Dr.

Rabiya Ali House Officer Medical Unit IV

Objectives
Review basic science of the RBC
Define Anemia Review key aspects of history, physical and lab

evaluation Review a systematic approach to the differential diagnosis Case-based application of clinical concepts

What is blood?
Plasma (60%)

-Water -Dissolved ions and proteins Cellular components (40%) -WBCs -RBCs -Platelets

What is hemoglobin?
Tetramer of 4 globin chains (proteins)
Each with a heme group containing iron Can be distinguished by electrophoresis Chain types

Alpha Beta Gamma Delta Zeta and epsilon are embryonic

 Hemoglobin binds oxygen and carries it to tissues

Erythrocytes consist mainly of hemoglobin Function of red blood cell dependent on:

Hemoglobin type and content Membrane stability Energy production

Survival and production of RBCs

Formed in bone marrow
Pleuripotent stem cells Chemical regulation

Cytokines Erythroid specific growth factor Erythropoietin (EPO)

Erythrocytes
Life span is 120 days (+/- 20 days)
Cleared in spleen(engulfed and destroyed by

phagocytic cells of the reticuloendothelial system.)

Reticulocytes are newly formed RBC in circulation.

Reticulocytes remain in the circulation for approximately 1 day before reticulin is excised by reticuloendothelial cells with the delivery of the mature erythrocyte into circulation. Life span of Reticulocyte is 4 days. If no new production, Hb drops 1 gm/week.

Erythrocytes
Erythrocytes are highly deformable and increase their

diameter from 7 m to 13 m when they traverse capillaries with a 3-m diameter. They possess a negative charge on their surface, which may serve to discourage phagocytosis. Because erythrocytes have no nucleus, they lack a Krebs cycle and rely on glycolysis via the EmbdenMeyerhof and pentose pathways for energy. Many enzymes required by the aerobic and anaerobic glycolytic pathways decrease within the cell as it ages.

Erythrocytes
In addition, the aging cell has a

decrease in potassium concentration and an increase in sodium concentration. These factors contribute to the demise of the erythrocyte at the end of its 120-day lifespan.

Other important elements

Iron Key element in the production of hemoglobin Absorption is poor Transferrin Iron transporter Measured by total iron binding capacity Ferritin Iron binder, measure of iron stores, *also acute phase reactant*

Definition of Anemia
Anemia is a condition that requires investigation to

determine the underlying etiology. Anemia is strictly defined as a decrease in red blood cell (RBC) mass. OR Values of hemoglobin, hematocrit or RBC counts which are more than 2 standard deviations below the mean for age.
HGB<13.5 g/dL (men) <12 (women) HCT<41% (men)

<36 (women)

ANAEMIA Physiologic: Hb below the level needed to deliver adequate oxygen to cells. Clinical Features:
DEGREE
Mild Moderate Severe

LEVEL OF Hb
10 - 11 7 10 <7

PRESENTATION
Mild dyspnea on exertion, palpitation As with MILD ANEMIA, may also have excessive fatigue Dyspnea at rest, tachycardia with pounding pulse, weakness, dizziness,syncope,headache,insomnia

Causes
Causes of anemia are numerous and multifaceted. A

family history may be useful in detecting hereditary etiology. Diet and exposure to drugs and chemicals can be useful. A geographic history and a thorough knowledge of the patient's health can be important in establishing an etiology.

Causes
Genetic -Hemoglobinopathies, -Thalassemias, -Enzyme abnormalities of the glycolytic pathways, -Defects of the RBC cytoskeleton -Congenital dyserythropoietic anemia -Abetalipoproteinemia -Fanconi anemia
-Iron deficiency -Vitamin B-12 deficiency -Folate deficiency -Starvation and generalized malnutrition

Nutritional

Hemorrhage Immunologic - Antibody-mediated abnormalities Physical effects -Trauma -Burns -Frostbite -Prosthetic valves and surfaces -Aplastic anemia -Megaloblastic anemia -Renal disease -Hepatic disease -Chronic infections -Neoplasia -Collagen vascular diseases -Viral - Hepatitis, infectious mononucleosis, cytomegalovirus -Bacterial - Clostridia, gram-negative sepsis -Protozoal - Malaria, leishmaniasis, toxoplasmosis

Drugs and chemicals

Chronic diseases and malignancies

Infections

Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome

Clinical Presentation

Case
Mr. ABC is a 64-year old male who has not had any

primary care for several years. When he tried to give blood last week, he was told that he was anemic. He presents to your clinic for evaluation. What would you do??

History

Is the patient bleeding??

Actively? In past?

-Melena -Hemorrhoidal blood loss -Inquire aboutgastrointestinal complaints that may suggest gastritis, peptic ulcers, hiatal hernias, or diverticula. -In a female petient carefully document pregnancies, abortions, and menstrual loss.

Is there evidence for increased RBC destruction?

Abnormal urine color Jaundice

PMH including medication review, toxin

exposure??

Is the bone marrow suppressed?

Obtain a history of :
-Fever -The occurrence of purpura, ecchymoses, and petechiae.

Is the patient nutritionally deficient? Pica?

A thorough dietary history is important

in a patient who is anemic. Specifically question patients regarding consumption of either clay or laundry starch. This history will not be provided spontaneously. These substances render iron less absorbable. Changes in body weight are important with regard to dietary intake and can suggest the presence of malabsorption or an underlying wasting disease of infectious, metabolic, or neoplastic origin.

 Nutritional deficiencies may be

associated with unusual symptoms that can be elicited by a history. Patients with iron deficiencies frequently chew or suck ice (pagophagia). In vitamin B-12 deficiency, early graying of the hair, a burning sensation of the tongue, and a loss of proprioception are common. Paresthesia or unusual sensations frequently described as pain also occur in pernicious anemia.

 Patients with folate deficiencies may have a sore

tongue, cheilosis, and symptoms associated with steatorrhea. Color, bulk, frequency, and odor of stools and whether the feces float or sink can be helpful in detecting malabsorption.

Is there any underlying disease??

Cold intolerance can be an important symptom of

hypothyroidism or lupus erythematosus, paroxysmal cold hemoglobinuria, and certain macroglobulinemias. Explore the presence or the absence of symptoms suggesting an underlying disease, such as cardiac, hepatic, and renal disease; chronic infection; endocrinopathy; or malignancy.

Inquire about any non specific symptoms

Tiredness
Lightheadedness Breathlessness Ankle swelling If patient had any co-existing disease like Angina there

could be worsening of that.

Physical Examination

 Stable or Unstable?
-ABCs -Vitals Pallor( conjuctiva and mucous membranes)

Jaundice
-Hemolysis Thinning of the lateral aspects of the eyebrows Coarseness of hair Puffiness of the face Angular stomatitis

 Gum hypertrophy Tongue : Colour and smoothness Nail defects(Koilonychia) Hands: perfusion, skin crease pallor Lymphadenopathy

-Infection or neoplasia Petechiae or purpura Telengiectasia Abnormal pigmentation Ankle Edema - Bilateral: cardiac, renal, or hepatic disease. -Unilateral: lymphatic obstruction due to a malignancy that cannot be observed or palpated.

Systemic Examination
Hepatomegaly
Splenomegaly Raised JVP Flow murmurs on cardiac auscultation Tachycardia Tachypnoea Postural hypotension Joints deformity, swelling or restricted movement

 Optic Fundi

-Haemorrhage -Hyperviscosity -Engorged veins -Papilloedema

Rectal examination Neurologic examination

WorkUp for anemia

 Initial Testing CBC with differential and platelets Evaluation of smear with red cell indices Reticulocyte count Peripheral blood smear

 Bleeding

-Serial HCT or HGB Iron Deficiency -Iron Studies (Iron/TIBC/Ferritin) Hemolysis -Serum LDH, indirect bilirubin, haptoglobin, urine for hemosiderin.Coombs(Direct & Indirect), coagulation studies Hemoglobin electrophoresis B12/folate level Bone Marrow Examination Workup for GI blood loss -Stool ( FOB and microscopy) - Gastroscopy, Sigmoidoscopy or colonoscopy

Differential Diagnosis
Classification by Pathophysiology Blood Loss Decreased Production Increased Destruction (hemolysis) Classification by Morphology Normocytic 80-100 fl Microcytic < 80 fl Macrocytic >100 fl

Decreased Production
Infectious
Neoplastic Endocrine Nutritional Deficiency Anemia of Chronic Disease

Neoplastic
Leukemia
Lymphoma/Myeloma Myeloproliferative Syndromes Myelodysplasia

Endocrine
Thyroid Dysfunction Hypothyroidism Erythropoietin Deficiency Renal Failure

Nutritional Deficiency
Iron
B12 Folate (B9) Vitamin B6 Vitamin C

Approach to Anemia

Microcytic Anemia
MCV <80
Reduced iron availability Reduced globin production Reduced heme synthesis

Reduced Iron Availability

Iron Deficiency
Deficient Diet/Absorption Increased Requirements Blood Loss Iron Sequestration

-Note: Make sure there is no source of GI bleeding Consider malignancy if there is GI bleeding Anemia of Chronic Disease Low serum iron, low TIBC, normal serum ferritin MANY!! Chronic infection, inflammation, cancer, liver disease

Reduced Globin Production

Alpha
Thalassemia

Beta Genetically determined, often familial. Defects in the production of Hb Two processes involved Decreased production of Hb Imbalance of globin chain production Smear Characteristics Hypochromia Microcytosis Target Cells Tear Drops

Reduced Heme Synthesis

Lead poisoning

-Blocks placement of Fe into heme - May cause neurological damage -Usually related to lead-based paints and industrial exposures -Characteristic smear finding: Basophilic stippling -Test for a SERUM LEAD LEVEL Acquired or congenital sideroblastic anemia -Ring sideroblasts in bone marrow

Diseases Iron Deficiency Anemia of Ch.Disease Ch. Hemolysis Hemochromatosis

Iron

TIBC

Ferritin

or

Pregnancy Sideroblastic anemia

Macrocytic Anemia
MCV > 100
Megaloblastic:

-Abnormalities in nucleic acid metabolism

B12, Folate,Cytotoxic drugs

Non-megaloblastic:

-Abnormal RBC maturation

Myelodysplasia

-Alcohol, liver disease, hypothryroidism,

Evolving Cobalamin Deficiency

Usual sequence:

Serum Cobalamin falls Serum methylmalonic acid & homocysteine rise MCV rises within the normal range, with -hypersegmentation of neutrophils MCV rises above normal Anemia and/or neuropathy

Macrocytosis of Alcoholism
25-96% of alcoholics
MCV elevation usually slight (100-110 fl) Minimal or no anemia Macrocytes round (not oval) Neutrophil hypersegmentation absent Folate stores normal

Normochromic,Normocytic Anemia
Most commonly caused by anemia of chronic disease
Early iron deficiency often causes normocytic anemia

as well
Normocytic MCV(80-100) Reticulocyte count

Marrow failure Aplastic anemia Myelofibrosis Leukemia/metastasis Renal failure Anemia of ch. disease

Acute blood loss Sickle cell disease G6PD deficiency Hereditary spherocytosis AIHA PNH

Anemia of Chronic disease

Common
Develops over 1 to 2 months Non-progressive Usually mild to moderate WBC, platelets normal or increased

 Thyroid disease

Causes

Collagen Vascular Disease

Rheumatoid Arthritis Systemic Lupus Erythematosus Polymyositis Polyarteritis Nodosa Inflammatory Bowel Disease Ulcerative Colitis Crohns Disease Malignancy Chronic Infectious Diseases Osteomyelitis Tuberculosis Familial Mediterranean Fever Renal Failure

Approach to hemolytic anemia

-Anemia of increased destruction
Normochromic, normochromic anemia Shortened RBC survival -Reticulocytosis Tests to define the cause of hemolysis: - Hemoglobin electrophoresis -Hemoglobin A2 (beta-thalassemia trait) - RBC enzymes (G6PD, PK, etc) - Direct & indirect antiglobulin tests (immune) -Cold agglutinins - Osmotic fragility (spherocytosis) -Acid hemolysis test (PNH) - Clotting profile (DIC)

Findings Consistent with Hemolysis

Serum unconjugated bilirubin Serum LDH (and LDH1:LDH2) Serum haptoglobin Urine hemoglobin Urine hemosiderin Urine urobilinogen Cr51-RBC lifespan Reticulocyte count Increased Increased Decreased Present Present Increased Decreased Increased

Treatment
The purpose of establishing the etiology of an anemia is to permit selection of a specific and effective therapy. Treatment of Iron deficiency anemia: Therapy for iron deficiency anemia includes treatment of its underlying cause and restoration of normal hemoglobin concentrations and iron stores. This can be accomplished by oral or parenteral administration. -Oral iron therapy -Parenteral iron therapy -Blood Transfusion packed RBCs should be reserved for patients who are actively bleeding and for patients with a severe and symptomatic anemia. Transfusion is palliative and should not be used as a substitute for specific therapy. -Erythropoietin therapy

Oral Iron therapy

Several iron salts are available in tablet or liquid form for oral ingestion,

All of these are fairly simple and cheap, but usually two or three doses are required daily. Ferrous sulfate, which supplies 65 mg of elemental iron per 200 mg tablet, is the most widely used oral iron preparation. Iron dose (Adults): -Recommended dose : 325 mg (65 mg elemental iron) tablets, 150 mg (30 mg elemental iron)per 5 mL syrup -250 mL bottle - 325 mg orally three times daily between meals separately from other medications OR - 10 mL syrup orally three times daily between meals separately from other medications. -Duration = 3 months -Will respond in 10-21 days -Hb should rise by 1gm/dL/week

Oral Iron
Adverse Effects:
-GI complaints -Contraindicated in: Hemosiderosis, hemochromatosis, and hemolytic anemia.
-Ferrous sulfate reduces absorption of levothyroxine and methyldopa

Parenteral Iron
Indications for the use of intravenous iron include :

-Intestinal malabsorption e.g. due to gastrointestinal disease or surgery. -Intolerance or nonadherence, -A hemoglobin level less than 6 g per dL (60 g per L) with signs of poor perfusion in patients who would otherwise receive transfusion (e.g., those who have religious objections). -Lack of effect of oral iron therapy. -Patients in whom the chronic iron loss exceeds the rate of replacement possible with oral iron. -Patients with a clinical need for rapid delivery of iron to iron stores, e.g. post operative and post partum patients or in cases of autologous blood donation. -Functional or absolute iron deficiency in connection to erythropoietin therapy (r-HuEPO).

Available products: -Dexferrum (iron dextran) -Ferrlecit (Na ferric gluconate complex) -Venofer (iron sucrose or iron saccharate complex) -Jectofer (iron sorbitol; for IM use only) The iron dose to give may be calculated from the following formula -Total iron deficit [mg] =
body weight [kg] x (target Hb-actual Hb) [g/dl] x 2.4* + depot iron [mg]

-* 2.4 is a factor that takes into account the patient's blood volume, hemoglobin iron content , and conversion from g/dL to mg/L -2.4 = 0.07 x 0.0034 x 10000: Where: Blood volume: ~7% of body weight Iron content of haemoglobin ~0.34% Conversion from g/dl to mg/l =10000 -Depot iron =500 mg.

Iron Sucrose Injection (Venofer ) Molecular weight: 34,000 60,000 Daltons

100 mg vial undiluted by slow intravenous injection over 5 minutes (20

mg/minute) one to three times per week OR 200 mg vial undiluted by slow intravenous injection over 10 minutes(20 mg/minute) one to three times per week OR 200 mg diluted in 100 mL normal saline given as a slow intravenous infusion administered over 30 minutes one to three times per week Should not exceed three doses per week.

S.E: -Anaphylactoid reaction,headache ,nausea, vomiting ,diarrhea fever, asthenia, malaise, chest pain, hypertension, elevated liver enzymes, abdominal pain, dizzy, dyspnea, pneumonia, cough, pruritus, and application site reaction

 Contraindications:

-Known hypersensitivity to iron sucrose , evidence of iron overload (ferritin > 800 ng/mL and/or TSAT > 50%), or evidence of severe infection (such as sepsis or osteomyelitis)

Erythropoietin therapy
Erythropoietin is available as a therapeutic agent

produced by recombinant DNA technology in mammalian cell culture. It is used in treating anemia resulting from chronic kidney disease and myelodysplasia, from the treatment of cancer (chemotherapy and radiation), and from other critical illnesses (heart failure). parenteral iron is given along with recombinant erythropoietin therapy.

Back to Mr. ABC-You appropriately decide to obtain more history!

Personal Hx: Ive been a little more tired than usual, but Ive

been busy at work. Im getting close to retirement. Nothing else is unusual. I avoid doctors if I can PMH: Inguinal hernia repair 20 yrs ago Family Hx: Father & mother had heart attack(age 80), brotheralcoholism SH: Married x44yr, smokes 1ppd, a couple beers/night MEDS: daily multivitamin ALLERGIES: none ROS:+fatigue, +urine seems a little darker lately

Examination Findings
T 98.4 HR 98 Resp 20 BP 112/70 Gen: NAD, appears younger than stated age skin and conjunctiva slightly pale NECK: no adenopathy or thyromegally

Chest: CTAB/L
CV: RRR, no murmur ABD: no HSM, soft, normoactive bowel sounds GU: normal male Rectal: no masses, prostate smooth/not enlarged, guaiac

negative stool

Initial Labs
Only a CBC w/ diff was obtained: WBC: 8.2, HCT 32.2, MCV 79, Platelets 221, differential normal

Initial Thoughts
Blood loss? Age places him at risk for colon CA Decreased Production? Alcohol use, Iron deficiency Increased Destruction? Darker urine lately

Further Workup
CAGE questions Peripheral Blood Smear Reticulocyte count Iron Studies
Ferritin TIBC % Saturation

Urinalysis FOBT or colonoscopy referal

More results
CAGE screen reveals no positive responses Smear reveals microcytic, microchromic RBCs Retic count is interpreted as low Urinalysis negative for hemoglobin FOBT: not completed by patient Iron Studies
Ferritin: 10 TIBC: 350 % Sat: 15

Whats next?
Rule out Sources of Bleeding
Counseling regarding colon CA and referral for

colonoscopy

Consider oral iron therapy Dietary counseling (iron sources, limiting etoh, etc) Encourage follow-up for health care maintenance
Vaccinations (Tetanus/pneumovax) Other cancer screening Cholesterol Screen

Diagnosis
Colonoscopy revealed small suspicious lesion in sigmoid colon, pathology revealing adenocarcinoma. Excised surgically, no mets. Routine labs, one year later, reveal an HCT of 40%. He feels better than ever!

References

Schrier, Stanley.Approach to the patient with anemia. Up to Date. 2004 Schrier, Stanley. Anemia of Chronic Disease. Up to Date. 2004 Schrier, Stanley. Anemias due to decreased red Cell Production. Up to

Date 2004 Schrier, Stanley. Causes and diagnosis of anemia due to iron deficiency. Up to Date. 2004 Tierney, et al. Anemias. Current Medical Diagnosis and treatment. 2003. Pp469-489 Ferri: Ferri's Clinical Advisor 2009, 1st ed. Copyright 2009 Mosby, An Imprint of Elsevier Cuciti C, Mayer DC, Arnette R, Spielman FJ. Int J Obstet Anesth. 2005 Oct;14(4):362-4. PMID: 16140521 Chandler G et al. Intravenous iron sucrose: establishing a safe dose. Am J Kidney Dis. 2001;38(5):988-91.

Acknowledgment
Dr.Yousuf Baig

Resident 2 Medical IV

 The noble profession

Medicine, the only profession that labours incessantly to destroy the reason for its existence. James Bryce (1838-1922), English diplomat and author; ambassador to the United states, 1907-13