Mutation of the GNAS gene constitutive activation of a stimulatory G protein [GsAlpha] one of the most common genetic alterations **Prolactinoma with hyperprolactinemia The most common pituitary tumor In women galactorrhea amenorrhea Caused by o Hypothalamic lesions or medications [methyldopa]interfere with dopamine Associated with estrogen therapy Somatotroph adenomawith hypersecretion of GH 2 nd most common pit tumor Causes: hepatic secretion of Insulin-like Growth factor [IGF-1 or somatomedin C] End organ effects are caused by GH and IGF-1 Gigantism o If adenoma develops in childhoodbefore epiphyseal closure Acromegaly o If adenoma develops after epiphyseal closure. Failure to suppress GH production in response to overload Glucose [most sensitive test] Local compression effects due to expansion of tumor within sella turcica Corticotroph adenomahypersectriction of ACTH [Adrenocorticotropic hormone] Cushing syndrome: o Excess production of ACTH hypersecretion of cortisol [hypercortisolism] o Secondary to an adrenal adenoma or carcinoma Cushing Disease o Excessive production of ACTH by the pituitary o Elevated serum cortisol secondary to corticotroph cell pituitary adenoma o Weight gain, truncal obesity, abdo striae, buffalo hump, etc Hypercortisolism may be caused by ectopic ACTH production by tumors [small cell carcinoma of lung]*** o Anterior Pituitary Hypofunction Hypopituitarism: can result from ANY process that destroys the pituitary Pituitary tumors Postpartum pituitary necrosis [Sheehan syndrome] o Caused by ischemic necrosis [infarction] of the pituitary o Associated with hemorrhage and shock during childbirth Selective Deficiency of one or more pituitary hormones Deficiency of GH o Pituitary dwarfism: In children results in growth retardation o In adultsincreased insulin sensitivity with hypoglycemia, decreased muscle strength, and anemia Deficiency of gonadotrophins o In preadolescent children: retarded sexual maturation o In adults: loss of libido, impotence, loss of macular mass, and decreased facial hair in men, and amenorrhea and vaginal atrophy in women Deficiency of TSH secondary hypothyroidism Deficiency of ACTH secondary adrenal failure No hyperpigmentation of the skin, because of lack of ACTH and MSH Primary adrenal failure [ADDISON DISEASE], increased ACTH hyperpigmentation Posterior Pituitary [Neurohypophysis] o Hormones are synthesized in the hypothalamaus and store within the axon terminals Oxytocin: induces uterine contraction during labor and ejection of milk AntiDiuretic HormoneADH, Vasopression: promotes water retnention through action on the renal collecting ducts o Deficiency of ADH Diabetes Insipidus [DI] Excretion of large volumes of dilute urine with an inappropriately LOW specific gravity Serum sodium and osmolality are increased as a result of excessive renal loss of free water thirst and polydipsia Administration of ADH increases URINE osmolality in central DI, but no change in nephrogenic DI o Syndrome of Inappropriate Anti Diuretic Hormone [SIADH] Secretion Most commonly caused by ECTOPIC production of ADH [small cell carcinoma of the lung] Retention of water with consequent hyponatremia and reduced serum osmolality Cerebral edema, and resultant neurologic dysfunctionPeripheral edema DOES NOT develop Nonfunctioning Pituitary Tumors o Dysfunction results because of LOACAL MASS EFFECT Manifestations: hypopituitarism, headache, visual disturbances [bilateral hemianopsia: loss of peripheral visual fields] due to pressure on optic chiasm] o Crangiopharyngioma Benign childhood tumor is derived from remnants of Rathke pouch Characteristics include: Bests and cords of squamous cells in a Loose Stroma Often cystic, the lining epithelium of flat or columnar cells often expands into papillary projections Radiographic detection is often possible because of tumor calcification Other causes of pituitary hypofunction o Pituitary APOPLEXY A sudden hemorrhage into the pituitary glandoften into a pituitary adenoma Can cause the sudden excruciating headache, diplopia, cardiovascular collapse, and loss of consciousness o Empty Sella Syndrome Caused by any condition that destroys the pituitary gland Primary empty sella syndrome Defect in diaphragma sella allows the arachnoid and CSF to herniated into the sella expansion of sella and compression of pituitary [obese women with multiple pregnancies] Secondary empty sella syndrome Mass enlarges the sella, then ablated by surgery or radiation, or undergoes SPONTANEOUS necrosis o Nelson Syndrome Development of large pituitary adenomas following bilateral adrenalectomy, due to loss of feedback inhibition on growth of preexisting pituitary microadenomas
Thyroid Gland o Thyroid Hormones Include Thyroxine [T4] and triiodothyronine [T3] Their synthesis depends on sufficient quantities of iodine from dietary sources Serum T3 and T4 are bound to thyroid-binding globulin [TBG] The rate of extraction of iodine from the bloodstream and the rate at which T4 and T3 are synthesized, released, and secreted into the bloodstream are regulated by TSH Feeback mechanisms regulate pituitary production of TSH o Hyperthyroidism [thyrotoxicosis] C/F Tremor Restlessness, irritability, fatigability Heat intolerance; sweating; warm, moist skin [palms] Tachycardia, arrhythmia, palpitationsometimes high-output cardiac failure Muscle wasting and weight loss despite increased appeptitie Fine hair Diarrhea, menstrual abnormalitiescomonly amenorrhea or oligomenorrhea Greatly INCREASED free T4 and greatly REDUCED TSH Total T3 and T4 resin uptake are both Increased Other causes of hyperthyroidism Plummer disease is a combination of hyperthyroidism, nodular goiter, and absence of exophthalmos o The HOT nodules can be adenomas or non-neoplastic areas of nodular hyperplasia Pituitary hyperfunction can cause excess production of TSH and secondary hyperthyroidism Struma ovarii is an ovarian teratoma made up of thyroid tissue; can be hyperfunctional Exogenous administration of thyroid hormone o Hypothyroidism Lab abnormalities: decreased serum free T4, increased TSH Clinical syndromes Cretinism in children o Causes: iodine deficiency, deficiency of enzymes necessary for the synthesis of thyroid hormones, maldevelopment of thyroid gland, placental transfer f antithyroud antibodies from a mother with autoimmune thyroid disease o Clinical Features: severe mental retardation, short stature, coarse facial features, a protruding tongue, and umbilical hernia Myxedema: hypothyroidism manifestation in adults o More common in women than in men o Causes Iodine deficiency is most important cause in non-iodine deficient regions Therapy for hyperthroidism with surgery, irradiation, or drugs Hashimoto thyroiditis Primary idiopathic myxedmea is a poorly defined form of myxedma , which may be of autoimmune origin [TSH receptor blocking antibodies have been identified] o Clinical characteristics of myxedema Insidious onset Slowing of physical and mental activity: fatugue, apathy, and mental sluggishness Cold intolerance and overweigh Reduced cardiac output, shortness of breath, and decreased exercise capacity Accumulation of matrix substances in skin, subcutaneous tissue, and visceral site: enlargement of tongue and deepening of the voice o Thyroiditis Hashimoto thyroiditis Occurs more often in women than in men Cause of hypothyroidism: may occasionally have an early transient hyperthyroid phase Autoimmune disorder: associated with autoantibodies o Most predominantly: antithyroglobulin, antithyroid peroxidase, anti-TSH receptor, and anti-iodine receptor antibodies May also be associated with an increased incidence of other autoimmune disorders such as pernicious anemia, diabetes mellitus, and Sjogren syndrome; increase is increased in HLA-DR5 and HLA-B5 + individuals Clinical characteristics o A slow, often inapparent course and a modestly enlarged and nontender thyroid o Patient is most often eurythroid at first, but transient hyperthyroidism may occur; hypothroidism develops LATE when the gland has shrunken and scarred Histo o Massive infiltrates of lymphocytes with germinal center formation. Thyroid follicles are atrophic and Hurthle cells are important Subacute [deQuervain, granulomatous] Thyroiditis More common in women than in men **Characteristic**Focal destruction of thyroid tissue and granulomatous inflammation Causes a variety of viral infectionmumps or coxsackie Subacute Thyroiditis follows a self-limited course of several weeks duration consisting of a flu-like illness along with pain and tenderness of the thyroid sometimes with transient hyperthyroidism Riedel Thyroiditis Characterized by thyroid replacement by fibrous tissue [may extend to local structureairways]; unknown origin. It can clinically mimic aplastic carcinoma Hard as wood tender thyroid gland Young women o Graves Disease General Occurs more frequently in women than in men Incidence is increased in HLA-DR3 and HLA B8 + individuals Exophthalmos, possibly due to autoimmune mechanisms and independent of thyroid hyperfunctioncharacteristic Manifestations: signs and symptoms of hyperthyroidism Mechanism Thyroid-Stimulating Immunoglobulin, an IgG antibody, reacts with thyroid follicle TSH recepetors and stimulates thyroid hormone production Thyroid growth-stimulating immunoglobulins: proliferation of thyroid follicular epithelium [hyperplasia and enlargement] TSH-binding inhibitor immunoglobulinsprevent TSH from binding normally to its receptor o Goiter general term for enlargement of the thyroid Causes: Physiologic enlargement is not uncommon in puberty and pregnancy Iodine deficiency occurs in geographic areas in which the diet is deficient in iodine Hashimoto Thyroiditis Gointrogens [food and drugs] suppress synthesis of thyroid hormones Dyshormonogenesis, or partial or complete failure of thyroid hormone synthesiscan be aused by various enzyme deficiencies Terminology Diffuse nontoxic [simple] goiter o Is without thyroid hormone dysfunction o Patients are euthryoid or hypothroid Toxic goiter o Associated with hyperthyroidism Endemic goiter is occurring with high frequency in iodine-deficient geographic areas. o Term: sporadic goiter is used for goiter caused by similar mechanisms in non- iodine deficient areas Colloid goiter: o If dietary iodine increases or if the demand for thyroid hormone decreases, the goiter invilutes to form an enlargem colloid-rich gland Nodular goiter o Irregular enlargement of the thyroid resulting in nodule formation o Nodules may be single or multiplemultinodular goiter o Most nodules are hypoplastic and do not take up radioactive iodine [cold nodules] o Occasionally nodules are hyperplastic and actively produce thyroid hormone and take up radioactive iodine [hot nodules] o Benign tumors [adenomas] of the thyroid Typically discrete, solitary masses, derived from follicular epithelium, and are also know as folllicular adenomas Follicular adenoma Encapsulated lesion that is well demarcated from surround thyroid parenchyma. Neoplastic cells are demarcated by a well-defined,intact CAPSULE Most oftennonfunctional, but they can occasionally cause hyperthyroidism o Malignant tumors of the thyroid Papillary carcinoma Most common thyroid cancer Histo o Papillary projections into gland-like spaces; nuclei of papilarry carcinoma have optically clear or empty appearance: ground glass//Orphan Annie nuclei o Concentrically calcified structurespsammoma bodies may be present Have better prognosis than other forms of thyroid cancer; even when adjacent LN are involved Can be associated with changes in chromosomeparacentric inversion of chrom 10 or reciprocal translocation between chroms 10 and 17] constitutively activate tyrosine kinase domain of RET [novel fusion genes formed are RET/PTC] Can be long-term consequence of prior radiotherapy to the neck Follicular Carcinoma Characterized histo: relatively uniform follicles Deficiency of dietary iodine [assc with goiter] is linked with a higher freq of follicular carcinoma. Poorer prognosis than papillary carcinoma Gain of function POINT mutation: RAS, PIK3CA Loss of function of PTEN Unique (2;3)(q13;p25) translocated fusion of PAX 8 with PPARG 1/3 to of follicular carcinomas [PAX8-PPARG fusion genes] Distinction from follicular adenoma requiresextensive histo sampling of tumor capsule thyroid interfaceto exclued CAPSULAR AND/OR VASCULAR INVASION Medullary carcinomas Originates from parafollicular cells [C cells] of the thyroidproduces CALCITONIN Histologic characteristics include sheets of tumor cells in an amyloid stroma Familial medullary thyroid carcinomas occur in MEN2 and are associated with RET proto-oncogene mutations lead to constitutive activation of the receptor RET mutations are also seen in approximately of nonfamilial [sporadic] medullary thyroid cancers Undifferentiated carcinoma Tends to occur in older patients and has a very poor prognosis RAS or PIK3CA mutations are at a significantly higher rate Inactivation of p52 or activating mutations of beta-cateninrestricted to ANAPLASTIC carcinoma o Congenital anomalies Thyroglossal duct cystmost common thyroid anomaly!! Vestigial remnant of the Tubular development of the thyroid gland
Parathyroidism [PTH] o Parathyroid Homrone [PTH] The parathyroid glands are responsive to the plasma concentration of ionized calcium; decreased calcium concentration stimulates PTH production Hypercalcemia is induced by elevated levels of PTH. Malignancy is MOST common cause of clinically apparent hypercalcemia o Hyperparathyroidism Primary hyperparathyroidism Most often, the cause is parathyroid adenoma; a few cases are caused by primary parathyroid hyperplasia; carcinoma is RARELY a cause Less often, the cause is production of PTH-like hormone by nonparathyroid malignant tumors such as bronchogenic squamous cell carcinoma or renal cell carcinoma Primary parathyroidism can occur as part of MEN-1 and MEN-2A Primary hyperparathyroidism is a more common cause of asymptomatic elevated blood calcium Lab Findings: o Hypercalcemia and hypercalciuria o Decreased serum phosphorus, decreased tubular reabsorption of phosphorus, and increased urinary phosphorus o Increased serum alkaline phosphatase o Increased Serum PTH Clinical characteristics o Osteitis fibrosa cystica, cystic changes in bone due to osteoclastic resorption; fibrous replacement of resorbed bone formation of non-neoplastic tumor-like masses brown tumor o Metastatic calcification affecting various tissueskidneys [nephrocalcinosis] o Renal calculi, frequent complication o Peptic duodenal ulcer; hypercalcemia predisposes to peptic ulcer Secondary hyperparathyroidism Compensatory parathyroid hyperplasia occurs in response to decreased concentration of serum ionized calcium The most common cause is hypocalcemia of chronic renal disease o Reduced alpha-1hydroxylase necessary for the synthesis of active form of Vitamin Dwhich reduced intestinal absorption of calcium o The increased serum phosphorus of renal disease induces a reciprocal decrease in serum calcium Characteristics: o Decreased serum calcium, increased serum phosphorus, and increased serum alkalin phosphatase o Diffuse osteoclastic bone disease o Metastatic calcification o PTH increased Teritiary hyperparathyroidism Persistent parathyroid hyperfunction occurs inspite of correction of hypocalcemia and preexisting secondary hyperparathyroidism Often, the cause is development of an adenoma in previous hyperplastic gland o Hypoparathyroidism The most common cause is accidental surgical excision during thyroidectomy In rare instances, this disorder is associated with congenital thymic hypoplasia [DiGeorge syndrome] Severe hypocalcemia manifest clinically by increased neuromuscular excitability and tetany**characteristic** o Pseudohypoparathyroidism Decreased calcium, increased phosphate, and increased PTH Characterized: multihormone resistance involving PTH and pituitary hormones: TSH, LH, and FSH Additional characteristics include End organ unresponsiveness of the kidney to PTH, as well as shortened 4 th and 5 th
metacarpals and metatarsals, short stature, and other skeletal abnormalities Endocrine Pancreas o Type I DIABETES MELLITUS Epidemiologic and etiologic factor Often begins early in life, usually before 30 years of age Less common than type 2 disease Type 1 diabetes is due to failure of insulin synthesis by BETA cells of the Islets of Langerhans in the Pancreas The cause maybegenetic predisposition complicated by autoimmune inflammation of islets [insulitis] triggered by viral infection or environmental factors Incidence is greatly increased in individuals with a specific point mutation in HLA-DQ gene Incidence is markedly increased in HLA-DR3 and HLA-DR4 + individuals Characteristics Unless insulin is replaced, type 1 diabetes marked carbhohydrate intolerance with hyperglycemia LEADING to Polyuria, polydipsia, weight loss despite increased appeitie, ketoacidosis, coma and death Diabetic Ketoacidosis from increased catabolism of fat, with production of ketone bodies o Type 2 Diabetes Epidemiologic and etiologic factors Type 2 diabetes is much more common. A + family history is more frequent than in type 1. Characteristically begins later in life [middle age] 2 metabolic defects characterize Type 2 Diabtetes o Insulin resistance: a decreased response of peripheral tissues to insulin o Beta-Cell Dysfunction: manifested as inadequate insulin secretion Obesity has an important relationship with insulin resistance Risk factors for diabetes increases as BMI increases Other players include o Nonesterfied Fatty Acids [NFAs, lipotoxicity] and the PPAR-gamma receptor, which promotes secretion of anti-hyperglycemic adipokines and shifts deposition of NEFAs toward adipose tissue Characteristics The plasma insulin concentration is NORMAL and often INCREASED Mild carbohydrate tolerance can be managed by diet and oral antidiabetic agents In decompensated state, type 2 diabetics may develop hyperosmolar ketotic coma. Ketoacidosis is unusual but does occur, precipitated by stress such as infection or surgery o Maturity-onset Diabetes Mellitus of the young [MODY] This AUTOSOMAL dominant syndrome is characterized by: Mild hyperglycemia and hyposecretion of insulin NO loss of beta-cells Earlier onset than dibatetes mellitus type 2 Caused by a diverse group of single gene defects o Secondary diabetes mellitus occurs as a secondary phenomenon Pancreatic disease Hereditary hemochromatosis [bronze diabetes] Characteristics: excess iron absorption and parenchymal deposition of hemosiderin, with reactive fibrosis in various organspancreas, liver, and heart Pancreatitis: o Acute pancreatitis: hyperglycemia o Chronic pancreatitis: result in islet cell destruction and secondary diabetes mellitus Carcinoma of pancreasDiabetes Mellitus maybe presenting sign Other endocrine diseases Cushing syndrome: o Produces hyperglycemia as a result of increased gluconeogenesis and impaired peripheral utilization of glucose Acromegaly o Produces hyperglycemia due to the anti-insulin-like effect of GH Glucagon hypersecretion o Promotes: Glycogenolysis o Characteristically caused by: islet alpha cell tumor [glucagonoma] Other endocrine disorders o Pheochromocytoma and hyperthyroidism sometimes associated with hyperglycemia Pregnancy Pregnancy may be associated with transient diabetes mellitus [gestational diabetes]; over nongestational diabetes sometimes develops later DM is characteristically associated with increased fetal birth weight and increased fetal mortality; notably from neonatal Respiratory Distress Syndrome [hyaline membrane disease] When a mother has hyperglycemia, her infant may be born with hyperplasia of pancreatic islets and hypoglycemia! o Long term complications of DM Pathogenesis of the long-term complications of DM is similar in both types Persistent hyperglycemia is key mediator Assessment of glycemic control has been based on glycosylated hemoglobin [Hb1AC] HB1AC provides a measure of glycemic control over the lifespan of a red cell [120 days, little affected by day-day variations] Three underyling mechanisms Formation of advanced glycation end products [AGEs] through nonenzymatic glycosylation Activation of intracellular protein kinase C [PKC] Accumulation of intracellular sorbitol Pancreatic islets Type 1 diabetes o Islets are small and beta cells are greatly decreased in number or are absent o Insulitis marked by lymphocytic infiltration is a highly specific early change Type 1 Diabetes o Amyloid replacement of islets is a characteristic finding with long-standing type 2 DM islet amyloid deposition Is thought to interfere either with the conversion of proinsulin to insulin or with the sensing of insulin by beta-cells Kidney Thickening of glomerular basement membrane: is the earliest and most common renal manifestation Diffuse glomerulosclerosis, nodular glomerulosclerosis [Kimmelstiel-Wilson disease], arteriolar lesions, and exudative lesions fibrin cap or capsular drop Pyelonephritis is a frequent complication that may be compounded by renal papillary necrosis CVS Incidence of atherosclerosis is greatly increased Clinically significant atherosclerotic complications occur at a MUCH earlier age than in nondiabetics The incidence in women, both premenopausal and postmenopausal, is GREATLY increased Myocardial infarction and Peripheral Vascular Insufficiency [gangrene of lower extremities] Capillary Basement Membrane THICKENING occurs in multiple organs and is due to nonenzymatic glycosylation of membrane protein Eye Cataract formation is common Proliferative retinopathy [retinal exudates, edema, hemorrhages, and micro-aneurysms of small vessels] can lead to blindness Nervous System Peripher Neuropathy and changes in brain and spinal cord Liver Fatty change is seen Skin XANTHOMAS: collection of lipid-laden macrophages in the dermis Furnuncles and abscesses because of increased propensity to infection Frequent fungal infectionespecially Candida o Endocrine tumors [islet cell tumors] Insulinomabeta cell tumor: most COMMON islet cell tumor Characterized by greatly increased secretion of insulin Can be benign or malignant Circulating C-Peptide is increased in patients with insulinoma In contrast C-peptide is NOT increased by exogenous insulin adminstration Clinical characteristics= TRIAD o 1. Episodic hyperinsulinemia and hypoglycemia o 2. CNS dysfunction related to hypoglycemia [confusion, anxiety, stupor, convulsions, coma] o 3. Dramatic reversal of CNS abnormalities by glucose administration Gastrinoma is often malignant and sometimes occurs in extrapancreatic sites It results in gastrin HYPERSECRETION and HYPERGASTRINEMIA Associated with Zollinger-Ellison syndromemarked gastric hypersecretion of HCl, recurrent peptic ulcer disease and hypergastrinemia Glucagonoma [Alpha cell tumor] rare Results in secondary diabetes mellitus Causes a characteristic skin lesion: necrolytic migratory erythema VIPoma is rare Marked by secretion of vasoactive intestinal peptide [VIP] Associated with Water Diarrhea, Hypokalemia, and Achlorhydria [WHDA] Syndrome Adrenal Glands Cushing Syndrome [HYPERCORTISOLISM] o Causes: increased circulating glucocorticoidsprimarily cortisol Exogenous corticosteroid medication [most common] Hyperproduction of ACTH by corticotrophs of the pituitary Adrenal cortical adenoma or adrenal carcinoma [less common than adenoma] Ectopic production of ACTH by nonpituitary tumors Especially small cell carcinoma of lung**** Hypercortisolism is autonomous and cannot be suppressed by exogenous adrenal steroids [dexamethasone suppression test] The autonomous ACTH stimulation elimates the normal circadian rhythm of cortisol production o Clinical characteristics of CUSHING Syndrome Central pattern of adipose tissue deposition becomes apparent: truncal obesity, moon facies, and buffalo hump; often with relatively thin extremities caused by muscle wasting Skin atrophy with easy bruising and purplish striae, especially over abdomen; Hirsutism Muscle weakness, osteoporosis, amenorrhea, HTN, Hyperglycemia, and psychiatric dysfunction o Morphological changes of Cushing syndrome in adrenal gland Bilateral hyperplasia of adrenal Zona Fasciculata occurs when results from ACTH stimulation Adrenal cortical atrophyseen when exogenous glucocorticoid medication is the cause Adrenal cortical adenoma** or carcinoma o ACTH determinations are useful diagnostic measures in determining the cause of hypercorticism ACTH is Increased in pituitary hypercorticism and in ectopic ACTH production [S.C.C of lung] Low when hypercorticolism is of ADRENAL origin Determing the cause depends on SERUM ACTH and measurement of urinary steroid excretion after administration of Dexamethasone {Dexamethasone suppression test} ACTH Cortisol Interpretation Elevated Elevated; not suppressed by LOW doeses, but suppressed by HIGH doses [suppression of urinary steroid secretion] Pituitary Cushing Syndrome [Cushing Disease] Elevated Elevated; not suppressed by HIGH or LOW doses [insensitive to exogenous dexamethasone] Ectopic ACTH secretion: ACTH- secreting tumors [S.C.C of lung] Low Elevated; not suppressed by HIGH or LOW doses Primary Cushing Syndrome problem with adrenal gland itself
Hyperaldosteronism o Primary Aldosteronism The cause is primary hyperproduction of adrenal MINERALCORTICOIDS Usually results from an aldosterone producing adrenocortical adenoma [Conn Syndrome] It can also result from hyperplasia of Zonal glomerulosararely may be caused by adrenocortical carcinoma Clinical Characteristics: Hypertension, sodium and water retention, and hypokalemiaoften with hypokalemic alkalosis Decreased serum RENIN occurs due to FEEDBACK inhibition of increased blood pressure of rennin secretion. o Secondary Aldosteronism This condition is secondary to renal ischemia, renal tumors, and edema [cirrhosis, nephritic syndrome, and cardiac failure] The cause is stimulation of RAAS Serum Renin is increased; in contrast to primary aldosteronism Adrenal VIrilism [Adrenogenital System] o Congenital ENZYME defects diminished cortisol production and compensatory increased ACTH with resultant adrenal hyperplasia with androgenic steroid produ ction 21-HYDROXYLASE DEFICIENCY!!! Most common, in its most severe salt-wasting form results in SALT losss and HYPOTENSION 11-Hydroxylase Deficiencymuch less common results in SALT retention and hypertension o Can also be caused by tumors of the adrenal cortex o Clinical charcateristics: Virilism in females and precocious puberty in males Adrenocortical InsufficiencyHypofunction o Primary adrenal disease [primary hypoadrenalism] o Decreased stimulation of adrenal glands due to deficiency of ACTH secondary to hypothalamic or pituitary dysfunction [secondary hypoadrenalism] o Deficiency of glucocorticoids [primary cortisol], often with associated mineralcorticoid deficiency characteristic Chronic Adrenocortical InsufficiencyAddison Disease o The most commonly due to idiopathic adrenal atrophyautoimmune adrenalitis o It can also be caused by TB, AIDS, and metastatic cancers o Characteristics Hypotension Increased pigmentation of skin Decreased serum sodium, chloride, glucose, and bicarbonae Increased Potassium Waterhouse-Friderischen Syndrome o Massive bilateral adrenal hemorrhage with rapidly developing adrenocortical insufficiency due to hemorrhagic necrosis of the adrenal cortex o Often associated with Disseminated Intravascular Coagulation o Overwhelming bacterial infectionespecially Neisseria meningitides septicemia [meningococcemia] Tumors of Adrenal Medulla o Pheochromocytoma Derived from chromaffin cells of the adrenal medulla; paragangliomaif it is derived from extra-adrenal chromaffin cells Most often benign 10% malignant HTN results from hyperproduction of catecholamines [epinephrine and norepinephrine] HTN= paroxysmal and surgically correctable Increased urinary excretion of catecholamines and their metabolites [metanephrine and vanillymandelic acid]**Characteristic** Can be part of MEN-2 Can be associated with Neurofribomatosis or with von Hippel-Lindau Multiple Endocrine Neoplasia [MEN] Syndromes o MEN-1 [Wermer Syndrome] Includes hyperplasias or tumors of the pituitary, parathyroid, or pancreatic islets [3 Ps] In addition may include hyperplasia/tumors of thyroid or adrenal cortex It is linked to mutations in the MEN 1 gene May manifest its pancreatic component by Zollinger-Ellison syndrome, hyperinsulinism, or pancreatic cholera o MEN 2A- Sipple Syndrome Includes pheochromocytoma, medullary carcinoma of the thyroid, and hyperparathyroidism due to hyperplasia/tumor Linked to mutations in the RET oncogene. When a diagnosis of pheochromocytoma is madethe finding CHARACTERISTIC RET mutations would justify prophylactic thyroidectomy o MEN 2B Includes pheochromocytoma, medullary carcinoma, and multiple mucocutaneous neurons or ganglioneuromas No hyperparathyroidism A single amino acid change in RET-!!