Steve Hawking's Electronic Endocrine Enigma Flashcards
Thyroid development
Thyroid diverticulum arises from floor of primitive pharynx, and descends into neck. Connected to tongue by thyroglossal duct (may persist as pyramidal lobe of thyroid);
Foramen cecum is normal remnant of thyroglossal duct. Most common ectopic thyroid tissue site is the tongue.
How does a thyroglossal duct cyst present
Presents as an anterior midline neck mass that moves with swallowing or protrusion of the tongue (vs. persistent cervical sinus leading to branchial cleft cyst in lateral neck)
Adrenal medulla and cortex are derived from what embryonic structures
Adrenal cortex: mesoderm
Adrenal medulla: neural crest
Zona Glomerulosa
outer most layer of the aderenal cortex; regulated by renin-angiotensin; secretes Aldosterone
Zona Fasiculata
Middle layer of the adrenal cortex (thickest of the 3); regulated by ACTH and CRH; secretes Cortisol, sex hormones
Zona Reticularis
Inner most layer of the adrenal cortex; regulated by ACTH and Sympathetic fibers; releases sex hormones like androgens
Adrenal Medulla
made up of chromaffin cells; derived from neural crest cells; regulated by preganglionic sympathetic fibers; releases catecholamines (norepi, epi)
Adrenal Gland drainage
Left adrenal gland into the left adrenal vein into the left renal vein into the IVC; or Right adrenal gland into the right adrenal vein into the IVC (Same as left right gonadal vein)
Posterior Pituitary
Neyrohypophysis; secretes vasopressin (ADH), and oxytocin, made in hypothalamus, and shipped to posterior pituitary via neurophysins (carrier proteins); Derived from neuroectoderm (diencephalon)
Anterior Pituitary
Adenohypophysis; secretes FSH, LH, ACTH, TSH, prolactin, GH, melanotropin (MSH); derived from oral ectoderm (rathke pouch); Alpha subunit- Hormone subunit common to TSH, LH, FSH, hCG; Beta subunit- determines hormone specificity
Acidophils in anterior pituitary release what
GH, prolaction
Basophils in Anterior pituitary release what
B-FLAT; Basophils- FSH, LH, ACTH, TSH
Endocrine pancreas cell types
Islets of langerhans are collections of alpha and beta and Delta endocrine cells. Islets arise from pancreatic buds. alpha=glucagon (peripheral), beta=insulin (Central); delta=somatostatin (interspersed).
Synthesis of insulin
Preproinsulin (synthesized in RER) gets cleaved of “presignal” making proinsulin (stored in secretory granules) then cleavage of proinsulin then you get exocytosis of insulin and C-peptide equally. Insulin and C-peptide and increase in insulinoma, whereas exogenous insulin lacks C-peptide.
Effects of insulin
Anabolic effects of insulin: increase glucose transport in skeletal and adipose tissue; increase glycogen synthesis and storage, increase triglyceride synthesis and storage, increase triglyceride synthesis, increase Na retention (kidneys), increases protein synthesis (muscles), increase cellular uptake of K and amino acids, decrease glucagon release.
Insulin dependent glucose transporter
GLUT-4: in adipose and skeletal muscle
Insulin independent glucose transporters
GLUT-1: RBCs, Brain, Cornea;
GLUT-2 (bidirectional): beta islet cells, liver, kidney, small intestine;
GLUT-5 (Fructose): Spermatocytes and GI tract
What does the brain use for its energy source
Fed state: glucose;
Starvation: ketone bodies
What do RBCs use for energy
Always use glucose; they lack mitochondria
Regulation of insulin release
Glucose enters the cell via glut-2; Glucose goes through glycolysis and increase ATP/ADP; ATP closes ATP sensitive K channels; this leads to depolarization; voltage gated Ca channels open; intracellular Ca increases; Exocytosis of insulin granules
Glucagon
Made from alpha cells of pancreas; Catabolic effects include: Glycogenolysis, gluconeogenesis, lipolysis and ketone production; Regulation: secreted in response to hypoglycemia, inhibited by insulin, hyperglycemia, and somatostatin
What is this hormones function: CRH
increased ACTH, MSH, beta endorphin; decrease in chronic exogenous steroid use
What is this hormones function: Dopamine
Decreases prolactin; Dopamine antagonists (like antipsychotics) can cause galactorrhea
What is this hormones function: GnRH
Increases FSH, LH; Regulated by prolactin, Tonic GnRH suppresses HPA axis, Pulsatile GnRH leads to puberty, fertility
What is this hormones function: Prolactin
Decreases GnRH; Pituitary prolactinoma can lead to amenorrhea, osteoporosis
What is this hormones function: Somatostatin
Decreases GH, TSH; Analogs used to treat acromegaly
What is this hormones function: TRH
increases TSH, prolactin
Prolactin: secreted from
Secreted from anterior pituitary
Prolactin: function
Stimulates milk production in breast; inhibits ovulation in females and spermatogenesis in males by inhibiting GnRH synthesis and release; Excessive amounts of Prolactin can lead to decreased libido
Prolactin: Regulation
Prolactin secretion from anterior pituitary is tonically inhibited by dopamine from hypothalamus. Prolactin in turn inhibits its own secretion by increasing dopamine synthesis and secretion from hypothalamus. TRH increases prolactin secretion.
What does Dopamine do to Prolactin
Dopamine agonists (bromocriptine) inhibit prolactin secretion and can be used in treatment of prolactinoma. Dopamine antagonists (most antipsychotics) and estrogens (OCPs, pregnancy) stimulate prolactin secretion.
Growth Hormone (somatotropin): Source
Secreted mainly by anterior pituitary
Growth Hormone (somatotropin): Function
Stimulates linear growth and muscle mass through IGF-1/somatomedin secretion. Increased insulin resistance (diabetogenic).
Growth Hormone (somatotropin): Regulation
Released in pulses in response to growth hormone-releasing hormone (GHRH). Secretion increases during exercise and sleep. Secretion inhibited by glucose and somatostatin.
Excess secretion of GH (pituitary adenoma) may cause acromegaly (adults) or gigantism (children).
Antidiuretic hormone: Source
Synthesized in hypothalamus (supraoptic nuclei), release by posterior pituitary.
Antidiuretic hormone: Function
Regulates serum osmolarity (V2 receptor) and blood pressure (V1 receptor). Primary function is serum osmolarity regulation (ADH decreased serum osmolarity, increased urine osmolarity) via regulation of aquaporin channel transcription in principal cells of renal collecting duct.
Antidiuretic hormone: diabetes insipidus
decreased ADH in central; normal or increased in nephrogenic DI or primary polydipsia. Nephrogenic DI can be caused by mutation in V2 receptor.
Desmopressin (ADH analog) = treatment for central DI
Antidiuretic hormone: How is it regulated
Osmoreceptors in hypothalamus (primary); hypovolemia (secondary)
17 alpha hydroxylase deficiency
Increase in Mineralcorticoids, decreased cortisol and sex hormones; Labs would show HTN, Hypokalemia, decreased DHT; Presents two main ways: XY presentation would be pseudohermaphroditism (ambigous genitalia, undescended testes). XX lack secondary sexual development.
21 hydroxylase deficiency
decreased mineralcorticoids and cortisol; increased sex hormones; labs show hypotension, hyperkalemia, increased renin activity, increased 17-hydroxy-progesterone; most commonly presents in infancy (salt wasting) or childhood (precocious puberty, XX would be virilization
11beta hydroxylase deficiency
decreased aldosterone but increased 11-deoxycorticosterone (aldosterone intermediate), decreased cortisol, increased sex hormones; HTN with low renin; XX presents with virilization
Cortisol: source
adrenal zona fasiculata; bound to corticosteroid-binding globulin,
Cortisol: function
increased blood pressure (upregulates alpha 1 receptors on arterioles causing increased sensitivity to Epi, NE), Increased insulin resistance (diabetogenic) increased gluconeogenesis lipolysis proteolysis, decreased fibroblasts activity (causes striae), decreased inflammatory responses (inhibits production of leukotrienes and prostaglandins, inhibits leukocyte adhesion leading to neutrophilia, blocks histamine release from mast cells, reduces eosinophils, blocks IL-2 production; decreased born formation (Decreased osteoblast activity); Cortisol is a BIG FIB, exogenous corticosteroids can reactivate TB and candidiasis (blocked IL-2 production)
Cortisol: regulation
CRH (from hypothalamis) stimulates ACTH release (pituitary), causing cortisol production in adrenal zona fascilulata, excess cortisol decreases CRH, ACTH and cortisol. Chronic stress induces prolonged secretion
PTH: source
Chief cells of parathyroid gland
PTH: Function
Increased bone resorption, increased kidney reabsorption of Ca in distal convoluted tubule, decreased reabsorption of PO4 in proximal convoluted tubule, Increased 1,25 (OH)2 D3 (calcitrol) production by stimulating kidney 1alpha-hydroxylase. PTH increases serum Ca, decreases serum phosphate, uncreased urine phosphate. Increased production of macrophage colony-stimulating facotr and RANK-1 (activator of NF-kappaB ligand), RNAK-L binds RANK on osteoblast causing osteoclast stimulation and increased Ca.
PTH related peptide
PTHrP functions like PTH and is commonly increased in malignancies (e.g. paraneoplastic syndrome)
PTH: regulation
Decreased serum Ca leads to increased PTH secretion;
Decreased serum Mg leads to increased PTH secretion;
Massively decreased MG leads to decreased PTH secretion;
Common causes of decreased mg include diarrhea, aminoglycosides, diuretics, and alcohol abuse.
Calcium homeostasis
Plasma Ca exists in three forms: ionized (~45%), Bound to albumin (~40%), Bound to anions (~15%); Increase in pH causing increased affinity of albumin (negative charge) to bind Ca causing clinical manifestations of hypocalcemia of hypocalcemia (cramps, pain, paresthesias, carpopedal spasm).
Vitamin D (cholecalciferol): Source
D3 from sun exposure in skin. D3 ingested from plants. Both converted to 25-OH in liver and to 1,25 (OH)2 (active form) in kidney. 24,25-(OH)2 D3 is an inactive form of vitamin D. Vit D absorbed in ilium.
Vitamin D (cholecalciferol): Deficiency
Causes rickets in kids and osteomalacia in adults. Cause by malabsorption, decreased sunlight, poor diet, chronic kidney failure.
Vitamin D (cholecalciferol): Function
Increased absorption of dietary Ca and PO; increased bone resorption causing increased Ca and PO; PTH leads to increased Ca reabsoprtion and decreased PO4 reabsorption in the kidney whereas 1,25 OH leads to increased absorption of both Ca and PO in the gut.
Vitamin D (cholecalciferol): Regulation
Increased PTH, decreased Ca, decreased PO3 all causine increasd 1,25 (OH)2 production. 1,25 (OH)2 feedback inhibits its own production
Calcitonin: Source
Parafollicular cells (C cells) of thyroid
Calcitonin: function
decreased bone resorption of Ca; calcitonin opposes action of PTH. Not important in normal Ca homeostasis.
Calcitonin: regulation
Increased serum Ca causes calcitonin secretion
What hormones work through cAMP pathway
FLAT ChAMP: FSH, LH, ACTH, TSH, CRH, hCG, ADH (v2 receptor, MSH, PTH, calcitonin, GHRH, glucagon
What hormones work through the cGMP pathway
ANP, NO (EDRF); think vasodilators
What hormones work through the IP3 pathway
IP 3 GOAT HAGs: GnRH, Oxytocin, ADH (V1 receptor), TRH, Histamine (H1 receptor), Angiotensin II, Gastrin
What hormones work through Steroid receptor
VETTT CAP: Vit D, Estrogen, Testosterone, T3/T4, Cortisol, Aldosterone, Progesterone
What hormones work through the intrinsic tyrosine kinase pathway
MAP kinase pathway, think growth factors: Insulin, IGF-1, FGF, PDGF, EGF
What hormones work through the receptor associated tyrosine kinase
JAK/STAT pathway, think acidophiles and cytokines: PIG; Prolactin, Immunomodulators (cytokines, IL2, IL6, IL8, IFN), GH
Signal pathway of steroid: how do they travel through the blood
Are lipophilic and therefore must circulate bound to specific binding globulins, which increase their solubility
Signaling pathway of steroids: In men, what happens when you increases SHBG
Increased sex hormone-binding globulin (SHBG) lowers free testosterone leading to gynecomastia
Signaling pathway of steroids: In women, what happens when you decrease SHBG
Decreased sex hormone-binding globulin (SHBG) raises free testosterone levels leading to hirsutism
Signaling pathway of steroids: In pregnancy, what happens to SHBG and free estrogen
Pregnancy increases SHBG but free estrogen levels remain the same
What are thyroid hormones
T3 and T4;
Iodine containing hormones that control the body’s metabolic rate;
T3 is the major active one, T4 is converted to T3, but there is more T4 in the body
Thyroid hormones: functions
Bone growth (synergistic with GH), CNS maturation; increased beta 1 receptors on the heart= increased CO, HR, SV, contractility; Increased metabolic rate via increased Na/K atpase activity= increased O2 consumption, RR, body temperature; Increased glycogenolysis, gluconeogenesis, lipolysis
Thyroid function: Regulation
TRH from hypothalamus, stimulates TSH in pituitary, which stimulates follicular cells. Negative feedback from T3/T4 to anterior pituitary decreases sensitivity to TRH.
Wolff-Chaikoff effect
Excess iodine temporarily inhibits thyroid peroxidase causing decrease iodine organification causing decreased T3/T4 production.
T4 is converted to T3 by
5’-deoidinase; located in the peripheral tisuue
Thyroxine binding globulin: what is it, what effects it
TBG binds T3 and T4 in the blood (makes them inactive), Get decreased TBG in hepatic failure, Increased estrogen (OCPs or pregnancy) increases TBG
Thyroid hormone and peroxidase
Peroxidase is an enzyme responsible for the oxidation and organification of monoiodotyrosine (MIT) and diiodotyrosine (DIT); 2 DIT on a thyroglobulin is a T4, One MIT and one DIT on a thyroglobulin make T3
Etiology of Cushing Syndrome
Increased cortisol due to a variety of causes:
Exogenous corticosteroid-#1 cause, results in decreased ACTH, bilateral adrenal atrophy;
Primary Adrenal adenoma, hyperplasia, or carcinoma-Results in decreased ACTH, atrophy of uninvolved adrenal gland, can also present as primary aldosteronism (Conn syndrome);
ACTH-secreting Pituitary adenoma (AKA cushing disease), paraneoplastic ACTH secretion (like small cell lung cancer, bronchial carcinoids)-results in increased ACTH, bilateral adrenal hyperplasia. Cushing disease is responsible for the majority of endogenous cases of Cushing syndrome
Findings in Cushing Syndrome
HTN, weight gain, moon facies, truncal obesity, buffalo hump, hyperglycemia (insulin resistance), skin changes (thinning and striae), osteoporosis, amenorrhea, and immune suppression.
Diagnosis of Cushing syndrome
Screening tests: increased free cortisol on 24 urinalysis, midnight salivary cortisol, and overnight low dose dexamethasone suppression test (measure serum ACTH. if decreased, suspect adrenal tumor. If increased, distinguish between Cushing disease and ectopic ACTH secretion with a high dose (8mg) dexamethasone suppression test and CRH stimulation test. Ectopic secretion will not decreases with dexa because it doesn’t respond to negative feedback. Ectopic secretion will not increase with CRH because pituitary ACTH is suppressed.
Primary hyperaldosteronism
Caused by adrenal hyperplasia or an aldosterone secreting adrenal adenoma (Conn syndrome), resulting in HTN, Hypokalemia, metabolic alkalosis (alpha intercalated secrete H+ when aldosterone hits it), and low plasma renin (kidneys be like NOOOO). Normal sodium and no edema. May be bilateral or unilateral
Secondary hyperaldosteronism
Renal perception of low intravascular volume leads to overactive Renin-Angiotensin system (think renal artery stenosis, CHF, cirrhosis, or nephrotic syndrome. Associated with high plasma renin.
Addison disease
Chronic primary adrenal insufficiency; due to adrenal atrophy or destruction by disease (like autoimmune, TB, metastasis). Deficiency of aldosterone and cortisol, causing hypotension (hyponatremic volume contraction), hyperkalemia, acidosis, and skin and mucosal hyperpigmentation (due to MSH, a by product of increased ACTH) from pro-opiomelanocortin (POMC). Characterized by adrenal atrophy and absence of hormone insufficiency (decreased pituitary ACTH production), which has no skin/mucosal hyperpigmentation and no hyperkalemia.
Waterhouse-Friderichsen Syndrome
Acute primary adrenal insufficiency due to adrenal hemorrhage associated with Neisseria meningitidis septicemia, DIC, and endotoxic shock
Neuroblastoma
The common tumor of the adrenal medulla in children, usually
Pheochromocytoma: etiology
Most common tumor of the adrenal medulla in adults. Derived from chromaffin cells (arise from neural crest); Rule of 10s: 10% malignant, 10% bilateral, 10% extra-adrenal, 10% calcify, 10% kids
Pheochromocytoma: symptoms
Most tumors secrete Epi, NE, and dopamine, which can cause episodic HTN. Associated with Von-Hippel-Lindau disease, MEN 2A and 2B. Symptoms occur in spells that relapse and remit;
Episodic hyperadrenergic symptoms (5 p’s): Pressure (increased BP), Pain (headache), Perspiration, Palpatation (tachycardia), Pallor
Pheochromocytoma: treatment
Irreversible alpha antagonists (phenoxybenzamine) and beta blockers followed by tumor resection. Alpha blockade must be achieved before giving beta blocker to avoid HTN crisis. Alpha blockers must be given during surgery because surgeon might squeeze out some Epi, NE, and dopamine when he cuts it out.
Signs and symptoms of Hypothyroidism
Cold intolerance (decreased heat production), Weight gain, decreased appetite, Hypoactivity, Lethargy, fatigue, weakness, constipation, decreased reflexes, myxedema (facial/periorbital), Dry cool skin, brittle hair, Bradycardia, dyspnea on exertion.
Lab findings in hypothyroidism
increased TSH (sensitive test for primary hypothyroidism), decreased free T3 and T4, Hypercholesterolemia (due to decreased LDL receptor expression)
Symptoms of Hyperthyroidism
Heat intolerance (increased heat production), weight loss, increased appetite, hyperactivity, Diarrhea, increased reflexes, pretibial myxedema (graves disease), periorbital edema, warm moist skin, fine hair, Chest pain, palpatations, arrhythmias, increased number and sensitivity of beta receptors
Lab findings in hyperthyroidism
Decreased TSH (if primary), increased free or total T3 and T4, Hypocholesterolemia (due to increased LDL receptor expression)
Hashimoto thyroiditis
Most common cause of hypothyroidism in iodine-sufficient regions; an autoimmune disorder (anti-thyroid peroxidase, anti-thyroglobulin antibodies). Associated with HLA-DR5. Increased risk of non-Hodgkin B cell lymphoma. May be hyperthyroid early in course due to thyrotoxicosis during follicular rupture. Histology shows: Hurthle cells, lymphoid aggregate with germinal centers. Findings: moderately enlarged, nontender thyroid.
Congenital hypothyroidism (cretinism)
Severe fetal hypothyroidism due to maternal hypothyroidism, thyroid agenesis, thyroid dysgenesis (most common cause in the US), iodine deficiency, dyshormonogenic goiter.
Findings: Pot-bellied, Pale, Puffy-face child, with protruding umbilicus, protuberant tongue, and poor brain development: the 6 P’s;
At birth baby can be normal due to placental transfer of T4 from mom;
can get secondary decrease in Growth Hormone
Subacute granulomatous thyroiditis (de Quervain)
Self-limited hypothyroidism often following a flu-like illness;
May be hyperthyroid early in course.
Histology shows granulomatous inflammation.
Findings: increased ESR, jaw pain, early inflammation, very tender thyroid!!!! The tender thyroid with granulomatous inflammation is a give away!
Riedel Thyroiditis
Thyroid replaced by fibrous tissue (hypothyroid). Fibrosis may extend to local structures (e.g. airways), mimicking anaplastic carcinoma. Considered a manifestation of IgG4 related systemic disease.
Findings: fixed, hard, rock like, and painless goiter.
Toxic multinodular goiter
Causes hyperthyroidism. Focal patches of hyperfunctioning follicular cells working independently of TSH due to mutation in TSH receptor. Increase release of T3 and T4. Hot nodules are rarely malignant.
Jod-Basedow phenomenon
Thyrotoxicosis if a patient with iodine deficiency goiter is made iodine replete
Graves disease
Most common cause of hyperthyroidism. IgG autoantibodies stimulate TSH receptors on thyroid (hyperghyroidism, diffuse goiter), retro-orbital fibroblasts (exophthalmos: proposis, extraocular muscle swelling), and dermal fibroblasts (periorbital myxedema). Often presents during stress (e.g. childbirth)
Thyroid storm
Stress-induced catecholamine surge seen as a serious complication of Graves disease and other hyperthyroid disorders. Presents with agitation, delirium, fever, diarrhea, coma, and tachyarrhythmia (Cause of death). May see increased ALP due to Increased bone turnover. Treat with the 3 P’s: Propanolol (beta blocker), Propylthiouracil, Prednisolone (corticosteroids).
Thyroid cancer
Thyroidectomy is treatment option for thyroid cancers and hyperthyroidism. Complications of surgery include hoarseness (recurrent laryngeal nerve damage), hypocalcemia (Due to removal of parathyroid glands), and transection of inferior thyroid artery.
Papillary carcinoma
Most common, excellent prognosis. Empty-appearing nuclei (orphan annie eyes), Psammoma bodies (concentric calcifications), nuclear grooves, increased risk with RET and BRAF mutations, childhood irradiation.
Described as “fibrous stroma, microscopic blood vessels, with cell clusters. A cancer of thyroid epithelial cells”
Follicular carcinoma
Good prognosis, invades thyroid capsule (unlike follicular adenoma), uniform follicles, If you do Fine Needle biopsy you may not be able to tell if disease if follicular (may not see invasion).
Medullary carcinoma
From parafollicular “C Cells”; Produces calcitonin, sheets of cells in an amyloid stroma. Associated with MEN 2A and 2B (RET mutations).
Undifferentiated/Anaplastic carcinoma
Older patients; invades local structure like lungs, very poor prognosis
Thyroid cancer: Lymphoma is associated with
Associated with Hashimoto thyroiditis
Primary hyperparathyroidism
Usually an adenoma; Hypercalcemia, hypercalciuria (Renal stones), hypophosphatemia, increased PTH ALP cAMP in urine; Can be asymptomatic, My present as weakness and constipation (Groans), abdominal/flank pain (kidney stones or acute pancreatitis), depression (psychiatric overtones); Get Osteitis fibrosa cystica- Cystic bone spaces filled with brown fibrous tissues (bone pain).
“Stones, Bones, Groans, and Psychiatric Overtones”
Secondary Hyperparathyroidism
Secondary hyperplasia due to decreased gut Ca absorption and increased PO4, most often in chronic renal disease (Causes hypovitaminosis D causing decreased Ca absorption). Hypocalcemia, hyperphosphatemia in chronic renal failure vs hypophosphatemia with most other causes, increased ALP, increased PTH
Renal osteodystrophy
Due to Secondary or Tertiary hyperparathyroidism. Bone lesions in kidneys, due in turn to renal disease.
Tertiary Hyperparathyroidism
Refractory (autonomous) hyperparathyroidism resulting from chronic renal disease. Massively increased PTH and increased Ca
Cortisol’s effect on glycogenolysis
It decreases glycogenolysis and increases glycogen synthesis, via increasing cAMP
Hyperparathyroidism
Due to accidental surgical excision, autoimmune destruction, or DiGeorge syndrome;
Findings- Hypocalcemia, tetany, Chvostek sign (tapping of facial nerve and the facial muscles contract), Trosusseau sign (occulsion of brachial artery with BP cuff leads to carpal spasms)
Psuedohypoparathyroidism
AKA albright hereditary osteodystrophy; autosomal dominant; unresponsiveness PTH receptors to PTH. Get Hypocalcemia, shortened 4th and 5th digits, short stature. You won’t see urinary cAMP increase after giving PTH (remember that PTH works through Gs)
Pituitary adenoma
Most commonly a prolactinoma (benign). Can be functional (makes hormone) or nonfunctional (silent). Can get mass effect (bitemporal hemianopia, hypopituitarism, headache).
Treatment for prolactinoma
Dopamine agonists like bromocriptine or cabergoline
Findings in Acromegaly
Large tongue with deep furrows, deep voice, large hands and feet, coarse facial features, impaired glucose tolerance (insulin resistance).
How to diagnose acromegaly
Uncreased serum IGF-1; failure to suppress serum GH following oral glucose tolerance test; pituitary mass seen on brain MRI
Treatment for acromegaly
Pituitary adenoma resection (most common cause). If not cured, treat with octreotide (somatostatin analog) or pegvisomant (growth hormone receptor antagonist)
Increased GH in children leads to
Gigantism; increased linear bone growth; cardiac failure most common cause of death.
Symptoms of Diabetes insipidus
Characterized by intense thirst and polyuria with inability to concentrate urine due to lack of ADH function.
Central Diabetes insipidus
Etiology: Pituitary tumor, autoimmune, trauma, surgery, ischemic encephalopathy, idiopathic;
Findings: Decreased ADH, urine specific gravity 290, Hyperosmotic volume contraction;
Diagnosis: Water restriction test shows >50% increase in urine osmolarity
Treatment: intranasal DDAVP, hydration
Nephrogenic Diabetes Insipidus
Etiology: Hereditary, secondary to hypercalcemia/lithium/demeclocycline (ADH antagonist);
Findings: normal ADH levels, Urine specific gravity 290, Hyperosmotic volume contraction;
Diagnosis: Water restriction test leads to no change in urine osmolarity;
Treatment: HCTZ, indomethacin, amiloride, Hydration
SIADH
Syndrome of inappropriate antidiuretic hormone secretion: Excessive water retention, Hyponatremia with continued Na urine excretion, Urine osmolarity > Serum osmolarity;
Body responds to water retention with decreased aldosterone (causing hyponatremia) to maintain near normal volume status. Very low serum Na levels can lead to cerebral edema, seizures. Corrects slowly to prevent central pontine myelinolysis.
Causes of SIADH
Ectopic ADH (small cell lung cancer); CNS disorders/head trauma, Pulmonary disease, Drugs (like cyclophosphamide)
Treatment for SIADH
Fluid restriction; IV hypertonic saline, conivaptan, tolvaptan, demeclocycline.
Hypopituitarism
Undersecretion of pituitary hormones due to: Nonsecreting pituitary adenoma, craniopharyngioma, Sheehan syndrome, Empty Sella Syndrome (common in obese women), Brain injury, hemorrhage (pituitary apoplexy), radiation;
Treatment: Hormone replacement therapy
Acute manifestations of Diabetes
Polydipsia, polyuria, polyphagia, weight loss, DKA (type 1), Hyperosmolar coma (type 2); rarely can be caused by unopposed secretion of GH and Epi
Chronic manifestations of Diabetes
Nonenzymatic glycosylation: Small vessel disease (defuse thickening of the basement membrane) causing retinpathy, glaucoma, nephropathy; Large Vessel Atherosclerosis, CAD, peripheral vascular disease, and gangrene causing limb loss, cerebrovascular disease. MI most common cause of death. Osmotic damage (sorbitol accumulation in organs with aldose reductase and decreased or absent sorbital dehydrogenase): nephropathy, Cataracts;
When is an A1C test inaccurate
When you have a condition that is extending the life of RBCs; like b12/folate deficiency, iron deficiency (increased life of RBC leads to increased A1C)
Genetic predisposition of type 1 and type 2 diabetes
Type 1: weak (50% concordance in identical twins), polygenic
Type 2: Relatively strong (90% concordance in identical twins, polygenic)
Type 1 diabetes is associated with what HLA
HLA-DR3 and 4
Histology of pancreas in type 1 and type 2 diabetes
Type 1: Islet leukocytic infiltrate
Type 2: Islet amyloid polypeptide (IAPP) deposits
Diabetic Ketoacidosis: signs/symptoms
Kussmaul respirations (rapid/deep breathing), nausea/vomiting, abdominal pain, psychosis/delirium, dehydration, fruity odor (due to exhaled acetone).
Diabetic Ketoacidosis: labs
Hyperglycemia, Increased H+, decreased HCO3- (anion gap metabolic acidosis), increased blood ketone levels, leukocytosis, hyperkalemia, but depleted intracellular K+ due to transcellular shift from decreased insulin.
Diabetic Ketoacidosis: Complications
Life-threatening mucormycosis (usually called by Rhizopus infection), cerebral edema, cardiac arrhythmias, heart failure.
Diabetic Ketoacidosis: Treatment
IV fluids, IV insulin, and K+ (to replete intracellular stores); glucose if necessary to prevent hypoglycemia.
Insulinoma
Tumor of Beta cells of pancreas leads to overproduction of insulin leading to hypoglycemia. Whipple triad of episodic CNS symptoms: lethargy, syncope, and diplopia/ Symptomatic patients have decreased blood glucose and increase C-peptide levels (vs. exogenous insulin use). Treatment: surgical resection
Carcinoid syndrome
Rare syndrome caused by carcinoid tumors (neuroendocrine cells), especially metastatic small bowel tumors, which secrete high levels of serotonin (5-HT), not seen if tumor is limited to GI tract (5-HT degraded by liver), Results in recurrent diarrhea, cutaneous flushing, asthmatic wheezing, and right sided valvular disease (lungs degrade 5-HT). Increased 5-HIAA in urine, niacin deficiency. Treat: resection, somatostatin analog (octreotide). Rule of 1/3: 1.3 metastasize, 1/3 Present with 2nd malignancy, 1/3 are multiple.
Zollinger Ellison syndrome
Gastrin secreting tumor in pancreas or duodenum. Acid hypersecretion causes recurrent ulcers in distal duodenum and jejunum. Presents with abdominal pain (Peptic Ulcer Disease, distal ulcers), diarrhea (malabsorption). May be associated with MEN 1.
MEN 1 (Wermer Syndrome): Where do you get tumors
Remember the diamond;
Parathyroid, Pituitary (prolactin or GH), Pancreatic Tumors (Zollinger-Ellison syndrome, insulinomas, VIPomas, glucagonomas are rare);
Commonly presents with kidney stones and stomach ulcers
MEN 2A (Sipple Syndrome): where do you get problems
Remember the Box;
Parathyroid hyperplasia, Pheochromocytoma, Medullary thyroid carcinoma (secretes calcitonin)
MEN 2B: where do you get problems
Medullary Thyroid cacinoma (secretes calcitonin), Pheochromocytoma; Oral/intestinal ganglioneuromatosis (mucosal neuromas), Associated with marfanoid habitus (tall, thin, hyper-extendable joints, long fingers)
Inheritance of MEN (multiple Endocrine Neoplasias
Autosomal dominant
Diabetes drugs: treatment strategies
For DM1: low-sugar diet, insulin replacement;
For DM2: Dietary modification and exercise for weight loss, oral agents, non-insulin injectables, insulin replacement;
Gestational DM: dietary modifications, exercise, insulin replacement if lifestyle modification fails
Rapid acting insulin drugs
Lispro, Aspart, Glulisine;
Bind insulin receptor (tyrosine kinase);
Liver: increased glycogen
Muscle: increased glycogen and protein synthesis, Increased K+ uptake
Fat: increased TG stores
For postprandial glucose control of all DM types
Short Acting Insulin drugs
Regular;
Bind insulin receptor (tyrosine kinase);
Liver: increased glycogen
Muscle: increased glycogen and protein synthesis, Increased K+ uptake
Fat: increased TG stores
For all DM types and DKA, and hyperkalemia
Intermediate acting insulin drugs
NPH Bind insulin receptor (tyrosine kinase); Liver: increased glycogen Muscle: increased glycogen and protein synthesis, Increased K+ uptake Fat: increased TG stores For all DM types
Long Acting Insulin Drugs
Glargine, Determir Bind insulin receptor (tyrosine kinase); Liver: increased glycogen Muscle: increased glycogen and protein synthesis, Increased K+ uptake Fat: increased TG stores For basal control of all DM types
Biguanides
Metformin;
Exact mechanism is unknown. decreased gluconeogenesis, increased glycolysis, Increased peripheral glucose uptake (insulin sensitivity);
Oral, first line therapy of DM2, can be used in patients without islet function;
Get GI upset, can get lactic acidosis so contraindicated in renal failure
Sulfonylureas: first generation drug names
Tolbutamide, Chlorpropamide
Sulfonylureas: Second generation drug names
Glyburide, Glimerpiride, glipizide (sulfa drug)
Sulfonylureas: mechanism, uses, side effects
Closes K+ channels on Beta cells leading to depolarization then calcium comes in and releases insulin vesicles.
Need islet function so only useful in DM2;
Hypoglycemia in renal failure, 1st gens cause disulfiram like effects, 2nd gens cause hypoglycemia
Glitazones and thiazolidinediones
Pioglitazone, Rosiglitazone;
increases insulin sensitivity in peripheral tissue. Binds to PPAR gamma nuclear transcription factor.
Used in DM2, can cause GI problems, DO NOT USE IN HEART FAILURE
Alpha glucosidase inhibitors
Acarbose, Miglitol;
inhibits intestinal brush border alpha glucosidases; Delay sugar hydrolysis and glucose absorption leading to decreased postprandial hyperglycemia.
Uses: DM2;
Can cause GI problems
Amylin analogs
Pramlintide;
Action: decreases gastric emptying, decreases glucagon;
Uses: DM 1 and 2
Toxicities: Hypoglycemia, nausea, diarrhea
GLP-1 Analogs
Exenatide, Liraglutide
increase insulin, decrease glucagon release’
For DM 2;
Can get Nausea, vomiting, pancreatitis;
DPP-4 inhibitors
Linagliptin, Saxagliptin, Sitagliptin;
Work to increase insulin, decreased glucagon release;
Used in DM2;
Can get mild urinary or respiratory infections
Propylthiouracil and Methimazole: Mechanism
Block thyroid peroxidase, inhibiting the oxidation of iodide and the organification of Iodine causing inhibition of thyroid synthesis. Propylthiouracil also block 5’-deiodinase blocking the conversion of T4 to T3 in the periphery.
Propylthiouracil and Methimazole: Clinical use
Hyperparathyroidism; PTU blocks Peripheral conversion, used in Pregnancy
Propylthiouracil and Methimazole: Toxicity
Skin rash, agranulocytosis, aplastic anemia, hepatotoxicity, methimazole is a possible teratogen (aplastic crisis)
Levothyroxine, Triiodothyronine:
Thyroxine replacement;
Used for hypothyroidism, myxedema;
Can cause tachycardia, heat intolerance, tremors, arrhythmias
Hypothalamic/pituitary drugs: GH
Used for GH deficiency and Turner’s Syndrome
Octreotide
Somatostatin analog;
Used for Acromegaly, Carcinoid, Gastrinoma, Glucagonoma, Esophageal varices.
Hypothalamic/pituitary drugs: Oxytocin
Stimulates labor, uterine contractions, milk let-down, controls uterine hemorrhage
Hypothalamic/pituitary drugs: ADH
Also called DDAVP;
Used to treat Central DI
Demeclocycline
Mechanism: ADH antagonist (member of the tetracycline family);
Clinical Use: SIADH;
Toxicity: Nephrogenic DI, photosensitivity, abnormalities of teeth and bone
Glucocorticoids: Name them
Hydrocortisone, Prednisone, Triamcinolone, Dexamethason, Beclomethasone, Fludrocortisone (has gluco and mineralcorticoid activity)
Glucocorticoids: Mechanism
Metabolic, catabolic, anti-inflammatory, and immunosuppressive effects mediated by interactions with glucocorticoid response elements and inhibition of transcription factors such as FN-kappaB.
Glucocorticoids: Uses
Addison disease, inflammation, immune suppression, asthma
Glucocorticoids: Toxicity
Iatrogenic cushing syndrome- Buffalo hump, moon facies, truncal obesity, muscle wasting, thin skin, easy bruisability, osteoporosis (treat with bisphosphonates), adrenocortical atrophy, peptic ulcers, diabetes if chronic. Adrenal insufficiency when stopped abruptly after chronic use
Patient on propylthiouracil or methimazole reports arthralgias fever and sore throat, what do you do
This is their awful side effect, they have agranunulocytosis and you need to give them a med to increase granulocyte colony stimulation.
3 P’s of MEN1
Pancreatic, Pituitary, Parathyroid tumors
renal failure and parathyroid
You will get secondary parathyroidism due to the inability to excrete Phosphate.
Alcoholics with Trousseau’s sign
They will have low magnesium which leads to short term increase in PTH, but chronically low magnesium actually decreases PTH so you get decrease in Serum Calcium.
Treat by giving magnesium (and get the drunkard to stop drinking)
What hormones does somatostatin inhibit
GH and TSH (octreotide, a somatostatin analog will inhibit both as well)
If you get a patient with Type 1 diabetes in your office really early on in the disease process, what antibodies can you find in their blood?
Glutamic acid decarboxylase (GAD65) antibodies;
This is a Beta cell enzyme
