Adrenal, parathyroids, Thymus, Pineal study notes Adrenal Cortex - three zones: 1) zona glomerulosa - mineralcorticoid production; thin 2) zona faciculata - glucocorticoid production, resting cells, yellow 3) zona reticularis - glucocorticoid production, androgen and estrogen production, grossly darker than other layers; brown mnemonic - sugar, salt, sex, the deeper you go the sweeter it gets Ectopic Adrenal Cortical Tissue - most common in the capsule, but it can occur anywhere in the retroperitoneum, or under capsules of liver, kidney, ovary, or testis - ectopic adrenal caused problems when surgical adrenalectomy was very popular Hypoadrenalism - Addisonism; insufficient glucocorticoid (and usually unsufficient mineralcorticoid) production - chronic hypoadrenalism - trouble starts when 80% of the gland is gone - etiologies: - infectious - most pts had bovine TB of the adrenals; worldwide fungal, leprosy, and AIDS are important causes too - autoimmune - most prevalent non-iatrogenic cause of Addison's today; Jack Kennedy - most pts have antibodies against 21-hydroxylase - often occurs jointly with Hashimoto's thyroiditis, type I diabetes, vitiligo, gluten enteropathy, and/or pernicious anemia - iatrogenic - resilts from too rapid withdrawal of glucocorticoid medication, ketoconazole, post-adrenalectomy, etc. - others - amyloidosis, congenital hypoplasia, hemochromatosis, sarcoidosis, metastatic cancer to adrenals, anticoagulant therapy, CMV infection - ACTH deficiency (secondary hypoadrenocorticism) - these pts have almost always lost their adenohypophysis and have panhypopituitarism; less often, they have selective, presumably autoimmune, loss of ACTH producing cells - clinical picture - Addisonism pts show weakness, nausea, and weight loss, and are usually hypotensive - in primary hypoadrenocorticism, the skin and buccal mucosa will usually be hyperpigmented, due to an increased ACTH - typically show hyponatremia, hyperkalemia, metabolic acidosis, hypoglycemia, low serum cortisol, low urinary 17-OH-steroids, and failure to respond to various stimulation tests by inreasing cortisol output - replacement therapy is life-saving - selective hypoaldosterism - rarely due to primary disease of the adrenal cortex - much more often, the problem is really that the JGA is not producing renin - usually the problem is diabetic arteriolar disease; less often, it is one of the diseases of the renal tubules and/or interstitium - acute hypoadrenocorticism - sudden collapse, often fatal - it may result from undiagnosed adrenal insufficiency, or from known Addison's disease when extra glucocorticoids are not provided during stress - Waterhouse-Friderichsen syndrome - cause of death is probably myocarditis rather than adrenal failure - occurs when there is overwhelming sepsis with hemorrhage into, and destruction of, the adrenals - pts develop purpura, shock, and die in a few hours - classically N. meningitidis, also staph, strep, pneumococci, and H. influenze - not rare, and often overlooked Cushing's Syndrome - too much glucocorticoid; etiologies, from most to least common: 1) iatrogenic - preventable in part by giving alternate day glucocorticoid therapy 2) ACTH-producing pituitary lesion - usually a basophilic microadenoma - the adrenals will be nodular, often with one or more large nodules - Nelson's syndrome - rapid enlargement of the pituitary adenoma leading to hyperpigmentation, blindness, and death 3) Adrenal cortical adenoma or carcinoma - tumor may be primary, or an autonomous adrenal tumor may develop after years of pituitary Cushingism 4) ACTH- (or CRH-) producing cancers of other organs - oat cell carcinoma, carcinoid, medullary thyroid carcinoma, islet cell carcinoma, islet cell cancer - both Cushing's disease and glucocorticoid-secreting adenomas are most common in women ages 15 to 45, but can hit anybody - signs and symptoms of Cushing's - truncal obesity with buffalo hump and moon face - increased appetite - insomnia and mental changes - vascular and connective tissue changes; thinning of the dermis, poor healing - high blood pressure - glucose intolerance - osteoporosis - loss of normal circadian rhythm of cortisol secretion Primary Hyperaldosteronism (low-renin hyperaldosteronism) - too much mineralcorticoid - an important cause of surgically-correctable high blood pressure - pts exhibit hypokalemia, alkalosis, and low renin, and a failure of plasma aldosterone levels to increase significantly when the pt goes from supine to standing position - pts do not have edema (excess aldosterone prevents the action of hADH) - the usual cause is autonomous adrenal cortical adenoma (Conn's syndrome), it produces aldosterone - some pts have idiopathic hyperaldosteronism with normal or hyperplastic adrenals - these pts usually remain hypertensive after adrenalectomy - a few pts have glucocorticoid-correctable hyperaldosteronism and hypertension; autosomal dominant; now clear that there is a chimeric B-hydroxylase/aldosterone synthetase gene - secondary aldosteronism is much more common - part of the picture of CHF, cirrhosis, nephrotic syndrome, Goldblatt hypertension, and others - don't confuse this with salt-retaining congential adrenal hyperplasia Congenital Adrenal Hyperplasia - autosomal recessive virilization syndromes that affect young children - deficiencies of the enzymes result in decreased production of cortisol and other hormones - this results in increased ACTH, with resulting adrenal cortical hyperplasia - steroid precursors are shunted into the production of abnormally large amounts of androgens - remember these two types: - 21-hydroxylase deficienccy - no cortisol, aldosterone, or DOC, hence salt wasting - 11-betahydroxylase deficiency - huge amounts of DOC, causing salt retention and high blood pressure - full-blown congenital adrenal hyperplasia is a devastating illness, especially for women Adrenal Cortical Adenomas - these are round, yellow nodules - adrenal cortical adenomas are surprises at around 2% of autopsies and abdominal CTs - they can cause Cushing's syndrome, Conn's syndrome, or virilization - but the vast majority produce nothing Adrenal Cortical Carcinoma - these are rare cancers with dismal prognosis; most are hormonally active - cancer in the adrenals is usually metastatic carcinoma; half of all lung cancers metastasize to the adrenals The Adrenal Medulla - not essential to life - the source of adrenalin; at autopsy, it is grey, unless it has autolysed - the only diseases are two tumors which may arise here or at the other chromaffin tumor masses - pheochromocytoma and neuroblastoma Pheochromocytoma - this tumor is named for its colorful reaction in fixatives containing chromic acid salts - pheochromocytomas secrete NE and/or Epi - even a tiny benign pheochromocytoma can make a person sick - most occur in the adrenal medulla; other sites are the organ of Zuckerkandl, paravertebral sympathetic chain, urinary bladder, or paraganglia such as the carotid body - ten percent of pheo cases involve both adrenals, and many of these are also among the 10% that are familial - you will often be reminded of the MEA - common autosimal dominant conditions that predispose pts to certain endocrine tumors; prenatal diagnosis is available for these syndromes: - MEA I : PPP (Wermer's syndrome) - parathyroid adenomas, pituitary adenoma, pancreatic islet cell adenoma - MEA IIa: PAC (Sipple's syndrome) - parathyroid adenomas, adrenal medullary tumor, calcitonin-producing hyperplasia-carcinoma of the thyroid - MEA IIb: - similar to MEA IIa; the pts have Marfanoid body habitus and mucosal neuromas, and are less likely to have parathyroid problems - grossly, pheos are very bloody, and often show fibrosis, calcification, cystic change, or even fatty change - there is no histologic criteria for malignancy, not even vascular invasion - regardless of location and appearance, the pt will report anxiety, HA, palpitations, panic attacks, sweating, dizziness, etc. - textbook pheo pts have paroxysms of severe hypertension - present in fewer than 1% of people with high BP - high levels of circulating catecholamines can damage the myocardium - screening tests for pheos detect increased amounts of catecholamines or their metabolites in blood or urine - treatment is surgical, with very careful management of fluid status and blood pressure before and after surgery Neuroblastoma - the second most commonest solid pediatric cancer (after Wilm's tumor) - it is derived from primitive nerve elements - around half arise near the adrenals - grossly, they are soft, white tumors - portions often undergo dystrophic calcification - tumor of small blue cells, with scanty cytoplasm - most produce catecholamines, resulting in elevated urinary metabolites - classic test is testing urine for homovanillic acid (HVA) and vanilylmandelic acid (VMA) - prognosis is better for younger pts - in a neonate, the tumor is likely to regress/differentiate - in a child over 1 year old, spontaneous remission is less likely, but even metastatic disease is often cured by chemotherapy - oncogenes, especially N-myc, are clearly important in the origin and progression of neuroblastoma - N-myc amplification is common and predicts a poor outcome - retinblastomas, medulloblastomas, pinealoblastomas, and adult neuroblastomas are related pediatric tumors that look like neuroblastomas microscopically Parathyroid Glands - arise from the third and fourth branchial clefts - chief cells - typically hormone-secreting endocrine cells - oxyphils - large, pink-staining cells which appear after puberty and occur in clusters - water-clear cells - seen in some; full of glycogen - fat cells - after puberty - parathyroid hormone - the major regulator of calcium homeostasis in humans - its production-secretion is regulated by serum calcium - the N-terminal assay measures the active hormone, though the form measured by the C-terminal portion stays around longer - effects: - kidney - increases calcium absorption from the gut - promotes resorption of calcium from the glomerular filtrate, and promotes loss of phosphate - serum parathyroid levels are accurately reflected by measuring urinary cAMP concentrations - bone - promotes resorption of calcium by osteoclasts - increased levels of hormone cause proliferation of osteoclasts - gut - promotes calcium absorption Hyperparathyroidism - primary hyperparathyroidism - 80% parathyroid adenoma 5% parathyroid carcinoma 15% parathyroid hyperplasia <1% iatrogenic seeding causing lots of little glands - affects 1 of every 1000 - elevated serum calcium on routine screening - mental changes - kidney stones - nephrocalcinosis - bone changes - gastric ulcers - hypertension - pancreatitis - pseudogout - labs - increased serum calcium, 24-hour urine clacium excretion, urinary cAMP, and serum parathyroid hormone - decreased serum phosphate Parathyroid Adenoma - the commonest cause of primary hyperparathyroidism - these tumors are most common in older women, but may occur in anyone - basic biology involves translocation that deregulate the oncogene PRADI-1 - the surgeon finds three normal glands and an adenoma which is easily removed - the adenoma often has a rim of compressed normal gland at the edge, and will not contain fat - often lack 11q13 Parathyroid Carcinoma - a rare cause of primary hyperparathyroidism - this cancer arises in a parathyroid gland and produces parathyroid hormone - these cancers are not very aggressive, and are generally cured by local excision Parathyroid Hyperplasia - the second most important cause of primary hyperparathyroidism - all four glands are enlarged and lack the usual fat - the bulk of the parathyroid tissue must be removed, leaving a small amount behind - secondary hyperparathyroidism - parathyroid hyperplasia due to hypocalcemia for some other cause, usually renal failure - less common causes are intestinal malabsorption, calcitonin-producing tumors, and rickets - serum calcium is below normal - bone disease is a big problem - tertiary hyperparathyroidism - hypercalcemia develops in a setting of secondary hyperparathyroidism - one or more glands has become autonomous and overproduces parathyroid hormone - probably this means it has lost the MEN-I anti-oncogene on chromosome 11 Hypoparathyroidism - etiology is iatrogenic, rarely autoimmune - signs and symptoms begin with mental changes, circumoral paresthesia, Chvostek's sign, Trousseau's sign, and progress to carpopedal spasm, convulsions, and tetany - diagnosis by low serum calcium and high serum phosphate - pseudohypoparathyroidism - a family of dominant disorders with skeletal abnormalities and renal unresponsiveness to parathyroid hormone - pts have hypocalcemia and hyperphosphatemia and fail to increase urinary c-AMP on administration of parathyroid hormone - the defect is in the G unit of adenylate cyclase, and these pts actually have lack of response to several hormones that work via cyclic AMP Thymus - originates from the third and fourth pharyngeal pouches - large in neonates, it starts to involute after puberty, and is usually just a mass of fat in older people - the cortex and medulla have as their basic structural unit an unusual stellate epithelial cell - thymic hyperplasia is said to present when there are germinal follicles in the organ - pts with myasthenia gravis, an autoimmune disease caused by anti-NMJ antibodies, also show hyperplasia, and thymectomy is the best treatment for myasthenia gravis - thymoma - a tumor of the epithelial cells of the thymus gland; there are lymphocytes mixed in, but these are non-neoplastic - gross appearance is most important for prognosis - myasthenia gravis occurs in around 50% - acquired pure red cell aplasia occurs in around 20% - other thymus tumors - lymphomas arise in the thymus