 1. Infertility most common complaint. 2. Menstrual abnormalities menorrhagia or secondary amenorrhea. Investigation: 1. D and C best method. Time during the week before menstruation. 2. First day menstrual fluid examination. 3. HSG is contraindicated in a proven case of genital TB. Features on HSG: i. A rigid non-peristaltic pipe-like tube called the lead pipe appearance. ii. Beading and variation in filling density. iii. Tobacco-pouch appearance. 4. Biopsy. 5. Marker CA 125. Treatment: 1. Antitubercular chemotherapy is the treatment of choice. 2. Surgery is reserved for persistent or complicated cases. Surgery of choice total hysterectomy with bilateral salpingo-oophorectomy. Outcome: Pregnancy is rare, and if occurs, chance of ectopic pregnancy is more. URINARY TRACT INFECTION Pathogenesis: Two categories of UTI: a. Lower tract infection urethritis, cystitis and prostatitis. b. Upper tract infection acute pyelonephritis, renal and perinephric abscess.

Infectious Diseases

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Route: Lower UTI ascending infection Upper UTI hematogenous. Epidemiology: Two types 1. Catheter associated (nosocomial) and 2. Non-catheter associated (community-acquired). Etiology: 1. Community acquired UTI E. coli (most common). 2. Nosocomial UTI proteus, klebsiella, pseudomonas, serratia. 3. UTI associated with renal calculus proteus, klebsiella. 4. Gram +ve organism coagulase negative staphylococcus saprophyticus; enterococci and Staphylococcus aureus in patients with calculi or previous instrumentation. Risk factors: 1. Catheterization. 2. Renal stone. 3. Urogenital anomalies. 4. Pregnancy high incidence of asymptomatic bacteruria. 5. BHP in older males. 6. Vesicoureteric reflux common in children. Clinical feature: UTI is most common in sexually active young females. Acute urethral syndrome dysuria, urgency and frequency. Pyelonephritis fever (temperature > 103oF) with chills. Nausea, vomiting and diarrhea. Tachycardia. Generalized muscle tenderness. Abdominal pain. Diagnosis: Significant Bacteriuria Sample mid-stream clean catch urine. Count quantitative assay. Bacteria count > 105/ml is significant. Count less than 104/ml is of no significance and are due to contamination during voiding.

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A Systematic Review of Subjects for PGMEE

Note: Children less than 2 years of age samples are collected by suprapubic aspiration or catheterization. Conditions where count < 104/ml may be significant i. Symptomatic patients. ii. Samples collected by suprapubic aspiration or inand-out catheterization and in samples from a patient with indwelling catheter. iii. Patients on antibacterial or diuretic therapy. iv. Samples show evidence of some bacteria like Staphylococcus aureus. UTI in Pediatric Age Group Incidence: During infancy same in both sexes because the route of infection is hematogenous. Beyond infancy more common in girls. Predisposing factors: 1. Obstructive uropathy (e.g. posterior urethral valve) in boys. 2. Vesicoureteric reflux most common cause. 3. Neurogenic bladder in girls. Clinical feature: Fever, jaundice, diarrhea. Distal UTI in older children dysuria, hypogastric pain, frequency and urgency, convulsions. Pyelonephritis is suggested by fever with chills and rigor, flank pain. Diagnosis: Uncentrifuged urine culture presence of > 10 WBC/ cu. mm are abnormal. Grams stain > 2 bacteria/field is significant. Significant bacteriuria see above. Treatment: In infants ampicillin + gentamicin/amikacin or 3rd generation cephalosporin. Older children cotrimoxazole/ampicillin. Post-treatment investigation: To detect obstruction or VUR i. USG. ii. MCU (for posterior urethral valve, ureterocele).

Infectious Diseases

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iii. Renal cortical 99mTc DMSA scan to detect acute pyelonephritis. Indication for detailed radiological studies: i. Age < 3 years with first UTI. ii. Symptoms of pyelonephritis. iii. Recurrent UTI. iv. Abnormal voiding/persistently distended bladder. v. Family h/o UTI or hypertension. INFECTIONS FROM BITES Human peptostreptococcus, Streptococcus viridans (most common), Staphylococcus aureus. Dog Eikenella corrodens, DF-2. Cat Pasteurella multicoda. Rat Streptobacillus moniliformis, spirillum minor. Snake Pseudomonas. INFECTIONS IN TRANSPLANT RECIPIENTS After Bone Marrow Transplantation
Viruses CMV EBV HSV Hepatitis B and C HIV Fungi Candida Histoplasma Cryptococcus Parasites P. falciparum T. gondii Strongyloides T. cruzi

After Kidney Transplantation


Early, < 1 month Bacteria E. coli, klebsiella UTI and pneumonia (legionella) Middle, 1-6 months UTI/lungs CMV CNS L. monocytogenes Late, > 6 months Nocardia Aspergillus CMV retinitis

Note: CMV is the most common opportunistic infection in organ transplant patients. NOSOCOMIAL INFECTION Cause: Pseudomonas aeruginosa (gram ve bacilli) most common cause of nosocomial pneumonia. Staphylococcus aureus, Streptococcus pyogenes.

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A Systematic Review of Subjects for PGMEE

Klebsiella pneumoniae. Enterobacteriaceae are the most common cause of nosocomial infections. Route: Infected hands of doctors, nurses and medical staffs. Control: Washing of hands before and after examining a patient best approach. Note: Most common nosocomial infection is UTI. Staphylococcus epidermidis is the most common cause of surgical site infection. Bacteremia is most common with Staphylococcus epidermidis.

GENERAL CONSIDERATION
BACTERIAL MORPHOLOGY AND PHYSIOLOGY Bacteria are unicellular and prokaryotes. Shape Actinomycetes branching filamentous bacteria. Mycoplasma cell wall deficient and hence do not posses a stable morphology. Grouping Cocci may be grouped as Chain streptococci. Grape-like clusters staphylococcus. Eight sarcina. Cell Wall Composition: The cell wall is composed of mucopeptide scaffolding formed by N acetyl glucosamine and N acetyl muramic acid molecules in alternating chains which are linked by peptide chains. Lipopolysaccharides (LPS): LPS is present on the cell wall of gram ve bacteria. Role endotoxic activity, O antigen specificity.

Infectious Diseases

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Porins: Transmembrane pores that serve as diffusion channels. Comparison:


Gram +ve Aromatic and sulphur containing amino acids Teichoic acid Absent Present Gram ve Present Absent

Cytoplasm Bacteria do not show protoplasmic streaming. They do not possess endoplasmic reticulum or mitochondria. Ribosomes This is the most active enzymatic site in bacteria. Mesosomes Organ of respiration. More prominent in gram +ve bacteria. Nucleus Bacterial nuclei have no nuclear membrane or nucleolus. Genome single molecule of double-stranded DNA arranged in a circle. Capsule It is polysaccharide (e.g. in pneumococcus) or polypeptide (e.g. in anthrax bacilli) in nature. Capsulated bacteria are Pneumococcus, B. anthracis, Klebsiella, H. influenzae. Diagnosis: By i. Capsule swelling or Quellung phenomenon. ii. Negative staining. Flagella They are the organs of locomotion. Arrangement: All around the cell peritrichous (typhoid bacilli).

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A Systematic Review of Subjects for PGMEE

Single polar monotrichous (cholera vibrios). Polar in tufts lopotrichous (spirila). At both ends amphitrichous. Diagnosis: By dark ground illumination. Fimbriae Function organs of adhesion Spores Spores are highly resistant resting stages of bacteria. Seen in Bacillus and clostridium. Sporulation occurs at stationary phase of development. Spores are destroyed by Autoclaving at 120oC for 15 minutes. Staining Acid fast. Others Forms Cell wall deficient states: In hypertonic solution or by penicillin. Protoplast Gram +ve bacteria. Spheroplast - Gram ve bacteria. Involution forms: Swollen and aberrant cells in aging culture. Seen in Plague bacilli and gonococcus. L- Forms: They resemble mycoplasma. Toxins
Exotoxins 1. Produced by Gram +ve bacteria. Also some gram ve bacteria viz. S. dysentery I, V. choleri and ETEC 2. Proteins 3. Released by bacteria 4. Heat labile 5. Highly potent 6. Highly antigenic 7. Can be toxoided 8. Specific pharmacological effect for each exotoxin Endotoxins Gram ve bacteria

Polysaccharideproteinlipid complex Part of bacterial cell wall Heat stable Poor potency Poor antigens Can not be toxoided Action non-specific, all endotoxins have same effect

Infectious Diseases

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Note: L. monocytogenes is the only Gram +ve organism producing endotoxin. BACTERIAL GENETICS Transmission of Genetic Materials Transformation It is the transfer of genetic information through the agency of free DNA. Transformation has been studied in Pneumococcus bacillus, H. influenzae (mnemonic BHP). Transduction Transfer of a portion of DNA from one bacterium to other by a bacteriophage. The phage only acts as a vector. It has been studied in lambda phage of E. coli Materials transferred DNA, episomes, plasmids. Importance The plasmids determining penicillin resistance are transferred by transduction. This has been proposed as a method of genetic engineering. Lysogenic Conversion The phage DNA is incorporated in bacterial chromosomes, multiplies synchronously with it and transferred to the daughter cells. Seen in Corynebacterium diphtheriae. Conjugation Mediated by plasmids. The F factor: Or the fertility factor. It contains the genetic information necessary for the synthesis of the sex pilus and for self-transfer. But it is devoid of other identifiable genetic markers such as drug resistance. F+ cells can transfer chromosomal genes to recipient cells with high frequency and are known as Hfr cells. Col factor: Antibiotic substances which are lethal to other bacteria. Produced by E.coli, pseudomonas (pyocin), diphtheria (diphthericin).

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A Systematic Review of Subjects for PGMEE

Resistance transfer factor (RTF): This is responsible for the spread of multiple drug resistance among bacteria. It is plasmid mediated and transferred by conjugation. It has been demonstrated in E.coli and Shigella. Notes: Plasmids are extrachromosomal circular DNA present in the cytoplasm, capable of autonomous replication. Transporons are cytoplasmic genetic materials which can move from site to site on the same or different DNA molecules (transposition). Such elements are called jumping genes. They can not replicate by themselves but contain resistance and other genes.

STERILIZATION AND DISINFECTION


Definition Sterilization: is the process of destroying all microorganisms either in the vegetative or spore state. Disinfection: is the killing of all pathogenic organisms outside the body by direct exposure to chemicals or physical agents. Antisepsis: is prevention of infection by inhibition of growth of microorganisms. Antiseptics are agents applied on skin to eradicate pathogenic microbes. METHODS Dry Heat Incineration: Best method of disposal of hospital waste and waste from slaughter house. Hot air oven: Holding period 160oC for 1 hour. Articles sterilized are glassware, syringes, swabs, dressings, sharp instruments, liquid paraffin, fat and grease and dusting powder.

Infectious Diseases

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Moist Heat Temperature below 100oC Pasteurization: Holder method 63oC for 30 minutes. Flash method (HTST or high temperature short time method) 72oC for 15-20 seconds. Both processes are followed by rapid cooling to 13oC. Result: Pasteurization kills nearly 90 percent of the bacteria in milk including the heat-resistant tubercle bacillus and Q fever organism (Q fever may survive the Holder method). It does not kill thermoduric bacteria (like Staphylococcus aureus, Streptococcus fecalis) and spores. Tests for pasteurized milk: i. Phosphatase test ii. Standard plate count iii. Coliform count Methylene blue reduction test is an indirect method of detecting microorganisms in milk before pasteurization. Temperature at 100oC Boiling: Boiling does not kill spores or viruses. It is not used to sterilize sharp instruments. Tyndallisation or intermittent sterilization: Method steam at atmospheric pressure (100oC). For media containing sugars or gelatin, an exposure of 100oC for 20 minutes on 3 successive days is used. Principle: First exposure kills all vegetative bacteria. Spores, being in a favorable medium, germinate and are killed on the subsequent exposure. Temperature above 100oC Autoclaving: Method steam at 121oC at 15 lbs/sq. inch. pressure for 15 minutes with air removed.

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A Systematic Review of Subjects for PGMEE

Articles dressings, linen, gloves, certain instruments, culture media, suture materials except catgut. Not suitable for plastics and sharp instruments. Sterilization control B. stearothermophilus (thermophilic bacteria). Note: Vaccines are sterilized by heat inactivation. Filtration Types: 1. Candle filters a. Unglazed ceramic filters, e.g. Chamberland filter. b. Diatomaceous earth filters Berkfeld and Mandler filters. 2. Asbestos filters e.g. Seitz filter. 3. Sintered glass filter. 4. Membrane filters made of cellulose esters (most commonly used). Uses: For water purification most common use. For separation of sera, toxins, etc. Radiation a. Non-ionizing radiation i. Infrared radiation produce considerable heat, hence considered as a form of hot air sterilization. Use for rapid mass sterilization of syringes. ii. UV radiation for disinfection of closed chambers such as operation theatres. b. Ionizing radiation X-rays, gamma rays and cosmic rays. Mechanism of action: Lethal to DNA. They do not produce heat, hence referred as cold sterilization. Use: For commercial sterilization (sharp instruments). Chemicals Alcohols: They are not effective against spores (hence, not a complete sterilizing agent). To be effective, they must be used at a concentration of 60-70 percent in water. Isopropyl alcohol is used as disinfectant for catgut. Ethyl alcohol surface disinfectation of thermometer, skin disinfectant.

Infectious Diseases

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Aldehyde: Formaldehyde Used as 2-3 percent solution (20-30 ml of 40% formalin in 1 liter of water). Uses formaldehyde gas is most commonly used for disinfection of rooms. 40 percent formalin is used to sterilize all microbes and spores. Glutaraldehyde Cidex is 2 percent glutaraldehyde. Use to sterilize cystoscopes and bronchoscopes. Spores are disinfected by glutaraldehyde. Holding time 20 minutes. Halogens Bleaching powder: Contains 33 percent of available chlorine. It is an unstable compound. 5 percent solution is used to disinfect feces and urine. Hypochlorites: Most commonly used form of chlorine. Chlorination does not affect hepatitis A, cysts of B.coli and Giardia. Use water purification, wound dressing and disinfection of instruments soiled with blood. Iodine: 1-2 percent alcoholic solution (tincture iodine) is most effective skin disinfectant. Disadvantage allergic reaction in some patients. Phenols Lysol: Most powerful chemical disinfectant. It is not effective against spores. Ethylene Oxide Gas Alkylating agent. Effective against all kinds of microorganisms including viruses and spores. Use commercial sterilization of heat-sensitive medical devices (such as prosthetic valves). Disadvantage explosive, so can not be used as fumigant.

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A Systematic Review of Subjects for PGMEE

Testing of Disinfection Rideal Walker or phenolic co-efficient: It is used to determine the quality or efficacy of a disinfectant. Note: Complete sterilizing agents i.e. those kill spores, too are i. Glutaraldehyde. ii. Hydrogen peroxide. iii. Sodium hypochlorite.

STAPHYLOCOCCUS
STAPHYLOCOCCUS AUREUS Biochemical Reaction
Staphylococcus aureus Phosphatase Coagulase Mannitol fermentation Positive Positive Positive Staphylococcus epidermidis Negative Negative Negative

Toxins 1. Exotoxins , , and . lysin exhibits hot-cold phenomenon or Arhenius phenomenon. 2. Enterotoxin responsible for food poisoning. Enterotoxin F is responsible for toxic shock syndrome (also enterotoxins b and c). 3. Exfoliative toxin (ET) produces staphylococcal scalded skin syndrome (SSSS). 4. Toxic shock syndrome toxin (TSST) TSST1 (formerly called the enterotoxin F or pyrogenic exotoxin C) is responsible for most cases of TSS. 5. Leucocidin. Pathogenicity Carriers: Harbor the organism in mucous membrane of anterior nasopharynx, throat and skin.

Infectious Diseases

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Toxic shock syndrome: Predisposing factors: i. Menstruation. ii. Barrier contraception highly absorbent bands or vaginal tampons. iii. Puerperium. iv. Septic abortion. Clinical feature: Fever (temperature > 102oF). Rash diffuse macular erythema (sun burn rash). Hypotension (SBP 90 mmHg). Multiorgan dysfunction. Desquamation within 2 weeks of onset, typically on palms and soles. Staphylococcal scalded skin syndrome: Termed as Ritters disease in newborns and toxic epidermal necrolysis (TEN) in adults. Others pemphigus neonatorum, bullous impetigo. Food poisoning : See above. Skin and soft tissue infections: Boils, folliculitis, furuncles and carbuncle. Boil infection of hair follicles. Carbuncle infective gangrene of subcutaneous tissue, more common in diabetics. Penicillin and excision is the treatment of choice. Respiratory tract infection: Sinusitis, pharyngitis (sore throat), pneumonia most commonly following tracheal intubation and viral infection. CNS: Brain abscess, subdural empyema, spinal epidural abscess, septic intracranial thrombophlebitis. CVS: Endocarditis of both native and prosthetic valves. Musculoskeletal: Acute osteomyelitis most common cause of. Chronic osteomyelitis. Septic arthritis most common cause of. Psoas abscess.

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A Systematic Review of Subjects for PGMEE

Treatment PenicillinG remains the drug of choice for susceptible organisms. -lactamase resistant penicillin methicillin, nafcillin, oxacillin, cloxacillin. Methicillin resistant Staphylococcus aureus (MRSA) vancomycin. Vancomycin resistant Staphylococcus aureus (VRSA) teicoplanin and lenizoid. Prevention Staphylococcus aureus is the second most common cause of nosocomial infection. It can be prevented by meticulous hand washing before and after contact with patients. COAGULASE NEGATIVE STAPHYLOCOCCUS Staphylococcus epidermidis It has a predilection for growth on implanted foreign bodies such as artificial heart valves, shunts, intravascular catheters and prosthetic appliances. It attains antibiotic resistance by slime production due to biofilm formation, e.g. on catheter. It causes stitch abscess (surgical site infection), prosthetic valve endocarditis, nosocomial bacteremia. Staphylococcus saprophyticus Important cause of UTI in sexually active young women.

STREPTOCOCCUS
Classification
Streptococcus Aerobes and facultative anaerobes Hemolysis Obligate anaerobes Peptostreptococcus

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Alpha hemolytics Beta hemolytics Gamma no - Greenish - sharply defined hemolysis discoloration clear colorless zone Enterococcus with partial of complete hemolysis hemolysis Streptococcus | Group specific carbohydrate C viridans antigen (precipitation) 19 Lancefield groups (A to U except I and J) Group A hemolytic Streptococcus pyogenes M protein (agglutination) Griffith typing (1, 2, 3.... up to 80)

STREPTOCOCCUS PYOGENES Group A -hemolytic streptococcus. Virulence 1. Capsule strains with well marked capsule produce mucoid colonies, corresponding in virulence to the matt type. This is due to production of hyaluronic acid. 2. M protein acts as a virulence factor by inhibiting phagocytosis. Antibody to M protein is protective. Note: Capsular hyaluronic acid cross reacts with human synovial fluid. Toxins 1. Streptolysin (hemolysin) Streptolysin O oxygen labile. ASO titer is increased in serum in recent infection with streptococcus. Streptolysin S oxygen stable, produces -hemolysis on blood agar. 2. Erythrogenic/pyrogenic toxin Produces Scarlet fever. Pyrogenic exotoxin A causes toxic shock like syndrome. Pathogenesis 1. Pharyngitis (sore throat): Most common streptococcal lesion. Diagnosis throat culture. 2. Scarlet fever: Rash papules (sandpaper texture of skin), strawberry tongue, Pastias lines accentuation of the rash in skin folds. Diagnosis Schultz Charlton reaction, Dick test.

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A Systematic Review of Subjects for PGMEE

3. Skin and subcutaneous tissue: Impetigo superficial infection of the skin. Cause Streptococcus pyogenes, Staphylococcus aureus. In rugby players it can spread to teammates called scrum pox. Cellulitis (erysipelas) May also be caused by Staphylococcus aureus. Predisposing lesion chronic lymphedema. Ecthyma 4. Deep tissue: Necrotizing fasciitis (Fourniers gangrene most common in genitalia), myositis. 5. Streptococcal toxic shock-like syndrome: Fever, hypotension, renal impairment and respiratory distress syndrome. Associated with necrotizing fascitis, myositis, and cellulitis. 6. Non-suppurative complication: Acute rheumatic fever produced by any serotype of streptococcus pyogenes, usually follow pharyngitis. Acute glomerulonephritis produced by nephritogenic types, most commonly type 12, usually follow skin infection. Laboratory Diagnosis Transport medium Pikes medium. ASO titer value above 200 is significant. High values are found in acute rheumatic fever but not in glomerulonephritis. In glomerulonephritis, titers are often low. The streptolysin test passive slide agglutination test. It is a sensitive and specific screening test. STREPTOCOCCUS AGALACTIAE Group B -hemolytic streptococcus. Pathogenesis: Neonatal meningitis and septicemia. Endometritis and fever in parturient women. Diagnosis: CAMP test.

Infectious Diseases

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GROUP C -HEMOLYTIC STREPTOCOCCI Streptococcus equisimilis Commercial source for streptokinase. GROUP D (ENTEROCOCCUS) E.g. Streptococcus fecalis, Streptococcus faecium. Characteristics: i. Ability to grow in presence of 40 percent bile, 6.5 percent NaCl. ii. Usually nonhemolytic, but may produce alpha or beta hemolysis. iii. Strains resistant to penicillin and other antibiotics occur frequently. iv. Ability to grow at pH 9.6, temperature 45oC, and in 0.1 percent methylene blue milk. Pathogenesis: UTI, may also cause endocarditis, intraabdominal abscess, peritonitis. Treatment: Combination of penicillin or ampicillin with an aminoglycoside. Non-enterococcus Group D Grow in the presence of bile but inhibited by 6.5 percent NaCl. Non-hemolytic. Causes endocarditis and are common in colon Ca. THE VIRIDANS STREPTOCOCCUS Normal resident in the mouth and upper respiratory tract. Produces alpha hemolysis. Pathogenesis Most common cause of bacterial endocarditis. Endocarditis: Streptococcus sanguis is the most common organism. Produce subacute endocarditis in native damaged valves or late onset endocarditis in prosthetic valves. Dental extraction is the most common source. Dental caries: Is produced by Streptococcus mutans.

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A Systematic Review of Subjects for PGMEE

PNEUMOCOCCUS
Gram-positive diplococci. Capsulated. Culture On blood agar, produce alpha hemolysis. Colonies have raised edges and central umbonation, so that concentric rings are seen when viewed from above Draughtsman or carom coin appearance. Smear flame shaped or lanceolate appearance. Biochemical Reaction
Pneumococcus Streptococcus viridans Bile solubility Inulin fermentation Optochin sensitivity + + +

But pneumococcus is catalase and oxidase negative. Antigenic Properties 1. Capsular polysaccharide or specific soluble substance It inhibits phagocytosis. It determines virulence. It exhibits Quellung reaction or Neufeld-capsular swelling or capsular dilineation. It is sero-specific and antibody to it is protective. Note: Type 3 pneumococcus is most virulent. 2. C reactive protein An abnormal protein that precipitates with the somatic C antigen of pneumococcus. It appears in the acute phase sera of cases of pneumonia. It is not an antibody. Produced by hepatocytes. Its production is stimulated by bacterial infections, inflammation, malignancies. Also increased in liver diseases, TB, rheumatoid arthritis, myocardial infarction and burn. Test by capillary precipitation of the patients sera or passive agglutination test. Note : Other acute phase proteins are haptoglobulin, ceruloplasmin, transferrin, complements and autolysin.

Infectious Diseases

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3. Pneumolysin and autolysin virulence depends on pneumolysin, too. Pathogenesis 1. Acute otitis media and acute sinusitis: Most common cause of. 2. Meningitis: Most common cause in adults. Route by direct extension from mid-ear or sinuses or by bacteremia. CSF shows pleocytosis with predominant PMNs, increased protein and decreased glucose. 3. Pneumonia: It is most common in extremes of age. Characterized by: Symptoms fever (temperature > 102-103oF), cough with production of rusty sputum, pleuritic chest pain. Signs gray and anxious appearance, tachycardia, tachypnea, dullness and increased vocal fremitus on percussion, bronchial or tubular breath sounds, crackles. X-ray chest: Areas of infiltration involving less than a full segment, lobar consolidation. Complication: Empyema most common complication. Persistence of pain especially after first day or two of treatment indicates empyema. Treatment is water-seal drainage. Treatment Pneumonia penicillin, Meningitis cefotaxime + vancomycin. Prevention Pneumococcal vaccines: Indications All persons above 65 years, chronic pulmonary disease, advanced cardiovascular disease, diabetes mellitus, alcoholism, chronic renal failure, sickle cell anemia. Second category splenectomy, multiple myeloma, lymphoma, HIV infection, organ transplantation.

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NEISSERIA
Gram negative, diplococci. MENINGOCOCCUS Morphology Intracellular (intracytoplasmic), capsulated. Biochemical Reaction Catalase and oxidase positive. Ferments glucose and maltose (c.f. gonococci ferment glucose only). Epidemiology Source of infection nasopharynx of cases and carriers. Carriers 5-30 percent of normal population may harbor the organism in nasopharynx during interepidemic period. Incubation period 3-4 days (may vary from 2-10 days). Case fatality of typical untreated cases is about 80 percent. It has now declined to < 10 percent. Season dry and cold months. Pathogenesis Meningococcemia: Clinical feature fever (temperature 39-41oC). Rash most characteristic. It may be maculopapular, petechial or ecchymotic involves skin and mucosa early in the disease. Pathogenic agent in meningococcal disease is an endotoxin. Neisseria bacteremia is favored by complements (C5C9) deficiency. Fulminant meningococcemia or Waterhouse-Friderichsen syndrome: Meningococcal septicemia, profound shock, DIC and multiorgan failure (adrenal hemorrhage). Meningitis: Common in children and young adults.

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Treatment Cases 95 percent lives can be saved if antibiotics are started within 2 days of onset of infection. Penicillin G is the drug of choice. Carrier rifampicin is the drug of choice. Presence of shock is an indication of corticosteroid therapy. Prevention Meningococcal vaccine: Containing the capsular polysaccharide of groups A, C, Y and W135. They induce good immunity in older children and adults, but are of little value in infants. Contraindication pregnancy. Not recommended in infants and children less than 2 years of age. Effective for 3 years. Booster every 3 years. GONOCOCCUS Morphology It is found predominantly within polymorphs (neutrophils). Pili promote virulence. Non-capsulated (c.f. meningococci). Culture Selective medium Thayer-Martin medium. Biochemical Reaction Gonococci ferment only glucose not maltose. Pathogenesis 1. Gonorrhea: (means flow of seed) Incubation period 2-8 days. Clinical feature acute urethritis with mucopurulent discharge. Complication Watercan perineum, urethral stricture. 2. Disseminated infection: Blood invasion may occur from the primary site and may lead to metastatic lesions such as arthritis (most common), ulcerative endocarditis and rarely meningitis.

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3. Ophthalmia neonatarum: Only nonveneral infection. Results form direct infection during passage through birth canal. Prophylaxis: CREDEs method installation of 2 percent silver nitrate solution into the eyes of all newborn babies. Laboratory Diagnosis Materials: Urethral discharge, cervical swabs, Serological tests: CFT, passive agglutination with pilus protein. Treatment Single dose of ceftriaxone/cefixime/ciprofloxacin/ ofloxacin + doxycycline. Alternatively penicillin G. For pregnant and multi-drug resistant cases Spectinomycin (not effective in gonococcal pharyngitis).

CORYNEBACTERIUM
CORYNEBACTERIUM DIPHTHERIAE Gram positive, non-sporing, non-capsulated and nonmobile. Morphology Volutin or Babes Ernst granules: Composed of polymetaphosphate. Stained with Loefflers methylene blue, they take up a bluish purple color, hence called metachromatic granules. Special stain Alberts Stain. Culture Media Loefflers serum slope and Tellurite blood agar. Advantage: Diphtheria bacilli grow on Loefflers slope media very rapidly and colonies can be seen in 6-8 hrs. So it is the culture medium of choice. Colony: Gravis daisy head colony. Intermedius frogs egg colony.

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Mitis Poached egg colony. On smear diphtheria bacilli are arranged in clusters (Chinese letter or cuneiform arrangement) or parallel rays (palisade). Toxin Type: Exotoxin. Production: Toxin production is dependant on a phage called tox+ phage. Nontoxigenic strains may be rendered toxigenic by infecting them with tox+ phage ( phage). This is called lysogenic or phage conversion. Toxin production is influenced by concentration of iron in medium. While low concentration favors toxin production, high iron concentration inhibits it. Mechanism of action: It catalyzes the transfer of adenosine diphosphate ribose moiety from NAD to a modified his residue on elongation factor 2 inactivation of EF2 inhibition of protein synthesis. Source: The strain most commonly used for toxin production is the Park Williams 8 strain. Action: DT acts both locally and systematically. Local produce dermonecrosis and formation of pseudomembrane. Systemic produce myocarditis neuritis and focal necrosis in various organs. Epidemiology Reservoir of infection human beings. Carriers are the main sources of infection. Nasal carriers are more dangerous than throat carriers. Immunization does not prevent carrier state. Incubation period 2 to 6 days. Period of infectivity 14 to 28 days from the onset of the disease. Host: Age: particularly affects children aged 1 to 5 years. Immunity: A herd immunity of over 70 percent is considered necessary to prevent epidemics.

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Clinical Feature Respiratory tract: Faucial diphtheria is the most common type. Sites: Tonsillopharyngeal most common site. Laryngeal causes maximum mortality. Nasal more important carriers. Tracheobronchial. Characterized by: Fever, dysphagia, cough, hoarseness of voice. Pseudomembrane formation: It extends beyond the margin of the tonsils onto the tonsillar pillars, palate and uvula. Gray white color. Dislodgement of membrane causes bleeding D/D Streptococcus pyogenes pharyngitis, infectious mononucleosis, viral pharyngitides, Fusobacterial infection, Candidiasis. Bull neck: Produced by cervical lymphadenopathy. Marked edema of the submandibular and anterior portion of the neck is seen. Cutaneous diphtheria: Complications 1. 2. 3. 4. Myocarditis most common cause of death. Polyneuritis palatal and pharyngeal paralysis. Pure motor neuropathy descending paralysis. Ophthalmoplegia.

Diagnosis Culture of throat swabs: The tellurite medium is particularly important in isolation of bacilli from convalescents, contacts and carriers. Colonies grow faster on Loefflers serum slope. Eleks gel precipitation test: in vitro virulence test. Schick test: Susceptibility test Aim: I. Detect the presence of antitoxin and hence the immunity status (resistance).

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II. The state of hypersensitivity to diphtheria toxin. Result: Readings are made 1-2 days and 5-7 days later. Reading erythematous reaction. I. No reaction on either arm this is negative reaction and indicates immunity. II. Positive reaction on test arm positive reaction indicates susceptibility. III. Positive reaction on both arms pseudoreaction, indicates immunity as well as hypersensitivity to DT. Note: Schick test is a test where negative reaction indicates immunity. Schick test has been replaced by hemagglutination test. Treatment Case: Diphtheria antitoxin (10,000 80,000 U) IM or IV + penicillin / erythromycin. Carriers: Erythromycin is the drug of choice. Contacts: Nonimmunized close contacts should receive prophylactic penicillin or erythromycin + 1000 2000 U of antitoxin + active immunization. They should be examined daily (by throat swabs) for evidence of bacteria for at least 1 week after exposure. DPT Vaccine Composition: Diphtheria toxoid: 25 Lf per 0.5 ml. Tetanus toxoid: 5 Lf per 0.5 ml. B. pertussis: 20,000 million per 0.5 ml Aluminium phosphate: used as adjuvant. Rationale: Pertussis component enhances the potency of DT. Storage: Between 4-8oC. should never be frozen. When issued to a sub-center, the vaccine should be used within a week. Age: It can be safely and effectively administered as early as 6 weeks after birth. Administration: Deep IM in lateral aspect of thigh.

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Complications: Excessive crying, neurological complication including convulsions. Contraindications: Seriously ill or hospitalized child persistent screaming, progressive convulsions only DT is used in such cases. C. minutissimum Produces erythrasma. C. pseudotuberculosis Preisz Nocard bacillus.

BACILLUS
They are Sporogenous, Gram positive, aerobic bacilli. Motility: They are generally motile with peritrichous flagella except bacillus anthracis. B. ANTHRACIS Morphology Arrangement: In long chains giving a characteristic bamboo stick appearance. Capsule: Made of polymer of d(-) glutamic acid. It can be demonstrated by MFadyeans reaction. Culture On agar plates: Medusa head colonies. Frosted glass appearance. On solid medium: String of pearl reaction (differentiates with other bacilli). On gelatin stab culture: Inverted far free appearance. Pathogenesis Virulence Factors 1. Capsular polypeptide: promotes virulence by inhibiting phagocytosis. Loss of plasmid that controls capsule production leads to loss of virulence.

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2. Toxin: It has 3 components protective antigen (PA), Edema factor (EF) and Lethal factor (LF). Anthrax It is a zoonosis. Cutaneous anthrax (hide porters disease): Most common form. Characterized by a localized skin lesion with a central eschar surrounded by marked edema. Satellite lesions are present around it. It is called malignant pustule. Cutaneous anthrax generally resolves spontaneously. Mode of transmission introduction through skin cuts (direct contact), insect bite. Pulmonary anthrax (wool sorters disease): Mode: Inhalation of dust from infected wool. Feature: Hemorrhagic mediastinitis. Complication: Meningitis Gastrointestinal anthrax: Mode: Ingestion of contaminated meat. Diagnosis Ascolis thermoprecipitin test: demonstration of the anthrax antigen in tissue extracts. Treatment Drug of choice Penicillin G. Others Streptomycin. B. CEREUS Produces preformed enterotoxin. Causes food poisoning (see above in food poisoning). Diagnosis MYPA medium useful in isolating B. cereus (Mannitolegg yolkpolymyxin agar).

CLOSTRIDIUM
Gram positive, obligate anaerobic, spore forming bacilli. Motility They are motile with peritrichate flagella except Cl. perfringens and Cl. tetani type VI.

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A Systematic Review of Subjects for PGMEE

Spores 1. Central Spindle shaped bacilli Cl. bifermentans 2. Subterminal Club shaped bacilli Cl. perfringens. 3. Oval, terminal tennis racket shaped bacilli Cl. tertium. 4. Round, terminal drumstick shaped bacilli Cl. tetani. Pathogenesis Cl. perfringens: Gas gangrene caused by exotoxin production, local tissue invasion and even septicemia. Cl. tetani: Tetanus is caused by exotoxin. Cl. botulium: Noninvasive and non-infections, Botulism is caused by ingestion of preformed toxin in food. CL. PERFRINGENS They are capsulated and nonmotile. Culture Medium: Robertsons cooked meat broth, Produce Strong fermentation. Colonies: Target hemolysis resulting from a narrow zone of complete hemolysis due to theta toxin and a much wider zone of incomplete hemolysis due to alpha toxin. Toxins 4 major toxins are alpha, beta, epsilon and iota.

toxin: It is phospholipase (lecithinase C). Responsible for the profound toxemia of gas gangrene. The hemolytic anemia and hemoglobinuria seen in advanced gas gangrene is due to toxin.
Nagler reaction: Detection of lecithinase effect. Method: 5 percent Fildes peptic digest of sheep blood antitoxin on one half Colonies on the other half will be surrounded by a zone of opacity.

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Pathogenesis 1. Gas gangrene Predominant agent Cl. perfringens type A. Two factors are essential for severe disease are tissue necrosis and low redox potential. Clinical feature: Sudden onset of pain at the site of trauma with local swelling and edema accompanied by thin often hemorrhagic exudates. Skin is tense, white, marbled with blue and cool. Systemic Hypotension, tachycardia, body temperature normal, renal failure, body crepitus. Death is due to circulatory failure (shock). Liver foaming liver. Treatment: Surgery Most important prophylactic and therapeutic measure in gas gangrene. Antibiotics Effective in prophylaxis. Drug of choice metronidazole IV before surgery and repeated 8 hourly for 24 hours. Blood transfusion to correct hypotension. Passive immunization with antigas gangrene serum. It contains antitoxin to Cl. perfringens, Cl. novyi and Cl. septicum. 2. Food poisoning Cl. perfringens type A (See above) which produce heat labile enterotoxin. CL. SEPTICUM Cl. septicum produces fatal septicemia in patients with malignancy. Diagnosis: Citron bodies and boat or leaf shaped pleomorphic bacilli with irregular staining. CL. TETANI Morphology: Gram positive with terminal spores (drumstick appearance).

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Culture: The growth has marked tendency to swarm; swarming is prevented with 4 percent agar. Chemical reaction: Cl. tetani is week proteolytic but not saccharolytic. Toxin: Exotoxin. Tetanospasmin a neurotoxin is responsible for the clinical manifestation of tetanus.
Sites 1. Presynaptic nerve terminals Action Inhibition of release of inhibitory NTs glycine and GABA leads to sustained motor neuron discharge and rigidity. Sympathetic over activity leads to increased release of catecholamines

2. Preganglionic sympathetic nerve terminals in lateral gray matter of spinal cord 3. Muscle end plate Inhibit NT release at NM junction leading to weakness and paralysis 4. Brain

Note: Tetanospasmin resembles strychnine in its effect. But it acts presynaptically, whereas strychnine acts postsynaptically. Types: 1. Local tetanus only the nerves supplying the affected muscle is involved. 2. Ascending tetanus on IM injection of toxin. 3. Descending tetanus produced on IV injection of toxin. It resembles the naturally occurring tetanus. Epidemiology: Incubation period commonly 6-12 days. Tetanus occurring after 30 days is called delayed. Prognosis: 1. Short IP is associated with bad prognosis. 2. Short interval between the first symptom (trismus) and the onset of spasms (period of onset) is also associated with bad prognosis. Immunity: There is no herd immunity against tetanus. Tetanus Generalized tetanus (most common form of tetanus) is characterized by increased muscle tone and generalized spasm (spastic paralysis).

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First muscle to be involved is masseter and first symptom is trismus of lockjaw. The spasticity spreads downwards (descending paralysis). Contration of facial muscles may produce characteristic facies risus sardonicus. Contraction of muscles of back may cause the body to bend (opisthotonus). Autonomic dysfunction- hypertension, tachycardia, hyperpyrexia, profuse sweating (due to release of catecholamines). Post-exposure prophylaxis 1. Surgical management of the wound. 2. Antibiotic long acting penicillin G is drug of choice. 3. Passive immunization with ATS or human antitetanus Ig (TIG) preparation of choice. Dose 250 U of TIG. 4. Active immunization Most effective method of prophylaxis. Agent: Tetanus toxoid. Course: 3 doses of TT, first two at an interval of 4-6 weeks and third 6-12 months after the second. Schedule:
Wound Wound less than 6 hours old, clean, nonpenetrating wounds Status A B C D Treatment Nothing TT 1 dose TT 1 dose TT full course Status A B C D Other wounds Treatment Nothing TT 1 dose TT 1 dose + TIG TT full course + TIG

A B C D

complete course within 5 years. complete course > 5 years but < 10 years. complete course >10 years. No course or unknown status.

Treatment: 1. Antibiotic penicillin G or metronidazole. 2. Diazepam to control spasms. 3. Human TIG 10,000 IU slow IV infusion (Paniker), 3000-6000 IU IM in divided doses(Harrison).

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A Systematic Review of Subjects for PGMEE

Neonatal Tetanus Cause: Infection of umbilical stump after birth. Clinical feature: Onset within 2 weeks (5 15 days) after birth but never in the first 2 days. Symptom Excessive crying, poor feeding, apathy (common initial symptoms), muscle spasm. Prophylaxis: 1. Immunization of all pregnant women with 2 doses of TT between 16-36 weeks. 2. 3 cleans during delivery clean hands (clean blade), clean delivery surface (clean cord tie), clean cord care (no application on cord stump). Note: Criteria for neonatal tetanus elimination i. Rate < 0.1 / 1000 live births. ii. TT2 coverage > 90 percent. iii. Attended delivery > 75 percent. CL. BOTULINUM Toxin 8 types of exotoxins are produced by Cl. botulinum. Among them C 2 is cytotoxic and all others are neurotoxic. Only types A, B, E and F cause human disease. Botulinum toxin is the most toxic substance known. Uses of BT: Therapy for strabismus, blepharospasm, other dystonias. Pathogenesis Cl. botulinum is non-invasive and non-infectious. Its pahthogenicity is due to its toxin. Three types of botulism exists 1. Food-borne botulism from ingestion of preformed toxin in contaminated food. 2. Wound botulism from toxin produced in wounds contaminated with organism. 3. Infant botulism most common form. Due to ingestion of spores and production of toxin in the intestine of infants.

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Mechanism of action of BT: The toxin enters the vascular system and is transported to peripheral cholinergic nerve terminals (including NM junction, postganglionic parasympathetic nerve terminals and peripheral ganglia), which leads to decrease in release of ACh (parasympatholytic) and paralysis of muscle. Clinical Feature Food-borne botulism: Symmetric descending paralysis without sensory involvement. Cranial nerves are involved first producing diplopia, dysarthria and dysphagia. The paralysis extends caudally to involve extremities. GIT Nausea, vomiting, abdominal pain, severe constipation, dry mouth, occasionally sore throat. Eye ptosis, blurred vision, fixed or dilated pupil. Reflexes Depressed pupillary reflex, suppressed Gag reflex, deep tendon reflexes normal or depressed. Others No fever, urinary retention. Death is due to respiratory failure. Infant botulism: Source: honey. Clinical feature: Failure to thrive, floppy baby, constipation, fulminant severe paralysis with respiratory failure may cause sudden infant death. D/D Myasthenia gravis, Eaton-Lambert syndrome, GB. syndrome, poliomyelitis, tick paralysis, mushroom intoxication, diphtheria, hypomagnesemia. Laboratory Diagnosis Demonstration of the bacillus or its toxin in food or feces. The toxin in only occasionally demonstrable in the patients blood. Retrospective diagnosis by demonstration of antitoxin in patients blood. CL. DIFFICILE It causes antibiotic associated colitis or pseudomembranous colitis by producing an enterotoxin and a cytotoxin.

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A Systematic Review of Subjects for PGMEE

Causative antibiotics: Ampicillin, tetracycline, chloramphenicol, Clindamycin and lincomycin most common, Cephalosporins. Treatment: Metronidazole is the drug of choice. Vancomycin equally effective.

LISTERIA MONOCYTOGENES
Gram positive cocco-bacilli with a tendency to occur in chain. They show characteristic tumbling motility at 25oC (nonmotile at 37oC). Intracellular pathogen. Only gram positive bacillus to produce endotoxin. Pathogenesis Source of infection contaminated milk, Listeria infections occur in neonates, pregnant women and adults with deficient cell-mediated immunity. Clinical Feature They may show -hemolysis and are catalase positive. Neonatal listeriosis: Meningitis and meningoencephalitis - CSF shows pleocytosis, increased protein and normal glucose levels. Granulomatosis infantisepticum. Pregnancy associated listeriosis: Can occur in any stage but most common in third trimester. Cause chorioamnionitis, premature labour, abortion, IUGR, stillbirth. Laboratory Diagnosis Cold enrichment technique for serial culture. Anton test. Treatment Ampicillin is the most effective drug.

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MORAXELLA (BRANHAMELLA) CATARRHALIS


Gram negative cocci. Clinical Feature Acute exacerbation of chronic bronchitis. Purulent tracheobronchitis. Pneumonia characterized by cough and purulent sputum.

NON-SPORING ANAEROBES
ANAEROBIC COCCI Peptostreptococcus: Common cause of puerperal sepsis. ANAEROBIC BACILLI Gram negative. B. fragilis Strict anaerobes. Pathogenesis: Brain abscess, peritonitis. Feature: Pus produced by anaerobes is characteristically putrid. B. melaninogenicus Cultures or even dressings from wounds infected with the bacillus give a characteristic red fluorescence when exposed to UV light. Leptotrichia buccalis (Fusobacterium fusiforme) Vincents stomatitis or trench mouth: Necrotizing infection of gum. Clinical feature: Tender bleeding gums, foul breath, bad taste, gray exudates over gingival mucosa which can be removed on gentle pressure.

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A Systematic Review of Subjects for PGMEE

Cancrum oris or noma: Gangrenous infection of buccal mucosa, teeth and mandible or maxilla, resulting in widespread destruction of bone and soft tissue. It is seen in malnourished and debilitated children.

ENTEROBACTERIACEAE
Gram negative bacilli, Motile by peritrichate flagella or non motile (Shigella and Klebsiella). Ferment glucose, reduce nitrates to nitrites. Form catalase but not oxidase. Classification Derived from the use of lactose in MacConkeys medium. 1. Lactose fermentors: E. coli, Klebsiella. 2. Late lactose fermentors: Shigella sonnei. 3. Nonlactose fermentors: Salmonella, Shigella. E. COLI Gram negative, motile rod. Aerobe and facultative anaerobe. Culture On MacConkeys medium, colonies are bright pink due to lactose fermentation. Chemical Reaction Urease ve, IMViC ++ Antigenic Structure Serotyping of E. coli is based on three antigens the somatic O antigen, the capsular K antigen and the flagellar H antigen. Fimbriae: Promote virulence. They are present as surface antigens. E.g. K88 and K99 antigens causing diarrhea in animals, CFA and CS2 causing diarrhea in man and P-pilli for pyelonephritis.

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Toxins Produce three enterotoxins (exotoxins) 1. Heat labile toxin (LT) acts by binding to GM1 ganglioside receptors in enterocyte and activates adenyl cyclase to form cAMP , like cholera toxin. 2. Heat stable toxin (ST) acts by activation of cGMP . 3. Verotoxin (VT)/Shiga like toxin Similar to shigella dysenteriae type 1 toxin. VT is cytotoxic to Vero or HeLa cells. Clinical Feature Enteric infections: a. Enteropathogenic E. coli (EPEC): They cause diarrhea in infants and children; can cause sudden infant death. Pathogenesis The bacilli remain adherent to the mucosa of upper small intestine (non-invasive and does not produce enterotoxin). b. Enterotoxigenic E. coli (ETEC): Causes Travelers diarrhea (See above). Produces both LT and ST. c. Enteroinvasive E. coli (EIEC): Like shigella infection. Non-motile, do not ferment lactose. Pathogenesis: Invades the host cell and provokes significant inflammatory reactions. Feature: Fever, bloody diarrhea. Diagnosis: Sereny test, cell penetration in HeLa or HEP2 cells. d. Enterohemorrhagic E. coli (EHEC): Produce VT or shiga-like toxin. Clinical feature: EHEC, especially serotype O157:H7, causes HUS. Diagnosis: Demonstration of the bacilli or VT in stool directly or in culture. Failure to ferment sorbitol (strain O157). (Remember: P for paedi, T for traveler, H for HUS) UTI: E. coli is the most common cause of naturally acquired UTI. Strains: Those normally found in feces, O group 1, 2, 4 etc. Only one serotype is isolated from infected urine at a time.

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Strains carrying K antigens are more commonly responsible for pyelonephritis, while most isolates from cystitis lack K antigens. Diagnosis Detection of ETEC enterotoxins.
Test 1. 2. 3. 4. Rabbit ileal loop Infant mouse intragastric Tissue culture (Y1 mouse adrenal cells, Chinese hamster ovary cells) Precipitin (Eikens) test LT + + ST + + -

KLEBSIELLA Or Friedlanders bacillus. Non-motile. Chemical reaction: Urease + (Urease +ve bacteriae are Klebsiella, proteins and Staphylococcus). IM ViC ++ Klebsiella pneumoniae Pneumonia: Common in alcoholic men over 40 years of age with underlying conditions like diabetes mellitus, COPD. Features: Mimics pneumococcal pneumonia except it progresses to produce lung abscess or empyema (red current jelly sputum). CXR Bulging fissure sign. Treatment Cephalosporins. Nosocomial Infections: UTI, RTI, etc. PROTEUS Chemical Reaction Pr. mirabilis is indole ve, whereas all others are indole +ve. PPA test: Deamination of phenylalanine to phenylpyruvic acid (PPA).

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Culture Characteristic fishy or seminal smell. On moist agar media, Pr. Mirabilis and Pr. vulgaris swarm over the media. Swarming does not occur on MacConkeys medium. Pathogenesis 1. UTI Important cause of chronic UTI often associated with instrumentation. Proteus possesses the enzyme urease which splits urea into ammonium hydroxide and increases urinary pH (alkali urine) that favors the formation of struvite stones. 2. Nosocomial infection. Weil-Felix Reaction Proteus (X strain) shows agglutinations with sera from typhus fever patients - important in diagnosis of rickettsial infections. SHIGELLA Culture Selective media: Deoxycholate citrate agar (DCA) for both Shigella and Salmonella. Wilson and Blairs bismuth sulphite selective for Salmonella. Growth of Shigella is inhibited. KLD Best selective medium. Biochemical Reaction Lactose fermentation : negative except Shigella sonnei which is a late lactose fermentor. Glucose fermentation produce only acid but no gas. Mannitol fermentation produce only acid except Shigella dysenteriae which does not ferment it. Note: Mannitol fermentation has been used to divide shigella into subgroups. Classification 1. Shigella dysenteriae: especially type I is the most virulent type. Produce 3 types of toxins

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A Systematic Review of Subjects for PGMEE

i. Neurotoxin ii. Enterotoxin iii. Exotoxin or Verotoxin earliest example of a gram negative organism producing exotoxin. Mechanism of action of VT: The active (A 1) component of VT binds with host 60S ribosome and inhibits protein synthesis. (also DT and pseudomonas toxin). 2. Shigella flexneri: most common pathogen in India. 3. Shigella sonnei: most common pathogen in developed countries. Produces asylum dysentery. 4. Shigella boydii. Pathogenesis Shigella species characteristically invade the intestinal mucosa. Invasiveness can be demonstrated by rabbit ileal loop test. Sereny test, penetration of HeLa or Hep2 cells (c.f. EIEC). Shigella is infective even in very low doses. The invasiveness depends upon a plasmid mediated outer membrane protein called virulence marker antigen (VMA). Detection of VMA by ELISA serves as a virulence test for Shigella (also for EIEC). Bacillary dysentery: Source: Ingestion of contaminated food. Incubation period: 1-7 days (usually 48 hours). Clinical feature: Frequent passage of loose, scanty stool containing blood and mucus. Griping pain and tenesmus. Fever and vomiting may be present. Pathology: Invasion of distal colon with hemorrhagic ulcers. Extraintestinal manifestation: Most common with Shigella dysenteriae type I. i. Hemolytic uremic syndrome most common cause in India. ii. Reactive arthritis (Reiters syndrome). iii. Toxic neuritis. iv. Conjunctivitis. v. Parotitis. Laboratory Diagnosis Isolation of bacilli from stool culture.

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SALMONELLA Culture Media: Wilson and Blairs bismuth sulphite medium: Selective for salmonella. Produce jet black colonies with a metallic sheen due to production of H2S. (Except S. paratyphi A which does not produce H2S). Selenite F and tetrathionate both are commonly employed as enrichment media. Biochemical Reaction All ferment glucose to produce acid and gas except S. typhi which produces acid only (anaerogenic). Lactose not fermented. Antigenic Structure 1. H antigen: Flagellar antigen. H suspensions agglutinate rapidly and produce large, loose, fluffy clumps. Antibody to H antigen is formed rapidly in large amounts and persists longer. 2. O antigen: Cell wall antigen. O agglutination occurs slowly and produce compact, chalky granular clumps. 3. Vi antigen: It covers the O antigen and hence O agglutination does not occur in fresh isolates. Persistence of antibody to Vi antigen indicates carrier state. Vi antigen helps in epidemiological typing of S. typhi according to Vi bacteriophage. Typing Salmonella are classified into groups on the basis of presence of O antigen factors. Within each group, serotyping is done by phase 1 and phase 2 flagellar antigens. For serotyping, it is necessary to identify flagellar antigens of both phases.

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A Systematic Review of Subjects for PGMEE

Enteric Fever Pathogenesis: Ingestion of bacilli attach to epithelial cells of intestinal villi and penetrate lamina propria and submucosa phagocytosed by polymorphs and macrophages, in which they multiply enter the mesenteric lymph nodes and multiple enter blood stream via thoracic duct invades gallbladder and multiply sheded in intestine and invades Payers patches. Epidemiology: Reservoir of infection: Man is the only reservoir. Source of infection: Carriers > cases. It is endemic in India. Highest incidence of the disease occurs in 5-20 years age group. Carriers: Patients who continue to shed bacilli after clinical cure For 3 weeks to 3 months convalescent carrier. For 3 months to 1 year temporary carrier. For > 1 year chronic carrier. Chronic carriers are common in women over 50 years with gallstones. Fecal carriers are more frequent than urinary carriers, but urinary carriers are more dangerous. Case fatality rate (in untreated cases) 10 percent. Clinical feature: Gradual onset with headache, fever and anorexia. Fever prolonged persistent fever with stepBladder pattern, constipation or diarrhea, bradycardia, hepatosplenomegaly. Rose spots appear on skin during 2nd or 3rd week. Epistaxis. Complications: 1. Cholecystitis. 2. Typhoid ulcer may cause intestinal perforation and hemorrhage in 3rd or 4th week of illness. Laboratory diagnosis: 1. Blood culture: diagnostic. 90 percent +ve in first week, also +ve in subsequent weeks. Blood culture + bone marrow culture 100 percent +ve.

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2. Feces culture: + ve in both cases and carriers (75% in 3rd week) 3. Urine culture: +ve in 2nd and 3rd weeks. 4. Widal reaction: Tube agglutination test. Measurement of H antigens of S. typhi, S. paratyphi A and B and O antigens of only S. typhi . It is maximally +ve in 3rd week. Results: O titer 1/100 and H titer 1/200 are significant. Demonstration of rise of titer (4 folds or more) in serial tests are more useful. Amnestic reaction may occur in persons who have had prior infection or immunization. So Widal test is not diagnostic in endemic areas. 5. Latex agglutination and coagglutination tests for the Vi antigen much more specific and sensitive than classical Widal test. 6. Diagnosis of carriers: By stool or urine culture. 7. Blood count: Leukopenia with relative lymphocytosis. Leukocytosis indicates complication (e.g. perforation). Prevention: Isolation of cases: For a period till 3 bacteriologically negative stools and urine culture are obtained on 3 separate days. Vaccines: Acetone killed vaccines. Gives protection about 70-85 percent for 3-4 years. Types: i. Monovalent S. typhi vaccine: Vaccine of choice in India. ii. Divalent S. typhi and S. paratyphi A vaccine. iii. TAB vaccine. Oral vaccine Live attenuated vaccine. Treatment: Ciprofloxacin is the drug of choice. Note : S. typhimurium most common cause of food poisoning and gastroenteritis. S. cholerae suis may cause septicemic disease.

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OTHER SALMONELLA SPECIES Salmonella gastroenteritis S. typhimurium is the most common species. Source: Poultry and dairy products. Clinical feature: Incubation period 24 hours. Diarrhea, vomiting, abdominal pain and fever. Salmonella septicemia Most common cause is S. cholera suis.

HELICOBACTER PYLORI
Gram negative bacilli with lopotrichate flagella. Complete genomic sequence of H. pylori has been recognized (also E. coli). Epidemiology Prevalence: 80 percent in developing countries, 30 percent in developed countries, prevalence varies with age. Risk factors: i. Age Most infections are acquired in childhood, but no immunity develops. ii. Low socio-economic status. Reservoir of infection: Man. Route of infection: Fecal-oral or oral-oral. Clinical Feature Most are asymptomatic. Diseases associated with H. pylori infestation are 1. Gastritis It is antral predominant in developed countries and pangastritis in developing countries. 2. Peptic ulcer. 3. Adenocarcinoma of stomach other than those arising in the cardia. 4. Primary gastric non-Hodgkins lymphoma. 5. MALT lymphoma. 6. Large B-cell lymphoma.

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Diagnosis Invasive: 1. Endoscopy based biopsy urease test quick test. 2. Microbiological culture most specific. Typical spiral appearance on Gram stain. Special stains Giemsa stain, silver stain (WarthinStarry stain). Noninvasive: 3. Urea breath test most sensitive. 4. Serology (ELISA) epidemiological test. Note: Urease activity provides protective environment to the bacilli against gastric acidity. Treatment Standard triple-therapy: 1. Bismuth subsalicylate. 2. Tetracycline HCl. 3. Metronidazole. Duration 2 weeks. Triple-therapy with acid-reduction: 1. Omeprazole. 2. Clarithromycin. 3. Metronidazole or Amoxicillin. Duration 1 Week.

VIBRIO
Gram negative bacilli, actively motile with polar flagellum. Discovered by Koch. VIBRIO CHOLERAE Morphology Comma shaped bacilli, in stained films fish in stream appearance. Motility darting type, in culture suggests a swarm of gnats.

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Culture Strongly aerobic. Growth is better in alkaline medium. Media: a. Holding or Transport media: 1. Venkataraman-Ramakrishnan (VR) medium. 2. Cary-Blair medium. b. Enrichment media: Alkaline peptone water. c. Selective media: TCBS medium Best selective medium. BSA (alkaline bile salt agar) and GTTA medium. Note: Vibrio colonies can be identified by string test. Biochemical Reaction Indole is formed and nitrates are reduced to nitrites. Cholera red reaction due to formation of nitrosoindole compound. Enzymes liberated by vibrios Neuraminidase, catalase oxidase. Resistance Cholera vibrios are susceptible to heat, drying and acids. They are resistant to alkali. Classification Based on common flagellar antigen (H) Group A and B. Based on common somatic (O) antigen Group A has been divided into serogroup O1 and non-serogroup O1. V. choleriae O-1 exists in 2 biotypes Classic and ElTor. Each biotype is divided into serotypes Ogawa, Inaba, Hikojima. Note: Most infections are due to V. choleriae O1. Most of ElTor biotypes isolated today belong to serotype ogawa.
V. Cholerae O1 Features 1. 2. 3. 4. 5. 6. Hemolysis of sheep RBC V-P reaction Chick embryo agglutination Gr. IV phage susceptibility ElTor phage S susceptibility Polymyxin B sensitivity Classic Vibrio + + ElTor + + + +

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Note: ElTor vibrios are resistant to Gr. IV phage and polymyxin. All other tests are +ve with ElTor. Epidemiology History: Most of the epidemics before 1961 were due to classic vibrio O1. ElTor vibrios emerged as the major pathogen in 1961 during the 7th (current) pandemic. In 1992, a novel strain was found to cause epidemics in Madras. This belongs to non O1 serogroup and was termed O-139 strain. It is likely that this strain will cause the next pandemic. Natural habitat: Costal salt water and brackish estuaries. Reservoir of infection: No known animal reservoir. Mode of infection: By incidence. Most common source is contaminated water. Age group: In endemic areas, cholera is predominantly a pediatric disease. But it does not occur in children less than 2 years of age probably due to passive immunity acquired by breast milk. In a virgin population, it affects children and adults equally. Blood group: Maximum risk with group O. Minimum risk with group AB. Distribution: Currently, larger endemic foci are found in Maharashtra. Carriers: Who shed bacilli.
Incubatory carrier Convalescent carrier Contact or healthy carrier Chronic carrier During incubation period (1-5 days) During convalescence for 2-3 weeks Subclinical infection < 10 days For months to years

Longest carrier state over 10 years. Chronic carriers are more frequent with ElTor infection. Toxin Cholera toxin (CT): Similar to LT of ETEC. Mechanism of action: B subunit binds to Gm1 ganglioside receptors. A1 fragment causes activation of cellular adenyl cyclase leading to increased intracellular accumulation of cAMP and secretory diarrhea.

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A Systematic Review of Subjects for PGMEE

Clinical Feature Painless watery diarrhea with vomiting. No fever. Stool rice water appearance. It is isotonic with plasma but contains more K+ and HCO3. Metabolic changes: decreased HCO3 level in blood. Increased anion gap, metabolic acidosis. ElTor cholera: Mild asymptomatic infection. Greater endemic tendency, increased carrier rate. Less secondary attack rate. Laboratory Diagnosis Specimen- Stool is the best. Vomitus never used. Medium TCBS medium. Control 1. Verification of diagnosis it is the first step in the investigation of a cholera epidemic. 2. Notification Cholera is a notifiable disease within 24 hours to WHO. 3. Rehydration: a. Oral: By ORS.
Ingredient (in gram) NaCl NaHCO3 KCl Glucose Potable water Or trisodium citrate dehydrate in place of NaHCO3 3.5 2.5 1.5 20 1 lit. 2.9 Quantity (in mmol/L) Na + K+ ClCitrate Glucose Total 90 20 80 10 110 310

Note: Addition of glucose promotes absorption of Na+ in the intestine. Citrate based ORS has 2 advantages i. More stable increased shelf life. ii. Direct action of citrate to increased intestinal absorption of Na+ and water. b. Parenteral: For severe dehydration. Ringers lactate is the fluid of choice. Composition of RL: Na+ - 130 mmol/L K+ - 4 mmol/L

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Cl- 109 mmol/L Base 28 mmol/L Total 271 mmol/L. Adjuvant drug therapy: i. Doxycycline 300 mg once drug of choice in adults. ii. Cotrimoxazole drug of choice in children iii. Furazolidone drug of choice in pregnant women. 5. Disinfection: Most effective is cresol. Bleaching powder a 5 percent solution (50 gm/lit) is used to disinfect cholera stool. 6. Chemoprophylaxis: For household contacts. Tetracycline is the drug of choice. Dose 500 mg BD for 3 days (adults). But mass chemoprophylaxis is not recommended. 7. Vaccination: Parenteral vaccine: Killed vaccine. Contains Ogawa and Inaba sreotypes of V. cholerae O1. Give protection against both classic and ElTor vibrio but not against serotype O139. Dose 2 equal doses at 4-6 weeks apart. Boosters every 6 months. Protective value 50 percent for a period of 3-6 months. (Park). 50 percent over a 3-year evaluation period (Harrison). Not effective in epidemics. 4. V. PARAHEMOLYTICUS Clinical feature: Food poisoning. Source: Marine foods (sea fish). Culture: It grows only on media containing NaCl. Virulence: Produces no toxin, acts by direct invasion of the intestinal epithelium.

V. VULNIFICUS It also requires saline environment for growth. Clinical feature: Two distinct syndromes are produced 1. Primary sepsis in patients with liver disease. 2. Primary wound infection following contact of open wounds with sea water.

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AEROMONAS HYDROPHILA It causes Red leg disease.

PSEUDOMONAS
Gram negative motile bacilli. Obligate aerobe. PSEUDOMONAS AERUGINOSA Culture On nutrient agar, iridescent patches with a metallic sheen are seen in cultures (greenish color of colonies). Selective media: cetrimide agar. Pigments Pyocanin bluish green. Fluorescein greenish yellow. Pathogenesis Produces Blue pus. Most common cause of infections in burns. Outside hospital, most common disease is chronic suppurative otitis. Skin Ecthyma gangrenosum. Toxin Exotoxin A functions as NADase and inhibits protein synthesis (like diphtheria toxin). Treatment Antibiotics effective against pseudomonas a. Amino glycosides: Gentamicin, amikacin b. Third generation cephalosporin: Ceftazidine, Cefoperazone. c. Extended spectrum penicillin: Ticarcillin, piperacillin. d. Carbapenems: Imipenem, Meropenem. e. Monobatams: Aztreonam. f. Fluoroquinolones: Ciprofloxacin, norfloxacin.

Infectious Diseases

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HAEMOPHILUS INFLUENZAE
Gram negative with variable shape (pleomorphic coccobacilli). Capsulated. Uncapsulated strains can colonize in upper respiratory tract. Culture Growth requires growth factor X and V. X factor is hemin and V factor is NAD. H. influenzae grows poorly on blood agar (as V is located inside RBCs) but grows well while it is heated to chocolate agar. Satellitism: Growth of H. influenzae is better when cultured with Staphylococcus aureus which provides V factor on blood agar. Best medium: Fildes agar. Antigenic Properties Based on capsular polysaccharide antigen (PRP), Haemophilus is divided into types a to f. Most common type is type b. Antibody to PRP is protective. Clinical Feature H. influenzae type b (Hib): 1. Meningitis: Age 6 months to 3 years. Complication Subdural effusion. 2. Epiglotitis most common cause of. 3. Pneumonia in infants. Non-typable H. influenzae: 1. Community acquired pneumonia in adults. Second most common cause (after pneumococcus). 2. Childhood otitis media third most common cause (after pneumococcus and moraxella). H. ducreyi It causes chancroid or soft-sore (see above in veneral diseases).

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A Systematic Review of Subjects for PGMEE

Gram negative coccobacilli (c.f. gonococcus) but may be gram positive (bipolar stain). Bacilli are arranged in chains School of fish or rail road track appearance. Culture: Chocolate agar with isovitalex is a selective medium. Fresh clotted rabbit blood. Chorioamniotic membrane.

BORDETELLA PERTUSSIS
Gram negative coccobacilli. Obligate human parasite. Culture Most commonly used medium Bordet Gengou agar. Appearances Thumb print appearance, bisected pearls or mercury drops and aluminum paint appearances. Toxin 1. 2. 3. Agglutinogens. Pertussis toxin (PT). Filamentous hemagglutinin (FHA) PT and FHA promote secondary bacterial infection a phenomenon called piracy of adhesions.

Pathogenesis Colonization of respiratory tract leads to adhesion to cilia and local tissue destruction (does not invade blood stream). Epidemiology Source of infection: a case. The disease is never subclinical and a chronic carrier state never occurs. Infective period: Most infective during catarrhal stage. Infectivity lasts up to 3 years after onset of paroxymal stage. Secondary attack rate 90 percent. Age: Disease of infants and preschool children. Median age 20-30 months.

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Immunity: Maternal antibody does not protect the newborn. Incubation period: 7 to 14 days. Clinical Feature Three stages i. Catarrhal stage. ii. Paroxymal stage. iii. Convalescence. Each stage lasts for two weeks. Complications: 1. Due to pressure effect Subconjunctival hemorrhage, subcutaneous emphysema. 2. Respiratory due to secondary infection; bronchopneumonia and lung collapse, bronchiectasis. 3. Neurological convulsions, coma (encephalopathy), sensory ataxia. Diagnosis Culture from nasopharyngeal secretion (prenasal swab). Positive only in catarrhal and early paroxymal stages. Blood Lymphocytosis. Treatment Cases: Erythromycin is the drug of choice (prevents secondary infection). Protection of contacts: Chemoprophylaxis: Erythromycin (prevents spread of infection). Vaccine: Booster dose of DPT/ DT to his siblings before he is born Best. Vaccine: Killed whole cell preparation. Effectivity: 70-90 percent Contraindications: H/O epilepsy, convulsions or other neurological disease. Acute febrile episode. Acellular vaccine: inactivated pertussis toxin, provides protection against disease but not against infection.

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A Systematic Review of Subjects for PGMEE

BRUCELLA
Gram negative bacilli. Brucellosis is a bacterial zoonosis. B. MELITENSIS Most common organism. Primarily affects goats, sheep. Epidemiology Route: 1. Ingestion of raw milk and milk products most common route. 2. Direct contact. 3. Air-born infection. Pathology Brucellosis is primarily a disease of the RE system. Immunity Mainly cell mediated. Activated macrophages kill the bacteria. Clinical Feature Undulant or Malta fever: 1. Fever Swinging pyrexia wit chills and rigors. May present as PUO. 2. Sweating. 3. Headache, insomnia. 4. Joint and back pain. 5. Lymphadenopathy. 6. Mild hepatosplenomegaly. 7. Monoarticular septic arthritis. Diagnosis 1. Blood culture most definitive method. It is positive in only 30-50 percent cases. Castaneda method of blood culture is employed. 2. Serology tube agglutination test most important in acute cases.

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3. Rapid diagnosis in cattle Rose Bengal card test. 4. Test for food Milk ring test. 5. For chronic infection Complement fixation test, Coombs test, ELISA are useful. Treatment Combination of doxycycline + rifampicin Most effective regimen. Prevention Pasteurization of milk.

LEGIONELLA PNEUMOPHILA
Gram negative bacilli. Culture Selective medium: Buffered charcoal, yeast extract (BCYE) agar. Special stain: DFA stain. Epidemiology Source: Human infection is typically acquired by aerosols produced by air conditioners and showerheads. It is common in elderly male. No man-to-man transmission. No animal reservoir. Risk Factors 1. 2. 3. 4. 5. Cigarette smoking most important. Alcoholism. Chronic lung disease. Advanced age. Immunodeficiency.

Clinical Feature 1. Legionnaires pneumonia: A cause of atypical pneumonia. Characterized by high fever, nonproductive cough and dyspnea with relative bradycardia. Diarrhea and encephalopathy are common. Hyponatremia, myocarditis (most common extrapulmonary site).

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A Systematic Review of Subjects for PGMEE

2. Pontiac fever: acute, self-limited, flu-like disease; fever, myalgia, fatigue. Diagnosis 1. Detection of bacilli from sputum (best) or BAL. (most sensitive and specific). 2. Direct fluorescent antibody (DFA) test. 3. Urinary antigen testing by latex agglutination ELISA. 4. Antibody serology by indirect IF study. 5. CXR Bilateral pulmonary infiltrates. Treatment Erythromycin was the drug of choice. Now azithromycin is drug of choice. Does not respond to -lactam drugs or aminoglycosides.

YERSINIA PESTIS
Morphology Gram negative bacilli. In smears stained with Giemsa or methylene blue, it shows bipolar staining (safety pin appearance). Culture On ghee broth, it produces stalactite growth. Pathogenesis Plague bacilli are the most invasive bacteria known. Epidemiology Plague is a zoonosis. Reservoir of infection: Tatera indica (field mice). Vectors: Rat fleas: Xenopsylla cheopis in north India, Xenopsylla astia in south India. Partially blocked flee is most dangerous in transmission. Flea index: Is the average number of fleas of all species per rat.

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Transmission: Propagative. The bacilli merely multiplies in vector, but no change in form. Plague Bubonic plague: Most common form. Mode Bite of rat fleas. IP 2-7 days. Clinical feature: Fever with chills. Headache, arthralgia and myalgias. Lymphadenopathy (Bubo) Inguinal and femoral nodes most common affected. It is hard, painful and moves under the skin. It often suppurates. Contains large number of bacilli. Pneumonic plague: Most serious, least common. Mode droplet infection. IP 1-3 days. Clinical feature: Hemorrhagic pneumonia, cyanosis very prominent, cough productive of bloody sputum. CXR Pleural effusion. Septicemic plague: Clinical feature: Petechiae, ecchymoses, bleeding from orifices, DIC, ARDS. Treatment Streptomycin is the drug of choice. Buboes may require surgical drainage. Prevention Chemoprophylaxis: Tetracycline is the drug of choice. Flea control: Insecticides of choice are DDT and BHC. Pouring kerosene oil over the carcass is a simple method of elimination of the fleas. Within 48 hours of application of insecticides, the flea index should drop to zero.

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A Systematic Review of Subjects for PGMEE

Vaccine Killed vaccine. Vaccination gives some protection against bubonic plague, but not against pneumonic plague. Indication: Only for prevention, not for control. Effectiveness: Immunity lasts for about 6 months.

FRANCISELLA TULARENSIS
Gram negative pleomorphic. Tularemia 1. Ulceroglandular/Glandular tularemia most common type. Characterized by lymphadenopathy with local ulceration. 2. Oculoglandular type. 3. Oropharyngeal and gastrointestinal type. 4. Pulmonary tularemia. 5. Typhoidal tularemia.

BARTONELLA
Gram negative bacilli.
Species B. bacilliformis B. henselae B. quintana Disease Oraya fever, Verruga Peruana Cat-scratch disease, Bacillary angiomatosis in AIDS patients Bacillary angiomatosis in AIDS patients, Trench fever

Cat-scratch Disease Causative agent: B. henselae Clinical feature: Painful regional lymphadenopathy in the axilla and neck. Pathology: Granulomatous inflammation with stellate necrosis.

MYCOBACTERIUM
Classification a. Tubercle bacilli: 1. Human M. tuberculosis. 2. Bovine M. bovis.

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b. Lepra bacilli: Human M. leprae. c. Causing skin ulcers M. ulcerans. d. Atypical mycobacteria 1. Photochromogens. 2. Scotochromogens. 3. Nonphotochromogens. 4. Rapid growers. e. Johnes bacillus M. paratuberculosis (pathogenic in animals not in human being). Biochemical Reaction
Test Niacin test Aryl sulphatase test Catalase test Peroxidase test Nitrate reduction Human bacilli +ve -ve +ve +ve +ve Bovine bacilli -ve -ve +ve +ve -ve Atypical bacilli +ve +++ve -ve

M. TUBERCULOSIS Morphology Gram positive bacilli. Straight or slightly curved rods. Acid fact (by Ziehl-Neelsen method). Acid fastness is due to presence of mycolic acid and integrity of cell wall. Generation time 14-15 hours. Culture Obligate aerobe. Selective media: Egg containing solid media: Lowenstein-Jensen medium Best. Composition Coagulated hens egg (without starch), mineral salt solution, asparagines and malachite green. Dorset egg medium. Liquid media: Virulent strains produce serpentine cords. The cord factor by itself is not responsible for virulence. Cord factor prevents phagocytosis of TB bacilli.

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A Systematic Review of Subjects for PGMEE

Pathogenesis Risk factors: 1. HIV infection. 2. Chronic renal failure. 3. IDDM. 4. Malnutrition gastrectomy or jejunal bypass surgery. Primary TB Common in children up to 4 years of age. Source: Droplet infection. Course: Asymptomatic with spontaneous healing. Site: Pulmonary TB. Most common sites are lower lobe or lower part of upper lobe. Pathology: Primary focus is peripheral or subpleural (Ghon focus) with hilar and paratracheal lymphadenopathy. CXR: Normal. Fate: Fibrosis, consolidation or calcification (Ghon lesion). Complication: rare. Local spread involvement of pleura leads to pleural effusion and empyema. Hematogenous spread miliary tuberculosis, tubercular meningitis. Tubercle: Granulomatous lesion composed of central zone containing giant cells with or without caseation necrosis, surrounded by epithelioid cells and peripheral zone of lymphocytes and fibroblasts. Postprimary or Secondary TB Age: In adults. Most common in late adolescence and early adulthood. Source: Reactivation of primary infection most common. Reactivation occurs due to high PaO2. Reinfection TB is exclusively confined to lungs. Exogenous reinfection. Site: Lesion localized to the apical and posterior segments of upper lobe, superior segments of lower lobes.

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Pathology: Extensive parenchymal involvement with satellite lesions and cavity formation. Symptoms: Cough. Hemoptysis due to rupture of bronchial arteries. Rasmussens aneurysm rupture of a dilated vessel in a cavity may also lead to hemoptysis. Fate: May heal by resorption, fibrosis and occasionally calcification; or progress to chronic fibrocaseous tuberculosis with tubercle formation, caseation, cavitation and shedding of bacilli in sputum (open TB). Extrapulmonary TB 1. Tubercular lymphadenitis: Most common extrapulmonary site. Most commonly involved are cervical and supraclavicular nodes. Most common in HIV patients, children and young adults. Concomitant lung disease may or may not be present. H/O contact or drinking infected milk. 2. Pleural TB: a. Pleural effusion: Exudative, straw colored or hemorrhagic. Chemical protein > serum protein. Glucose serum glucose. pH < 7.2. Cytology: Neutrophils in early stage but mononuclear cells (lymphocytes) in late stage is typical. Microbiology: AFB are rarely seen on direct smear. Diagnosis: Needle biopsy of pleura is often needed. b. Tuberculous empyema: Cause: Rupture of cavity or bronchopleural fistula. Treatment: Chemotherapy with surgical drainage. 3. TB pericarditis: Nature: Exudate, often hemorrhagic. Diagnosis: culture of fluid may detect AFB; biopsy. Compilation: Chronic constrictive pericarditis.

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A Systematic Review of Subjects for PGMEE

4. Genitourinary TB: Cause: hematogenous spread from a primary focus. Diagnosis: Culture ve (sterile) pyuria in acidic urine. Culture of 3 morning urine specimen yields a definitive diagnosis in about 90 percent cases. IVU earliest diagnosis. 5. Skeletal TB: Cause: Reactivation of hematogenous foci or spread from adjacent paravertebral LN. Site: Upper thoracic spine in children most common. Lower thoracic and upper lumber in adults (most common). 6. Gastrointestinal TB: Source: Swallowing of infected sputum most common. Hematogenous spread. Ingestion of milk from cows affected by bovine TB (rare). Most common site terminal ileum and caecum. Tubercular peritonitis: Diagnosis: Peritoneal biopsy. 7. Miliary TB: Clinical feature: Hepatosplenomegaly, lymphadenopathy. Choroidal tubercle pathognomonic of miliary TB. Diagnosis: CXR interstitial infiltrates (miliary mottling). Sputum smear negative in 80 percent cases. Tuberculin test negative in 50 percent cases. BAL and transbronchial biopsy more likely to permit bacteriological confirmation. Cryptic miliary TB: Occurs in adults with meningeal involvement to death. Nonreactive miliary TB: Rapidly fatal. 8. TB meningitis and tuberculoma: Source: Hematogenous spread of primary or postprimary pulmonary disease or rupture of a subependymal tubercle into the subarachnoid space. Clinical feature: Cranial nerve palsy (most commonly ocular nerves). Involvement of cerebral arteries may prduce focal ischemia. Hydrocephalus. Diagnosis: Lumbar puncture CSF shows increased leukocyte count (predominantly lymphocytes), increased protein and decreased glucose.

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CSF culture is diagnostic in 80 percent cases. CT and MRI: show hydrocephalus and abnormal enhancement of basal cisterns or ependyma. Treatment: Steroids are useful adjunct to chemotherapy. Tuberculoma: Appears as SOL in brain. 9. Cutaneous TB: i. Lupus vulgaris: most common type. Source: From lesions elsewhere in the body usually in the lung or lymph nodes. Clinical feature: Most common site head and neck. Apple jelly nodules. Lesion with central scaring. May be associated with nasal TB (butterfly appearance) produces perforation of septal cartilage. ii. Scrofuloderma: Source: Direct extension of infection from underlying focus, i.e. infected LN, muscles or bones. Diagnosis 1. Chest X-ray: Normal in primary TB. Classic picture upper lobe infiltrates with cavitation. Atypical picture in late stages of HIV infection diffuse interstitial or miliary infiltrates with little or no cavitation (resembling primary TB). 2. AFB microscopy: Sputum smear examination by direct microscopy is now considered the method of choice for diagnosis of pulmonary TB. At least 10000 acid fast bacilli should be present per ml of sputum for them to be readily demonstrable in direct smears. The frequency of sputum smear negativity is increased in HIV patients. Rapid diagnosis: Auraminerhodamine staining and fluorescent microscopy is the quickest method of diagnosis. 3. Culture: Very sensitive in detecting tubercle bacilli. Media: Solid medium LJ medium.

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A Systematic Review of Subjects for PGMEE

Liquid medium with radiometric growth detection (e.g. BACTEC 460) and identification of isolates by nucleic acid probes is more commonly used now. 4. Biopsy: Often needed in extrapulmonary TB (e.g. pleural or peritoneal TB). The specimen should not be preserved in formaldehyde. 5. Tuberculin test: For screening. It detects the prevalence of infection. Reagent: Purified protein derivative (PPD). The standard PPD contains 50000 TU/mg. 1 TU = 0.00002 mg PPD. Dose: Three doses 1TU, 5TU and 250TU. For routine testing, 1 TU dose is advocated in India. Test: 1TU of PPD in 0.1 ml is injected intradermally on the flexor aspect of forearm with a tuberculin syringe, raising a wheal. Result: Read after 72 hours. Indurations is read. > 10 mm Positive. < 6 mm negative. 6-9 mm doubtful. Interpretation: Positive tuberculin test: It indicates hypersensitivity to tuberculoprotein, denoting infection or BCG immunization, recent or past, with or without clinical disease. The test becomes positive 4-6 weeks after infection or immunization. A positive test is significant in children < 2 years and indicate evidence of active lesion. False negative test: Occurs in immunosuppression, e.g. malignancy, Hodgkins disease, defective CMI, miliary TB, convalescence from measles, sarcoidosis, severe malnutrition, steroid therapy. A positive reaction may occasionally revert to negative upon INH therapy. Epidemiology Prevalence of infection: It is the percent of individuals who show a positive reaction to the standard tuberculin test. Prevalence in India is about 30 percent.

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Incidence of infection (Annual infection rate): It is the percent of population under study who will be newly infected with M. tuberculosis. In India 1 to 2 percent. Also known as tuberculin conversion index. It is one of the best indicators for evaluating TB problem and its trend. Prevalence of disease: 4 cases/1000 i.e., 0.4 percent. It is the percent of individuals whose sputum is positive for tubercle bacilli on microscopic examination. It reflects the case load in a community. Incidence of disease: 1.5 cases/1000 = 0.15 percent. New case: A patient with sputum positive pulmonary tuberculosis who has never had treatment for tuberculosis or has taken anti-tuberculosis drugs for less than 4 weeks. Failure case: Smear positive at 5 months or later. Default: Smear positive after having left treatment for at least 2 months. Treatment Long-course regimens: a. Daily regimens most frequently used combination in India is INH plus thioacetazone. Duration 18 months. b. Bi-weekly regimens Streptomycin + INH + Pyridoxine supervised. Short-course chemotherapy: Advantages: 1. Rapid bacteriological conversion. 2. Lower failure rates. 3. Reduction in frequency of emergence of drug-resistance. 4. Low toxicity. Disadvantages: High cost. Course: Intensive phase HRZE 2 months; Continuation phase HT 6 months.

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A Systematic Review of Subjects for PGMEE

DOTS:
DOTS (directly observed treatment, short-course) Category Type of patients I. New case Seriously ill sputum smear ve Extrapulmonary TB Relapse Failure Sputum ve or Extrapulmonary not seriously ill Regimen 2(HRZE)3 4(HR)3 Test at month 2 Reviews 4 and 6 months

II.

III.

2(HRZES)3 1(HRZE)3 5(HRE)3 2(HRZ)3 4(HR)3

5 and 6 months

Drugs taken on alternate days, i.e. thrice a week. H = Isoniazid (600 mg) R = Rifampicin (450 mg or 10 mg/ kg in children) Z = Pyrazinamide (1500 mg) E = Ethambutol (1200 mg) S = Streptomycin (750 mg) Patients > 60 kg should receive additional 150 mg of R. Pyridoxine 10 20 mg daily to prevent INH induced neuropathy.
Extrapulmonary TB Serious Meningitis Miliary TB Pericarditis Spinal/GI tract Category I Not serious Lymph node Peripheral joint Skin Category III

During intensive phase all the drugs are administered under supervision. During continuation phase drugs are selfadministered. Medicines for 1 week are supplied in a multiblister combipack of which the first drug is swallowed under supervision. Domiciliary treatment: Advantages Cheaper than hospital treatment. Disadvantages Irregular treatment. Monitoring for antitubercular chemotherapy: With standard 6 months regimen, more than 80 percent patients should have negative sputum at the end of 2nd

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month. By the end of third month, virtually all patients should be sputum ve. When patients sputum culture remains +ve at or beyond 3 months, treatment failure or drug resistance should be suspected. Smears +ve after 5 months should be considered indicative of treatment failure. Special cases: Renal failure: INZ + RM + PZ. Pregnancy: INZ + RM for 9 months (2HRZ + 4HR) + E for first 2 months. Breastfeeding: Continue + ATT to mother + INH prophylaxis and BCG vaccination to baby, Prevention BCG vaccination: Live attenuated vaccine consisting of bovine strain of tubercle bacilli. WHO recommendation Danish 1331 strain. Diluent: Normal saline. Dose: 0.1 mg in 0.1 ml. Administration: Intradermal injection. Storage: 4oC (2-8oC) Reaction: Papule reaches a diameter of 4-8 mm at 5 weeks subsides or form a shallow ulcer usually covered with a crust spontaneous healing occurs within 6-12 weeks. Contraindication: Generalized eczema, infective dermatosis, hypogammaglobulinemia, immunodeficiency BCG is not effective in AIDS. Protective value: 80 percent, varies in different parts of the world. ATYPICAL MYCOBACTERIA General features: 1. They are not transmitted directly form man-to-man. 2. They are resistant to antitubercular drugs. Runyons Classification Group I: Photochromogens: Produce yellow-orange pigment in light. M. Kansasii: Most important pathogen. Produces chronic pulmonary disease in old persons with pre-

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existing lung disease lady Windermeres syndromes. It is sensitive to AT drugs. M. marinum: Produces swimming pool granuloma. Group II: Scotochromogens: Produce pigmented colonies even in the dark. M. scrofulaceum: May cause scrofula (cervical adenitis in children. Group III: Nonphotochromogens: Don not produce any pigment. M. avium intracellular: Common in AIDS patients with CD4 count <50/l. Group IV: Rapid growers: M. smegmatis and M. phlei: Saprophytes and incapable of infecting humans. Skin Pathogens M. ulcerans produces Buruli ulcer. M. marinum swimming pool granuloma.

MYCOBACTERIUM LEPRAE
Morphology Acid fast bacilli. Globi: are spheroidal mass of bacilli arranged in a cigar bundle appearance found within the lepra cells. Virchow or lepra cells: Foaming macrophages laden with acid-fast bacilli (large undifferentiated histiocytes). Culture Lepra bacilli cannot be cultured in artificial media or tissue culture. They can be propagated in the footpads of mice and the nine-banded armadillo. Generation time of lepra bacillus 12-13 days. Epidemiology Prevalence: It is highest in Orissa. Overall prevalence 6.7/10000. Leprosy is considered to be a public health problem when the prevalence exceeds 1 in 10000.

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Transmission: 1. Droplet infection. 2. Contact transmission. 3. By insect bite, breast milk, tattooing. Incubation period: Is calculated from mode. Classification a. Early or Intermediate leprosy: Hypopigmented patch with definite sensory impairment. Peripheral nerves are normal. May heal spontaneously. b. Tuberculoid leprosy: CMI is high and bacillary load is low (Lepromin +ve). Clinical feature: Hypopigmented macule with hypoesthesia-usually single or a few. Nerve involvement superficial nerves [such as the ulnar nerve (most common), common peroneal nerve and greater auricular nerves] maybe enlarged. Muscle atrophy (due to neural involvement) is common in small muscles of hand. Clumsiness in hand is due to involvement of interossei muscles. Neuropathy: Sensory changes are more marked. DTR are never lost. Loss of fine touch, pain and temperature but position and vibration senses are spared. Plantar ulceration of metatarsal head is the most common complication. Histology: Noncaseating granuloma in nerve with epithelioid and giant cells. c. Lepromatous leprosy: CMI is low and bacillary load is high (Lepromin ve). Clinical feature: Widespread bilateral cutaneous involvement. Lesions vary from macules, nodules, and plaques to papules (never vesicles), non-anesthetic. Facial involvement: Madorasis loss of lateral portions of eyebrows. Leonine facies due to loss of nasal septum. Sterility, gynecomastia. Nerve involvement is infrequent.

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Histology: Lepra cells with globi, no epitheloid or giant cells (subepithelial free zone); normal skin contain bacilli demonstrable by staining. Note: Lazarine leprosy is a variant of LL. Note: ovary is not involved in leprosy. Testes not in gonorrhea. Vas not in syphilis. Note: Iris pearls are seen in leprosy. d. Borderline leprosy: All kinds (bizarre) of lesions in a single patient distributed asymmetrically. Inverted saucer shaped lesions are seen. Borderline tuberculoid: Most common type in India. BB represents the most unstable form of leprosy. Shows satellite lesions. Multibacillary leprosy: Includes Borderline, BL and LL. Bacterial index 2. Bacilli are present in large numbers in the skin granulomas. Paucibacillary leprosy: Includes BT and TT and intermediate leprosy. Bacterial index < 2. WHO study group classification for treatment:
Treatment

Paucibacillary

Multibacillary

Single skin lesion

2-5 skin lesions

>5 skin lesion

Immunity Cell mediated immunity is deficient in leprosy. CMI deficiency is very specific for lepra bacilli and other infections (e.g. viral, parasitic) are not increased. Patients with LL show increase in CD8 cell count. Patients with TT show increase in CD4 cell count. The albumin: Globulin ratio is reversed. TT is associated with HLA DR2 and LL is associated with HLA MT1 and HLA DQ1.

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Reactional States Type 1 or Reversal reaction: Seen in BT (most common), BB, BL patients. Mechanism - Cell mediated hypersensitivity. Clinical feature Painful tender nerves, loss of function, swollen and erythematous skin lesions and new lesions may appear. No fever. Treatment Mild Aspirin; Severe Prednisolone. Type 2 or Erythema Nodosum Leprosum (ENL): Seen in LL and BL patients. Most frequently in the latter half of initial year of treatment. Mechanism immune complex (Arthrus reaction) Clinical feature Tender, inflamed subcutaneous nodules, may ulcerate. Fever, arthralgia, iritis, orchitis. Treatment MildAspirin; Severe Thalidomide (100 300 mg / day), clofazimine, steroids, chloroquine. Downgrading reaction: Clinically similar to reversal reactions. Common in untreated patients and in women during the third trimester of pregnancy. Complications Lucio phenomenon: Characterized by arteritis, seen in patients with diffuse, infiltrative non-nodular lepromatous leprosy. Secondary amyloidosis: in severe LL especially those complicated by ENL reaction. Diagnosis 1. Skin biopsy: Shows periappendageal lymphocytes. It is ve in primary neuritic leprosy. 2. Bacterial index: Seven sites should be examined at least. These include four skin lesions, nasal smear and both ear lobule. WHO grading of smears: Negative: No bacilli in 100 fields. + : 1 bacilli in each field. ++ : Bacilli found in all fields. +++ : Many bacilli in all fields.

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Use: 1. Only objective way of monitoring the benefit of treatment. 2. Classification of leprosy as paucibacillary (with BI <2) and multibacillary (BI 2) 3. Lepromin test: Delayed hypersensitivity test. i. Early Fernandez reaction: Read at 48 hours. Consists of erythema and indurations. ii. Late Mitsuda reaction: Read at 21 days. Consists on an indurated skin nodule that may ulcerate. Use: Not diagnostic. 1. To test the status of CMI of leprosy patients. 2. To assess the prognosis and response to treatment. 3. To classify the lesions Lepromin test is +ve in TT, it is ve in LL and equivocal in intermediate leprosy. 4. Tests for humoral response: i. FLAABS: Used to identify subclinical infection. ii. Monoclonal antibodies. iii. ELISA test. 5. Morphological index: Is the percent of solid staining bacilli in stained smears. 6. Histamine test: Very reliable in detecting at an early stage peripheral nerve involvement due to leprosy. 7. Mice footpad culture. Treatment Multidrug chemotherapy: WHO regimen: Multibacillary leprosy Rifampicin 600 mg once monthly supervised. Dapsone 100 mg daily, self-administered. Clofazimine 300 mg once monthly, supervised and 50 mg daily self-administered Duration 2 years (1 year now). Paucibacillary leprosy Rifampicin 600 mg once monthly supervised. Dapsone 100 mg daily, self-administered. Duration 6 months. Drugs should be continued till the signs of disease activity have subsided.

Infectious Diseases

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Surveillance: Multibacillary: Both clinically and bacteriologically at least once a year for 5 years after completion of therapy. Paucibacillary: Only clinically at least once a year for 2 years after completion of therapy. Reaction states: Type 1: High dose prednisolone. Type 2 (ENL): Thalidomide (200 mg BD), clofazimine. Note: Rifampicin is most rapidly acting and most potent bactericidal drug in leprosy. Clofazimine is used both in chronic and acute (reactional states) stages of leprosy. Treatment of nerve abscess in leprosy surgical excision. Treatment of single skin lesion Rifampicin + Ofloxacin + Minocyclin (ROM regimen). Prevention Best method is early detection and treatment (secondary prevention). Early detection: By Contact survey in areas with low prevalence (< 1 case per 1000). Group survey in areas with prevalence 1 in 1000 Mass survey in hyperendemic areas prevalence 10 in 1000. Treatment by multidrug therapy. Only bactericidal drugs are used. Evaluation Incidence rate: Most sensitive index of transmission of disease. Also the only index for measuring the effectiveness of measures taken, i.e. reduction in transmission. Bacteriological index: Only objective way of monitoring the benefit of treatment.

SPIROCHETES
TREPONEMA Pathogens 1. T. pallidum Veneral syphilis. 2. T. endemicum Endemic syphilis or Bejel.

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3. T. pertenue Yaws. 4. T. carateum Pinta. [mnemonic: P not for P] T. PALLIDUM Discovered by Schandiun and Hoffmann. Morphology Actively motile spiral rods. They are seen by negative staining with Indian ink. Dark ground or phase contrast microscopy. Stained by Silver impregnated method. Fontanas method for staining film and Levaditis method for tissue sections. Cultivation They do not grow on artificial culture media. Strains can be maintained by serial testicular passage in rabbits. Nichols strain is the strain used for diagnostic and research purposes. Non-virulent strains can be grown on artificial media e.g. Reiter strains used in group specific tests for syphilis. Syphilis Routes of transmission: 1. Sexual contact most common. 2. Direct contact. 3. Transplacental. 4. Blood transfusion. Incubation period: 10 to 90 days. Manifestations Primary syphilis: Chancre: Painless papule, indurated, superficially ulcerated. Most common sites: In heterosexual male - penis; in homosexual male rectum and anal canal. In female - cervix and labia. Primary chancre heals within 4-6 weeks leaving a scar. Regional lymphadenopathy firm, rubbery, non-tender and non-suppurative.

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Secondary syphilis: Occurs 2-6 months after primary lesion heals. Features: May be asymptomatic. Diffuse symmetrical mucocutaneous lesions ranges from macules, papules, papulosquamous and pustular (but not vesicular). Occurs on trunk and extremities, face and scalp, palm and soles, (non-itching). In mouth superficial erosions cause snail-track ulcers. Generalized non-tender lymphadenopathy. Condyloma lata: Seen in secondary syphilis. Broad, moist pink papules in moist, warm areas perianal area, vulva, scrotum, axillae, etc. Highly infectious. Constitutional symptoms. Complications: Hepatitis, nephropathyproteinuria, G.I. involvementgastritis, UC, arthritis, periostitis, moth eaten alopecia. Latent syphilis: Quiescent stage, lasts from 2 years to a lifetime. No clinical features and normal CSF study but positive serological tests. Late syphilis:(Tertiary): Occurs only in 35 percent untreated patients after 5-15 years. a. Neurosyphilis: Meningeal: Meningovascular most common presentation is a stroke syndrome involving the MCA in young adults. General paresis includes abnormalities of itals personality, affect, reflexes increased, eye (Argyll Robertson pupil), sensorium (illusions, delusions, hallucinations), intellect (decrease recent memory) and speech. (Mnemonic PARESIS). Tabes dorsalis: Demyelination of posterior columns, dorsal roots and dorsal root ganglia. Symptoms: Ataxic wide based gait (sensory ataxia), paresthesia, bladder disturbance, impotence, areflexia, and loss of position, deep pain and temperature sensations.

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Charcots joint: Trophic joint degeneration due to loss of pain sensation. Most commonly in the knees. Optic atrophy. b. Cardiovascular syphilis: Affects the vasa vesorum (endarteritis obliterans leads to medial necrosis) of mainly ascending and transverse segments of aortic arch. Clinical feature Aortic regurgitation, saccular aneurysm, coronary osteal stenosis. Symptoms appear 10-40 years after infection. X-ray shows linear calcification of the ascending aorta. c. Eyes: Pain, photophobia, dimness of vision, chorioretinitis, fixed pupil. d. Gumma It is a late benign lesion. Most common in skin. Histology: Granulomatous inflammation with central necrosis surrounded by mononuclear, epithelioid and fibroblastic cells; occasionally giant cells and perivasculitis are seen. Treponema are scant in gumma and difficult to demonstrate. Gumma in liver may produce hepar lobatum. Sloughing of a subcutaneous gumma produces painless, punched out ulcer with a wash-leather base. Congenital Syphilis Transplacental transmission can occur at any stage of pregnancy but the lesions generally develop after the fourth month of gestation. Results: Stillbirth, abortion, prematurity, neonatal death, congenital syphilis. Manifestations of congenital syphilis: Early manifestations within 2 years of life. Features: Earliest sign is rhinitis (snuffles). Mucocutaneous lesions primary bullous lesions (syphilitic pemphigus) vesicles.

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Note: Bullae / vesicles are only seen in congenital syphilis. Osteochondritis and osteitis most common early manifestation. Involves the metaphysis of long bones. Hepatosplenomegaly, lymphadenopathy, jaundice, thrombocytopenia, leukocytosis. Late manifestations appears after 2 years. Consists of Hutchinsons classic triad of late congenital syphilis i. Interstitial keratitis, ii. 8th nerve deafness (seen in tertiary congenital syphilis) iii. Hutchinsons teeth. Recurrent arthropathy. Cluttons joint: Bilateral knee effusions. Residual stigmata (in late disease as a sequele of early disease) Hutchinsons teeth centrally notched, widely spaced, peg shaped upper central incisors. Mulberry molars (Moons molars). Facies Frontal bossing, saddle nose and poorly developed maxillae, collapsed nasal septum (perforation of bony septum). Saber tibia. Rhagades linear scars at the angles of mouth and nose, caused by secondary bacterial infection. Perforation of palate. Note: Thymus gland abscess in congenital syphilis is called Dubois abscess. Diagnosis Serological tests: 1. Non-specific (Reagin antibody) tests: Using cardiolipin antigen (standard tests for syphilis)E.g. Wasserman CFT, Kahn tube flocculation test, VDRL slide flocculation test, Rapid plasma regain (RPR) test. STS become positive 7-10 days after appearance of primary chancre (3-5 weeks after acquiring infection). 2. Group specific Reiter protein CFT. 3. Species specific tests Using Nichols strain. FTA-ABS and TPI are both equally specific called standard reference test.

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A Systematic Review of Subjects for PGMEE

Note: Sensitive tests RPR and VDRL. Specific tests TPHA and FTA-ABS TPI test is most specific. FTA-ABS is the earliest test to be +ve (most sensitive). Uses of serology: 1. For screening and diagnosis RPR and VDRL. 2. For monitoring the response to therapy VDRL, RPR. 3. For confirmation of diagnosis FTAABS or MHA TP . Causes of biological false positive VDRL and RPR tests a. Acute (< 6 months) i. Recent viral infection (genital herpes, HIV). ii. M. pneumonia. iii. Malaria. iv. Parenteral drug use. b. Chronic (> 6 months) i. Aging. ii. Autoimmune disorders SLE, RA. iii. Parenteral drug use. 4. Detection of specific IgM antibodies IgM antibodies disappear soon after elimination of infection by treatment. Presence of IgM in neonatal serum confirms the diagnosis of congenital syphilis (because IgM does not cross the placenta). Tests for detection of IgM: VDRL test. 19S IgM FTAABS used to diagnose congenital syphilis. Treatment Benzathine penicillin G is drug of choice for all stages. Neurosyphilis use of Benzathine penicillin G alone is not recommended. Syphilis in pregnancy drug of choice is penicillin G. Monitoring: By VDRL and RPR (become ve after treatment). The FTA-ABS and hemagglutination tests remain +ve in most patients treated for seropositive early syphilis so they are not recommended for monitoring.

Infectious Diseases

571

To indicate effective control VDRL titer should fall 4 fold. Jarisch-Herxheimer Reaction: Follow the initiation of treatment of syphilis most commonly in secondary syphilis. Features: Fever, headache, myalgias, tachycardia, tachypnea, increased circulating neutrophil count, mild hypotension. ENDEMIC SYPHILIS Transmission: Nonvenerally. Clinical feature: Common in children, primary chancre is not usually seen except sometimes on the nipples of mothers infected by their children. The disease mimics secondary syphilis. YAWS Causative organism: T. pertenue which is antigenically and morphologically indistinguishable from T. pallidum. Transmission: By direct contact (not STD). Clinical feature: Primary lesion is an extragenital papule that enlarges and breaks down to form an ulcerating granuloma. (Most commonly seen on legs of children). Secondary and tertiary stages are seen. PINTA Causative organism: T. carateum which is antigenically different from T. pallidum. Clinical feature: Primary lesion extragenital papule that does not ulcerate but develops into a lichenoid or psoriaform patch. Skin is involved and hypo/ hyperpigmentation is seen in secondary stage. BORRELIA Organisms B. recurrentis Relapsing fever. B. burgdorferi Lyme disease. B. vincenti Vincents angina.

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A Systematic Review of Subjects for PGMEE

Relapsing Fever Vector: Louse and soft tick. Clinical feature: Fever and bacteremia which is followed by afebrile episodes, splenomegaly, jaundice. Culture: BSK medium. Lyme Disease Vector: Ticks (ixodes). Clinical feature: Expanding annular skin lesion (erythema chronicum migrans) with fever, headache, myalgia and lymphadenopathy. Arthritis is a late sequel. Vincents Angina B. vincenti is always associated with fusiform bacilli (Fusobacterium fusiforme). This symbiotic infection is known as fusospirochetosis. Clinical feature: Ulcerative gingivostomatitis or oropharyngitis. LEPTOSPIRA Weils Disease Causative organism: L. icterohemorrhagiae (belongs to genus L. interrogans). Vector: Rat. Route: Water contaminated with urine of vector animal. Clinical feature: High fever with chills, jaundice, and hemorrhagic diasthesis purpura, Renal dysfunction albuminuria is a constant feature. Farm workers in rice fields are in greatest risk. Diagnosis: Microscopic agglutination test (MAT), antibody titer 1:100 in MAT is significant. Isolation of organism in EMJH medium. Indirect hemagglutination test. Treatment: Penicillin G is the drug of choice.

Infectious Diseases

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MYCOPLASMA
Smallest freeliving microorganism. Cell wall deficient (so resistant to lactam antibiotics). Mycoplasma represents stable L forms. But current evidences are against this possibility. Not an obligate parasite. They can pass through bacterial filters (Eaton agent). Multiply by binary fission. Can grow in cell free media. M. PNEUMONIAE Culture Colonies have fried egg appearance. Staining by Dienes method. Clinical Feature Common in older children and adolescents. Tracheobronchitis most common manifestation; bronchiolitis pharyngitis. Walking or atypical pneumonia: Symptoms: Fever with chills, headache, sore throat, paroxysmal cough with blood stained sputum. Characteristically paucity of physical findings but marked radiological features. CXR: Evidence of consolidation, usually unilateral, involving lower lobe, starting at the hilum and fanning out to the periphery. Complications: Bullous meningitis and otitis, meningoencephalitis, erythematous maculopapular and vesicular exanthems, hemolytic anemia (cold agglutinins). Diagnosis Routine laboratory tests are often normal. Cold agglutinins are produced in less than 50 percent cases. Serology ELISA is preferred. Clinical, radiological and laboratory findings are indistinct to sever as a basis for accurate diagnosis. Treatment Erythromycin is the drug of choice.

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A Systematic Review of Subjects for PGMEE

UREAPLASMA UREALYTICUM Second most common cause of non-gonococcal urethritis. In men urethritis, proctitis, balanoposthitis and Reiters syndrome. In women acute salpingitis, PID, cervicitis and vaginitis. OTHER MYCOPLASMA M. hominis postpartum fever, salpingitis. M. genitalium urethral infection.

RICKETTSIA
Morphology Gram negative bacilli, obligate intracellular pathogen; they are parasites in arthropods. Culture Can not grow in cell free media. Classification
Diseases Typhus group a. Epidemic typhus b. Endemic typhus (murine) c. Scrub typhus Spotted fever group a. Rocky mountain spotted fever b. Indian tick typhus c. Rickettsial pox Others a. Q fever b. Trench fever Species R. prowazekii R. typhi R. tsutsugamushi R. rickettsii R. conorii R. akari C. burnetii R. quintana Vector Louse (Pediculosis corporis) Rat Flea Mite Tick Tick Mite No vector for human infection Louse

Pathogenesis They are maintained by transovarian transmission in mite (i.e. scrub typhus and R. pox). They multiply in the endothelium of small vessels.

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Epidemic Typhus Fever and chills. Characteristic rash macular of maculopapular. Starting on the trunk and spreading over the limbs but sparing the face, palms and soles. Clouding of consciousness. Rocky Mountain Spotted Fever (Indian Tick Typhus) Resembles epidemic typhus except the rash. Rash is macular initially and becomes petechial later. Appears first on the flexor aspects of the wrist and ankle and then spreads all over the body including the palms, soles and even the buccal mucosa. Rickettsial Pox Mildest of rickettsial infection. Q Fever Highly infectious zoonotic disease. Ticks act as vectors as well as reservoir. There is no vector in human disease. Human Q fever is by inhalation of infected dust fro soil previously contaminated by urine or faeces of diseased animals. It is also transmitted by milk. Clinical feature: There is no rash. May cause pneumonia. Diagnosis Neill-Mooser or Tunica reaction: Positive in endemic typhi. Helps to differentiate between epidemic and endemic typhi. Well-Felix reaction: Antigen O antigen of proteus.
Disease Antigens Epidemic typhus Endemic typhus Spotted fever Scrub typhus Q fever OX 19 +++ +++ Agglutination with OX2 OXK +++

++

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A Systematic Review of Subjects for PGMEE

ACTINOMYCETES
They are gram positive, filamentous true bacteria. ACTINOMYCES Anaerobic actinomycetes. Most common organism is Actinomyces israelli which causes human disease. Actinomycosis Pathology: Chronic granulomatous infection with development of indurated swelling which suppurates and discharges sulphur granule. The lesion often points towards the skin leading to multiple draining sinuses. Clinical feature: Three types: 1. Cervicofacial Indurated lesions on cheek and submaxillary region (jaw) most common type. 2. Thoracic Lungs and pleura. 3. Abdominal Liver. 4. Pelvis Most commonly with the use of IUD. Diagnosis: a. Demonstrating lesion by microscopy. b. Isolation in culture. Specimen Pus. Findings: Sulphur granules which are white to yellow. These represent bacterial colonies. Surrounded by club shaped structures which represent antigen-antibody complex and gives a sun-ray appearance. Treatment: Penicillin. Nocardia Aerobic actinomycetes. Acid fast, gram positive, filamentous. Pathogenesis: Cutaneous Local abscess, cellulitis and lymphocutaneous lesions. Subcutaneous Actinomycotic mycetoma. Systemic Pulmonary disease (pneumonia most common disease). Diagnosis: Culture on paraffin bait.

Infectious Diseases

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Actinomycotic Mycetoma (Maduramycosis) Granulomatous lesion of subcutaneous tissue. Common sites foot and less often the hands. Features Multiple sinuses that discharge white to yellow granules (c.f. mycotic mycetoma which discharges black granules). Treatment: Sulfonamides are drug of choice.

CHLAMYDIAE
Obligate intracellular pathogen (hence considered to be virus once). Gram negative bacteria. They are bacteria because they i. Possess both DNA and RNA. ii. Have cell walls and ribosomes. iii. Replicate by binary fission. iv. Susceptible to antibiotics. Morphology They occur in two forms 1. Elementary body: Extracellular and infective form. 2. Reticulate body: Intracellular and replicative form. The developing intracellular Chlamydial micro colonies are called inclusion bodies. Human Diseases
Species Chl. trachomatis Chl. trachomatis Serotype A, B, C D to K Disease

Trachoma Inclusion conjunctivitis (neonatal and adult). Genital chlamydiasis. Infant pneumonia. Chl. trachomatis L1, L2, L3 Lymphogranuloma venereum. Chl. psittici Psittacosis. Chl. pneumoniae Only one serotype Acute respiratory diseases.

Trachoma Signs: 1. Papillary hypertrophy. 2. Follicular hypertrophy seen in upper tarsal conjunctiva, the limbus (leading to Herberts pit

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A Systematic Review of Subjects for PGMEE

pathognomonic), the bulbar conjunctiva (also pathognomonic). 3. Pannus Sub-epithelial neovascularization. 4. Cicatrization Stellate shaped scar on cornea; late sequele. MacCanans Classification: Stage I : Incipient trachoma, immature follicles in upper palpebral conjunctiva with no scarring. Stage II : Established trachoma. IIA: Follicular hypertrophy predominant IIB: Papillary hypertrophy predominant. Stage III : Cicatrizing trachoma follicles and scarring at upper tarsal conjunctiva. Stage IV : Healed trachoma. Diagnosis: Any two of the following criteria should be present 1. Follicles at upper tarsal conjunctiva. 2. Limbal follicles and Herberts pit. 3. Stellate shaped scar. 4. Vascular pannus mostly at upper limbus. Complications: Entropion. Treatment: i. Oral sulphonamide in full dose. ii. Local sulphacetamide drop. Note: Prevalence of trachoma > 5 percent (in children < 10 years) is an indication for mass or blanket treatment. Treatment Veneral infection Tetracycline. Neonatal conjunctivitis and infant pneumonia Erythromycin. Diagnosis a. Non-cell culture: 1. Direct IF antibody (DFA) Sensitivity 70-85 percent. 2. ELISA Sensitivity 60-80 percent; Specificity 97-99 percent. 3. Ligase chain reaction and PCR Most sensitive.

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b. Serology: CFT and micro IF test (for infant pneumonia). c. Microscopic demonstration of inclusion or elementary bodies by Giemsa stain (in conjunctivitis) or iodine stain. d. Isolation in yolk cell, mice brain and cell cultures (McCoy, HeLa and BHK cell lines).

VIROLOGY
GENERAL PROPERTIES Viruses are obligate intracellular parasites. They contain only one type of nucleic acid ether DNA or RNA. Morphology Size: Virion The extracellular infections virus particle is called the virion. Elementary bodies Stained viruses seen under light microscope (e.g. poxvirus). Largest virus Poxvirus. Smallest virus Parvovirus. Structure and shape: The virion consists of a nucleic acid core surrounded by a protein coat, the capsid. 2 types of symmetry are met within the capsid icosahedral (cubical) and helical. Peplomers: Protein subunits projecting as spikes on the surface of envelope. Influenza virus carries two types of peplomers the hemagglutinin and the neuraminidase. Shape: Rabies virus is bullet shaped. Poxviruses are brick shaped. Resistance: Lyophilisation or freeze drying drying the frozen virus under vacuum. Use for prolonged storage of viruses. Hemagglutination: Elution Release of virus from hemagglutinated red cells. It is seen only in myxovirus that possesses neuraminidase.

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A Systematic Review of Subjects for PGMEE

Viral biosynthesis: Positive strand RNA viruses the viral RNA itself acts as the mRNA. E.g. picorna, togaviruses. Negative strand RNA viruses possess their own RNA polymerase for mRNA transcription. E.g.rhabdo -, orthomyxo -, paramyxoviruses. Retroviruses oncogenic RNA viruses. Contain reverse transcriptase (RNA dependent DNA polymerase) that converts ssRNA to dsDNA. Abnormal replication: Von Magnus phenomenon the virus yield will have high hemagglutination titer but low infectivity. Cultivation 1. Animal inoculation. 2. Embryonated egg. Inoculation on the chorioallantoic membrane (CAM) produces visible lesions (Pocks). Pock count can be used for the assay of pock forming viruses such as variola and vaccinia. Chick embryo vaccines influenza vaccine, 17D vaccine (yellow fever), flury strain (rabies). 3. Cell cultures most widely employed. Types: i. Primary cell cultures normal cells freshly taken from body and cultured. ii. Diploid cell culture. iii. Continuous cell line usually derived from cancer cells. Capable of continuous serial cultivation infinitely. E.g. HeLa, Hep2, KB cell lines. Cell line: HeLa Ca cervix, Hep-2 Ca larynx. KB Ca nasopharynx. Detection of virus growth in cell cultures: 1. Cytopathic effect enterovirus, measles virus, herpes, adenovirus. 2. Hemadsorption when hemagglutinating viruses (e.g. influenza and parainfluenza) grow in cell cultures, their presence can be indicated by addition of guinea pig erythrocytes to the cultures. 3. Interference one virus inhibits simultaneous or subsequent growth of another virus.

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Assay of infectivity: a. Quantal assay only indicate the presence (or absence) of infectious viruses (e.g. tissue cultures). b. Quantitative assay measures the actual number of infectious particles in the inoculum. Types: Plaque assay in monolayer cell culture. Pock assay in chick embryo (CAM). i. Plaque assay: Each plaque indicates infectious virus. Plaque test is used to separate specific clone of virus. ii. Pock assay: E.g. Vaccinia. Classification DNA viruses: All contain dsDNA except parvovirus. 1. Poxviridae. 2. Herpesviridae. 3. Adenoviridae. 4. Parvoviridae genome consists of ssDNA. 5. Hepadnaviridae Hepatitis B virus. 6. Papovaviridae. RNA viruses: All contain ssRNA except reoviridae. 1. Picornaviridae Entero (polio), Coxsackie, Echo, Rhinovirus. HeparnaHepatitis A. 2. Orthomyxoviridae Influenza virus. Genome contains ssRNA in 8 pieces (segmented). 3. Paramyxoviridae. 4. Toga. 5. Flavi. 6. Bunya. 7. Arena. 8. Rhabdoviridae rabies virus. 9. Reoviridae genome contains dsRNA in 10-12 pieces. Reovirus, orbivirus, rotavirus. 10. Corona. 11. Retroviridae. 12. Calci. 13. Filo. Note: Segmented genome is seen in bunyavirus, orthomyxovirus, reovirus and arenavirus (mnemonic BORA).

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Some Definitions Virusoids: Virusoids are nucleic acids that depend on helper viruses to package the nucleic acids into virus like particles. Viroids: Subviral agents without an extracellular dormant phase (i.e. virion) and contain a much smaller genome. Prions: Prions are abnormal cellular proteins that can spread from cell to cell and effect changes in normal cellular proteins, thereby disrupting cellular function and propagating themselves. Prion diseases: Creutzfeldt-Jacob disease, Kuru, Gerstmann-Strassler syndrome, Bovine spongiform encephalopathy. VIRUS INFECTIONS Inclusion Bodies Negri bodies (intracytoplasmic eosinophilic) Rabies. Guarnieri bodies Vaccinia. Bollinger bodies Fowl pox. Henderson Peterson bodies Molluscum contagiosum. Cowdry type A Herpes virus.

Note: Poxvirus contains intracytoplasmic inclusions. Herpes virus contains intranuclear inclusions. Measles contains both. Inclusions of adenovirus are basophilic. Interferon Nature: Protein. Species specific. Production: Produced by cells on induction by viral and nonviral inducers. Mechanism of action: They have no direct action on viruses. They act on other cells of the same species, rendering them refractory to virus infection. On exposure to IFN, cells produce translation inhibiting protein which selectively inhibits translation of viral mRNA. Types: IFN: (leukocyte IFN) produced by leukocytes. IFN: (fibroblast IFN) produced by fibroblasts and epithelial cells. IFN: (immune IFN) produced by T lymphocytes.

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Uses: IFN i. Chronic HBV infection. ii. Chronic hepatitis non-A, non-B/C infections. iii. Condyloma acuminata. iv. Hairy cell leukemia. v. Kaposis sarcoma. IFN has significant activity in Bladder CA, Laryngeal papilloma, non-Hodgkins lymphoma, and Cutaneous T cell lymphoma. IFN therapy also effective in Herpes keratitis, HZ varicella infection, Rhinovirus infection, CMV infection. IFN Chronic granulomatous disease. Side effects: Hypotension, prostration, fever, abnormal liver function. Bacteriophage Life cycle: 2 types 1. Virulent or lytic cycle: intracellular multiplication of the phage culminates in the lysis of the host bacterium and the release of progeny virions. 2. Temperate or Lysogenic cycle the phage DNA becomes integrated with the bacterial genome, replicating synchronously with it, causing no harm to host cell. Phage typing: Application: Intra-species typing of bacteria, as in the phage typing of S. typhi and staphylococci. Also V. cholerae. Bacteriophage are mostly used for epidemiology.

POXVIRUSES
VARIOLA AND VACCINIA Morphology Brick shaped virion. Can be seen under light microscope. Culture CAM: Both viruses form pocks on CAM.

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Tissue culture: Eosinophilic inclusion bodies called Guarnieri bodies. MOLLUSCUM CONTAGIOSUM Clinical feature: Umbilicated skin lesion especially in genital region. Transmission: By close contact (sexual intercourse). Diagnosis: Eosinophilic hyaline inclusion bodies Henderson-Peterson bodies. Treatment: Physical ablation.

HERPES VIRUS
Morphology The nucleocapsid is surrounded by a lipid envelope. Intranuclear inclusion bodies (Cowdry type A Lipschutz) are seen. Classification Herpes Herpes Herpes Herpes Herpes virus type 1 Herpes simplex virus 1. virus type 2 Herpes simplex virus 2. virus type 3 Varicella-Zoster. virus type 4 Epstein-Barr virus. virus type 5 Cytomegalovirus.

Herpes Simplex Pathogenesis: HSV1: Lesions in and around the mouth. Transmitted by direct contact or droplet spread. HSV2: Genital tract infections. Transmitted by sexual contacts. The virus remains latent in ganglia, particularly of the trigeminal nerve (HSV1) and sacral (HSV2) nerves. Clinical feature: 1. Cutaneous lesions: Most common site is the face. Fever blisters or herpes febrilis is due to viral reactivation in febrile patients. Herpetic whitlow is seen in doctors, nurses. Eczema herpeticum caused by HS hominis virus.

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2. Mucosal: Most common site is buccal mucosa. Gingivostomatitis and pharyngitis primary infection. Recurrent herpes labialis. 3. Ophthalmic: Most common cause of corneal blindness in USA. Acute keratoconjunctivitis. Follicular conjunctivitis. 4. CNS: HSV encephalitis most common viral infection in CNS. Caused by HSV1. Clinical feature Acute onset of fever and focal neurological (especially temporal lobe) symptoms. Diagnosis Most sensitive noninvasive method is demonstration of HSV DNA in CSF by PCR. Treatment IV acyclovir. 5. Visceral: Esophagitis. 6. Genital: HSV2 (also caused by HSV1). Male lesions on the penis, urethra urethritis. Female cervix, vagina, perineum and vulva. 7. Congenital: Most commonly due to HSV2. Mode due to contact with genital secretions at the time of delivery. Prevention Elective CS in women with genital herpes lesions. Clinical feature Hallmark vesicular ulcerative skin lesion, skin lesion may be absent in 1/3 rd cases, Neonatal encephalitis. Diagnosis: 1. Microscopy Tzanck smear. 2. Tissue culture Method of choice for virus isolation. On CAM produce white shiny pocks. 3. Serology. Treatment: Acyclovir is the most commonly used drug. Idoxuridine is the drug of choice for H. simplex keratoconjunctivitis. Chickenpox Epidemiology: Agent: the virus can be grown in tissue culture. VaricellaZoster virus (herpes virus type 3).

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A Systematic Review of Subjects for PGMEE

Infectivity: From 1-2 days before the appearance of rash to 4-5 days thereafter. Scabs are not infective. Transmission: Droplet infection from a case most common. Transplacental transmission. Incubation period: 14-16 days. Secondary attack rate: 90 percent. Clinical feature: Prodrome of 1-2 days. Rash: appears on the day the fever starts. Rashes first appear on trunk and face and then spread centripetaly. Rashes are seen in various stages of development macule, papule, vesicles and scabs (pleomorphism). Vesicles are filled with clear fluid and look like dew drops (most characteristic lesion). Symmetrical in distribution. Complications: 1. Secondary bacterial infection most common complication. Causative organism Streptococcus pyogenes and Staphylococcus aureus. 2. Varicella pneumonia most serious complication in adults. 3. CNS most common extracutaneous site in children. Clinical feature: acute cerebellar ataxia, meningeal irritation. Aseptic meningitis. Encephalitis. Transverse myelitis. G-B syndrome. Reyes syndrome Acute encephalopathy with fatty liver. 4. Hemorrhage. 5. Glomerulonephritis. 6. Arthritis. 7. Hepatitis. Perinatal Varicella Associated with high mortality rate when maternal disease develops within 5 days before delivery or within 48 hours thereafter. Congenital varicella limb hypoplasia. cicatrical skin lesions, microcephaly at birth. Herpes Zoster (Shingles) Cause: Reactivation of latent VZV from the dorsal root ganglia.

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Clinical feature: Neuritic pain that precedes rash. Rash: Unilateral vesicular eruption within a dermatome with severe pain. Most common dermatomes involved are T3 to L3 (thoracic region) and ophthalmic branch of trigeminal nerve (Zoster ophthalmicus). Risk factors: Immunodeficiency, Hodgkins and nonHodgkins lymphoma. Diagnosis: Tzanck smear shows multi-nucleated giant cells (Ballooning). Ramsay-Hunt syndrome: Cause: Involvement of facial nerve (the geniculate ganglion of the sensory branch of facial nerve). Clinical feature: Pain and vesicles in external auditory canal and tympanic membrane. Loss of taste in the anterion 2/3 of tongue. Ipsilateral facial nerve palsy. Treatment: Indications of systemic antiviral therapy 1. Involvement of mandibular nerve. 2. Involvement of motor nerve. 3. Very painful cutaneous lesions. Epstein-Barr Virus Pathogenesis: EB virus specifically affects B lymphocytes. EB virus receptors (CD21) are present on the surface of B cells and epithelial cells. Acute infection with EBV causes polyclonal activation of B cells and antibodies are produced to both host cell and viral proteins. The number of T cells are increased with inverted CD4:CD3 ratio. In vitro, infected B cells are transformed so that they can proliferate indefinitely. Disease associations: 1. Infectious mononucleosis. 2. Malignancies i. Nasopharyngeal carcinoma. ii. Burkitts lymphoma. iii. Hodgkins disease mixed cellularity type. iv. T cell lymphoma. v. Thymoma. vi. Gastric carcinoma.

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vii. Primary CNS lymphoma (especially in AIDS patients). 3. Others Chronic fatigue syndrome. Meningoencephalitis. Infectious mononucleosis (Glandular fever) Route: Intimate oral contact as in kissing; called the kissing disease. Clinical feature: Most infections in infants and young children are asymptomatic, whereas most infections in adolescents present as IM. Symptoms Fever, sore throat, abdominal pain, nausea, vomiting. Sign Lymphadenopathy, pharyngitis or tonsillitis, hepatosplenomegaly, rash. Laboratory findings: Blood increased WBC count, anemia, lymphocytosis with > 10 percent atypical lymphocytes, thrombocytopenia. LFT Increased serum levels of aminotransferase and alkaline phosphatase. Complications: Disease is usually self-limited. Meningitis and encephalitis are the most common neurologic complications. Autoimmune hemolytic anemia (Coombs +ve). Hepatitis, myocarditis, pneumonia. Diagnosis: Heterophile antibody test (IgM type) cold antibody. Standard test PaulBunnel test. Sensitive test Monospot test. Cytomegalovirus Congenital CMV infection Most common viral infection of the fetus. The disease is called cytomegalic inclusion disease. Clinical feature: Petechial rash (due to thrombocytopenia).

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Hepatosplenomegaly, jaundice. Microcephaly most common cause. Chorioretinitis. Cerebral calcification Sparse (c.f. toxoplasma) and usually periventricular. Inguinal hernia, 1UGR and prematurity. CMV mononucleosis Most common clinical manifestation in normal hosts beyond neonatal period is a heterophile-negative mononucleosis syndrome (c.f. EB virus with is heterophile +ve). CMV infection in immuno compromised host Most common infection in organ transplant recipient. Organ transplant Febrile leukopenia. BM transplant Pneumonia, gastrointestinal disease. AIDS infection occurs when CD4+ cell count falls below 50 100 / L. CMV retinitis is the most common manifestation.

Treatment: 1. CMV immunoglobulin. 2. Ganciclovir. 3. Foscarnet. Vaccine: Live attenuated vaccine (Tower strain). Not effective in immunodeficient patients. Human Herpes Virus Type 6 HHV-6B causes exanthem subitum (roseola infantum or sixth disease). It is common in early infancy. Clinical feature: Fever with subsequent rash which disappears in 12 days without pigmentation or desquamation.

PARVOVIRUS
Smallest virus. Genome contains single stranded DNA. B19 strain is a human pathogen.

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Clinical Feature 1. In children Erythema infectiosum or 5th disease. Characterized by facial rash with a slappedcheek appearance. Spreads to involve palm and soles. Rash disappears in 2 weeks. There is no fever. 2. In adults Acute arthralgia and arthritis. 3. Most common cause of transient aplastic crisis developing suddenly in patients with chronic hemolytic disease. 4. May produce non-immune hydrops in fetus.

PAPOVAVIRUS
Classification
Papovaviridae Polyomavirus Simian vacuolating virus (SV40) and polyomavirus Both produce malignant tumors in mice Papillomavirus Human papilloma virus (HPV)

Morphology Non-enveloped, icosahedral virus containing DNA (also adenovirus). Diseases by HPV 1. Common warts (verruca vulgaris) occurs on hands in young children. 2. Plantar warts (verruca plantaris) painful, occurs in adolescent and young adults (myrmecia warts). 3. Flat warts (verruca plana) most common in children. Occur on face, neck, chest and flexor aspects of forearms and legs. 4. Condyloma acuminata (or anogenital warts) Sexually transmitted. Most common pathogens HPV 6 and 11. Sites in men frenum or coronal sulcus of penis. In female appears first at the posterior introitus and adjacent labia. Features moist, soft, pedunculated wart on external genitalia.

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Treatment Cryosurgery is the initial treatment of choice. Also used Topical podophyllin preparation (C/I in pregnancy), IF. Imiquimod drug of choice in women. 5. CIN by HPV 16, 18, 31, JC Virus Produces progressive multifocal leukoencephalopathy (PML).

ADENOVIRUS
Morphology Non-enveloped, possesses DNA and a capsid with icosahedral symmetry. Diseases 1. 2. 3. 4. 5. 6. In children acute URTI with prominent rhinitis. In adults acute respiratory disease in military recruits. Epidemic keratoconjunctivitis. Acute follicular conjunctivitis. Acute hemorrhagic cystitis. Diarrhea by enteric types (types 40, 41) that produce enterotoxins.

PICORNAVIRUSES
ENTEROVIRUS Polio Virus Morphology: Virion shows icosahedral symmetry with genome containing single stranded RNA. Epidemiology: Prevalence: A rough estimate of all clinical cases of poliomyelitis can be done by multiplying the prevalence rate of residual paralysis due to polio by 1.33, i.e. prevalence of polio = prevalence of residual paralysis1.33. But prevalence of residual paralysis = prevalence of lameness1.25.

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Agent: Most outbreaks of paralytic polio are due to type 1 virus. Most cases of vaccine induced paralysis are due to type 3 virus. Type 2 most effective antigen. For 1 clinical case, there may be 1000 subclinical cases in children and 75 in adults. Route: Fecal-oral route most common. Droplet infection may occur in the acute phase. Manifestations: a. Inapparent (subclinical) infection 95 percent cases, most common manifestation. b. Abortive polio or minor illness fever, headache, sore throat and malaise. c. Nonparalytic polio (aseptic meningitis) 1 percent of cases, fever comes back along with headache and neck rigidity. Lasts for 2-10 days. d. Paralytic polio least common manifestation (<1%). Asymmetrical flaccid paralysis. Proximal more than distal. Usually involves the legs. Descending, i.e. starting at the hip and moving down to distal parts. Decreased muscle tone. Decreased or absent reflexes. No sensory loss (pure motor neuropathy). May be precipitated by fatigue, trauma, IM injection. Note: Most common muscle affected is the quadriceps. The muscle which undergoes complete paralysis is the tibialis anterior. The muscle in the hand affected most commonly is the opponens pollicis. Deformities: Triple deformity (at knee) flexion, posterior subluxation and external rotation. Equinovarus deformity at the foot. Tests: Tripod sign, Kiss the knee test, Head drop sign (in non-paralytic polio). Death is due to respiratory failure (bilateral phrenic nerve palsy is seen in polio).

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Laboratory diagnosis: Isolation of virus from throat in early stage, feces throughout the course of the disease and the convalescence. Serodiagnosis is least commonly employed. Prevention: Polio vaccine: 1. Inactivated (Salk) vaccine Course 4 doses. One or two doses of OPV can be given as boosters. Disadvantages i. It induces humoral antibodies, but does not induce intestinal or local immunity. The circulating antibodies protect against paralytic polio but do not prevent reinfection of gut by the virus no herd immunity. ii. It is unsuitable during epidemics. Advantage Safe to administer in persons with immunodeficiency. 2. OPV: Live attenuated vaccine containing 300,000 TCID50 of type 1 virus. 100,000 TCID50 of type 2 virus. 300,000 TCID50 of type 3 virus. Result It results in widespread herd-immunity. Contraindication -immunodeficiency. Complication vaccine-associated paralytic polio due to type 3. Dose 3 drops. Storage stabilization by adding MgCl2 can be stored at 4oC for a year. Non-stabilized vaccine should be stored at 20oC in a deep freeze. Administration: Polio is subject to international surveillance. All cases of AFP should be followed up for 60 days to detect residual paralysis. Even a single case is scaled as an outbreak. Reporting of all cases with AFP in children less than 15 years is mandatory. Treatment of deformities: Tendon transfer operation should not be performed before 5 years of age.

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Coxsackie Virus Epidemiology: Transmission by fecal-oral rout. The virus is shed in stool. Diseases: 1. Herpengina (vesicular pharyngitis) Coxsackie group A. 2. Aseptic meningitis Group A and B. 3. Hand, foot and mouth disease. 4. Epidemic pleurodynia or Bornholm disease Group B. 5. Myocarditis and pericarditis in newborn Group B. 6. Juvenile diabetes Group B4. 7. Orchitis. 8. Acute follicular conjunctivitis Coxsackie A-24. Echo Virus Also called the orphan virus. It is the most common cause of aseptic meningitis. Others Acute hemorrhagic conjunctivitis caused by enterovirus type 70 and Coxsackie type A24. It occurs in pandemic. Note: Viruses causing conjunctivitis: 1. Adenovirus Acute follicular conjunctivitis, also epidemic keratoconjunctivitis. 2. Enterovirus (type 70) Hemorrhagic (pandemic) conjunctivitis. 3. Coxsackie A24. 4. HSV follicular conjunctivitis.

ORTHOMYXOVIRUS
INFLUENZA Morphology Genome contains single stranded RNA in 8 pieces (segmented). Hemagglutination Influenza virus agglutinates RBC due to presence of hemagglutinin. This is followed by release of virus form the agglutinated cell surface due to presence of neuraminidase. This is called elution.

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Antigenic Structure Internal antigen: Ribonucleoprotein or RNP antigen which is type specific. Surface antigen: Hemagglutinin and neuraminidase which are strain specific. Antigenic variations: Antigenic drift: (Gradual change at frequent intervals) Cause: Mutation and selection. Effect: causes epidemics by type. Antigenic shift: (Abrupt drastic discontinuous variation) Cause: Genetic recombination of human with animal or avian virus. Effect: Major pandemics by type A. Antigenic variation is highest in type A virus, less in type B virus. Type C virus is antigenically stable. Note: H5N1 is a novel strain causing human infection. It is the Avian flue influenza a virus, also called the bird flu virus. Complications 1. Pneumonia most common complications. It is mostly due to mixed bacterial and viral infection. Secondary bacterial infection most commonly due to Streptococcus , Staphylococcus aureus and H. influenzae. 2. CVS congestive failure or myocarditis. 3. CNS encephalitis. 4. Reyes syndrome most common complication of type B infection. Laboratory diagnosis Rapid diagnosis: By demonstration of virus antigen of the surface of the nasopharyngeal cells by immunofluorescence. Treatment Amantadine active only against influenza A. Prevention Chemoprophylaxis with amantadine. Vaccine: Live attenuated vaccine. May be administrated as nasal drops.

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PARAMYXOVIRUSES
PARAMYXOVIRUSES Mumps Pathogenesis: Infection is acquired by droplet inhalation. The virus replicates in the epithelium of URT. Epidemiology: Incubation period 14 to 18 days. Immunity one attack provides life long immunity. Clinical feature: 30-40 percent cases are clinically inapparent. Parotid swelling is often the first symptom. It is generally bilateral and painful. The orifice of Stensens duct is red and swollen. The swelling subsides in 6-10 days. Submandibular and sublingual glands are also affected. No fever. Complication: 1. Meningoencephalitis most common complication in children. Aseptic meningitis Occurs in both children and adults. Self- limited, may lead to cranial nerve palsy with permanent sequele, particularly deafness. Other CNS problems cerebellar ataxia, facial nerve palsy. 2. Orchitis most common complication in postpubertal male. It is usually unilateral, may lead to testicular atrophy. If bilateral, may lead to sterility (rare). 3. Pancreatitis. 4. Oophoritis in female. 5. Nephritis. Prevention: Vaccine: Live attenuated vaccine (from Jeryl-Lynn strain). Recommended after one year of age because of possible interference with maternal antibodies earlier than that. Isolation: Till the swelling subsides. Gestational mumps: May lead to spontaneous abortion if occurs in first trimester. PNEUMOVIRUS Respiratory Syncytial Virus RSV is the most common cause of lower respiratory tract infection in infants. (Bronchiolitis).

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Epidemiology: Transmission through close contact, through contaminated fingers and fomites. Common in winter season. Most common in the age group 1-6 months. Clinical feature: The disease starts as febrile rhinorrhea with cough and wheezing. May progress to pneumonia, bronchiolitis, tracheobronchitis. Breathing is fast with respiratory distress. Retraction of lower intercostals spaces and suprasternal notch, cyanosis. Auscultation Rales and ronchi, breadth sounds are faint. Respiratory distress is out of proportion to the extent of the physical signs in the lungs. CXR: Hyperinflation and infiltrates. Course: Self - limited. Chance of development of bronchial asthma in later life. Treatment: Humid atmosphere. O2 is the mainstay of treatment. Antibiotics have no role. Antiviral Ribavirin. MORBILLIVIRUS Measles Epidemiology: No secondary attack rate, no subclinical infection, most common in the age group 6 months to 3 years. Infants are protected with maternal antibody up to 6 months of age. Measles tend to be severe in malnourished child. Incubation period 10 days from exposure to onset of fever, 14 days from exposure to appearance of rash. Clinical feature: (Note the sequence.) 1. Prodrome (2-4 day) malaise, cough, coryza, lacrimation, fever. 2. Kopliks spots appear 1-2 days before the appearance of rash. Blue white spots on a bright red background on buccal mucosa opposite the first and second upper molars. The spots disappear as rashes appear.

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3. Rash appears on 4-5th day as fever subsides. Erythematous, non-pruritic maculopapular rash. First appears behind the ears, near the hairline and spreads down the trunk and limbs to involve palms and soles. By fourth day, rash begins to fade in the order in which it appeared, leaving a brownish discoloration of skin and desquamation. Moderate generalized lymphadenopathy. Morphology: Lymphoid organs contain giant cell called Warthin-Finkeldey cells. Complications: a. Respiratory tract : 1. Otitis media most common complication in children, 2. Interstitial pneumonia and bronchopneumonia occurs due to immunomodulation. b. CNS encephalomyelitis, transverse myelitis, subacute sclerosing panencephalitis (SSPE). c. GI tract diarrhea, appendicitis. d. CVS myocarditis. e. Blood thrombocytopenic purpura. f. Malnutrition all patients should receive vitamin A as vitamin A deficiency can lead to keratomalacia and corneal blindness. g. Death due to measles are almost always due to pneumonia. Prevention: Vaccine: Live attenuated vaccine. Administration: Subcutaneous injection. The vaccine once opened should be used within 1 hour. Storage: In Freezer compartment (heat labile). The reconstituting fluid is stored at 4-8oC. Immunity: Develops 11-12 days after vaccination. 1 dose provides 95 percent protection. Contacts: Incubation period of measles induced by vaccine is about 7 days. Hence post-exposure prophylaxis is effective if given within 3 days.

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Contraindication: Pregnancy. Note: Heat stable vaccine has also been developed.

RUBELLA
Congenital Rubella Transmission: Maximum chance of infection and maximum congenital abnormalities during first trimester. (Max. first 5-6 weeks, chance 90%). Features: Causes maximum abnormalities among the congenital infection. 1. Sensorineural deafness most common abnormality. 2. Cardiac PDA (most common cardiac anomaly), PS, VSD. 3. Eye Cataract, retinopathy, glaucoma. 4. Neurology Microcephaly, mental retardation. 5. Hepatosplenomegaly Jaundice. 6. Blood Thrombocytopenia. 7. IUGR. Diagnosis: Serology demonstration of IgM antibody in fetal blood by ELISA. Postnatally Acquired Rubella Clinical feature: 1. Fever. 2. Lymphadenopathy Posterior auricular, cervical and suboccipital. 3. Rash Maculopapular, first appears on the face and spreads down the body. Rapidly progressive and clears in 4 days. Forschheimer spots: Petechial exanthem on the soft palate. Complications: 1. Conjunctivitis. 2. Arthritis. 3. Hemorrhage due to thrombocytopenia. 4. Encephalitis more common in adults. Rubella vaccine: Live attenuated vaccine. Absolute contraindication Pregnancy.

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ARBOVIRUSES
These are arthropod-borne viruses. TOGAVIRUS Alphavirus Chikungunya fever: The only group A arbovirus (alphavirus) causing epidemic disease in India is Chikungunya fever. FLAVIVIRUS Japanese Encephalitis Epidemiology: Incidence: Ratio of overt disease to inapparent infection is 1:300 to 1:1000 (i.e. cases show only the tip of iceberg). Host: Pond herons act as reservoir host. Pigs amplifier host. Man accidental, deadend host. Transmission: Bite of infected mosquito. Man-to-man transfer has not been recorded. Vector: Culex tritaeniorhynchus. Culex vishnui. Case fatality rate: 20-40 percent. Control: Vector control Vector mosquitoes of JE are widely scattered and not easily amenable to control. Vaccine: Protective immunity develops in about a months time after the second dose. Revaccination after 3 years. Yellow Fever Causative agent: Flavivirus fabricus. Vector: Aedes aegypti. Vaccine: 17D vaccine a live attenuated vaccine. Immunity appears on 7th day. Quarantine: For 6 days from the date of leaving an infected area. Airports and seaports are kept free from the breeding of insect vectors over an area extending at least 400 meters around their perimeters. The Aedes aegypti is kept below 1.

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International certificate of vaccination: India requires this even if the traveler has been in transit. Validity begins 10 days after immunization and lasts for 10 years. Dengue Syndrome Epidemiology: Agent: Dengue virus has 4 serotypes. All the serotypes are found in India. Agent: Aedes aegypti. Transmission: Transovarian transmission occurs. Clinical feature: a. Dengue fever: Fever: typically biphasic (saddle back fever). Pain in the back and limbs (breakbone fever). Associated with lymphadenopathy, maculopapular rash. b. Dengue hemorrhagic fever: Occurs due to double infection with dengue virus. More common in previously healthy children in the indigenous populations of the endemic areas. Clinical feature: Fever acute onset, high and continuous. Hemorrhagic manifestation Purpura, gum bleeding, decrease platelet count, positive tourniquet test. c. Dengue shock syndrome: Treatment: Fluid replacement with 5 percent DNS. Aspirin should be avoided particularly in endemic areas as it may cause gastritis, bleeding and acidosis. Note: IgM ELISA is the most common test for dengue. Neutralization test is most sensitive and specific. Kyasanur-Forest Disease Vector: Ticks (Haemaphysalis spinigera and H. turtura). Reservoir: Monkeys. Incubation period: 3-8 days. Distribution: In Karnataka state. Clinical feature: Hemorrhagic fever. Control: i. Spraying. ii. Restriction of cattle movement. iii. Killed KFD vaccine. iv. Personal protection.

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A Systematic Review of Subjects for PGMEE

West Nile Fever Endemic in India. Note: Arboviruses prevalent in India Chikungunya fever, Dengue, KFD, JE, West Nile. BUNYAVIRIDAE Hantavirus RNA virus. Natural pathogen of rodents. Transmission to human is by inhalation of virus in rodent urine and feces. Causes hemorrhagic fever with renal syndrome (HFRS) also called epidemic nephrosonephritis. RHABDOVIRUS Rabies Morphology: Virion is bullet shaped. RNA virus (single stranded with a negative sense). It has only a single serotype. Epidemiology: Distribution: Rabies virus is not present in Australia and Antarctica. In India, it is not found in Andaman and Lakshadweep. Mode of transmission: i. Animal bites. ii. Licks. iii. Aerosols. Incubation period: Highly variable, commonly 3-8 weeks following exposure. It depends on the site of injury and the distance of brain form it. Clinical feature: Stages: i. Prodrome. ii. Acute encephalitis. iii. Brainstem dysfunction. iv. Death or recovery (very rare). Pathology: Pathological hallmark is Negri bodies intracytoplasmic inclusions with characteristic basophilic

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inner granules. Most commonly found in cerebellum and hippocampus. Diagnosis: Fluorescent antibody staining for detection of viral antigen of skin biopsy. Antemortem corneal smears, facial skin biopsy Specimen Postmortem - brain Prevention: Post-exposure prophylaxis: a. Local wound toilet Rabies is sensitive to ethanol. b. Immunization fixed virus is used for vaccine preparation. Vaccine 3 types (killed inactivated vaccine) 1. Nervous tissue vaccine e.g. BPL vaccine from adult sheep brain (Semple type). Complication neurological complication. 2. Duck embryo vaccine. 3. Cell culture vaccine, e.g. Human diploid cell culture (HDCC) vaccine. Advantages Less immunologic reaction. Note: Inactivation is done by treatment with phenol or propionolactone. Doses:
BPL vaccine Category I. Lick on intact II. Minor scratches or abrasions without bleeding. Licks on broken skin III. Single/multiple transdermal bites or scratches Dose 2 ml 5 ml Duration 7 days 10 days Booster 1 after 3 weeks 2 after 7 days and 21 days

5 ml

10 days

HDCC vaccine: 6 doses on days 0, 3, 7, 14, 28 and 90 IM (in deltoid). Antirabies serum: Should be given within 24 hours. c. Pre-exposure prophylaxis: 3 doses at 0, 7 and 28 days of HDCC vaccine. Control of urban rabies: 1. Elimination of stray and ownerless dogs.

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2. Program of swift mass immunization. 3. Registration and licensing of all domestic dogs.

SLOW VIRUSES
Classification Group A: 1. Visna. 2. Maedi. Group B: 3. Scrapie. 4. Crautzfeldt-Jacob disease equivalent to mad cow disease. Characterized by Spongiform degeneration of the brain. 5. Kuru. Group C: 6. Subacute sclerosing panencephalitis (SSPE). 7. Progressive multifocal leucoencephalopathy (PML) JC virus.

FILOVIRIDAE
Marburg disease, Ebola fever (hemorrhagic fever).

ROTAVIRUS
It is the most common cause of diarrhea in infants and children. It has 5 antigenic groups (A to E). Diagnosis: Serology for demonstration of viral antigen in stools. Human rotavirus does not grow readily in cell cultures. Only some Rota A can be cultivated. Pathogenesis: Increased secretion by villi leads to secretory diarrhea. Pathology: Terminal ileum villi destroyed.

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Vaccines: Life attenuated vaccine produced by genetic reassortment. Rotavirus immunity develops by the age of 3 years.

ONCOGENIC VIRUSES
RNA VIRUSES Retrovirus Morphology: The genome consists of 2 single stranded RNA. The virion contains RNA dependant DNA polymerase or Reverse transcriptase. It prepares a DNA copy of the retroviral RNA genome. Classification: 1. The avian leukosis complex. 2. Human T cell leukemia (lymphotropic) viruses (HTLV) HTLV-I causes T cell lymphoma (Mycosis fungoides). Adult T cell leukemia (Sezarys syndrome). Tropical spastic paraparesis. HTLV-II causes Hairy cell leukemia. Slow transforming viruses: E.g. chronic leukemia viruses. They are so called because they have a low oncogenic potential and induce malignant changes after a long latent period. DNA VIRUSES Papovavirus: HPV 16, 18 and 31 Ca cervix. EB virus: see above. Hepatitis B virus: Hepatocellular Ca.

MYCOLOGY
GENERAL CONSIDERATION Classification Morphology: 1. Yeast Unicellular, possess true nuclei with nuclear membrane and paired chromosomes. The only pathogenic yeast is Cryptococcus neoformans.

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2. Yeast like fungi partly as yeast and partly as pseudohyphae, e.g. Candida albicans. 3. Moulds or filamentous fungi form true mycelia, e.g. dermatophytes. 4. Dimorphic fungi they are rounded yeast in tissue but grow like moulds when cultured at room temperature. e.g. Histoplasma, blastomyces, sporotrichos, rhinosporidium, coccidioidomyces, paracoccidioidomyces. Most fungi causing systemic infections are dimorphic. Systemic classification: Four classes.
Classes 1. Phycomycetes 2. Ascomycetes (yeast + moulds) 3. Basidiomycetes 4. Fungi imperfecti Sexual spores Oospores, zygospores Ascospores Basidiospores No sexual phases Asexual spores Sporangiospores Conidia Conidia

Diagnosis Media most common medium is Sabourauds glucose agar. Stain PAS and methanamine silver strains.

SUPERFICIAL MYCOSIS
DERMATOPHYTOSES (TINEA OR RING WORM) Pathogenesis Infect only superficial keratinized tissues skin, hair. Involve only the stratum corneum in skin. Epidemiology According to habitat, they are of 3 types 1. Anthropophilic in man 2. Zoophilic natural parasites of animals, e.g. T. verrucosum in cattle. 3. Geophilic in soil. Classification According to asexual spores (conidia) they produce:

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1. Trichophyton Microconidia are abundant. They infect skin, hair and nails. T. rubrum is the most common species affecting human beings. 2. Microsporum Macroconidia are predominant (single) and single microconidia. Infect only skin and hair. 3. Epidermophyton: Microconidia are absent. Macroconidia in groups. Infect only skin and nails. Remember - T all, M not N (Nail), E not H (Hair). Clinical Feature According to site involved 1. Tinea capitis: Infection of scalp. Most common species Trichophyton tonsurans. Endothrix the hair shaft breaks at skin surface, leaving the hairs visible as black dots on the scalp. Favus chronic infection with crust (scutula) formation lead to alopecia and scarring. Kerion boggy lesion with marked inflammatory reaction (easily plicable hair). 2. T. corporis: On smooth or non-hairy skin. May produce typical annular appearance of ring worm. 3. T. pedis: Most common infection. Also called athletes foot. The web space between 4th and 5th toes is almost invariably involved. 4. T. cruris: groin, most common in male. 5. T. barbae: On bearded skin. 6. T. unguinum: infection of nail plate (onychomycosis). Diagnosis Routine method: Examination of KOH mounts.

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Treatment Topical Imidazoles. Topical therapy is not effective in T. capitis and T. unguinum. Oral griseofulvin is the drug of choice. Note: Ciclopirox, oleamine new drugs. PITYRIASIS (TINEA) VERSICOLOR Causative organism: Malassezia furfur. Clinical feature: Scaly, hypo/hyperpigmented macule on trunk with branny scales. Coupid nale or stoke of the nail. Treatment: Selenium sulfide shampoo. Ketoconazole/Clotrimazole. Diagnosis: KOH smear. Woods lamp pale yellow fluorescence. TINEA NIGRA Causative organism: Exophiala wernickii. Clinical feature: Infection of stratum corneum, particularly of the palms, producing black or brownish macular lesions. PIEDRA Causative organism: Black piedra Piedraia hortai. White piedra Trichosporon beigellii. Clinical feature: Infection of hair. Appearance of firm, irregular nodules along the hair shaft. CANDIDIASIS Morphology Yeast like fungus. Hyphae and pseudohyphae are formed (except C. glabrata). Pathogenesis Commensals of humans. Candidiasis is an opportunistic endogenous infection.

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Predisposing factors: 1. Diabetes mellitus most common. 2. OCP . 3. Pregnancy. 4. Immunodeficiency. 5. Leukemia. Diseases a. Cutaneous candidiasis: Sites Intertriginous (in skin folds) and paronychial. Intertriginous infection occurs in macerated skin. Paronychial infection associated with frequent hand washing. Chronic mucocutaneous candidiasis or candida granuloma Circumscribed hyperkeratotic skin lesions, common in immunodeficiency. b. Mucosal candidiasis: Vaginitis common in 3rd trimester of pregnancy. Oral thrush common in bottle fed neonates. Clinical feature creamy white patches appear on the tongue or buccal mucosa that leave a red oozing surface on removal. c. Intestinal candidiasis: Sequel to oral antibiotic therapy. May present as diarrhea not responding to treatment. d. Bronchopulmonary candidiasis. e. Systemic infections: Septicemia, endocarditis and meningitis. Common in immunosuppressed persons. Chronic disseminated candidiasis common in patients with acute leukemia. Note: 1. C. parapsilosis may cause endocarditis. 2. C. tropicalis causes deep infection in neutropenic patients. Diagnosis Superficial Infection: Demonstration of pseudohyphae on wet smear. Confirmation by culture on Saboureuds media produce white creamy colonies. Deep infection: By histological section of biopsy specimen. Culture of blood, CSF , joint fluid or surgical specimens.

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Characteristics of C. albicans: 1. Formation of chlamydiospores. 2. Presence of hyphal elements in addition to yeast forms in stained specimen. 3. Ability to form germ tubes in serum rapid diagnosis method (called Reynolds-Braude phenomenon). 4. Biochemical sugar assimilation and fermentation tests.

DEEP MYCOSIS
SUBCUTANEOUS INFECTIONS Mycotic Mycetoma Commonly affects the foot. Clinical Feature: Subcutaneous nodule which enlarges, burrowing into deep tissue and tracking to the surface as multiple sinuses discharging viscid, seropurulent fluid containing granules. Diagnosis: The granules are microcolonies and their demonstration is of diagnostic valve. Chromoblastomycosis Also called verrucous dermatitis. Causative organism: Soil inhabiting fungi called Dematiacea. F. pedrois, P. verrucosa, and Cladosporum carrionii. Clinical feature: Warty cutaneous nodules that resemble the florets of cauliflower. Diagnosis: The fungi present as dark brown, yeast like bodies with septae, called sclerotic cells. Sporotrichosis Causative organism: Sporothrix schenckii a dimorphic fungi. Clinical feature: Development on the skin, in subcutaneous tissues and in lymph nodes, of nodules which soften and break down to form indolent ulcer. Common in wood cutters. Diagnosis: Asteroid bodies.

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Rhinosporidiosis Causative organism: R. seeberi a dimorphic fungi. It has been successfully cultivated in epithelial cell culture. SYSTEMIC INFECTIONS Cryptococcosis Causative organism: Cryptococcus neoformans. It has a polysaccharide capsule. It has 4 serological types (A to D) based on capsular polysaccharide. It is particularly abundant in feces of pigeons. Route: Acquired by inhalation. Initial site of cryptococcal infection is lung. Clinical feature: 1. Pulmonary cryptococcosis. 2. Meningitis most serious infection. Common in HIV and neutropenic patients. 3. Infections of bones and joints. 4. Cutaneous infection. Diagnosis: 1. Grows at 37oC. 2. Hydrolyses urea. 3. Staining With methenamine silver or PAS. A strongly positive result upon mucicarmine staining of tissue is diagnostic. 4. Demonstration of capsules in Indian ink preparations. 5. Serology demonstration of capsular antigen in CSF or serum by latex agglutination test. Treatment: Patients with AIDS and cryptococcosis are treated initially with IV amphotericin B and later with fluconazole. Immunity: Anticapsular antibodies appear but are not protective. Blastomycosis Dimorphic fungi. Disease is largely confined to North America North American disease. Clinical feature: Formation of suppurative and granulomatous lesions in any part of the body but with a marked predilection for lungs and skin.

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Diagnosis: Grows as mould at room temperature. But appears yeast like in body or at 37oC. Paracoccidioidomycosis South American disease. Coccidioidomycosis Causative organism: C. immitis Dimorphic fungi. Clinical feature: Produces valley fever or desert rheumatism fever with arthralgia. Diagnosis: Demonstration of spherule containing endospores (endosporulating spherules) in tissue. Histoplasmosis Causative organism: H. capsulatum Dimorphic fungi. Clinical feature: Majority of infections are asymptomatic or mild. Disease resembles TB with cough, fever and CXR showing hilar adenopathy with or without infiltrates. Chronic infections may lead to granuloma formation. OPPORTUNISTIC SYSTEMIC MYCOSIS Aspergillosis Causative organism: A. fumigatus most common. Pathogenesis: It is common in immunodeficient and neutropenic patients. Aspergillus infection is characterized by hyphal invasion of blood vessels, thrombosis, necrosis and hemorrhagic infarction. Chronic granulomatous disease of childhood also predisposes to invasive pulmonary aspergillosis. Aspergillus infection is a combination of type I and type III hypersensitivity. Diseases: Most common infection is otomycosis (Aspergillus niger is the most common organism).

Infectious Diseases

613

Pulmonary aspergillosis: 1. Aspergillus asthma occurs in atopic individuals (allergic bronchopulmonary aspergillosis) with eosinophilia and IgE antibody to aspergillus. Malt workers lung. 2. Bronchopulmonary aspergillosis the fungus grows within the lumen of bronchioles which are blocked by fungus plugs. 3. Aspergilloma occurs in preexisting pulmonary cavity e.g. in tuberculosis usually in the upper lobe and visible on CXR. The disease presents as massive hemoptysis. Disseminated aspergillosis: May produce cerebral infarcts. Diagnosis: Aspergilli have septate hyphae. Immediate type hypersensitivity reaction to aspergillus protein. Treatment: Aspergilloma may require surgical removal. Mucormycosis Caused by Phycomycetes. Aseptate hyphae. Predisposing factors: 1. Diabetes mellitus. 2. Organ transplantation. 3. Leukemias. 4. Long-term desferoxamine therapy. Clinical feature: Most commonly invades the nose and paranasal sinuses. May spread to adjacent tissues e.g. Orbit produce blindness. Brain cavernous sinus thrombosis.

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A Systematic Review of Subjects for PGMEE

PARASITOLOGY
Classification
Parasites

Protozoa (unicellular)

Helminths (multicellular)

Amoebae

Flagellates

Sporozoa

Ciliates

Cestodes Cestodes Feature: Tape like, segmented Absent Absent Not separate Hooks an suckers

Nematodes Nematodes Elongated, cylindrical, unsegmented Complete Present Separate No hooks or suckers

Trematodes Trematodes Leaf-like, unsegmented Incomplete Absent Not separate Only suckers

Alimentary canal: Body cavity: Sex: Head:

AMOEBAE Intestinal Amoeba Entamoeba histolytica Morphology: It exists as 2 forms cyst and trophozoite. Cyst: 12-15 m (5-20 g). Contains 1-4 refractile chromatid bars and a glycogen mass which stains brown with iodine. Contains 1-4 nuclei. Trophozoite: Single nucleus with centrally located karyosome. Life cycle: Cyst is the infective form. Both cyst and trophozoite are found in colon. Pathogenesis: Trophozoites attach to epithelium in the caecum, sigmoid colon or rectum and produce microulceration (earliest change). Amoebic ulcer: Button-hole size. Flask shaped.

Infectious Diseases

615

Liver abscess: Always preceded by intestinal colonization which may be asymptomatic. Infection reaches liver from colon via portal vein. Liver parenchyma is replaced by necrotic material called anchovy paste. It is bacteriologically sterile with few or no cells. Trophozoites may be found in parenchyma. Epidemiology: Reservoir man is the only reservoir. Incubation period 2 to 4 weeks. Young adults of low socioeconomic status are most commonly affected by massive amoebiasis. Clinical feature: Intestinal amoebiasis: Most cases (90 percent) are asymptomatic. Produces amoebic dysentery. Amoeboma chronic granulomatous mass usually in colon. Amoebic liver abscess: Usually single, located in superoanterior quadrant of right lobe. Point tenderness over liver and right sided pleural effusion are common. Less than 1/3rd patients have active diarrhea. Always have increased ESR. Complications: Pleuropulmonary involvement - sterile effusion, contiguous spread from liver, rupture into pleural sac. Other extraintestinal sties: Genitourinary, lung, brain. Cutaneous amoebiasis It is a spreading necrotizing inflammation of skin and subcutaneous tissue. Occurs by direct contact. Diagnosis: Stool: Presence of Charcot-Leyden crystals. Trophozoites which show erythrophagocytosis and motility. Pathogenic and non-pathogenic strains can be differentiated by the electrophoretic study of zymodens.

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A Systematic Review of Subjects for PGMEE

Serology: For extraintestinal amoebiasis. i. ELISA most sensitive (best test). ii. Indirect hemagglutination most widely used. Liver biopsy: Shows presence of trophozoites. Imaging: USG most commonly used. CT scan Imaging of choice. Treatment: 1. Invasive intestinal amoebiasis Metronidazole/ Tinidazole drug of choice. 2. Chronic intestinal amoebiasis/asymptomatic cyst passers Diloxanide furoate drug of choice (luminal amoebicide). 3. Extraintestinal amoebiasis Metronidazole/Tinidazole drug of choice. Chloroquine is also used. Free-living Amoebas Naegleria fowleri Causes Acute primary amoebic meningoencephalitis (PAM). Diagnosis Mobile trophozoites in wet mounts of fresh spinal fluid. Acanthamoeba infections Causes: 1. Granulomatous amoebic encephalitis (GAE). Presents as SOL in brain. Common in chronically ill and immunosuppressed patients. 2. Acanthamoeba keratitis. Risk factors: i. Contact lens Extended wear, homemade saline, wearing of lenses while swimming, inadequate disinfection. ii. Trauma Vegetable foreign body. Clinical feature: Severe pain, paracentral ring-shaped ulcer. Treatment: 1st line drug chlorhexidine or polyhexamethylin biguanides. 2nd line drug Propamidine isethionate, neomycin. Keratoplasty. Note: Neuropathogenic amoebae are Naegleria and Acanthamoeba.

Infectious Diseases

617

SPOROZOA
MALARIA History Laveran discovered the malaria parasite. Ronald Ross discovered the transmission by anopheline mosquito. Life Cycle Hosts: Two hosts 1. Man: Intermediate host. Occurs in liver and RBC, asexual cycle (Schizogony) and products are merozoites and gametocytes. 2. Mosquito: Female anopheles mosquito definitive host. Anopheles is the main vector of urban malaria. Sexual cycle (Sporogony) and products are called sporozoites. Life cycle in mosquito is cyclopropagative i.e. the parasites change in form and number in mosquito. Vectors: Of major importance are Anopheles culicifacies in rural areas and Anopheles stephensi in urban area. Cycle:
Sporozoites in saliva Mosquito Human liver (exoerythrocytic schizogony) - Produces schizonts which are not found in blood Releases merozoites RBC RBC Erythrocytic schizogony Duration 72 hours for P. malariae and 48 hours for the rest. Forms trophozoites

Gametocytes

Hypnozoites in liver are the cause of relapse in P. vivax and P. ovale infections. P. malariae relapse occurs due to persistence in blood rather than in liver. Epidemiology Extrinsic incubation period: time for sexual cycle in mosquito. It is about 10-20 days. Measurements: 1. Spleen rate measures the endemicity of malaria.

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A Systematic Review of Subjects for PGMEE

2. Infant parasite rate most sensitive index of recent transmission of malaria in a locality. 3. Annual parasite incidence (API) API = (Confirmed cases during one year)/(Population under surveillance) 1000 It measures malaria incidence. It is based on active and passive surveillance. Cases are confined by blood examination. 4. Annul blood examination rate (ABER) It is an index of operational efficiency. In MPO, a minimum prescribed is 10 percent of the population in a year. 5. Others Slide positivity rate. Provide information on the Slide falciparum rate. trend of malaria transmission Methods of transmission: i. Sporozoite induced: By mosquito bite. ii. Trophozoite induced: Transfusion malaria, congenital malaria, malaria in drug addicts. Characteristically pre erythrocytic schizogony is absent. Protection against malaria: 1. Duffy negative persons are resistant to vivax malaria. 2. G6-PD deficiency, sickle cell disease, thalassemia protect from death due to falciparum malaria. 3. Newborns and persons with sickle cell trait are resistant to P. falciparum infection due to high concentration of HbF in RBC. Plasmodium Parasites
Features P. falciparum P. vivax 14 P. ovale 14 P. malariae 30 (Max.)

Incubation 12 period (days) RBC affected Any age (multiple infection) Morphology Ring (in peripheral trophozoites, blood) bananashaped gametocytes Maurers dot Pigment Black (contains iron, porphyrin, hematin)

Reticulocytes Reticulocytes Old cells (young) (young) All forms, enlarged RBC, Schuffners dots Yellow brown Enlarged oval RBC, James dots Band trophozoites Ziemanns dots Brown black

Dark brown (does not occur in India)

Infectious Diseases

619

Clinical Feature 1. Fever: Three stages the cold stage, the hot stage, the sweating stage. P. vivax causes benign tertian malaria interval 48 hours. P. falciparum malignant tertian malaria interval 48 hours. P. malariae quartan malaria interval 72 hours. P. ovale tertian malaria- interval 48 hours Interval corresponds to erythrocytic schizogony. 2. Anemia normocytic normochromic. 3. Splenomegaly. Complications Severe falciparum malaria: i. Cerebral malaria: Diffuse symmetric encephalopathy leads to convulsions and coma. Focal neurological signs and signs of meningeal irritation are absent. Tendon reflexes variable. Plantar reflexes flexor or extensor. Abdominal and cremasteric reflexes absent. Eye retinal hemorrhage. DIC signs of bleeding. ii. Metabolic hypoglycemia, hyperkalemia, hypoalbuminemia, lactic acidosis. iii. Hematological anemia, mild thrombocytopenia, hypogammaglobulinemia. Note: Pancreatitis is the most rare complication of falciparum malaria. Tropical splenomegaly: Features: Splenomegaly, anemia, pancytopenia. Increased serum IgM against CD8 and CD5. Increased CD4:CD8 ratio. Nephropathy: Nephrotic syndrome may occur in P . malariae infection (Quartan malaria). Other Entities Transfusion malaria: Most commonly due to P. vivax.

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A Systematic Review of Subjects for PGMEE

Infective form is trophozoite. No pre-erythrocytic stage. Most common sources are whole blood and packed RBCs. Screening IFA test. Pernicious malaria: Results from anoxia due to obstruction of capillaries in various organs followed by necrosis of tissues. Malaria in pregnancy: Malaria in primi and secundigravida is associated with LBW. Falciparum malaria is an important cause of fetal death. Diagnosis Thick smear preparation. Best detected if blood films are taken during chills. Other methods: Plasmodium LDH test. PfHRP2 test. Microtube concentration method with acridine orange staining. Treatment 1. In high-risk areas (Pf. predominant and drug resistance areas): a. Presumptive treatment Tab. Chloroquine 600 mg in 1st and 2nd days, 300 mg on 3rd day. Tab. Primaquine 45 mg on 1st day. b. Radical treatment P. vivax Tab. Primaquine 15 mg daily for 5 days. P. falciparum no further treatment required. 2. Severe and complicated cases: Choice of antimalarial is quinine injection. Others Artemisinin. Chemoprophylaxis: Chloroquine + Proguanil (drug of choice). It should begin a week before arrival in the malarious area and continued for at least 4 weeks or preferably 6 weeks after leaving the area. Treatment for tropical splenomegaly: In endemic areas Proguanil. In non-endemic areas Antimalarials. In chloroquine resistant Pf. cases: Combination of Sulfalene/Sulfadoxine and Pyrimethamine single dose.

Infectious Diseases

621

In chloroquine and sulfa-pyrimethamine resistant cases of Pf. infection (Multi-drug resistant): Halofantrine. Also Mefloquine. TOXOPLASMA GONDII Life Cycle Hosts: Definitive host - Cat Host Intermediate host - Man Cycle:
Cysts containing bradyzoites or sporulated oocyst Cat Man

Gametocytes

Tachyzoites

Transmission: 1. Oral ingestion of sporulated oocyst from soil or bradyzoites from under cooked meat. 2. Direct transmission by blood or organ products during transplantation. 3. Transplacental: In 1st trimester Lowest chance but severe disease in newborn. In 3rd trimester Greatest transmission but asymptomatic in newborn. Women who are seropositive are protected against acute infection and do not cause congenital infection. Clinical Feature In normal individuals, infection is usually asymptomatic. Toxoplasmosis in immunocompetent persons: Cervical lymphadenopathy most common manifestation, chorioretinitis. In immunocompromised person: CNS disease encephalopathy. Congenital Toxoplasmosis 1. Fever, rash. 2. Bone age < chronological age. 3. CNS convulsions, seizures, hydrocephalus or microcephaly, mental retardation, cerebral calcification (dense) c.f. CMV infection.

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A Systematic Review of Subjects for PGMEE

4. Eye chorioretinitis, cataract, glaucoma. 5. Hepatosplenomegaly. 6. Thrombocytopenia. Diagnosis Serology: The Sabin-Feldman dye test for detection of IgG antibody against toxoplasma. Congenital toxoplasmosis: Definitive diagnosis is by direct inoculation of placental tissue or of newborn blood or CSF into susceptible mice. Presence of IgM specific antibody in serum. Double sandwich ELISA most sensitive. Treatment Pyrimethamine + Sulfadiazine/Clindamycin. In pregnant women Spiramycin decrease the risk of transplacental transmission of infection and prevents recurrent abortion.

FLAGELLATES
BLOOD AND TISSUE FLAGELLATES (HAEMOFLAGELLATES) Characteristics: 1. They all require and insect vector as an intermediate host. 2. Most haemoflagellates can be cultured in vitro. 3. They possess an undulating membrane in their structure. Leishmaniasis L. donovani visceral leishmaniasis or Kala-azar. L. tropica cutaneous leishmaniasis (oriental sore of Chicleros disease). L. braziliensis mucocutaneous leishmaniasis (Espundia or New world leishmaniasis).

Infectious Diseases

623

L. donovani Kala-azar Life cycle: Vertebrate (man) amastigote form of LD body 2 Hosts Insect (sand fly) promastigote form Epidemiology: Vector: Female phlebotomus sand fly, P. argentipes in India. Reservoir: Indian Kala-azar is non-zoonotic with man as the sole reservoir. Habitat: Amastigote forms are seen in reticuloendothelial cells of vertebrate hosts. Clinical feature: Fever, hepatosplenomegaly, anemia, weight loss. Darkening of skin. Diagnosis: a. Blood: Anemia, leukopenia (neutropenia with relative lymphocytosis and monocytosis), thrombocytopenia (pancytopenia). Hypergammaglobulinemia (increase IgG). Reversed albumin-globulin ratio. The normal WBC:RBC ratio of 1:750 is altered to 1:1500. ESR increased. Note: Antibodies are not protective. b. Napiers aldehyde test: Usually becomes +ve 2-3 months (8 weeks) after onset of the disease. Use not diagnostic, useful in surveillance. c. Demonstration of LD bodies in tissue aspirates: diagnostic. Aspirates are taken from spleen (most sensitive), bone marrow, liver and lymph nodes. d. Culture: Medium NNN medium. e. Serology: ELISA and indirect fluorescent antibody test (IFAT) are most suitable. CFT. Treatment: Sodium stibogluconate drug of choice (if fails) Pentamidine isethionate (if fails) IV Amphotericin B. Resistant Kala-azar: Persistence of splenomegaly, hyperglobulinemia and LD bodies in > 5 percent cells in BM despite adequate therapy.

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A Systematic Review of Subjects for PGMEE

Sequel: Post-kala-azar dermal leishmaniasis (PKDL): It occurs in 2-10 percent cases of visceral leishmaniasis in endemic areas (e.g. India) about 2 years after recovery form visceral disease. Clinical feature: Depigmented macules, erythema or nodules never ulcerate (differentiates from oriental sore and espundia). Diagnosis: Biopsy from skin lesions. Treatment: Pentavalent antimonials. L. tropica Cutaneous Leishmaniasis Vector: P. sergenti. Clinical feature: Painful ulcers over legs, arms or face. Starts as papule leads to ulcer with central depression surrounded by raised border (prominent central crusting). Diagnosis: Skin biopsy. L. braziliensis Mucocutaneous Leishmaniasis Ulcerative granuloma of skin that extends to mucosa especially in mouth, nose, pharynx and larynx. Treatment: Pentavalent antimonials. TRYPANOSOMA Chagas Disease (American trypanosomiasis) Agent T. cruzi. Vector Reduvid bugs. Clinical feature: Romanas sign facial swelling and pronounced edema of the eyelids. Chagoma Skin erythema and swelling. Heart (most commonly involved) arrhythmia, cardiomyopathy and thromboembolism. Sleeping sickness (African trypanosomiasis) Agent T. brucei. Vector Tsetse fly.

Infectious Diseases

625

Clinical feature: Trypanosomal chancre. Winterbottoms sign posterior cervical lymphadenopathy. Keranadels sign Pressure on palms or ulnar nerve produces pain after the pressure is removed. INTESTINAL FLAGELLATES Giardiasis Agent: Giardia lamblia. Habitat: Duodenum and upper part of jejunum. Morphology: It exists in two forms trophozoites (tennis racket appearance) and cyst. Transmission: Waterborne. Cyst is the infective stage. Pathology: Trophozoites only adhere to the epithelium but do not cause invasive or locally destructive lesions. Risk factors: Hypogammaglobulinemia. Common variable immunodeficiency is associated with chronic giardiasis (also Xlinked agammaglobulinemia of Bruton). Clinical feature: Fulminant diarrhea. Lactose intolerance, malabsorption. Fever and blood in stool uncommon. Diagnosis: Stool contains only cyst. But liquid stool contain both cyst and trophozoite. Intestinal biopsy shows atrophy of villi, nodular lymphatic hyperplasia, increase in intraepithelial lymphocytes and cellular infiltration of the lamina propria. Treatment: Metronidazole drug of choice. Trichomonas vaginalis Most common trophozoite infection as STD. Occurs in only trophozoite form. No cystic form. Habitat: Lower genital tract in females, urethra and prostrate in males. Treatment: Metronidazole drug of choice.

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A Systematic Review of Subjects for PGMEE

CILIATES Balantidium coli Largest protozoan. OTHERS Babesiosis Vector: ticks. Habitat: RBCs in human blood. Co-exists with Lyme disease. Cryptosporidiosis Agent: Cryptosporidium parvum. Clinical feature: Chronic persistent diarrhea in AIDS patients. May cause diarrhea in immunocompetent hosts, too. Diagnosis: Stool shows small oocysts. Treatment: Paromomycin. Isosporiasis Agent: Isospora belli. Clinical feature: In AIDS patients diarrhea, malabsorption. Pneumocystis carinii Most common opportunistic infection in AIDS. It is now regarded as a fungus. Clinical feature: Pneumonia (interstitial plasma cell pneumonia), fever, cough (nonproductive) and shortness of breath. Diagnosis: CXR diffuse mottling in lung fields. Demonstration of octanucleate cyst in sputum, BAL or biopsy. Stain Methenamine silver. Immunofluorescence. Treatment: Co-trimoxazole drug of choice.

Infectious Diseases

627

HELMINTHS
NEMATODES Tissue Nematodes Trichinella spiralis: Smallest nematode. Trichinosis:
Phase Enteric invasion Larva migrans Muscle encystment Symptoms Diarrhea Eosinophilia Retinal hge, splinter hge, myocarditis

Treatment: Albendazole. Thiabendazole is drug of choice for muscle symptoms. Visceral and ocular larva migrans: Causative organism: Canine ascarid Toxocara canis. Clinical feature: Liver is the most common viscus involved. Treatment: Diethylcarbamazine. Cutaneous larva migrans: Causative organism: Dog and cat hookworm Ancylostoma braziliense. Clinical feature: Creeping eruption serpiginous skin eruption caused by burrowing larvae. Treatment: Thiabendazole, Ivermectin. Angiostrongylus cantonensis: Causes: Eosinophilic meningoencephalitis. Dracunculiasis Causative agent: Drucunculus medinensis (Guinea worm). Also called Dragon or Serpent worm. It is the largest nematode. Life cycle: Definitive host: Man Host Intermediate host or vector: Cyclops Location: Adult female worm resides in subcutaneous tissue.

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A Systematic Review of Subjects for PGMEE

Epidemiology: India is free of dracunculiasis. Methods of eradication: 1. Provision of safe drinking water. 2. Control of Cyclops. 3. Health education. 4. Surveillance. Treatment: No drug is suitable for effective mass treatment. Niridazole (drug of choice). Metronidazole. Intestinal Nematodes
Features Ascaris lumbricoides (Round worm) Necator americanus Ancylostoma duodenale (Hookworm) Falciform larva Percutaneous Strongyloides stercoralis Trichuris trichuria (Whip worm) Enterobius vermicularis (Pin worm) Egg Oral or retroinfection Caecum, appendix No

Infective stage Route of infection

Egg Oral

GI Jejunum location (lumen) Pulmonary Yes passage of larvae (produce eosinophilia) Symptoms Fever, cough, dyspnea, rarely GI or biliary obstruction. Anorexia Malabsorption Diagnosis Others Egg in stool

Jejunum (mucosa) Yes

Falciform larva Percutaneous or autoinfection Sexual transmission Small bowel mucosa Yes

Egg Oral

Caecum, colon No

Larvae in stool Egg in stool CXR: Infective stage Common in eosinophilic - Rhabditiform immunopneumonitis larva after 2 compromised (Loefflers moldings. patients. syndrome) Chandlers Completes In children index: average entire life usually number of cycle in man asymptomatic eggs per gram of faeces
+

Pruritic dermatitis, abdominal pain, diarrhea, iron deficiency anemia Egg in stool

Recurrent Colitis, urticaria anemia (larva currens)

Perianal pruritus, vaginitis, abdominal pain

Egg from skin Also called Threadworm, Seatworm

(Contd...)

Infectious Diseases (Contd...)


Features Ascaris lumbricoides (Round worm) Necator americanus Ancylostoma duodenale (Hookworm) Strongyloides stercoralis Trichuris trichuria (Whip worm)

629

Enterobius vermicularis (Pin worm) Mebex, PP

Treatment

Mebendazole Mebex, PP (Mebex), Pyrantal pamoate (PP), levimasole tonic paralysis

Thiabendazole, Mebex Ivermectin Drug of choice.

Note: Autoinfection occurs in Strongyloides, Enterobius (also H. nana)

FILARIASIS
Features Vector Location of adult Microfilarae Sheath Tail tip Wuchereria bancrofti Culex fatigans Lymphatics Blood + Free of nuclei Brugia malayi Mansonia Lymphatics Blood + 2 terminal nuclei, blunt Loa loa Deerfly Subcutaneous tissue Blood + Nuclei up to tail tip, pointed Onchocerca volvulus Blackfly Subcutaneous tissue Skin, eye Free

W. bancrofti Life cycle: Definitive host: Man Host Intermediate host: Culex mosquito In mosquitoes, the parasite does not multiply but undergoes only cyclic change cyclo-developmental transmission. Third stage larva is infective. Female parasites are viviparous. Adult parasites live in lymphatics in man. Clinical feature: In endemic areas most cases are asymptomatic with microfilarae in blood. Hydrocele. Lymphangitis: develops in retrograde or descending fashion. Lymphatic obstruction: by adult worms. Elephantiasis brawny edema of skin followed by pitting edema,

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A Systematic Review of Subjects for PGMEE

thickening of subcutaneous tissue (hyperkeratosis), fissuring of skin and hyperplasia. Complications: Secondary bacterial infection, dilatation and rupture of lymphatics may lead to chyluria, chylothorax, chylous ascites. Site: most commonly the legs. Other sites are scrotum, arms, penis, vulva and breasts. Occult filariasis: No classical symptoms, no microfilarae in blood. Cause: hypersensitivity to filarial antigens. E.g. tropical pulmonary eosinophilia. Diagnosis: Demonstration of microfilarae in blood by concentration method (passage of fluid through a polycarbonate cylindrical pore filter with pore size 3 m or by centrifugation of fluid in 2 percent formalin Knotls technique) in early adenolymphangitis stage. Blood is best collected between 10 pm and 2 am. Blood: Eosinophilia. Increase serum IgE and antifilarial antibody. Epidemiology: Extrinsic incubation period 10 to 14 days. Parasitological parameters: 1. Microfilaria rate. 2. Filarial endemicity rate - percent of persons examined showing microfilarae in blood or disease manifestation or both. 3. Microfilaria density. Entomological parameter: Percent of mosquitoes positive for infective (stage III) larvae. Endemic areas: UP , Bihar, Orissa, Tamil Nadu. Treatment: DEC is the drug of choice. Note: DEC has highly selective action on microfilarae. Prolonged use may kill adult worm of B. malayi and W. bancrofti. Control: Best measure is personal prophylaxis (avoidance of mosquito bite).

Infectious Diseases

631

B. malayi Similar to W. bancrofti except that it rarely involves genital organs. B. malayi is the most common nematode in south India. Tropical Pulmonary Eosinophilia Caused by lymphatic filarial species (W. bancrofti and B. malayi). Pathology: Hypersensitivity to filarial antigens. Clinical feature: Paroxymal cough and nocturnal wheezing. Diagnosis: Blood pronounced eosinophilia (> 3000 / l). CXR increased bronchovascular markings, diffuse miliary lesions or mottled opacities in middle or lower lung fields. Loiasis Clinical feature: Produces Calabar/Fugative swelling. Diagnosis: Isolation of adult worm from eye or from subcutaneous biopsy. Treatment: DEC. Onchocerciasis Primarily affects skin, eyes and lymph nodes. Damage is produced by adult worms (c.f. lymphatic filariasis). Clinical feature: Pruritus and rash most common manifestation. Onchocercomata subcutaneous nodules. Eye visual impairment (river blindness). Diagnosis: Microfilarae in skin snip. Treatment: Ivermectin drug of choice. Surgery for nodules on head.

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A Systematic Review of Subjects for PGMEE

TREMATODES-FLUKES Schistosomiasis Life Cycle: Definitive host: Man Host Intermediate host: Snails Infective stage is called cercariae. Difference with other trematodes: 1. Both sexes are separate. 2. Adult worm resides in bloodstreams. 3. Humans are infected by free-swimming cercariae that invade the skin. Mode of transmission: Fresh water, undercooked fish, crustacea, contaminated vegetations. Pickled or smoked fish. Species: S. mansoni Reside in the venules of intestine S. japonicum and produce acute disease of liver S. hematobium Resides in venules of urinary tract and causes lesions primarily in ureter and bladder. Clinical feature: 1. Acute disease: Katayama fever. 2. Liver fibrosis: most important complication of intestinal schistosomiasis. Features: Periportal or Symmers fibrosis and portal hypertension (hepatosplenic schistosomiasis). 3. Glomerulonephritis and pulmonary hypertension: complication of the above. Diagnosis: Eosinophilia in acute stage. Definitive diagnosis: 1. Eggs in stool or sputum.
S. mansoni Eggs: Lat. Spine S. japonicum Round with small knob S. hematobium Terminal spine

2. Biopsy of infected tissue.

Infectious Diseases

633

Treatment: Praziquantel is the drug of choice for all trematode infections except fascioliasis (F. hepatica) for which Bithionol is the drug of choice. Clonorchis sinensis 3 hosts: Man, snail and cyprinoid fish. Habitat: Bile duct and gallbladder. Complication: Ascending cholangitis, cholangiocarcinoma, pancreatic Ca. Fasciola hepatica Habitat: Liver. May cause biliary obstruction. Fasciola buski Largest trematode. Habitat: Intestine. Paragonimus westermani Habitat: Lung. CESTODES-TAPEWORM They produce hexacanth embryo. Host:
Organism T. solium T. saginata Diphylobothrium H. nana Echynococcus Definitive host Man Man Man Man Dog Intermediate host Pigs Cow or buffalo 1st Cyclops 2nd Fresh water fish Man

Note: H. nana requires no intermediate host. Taeniasis solium Pathogenesis: Adult tapeworm in intestine (upper jejunum). Source: Ingestion of undercooked pork containing cysticerci (T. saginata by uncooked beef). Clinical feature: Epigastric discomfort, nausea, hunger, weight loss.

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A Systematic Review of Subjects for PGMEE

Diagnosis: Eggs in stool. Treatment: Praziquantel drug of choice. Niclosemide is not given. Cysticercus cellulose - Cysticercosis Pathogenesis: Larvae (cysticercus cellulose) in tissues. Site: Brain most common, striated muscle of neck, tongue and trunk, eye and subcutaneous tissue. Source: Ingestion of food contaminated with eggs, autoinfection. Clinical feature: Neurocysticercosis most common manifestation of cysticercosis. Seizures most common manifestation of neurocysticercosis. Focal neurological deficits, hydrocephalus, meningitis. Signs of increase ICT: headache, nausea and vomiting, changes in vision, confusion. Abnormal psychiatric manifestation. Recemose form: Characterized by grapelike clusters of proliferating larva membranes. Site: base of the brain or subarachnoid space. Clinical feature: chronic meningitis and arachnoiditis. Diagnosis: CT scan shows multiple calcified (or noncalcified) cysts in brain. MRI cysts with highintensity rim around them. Serology Immunoblotting. Treatment: Praziquantel or Albendazole (drug of choice)/ Flubendazole. Niclosemide is ineffective. Echynococcus granulosus (Hydatid disease) Definitive host: Dog. Sites in human body location of cysts: Liver (most common 70%), lungs, brain, kidneys, spleen, bones.

Infectious Diseases

635

Clinical feature: Most common manifestation of hepatic cyst is asymptomatic. May produce SOL abdominal pain and right upper quadrant mass. Lungs pain, cough, hemoptysis, most common in lower lobes. Rarely associated with liver cyst. Brain SOL. May produce spinal cord compression. Kidneys Hematuria. Diagnosis: Imaging CT scan (most sensitive), USG, MRI. Test for hypersensitivity Casonis test. Serology detection of antibody to echynococcus antigen 5 (C5 antigen). Treatment: Albendazole (medical management indicated in moribund patients). Surgery is the definitive treatment (enucleation). Complication: Rupture may produce allergic symptoms. Calcification least common in lung, most common in liver. Diphyllobothrium latum (Fish Tapeworm) Size: Largest tapeworm (may be as long as 15 mt). Intermediate hosts: First cyclops Two Second Fresh water fish