PARATHYROID • 4 located within thyroid (2 on each side) • composed mainly of Chief cells a) secrete PTH • controlled mainly by blood Ca++ and NOT by any throphic hormone(s) a) levels of free ionized Ca++ stimulate synthesis and secretion • PTH receptor (G protein) a) activation of adenyl cyclase cAMP • PTH actions: ( calcium - hypercalcemia) a) activates osteoclasts b) renal tubule Ca++ reabsorption c) Vit D conversion to active form d) GI absorption of Ca++ e) these listed actions Ca++ i) negative feedback controls PTH • hypercalcemia is common complications of malignancy a) most common cause of hypercalcemia i) poorest outcome (advanced cancers) • primary hyperparathyroidism is, however, the most common cause of asymptomatic hypercalcemia • Hyperparathyroidism a) 2 major forms – primary and secondary (less common is tertiary) • Primary hyperparathyroidism a) autonomous overproduction of PTH b) one of most common endocrine disorders i) important cause of hypercalcemia c) typical causes: i) adenomas (~ 80% of cases) ii) 1O hyperplasia (diffuse or nodular) iii) parathyroid carcinoma (< 5%) d) female predominance (3:1) e) adult disease (50’s and >) f) over 95% due to sporadic adenoma/cell g) genetic influences i) MEN-1 syndrome (discussed later) ii) MEN-2 syndrome (tyrosine kinase receptor mediated) - MEN-2A specific iii) familial hypocalciuric hypercalcemia h) clinical presentation: i) asymptomatic - Ca++ ; PTH hypophosphatemia; Urine excretion of both calcium and phosphate ii) PTH is low in hypercalcemia due to non parathyroid disease iii) symptomatic “painful bones, renal stones, abdominal groans and psychic moans” • Secondary hyperparathyroidism a) anything causing plasma Ca++ i) renal failure most common cause - chronic renal failure serum PO4 directly depress serum Ca++ parathyroid activity • Tertiary hyperparathyroidism a) in small number of cases, parathyroid gland may become autonomous and excessive • Hypoparathyroidism a) less common than hyper- b) causes: i) surgical induced ii) congenital absence iii) familial hypoparathyroidism iv) idiopathic c) hypocalcemia is result and causes: i) tetany!! (hallmark) characterized by neuromuscular irritability - Chvostek sign: tapping along the facial nerve causes contraction of muscles of eye, mouth or nose - Trousseau sign: occluding circulation to forearm induces carpal spasms ii) emotional instability, anxiety, depression, hallucinations, etc… iii) CV – conduction abnormalities (i.e., prolonged QT interval) iv) ocular disease – cataract formation v) dental – caries, etc… • Pseudohypoparathyroidism a) end-organ resistance to PTH ADRENALS • Adrenal Cortex • Adrenocortical Hyperfunction (hyperadrenalism) • Adrenal secretes 3 major groups of steroid hormones a) glucocorticoids (cortisol) – Cushing Syndrome b) mineralocorticoids (aldosterone) – hyperaldosteronism c) androgens – virilizing syndromes 1.Cushing Syndrome a) any factor that causes cortisol (i.e., glucocorticoids) i) mainly due to administration of glucocorticoids (iatrogenic) ii) hypersecretion of ACTH iii) hyperplasia or neoplasia iv) ectopic secretion of ACTH • In hypersecreting ACTH (ii above) “Cushing Disease” a) more often in women b) 20-30 yrs c) in most patients, pituitary usually has small ACTH secreting adenoma i) less sensitive to (-) feedback control on ACTH release d) anterior pituitary has areas of corticotroph-cell hyperplasia without adenoma e) CRH from hypothalamus f) neoplasia/hyperplasia ~30% of cases of Cushing syndrome g) most other case caused by ectopic sites of ACTH secretion (usually small carcinoma of lung) i) other sites have included pancreas, thyroid • Clinical a) patients who have exogenous glucocorticoids (i.e., cortisol) i) adrenals are atrophied due to ACTH release b) endogenous ACTH adrenal hyperplasia c) known affects of glucocorticoids i) hypertension ii) weight gain (“moon face” “buffalo hump”) iii) atrophy of fast (type II) twitch myofibers muscle atrophy and limb weakness iv) hyperglycemia and glucosuria v) proteolysis and bone resorption (osteoporosis) vi) suppresses immune system risk for infections vii) hirsuitism viii) CNS mood changes Hyperaldosteronism • Excessive levels of aldosterone a) sodium retention b) potassium excretion c) which results in BP and hypokalemia • Primary or Secondary a) primary i) autonomous overproduction of aldosterone renin-angiotensin system ii) caused by adrenocortical adenoma or by hyperplasia iii) primary aldosterone secreting adenoma (in >80%) – “Conn syndrome” iv) carcinomas are rare v) no ACTH (-) feedback; therefore other regions of adrenals are not atrophic vii) Conn syndrome more often in adults whereas hyperplasia occur more often in children Adrenogenital Syndrome • Caused by variety of diseases a) primary gonadal disorders and b) primary adrenal disorders • Adrenal cortex a) secretes i) dehydroepiandrosterone ii) androstenedione b) both require conversion to testosterone in peripheral tissues c) these adrenal androgen formation requires ACTH i) secretion can occur de novo or through ii) excess ACTH secretion (e.g., Cushing Syndrome) d) adrenal causes of androgens i) neoplasms (more likely to be carcinomas) ii) adrenal hyperplasia - group of autosomal recessive disorders causing cortisol production with feedback in ACTH with resultant adrenal hyperplasia (e.g., congenital) - the most common enzymatic defect in congenital adrenal hyperplasia is 21-hydroxylase deficiency which accounts for ~95% of cases. • Clinical: a) congenital adrenal hyperplasia i) bilateral adrenal hyperplasia - driven by ACTH b) hyperplasia of ACTH producing cells is present in anterior pituitary c) clinical manifestation determined by specific enzyme deficiency i) androgens ii) sodium homeostasis iii) depending on severity of diseases, S & S usually present during infancy and early childhood and less commonly during childhood. d) 21-hydroxylase deficiency causes excessive androgenic activity i) masculinization in females - hirsutism - oligomenorrhea ii) in males, enlargement of external genitalia e) some rare forms of congenital adrenal hyperplasia i) 17--hydroxylase deficiency ii) in other forms of congenital adrenal hyperplasia (e.g., 11-hydroxylase deficiency) - accumulated intermediates steroids have sodium retention properties and subsequent hypertension f) congenital adrenal hyperplasia should be suspected in neonate with ambiguous genitalia i) severe enzyme deficiency in infancy can be life threatening - vomiting - diarrhea - sodium loss (dehydration) ii) in all cases, an androgen producing neoplasm in the ovary must be R/O Adrenal Insufficiency (adrenocortical hypofunction) • May reflect either primary adrenal disease (i.e., primary hypoadrenalism) or secondary via decreased stimulation of the adrenals caused by ACTH deficiency (e.g., Sheehan syndrome, nonfunctioning pituitary adenomas and/or lesions of hypothalamus, etc.) • Further divided (primary adrenocortical insufficiency) a) chronic primary adrenocortical insufficiency (Addison Disease) or b) acute primary adrenocortical insufficiency 1. Addisons Disease (chronic) • Progressive destruction of adrenal cortex a) S & S usually do not appear until ~90% of adrenal gland has been compromised • Causes: a) autoimmune adrenalitis i) ~75-90% of all cases of Addison disease in developed countries ii) sporadically or familial component iii) In ~50% of patients, autoimmune cause affects only the adrenal glands whereas the remaining patients also exhibit other autoimmune disorders - Hashimoto - Pernicious anemia - Type I diabetes - idiopathic Hypoparathyroidism iv) Type I and II polyglandular syndrome -Type I: - autosomal recessive; mutations located on chromosome 21q -Type II: - strong link to histocompatibility antigens (HLA-B8, HLA- DR3 and HLA-DQ5) v) circulating antibodies to several steroidal enzymes (e.g., 21 and 17-hydroxylase) have been found in all types of autoimmune adrenalitis b) Infections i) TB (accounted for ~90% of primary chronic adrenocortical insufficiency) antituberculosis drugs have the incidence of Addisons disease ii) Fungi (Histoplasma capsulatum and coccidioides immitis) iii) AIDS, due to contracting a variety of infections c) Metastatic neoplasms i) common site of metastatic disseminated carcinomas ii) carcinomas of breast and lung are source of majority of metastases in the adrenals iii) other neoplasms from GI, melanomas and hematopoietic neoplasms may also metastasize to the adrenals • Clinical a) insidious onset with progressive weakness and easy fatigability b) GI disturbances are common complaint i) anorexia, vomiting, nausea, weight loss and diarrhea c) In patients with primary disease, melanocytes are stimulated with hyperpigmentation (via ACTH precursor hormone stimulation) i) face, axilla,nipples, areola, perineum ii) hyperpigmentation is not seen in primary pituitary or hypothalamic disease d) Primary adrenal insufficiency i) aldosterone Na+ loss; K+ retention; volume depletion hypotension ii) heart smaller than normal (? Chronic hypovolemia) iii) hypoglycemia (via glucocorticoid deficiency) and impaired gluconeogenesis iv) acute stress in the patients (e.g., infections, surgical procedures, trauma) may initiate an “acute adrenal crisis” - intractable vomiting - abdominal pain - hypotension, vascular collapse, - coma - death unless corticosteroids are replaced immediately. 2. Acute Adrenocortical Insufficiency • Rapid withdrawal of steroids (from previous treatment) • Massive adrenal hemorrhage a) destroy adrenal cortex i) may occur in patients maintained on chronic anticoagulant therapy ii) pregnancy iii) DIC iv) overwhelming sepsis (i.e., Waterhouse-Friderichsen syndrome) - classically associated with Nisseria meningitides septicemia - also can be caused by pneumococci, Haemophilus influenza and pseudomonas sp. - pathogenesis unclear (may involve ETX induced vascular damage?) - DIC, shock, skin purpura - more common in children - massive adrenal clots Adrenocortical Neoplasms • May be responsible for a variety of hyperadrenalisms a) functional adenomas most commonly associated with hyperaldosteronism and Cushing syndrome • A virilizing neoplasm high incidence to be carcinogenic • Functional and non-functional adrenocortical neoplasms cannot be differentiated solely on basis of morphology a) hormone measurements b) most adrenocortical adenomas do not cause hyperfunction • Adrenocortical carcinomas are rare a) two rare inherited adrenal cortical carcinomas i) Li-Fraumeni syndrome - autosomal dominant - predisposition to develop other cancers due to mutations in p53 ii) Beckwith-Wiedemann syndrome • Generally, adrenal adenomas are small (1-2cm) whereas adrenal carcinomas are large, invasive lesions a) adrenal carcinomas metastasize via lymphatics and inferior vena cava i) mean survival is ~2 yrs. Adrenal Medulla • Most important diseases of adrenal medulla are the neoplasms a) neuronal i) neuroblastoma ii) mature ganglionic cell tumors b) chromaffin cells i) pheochromocytoma • Pheochromocytoma a) neoplasm composed of chromaffin cells i) synthesize and release catecholamines b) familial syndromes (~10%) i) MEN2A and MEN2B ii) type I neurofibromatosis iii) Von Hippel-Lindau disease iv) Sturge-Weber syndrome c) Extra-adrenal source (~10%) i) carotid body ii) organ of Zuckerkandl d) are bilateral (~10%) i) may be as high as 50% in familial cases e) malignant (~10%) i) more common when arise in extra- adrenal sites f) clinical i) hypertension! - chronic, elevated BP (~70% of cases) ii) other hormones can be secreted - ACTH - somatostatin iii) dx urinary excretion of catecholamines and metabolites - vanillylmandelic acid - metanephrines iv) isolated pheochromocytomas treated surgically - multifocal medically treated Multiple Endrocrine Neoplasia Syndromes (MEN) • Group of inherited diseases a) hyperplasias, adenomas and carcinomas of multiple endocrine organs i) occur at younger age vs. cancers ii) arise in multiple endocrine organs iii) even in one organ, they are multifocal iv) tumors preceded by hyperplasia v) more aggressive and recur more frequently vs. sporadic tumors • MEN-1 a) inherited as autosomal dominant b) is a tumor suppressor gene i) loss of MEN-1 therefore causes tumor genesis - parathyroid (95% involved) - pancreas (>40%) - pituitary (>30%) • Parathyroid gland a) primary hyperparathyroidism arising from hyperplasia is a common feature of MEN-1 • Pancreas a) leading cause of death in MEN-1 b) aggressive c) often functional tumors i) gastrinomas (Zollenger-Ellison syndrome) ii) insulinomas and resultant hypoglycemia • Pituitary a) most common in MEN-1 is prolactinoma • MEN-2b (William syndrome) a) involve also the thyroid b) adrenal (medulla) c) major differences between MEN-2a and MEN-2b is i) do not develop primary hyperparathyroidism (MEN-2b) ii) develop at extra endocrine sites - lips - tongue - GI tract • MEN-2 carry RET Protooncogene a) persons are advised to have prophylactic thyroidectomy to prevent carcinoma.