Endocrine #1

Hypopituitarism

Diminished or absent secretion of 1+ pituitary hormones. The #1 cause of hypopituitarism in adults is pituitary tumors, which are most often prolactin-secreting (50%) or non-functioning (38%; 75% secrete alpha subunit of pituitary glycoprotein hormones (TSH, FST, LH), which has no biologic activity, so there is only hormone excess with stalk effect/mass effect causing hyperprolactinemia because DA can't make it to the pituitary to inhibit prolactin release). The most common cause in adults is pituitary tumors (almost always adenomas). Other causes include craniopharyngiomas, CNS hypothalamic tumors, metastases in the hypothalamus or pituitary. Infiltrative disease (sarcoid, TB, lymphoma) can destroy the hypothalamus, and anorexia nervosa, excessive exercise/calorie deficiency, and psychosocial stressors can cause functional hypothalamic decline. Hemorrhage/infarct can affect the pituitary (apoplexy of an adenoma, Sheehan's syndrome, trauma) and surgery or radiation can destroy the pituitary. Pituitary tumors are usually prolactin-secreting (50%) or non-functioning (38%). Patients may present with symptoms of hormone secretion, mass effect symptoms (hypopituitarism, headache, visual field defects, CN palsies [usually eyes down and out from CN3]), or incidentally with screening. Symptoms of hypopituitarism often develop slowly/insidiously, and multiple hormones are often affected, starting with GH loss > LH/FSH > TSH > ACTH > prolactin (rarely). Always inquire about early development, even in adults with suspected hypopituitarism (delayed/incomplete puberty, poor growth). Secondary hormonal deficiencies include: ACTH deficiency (secondary hypoadrenalism) - fatigue, anorexia, weight loss, postural hypotension, decreased skin pigmentation TSH deficiency (secondary hypothyroidism) - fatigue, cold intolerance, constipation, dry skin, hair loss FSH/LH deficiency (secondary hypogonadism) - loss of sexual hair, oligo/amenorrhea, vaginal dryness, hot flashes, loss of libido, erectile dysfunction, diminished strength (men). GH deficiency - increased adiposity, reduced strength and muscle mass. To diagnose pituitary hormone deficits, target-organ and pituitary hormone lab results will be low (or abnormally "normal"). Stimulation testing is not usually needed for FSH/LH or TSH, but if performed, GnRH or TRH would produce a blunted/delayed response. ACTH deficiency requires stimulation testing to diagnose - insulin-induced hypoglycemia, metyrapone test, or ACTH stimulation test. Metyrapone blocks cortisol synthesis by reversibly inhibiting steroid 11β-hydroxylase. This stimulates ACTH secretion, which in turn increases plasma 11-deoxycortisol levels. Treat FSH/LH deficiency with estrogen/progestin or testosterone or LH/FSH injections for fertility. Monitor estradiol/testosterone levels, secondary sex characteristics, and ovulation/sperm counts. Treat TSH deficiency with Levothyroxine (daily pill) and monitor T4 or free T4 and hypothyroid symptoms. Treat ACTH with hydrocortisone, prednisone, or mexamethaxasone (mimics cortisol) and increase dose with stress. Monitor energy, weight, BP, and sodium levels. Hypopituitarism in children is most commonly caused by pituitary genetic mutations in primary transcription factors or the GH-1 gene. Mutations can affect a specific hormone or affect the g-protein coupled receptors, causing pseudohypoparathyroidism. Familial defects of the hypothalamus can also cause hypopituitarism in children and can present with midline CNS/facial defects (cleft lip, single upper central incisor). Neonates with hypopituitarism will present with hypoglycemia, mid-line defects, or micropenis in males. Children can present with decreased growth velocity, delayed/absent puberty, and TSH/ACTH deficiency. Family history of short stature as well as trauma/hypoxia during birth are also suggestive of hypopituitarism. When diagnosing pituitary deficits in children, there's no need to test FSH/LH because those levels should be low anyway before puberty. TSH deficiency may produce low or low-normal T4/T3 and normal TSH. Stimulation testing is not usually necessary, but a blunted or delayed response to TRH is seen. ACTH deficiency will produce low cortisol and low or abnormally normal ACTH. Use stimulation testing with metyrapone or ACTH, but *don't perform insulin-induced hypoglycemia stimulation testing in children.* Treat children in the same way you would treat adults with pituitary deficiencies, but start at lower doses and increase them over time to mimic hormone levels in a normal child. For treatment of ACTH, hydrocortisone is first line because it allows you to titrate the correct dose to the patient's size (too much can suppress growth).

Hyperprolactinemia

Hyperprolactinemia can be caused by prolactinoma (tumor secreting prolactin), acromegaly (usually from pituitary adenoma), sella turcica masses that compress the stalk, infiltrative disorders (sarcoidosis, amyloidosis), hypothalamic and pituitary stalk disease or damage. Other causes include primary hypothyroidism (resulting elevated TRH can stimulate lactotropes, so measure T4 and TSH in someone with suspected hyperprolactinemia), seizures, polycystic ovary disease, neurogenic (chest wall trauma or surgery, herpes zoster), renal insufficiency and cirrhosis (both decrease clearance of prolactin). Of all the pituitary tumors, prolactinoma is the most common (50%), followed by non-secretory tumors (38%). Pharmacologic causes of hyperprolactinemia include antihypertensives (verapamil, methyldopa, reserpine), GI meds (metoclopramide, domperidone, H2 blockers), antipsychotics (phenothiazines, butyrophenones, atypicals, chlorpromazine), antidepressants (tricyclics, MAO inhibitors, and SSRIs), as well as cocaine, opiates, and protease inhibitors. In women, high prolactin inhibits the hypothalamus from releasing GnRH, preventing the mid cycle surge in LH and FSH needed for fertility (so measure LH and FSH in someone with suspected hyperprolactinemia). Decreased LH reduces estrogen production by the ovary, so there is not enough to build up the uterine lining and have periods (oligomenorrhea). When prolactin level doubles, amenorrhea results and galactorrhea is usually present when amenorrhea appears. Gonadotrophin deficiency may also cause women to experience dysparenuria (painful sex), breast atrophy, and loss of secondary sexual hair. Hyperprolactinemia presents earlier in pre-menopausal women, who have menstrual abnormalities or infertility. Men and post-menopausal women present later, once the tumor is large and making so much prolactin that it's interfering with testosterone production (low libido, impotence, small/soft testes, loss of secondary hair) or causing visual field abnormalities or headache. 30-80% of women will have galactorrhea compared with <30% of men. After taking a history (medication usage) and physical, give a pregnancy test, TSH, free T4 (rule out hypothyroidism), creatinine (rule out renal impairment), and serum prolactin level. If plasma prolactin is >200ng/ml, there is a high probability of a pituitary adenoma, so perform an MRI. The first line treatment for hyperprolactinemia is dopamine agonist therapy rather than surgery or radiotherapy. Hyperprolactinemic patients without MACROacenomas can be followed without treatment if they are asymptomatic, are eugonadal (no loss of sex steroid production - loss of estrogen causes premature menopause and osteoporosis), and have stable prolactin levels. Dopamine agonists include cabergoline (2-3x per week, more effective) and bromocriptine (1-2x per day, more GI distress, but cheaper). DA agonist therapy can commonly cause nausea and vomiting (more with bromocriptine) and orthostatic hypotension. Uncommon side effects include nasal congestion, headache, fatigue, constipation, psychosis (reverse effects of antipsychotics), and sleep disturbances. Women who have microademomas, have undergone menopause and have no symptoms of hyperprolactinemia can choose to observe the size of the tumor and not treat it because most are small growing and may never cause a problem.

hyperthyroid epidemiology and causes

Hyperthyroidism is in <2% of the population and can be caused by excess production or thyroid hormones, excess release of preformed thyroid hormones, excess supplementation, or surreptitious use. 70% of endogenous production of thyroid hormone cases are caused by Graves' disease, 20% by toxic multi nodular goiter, 5% from toxic adenoma, and some from iodine load - excess iodine increases thyroid hormone production via Jod-Basedow phenomenon. Graves' disease is caused by thyroid stimulating immunoglobulins activating TSH receptors in thyroid cells. It's more common in females 20-50yrs but can also be in neonates and the elderly. In addition to the typical hyperthyroid symptoms, those with Graves' disease also have diffusely enlarged, symmetric, non-tender goiter +/- a *thyroid bruit or thrill*. *Graves' ophthalmopathy* (exophthalmos/proptosis, scleral injection, optic nerve damage, extra-ocular muscle entrapment) occurs in 30% - from proliferation of retro-orbital smooth muscle and fibroblasts stimulated by the TSIs. 2% have Graves' *dermopathy* (orange peel skin over shins), and 2% will have *acropachy* (clubbing and widening of the digits). Histologically, there will be lymphocytic infiltration and scalloped colloid from overactive follicular cells. Radioactive iodine uptake scan will show increased uptake throughout the thyroid. First line treatment is an anti-thyroid drug: Methimazole or Propylthiouracil (PTU). Radioactive iodine (131-I) is second line (most become hypothyroid and require thyroid hormone replacement), and subtotal or total thyroidectomy is used for those who can't tolerate anti-thyroid drugs or who have compressive goiter. Toxic multinodular goiter Goiter = thyroid enlargement occurs when nodules gradually develop autonomy over many years, leading to monoclonal expansion of follicles, sometimes with activating mutations in the TSH receptor. It usually occurs in older women and produces an asymmetric, nodular gland that can cause compressive symptoms with growth. Radioactive iodine uptake scan will show patchy iodine uptake with areas of increased and decreased uptake. Cytology will show abundant colloid with variable amounts of benign follicular epithelium in flat sheets of bland, evenly spaced round nuclei. Radioactive iodine is a first line treatment for toxic nodules. Toxic uninodular adenoma is similar to toxic multi nodular goiter but presents as a solitary nodule on exam and a hot nodule on scintigraphy. They are almost never malignant. Radioactive iodine uptake scan will show one hot nodule and the rest of the thyroid will be cold from down regulation. Radioactive iodine is a first line treatment for toxic nodules. Excess release of preformed thyroid hormones occurs in thyroiditis, which can be painless lymphocytic (including postpartum), subacute granulomatous (Quervain's thyroiditis), suppurative (bacterial) and Reidel's. There is no radioactive iodine uptake seen on imaging. Non-specific lymphocytic thyroiditis includes painless and postpartum thyroiditis and causes transient hyperthyroidism followed by hypothyroid and then normal in 80% after 6 months (20% stay hypo). You can treat symptoms with beta blockers if necessary. Granulomatous thyroiditis includes subacute, painful subacute, and De Quervian's and occur after a virus, causing painful, swollen thyroid with *increased eosinophil sedimentation rate* and mild transient hyperthyroidism. Grossly, the thyroid will be enlarged, asymmetric, and fibrotic. Histologically subacute thyroiditis shows initial acute inflammatory infiltrate, then granulomatous inflammation, then replacement of follicles by histiocytes and giant cells with patchy fibrosis. Take NSAIDs or prednisone for pain and ensure there's not a bacterial infection. Suppurative thyroiditis is bacterial infection of the thyroid, causing painful gland, fevers, neck pain, and acute illness - this is a surgical emergency. Exogenous causes include excessive hormone dosage - levothyroxine has a narrow therapeutic window so that 20% of patient on thyroid hormone are over treated. Those with eating disorders or secondary gain/factitious disorder can take unprescribed levothyroxine. There will be no radioactive iodine uptake.

Diabetes insipidus

*Excess urinary loss of water caused by deficiency of or insensitivity to vasopressin, characterized by plasma hyperosmolality with urinary hypoosmolality (hypernatremia without appropriate Na+ excretion). Osm = 2(Na+) + BUN/2.8 + glucose/18* Normal Na+ = 135-145 Normal BUN = 10 Normal glucose <100 Normal Osm = 289 Polyuria - urine output >300cc/kg/day or >3 liters/day. water deficit = .6* x premorbid wt (kg) x (1-140/[serum Na+]) (*.5 for a woman) Dipsogenic DI - primary polydipsia (psych condition where you drink too much) Gestational DI - placental vasopressinase (hormone degrades ADH) Nephrogenic DI - renal insensitivity to AVP caused by hypercalcemia, hypokalemia, drugs (lithium, amphotericin B, gentamicin, cisplatin), renal disease, and genetic causes (AVPR2 or AQP inactivating mutations). Central DI - AVP deficiency Central DI can be caused by destructive diseases of the hypothalamus and pituitary like tumors (craniopharyngioma, CNS lymphoma, meningioma), trauma (whiplash, neurosurgery), infiltrative/inflammatory disease (sarcoid, TB, amyloid, histiocytosis, meningitis, encephalitis), or radiation. Mutations and genetic syndromes can affect the hypothalamus and pituitary - AVP gene on chromosome 20, DIDMOAD gene on chromosome 4 (Wolfram syndrome), and septo-optic/pituitary dysplasia. Diagnose DI using the water deprivation test (Miller-Moses test) to stimulate ADH. Diagnose if high serum Na+ and osmolality with inappropriately low urine sodium and osmolality. Then test whether it's central or nephrogenic by giving the patient ADH while their serum Na+ is high (>148). Those with central DI will have a large increase in urine Osm while those with nephrogenic DI will not have an increase in urine Osm. Treat central DI with vasopressin analogues like dDAVP (desmopressin) every 12-24hrs, which selectively activate V2 receptors, so side effects are rare (but include headache, nausea, nasal congestion, flushing). dDAVP is used for DI and vonWillebrand's as well as bed-wetting. You can also use aqueous vasopressin (pitressin), which acts for 4-6 hrs and activates V1 and V2 receptors. Side effects include coronary spasm, HTN, GI cramping, vasoconstriction, and uterine contractions. Aqueous vasopressin is used as a second-line pressor and occasionally for inpatient DI. Also rehydrate the patient according to their water deficit. If they are thirsty and can drink, let them do so. Adjunctive treatments to treat nephrogenic DI include hydrochlorothiazide (decreases urine volume, impairs Na+ resorption, decreases free water excretion). *Amiloride is used to treat lithium induced DI* by blunting lithium uptake in the distal tubules and collecting ducts. Indomethacin inhibits prostaglandins, which normally inhibit ADH action.

Congenital adrenal hyperplasia

A defect in an enzyme involved in the production of an adrenal steroid hormone 21-hydroxylase deficiency 90-95% of CAH Prevents the formation of aldosterone (causing *hypotension*) and cortisol (weight loss, nausea, fatigue, anorexia, GI pain). Pregnenolone and progesterone are shuttled down the only functional pathway to make excess DHEA and androstenedione (weak adrenal androgens). Most will have primary adrenal insufficiency. Severe cortisol deficiency can cause vascular collapse, vomiting, and death in infancy, while partial deficiency can cause reduced stress tolerance. Severe aldosterone deficiency can cause polyuria, volume depletion, and hyperkalemia in infancy. Partial deficiency can be compensated with adequate salt intake. Severe adrenal androgen excess can cause masculinization of external genitalia in female infants and isosexual precocity in boys. Partial deficiency causes hirsutism and irregular menus in adult women. 11-hydroxylase deficiency 5% of CAH The deficient enzyme allows hormone production to go one step farther than with 21-hydroxylse deficiency, so that aldosterone and cortisol still can't be made and excess pregnenolone and progesterone are used to make DHEA and androstenedione, but also the "end" product of the aldosterone pathway, *11-deoxycorticosterone, causes hypertension.* Excess androgens can make females have ambiguous genitalia and cause both sexes to undergo postnatal virilization. Some will have primary adrenal insufficiency. 17alpha hydroxylase deficiency The enzyme responsible for converting pretnenolone and progesterone into forms that can enter the pathways to create cortisol and dihydrotestosterone is deficient, so they are used to make mineralocorticoids/aldosterone. This increases Na+ reuptake and vascular volume, causing hypertension, so renin is not released. Male infants will have ambiguous genitalia, and both men and women will have sexual infantilism from lack of androgens. Treat with exogenous hydrocortisone and induce menses in women with oral E2 and progesterone (provides negative feedback to decrease ACTH release).

Anterior pituitary hormones

ACTH Controls cortisol secretion in response to CNS effects, stress, and diurnal rhythm, the hypothalamus releases corticotropin releasing hormone (CRH) that stimulates the anterior pituitary to secrete ACTH, which stimulates the adrenal gland to secrete cortisol. Cortisol serves as negative feedback to decrease release of CRH and ACTH. Giving synthetic CRH (cortiocorelin) can help you determine what is causing low or high ACTH/cortisol states. Low ACTH/cortisol - CRH will cause ACTH to rise in hypothalamic disease, but ACTH won't rise as expected with pituitary disease. High ACTH/cortisol (Cushing's syndrome) - CRH will cause a rise in ACTH if there are ACTH secreting pituitary tumors (remain responsive to CRH but not negative feedback from cortisol), or there will be limited/no rise in ACTH if there is ectopic ACTH production or adrenal cortical tumors (don't respond to CRH). Thyroid stimulating hormone CNS effects and temperature stimulate the hypothalamus to release thyrotrophin releasing hormone that causes the anterior pituitary to release TSH, which stimulates the thyroid to release T3 and T4. T3/4 provide negative feedback to the hypothalamus and anterior pituitary. Synthetic TRH (protorelin) was historically used to localize the lesion in low TSH/thyroid hormone states - a rise in TSH signified hypothalamic disease, while limited/no rise in TSH indicated pituitary disease. Today, TSH and thyroid hormone assays are used instead. Leutanizing hormone and follicle stimulating hormone Control sex steroid secretion. CNS effects, nutrition, and stress affect the release of gonadotropin releasing hormone (GnRH) onto the anterior pituitary, which then releases LH and FSH from the same cell type. LH and FSH stimulate ovulation and the production of estrogen (E2) in females and spermatogenesis and testosterone production in males. Estrogen and testosterone provide negative feedback for the hypothalamus and pituitary. Synthetic GnRH (gonadorelin) is used to induce ovulation or spermatogenesis in hypothalamic disorders via pulsatile delivery from a diffusion pump. GnRH superagonists (leuprolide) strongly bind GnRH to reduce FSH and LF secretion, while GnRH antagonists (cetrorelix, ganirelix, degrarelix) bind to GnRH receptors to have the same effect. Superagonists and antagonists are used to delay puberty in precocious puberty, prevent ovulation, control estrogen-dependent uterine diseases (endometriosis, uterine fibroids), and suppress sex-steroid dependent tumors (breast/prostate cancer). Growth Hormone Controls growth and metabolism directly and via IGF-1, and is released by somatotrophic cells in the anterior pituitary, which make up 70% of it's mass and metabolic expenditure. CNS effects, diurnal rhythm, and glucose affect hypothalamic (pulsatile) release of GHRH onto the anterior pituitary, which releases GH that increases metabolism and bone growth and also stimulates the liver to produce IGF-1. IGF-1 also stimulates metabolism and bone growth, and also inhibits the anterior pituitary. IGF-1 and GH stimulate somatostatin release from the hypothalamus, which further inhibits the anterior pituitary. GH release can also be stimulated by deep sleep, fasting, stress, exercise, hypoglycemia, sex steroids, amino acids, and alpha-adrenergic system. GH release can be inhibited by malnutrition, illness, hyperglycemia, cortisol, and the beta-adrenergic system. Secretion is episodic, with low basal levels interrupted by circadian, episodic release during sleep. A better (more stable) measure of GH is IGF-1 and IGFBP-3 - the complex has a longer half life and stays more consistent to reflect overall GH levels (IGFBP-3 is a good indicator of IGF-1 due to nutritional deficiencies). To screen for acromegaly(adults) or gigantism (children), measure IGF-1. If the level is high, confirm the diagnosis by administering an oral glucose load and then measuring serial GH levels - a normal person will have GH decline while someone with acromegaly will have no change in GH. To diagnose, screen using IGF-1 and then confirm by administering a stimulus (insulin or arginine) and measuring serial GH levels - normal people will see GH rise while those with GH deficiency will not. Synthetic GHRH (sermorelin) is used to localize a lesion in low GH/IGF states - GH will rise with hypothalamic disease but not with pituitary disease. It could also be used to treat growth failure from hypothalamic disease (in practice, recombinant GH is always used though). Somatostatin analogs (octreotide, lantreotide) are used to treat excess secretion of growth hormone (acromegaly), insulin (insulinomas), TSH (TSH-secreting pituitary tumors), and VIP (from VIPomas - tumors of the non-beta islet cells of the pancreas that produce vasoactive interstitial peptide and cause diarrhea). Somatostatin analogs also reduce GI motility from other chronic diarrheal diseases. Prolactin CNS effects and diurnal rhythm affect the continual hypothalamic secretion of dopamine/prolactin inhibiting factor (PIF). Secretion of dopamine/PIF decreases during pregnancy, allowing the anterior pituitary to secrete prolactin that stimulates milk synthesis. After birth, suckling triggers receptors in the nipple that send afferent neurons to the hypothalamus to inhibit release of dopamine/PIF. At the same time, estrogens stimulate the pituitary to secrete more prolactin (taking estrogen pills can lead to prolactin increase even in the presence of ongoing dopamine prolactin inhibition). Prolactin secretion can also be increased by physical exertion. Dopamine agonists (bromocriptine, cabergoline) are used to treat prolactin-secreting tumors in women and men. Decreasing serum prolactin restores gonadal function (because too much prolactin decreases LH and FSH secretion) and shrinks tumor size. They also treat other causes of hyperprolactinemia. When trying to diagnose an anterior pituitary problem using laboratory tests, you must analyze anterior pituitary analytes and end organ analytes to interpret the findings (prolactin is the exception). Prolactin Growth hormone - IGF-1, IGF binding proteins ACTH - Cortisol LH/FSH - estradiol or testosterone TSH - T4/3, free T4/3 (to diagnose a posterior pituitary problem, you only need to look at the end effect analytes. For example, you don't look at ADH but at Na+ and osmolality).

Drug therapy of osteoporosis

Adequate intake of calcium and vitamin D via diet or supplements is recommended - 1000mg calcium and 800 IU vitamin D. Estrogen replacement in postmenopausal women may prevent excessive bone loss by activating osteoblast receptors to promote deposition. Estrogens should be given with progestin in women with a uterus to decrease cancer risk. However, *estrogen replacement for bone health alone is not recommended* because it increases risk for breast cancer and CV events. Calcitonin synthetic human or salmon calcitonin reduces bone resorption and increases bone density. Can be injected or give intranasally, and large doses have an analgesic effect. Reduces vertebral but not hip fractures. Selective estrogen receptor modulators *(SERMs) - *raloxifene synthetic estrogen analog to treat osteoporosis in postmenopausal women that acts as an estrogen agonist in bone but an antagonist in breast tissue and doesn't stimulate the endometrium (low cancer and CV risk). Reduces vertebral but not hip fractures. Side effects include blood clots and hot flashes. Bisphosphonates (-dronate) Agent of choice for postmenopausal women with osteoporosis or who have had a fracture. Resemble pyrophosphate and are incorporated into bone to inhibit osteoclast action and promote their death. They are the most commonly used drugs to inhibit resorption and promote increased mass. Weakly or monthly pill or yearly IV infusion (soledronate). Can also be given to reduce calcium levels in those with hypercalcemia (eg. bridge to surgery for hyperparathyroidism). Can cause esophageal irritation if taken orally and rarely osteonecrosis of jaw or atypical femoral fractures. A 40% decrease in NTx or CTx (collagen cross-links) after initiation of bisphosphonate therapy suggests efficacy. Denosumab Monoclonal antibody that binds to RANK-ligand so that it cannot activate the RANK receptor on osteoclasts to stimulate resorption. Improves bone density and reduces hip and vertebral fractures. Given as a twice yearly subQ injection. Side effects include serious skin infections and hypocalcemia. Teriparatide Low-dose synthetic analog of PTH and the only anabolic therapy. The amino-terminal biologically active fragment of PTH is given in small doses via daily injection to increase obstoblast activity and decrease death. This intermittent administration makes its effects very different from those of chronic hyperparathyroidism. It decreases risk for vertebral and non-vertebral fractures and is used in patients with very high fracture risk or who don't respond to other therapies. It has a black box warning for increasing risk of osteosarcoma and can be used for a max of 2 years. Monitor using DXA and sometimes lab tests of bone metabolism. Significant change can take up to 2 years. Loss of density or recurrence of fractures suggests considering alternative therapies. Lab tests include collagen cross-links (NTx or CTx), osteocalcin, and bone alkaline phosphatase and can be monitored within 2-6 months after initiation of antiresorptive therapy. For NTx and CTx, a 40% decrease after initiation of bisphosphonate therapy suggests efficacy.

Adrenal hormones

Aldosterone Aldosterone (mineralocorticoid) is synthesized in the zona glomerulosa (cortex) from cholesterol in response to angiotensin II, high K+, or low Na+. Principal cells in the renal collecting duct contain cytoplasmic aldosterone receptors, and the receptor/aldosterone complex enter the nucleus and induce gene transcription to make Na+/K+ channels on the apical side of the cells - this allows more Na+ to be reabsorbed and K+ to be excreted. Aldosterone production is increased when there is decreased extracellular fluid volume, arterial pressure, or Na+, because these factors stimulate renin release from the juxtaglomerular cells of the kidney. Renin converts alpha2-globulin to angiotensin I, which is converted to angiotensin II that interacts with receptors on adrenal cortex glomerulosa cells. The glomerulosa cells produce aldosterone, leading to renal Na+ and water retention and increased EC fluid volume and arterial pressure. These things inhibit renin procession and thus aldosterone production. Cortisol Cortisol (glucocorticoids) is made in the zona fasiculata (cortex) from cholesterol. CNS effects, stress, and diurnal rhythm increase the release of CRH from the hypothalamus onto the anterior pituitary, which releases ACTH. ACTH stimulates uptake of lipoproteins in fasiculata cells and the conversion of cholesterol to pregnenolone (rate limiting step), which is then converted to cortisol. Cortisol increases blood pressure and gluconeogenesis/lipolysis/proteolysis, and decreases bone formation, inflammation, and immune function - it mobilizes stores for immediate use. Cortisol is the main negative feedback mechanism to the hypothalamus and pituitary, decreasing CRH and ACTH release. Androgens Some androgens (dehydroepiandrosterone/DHEA) are produced from cholesterol in the zona reticularis (cortex) in response to ACTH, and others are produced in gonads (testosterone is produced and converted to estrogens by aromatase). In females, androgens promote development of pubic and axillary hair and contribute to libido. They play a less significant role in males, especially after puberty because testosterone from testicles is the major androgen. Excess adrenal androgen can be problematic in females and pre-pubertal males, as in congenital adrenal hyperplasia and with androgen-producing adrenal tumors. Catecholamines Catecholamines are released from the adrenal medulla in response to efferent nerve signals. They are made in advance from tyrosine and stored for quick release. Tyrosine > tyrosine hydroxylase > L-dopa > dopa decarboxylase > dopamine > dopamine beta-hydroxylase > NE > phenylethanolamine N-methyltransferase > Epi (phenylethanolamine N-methyltransferase is only found in the adrenal medulla, so all Epi is from here). Dopamine is broken down into homovanillic acid (HVA); NE is broken down into vanillyl mandelic acid (VMA) and normetanephrine; and epi is broken down into metanephrine. Overall, catecholamines increase glycogenolysis/lipolysis and decrease insulin release - mimicking the effects of SNS discharge. Dopamine acts at D1 receptors to cause vasodilation in the heart, kidney, and mesentery to increase blood flow to vascular beds. At high levels, DA binds beta1 receptors, and at very high levels it binds alpha receptors, increasing CO and PVR. NE acts on alpha and beta1 receptors to cause vasoconstriction and increase PVR. Epi acts on alpha receptors to cause vasoconstriction in the skin/viscera, and on beta2 receptors to cause vasodilation in skeletal muscle and stimulate cardiac muscle cells (doesn't change PVR, CO, and HR).

Measuring adrenal hormones

Aldosterone Plasma aldosterone levels are measured in conjunction with renin, usually when excess secretion is suspected, as with Conn's syndrome (benign adenoma of adrenal gland that produces aldosterone). Measurement will be affected by factors that increase or decrease renin. Low Na+ diet, volume depletion, diuretics, and upright posture will increase aldosterone. High Na+ diet, volume overload, saline infusion, and supine posture will decrease aldosterone. Cortisol Plasma or 24hr urine cortisol can be measured when concerned about cortisol excess (Cushing's syndrome) or insufficiency (Addison's). Plasma cortisol levels will be affected by the amount of cortisol-binding globulin in the blood (90% of cortisol is bound to CBG, 6% to albumin). Estrogen-containing OCPs increase CBG and thus plasma cortisol, and severe liver dysfunction decreases total measured cortisol. Urinary and salivary free cortisol levels are not affected though. Cortisol levels will also fluctuate with a circadian rhythm - highest just before waking and lowest in the evening before sleep. Androgens DHEA, androstenedione, testosterone, specific steroids, and DNA studies are generally performed when excess secretion is suspected, as with congenital adrenal hyperplasia. Catecholamines and metanephrines Catecholamines and metanephrines (Epi breakdown product) can be measured in the plasma or 24hr urine, usually when excess catecholamine secretion is suspected (pheochromocytoma, paraganglioma). Catecholamine release will be increased by factors that increase SNS stimulation - stress, excitement, anxiety, drugs (TCAs, SSRIs, caffeine, some BP meds), withdrawal (clonidine, alcohol). It's important to test under calm conditions and discontinue interfering meds if possible.

Primary hyperaldosteronism

Autonomous production of aldosterone causing up to 15% of all HTN. 1/3 of PHA is caused by unilateral adenoma/Conn's syndrome (aldosterone producing adenoma) and 2/3 is caused by bilateral adrenal hyperplasia/idiopathic adrenal hyperplasia. In PHA, increased fluid volume and BP still feed back to suppress renin, but low renin levels don't result in lower aldosterone. Excess aldosterone leads to the insertion of more Na+ channels on the luminal membrane and more Na+/K+ transporters on the apical side, leading to more Na+ reabsorption and K+ and H+ excretion (high CO2). High Na+ can cause HTN and edema and lead to MI, CVD, CHF, kidney disease, and eye disease. Chronic hyperaldosteronism, even if BP is treated, can cause remodeling in the heart leading to ischemic or fibrotic cardiac injury. Too much K+ excretion can cause hypokalemia in 25% which causes muscle weakness and cramps, fatigue, and arrhythmias. H+ excretion leads to metabolic alkalosis. Screen for PHA by getting a plasma aldosterone concentration (PAC), plasma renin activity (PRA) and calculate the aldosterone:renin ratio (ARR). Primary hyperaldosteronism will produce higher PAC (15+) and ARR (20+), but low PRA. Secondary HA will produce high PAC and PRA, but normal or low ARR. Confirm PHA using aldosterone suppression testing using IV saline infusion over 4 hours or oral salt loading for 3 days - if aldosterone fails to suppress, patient does have PHA. Localize the source of the PHA using CT/MRI of the adrenal glands. Treat people <40yrs with a clear unilateral adrenal mass with unilateral adrenalectomy. In all others, use adrenal vein sampling to make sure an identified mass is actually the source of the aldosterone or to figure out where it's coming from if you can't find a mass. If source of aldosterone is unilateral, remove that adrenal gland. If there is bilateral hyperplasia or you can't localize the source, use medication. Treat PHA with aldosterone-receptor blockers - spironolactone (cheap, but can cause gynecomastia in men) or epleronone (expensive, less effect on androgen receptors). Direct renin inhibitors, ACE-inhibirors, and ARBs can also be used.

Parathyroid and calcium testing

Calcium 99% of calcium is in the skeleton, 1% is in soft tissues, and <.02% is in the ECF, with a total of 1000g. Calcium in the ECF is 40-45% protein-bound (albumin, globulins), 5-10% complexed (PO4, HCO3, lactate), and 45-50% ionized (4.4-5.4mg/dL). The ionized form is the bioactive form. High levels of calcium increase the depolarization threshold, causing neuromuscular hypoexcitability. Low calcium decreases depolarization threshold causing increased neuromuscular excitability. Of 1g/day intake of calcium, .8g is excreted and .2g is absorbed in the gut. Ideally, mineralization and resorption are balanced, with .5g/day moving each way each day. 10g of calcium per day enter the kidney, 9.8g is retained and .2g is excreted. pseudohypocalcemia low measured total calcium concentration without a true change in overall body calcium, usually due to low albumin from poor nutrition, liver disease, renal disease, or CHF. There is a .8mg/dL loss of Calcium for every 1g/dL loss of albumin. Ionized calcium does not change and there are no signs or symptoms of hypocalcemia. Changes in pH change the measured ionized calcium but not the total calcium. Ionized calcium decreases with alkalemia and increase with acidemia (i.e. there's less protein binding as pH gets more acidic). Symptoms of hypo/hypercalemia can occur because ionized calcium levels are affected. Phosphorus Important for bone structure and cellular ATP generation. PTH stimulates renal excretion and increased gut absorption via vitamin D. Phosphorus is high in renal failure, hypoparathyroidism, and vitamin D toxicity. It's low in hyperparathyroidism and vitamin D deficiency. Magnesium Magnesium catalyzes the actions of cellular enzymes, including those utilizing/synthesizing ATP, and is necessary for PTH release (so release is blunted with hypomagnesemia). Magnesium is low with GI or renal wasting (causing apparent hypoparathyroidism). Creatinine In chronic kidney disease, serum calcium decreases from decreased activation of vitamin D (thus less gut absorption) and serum phosphorus increases (from decreased phosphorus excretion). This causes secondary hyperparathyroidism as PTH is elevated. Vitamin D Vitamin D in the skin starts as 7-dehydroxycholesterol (provitamin D3) and is converted to cholecalciferol (vitamin D3) by sunlight. 25-hydroxylase in the liver converts cholecalciferol into 25-OH-D3 (pro-hormone), which is used to assess vitamin D status. 1alpha-hydroxylase in the kidney is stimulated by parathyroid hormone to convert 25-OH-D3 to 1,25-OH2-D3, the active hormone used to assess calcium disorders. Vitamin D from supplements is ergosterol from yeast (provitamin D2) that is converted to ergocalciferol (vitamin D2) by irradiation. Ergocalciferol is converted to 25-OH-D2 by 25-hydroxylase in the liver. 1alpha-hydroxylase in the kidney is stimulated by PTH to convert it into 1,25-OH2-D2, the active hormone. 25-OH-D is the storage form of vitamin D and indicates vitamin D status. It's decreased with decreased exposure to sun, vitamin D intake, and absorption, as well as liver disease (no 25-hydroxylase). 25-OH-D is increased with high vitamin D ingestion. 1,25-OH2-D is the active form and an indicatory of 1alpha-hydroxylase activity, so it decreases with decreased kidney function and increases with some granulomatous diseases (sarcoid, TB) and hyperparathyroidism. Parathyroid hormone-related peptide acts the same as PTH at the kidney but is less likely to stimulate 1,25-OH-D formation, so there is less absorption from the gut. PTH-RP is important for teeth eruption, mammary gland development, and lactation (mobilized transfer of calcium to the milk). It's increased in humoral hypercalcemia of malignancy. Calcitonin is secreted by C-cells (parafollicular cells) in the thyroid causing the opposite effect as PTH in the bone, kidney, and gut, thus decreasing serum calcium. But it is much less potent than PTH so it doesn't play a role in calcium homeostasis or disorders. Calcitonin is used as a marker for medullary thyroid cancer recurrence.

Corticosteroids

Corticosteroids are use for primary and secondary adrenal insufficiency and congenital adrenal hyperplasia as well as non-adrenal disorders like allergies, collagen vascular diseases, pulmonary diseases, inflammatory bowel, skin disorders, eye diseases, neuro diseases, transplantation rejection, and rheumatologic diseases. Hydrocortisone is the used as the reference for glucocorticoid and mineralocorticoid potency. Fludrocortisone has the highest mineralocorticoid potency (125x) and all others are less potent than hydrocortisone. Dexamethasone has the highest glucocorticoid potency (30x) with no mineralocorticoid activity (fludrocortisone is second highest glucocorticoid potency - 10x) Primary adrenal insufficiency glucocorticoid replacement involves giving hydrocortisone or prednisone equivalent to basal cortisol secretion of 20-30mg/day, with increased dosing during periods of stress. Hydrocortisone is better for those with liver disease because it doesn't require activation by the liver. Primary AI mineralocorticoid replacement involves using fludrocortisone to maintain normal BP and vascular volume. Secondary adrenal insufficiency is treated in the same say as primary, but mineralocorticoid replacement is usually not required except when there is volume depletion.

Encapsulated and unencapsulated endocrine glands/tissues paracrine/autocrine/intracrine

Encapsulated: pineal, hypothalamus, anterior pituitary, posterior pituitary, thyroid, parathyroid, adrenals Unencapsulated heart, digestive tract wall, pancreas, liver, kidneys, gonads, ovaries, testes, fat Paracrine - signal reaches neighboring cells via interstitial fluid Autocrine - signal acts on the cell that synthesized the signal Intracrine - signal acts within the same cell that synthesized the signal Generally, each cell type only makes one hormone, with the exception of gonadotrophs in the anterior pituitary that make follicle stimulating hormone and leuteinizing hormone. In primary endocrine disorders, the endocrine gland is dysfunctional. In secondary endocrine disorders, the endocrine gland is responding normally but receiving too much or too little tropic hormone from the pituitary. Must measure both hormones to see where the cause lies.

Endocrine imaging

Endocrine imaging studies are only performed after precise clinical history is obtained, medications are reviewed, physical exam performed, and lab results have been scrutinized - to provide context to interpret the imaging studies. Transmission imaging includes X-ray, CT, US, and MR The energy source originates from outside the patient, travels through the patient, and a detector captures the energy as an image that provides very good spatial resolution. Emission imaging The energy source (radio-labeled pharmaceutical) is injected/ingested so that it is emitted from the patient, and a detector (gamma camera) captures the energy. Technicium-99m is most commonly used. Emission imaging has limited spacial resolution, so other imaging studies are needed to localize - a PET scan can be layered on top of a CT scan. Thyroid emission imaging Images taken with a gamma camera 4-6 hours after ingesting Iodine-123 capsule. The thyroid will normally take up iodine in a consistent fashion. Graves disease will have increased iodine uptake in both lobes (darker image), goiter will cause multi nodular hot and cold areas of uneven uptake, toxic adenoma will cause increased uptake in one nodule (darker) while suppressing uptake in the surrounding thyroid (lighter), and thyroiditis will decrease uptake. Thyroid cancer produces a cold nodule on emission imaging with iodine, but will have increased metabolic activity on PET. Thyroid mets can sometimes take up the iodine (and so may be hot rather than cold). Perform an ultrasound and US guided nodule biopsy if you find a cold nodule. Parathyroid imaging Patients are administered Tc-99m-Sestamibi IV before imaging, and uptake will be increased in a hyper functioning nodule. High uptake is normal in the salivary glands, heart, liver, bladder, and injection site. Pheochromocytoma imaging (tumor of the adrenal medulla) Administer metaiodobenzylguanidine radio labeled with I-131. Carcinoid imaging Administer IV Octreotide labeled with Indium-111 to look for carcinoid tumors and mets.

General notes about endocrine pathology

Endocrine neoplasia are benign adenomas MUCH more commonly than malignant adenocarcinomas. Their histopathology is often similar, so diagnose based on presence of metastases or local vascular/neural invasion. Verify the presence and type of intracellular hormone using immunohistochemistry. Hypofunction does not occur until 80-90% of the endocrine gland tissue is gone. Autoimmune endocrine disorders involve autoantibodies that interact with endocrine cell receptors to stimulate endocrine release (hyperfunction) or block release (hypofunction). Autoantibodies can also trigger cell or humoral-mediated immune injury (destruction) via lymphocytes, mitochondria, and plasma cells, leading to hypofunction.

Acromegaly

Excess growth hormone (and IGF-1) in adults causes bones growth (esp. in the hands, feet, jaw, and forehead - acral/peripheral bones), thickened skin, hypertension (loss of NO and thickening of vessel walls), neuromuscular and psych disorders, neoplasia (colorectal polyps/cancer), upper airway obstruction from soft tissue enlargement, and cardiomyopathy (from uneven growth). Patients can also have excessive sweating (gland hypertrophy), menstrual upset, headache, arthritis (unsymmetric cartilage enlargement), impaired glucose tolerance or diabetes (suppresses gluconeogenesis), decreased libido, HTN, visual field defect, obstructive sleep apnea, or galactorrhea. Diagnose acromegaly by measuring how GH levels respond to glucose administration - should normally drop to <1ng/mL. Also measure IGF-1 - diagnose if above 350ng/ml. IGF-1 can be used to measure disease severity and efficacy of treatment as values correlate with growth and other symptoms. Upon diagnosis, screen patients for comorbidities, including CV, respiratory, glucose metabolism/diabetes, osteoarticular, and cancer (colonoscopy at diagnosis and every 5 years). Live expectancy decreases 10 years in those who don't control their GH. Treat with a transsphenoidal hypophysectomy - removal of the tumor but not the pituitary gland. This produces an immediate decline in GH, eliminates/reduces tumor mass, and has low morbidity. But, CVA can occur and patients may need adrenal steroid, thyroid, and testosterone supplement from hypopituitarism. Medical therapy is second line treatment and is used if surgery is not able to remove all of the tumor. Somatostatin (octreotide) and DA (bromocriptine, cabergoline) analogs directly inhibit GH secretion, and growth hormone receptor antagonists block GH effects and directly inhibit IGF-1 secretion. But DA analogs are only effective in a minority of patients and don't shrink the tumors. Somatostatin analogs improve signs and symptoms in most, may control tumor growth, and are a once monthly intramuscular injection (octreotide LAR), but many patients' tumors don't have the corresponding somatostatin receptor subtype so 60% don't achieve IGF-1 normalization. Pegvisomant is a growth hormone receptor competitive antagonist that decreases IGF-1 and other GH responsive serum proteins, but requires daily injection, does not affect tumor size, and can rarely cause elevated liver function tests. Radiotherapy is another option that can control tumor growth and decrease GH but is not as rapid/effective and often causes hypopituitarism, and rarely secondary tumors and visual defects.

Growth hormone deficiency

GH deficiency in children is usually isolated or idiopathic (1 in 3800 live births), and there are increasing rates in older children as more survive childhood cancers with chemo and radiation. In adults, GH deficiency is usually from a pituitary tumor and coexists with other pituitary deficiencies. Children usually experience growth failure after a period of normal growth, and their pubertal age is <10-25th percentile. They can have increased subcutaneous fat around their trunk, immature face with prominent forehead and depressed mid facial development, delayed dentition and puberty, and small phallus in males. X-ray will show delayed bone maturation. In adults with GH deficiency, symptoms generally begin in the 30s or 40s and are nonspecific - decreased exercise performance, low energy and sense of wellbeing, depressed mood. They can also have decreased muscle mass and bone density, increased central adiposity, high LDL and low HDL cholesterol (more atherosclerosis), and impaired cardiac function. Screen for GH deficiency using IGF-1 (+/- IGFBP-3), but confirm with stimulus testing with insulin-induced hypoglycemia, CNS neuroactive agents (clonidine, glucagon, arginine), or GHRH stimulation. A normal person will respond with significantly increased GH production while someone with GH deficiency will have low/no GH rise. Treat GH deficiency with recombinant human growth hormone (hGH) daily via subcutaneous injections. hGH can also be used to treat other causes of short stature. Treat kids until they reach their final height or growth plates fuse (epiphyseal closure). Treat adults to improve strength, restore body composition, and improve quality of life. hGH can cause Na/H2O retention (arthralgia, edema, carpal tunnel), glucose intolerance, and intracranial HTN. Laron dwarfism is a type of GH receptor insensitivity from a receptor mutation. Laron dwarfs have almost no DM or cancer. Protein-calorie malnutrition can also decrease GH responsiveness.

Peptide and protein hormone Location and synthesis

Located in the hypothalamus, pituitary, parathyroid gland, thyroid gland (calcitonin), heart, GI system (insulin), adipose tissue, and kidney. Protein/peptide hormones circulate free/unbound to a carrier protein (except thyroid hormone) and thus have a short half life of only minutes. Receptors are usually located on the plasma membrane because the proteins can't penetrate through the lipid bilayer (thyroid hormone is the exception). Binding to the receptors triggers a rapid second-messenger response. Protein hormone production A hormone gene is transcribed in the nucleus into mRNA, which travels to a free ribosome in the cytoplasm that translates the mRNA signal peptide - the pre part of the preprohormone. The pre signal triggers the free ribosome to travel to the rough ER, where the signal peptide binds to the Signal Recognition Particle (SRP) on the rough ER. The peptide enters the lumen of the rough ER and is cleaved before the prohormone is translated, folded, and modified. The prohormone travels to the golgi apparatus, where it is packaged into secretory vesicles with processing enzymes that turn it into the final hormone. The hormone and enzymes remain in their storage vesicles until Ca+ mediated exocytosis of the hormone and pro hormone fragments occurs. Amino acid hormone production Catecholamines are produced from tyrosine in the nervous system and adrenal medulla: Tyrosine > (tyrosine hydroxylase) > L-dopa > (dopa decarboxylase) > Dopamine > (dopamine beta-hydroxylase) > NE > (phenylethanolamine N-methyltransferase) > Epi Catecholamines behave like peptide/protein hormones. Thyroid hormones (from the thyroid gland only) also come from tyrosine, but they behave like steroid hormones in every way except that their precursors are stored in the colloid of follicles. First, thyroglobulin is made by oxidizing iodine and adding it to tyrosine via thyroid peroxidase at the apical plasma membrane. Thyroglobulin is then stored in the colloid of follicles, and binding of TSH to receptors on the basal surface stimulates follicular cells to form apical pseudopods that engulf the colloid by endocytosis. The colloid droplets fuse with the lysosomes and hydrolysis of iodinated thyroglobulin frees T4/3 into the cytosol to enter the blood stream.

hCG

Measured to test for pregnancy, but can also be elevated with spontaneous pregnancy loss, exogenous hCG (fertility treatment, hCG diet), some tumors, pituitary hCG and heterophilic antibodies - some people make antibodies against the animal antigens used to detect hCG, binding the capture antibodies to the detection (signal/labeled) antibodies and giving a false positive (or binding to the capture protein only, preventing the detection protein from binding and giving false negatives). Pituitary hCG has the same heterodimer structure, but it is normally modified post-transcriptionally. It can cross-react with hCG immunoassays however. Pituitary hCG (and FSH) production increases in post-menopausal women because normally sex steroids from the ovaries serve as negative feedback to the hypothalamus and anterior pituitary. Decreased ovarian function removes this negative feedback, so that the anterior pituitary secretes more FSH, LH, and hCG (promiscuous production). 2 weeks of sex steroid replacement therapy reverses this.

Metabolic bone diseases

Osteitis Fibrosa Cystica aka brown tumor of hyperparathyroidism Excess action of PTH on bone from primary or secondary hyperparathyroidism causes suberiosteal bone resorption, bone cysts/swelling, bone pain, and diminished bone strength. PTH causes increased osteoclast activity, hemorrhage, cysts, and fibrosis, which can mimic bone neoplasms on Xray. Cinacalcet is a calcimimetic drug that activates the calcium sensing receptor at the parathyroid to decrease PTH release (side effect - hypocalcemia). Paget's disease of bone excessive bone resorption and formation causing accelerated remodeling and disordered architecture - a mosaic of bone/*woven bone* that is weaker, larger, more vascular, and more susceptible to fracture. X-rays show *cotton wool spots* from sclerosis in areas of previous lucency (see through/darker bone). Nuclear medicine scans show intense uptake in affected bone. Paget's in adults usually involves one or a few bones, generally in the axial skeleton or proximal long bones, and may be caused by a viral infection that initiates abnormal osteoclast activity. Prevalence increases with age from 3% of those >55yrs to 10% above 80yrs. Most patients are asymptomatic with *elevation of serum alkaline phosphatase and normal serum calcium, phosphorus, and PTH.* Rare symptoms include bone pain. Treat Paget's with anti-resorptive drugs - high dose bisphosphonates - in symptomatic people and those at risk of complications based on site of affected bone. Osteogenesis imperfecta inherited disorders with mutations in a bone collagen gene leading to defective or too little collagen. Diagnose based on recurrent low-trauma fractures in childhood, X-ray findings, family history, and *blue sclera* from transient collagen fibers in the sclera. Confirm diagnosis with collagen or DNA testing. Treat with bisphosphonates, surgical correction, and physical devices. Osteomalacia and rickets insufficient calcium and/or phosphorus to mineralize bone matrix, causing softening of bone. Osteomalacia refers to acquired cases in adults, who have bony pains, muscle weakness, and fracture. Rickets refers to osteomalacia in children, who have bowing of bones and dental problems. *vitamin D deficiency* is the most common cause. Those with chronic kidney disease may also have osteomalacia because they can't convert it to 1,25-OH2-D, the active form. *familial hypophosphatemic rickets* is caused by renal phosphate wasting. Treat by replacing vitamin D (active - calcitriol), calcium, and phosphorus. Osteoporosis the most common bone disorder worldwide, it's skeletal fragility characterized by reduced bone mass and microarchitectural deterioration from decreased formation and increased resorption. Bone mass is 50% environmentally/lifestyle determined and 50% heritable.

Osteoporosis

Osteoporosis - abnormal decrease in total amount of bone, leading to fractures after minimal trauma osteopenia - less severe decrease in bone density, determined by radiology Physical exam may reveal heigh loss, kyphosis (hump-backed), or scoliosis. *X-rays will only show bone loss after 30-50% of bone mass has been lost.* DEXA scans are much more accurate. Bone Mineral Density is measured in grams/cm^2 using a dual-energy X-ray absorptiometry (DEXA) scan of the spine, hip, and femoral head. A *T-score is the standard deviations the BMD differs from the average BMD of a 30yr old person matched for gender and ethnicity.* (Z-scores are also matched for age and are used for children, premenopausal women, and young men at risk for low bone mass). *each decrease in 1 SD in the T-score is associated with a doubling of fracture risk.* Normal T-score is -1 to +1, osteopenia is -1 to -2.5, and osteoporosis is <-2.5. primary/involutional osteoporosis accelerated loss of bone mass associated with aging. Secondary osteoporosis abnormal loss of bone mass due to other systemic illness or administration of drugs. *Corticosteroids or glucocorticoid excess* (Cushing's) at high doses inhibit osteoblasts and intestinal calcium absorption and increase urinary excretion of calcium and phosphorus. *Hyperthyroidism/thyroid hormones* increase bone turnover, with resorption occurring faster than deposition. *Growth hormone* induces IGF-1 formation, which stimulates osteoblasts, so GH deficiency increase risk. Hyperparathyroidism, hyperprolactinemia, and panhypopituitarism also cause secondary osteoporosis. Risk factors: white, female, old, low peak bone mass, estrogen deficiency, low body weight, current smoking, low calcium intake, drinking 3+ drinks per day, sedentary lifestyle Age is the most important determinant in men and women, and in women the next most important factor is onset of estrogen deficiency at menopause. Treatment Secondary osteoporosis bone mass improves if the underlying disease is treated. Primary osteoporosis can be improved with dietary supplements, hormone replacement, and anti-osteoporotic drugs. *These drugs are used in post-menopausal women and men 50+ with either: prior vertebral/hip fracture; BMD T-score -2.5 or lower at hip or spine (osteoporosis); or BMD T-score -1 to -2.5 at hip or spine (osteopenia) plus 10yr prob of hip fracture >3% or of any major osteoporotic fracture >20%.* Calculate using the fracture risk assessment tool (FRAX).

Posterior pituitary hormones and control

Oxytocin and Vasopressin (ADH/AVP) are peptide hormones that begin as pre-pro-hormones that include a signal peptide, a region for the binding protein/stabilization (neurophysin), and a signal peptide. they are synthesized in neurons of the supra-optic and paraventricular nuclei of the hypothalamus, and prohormones are transported intracellularly down axons into the posterior pituitary and stored in secretory granules at nerve terminals. The hormones dissociate from neurophysins at blood pH (pro hormones > hormones). Oxytocin causes uterine smooth muscle contraction in response to uterine distention and causes mammary smooth muscle contraction leading to milk ejection in response to suckling. There is one type of smooth muscle receptor for oxytocin. Synthetic hormone can be used to stimulate contractions and milk letdown, but there is no human disease of excess or deficiency. Vasopressin functions are receptor specific. V1 is responsible for vasoconstrictor activity in smooth muscle of blood vessels, GI, uterus, and heart; platelet activation and endothelial release of FVIII-vWF; and is low affinity, so a large dose is needed to achieve these effects. V2 is responsible for antidiuretic activity and affects mainly the kidneys with high affinity (only low dose needed). Binding of vasopressin to V2 channels stimulates cAMP production and PKA activation, which stimulates insertion of aquaporin channels into the luminal membrane to allow for more water reabsorption in the collecting ducts. V3 stimulates ACTH release from the pituitary. Hypothalamic osmoreceptors anterior to the 3rd ventricle detect changes in plasma osmolality to increase/decrease ADH accordingly (increase ADH when <280mOsm/kg). The carotid sinus and cardiac baroreceptors detect changes in blood pressure and there are inhibitory afferent neurons in CNIX and X that fire in response to high blood pressure and stop firing (release inhibition) in response to hypotension. A greater drop in pressure is needed to disinhibit ADH secretion (5-10% drop) than the osmolality increase needed to increase ADH secretion (1% increase), but disinhibition triggered by the baroreceptors will trigger a much steeper increase in ADH, stimulating not only V2 (antidiuretic) but also V1 (vasoconstriction). Thirst is stimulated when Posm reaches 290mOsm/kg, and is also triggered by hypovolemia. Nausea and pain can also stimulate ADH release.

Parathyroid adenoma and carcinoma

Parathyroid adenoma A single enlarged gland lacking the normal mixture of chief/oxyphil cells and adipose cells and is well circumscribed. Adenoma cells usually resemble normal chief cells. It's difficult to tell adenomas apart from the surrounding tissue grossly, so a pre and post serum PTH levels will be taken intraoperatively to ensure that the adenoma is removed (50% reduction in PTH after 15 min indicates success; also do this for other causes of hyperparathyroidism). Parathyroid hyperplasia Symmetrically enlarged parathyroid glands that may be homo or heterogeneous. Parathyroid carcinoma Rare, large mass with infiltrative borders and adherence to surrounding structures from invasion (capsular, vascular, or metastatic disease is required for diagnosis - not cytologic atypia). Local recurrence is common, and morbidity and mortality are often due to hypercalcemia and direct invasion rather than carcinomatosis (mets).

Parathyroid hormone

Parathyroid hormone is made by 4 glands on the posterior of the thyroid gland that are about 4-3mm in diameter and 3 grams each. The parathyroid glands are 25-40% fat cells, and the remaining cells are chief cells that secrete PTH in response to the body's calcium status. Pre-proPTH with 115 amino acids is cleaved to create proPTH, and then PTH and carboxyl fragments. PTH is released into the blood stream as 84 amino acid intact PTH - the bioactive form. The main effect of PTH is to increase serum calcium. Intact PTH binds to g-protein coupled receptors in bone to activate osteoblasts (reabsorption) and osteoclasts (release) as well as in the kidney to increase tubular calcium reabsorption and vitamin D activation. Vitamin D then increases calcium absorption by the gut (indirect effect). Another effect of PTH is decreasing serum phosphorus. PTH increases bone resorption and phosphorous release (direct effect) but has a greater effect on the kidney to increase phosphorus excretion. It also increases vitamin D activation at the kidney, thereby increasing phosphorus absorption in the gut. Calcium is the main regulator of PTH via negative feedback on calcium-sensing receptors on chief cells (CaSR). Phosphorus is a lesser regulator of PTH via a positive feedback loop - high levels of phosphorus stimulate PTH, which then decreases serum phosphorus.

Pituitary pathology

Pathology is most often neoplastic, and sometimes vascular or trauma related. Pituitary adenomas are very common in adults (in 25% of autopsies), and often don't cause symptoms. They arise from the anterior pituitary and are generally monoclonal (secrete 1 hormone). Functional adenomas increase hormone secretion, while small non-functional tumors do not. But any tumor if large enough can cause mass effects (macroadenoma >1cm). Adenomas are solid and can be named for their stain (acidophilic, basophilic, chromophobic) or for their secretory product: lactotroph/lactotrope/prolactinoma (26% - most common), Null cell (non-functional), corticotroph/corticotrope, somatotroph/somatotrope/growth hormone, mixed cell/plurihormonal, gonadotroph/gonadotrope, or thyrotroph/tyrotrope. Diagnose the cell type with immunohistochemistry (gold is positive) Craniopharyngiomas are benign , slow growing, non-functional tumors arising from the remnants of Rathke's pouch near the pituitary, representing <5% of intracranial neoplasms. They are more common in children/adolescents and in those >65 and present with symptoms of mass effect and/or increased intracranial pressure (headaches, nausea/vomiting, behavior changes, vision changes). These tumors have both cystic and solid regions and are more common suprasellar than intrasellar. Unlike other neoplasms, craniopharyngiomas appear *heterogenous histologically*, with nests/cords of stratified squamous cells edged with a periphery of columnar cells; keratin; cholesterol rich cysts; fibrosis; and calcification seen on X-ray. They *resemble germinal teeth.* They are surgically removed to relieve mass effect, and a central diabetes insipidus is a frequent complication (damage to hypothalamic nuclei secreting ADH) - treat with dDAVP (vasopressin analog). Vascular lesions Ischemic necrosis can occur with postpartum hypotension, DIC, shock, and sickle cell disease, causing hypopituitarism. Sheehan's syndrome is the most common form of ischemic necrosis - postpartum necrosis of the anterior pituitary that occurs after deliveries that involve much blood loss, which causes hypotension, leading to low flood flow through the venous system supplying the anterior pituitary (enlarges during pregnancy). Sheehan's symptoms can develop immediately or years/decades after the difficult birth and usually presents as failure to lactate and loss of menses. Pituitary aplopexy is a sudden expanding hemorrhage, usually into an adenoma, leading to destruction of adjacent pituitary cells and causing hypopituitarism, including loss of ACTH/cortisol that causes hypotension. Also causes sudden, severe headache and diplopia. Treat with fluids, glucocorticoids, and CV support. Traumatic/physical Empty sella syndrome - destruction or all or part of the pituitary from surgery, radiation, or congenital defect (absence of diaphragm allows CSF into sella). Diagnose on Xray. Mass lesions can impinge on the pituitary, causing panhypotituitarism (involves anterior and posterior pituitary).

Histology

Pituitary The anterior pituitary contains the pars distalis, the pars intermedia, and the pars tuberalis and is surrounded by a capsule. The pars distalis contains acidophilic (gold-staining) somatotrophs (GH) and mammotrophs/lactotrophs (prolactin). Somatotrophs line up in rows while lactotrophs are found alone, sitting like a cap onto of gonadotrophs. Basophilic (bluish) cells in the pars distalis include thyrotrophs (TSH), gonadotrophs (FSH/LH), and corticotrophs (ACTH). Thyrotrophs are more reddish and irregularly shaped, gonadotrophs are more dark blue and can have a mamotroph cap, and corticotrophs are the lightest staining of the basophils. The pars intermedia of the anterior pituitary contains colloid-filled cysts or follicles, and the space between it and the pars distalis represents the remnants of Rafske's Pouch. The pars nervosa of the posterior pituitary gland consists of large, unmyelinated axons and terminals, supporting glial cells (pituicytes), and large sinusoidal capillaries. Axons and terminals have neurosecretory granules that cluster to form reddish purple Herring bodies that contain oxytocin or ADH (not both). Thyroid The thyroid gland is surrounded by a capsule and contains septa and many follicles with cuboidal epithelium when active (simple squamous when inactive) to make thyroglobulin and T3/4. The follicular cells secrete thyroglobulin into the central compartment (colloid) of the follicle and then reabsorb it when stimulated by TSH, convert it to T3/4, and secrete it into blood vessels outside the follicle. White circles inside the follicles are resorption lacuna - empty space created by reabsorption of thyroglobulin. White specs inside the follicular cells themselves are phagolysosomes. There are dark purple mast cells near blood vessels. Lighter staining parafollicular C cells produce calcitonin and have large, lightly stained, vesicular nuclei. they can be found in the follicular wall or forming clusters in spaces between the follicles. Parathyroid Cells are arranged in cords or round clusters and can sometimes form small follicles. Most are chief cells with dark nuclei and pale or slightly pink cytoplasm that make parathyroid hormone to raise blood calcium levels. Oxyphil cells are larger than chief cells and have unknown function. Adrenal gland An outer capsule contains blood vessels that percolate between clusters of cells in the adrenal cortex. The outermost portion of the adrenal cortex is the zona glomerulosa where aldosterone (mineralocorticoid) is made and cells are arranged in spheres, followed by the zona fasciculata where cortisol is made and cells are arranged in sheets/rows, and then the zona reticularis where darker-staining cells make weak androgens. The zona fasciculata is very light staining because hormone precursors are lipids that are washed away during staining. Fasicular cells have mitochondria with tubular rather than flat christae because they are involved in lipid synthesis and modification. The adrenal medulla contains chromaffin cells that secrete epinephrine (lighter colored) and norepinephrine (darker colored). Cortical sinusoids empty into the medullary capillary network before draining out of the medulla. Pancreas Lighter colored islet cells in the islets of Langerhans produce glucagon, insulin, somatostatin, gastrin, and pancreatic polypeptide. Cells are very closely packed with little or no connective tissue between them, but do have capillaries/sinusoids in between them. Cells toward the center of the islet secrete insulin and those at the very edge secrete glucagon (they look the same though).

Hypocalcemia

Post surgical hypoparathyroidism, autoimmune hypoparathyroidism, and vitamin D deficiency are the most common causes. Signs and symptoms Agitation, hyperreflexia (decreased depolarization threshold), convulsions, hypotension, long QT, trousseau sign (inflation of BP cuff above systolic pressure causes loss of control of hand and fingers to pull inward), and chvostek sign (twitching in lower face in response to a tap on the cheek). Severe, untreated acute hypocalcemia can lead to prolonged QT interval and ventricular dysrhythmias, decreased contractility leading to CHF, hypotension, and angina. Those with chronic hypocalcemia can often adapt and don't develop symptoms until calcium drops much lower (compared with acute drop). Hypomagnesemia Low Magnesium caused by diarrhea, ahminoglycosides, diuretics, or alcohol abuse. Mg++ can exert similar effects on PTH release as Ca++ - decreased magnesium causes increased PTH, but really low magnesium actually prevents PTH release and decreases PTH levels. Treat with Mg++. Hypoparathyroidism is usually post-surgical (parathyroid surgery), and transient as the remaining normal parathyroid tissue recovers. Some patients can have severe and prolonged hypocalcemia despite normal/high PTH levels - "hungry bone syndrome." It usually occurs in those with more advanced bone disease preoperatively. It can also be autoimmune mediated and causes decreased calcium and PTH and increased phosphorus. Treat with calcium (calcium citrate or calcium carbonate) and 1,25-OH-D (calcitriol; low PTH decreases 1alpha-hydroxylase activity). Neuromuscular symptoms can persist even with treatment. DiGeorge Syndrome Autosomal dominant 22q11.2 deletion that causes cardiac abnormalities, abnormal facies, thymic aplasia, cleft palate, and hypocalcemia/hypoparathyroidism. Secondary hyperparathyroidism Chronic kidney disease and impaired vitamin D activation decreases Ca++ absorption and allows serum phosphorus to increase. In addition to low calcium and high phosphorus, there is high alkaline phosphatase (bone breakdown) and PTH. Can result in renal osteodystrophy - bone lesions from chronically high PTH. Treat with oral calcium, calcitriol (1,25-D), and phosphate binders. Pseudohypoparathyroidism/ PTH resistance/ Albright's Hereditary Osteodystrophy Increased PTH and phosphorus and decreased calcium caused by an inactivating mutation in GNAS associated with the PTH receptor, causing resistance to PTH. Maternal inheritance causes short 4th-5th metacarpal and metatarsal bones, hypocalcemia, and obesity and short stature. Paternal inheritance causes pseudopseudohypoparathyroidism (no PTH resistance, so normal lab values), shortened 4th and 5th digits, and sometimes obesity and short stature. Treat with oral calcium and calcitriol. Vitamin D related Low calcium, high PTH, and low/normal phosphorus Nutritional vitamin D deficiency 25-OH-D deficiency - Drugs that induce P450 enzymes (anticonvulsants) lead to increased catabolism of vitamin D. Renal failure and inactivation mutations in 1alpha hydroxylase (vitamin D dependent rickets type I) cause 1,25-OH2-D deficiency.

Special circumstances of hypothyroidism

Pregnancy Demand for thyroid hormone increases in early pregnancy 20-30%, and women with normal thyroid function can compensate but those with dysfunction can't and will often need levothyroxine dose increased by the 6th week. Untreated overt hypothyroidism affects brain development, cognition, and IQ, and increases risk of spontaneous miscarriage, preeclampsia, placental abruption, and LBW. Worldwide, iodine deficiency is a common cause and is the #1 cause of mental retardation in some areas. Consider screening women with high risk of hypothyroidism during pregnancy (family history, goiter, other autoimmune conditions). Total T4 is usually mildly elevated in normal pregnancy, so diagnose with high TSH and normal/low free T4. Cretinism - hypothyroidism in infants usually caused by an absent/underdeveloped thyroid (2x more in girls) or defects in thyroid hormone synthesis. Clinical features include poor brain development, growth, feeding and muscle tone; protruding tongue and umbilicus, pot-bell, puffy face, hoarse cry, and prolonged neonatal jaundice. Most cases in the US are detected with newborn screening. Hypothyroidism in children children generally have short stature, increased weight for height, delayed bone age, and poor school performance. Myxedema coma Severe hypothyroidism can cause bradycardia, hypotension, hypothermia, hypoventilation, stupor, and coma, and is usually seen with chronic non-compliance or undiagnosed hypothyroidism after a precipitating event - severe illness, surgery, sedatives, anesthetics. There is a high mortality rate. Treat the underlying cause, provide supportive care and thyroid hormone.

Adrenal insufficiency

Primary adrenal insufficiency Lack of cortisol and aldosterone secretion because of a deficiency within the adrenal gland, causing CRH and ACTH levels to rise along with renin and angiotensin (no negative feedback). Those with cortisol deficiency from primary or secondary adrenal insufficiency will experience fatigue, anorexia, weight loss, and hypotension, and sometimes abdominal pain, hyponatremia, postural hypotension, and hypoglycemia (cortisol stimulates gluconeogenesis). Those with cortisol deficiency from primary adrenal disease only can also have hyper pigmentation from increased ACTH, beta-lipotropin, and other POMC peptides (specific to primary adrenal insufficiency). Those with primary adrenal insufficiency can also have aldosterone deficiency, which causes hypovolemia, postural hypotension, hyperkalemia/hyponatremia (salt loss), and metabolic acidosis (unable to excrete H+). Those with secondary adrenal insufficiency don't usually have hyperkalemia because the RAAS system is not affected by reduced ACTH (but they can have hyponatremia from cortisol deficiency leading to water retention). Adrenal androgen deficiency from primary AI can cause lack of pubic and axillary hair in females. Causes of primary adrenal insufficiency include idiopathic/autoimmune (most common in US), iatrogenic, infections (TB, histoplasmosis, HIV), infiltrative diseases (mets, amyloidosis, hemochromatosis), hemorrhage (coagulation disorders), congenital hyperplasias (enzyme defects), and adrenal leukodystrophy. Causes of secondary adrenal insufficiency include anything that can damage the hypothalamus or pituitary. To evaluate adrenal insufficiency, first get baseline plasma cortisol and ACTH (ACTH will be high with primary AI). Then administer cosyntropin (synthetic ACTH) IV or intramuscularly and measure plasma cortisol 30 and 60 minutes later. In a normal person, a large dose of synthetic ACTH (cosyntropin) causes a large increase in plasma cortisol to >20mcg/dl. Those with secondary insufficiency will have baseline ACTH <20pg/ml and a very small increase in cortisol because the adrenal glad atrophies without stimulation for a long time, so it's unable to respond appropriately. Those with primary insufficiency will have baseline ACTH >200 pg/ml and even lower levels of cortisol and there will be no increase with cosyntropin. They can also have enlarged adrenal glands from constant stimulation by ACTH even though the adrenals can't respond. Treat primary adrenal insufficiency with hydrocortisone and flucrocortisone to replace glucocorticoids and mineralocortocoids. Glucocorticoid replacement should approximate physiologic needs at 20-30mg per day (more during stress with short term dexamethasone). Treat secondary adrenal insufficiency with hydrocortisone only.

Pheochromocytoma

Rare tumors of the adrenal medulla that cause <1% of HTN but are fatal if missed. The 10% tumor: 10% are bilateral, 10% are in the sympathetic ganglia outside the adrenal medulla (paraganglianoma), 10% are malignant, >10% are familial (autosomal dominant with variable penetrance from RET photo-oncogene mutation MEN2A and 2B) Pheos cause excess catecholamine secretion, causing episodic or sustained hypertension, postural hypotension, and weight loss (low appetite). Patients will have paroxysms/spells with a triad of *headache, diaphoresis, and palpitations,* and sometimes anxiety, tremors, fatigue, nausea/vomiting, abdominal pain and chest pain. The more specific diagnostic test is 24hr urine metanephrines (better measure of general/cumulative rise in catecholamines), and the more sensitive test is measuring plasma metanephrines. Measure plasma in those with a high risk of pheo (family history, symptom triad). Plasma catecholamines and metanephrines can be falsely elevated in stressed or sick patients. Localize the pheo with a CT or MRI of the abdomen, and use 123I-MIBG scan to look for mets if extra-adrenal sites are suspected (taken up by sympathetic neurons and medullary cells). Treat with adrenalectomy, only after taking medical steps to prevent a hypertensive crisis during surgery from a huge surge of catecholamines. First give an alpha-blockade (blocks NE) with phenoxybenzamine (irreversible) or prazosin/doxazosin (reversible), then give a beta blockade (starting beta-blockade first can worsen HTN because the main beta adrenergic effect is peripheral vasodilation). Vigorously hydrate the patient before surgery.

Hypercalcemia

Signs and symptoms Most are asymptomatic, but some will have nephrolithiasis (kidney stones) or hypercalciuria, bone pain and fractures, abdominal pain, anorexia, constipation, pancreatitis, lethargy, depression, anxiety, hypotonia, decreased reflexes, HTN, short QT, metastatic calcification, psychosis, and stupor/coma. (Stones, bonds, groans, psych overtones). Acute crisis hypercalcemia of malignancy causes anorexia, polyuria, dehydration, impaired mentation, and immobilization Primary hyperparathyroidism More common in older women and the most common cause of high PTH in an outpatient setting. Causes high serum and urine calcium, high PTH, high urine cAMP, and low phosphorus. Qephrocalcinosis and hypovolemia can impair kidney function, causing mildly elevated creatinine. It can cause osteitis fibrous cystica. Primary hyperparathyroidism is caused by adenoma 90% of the time, hyperplasia 10%, and <1% carcinoma. First line treatment is surgery to remove abnormal parathyroid tissue. Those with mild, asymptomatic disease or who are at high operative risk for surgery can be monitored with serial calcium, creatinine, and bone density. Bisphosphonates and calcitonin can be used to slow bone resorption but don't affect serum calcium levels. If calcium levels need to be lowered urgently before surgery, give saline hydration, loop diuretics, and IV bisphosphonates. Second line treatment is cinacalcet. Tertiary hyperparathyroidism Is a rare condition caused by chronic renal disease, usually as a result of renal transplant. The kidney is unable to create 1,25-OH-D, leading to low calcium levels that trigger an increase in PTH - secondary hyperparathyroidism. Over time, the parathyroid secretes too much PTH autonomously (even after kidney transplant enables calcium absorption), leading to hypercalcemia that is much more severe than primary hyperparathyroidism. Treat with surgery. Familial hyperparathyroidism Familial hypocalciuric hypercalcemia (FHH) - inactivating mutations of the CaSR, including those on the kidney, lead to hypocalciuria and hypercalcemia because receptors in the kidney don't sense calcium to stimulate excretion. If you are suspicious of FHH, test calcium of first degree relatives first. HPTH-jaw tumor syndrome - mutations in HRPT2 tumor suppressor causes hyperparathyroidism from adenomas (increased risk for carcinoma) and jaw fibromas. MEN I - mutations in MEN1 tumor suppressor cause multiple gland hyperplasia, pituitary adenoma, and pancreatic tumors in young men=women (<30yrs). MEN IIa - mutation in RET proto-oncogene, a tyrosine kinase, leading to multiple gland hyperplasia, medullary thyroid cancer, and pheochromocytoma in men=women <30yrs. Untreated severe hyperparathyroidism can cause nephrolithiasis, renal failure, osteopenia, pancreatitis, peptic ulcer disease, HTN, arthritis, and cardiac arrhythmias. McCune Albright syndrome Constitutively active GNAS G protein associated with the PTH receptor causes constant activation in some somatic cells (not inherited - mosaic pattern). Causes cafe au lait spots with a jagged border that respects the midline, fibrous dysplasia, precocious puberty from LH/FSH activation, and hyperthyroidism. Calcium, 1,25-OH-D, and alkaline phosphatase will be high, but PTH will be normal (when it should be low). Endocrine causes of mild hypercalcemia Hyperthyroidism from a direct effect of T3 on bone. TSH will be very low, but calcium, phosphorus, alkaline phosphatase will be high. Adrenal insufficiency, VIPoma, or pheochromocytoma from volume contraction changing the PTH set point Medications/supplements Vitamin D overdose, Milk-alkali syndrome (3+ g/day calcium intake with alkalosis and renal failure), lithium (reduces calcium clearance and alters set point for PTH release), and thiazide diuretics (potentiate PTH at receptor). Hypercalemia of malignancy The most common cause of hypercalcemia in hospitalized patients, as malignancies (SCLC) can secrete PTH-rp that mimics PTH, causing high calcium, low phosphorus, and low PTH. Malignancies of bone (multiple myeloma) can also cause hypercalcemia. Alkaline phosphatase will also be high. Granulomatous disease (sarcoid) can also cause hypercalcemia by elevating 1,25-OH2-D.

Hypothyroidism clinical features, diagnosis, treatment

Signs and symptoms are due to slowing of metabolism and target organ function as well as accumulation of glycosaminoglycans (GAGs). Symptoms include cold intolerance, *fatigue*, hoarseness (accumulation of GAGs in pharyngeal area), normocytic anemia, decreased HR and CO, increased PVR and *diastolic BP (narrowing pulse pressure - eg.130/96)*, increased cholesterol, pericardial/pleural effusions, menorrhagia (heavy periods), irregular periods, *myalgia*, proximal weakness, arthralgia, *poor concentration and memory, depression (especially in elderly),* paresthesias, delayed relaxation phase of reflexes, thick/yellowed skin, *dry skin/hair, non-pitting edema* (build up of GAGs), periorbital swelling, macroglossia, *constipation, and weight gain*. Test for hypothyroidism if patients have multiple symptoms and/or are at increased risk (family history, women 60+, using amiodarone/interferon/lithium, history of head/neck irradiation). Perform a TSH and add a free or total T4 if there is a high index of suspicion (usually TSH alone is enough for screening, but T4 can help you determine the best starting dose). Primary subclinical hypothyroidism will have a high TSH and normal FreeT4 and T3 (because TSH increases exponentially with increases in T4/3, it is outside normal range before T3/4). Overt hypothyroidism will have high TSH, low T4 and low/normal T3. Secondary hypothyroidism will have low/normal TSH, low FreeT4, and low/normal T3, and is caused by hypothalamic or pituitary disease. Test the functioning of other endocrine glands dependent on pituitary function, and given replacement hormones if needed, especially glucocorticoids. Patients with adrenal insufficiency will develop more severe cortisol deficiency if treated with thyroid replacement alone. Give hydrocortisone with or before thyroid replacement. Get an MRI of the brain/pituitary to look for tumor or structural disease. Non-thyroidal illness Abnormal thyroid function tests in seriously ill patients in the absence of any underlying thyroid problem, usually resembling secondary hypothyroidism. There can be decreased conversion of T4 to T3 and decreased production of thyroid binding proteins, such that total T4 is low, free T4 is normal, and TSH is normal. Patients usually recover normal levels after recovering from their illness. Similar lab findings will be seen with hereditary states of low TBG and in androgen-treated patients. Treat hypothyroidism with levothyroxine (synthetic T4/thyroxine) taken as a daily pill in the morning on an empty stomach (separate from calcium or iron supplements, multivitamins). It's the #2 chronically prescribed drug in the US. Monitor TSH levels (+/- freeT4) in those being treated every 6-8 weeks (takes this long for TSH levels to reflect T3/4). Patients likely to require a full replacement dose can be given 1.6mcg/kg per day if they are healthy, not old, and normal weight (use lower dose in those with low lean body mass). Children require higher doses, but start low and gradually increase to prevent imbalance in CSF, increased intracranial pressure, and headache. Patients likely to require less than the full replacement dose and those who are elderly or have CV disease can start at 25-50mcg/day and titrate up in 12-25mcg increments.

Hyperthyroidism symptoms, diagnosis, treatment

Signs and symptoms are from accelerated metabolism and target organ hyper function Symptoms include *heat intolerance, sweating, fatigue, weight loss, increased HR and systolic BP, palpitations, tachycardia, atrial fibrillation, increased contractility and CO, high-output CHF if left untreated,* angina, irregular periods, proximal muscle weakness, *stare/lid retraction, lid lag/lagophthalmos, anxiety, tremors, hyperactive reflexes,* hyperactivity, mania/psychosis, *moist skin,* scalp hair loss, onycholysis (peeling fingernails), *increased appetite, and hyperdefecation* (more frequent). Overt hyperthyroidism produces low/undetectable TSH and high T4/FT4 and T4/FT3. Subclinical hyperthyroidism produces low TSH (.1-.5) and normal T4/FT4 and T3/FT3. T3 thyrotoxicosis is when TSH is low and T3/FT3 is high, but T4/FT4 is normal (Graves' can present this way when the ratio of T3 to T4 production is skewed). Underlying etiology determines the course of treatment (unlike hypothyroidism, where levothyroxine is always the treatment). Diagnose using history and exam, thyroid function tests, antibody testing (high TSI/TSH-R Ab in Graves'), radioactive iodine uptake scanning, and thyroglobulin level if you suspect exogenous ingestion (thyroglobulin will be elevated from excess endogenous production/release but not from exogenous ingestion). Treatments include anti-thyroid drugs (methimazole or propyltiouracil), which are first line for Graves. Methimazole can be given once per day while propythiouracil is given multiple times per day and is used mainly in the hospital setting for more severe cases because it alone blocks the peripheral conversion of T4 to T3. Both drugs block thyroid peroxidase, organification of iodide, and coupling of iodotyrosines (MIT, DIT). Minor side effects include rash, muscle/joint aches, headache, nausea, and altered taste. Serious side effects (never use that drug or the other anti-thyroid drug again) include liver damage (more often in PTU; causes abdominal pain, nausea/vomiting, discolored urine) and potentially fatal agranulocytosis (stop meds if high fever or sore throat, check CBC with diff). Radioactive iodine is first line for toxic nodules, and is effective in 70-90% with control achieved in weeks to months. There is no evidence of increased thyroid cancer risk, but 50% develop hypothyroidism within 3 years (more common for Graves' patients, and can exacerbate Graves' ophthalmopathy). Surgery is used for large glands/nodules causing compression or for those where other treatment has failed or is contraindicated (pregnancy). Iodine is given short-term for severe hyperthyroidism and inhibits synthesis/release within 2-7 days (Wolff-Chaikoff effect), decreases vascularity of the thyroid (prep for surgery), and is administered as drops or solution. Beta-blockers are used for tremors, palpitations, or atrial fibrillation with rapid ventricular rate. Thyroid storm Very severe hyperthyroidism that causes fever, mental status changes, and CV collapse, often precipitated by surgery, sepsis, iodine loads, and postpartum. 20-50% die. Treat with high dose PTU, iodine 2 hrs after PTU, propranolol, dexamethasone, and treat the underlying cause.

Steroid hormones

Steroid hormones include cortisol, aldosterone, testosterone, estradiol, vitamin D, and cholesterol - all have a 4 ring structure. Steroid hormones are synthesized in the adrenal cortex, ovaries, testes, and adipose tissue. Steroid hormones and thyroid hormone travel in the blood stream bound to carrier proteins - the stronger the binding of a carrier protein, the slower the clearance rate of the hormone and the longer its half-life (hours). Hormones bound to proteins in the blood tend to have more chronic actions (regulate gene transcription over longer time frame). Receptors are usually within the cytosol or nucleus, or can be membrane associated. When measuring hormone levels, the total hormone is measured, which is bound hormone + free hormone (clinical symptoms reflect the amount of free hormone). Exogenous factors and clinical conditions can increase or decrease hepatic production of the binding proteins or their renal clearance, or affect their binding properties - this can affect the measured total hormone concentrations. Sometimes it's best to deter endocrine testing until after the patient has recovered from their severe illness (illness can temporarily decrease thyroid hormone production - transient central hypothyroidism). Lipid droplets travel through cell plasma membranes, and the cholesterol within them is used for steroid synthesis. Cholesterol enters mitochondria, where P450 enzymes on the inner membrane alter the cholesterol, which passes between the mitochondria and smooth ER to produce the final hormone, which then diffuses immediately into the blood (not stored in vesicles). In the mitochondria/smooth ER, cholesterol is converted to pregnenolone and then can take three paths. Pregnenolone can become corticosterone and then aldosterone. Pregnenolone can become 17-hydroxyprogesterone and then cortisol. Or pregnenolone can become dehydroepiandrosterone (DHEA - sex steroid precursor), which can become androstenedione (another sex steroid precursor).

Syndrome of inappropriate antidiuresis

Syndrome of inappropriate antidiuresis (SIAD) is hyponatremia with low plasma osmolality, urine osmolality greater than plasma osmolality, inappropriate renal sodium excretion >20mmol/L, in the absence of hypotension, hypovolemia, and edema-forming states in the setting of normal renal, adrenal and thyroid function. There are often no symptoms, but severe SIAD can cause headaches, nausea, vomiting, confusion, personality changes, seizures, and coma. Mild: 130-135 moderate: 125-129 Profound: <125 Diseases associated with SIAD include pulmonary cancer (SCLC, squamous cell, Hodgkin's), lung infections, and COPD; CNS infections, tumors, and bleeding; drugs that potentiate ADH or reduce free water clearance; and adrenal insufficiency and hypothyroidism (mimics SIADH). When you treat these processes, hyponatremia improves. The differential diagnosis for hyponatremia includes hypertonic hyponatremia - the movement of water from intracellular to extracellular because of hyperglycemia or mannitol. Non-hypotonic causes also include severe hyperlipidemia and paraproteinemia (multiple myeloma). Hypotonic hyponatremia in the setting of hypovolemia can be caused by GI fluid loss, primary adrenal failure, salt-losing nephritis, cerebral salt wasting, burns, and diuretics. Normovolemic hypotonic hyponatremia can be caused by SIADH, hypocortisolism, hypothyroidism, or primary polydipsia. Hypervolemic hypotonic hyponatremia can be caused by heart failure, cirrhosis, nephrotic syndrome, and renal failure. SIADH - inappropriate water retention from excess vasopressin activity that causes hyponatremia with inappropriate urinary sodium loss. Treat SIADH with fluid restriction <1L/day, treat the underlying disease, and give demeclocycline for chronic SIAD (antibiotic that reduces the responsiveness of collecting duct to ADH). If there are CNS symptoms (confusion, ataxia, etc.), give IV normal saline or 3% saline and loop diuretics and watch rate of Na+ correction to avoid pontine myelinolysis. V2 receptors antagonists (conivaptan and Tolvaptan) can also be given to increase free water clearance (aquaretics). Side effects of vasopressin antagonists include increased LFTs, so don't give to those with cirrhotic hyponatremia. (European endocrine society recommends against Vaptans and demeclocycline) When treating chronic hyponatremia rapidly increasing Na+ causes risk of cellular dehydration and central pontine myelinolysis. *Don't exceed correction rate of 10mmol/day (start at .5-1mmol/L per hour).* *When treating acute onset hyponatremia (<48hrs) and those at a high risk of dying (seizures, coma), give initial hourly correction of 2-3mmol/L and stop 3% normal saline when the patient become asymptomatic or reaches 120mmol/L. * Central pontine myelinolysis causes lethargy, changes in affect, ataxia, mutism, dysarthria, quadriplegia, seizures, coma, and death and can occur 1-21 days after hyponatremia correction (generally in 1 week). Risk for CPM is increased by malnutrition, hypokalemia, or liver disease (alcoholics). There is no known treatment.

hormone receptors Feedback

The ability of a cell to respond to a hormone depends upon the presence of receptors for that hormone, which can be in the plasma membrane, intracellular, or both. Peptide hormones bind to cell surface receptors associated with G-protein that activates adenylate cyclase, which activates cAMP and other second messengers to elicit the target cell response. Steroid hormones enter the cell and bind to a steroid receptor in the cytoplasm that carries the hormone into the nucleus, where the complex binds to receptor sites on chromatin, activating mRNA transcription. Some steroid hormones bind to membrane receptors instead. Hormone releasing cells also have receptors for other chemicals that enable feedback responses. Negative feedback is the most common, where a secondary hormone released in response to the primary hormone decreases the release of the primary hormone. Positive feedback can also occur, where the secondary hormone enables ongoing release of the primary hormone. Increased or decreased production of a hormone will cause target cells to down or up regulate their receptors for that hormone (sensitization/desensitization). Down regulation can occur with the receptor/hormone complex being endocytosed and sequestered in endosomes for destruction in lysosomes; receptors can be inactivated via phosphorylation; downstream response can be decreased.

Adrenal glands

The adrenal cortex produces aldosterone, cortisol, and androgens from cholesterol. The outermost cortex, the zona glomerulosa, produces aldosterone and other mineralocorticoids in response to Angiotensin II, High K+, or low Na+. Aldosterone targets the kidneys, blood vessels, and heart to regulate Na/K balance and BP. The middle cortical layer, the zona fasiculata, produces cortisol and other glucocorticoids in response to ACTH. Cortisol affects protein, fat, and carbohydrate metabolism. The innermost layer of the cortex, the zona reticularis, produces androgens (DHEA and androstenedione) in response to ACTH. Androgens stimulate sexual maturation and bone/muscle growth. The adrenal medulla produces catecholamines (Epi,NE, and DA) from tyrosine in response to sympathetic fibers. Catecholamines regulate cardiac stimulation and BP increase.

adrenal embryology/pathology

The cortex is derived from the mesoderm and the medulla from the neural crest (composed of post-ganglionic sympathetic cells/chromaffin cells) Primary hyperplasia of the cortex can occur rom congenital lack of synthetic enzyme (inability to respond to ACTH). Secondary cortical hyperplasia can occur from increased trophic factor (ACTH, renin/angiotensin). Cortical adenomas are single, solid, encapsulate, yellow masses. Histologically, they are pale (lipid-laden), well differentiated cells. Can be functional or non-functional. If it secretes cortisol (Cushing syndrome), this decreases ACTH secretion, leading to adrenal cortical atrophy. Primary hyperaldosteronism is Conn syndrome. Cortical atrophy can occur from prolonged medicinal glucocorticoids lowering ACTH and leading to bilateral adrenal cortical atrophy. If drugs are quickly withdrawal, atrophic adrenals can't secrete enough hormone - secondary acute adrenal insufficiency. Adrenal hemorrhage can occur from anti-coagulant therapy, DIC, and bacterial sepsis (Waterhouse Friderichsen Syndrome). Bilateral adrenal hemorrhage leads to acute hemorrhagic necrosis and primary acute adrenal insufficiency. Waterhouse-Friderichsen syndrome is usually caused by neisseria meningitidis (sometimes pseudomonas), leading to septicemia, hypotension and DIC, hemorrhage, etc. Extensive purpura can be seen. Autoimmune diseases causes early lymphoid infiltrates in the cortex that destroy normal tissue, leading to cortical fibrosis and sparing of the medulla. Primary chronic adrenal insufficiency is Addison disease. Neoplasms are really all that occurs in the medulla. Pheochromocytoma is a chromaffin cell neoplasm that can sometimes cause HTN. 10% are familial (AD), 10% bilateral, 10% malignant, 10% in children, and 10% extra-adrenal. Grossly they appear circumscribed, solid, red/brown. Histologically they have nests of neoplastic cells. Neuroblastoma is a malignancy composed of neural crest cells in the medulla (1/3), abdominal sympathetic chain (1/3) or thoracic sympathetic chain (1/5). Occurs in children <4yrs (most common extra cranial childhood tumor). Caused by sporadic mutation of the N-myc oncogene. Neuroblastoma has a heterogeneous interior of necrosis/hemorrhage and an irregular shape. Histologically there are small, round blue cells that form homer-wright rosettes. Labs will show increased urine NE, DA, homovanillic acid (HVA) and vanillylmandelic acid (VMA).

Pituitary structure embryology

The hypothalamus is part of the posterior forebrain composed of many nuclei that serves as the link between the nervous system and the endocrine system, controlling the pituitary gland beneath it. A normal pituitary is 1cm in length and rested in the sella turcica, attached to the hypothalamus by the infundibulum. it is near the optic chiasm (CN2) and cavernous sinuses that contain CN 3 (oculomotor), 4 (trochlear - superior oblique eye muscles), 5 (trigeminal, sensory to face/mouth; motor muscles of mastication), and 6 (abducens - lateral rectus eye muscles). The pituitary is supplied by a portal venous system. The superior hypophyseal arteries branch into fenestrated capillaries in the median eminence of the hypothalamus where stored hypothalamic releasing/inhibiting hormones enter the blood. These capillaries merge to form hypophyseal portal veins that descend in the infundibulum to the anterior pituitary gland. The veins then branch again to form a second fenestrated capillary bed were releasing hormones stimulate cells of the anterior pituitary to release their hormones. The anterior pituitary/adenophypophysis/pars distalis makes up 80% of the pituitary and contains different cell types that produce the anterior pituitary hormones - GH, PRL, ACTH, TSH, and FSH/LH (same cell produces both). Hypothalamic releasing and inhibiting factors are released by neurons onto portal veins that lead into the anterior pituitary. The posterior pituitary/neurohypophysis/pars nervosa makes up 20% of the pituitary and contains the axons of hypothalamic neurons that produce oxytocin or vasopressin (ADH), which are stored in nerve endings in the posterior pituitary and released onto capillary beds. The pars intermedia is a rudimentary division between the anterior and posterior pituitary. Embryology The anterior pituitary arises from the oral cavity invagination called *Rathke's/hypophyseal pouch* that extends dorsally and eventually loses connection with the oral cavity. The posterior pituitary arises from ventral extension of the hypothalamus

Secondary hyperaldosteronism

The most common cause of secondary hyperaldosteronism in adults is renovascular disease (renal artery stenosis). Those with arteriosclerosis and who have an abdominal bruit are at the most risk. Renin and aldosterone levels are high, while the aldosterone:renin ratio will be normal or low. If renal artery stenosis is suspected, perform a renal arteriogram to show high plasma renin activity from venous drainage of the affected kidney compared to peripheral circulation, and renal ultrasound or MRI/MRA to show the site of the blockage. Treat renovascular HTN with surgery or balloon angioplasty to open the stenosed segment of the renal artery - doing so reduces BP and reduces risk of losing function in the ischemic kidney. If surgery is not possible, ACE-inhibitors (-pril), ARBs (-sartan), and renin inhibitors (aliskiren) can be used to decrease efferent arteriole constriction, GFR in the affected kidney, and blood pressure but it doesn't reduce risk of progressive loss of function in the ischemic kidney.

Thyroid embryology and pathology

The thyroid is 2 lobes connected by the isthmus, 40% have pyramidal lobe, it's covered by a capsule and weighs <25g, extends from thyroid cartilage to tracheal ring 5-6 and attaches posteriorly to the cricoid and tracheal cartilages. Receives blood supply by the superior and inferior thyroid arteries. The superior and recurrent laryngeal nerves are nearby and can be compressed if thyroid enlarges. The thyroid arises in the inferior oral cavity within the developing tongue, and the site or origin remains visible as the foramen cecum on the dorsal tongue. The thyroid extends inferiorly/caudally into the neck, forming the thyroglossal duct. The thyroid forms at the bottom of the duct and the duct atrophies/disappears. Thyroglossal duct cyst can form when a region of the duct persists and enlarges, usually in the anterior midline of the neck around the hyoid bone. It *moves with tongue protrusion* and swallowing. Accessory thyroid tissue can develop anywhere in the thyroglossal duct. It's common in the thyroid itself, forming pyramidal lobe in 40%. Rarely it can be in the tongue, forming a lingual thyroid.

Goiter

Thyroid enlargement Nodular goiter usually involves hyperplasia, colloid accumulation, and/or nodule formation (heterogeneous). Thyroid nodules are very common. If TSH is low, order a thyroid uptake scan first to avoid fine needle aspiration of hot nodules. Most are benign and can be followed by exam +/- US. Benign nodules have low cellularity and much colloid. Non-toxic/euthyroid goiter is most common and involves diffuse enlargement due to iodine deficiency, goitrogens, or chronic lymphocytic thyroiditis/Hashimoto's. Endemic (iodine deficient) goiter is the most common worldwide. Thyroid iodine uptake scan shows multiple areas of increased and decreased uptake, and thyroid function tests are usually normal. Over time, overt hyperthyroidism can develop. Treatment is not required if there are no symptoms, normal TSH, and no concern for cancer. Observe with serial exams, +/- ultrasound if nodules are present and use FNA to sample cold nodules. Surgery is used for compressive symptoms. Pemberton's sign (face turns red when arms raised overhead) shows that venous congestion is preventing venous drainage from the head and neck. Toxic goiter causes hyperthyroidism (TSH low), and includes Graves' disease. Treat with radioiodine ablation or surgery. Growth factors that stimulate nodular goiters include TSH, IGF-1, transforming growth factor beta, fibroblast growth factors, and others. Diffuse goiters are caused by autoimmune disease (Hashimoto's, Graves), iodine deficiency, antithyroid drugs, lithium, amiodarone, and inherited defects in biosynthetic enzymes.

Thyroid and related hormones

Thyroid hormone synthesis Iodide from the blood is brought into follicular cells via Na/!- symporter. Inside the cells, the iodide is added to thyroglobulin (iodination/organification) by thyroid peroxidase (TPO) to create monoiodotyrosine and diiodotyrosine (MIT and DIT). Catalyzed by TPO, MIT and DIT are coupled to produce T3 (triiodothyronine) and two DITs are coupled to produce T4 (thyroxine). 80-90% of thyroid hormone is secreted as T4, which has a 7 day half life and is a pro-hormone that must be converted to T3. 10-20% is secreted at T3, which has a 1 day half life and is the active form. T3 binds to nuclear receptors of almost all body cells to modulate (usually stimulate) gene expression. T3 stimulates brain/CNS maturation and activity, bone growth (with GH), increases HR, SV, CO, and causes vasodilation, and increases basal metabolic rate by increasing Na+/K+ ATPase activity and O2 consumption, respiratory rate, and body temperature. (4 Bs - Brain, Bone, Beta-adrenergic/blood, BMR). Hypothalamus releases TRH, causing pituitary to release TSH, causing the thyroid gland to create and secrete T3 and T4. T3 is active and acts on target receptors in the nuclei of the liver, heart, bone, and CNS. T4 is converted in the liver to T3 by type 1 deiodinase, and in the brain by type 2 deiodinase so that T3 can provide negative feedback to the hypothalamus and pituitary. TSH a protein hormone with the same alpha subunit as FSH, LH, and HCG but with a unique beta subunit. TSH stimulates growth and vascularity of the thyroid and formation and release of thyroid hormones by increasing iodide uptake, TPO activity, and lysosomal activity. TSH has fairly stable secretion throughout the day. TSH is the best test to diagnose and follow primary disorders of thyroid function because it reflects ~6 weeks of FT3/FT4 feedback on the pituitary, and changes in FT4/FT3 cause an opposite, logarithmic change is TSH so that small changes are magnified (2x increase in FT4/FT3 causes 100x increase in TSH). T3 and T4 are 99% protein bound, with 60-75% bound to thyroxine binding globulin (TBG), 15-30% bound to transthyretin, and 10% to albumin. Free T4 and T3 make up <1% of total T4 and T3 but are the biologically active forms. Changes in binding proteins affect total T3/T4 measurement without causing biologic changes (or affecting TSH secretion because hypothalamus/pituitary responds to FT3, and levels of free hormone are not affected). Acquired causes of increased binding proteins include drugs (*estrogen*, opiates), *pregnancy*, and acute hepatitis (increase total T4 but not free T4). Decreased binding proteins can be caused by drugs (*androgens, glucocorticoids*), malnutrition, chronic liver disease/cirrhosis, and renal disease. Inherited causes of binding protein changes are very rare and include X-linked TBG deficiency and mutations in TBG. Thyroid peroxidase antibodies (TPOAb) and TSH-receptor antibodies (TRAb) are involved in autoimmune thyroid disease and can stimulate or block the thyroid, leading to cell lysis and inflammation and altered gland function. They can be useful to diagnose mild/early AITD. TPOAb are present in 90-95% of patients with AITD and about 12% of those without disease (no treatment required if thyroid is functioning normally), and risk of developing TPOAb increases with age in those with Hashimoto's (AI hypothyroidism). TSH receptor antibodies include Thyroid stimulating immunoglobulin (TSI) and thyrotropin-binding inhibitory immunoglobulin (TBII). They can be used to diagnose hyperthyroidism of unclear etiology and are used to detect fetal/neonatal thyrotoxicosis in pregnant women with Graves disease. Thyroglobulin antibodies (TgAb) are non-specific as many people have them without causing disease. Thyroid tumor markers Thyroglobulin (Tg) - normal protein in follicular cells that is used in surveillance of papillary/follicular thyroid cancer after treatment, but is not reliable in patients who make TgAb. Calcitonin - normal protein in C-cells used in surveillance of medullary thyroid cancer after treatment, but that can be elevated by liver/breast cancer, carcinoid, ZES, and pancreatitis.

Cushing's syndrome

Urine cortisol >90mcg/d (normal is 10-55) Glucocorticoid excess (hypercortisolism) causes muscle wasting, weakness, easy bruising, poor wound healing, central adiposity, glucose intolerance, and psych disturbances. Mineralocorticoid excess causes salt retention, HTN, edema, hypokalemia, metabolic alkalosis. Androgen excess causes hirsutism, acne, and amenorrhea. (Mineralocorticoid and androgen excess may not be present in iatrogenic Cushing's due to synthetic exogenous glucocorticoids.) Cushing's syndrome can be due to an adrenal adenoma that releases cortisol regardless of ACTH levels, producing high cortisol levels, low CRH, and low ACTH. It can also be due to an ectopic ACTH producing tumor, causing ACTH and cortisol to be high, but CRH to be low. Ectopic tumors are usually bronchial carcinoid tumors or small cell lung cancer. Cushing's disease is caused by an ACTH producing pituitary tumor that produces ACTH regardless of CRH levels, producing high ACTH and cortisol, but low CRH. Adrenal glands increase in size. Iatrogenic Cushings Syndrome is the most common form, and can be caused by glucocorticoid treatment that is too high in dosage, longer acting, treatment continues too long, and the glucocorticoid is systemically rather than localized/topically distributed. Dexamethasone has the longest half life and persistence of side effects (then prednisone, then hydrocortisone). Long term use of exogenous glucocorticoids decreases endogenous ACTH and cortisol so that patients must be slowly weaned off of the drugs to allow the pituitary and adrenals to begin making more and reverse atrophy. After finding that urine cortisol is >90mcg/d (24-hr urine free cortisol), determine the cause of Cushing's syndrome using a low (1mg) and high (8mg) dose dexamethasone suppression test. Low dose dexamethasone has no effect on any cause of Cushing's (decreases urine concentration in normal person). High dose will decrease urine cortisol to <5mcg/dl (or by >50%) in those with Cushing's disease (pituitary cushing's) and basal ACTH will be 50-200pg/ml (normal is 10-60). If someone has Cushing's disease, get an MRI of their brain to look for the tumor. If you can't see the tumor, use Inferior petrosal sinus sampling to see which side of the pituitary the tumor is on (shows the highest concentration of ACTH) High dose dexamethasone will not affect urine cortisol levels in those with an adrenal tumor or ectopic ACTH tumor, so you differentiate between them by basal ACTH - adrenal tumor will have ACTH <10pg/ml while ectopic ACTH tumor will have ACTH >100 pg/ml. If ACTH is low (adrenal tumor), perform an adrenal CT to confirm the location of the tumor. Treat Cushing's disease (pituitary) by removing the pituitary tumor transsphenoidally. If surgery is delayed, contraindicated, or ineffective, use pituitary irradiation, drugs, or bilateral adrenalectomy. Use drugs that block ACTH secretion by the tumor or steroid biosynthesis. Cabergoline and pasireotide decrease ACTH secretion by the pituitary tumor. Ketoconazole and aminoglutethimine inhibit steroidogenesis. Failure to remove the pituitary tumor can cause Nelson's Syndrome after bilateral adrenalectomy, in which a corticotroph tumor grows, causing mass effect and hyper pigmentation. Reduce this risk with pituitary irradiation before bilateral adrenelactomy. Treat primary adrenal tumors by surgical resection (usually successful for adenomas, not carcinomas) and drug therapy that blocks steroid biosynthesis (ketoconazole, aminoglutethimide) or break down androgens. Treat ectopic ACTH syndrome by removing/ablating the tumor (radiation), bilateral adrenalectomy, and/or drugs that block steroid biosynthesis. Mifepristone and spironolactone inhibit glucocorticoid and mineralocorticoid action at target tissues by blocking the receptors. After any of these treatments (or abrupt removal of glucocorticoid medication), the pituitary will not be able to secrete ACTH quickly enough to maintain cortisol levels (and the remaining adrenal gland may have atrophied in the case of adrenal tumor). Use glucocorticoid replacement and taper off slowly until the pituitary and adrenals can recover.

Thyroid cancer

While thyroid hyperplasia is caused by focal extrinsic activation of polyclonal cells, tumors are monoclonal and activated intrinsically. 50% of people by age 50 have a thyroid nodule viewed on autopsy/US, while only 5% at age 50 have a nodule that can be felt by palpation. Most thyroid disease are much more common in women than men. 5% of thyroid modules are hyperfunctioning and 5% are cancerous. Risk factors for malignancy include radiation exposure, MEN2a/2b (medullary thyroid cancer), <20yrs or >60yrs, males, and compressive symptoms (voice changes). Nodules <3-4cm that are firm and fixed, and if there is cervical/supraclavicular lymphadenopathy, it's more likely to be cancer. After a nodule is found, if TSH is normal, do a FNA for cytology with US guidance. 60-70% are benign - observe with exam/ultrasound for growth. 10-20% are indeterminate - repeat FNA, molecular testing, or diagnostic surgery. 5% are malignant - partial or total thyroidectomy. If TSH is low, order a radio iodine scan to see if the nodule is hot/hyperfunctioning because these have very low likelihood of malignancy and thus a FNA would not be needed. If nodule is cold, get a biopsy. When FNA cytology is performed, high amounts of colloid and low cellularity of epithelial cells suggest non-neoplastic - observe these lesions if asymptomatic. Low amounts of colloid and high cellularity of epithelial cells suggest neoplasm (benign or malignant). Cell morphology can be suggestive of neoplasm. If indeterminate, perform molecular tests for cancer mutations or remove the entire nodule. Papillary carcinoma 85% of malignant thyroid neoplasms are PTC, and they occur more often in women between 30-50yrs. 90% ten year survival rat, but tumor often spreads by lymphatic invasion to regional nodes. Cytology shows cellular aspirate with cohesive papillary groups or 3D clusters, reduced colloid, calcifications or *psammoma bodies,* and nuclei with powdery/finely dispersed chromatin, thickened nuclear membranes, *nuclear grooves, and intranuclear pseudoinclusions*. Follicular neoplasms Follicular adenomas are usually solid, cold nodules that occur more often in women and are completely encapsulated. Cytology shows cellular aspirate, monotonous population of follicular cells with no colloid. May have Hurthle/oncocytic (pink cytoplasm stuffed with mitochondria) or non-Hurthle cells. Follicular carcinoma makes up 10% of malignant thyroid neoplasms, and they are more common in women in their 40s-60s. FTC spreads by blood born metastases, usually to lung and bone. >70% 10-yr survival for encapsulated, <45% for widely invasive. Cytology can't distinguish between follicular adenomas and carcinomas. Remove the node so the pathologist can examine the entire capsule to distinguish adenoma from carcinoma. Treat PTC and FTC Lobectomy or total thyroidectomy +/- lymph node dissection are first line therapies. This may be followed by radioiodine and thyroid hormone replacement (in excess) to suppress TSH. Monitor with thyroglobulin levels, neck/cervical lymph node US, and whole body iodine scans. Medullary carcinoma 5% of malignant thyroid neoplasms, from parafollicular/C-cells. 80% of cases are sporadic and occur more often in females in their 40s-60s. 20% of cases are familial, with men=women, earlier onset, and usually caused by AD mutation in RET photo-oncogene. The hereditary form is classified as MEN-2 (multiple endocrine neoplasia) when it coexists with other endocrine tumors or conditions (MEN2A - hyperparathyroidism, pheochromocytoma; MEN2B - pheochromocytoma, enteric ganglioneuromas, marfanoid body habitus). 90% 10-yr survival if confined to the thyroid, 70% if spread to cervical lymph nodes, 20% if spread to distant sites. Histologically, there are packets of uniform round/oval cells and spindle shaped cells with salt and pepper chromatin. There is amyloid in the stroma from increased calcitonin production (serum calcitonin levels will be high). Radioiodine administration, thyroglobilin testing, or TSH suppression with levothyroxine are not performed because parafollicular cells don't concentrate iodine, produce thyroglobulin, or respond to TSH. Treat MTC with total thyroidectomy +/- lymph node direction, thyroid hormone replacement to achieve normal TSH, and monitoring of calcitonin (should be <5 or undetectable) and neck/cervical lymph node US. Also get RET photo-oncogene testing. Anaplastic thyroid carcinoma 1% of all malignant thyroid neoplasms and the most deadly, occurring more often in men in their 60s-80s. Most die w/i one year. Aspirates are highly cellular, widely atypical tumor cells, giant cells, spindle cells, and squamoid cells. May have necrosis and inflammation. US usually shows aggressive mass that has invaded outside the thyroid. Death usually occurs from invasion of neck structures. Surgery is not possible because of attachment to structures and it doesn't respond to radiation or chemo - palliative care.

Hypothyroidism epidemiology and causes

hypothyroidism - deficiency of thyroid hormone (95% primary, 5% from pituitary/hypothalamic disease or thyroid hormone resistance). 4-5% prevalence, 5-7x more often in women, and more common at older age (15% of those 80yrs old). The most common cause is autoimmune (Hashimoto's thyroiditis; >70%). Other causes include post-surgical/radioiodine ablation, congenital deficiency (all children are screened at childbirth), drugs (lithium, amiodarone, interferon), and iodine deficiency. Amiodarone causes hypothyroidism when patients fail to escape the Wolff-Chaikoff effect - excess iodine causes the body to temporarily decrease thyroid hormone production to prevent excess, but in some, levels can remain permanently decreased. Autoimmune Primary Hypothyroidism (Hashimoto's or chronic lymphocytic thyroiditis) involves autoimmune destruction of thyroid tissue and high titers of anti-thyroid peroxidase (TPO) antibodies. The gland becomes enlarged in early stages and then becomes firm, non-tender and small in later stages. Thyroid destruction is usually permanent. Histologically, you will see lymphocytes/plasma cells, germinal center formation, fibrosis in late disease, and oncocytic metaplasia/Hurthle cell formation - follicular cells degenerate and have large, pink cytoplasm with many mitochondria. Cytology will show hurtle cells and a mixture of large and small lymphocytes. Fibrous/Reidel's thyroiditis is very rare and causes dense fibrosis of the thyroid in young people, creating a stone hard gland with fixation to adjacent structure that can cause compressive symptoms and sometimes hypothyroid. It usually stabilizes over time and you don't need to remove it surgically (it will just grow back worse)