Familial hypocalciuric hypercalcemia
Autosomal dominantly inherited defective G-coupled Ca2+-sensing receptors (CaSR) in multiple tissues (eg, parathyroids, kidney).- Higher than normal Ca2+ levels required to suppress PTH. Excessive renal Ca2+ reuptake → mild hypercalcemia and hypocalciuria with normal to ↑ PTH levels.
Primary hyperparathyroidism
Usually due to parathyroid adenoma or hyperplasia. Hypercalcemia, hypercalciuria (renal "stones"), hypophosphatemia, ↑ PTH, ↑ ALP, ↑ cAMP in urine. - Most often asymptomatic. - May present with weakness and constipation ("groans"), abdominal/flank pain (kidney "stones", acute pancreatitis), polyuria ("thrones"), neuropsychiatric disturbances ("psychiatric overtones")- Osteoporosis in primary hyperparathyroidism is most pronounced in the cortical (compact) bone of the appendicular skeleton (eg, pelvic girdle, limbs). Cortical thinning is characteristic and appears radiologically as subperiostal erosions. Osteitis fibrosa cystica – cystic bone spaces filled with brown fibrous tissue ("brown tumor" consisting of osteoclasts and deposited hemosiderin from hemorrhages; causes bone pain). Characterized by granular decalcification of the skull ("salt-and-pepper skull"). Due to ↑ PTH, classically associated with 1° hyperparathyroidism.
Secondary hyperparathyroidism
2° hyperplasia due to ↓ Ca2+ absorption and/or ↑ PO43-, most often in chronic renal disease (causes hypovitaminosis D and hyperphosphatemia → ↓ Ca2+). Hypocalcemia, hyperphosphatemia in chronic renal failure (vs hypophosphatemia with most other causes), ↑ ALP, ↑ PTH. Renal osteodystrophy – renal disease → 2° and 3° hyperparathyroidism → bone lesions.
Nelson syndrome
Enlargement of existing ACTH-secreting pituitary adenoma after bilateral adrenalectomy for refractory Cushing disease (due to removal of cortisol feedback mechanism). Presents with hyperpigmentation, headaches and bitemporal hemianopia. Treatment: pituitary irradiation or surgical resection.
Acromegaly
Excess GH in adults. Typically caused by pituitary adenoma. Findings: Large tongue with deep furrows, deep voice, large hands and feet, coarsening of facial features with aging, frontal bossing, diaphoresis (excessive sweating), impaired glucose tolerance (insulin resistance), hypertension. ↑ risk of colorectal polyps and cancer. Diagnosis:- ↑ serum IGF-1- Failure to suppress serum GH following oral glucose tolerance test- Pituitary mass seen on brain MRI Treatment: Pituitary adenoma resection. If not cured, treat with octreotide (somatostatin analog) or pegvisomant (growth hormone receptor antagonist), dopamine agonists (eg, cabergoline). ↑ GH in children → gigantism (↑ linear bone growth). HF most common cause of death.
Laron syndrome (dwarfism)
Defective growth hormone receptors → ↓ linear growth. ↑ GH, ↓ IGF-1. Clinical features: - Short height- Small head circumference- Characteristic facies with saddle nose and prominent forehead- Delayed skeletal maturation- Small genitalia Treatment: IGF-1 (Mecasermin)
Diabetes insipidus
Characterized by intense thirst and polyuria with inability to concentrate urine due to lack of ADH (central) or failure of response to circulating ADH (nephrogenic). Central DI- Etiology: Pituitary tumor (especially craniopharyngioma), autoimmune, trauma, neurosurgery, ischemic encephalopathy, idiopathic- ↓ ADH- Water deprivation test: >50% ↑ in urine osmolality only after administration of ADH analog- Treatment: Desmopressin acetate, hydration Nephrogenic DI- Etiology: Hereditary (ADH receptor mutation), 2° to hypercalcemia, hypokalemia, lithium, demeclocycline (tetracycline, ADH antagonist)- Normal to ↑ ADH levels- Water deprivation test: Minimal changes in urine osmolality, even after administration of ADH analog- Treatment: Hydrochloridthiazide (leads to sodium depletion, which causes sodium and water reabsorption in the proximal tubules), indomethacin (inhibit integration of aquaporin channels in the collecting duct), amiloride (blocks lithiume entry through sodium channel), hydration, dietary salt restriction Urine specific gravity <1.006Serum osmolarity >290 mOsm/kgHyperosmotic volume contraction
Syndrome of inappropriate antidiuretic hormone secretion (SIADH)
Characterized by:- Excessive free water retention- Euvolemic hyponatremia with continued urinary Na+ excretion- Urine osmolality > serum osmolality Body responds to water retention with ↓ aldosterone and ↑ ANP and BNP → ↑ urinary Na+ secretion → normalization of extracellular fluid volume → euvolemic hyponatremia. Very low serum Na+ levels can lead to cerebral edema, seizures. Correct slowly to prevent osmotic demyelination syndrome (formerly known as central pontine myelinolysis). Causes include:- Ectopic ADH (eg, small cell lung cancer)- CNS disorders (eg, stroke, bleeding, infection, trauma)- Pulmonary disease (eg, pneumonia, COPD)- Drugs (eg, cyclophosphamide, carbamazepine, SSRIs) Treatment: fluid restriction, salt tablets, IV hypertonic saline, diuretics, conivaptan, tolvaptan, demeclocyline (ADH antagonist)
Glucagonoma
Tumor of α pancreatic cells → overproduction of glucagon. Presents with:- Dermatitis (necrolytic migratory erythema)- Diabetes (hyperglycemia)- Deep vein thrombosis- Declining weight- Depression Treatment: Ocreotide, surgery
Insulinoma
Tumor of β pancreatic cells → overproduction of insulin → hypoglycemia May see Whipple triad:1. Low blood glucose2. Symptoms of hypoglycemia (eg, lethargy, syncope, diplopia)3. Resolution of symptoms after normalization of glucose levels Symptomatic patients have ↓ blood glucose and ↑ C-peptide levels (vs exogenous insulin use) ~10% of cases associated with MEN 1 syndrome. Treatment: surgical resection
Somatostatinoma
Tumor of pancreatic δ cells → overproduction of somatostatin → ↓ secretion of secretin, cholecystokinin, glucagon, insulin, gastrin, gastric inhibitory peptide (GIP). May present with- Diabetes/glucose intolerance- Steatorrhea- Gallstones- Achlorhydria Treatment: surgical resection, somatostatin analogs (eg, ocreotide) for symptom control
Carcinoid syndrome
Rare syndrome caused by carcinoid tumors (neuroendocrine cells, prominent rosettes), especially metastatic small bowel tumors, which secrete high levels of serotonin (5-HT). Not seen if tumor is limited to GI tract (5-HT undergoes first-pass metabolism in liver). - Recurrent diarrhea- Cutaneous flushing- Asthmatic wheezing- Right-sided valvular heart disease (tricuspid regurgitation, pulmonic stenosis) due to lung MAO-A enzymatic breakdown of 5-HT before left heart return. ↑ 5-hydroxyindoleacetic acid (5-HIAA) in urine, niacin deficiency (pellagra).Associated with neuroendocrine markers chromogranin A and synaptophysin. Treatment: surgical resection, somatostatin analog (eg, ocreotide) Rule of 1/3s:1/3 metastasize1/3 present with 2nd malignancy1/3 are mulitpleMost common malignancy in the small intestine.
Multiple endocrine neoplasias
All MEN syndromes have autosomal dominant inheritance. MEN 1:- Pituitary tumors (prolactin or GH)- Pancreatic endocrine tumors: Zollinger-Ellison syndrome, insulinomas, VIPomas, glucagonomas- Parathyroid adenomas- Associated with mutation of MEN1 (menin, a tumor suppressor, chromosome 11), angiofibromas, collagenomas, meningeomas. MEN 2A:- Parathyroid hyperplasia- Medullary thyroid carcinoma – neoplasm of parafollicular or C cells; secretes calcitonin; prophylactic thyroidectomy required- Pheochromocytoma (secretes catacholamines)- Associated with mutation in RET (codes for receptor tyrosine kinase) in cells of neural crest origin MEN 2B:- Medullary thyroid carcinoma- Pheochromocytoma- Mucosal neuromas (oral/intestinal ganglioneuromatosis)- Associated with marfanoid habitus; mutation in RET gene
Diabetic ketoacidosis
Usually due to insulin noncompliance or ↑ insulin requirements from ↑ stress (eg, infection). Excess fat breakdown and ↑ ketogenesis from ↑ free fatty acids, which are then made into ketone bodes (β-hydroxybutyrate > acetoacetate). Usually occurs in type 1 diabetes, as endogenous insulin in type 2 diabetes usually prevents lipolysis. Symptoms:- Delirium/psychosis- Kussmaul respirations (rapid, deep breathing)- Abdominal pain, nausea, vomiting- Dehydration- Fruity breath odor (due to exhaled acetone) Labs: Hyperglycemia, ↑ H+, ↓ HCO3- (↑ anion gap metabolic acidosis), ↑ blood ketone levels, leukocytosis. Hyperkalemia, but depleted intracellular K+ due to transcellular shift from ↓ insulin and acidosis. Osmotic diuresis → ↑ K+ loss in urine → total body K+ depletion. Complications: Life-threatening mucormycosis (usually caused by Rhizopus infection), cerebral edema, cardiac arrhythmias, heart failure. Treatment: IV fluids, IV insulin, and K+ (to replete intracellular stores); glucose if necessary to prevent hypoglycemia.
Zollinger-Ellison syndrome
Gastrin-secreting tumor (gastrinoma) of pancreas or duodenum. Acid hypersecretion causes recurrent ulcers in duodenum and jejunum. - Presents with abdominal pain (peptic ulcer disease, distal ulcers), diarrhea (malabsorption). - Positive secretin stimulation test: gastrin levels remain elevated after administration of secretin, which normally inhibits gastrin release. - May be associated with MEN 1.
Insulin regulation
Glucose is the major regulator of insulin release. ↑ insulin response with oral vs IV glucose due to incretins (eg, glucagon-like peptide 1 [GLP-1], glucose-dependent insulinotropic polypeptide [GIP]), which are released after meals and ↑ β cell sensitivity to glucose. Release ↓ by α2, ↑ by β2 (2 regulates insulin) Glucose enters β cells → ↑ ATP generated from glucose metabolism closes K+ channels (target of sulfonylureas) and depolarizes β cell membrane. Voltage-gated Ca2+ channels open → Ca2+ influx and stimulation of insulin exocytosis.
Prolactin
Secreted mainly by anterior pituitary. Structurally homologous to growth hormone. Stimulates milk production in breast; inhibits ovulation in females and spermatogenesis in males by inhibiting GnRH synthesis and release.- Excessive amounts of prolactin associated with ↓ libido. Prolactin secretion is tonically inhibited by dopamine from tuberoinfundibular pathway of hypothalamus. Prolactin in turn inhibits its own secretion by ↑ dopamine synthesis and secretion from hypothalamus. TRH ↑ prolactin secretion (eg, in 1° or 2° hypothyroidism). Dopamine agonists (eg, bromocriptine) inhibit prolactin secretion and can be used in treatment of prolactinoma.Dopamine antagonists (eg, most antipsychotics) and estrogens (eg, OCP, pregnancy) stimulate prolactin secretion.
Antidiuretic hormone (vasopressin)
Synthesized in hypothalamus (supraoptic and paraventricular nuclei), stored and secreted by posterior pituitary. Function: Regulates serum osmolarity (V2-receptors) and blood pressure (V1-receptors). ADH ↓ serum osmolarity, ↑ urine osmolarity via regulation of aquaporin channel insertion in principle cells of renal collecting duct.- ADH level is ↓ in diabetes insipidus (DI), normal or ↑ in nephrogenic DI.- Nephrogenic DI can be caused by mutation in V2-receptor.- Desmopressin (ADH analog) is a treatment for central DI and nocturnal enuresis. Regulation: Osmoreceptors in hypothalamus (1°), hypovolemia.
VIPoma
Rare neuroendocrine tumor that secretes vasoactive intestinal pepide (VIP). - Most commonly arises in pancreas. - Associated with MEN-1. Primary symptom is secretory diarrhea. Associated with WDHA syndrome:- Watery diarrhea- Hypokalemia- Achlorhydria
Hypothyroidism vs hyperthyroidism
Hypothyroidism:- Metabolic: Cold intolerance, ↓ sweating, weight gain, (↓ basal metabolic rate → ↓ calorigenesis), hyponatremia (↓ free water clearance)- Skin/hair: Dry, cool skin (due to ↓ blood flow); coarse, brittle hair; diffuse alopecia; brittle nails; puffy facies and generalized nonpitting edema (myxedema) due to ↑ GAGs in interstitial spaces → ↑ osmotic pressure → water retention- Ocular: Periorbital edema- Gastrointestinal: Constipation (↓ GI motility), ↓ appetite- Musculoskeletal: Hypothyroid myopathy (proximal weakness, ↑ CK), carpal tunnel syndrome, myoedema (small lump rising on the surface of a muscle when struck with a hammer)- Reproductive: Menorrhagia and/or oligomenorrhea; ↓ libido, infertility- Neuropsychiatric: Hypoactivity, lethargy, fatigue, weakness, depressed mood, ↓ reflexes (delayed/slow relaxing)- Cardiovascular: Bradycardia, dyspnea on exertion (↓ cardiac output)- Lab: ↑ TSH, ↓ free T3 and T4, hypercholesterolemia (due to ↓ LDL receptor expression) Hyperthyroidism:- Metabolic: Heat intolerance, ↑ sweating, weight loss (↑ synthesis of Na+-K+ ATPase → ↑ basal metabolic rate → ↑ calorigenesis) - Warm, moist skin (due to vasodilation); fine hair; onycholysis; pretibial myxedema in Graves disease- Ocular: Ophthalmopathy in Graves disease (including periorbital edema, exophthalmos), lid lag/retraction (↑ sympathetic stimulation of levator palpebrae superioris)- Gastrointestinal: Hyperdefecation/diarrhea (↑ GI motility), ↑ appetite- Musculoskeletal: Thyrotoxic myopathy (proximal weakness, normal CK), osteoporosis/↑ fracture rate (T3 directly stimulates bone resorption)- Reproductive: Oligomenorrhea or amenorrhea, gynecomastia, ↓ libido, infertility- Neuropsychiatric: Hyperactivity, restlessness, anxiety, insomnia, fine tremors, ↑ reflexes (brisk)- Cardiovascular: Tachycardia, palpitations, dyspnea, arrhythmias (eg, atrial fibrillation), chest pain and systolic HTN due to ↑ number and sensitivity of β-adrenergic receptors, ↑ expression of cardiac sacrolemmal ATPase and ↓ expression of phospholamban- Lab: ↓ TSH, ↑ T3 and T4, ↓ LDL, HDL, and total cholesterol
Postpartum thyroiditis
Self-limiting thyroiditis arising up to 1 year after delivery. Presents as transient hyperthyroidism, hypothyroidism, or hyperthyroidism followed by hypothyroidism.- Majority of women are euthyroid following resolution. Thyroid usually painless and normal in size. Histology: lymphocytic infiltrate with occasional germinal center formation.
Papillary carcinoma
Most common, excellent prognosis. Histology: - Empty-appearing, ground-glass nuclei with central clearing ("Orphan Annie" eyes)- Psammoma bodies- Nuclear grooves.Characteristically large cells with overlapping nuclei containing finely dispersed chromatin, giving them an empty or ground-glass appearance. Numerous intranuclear inclusions and grooves can be seen due to invagination of the nuclear membrane. ↑ risk with RET/PTC rearrangements and BRAF mutations, childhood irradiation.
Follicular carcinoma
Good prognosis. Invades thyroid capsule and vasculature (unlike follicular adenoma), uniform follicles. Hematogenous spread is common. Associated with RAS mutation and PAX8-PPAR-γ translocations.
Medullary carcinoma
From parafollicular "C cells"; produces calcitonin. Sheets of cells in amyloid stroma (stains with Congo red). Associated with MEN 2A and 2B (RET mutations).
Undifferentiated/anaplastic carcinoma
Older patients, invades local structures. Very poor prognosis. DD: Riedel thyroiditis
Diabetes mellitus
Polydipsia, polyuria, weight loss, DKA (type 1), hyperosmolar hyperglycemic state (type 2).Rarely, can be caused by unopposed secretion of GH and epinephrine. Also seen in patients on glucocorticoid therapy. Chronic complications:Nonenzymatic glycation:- Small vessel disease (diffuse thickening of basement membrane) → retinopathy (hemorrhage, exudates, microaneurysms, vessel proliferation), glaucoma, neuropathy, nephropathy (nodular glomerulosclerosis, aka Kimmelstiel-Wilson nodules → progressive proteinuria [initially microalbuminuria; ACE inhibitors are renoprotective] and arteriolosclerosis → hypertension; both lead to chronic renal failure).- Large vessel atherosclerosis, CAD, peripheral vascular occlusive disease, gangrene → limb loss, cerebrovascular disease. MI most common cause of death.Osmotic damage (sorbitol accumulation in organs with aldose reductase and ↓ or absent sorbitol dehydrogenase)- Neuropathy (motor, sensory [glove and stocking distribution], and autonomic degeneration)- Cataracts Diagnosis:- HbA1c: ≥6.5%- Fasting plasma glucose: ≥126 mg/dL (fasting for over 8 hours)- 2-hour oral glucose tolerance test: ≥200 mg/dL (2 hours after consumption of 75 g of glucose in water)
Type 1 vs type 2 diabetes mellitus
Type 1:- Autoimmune destruction of β cells (eg, due to glutamic acid decarboxylase antibodies)- Insulin necessary in treatment- Age <30 years- Weak genetic predisposition (50% concordance in identical twins), polygenic- HLA-DR3 and -DR4- High insulin sensitivity- Ketoacidosis common- Classic symptoms of polyuria, polydipsia, polyphagia, weight loss- Histology: Islet leukocytic infiltrate Type 2:- ↑ resistance to insulin, progressive pancreatic β-cell failure- Age >40 years- Association with obesity- Strong genetic predisposition (90% concordance in identical twins), polygenic- No assication with HLA system- Histology: Islet amyloid polypeptide (IAPP) deposits
Hyperosmolar hyperglycemic state
State of profound hyperglycemia-induced dehydration and ↑ serum osmolality, classically seen in elderly type 2 diabetes with limited ability to drink. Hyperglycemia → excessive osmotic diuresis → dehydration → eventual onset of HHS. Symptoms:- Thirst- Polyuria- Lethargy- Focal neurological deficits (eg, seizures)- Can progress to coma and death if left untreated Labs:- Hyperglycemia (often >600 mg/dL)- ↑ serum osmolality (>320 mOsm/kg)- No acidosis (pH >7.35, ketone production inhibited by presence of insulin). Treatment: aggressive IV fluids, insulin therapy
PI3K/Akt/mTOR pathway
The PI3K/Akt/mTOR pathway is an intracellular signaling pathway that is important for cellular proliferation. - The proliferation is typically activated when a growth factor binds to its receptor tyrosine kinase, causing autophosphorylation of specific tyrosine residues within the receptor.- These phosphotyrosine residues activate phosphoinositide 3-kinase (PI3K), which then phosphorylates PIP2 found in the plasma membrane to PIP3.- This leads to activatino of protein Akt (or protein kinase B), a serine/threonine-specific protein kinase.- Subsequently, Akt activates mTOR (mammalian target of rapamycin), which translocates to the nucleus to induce genes involved in cell survival, anti-apoptosis, and angiogenesis. mTOR activation is inhibited by PTEN (phosphatase and tensin homolog), a tumor suppressor gene that removes the phosphate group from PIP3.
MAP-kinase pathway
- Receptor-linked tyrosine kinases (eg, EGFR) are activated by ligands (eg, EGF).- The EGRF becomes phosphorylated on tyrosine residues.- Docking proteins such as GRB2 contain a SH2 domain that binds to the phosphotyrosine residues of the activated receptor. This binds SOS.- SOS promotes the removal of GDP from Ras.- Ras can bind GTP and become active.- Ras activates RAF kinase.- RAF kinase phosphorylates MEK.- MEK phosphorylates MAPK.
Glucagon
Made by α cells of pancreas. Function: - Promotes glycogenolysis (↑ glycogen phosphorylase)- Gluconeogenesis (↓ PFK-2 → ↓ PFK-1, ↑ phosphoenolpyruvate carboxykinase, glucose-6-phosphatase)- Lipolysis, and ketogenesis (↑ hormone-sensitive lipase, ↓ acetyl CoA carboxylase → ↓ malonyl-CoA) - Elevates blood sugar levels to maintain homeostasis when concentration of bloodstream glucose falls too low (ie, fasting state). Regulation: Secreted in response to hypoglycemia. Inhibited by insulin, hyperglycemia, somatostatin.
Glucose uptake
Glucose is taken up by peripheral tissues by facilitated diffusion. Require insulin for effective uptake of glucose:- Skeletal muscle- Adipose tissue- Liver because of glucokinase stimulation Not affected by insulin:- Brain- RBCs- Nervous tissue- Kidney tubules- Intestinal mucosa- β-cells of pancreas
Adiponectin
Produced in adipose tissue and increases insulin sensitivity and tissue fat oxidation.- Low levels in type 2 diabetics Dysregulation of adiponectin may play a role in obesity, insulin resistance, anc cachexia. Thiazolidinediones (TZD) increase circulating levels of adiponectin via the PPAR-γ transcription factor.
Estrogen
Conserves bone integrity. - Induces synthesis of osteoprotegerin (binds RANK-L, thereby preventing it from binding onto precursor or osteoclast cells) - Reduces the secretion of cytokines by T-lymphoctes → ↓ differentiation of precursor cells into osteoclasts - Intially promote bone growth by increasing GH secretion, and then cause closure of epiphyseal plates
