Flashcards in Endocrine Deck (224)
The thyroid diverticulum arises from the floor of the primitive pharynx and descends into neck. It is connected to the tongue by the thyroglossal duct, which normally disappears but it may persist as pyramidal lobe of the thyroid. The foramen cecum is a normal remnant of the thyroglossal duct. The most common ectopic thyroid tissue site is the tongue. A thyroglossal duct cyst presents as an anterior midline neck mass that moves with swallowing or protrusion of the tongue (vs a persistent cervical sinus leading to a branchial cleft cyst in lateral neck).
It is derived from mesoderm and contains (from outside to inside) the zona glomerulosa (regulated by the renin-angiotensin system and secretes aldosterone), zona fasciculata (regulated by ACTH and CRH and secretes cortisol and sex hormones), and zona reticularis (regulated by ACTH and CRH and secretes sex hormones, eg androgens). GFR corresponds with Salt (Na), Sugar (glucocorticoids), and Sex (androgens). The deeper you go, the sweeter it gets.
It is derived from neural crest cells. The medulla contains Chromaffin cells, is regulated by preganglionic sympathetic fibers, and releases catecholamines (epinephrine and norepinephrine). Pheochromocytoma is the most common tumor of the adrenal medulla in adults. It causes episodic hypertension. Neuroblastoma is the most common tumor of the adrenal medulla in children. It rarely causes hypertension.
Anterior pituitary (adenohypophysis)
It secretes FSH, LH, ACTH, TSH, prolactin, GH (FLAT PiG). Melanotropin (MSH) is secreted from the intermediate lobe of the pituitary. It is derived from the oral ectoderm (Rathke pouch). The alpha subunit is the hormone subunit common to TSH, LH, FSH, and hCG. The beta subunit determines the hormone specificity. Acidophils produce GH and prolactin. Basophils (B-FLAT) produce FSH, LH, ACTH, TSH.
Posterior pituitary (neurohypophysis)
It secretes vasopressin (antidiuretic hormone or ADH) and oxytocin, made in the hypothalamus (supraoptic and paraventricular nuclei, respectively) and is transported to the posterior pituitary via the neurphysins (carrier proteins). It is derived from neuroectoderm.
Endocrine pancreas cell types
Islets of Langerhans are collections of alpha, beta, and delta endocrine cells. Islets arise from pancreatic buds. Alpha cells are located on the periphery and secrete glucagon. Beta cells are centrally located and secrete insulin. Delta cells are interspersed and secrete somatostatin.
Preproinsulin is synthesized in the RER. There is cleavage of presignal peptide, creating proinsulin that then gets stored in secretory granules. Within the granule, proinsulin get cleaved creating equal insulin and C-peptide, which both undergo exocytosis. Insulin and C peptides are increased in insulinoma and sulfonylurea use, whereas exogenous insulin lacks C-peptide.
Source of insulin
Pancreatic beta cells
Function of insulin
Insulin binds a tyrosine kinase receptor, inducing glucose uptake (carrier mediated transport) into insulin dependent tissue and gene transcription. Unlike glucose, insulin does not cross the placenta.
Anabolic effects of insulin
It increases glucose transport in skeletal muscle and adipose tissue; increases glycogen synthesis and storage; increases triglyceride synthesis, increases Na retention (kidneys), increases protein synthesis (muscles), increases cellular uptake of K and amino acids; decreases glucagon release. Organs that have insulin independent glucose uptake include the Brain, RBCs, Intestine, Cornea, Kidney, and Liver (BRICK L)
Insulin independent transporters, present in RBCs, brain, and cornea. The brain utilizes glucose for metabolism normally and ketone bodies during starvation. RBCs always utilize glucose because they lack mitochondria for aerobic metabolism.
Insulin independent transporters, present in beta islet cells, liver, kidney, and small intestine. It is bidirectional.
Insulin independent transporters, present in the brain
Insulin dependent glucose transporter, present in adipose tissue, striated muscle (exercise can also increase GLUT 4 expression).
Insulin independent transporters, present in spermatocytes and GI tract, and transports fructose.
Regulation of insulin release
Glucose is the major regulator of insulin release. Growth hormone, which causes insulin resistance leading to an increase in insulin release. Glucose enters beta cells increases ATP generated from glucose metabolism closes K channels (target of sulfonylureas) and depolarizes beta cell membrane. Voltage gated Ca channels open causes Ca influx and stimulation of insulin exocytosis.
Made in the alpha cells of the pancreas. It increases catabolic processes such as glycogenolysis, gluconeogenesis, lipolysis and ketone production. It is secreted in response to hypoglycemia. It is inhibited by insulin, hyperglycemia, and somatostatin.
It increases secretion of ACTH, MSH, and beta endorphin. It decreases with chronic exogenous steroid use.
Decreases prolactin release. Dopamine antagonists (eg antipsychotics) can cause galactorrhea due to hyperprolactinemia.
Growth hormone releasing hormone
Triggers growth hormone release. Analog (tesamorelin) is used to treat HIV associated lipodystrophy.
Gonadotropin releasing hormone
Triggers release of FSH and LH. It is regulated by prolactin. Tonic GnRH suppresses HPA axis. Pulsatile GnRH leads to puberty and fetility.
Decreases GnRH secretion. A pituitary prolactinoma causes amenorrhea, osteoporosis, hypogonadism, galactorrhea.
It decreases TSH and GH secretion. An analog is used to treat acromegaly.
TSH releasing hormone
Increases TSH and prolactin secretion.
It is secreted mainly by the anterior pituitary. It stimulates milk production in breast and inhibits ovulation in females and spermatogenesis in males by inhibiting GnRH synthesis and release. Excessive amounts of prolactin associated with decreased libido.
Regulation of prolactin release
Prolactin secretion from anterior pituitary is tonically inhibited by dopamine from the hypothalamus. Prolactin in turn inhibits its own secretion by increasing dopamine synthesis and secretion from the hypothalamus. TRH increases prolactin secretion (eg in primary or secondary hypothyroidism). Dopamine agonists (eg bromocriptine) inhibit prolactin secretion and can be used in treatment of prolactinoma. Dopamine antagonists (eg most antipsychotics) and estrogens (eg OCPs, pregnancy) stimulate prolactin secretion.
Growth hormone (somatotropin)
It is secreted by the anterior pituitary. It stimulates linear growth and muscle mass through IGF-1 (somatomedin C) secretion. It increases insulin resistance (diabetogenic).
Regulation of growth hormone secretion
It is released in pulses in response to growth hormone-releasing hormone (GHRH). Secretion increases during exercise and sleep. Secretion is inhibited by glucose and somatostatin release via negative feedback by somatomedin. Excess secretion of GH (eg pituitary adenoma) may cause acromegaly (adults) or gigantism (children).
Stimulates hunger (orexigenic effect) and GH release (via GH secretagog receptor). Produced by stomach. Increases with sleep loss and Prader Willi syndrome. Ghrelin makes you hunghre.
Satiety hormone. It is produced by adipose. It decreases during starvation. Mutation of leptin gene causes congenital obesity. Sleep deprivation causes a decrease in leptin production. Leptin keeps you thin.
Stimulate cortical reward centers increasing the desire for high fat foods. The munchies.
It is synthesized by hypothalamus (supraoptic nuclei), released by posterior pituitary. It regulates serum osmolarity (V2 receptors) and blood pressure (V1-receptors). Its primary function is serum osmolarity regulation (ADH decreases serum osmolarity and increases urine osmolarity) via regulation of aquaporin channel insertion in principal cells of renal collecting duct. ADH level is decreased in central diabetes insipidus (DI), normal or increased in nephrogenic DI. Nephrogenic DI can be caused by mutation in V2 receptor. Desmopressin acette (ADH analog) is a treatment for central DI.
There are osmoreceptors in hypothalamus in primary regulation. It is secondarily regulated by hypovolemia.
It converts cholesterol into pregnenolone in the zona glomerulosa. It is activated by ACTH and inhibited by ketoconazole.
3 beta hydroxysteroid dehydrogenase
Converts Pregnenolone into progesterone in the zona glomerulosa, 17 hydroxypregnenolone into 17 hydroxyprogesterione in the zona fasciculata, and dehdroepiandtroterone (DHEA) into androstenedione in the zona reticularis.
Converts progesterone into 11-deoxycorticosterone in the zona glomerulosa and 17 hydroxyprogesterone into 11-deoxycortisol in the zona fasciculata.
11 beta hydroxylase
Converts 11 deoxycorticosterone into corticosterone in the zona glomerulosa and 11 deoxycortisol into cortisol in the zona fosciculata.
17 alpha hydroxylase
It converts pregnenolone into 17 hydroxypregnenolone and progesterone into 17 hydroxyprogesterone.
Converts corticosterone into aldosterone in the zona glomerulosa.
Androstenedione into estrone and testosterone into estradiol
5 alpha reductase
Converts testosterone into dihydrotestosterone (DHT).
17 alpha hydroxylase deficiency
It blocks cortisol and sex hormones, thereby increasing mineralcorticoids, which increases blood pressure and decreases potassium. Labs show a decrease in androstenedione. XY presentation is pseudohermaphroditism (ambiguous genitalia, undescended testes). XX presentation is a lack secondary sexual development. All congenital adrenal enzyme deficiencies are characterized by an enlargement of both adrenal glands due to an increase in ACTH.
21 hydroxylase deficiency
It blocks mineralocorticoid and cortisol synthesis and increases sex hormone production. BP is low and K increases. Labs show an increase in renin activity and 17 hydroxyprogesterone. It is the most common adrenal deficiency. It presents in infancy due to salt wasting or in childhood due to precocious puberty. XX genotype will have virilization. All congenital adrenal enzyme deficiencies are characterized by an enlargement of both adrenal glands due to an increase in ACTH.
11 beta hydroxylase
It decreases aldosterone production but increases 11 deoxycorticosterone, resulting in an increase in blood pressure. It decreases cortisol production and increases sex hormone production. Blood pressure increases and K decreases. Labs will show a decrease in renin activity. XX genotype will have virilization. All congenital adrenal enzyme deficiencies are characterized by an enlargement of both adrenal glands due to an increase in ACTH.
Cortisol is produced in the adrenal zona fasciculata and gets bound to corticosteroid-binding globulin.
Function of cortisol
It increases blood pressure by up-regulating alpha 1 receptors on arterioles causes an increase in sensitivity to norepinephrine and epinephrine. At high concentrations, cortisol can bind to mineralocorticoid (aldosterone) receptors. It increases insulin resistance (diabetogenic). It increases gluconeogenesis, lipolysis, and proteolysis. It also decreases fibroblast activity, which causes striae. It also decreases inflammatory and immune responses by inhibiting production of leukotrienes and prostaglandins, inhibiting WBC adhesion leading to neutrophilia, blocking histamine release from mast cells, reducing eosinophils, and blocking IL-2 production. It also decreases bone formation by decreasing osteoblast activity. Cortisol is a BIG FIB (blood pressure, insulin, gluconeugenesis, fibroblast, inflammatory and immune, and bone). Exogenous corticosteroids can cause reactivation of TB and candidiasis through blocking of IL-2 production.
Regulation of cortisol release
CRH, released from the hypothalamus, stimulates ACTH release from the pituitary, leading to cortisol production in the adrenal zona fasciculata. Excess cortisol decreases CRH, ACTH, and cortisol secretion. Chronic stress induces prolonged secretion.
Plasma Ca exists in three forms: ionized (45%), bound to albumin (40%), and bound to anions (15%). An increase in pH causes an increases affinity of Ca to albumin by increasing its negative charge by removing hydrogen from albumin. This can cause hypocalcemia, which causes cramps, pain, paresthesias, and carpopedal spasm.
Sources of vitamin D (cholecalciferol)
D3 comes from sun exposure in skin. D2 is ingested from plants. Both get converted to 25-OH in the liver and to 1, 25-(OH)2 (active form) in kidney.
Function of vitamin D
It causes an increase in absorption of dietary Ca and PO4. It also causes an increase in bone resorption increases Ca and PO4 in serum.
Regulation of vitamin D
An increase in PTH, a decrease in Ca concentration, and a decrease in PO4 triggers an increase in 1, 25-(OH)2 production. 1, 25-(OH)2 feedback inhibits its own production.
Vitamin D deficiency
It causes rickets in kids and osteomalacia in adults. Causes include malabsorption, a decrease in sunlight, poor diet, and chronic kidney failure. 24, 25- (OH)2 D3 is an inactive form of vitamin D. PTH leads to an increase in Ca reabsorption and a decrease in PO4 reabsorption in the kidney, whereas 1, 25-(OH) D3 leads to an increase absorption of both Ca and PO4 in the gut.
Source of parathyroid hormone
Chief cells of the parathyroid.
Parathyroid hormone function
It increases bone resorption of Ca and PO4, increases kidney reabsorption of Ca in the distal convoluted tubule, decreases reabsorption of PO4 in proximal convoluted tubule. It also increases 1, 25-(OH)2 D3 (calcitriol) production by stimulating kidney 1 alpha-hydroxylase in proximal convoluted tubule. PTH increases serum Ca, decreases serum PO4, and increases urine PO4. It also increases production of macrophage colony-stimulating factor and RANK-L (receptor activator of NF-KB ligand). RANK-L (ligand) secreted by osteoblasts and osteocytes binds RANK (receptor) on osteoclasts and increases Ca. Intermittent PTH release can stimulate bone formation. PTH=Phosphate Trashing Hormone. PTH-related peptide (PTHrP) functions like PTH and is commonly increase in malignancies.
Regulation of parathyroid hormone
A decrease in serum Ca causes an increase in PTH secretion. An increase in PO4 causes an increase in PTH. A decrease in serum Mg causes an increase in PTH secretion. A large decrease in serum Mg causes a decrease in PTH secretion. Common causes of a decrease in Mg include diarrhea, aminoglycosides, diuretics, alcohol abuse.
It is produced in parafollicular cells (C cells) of thyroid. It decreases bone resorption of Ca. An increase in serum Ca trigger calcitonin secretion. Calcitonin opposes actions of PTH. It is not important in normal Ca homeostasis. CalciTONin TONes down Ca levels.
Signaling pathways involving cAMP
FSH, LH, ACTH, TSH, CRH, hCG, ADH (V2 receptor), MSH, PTH, calcitonin, GRH, glucagon. (FLAT ChAMP).
Signaling pathways involving cGMP
ANP, BNP, NO (EDRF). Think vasodilators.
Signaling pathways involving IP3
GnRH, Oxytocin, ADH (V1 receptor), TRH, Histamine (H1-receptor), Angiotensin II, Gastrin (GOAT HAG).
Signaling pathways involving intracellular receptor
Vitamin D, Estrogen, Testosterone, T3/T4, Cortisol, Aldosterone, Progesterone (VETTT CAP).
Signaling pathways involving intrinsic tyrosine kinase
Insulin, IG-1, FGF, PDGF, EGF. MAP kinase pathway. Think growth factors.
Signaling pathways involving receptor associated tyrosine kinase
Prolactin, Immunomodulators (eg cytokines IL-2, IL-6, TNF), GH, G-CSF, Erythropoietin, Thrombopoietin (PIGGlET). JAK/STAT pathway. Think acidophils and cytokines.
Signaling pathway of steroid hormones
Steroid hormones are lipophilic and therefore must circulate bound to specific binding globulins, which increase their solubility.
Signaling pathway of steroid hormones
Steroid hormones are lipophilic and therefore must circulate bound to specific binding globulins, which increases their solubility. In men, an increase in sex hormone binding globulin (SHBG) lowers free testosterone causing gynecomastia. In women, a decrease in SHBG raises free testosterone causing hirsutism. OCPs, pregnancy increases SHGB (free estrogen levels remain unchanged). When the hormone enters the cytoplasm, it binds the receptor either in the nucleus or in the cytoplasm. There is a transformation of the receptor to expose DNA binding domain, which than binds to an enhancer-like element in DNA.
Thyroid hormones (T3/T4)
Iodine containing hormones that control the body's metabolic rate.
Source of thyroid hormone
It is produced in the follicles of thyroid. Most T3 is formed in target tissues.
Function of thyroid hormone
It has synergism with GH by stimulating bone growth. It also stimulates CNS maturation. It increases beta 1 receptors in hear, increasing cardiac output, heart rate, stroke volume, and contractility. It increases basal metabolic rate by increasing Na/K ATPase activity, which increases O2 consumption, respiratory rate, and body temperature. It increases glycogenolysis, gluconeogenesis, lipolysis.
Regulation of thyroid hormone
TRH is secreted by the hypothalamus and stimulates TSH secretion from the pituitary, which stimulates follicular cells. Negative feedback by free T3 and T4 to anterior pituitary decreasing sensitivity to TRH. Thyroid stimulating immunoglobulins (eg TSH) stimulate follicular cells (eg Graves disease).
Wolff Chaikoff effect
Excess iodine temporarily inhibits thyroid peroxidase causing a decrease in iodine organification, decreasing T3/T4 production.
The 4 Bs: brain muturation, bone growth, beta-adrenergic effects, basal metabolic rate increases. T3 binds nuclear receptor with greater affinity than T4.
Thyroxine-binding globuline (TBG)
TBG binds most T3/T4 in the blood. Only free hormone is active. A decrease in TBG occurs in hepatic failure and steroid use. An increase in TBG occurs in pregnancy or OCP use (estrogens increase TBG).
Converts T4 to T3 in the peripheral tissue, since T4 is a major thyroid product.
It is responsible for oxidation and organification of iodide as well as coupling of monoiodotyrosine (MIT) and di-iodotyrosine (DIT).
inhibits both peroxidase and 5'-deiodinase.
inhibits peroxidase only.
Etiology of Cushing syndrome
An increase in cortisol due to a variaty of causes: exogenous corticosteroids results in a decrease in ACTH, bilateral adrenal atrophy. It is the most common cause. Primary adrenal adenoma, hyperplasia, or carcinoma can result in a decrease in ACTH, atrophy of uninvolved adrenal gland. It can also present with pseudohyperaldosteronism. ACTH secreting pituitary adenoma (Cushing disease) or paraneoplastic ACTH secretion (eg small cell lung cancer, bronchial carcinoids) can result in an increase in ACTH, bilateral adrenal hyperplasia. Cushing disease is responsible for the majority of endogenous cases of Cushing syndrome.
Findings with Cushing syndrome
Hypertension, weight gain, moon facies, truncal obesity, buffalo hump, skin changes (thinning, strae), osteoporosis, hyperglycemia (insulin resistance), amenorrhea, immunosuppression.
Diagnosis of Cushing syndrome
Screening tests include an increase in free cortisol on 24-hour urinalysis, an increase in midnight salivary cortisol, and no suppression with overnight low dose dexamethasone test. Also measure serum ACTH. If ACTH is low, suspect an adrenal tumor. If it is high, distinguish between Cushing disease and ectopic ACTH secretion with a high dose (8mg) dexamethasone suppression test and CRH stimulation test. Ectopic secretion will not decrease with dexamethasone because the source is resistant to negative feedback. Ectopic secretion will not increase with CRH because pituitary ACTH is suppressed.
Inability of adrenal glands to generate enough glucocorticoids with or without miceralocorticoids of the body's needs. Symptoms include weakness, fatigue, orthostatic hypotension, muscle aches, weight loss, GI disturbances, sugar and/or salt cravings. Diagnosis involves measurement of serum electrolytes, morning/random serum cortisol and ACTH, and response to ACTH stimulation test. Alternatively, metyrapone stimulation test can also be used. Metyrapone blocks the last step of cortisol synthesis (11-deoxycortisol into cortisol). Normal responce is a decrease in cortisol and compensatory increase in ACTH. In adrenal insufficiency, ACTH remains decrease after test.
Primary adrenal insufficiency
Deficiency of aldosterone and cortisol production due to loss of gland function causing hypotension (hyponatremic volume contraction), hyperkalemia, metabolic acidosis, skin and muscosal hyperpigmentation (due to MSH, a byproduct of increase ACTH production from pro-opiomelanocortin). Primary pigments the skin/mucosa. Autoimmunity is the most common cause of primary chronic adrenal insufficiency in the western world. It is associated with autoimmune polyglandular syndromes.
Acute primary adrenal insufficiency
Sudden outset (eg due to massive hemorrhage). It may present with shock in acute adrenal crisis.
Chronic primary adrenal insufficiency. It occurs due to adrenal atrophy or destruction by disease (eg autoimmune, TB, metastasis).
Acute primary adrenal insufficiency due to adrenal hemorrhage associated with septicemia (usually Neisseria meningitidis), DIC, or endotoxin shock.
Secondary adrenal sufficiency
Seen with a decrease in pituitary ACTH production. No skin/mucosal hyperpigmentation, no hyperkalemia (aldosterone synthesis preserved). Secondary Spares the skin/mucosa.
Tertiary adrenal sufficiency
Seen in patients with chronic exogenous steroid use, precipitated by abrupt withdrawal. Aldosterone synthesis is unaffected. Tertiary from Treatment.
The most common tumor of the adrenal medulla in children, usually under four years old. Originates from neural crest cells. Homer Wright rosettes (differentiated tumour cells grouped around a central region containing neuropil, therefore its association with tumors of neuronal origin). are characteristic. It occurs anywhere along the sympathetic chain. The most common presentation is abdominal distension and a firm, irregular mass that can cross the midline (ie Wilms tumor, which is smooth and unilateral). It can also present with opsoclonus-myoclonus syndrome (dancing eyes dancing feet). Homovanillic acid (HVA, a breakdown product of dopamine) and vanillylmandelic acid (VMA, a breakdown product of norepinephrine) is increased in urine. Bombesin and neuron specific enolase postitive. It is less likely to develop hypertension. It is associated with overexpression of N-myc oncogene.
Etiology of pheochromocytoma
It is the most common tumor of the adrenal medulla in adults. It is derived from chromaffin cells, which arise from neural crest. Rule of 10's: 10% malignant, bilateral, extra-adrenal, calcify, and kids.
Symptoms of pheochromocytoma
Most tumors secrete epinephrine, norepinephrine, and dopamine, which can cause episodic hypertension. It is associated with neurofibromatosis type 1, con Hippel-Lindau disease, MEN 2A and 2B. Symptoms occur in spells with relapse and remit. Episodic hyperadrenergic symptoms (5 Ps): pressure (increase in BP), pain (headache), perspiration, palpitations (tachycardia), pallor.
Findings of pheochromocytoma
An increase in catecholamines and metanephrines in urine and plasma. Enlarged pleomorphic nuclei are typical.
Treatment of pheochromocytoma
Irreversible alpha antagonists (eg phenooxybenzamine) followed by beta blockers prior to tumor resection, alpha blockade must be achieved before giving beta blockers to avoid a hypertensive crisis.
Symptoms of hypothyroidism
Cold intolerance (a decrease in heat production), weigh gain, decrease in appetite, hypoactivity, lethargy, fatigue, weakness, constipation, decrease reflexes, myxedema (facial/periorbital), dry cool skin, coarse brittle hair, bradycardia, dyspnea on exertion.
Lab findings with hypothyroidism
An increase in TSH (sensitive test for primary hyperthyroidism), decrease in free T3 and T4, hypercholesterolemia (due to a decrease in LDL receptor expression).
Symptoms of hyperthyroidism
Heat intolerance (increased heat production), weight loss, increase appetite, hyperactivity, diarrhea, increased reflexes, pretibial myxedema (graves disease), periorbital edema, warm moist skin, fine hair, chest pain, palpitations, arrhythmias, an increase in number and sensitivity of beta adrenergic receptors.
Lab findings with hyperthyroidism
A decrease in TSH (if primary), an increase free or total T3 and T4, hypocholesterolemia (due to an increase LDL receptor expression).
It is the most common cause of hypothyroidism in iodine-sufficient regions. It is an autoimmune disorder (anti-thyroid peroxidase, antimicrosomal and antithyroglobulin antibodies). It is associated with HLA-DR5. It increases the risk of non-Hodgkin lymphoma. There may be hyperthyroid early in course due to thyrotoxicosis during follucular rupture. Histological findings include Hurthle cells and lymphoid aggregate with germinal centers. Findings include moderately enlarged and nontender thyroid. It is a type III hypersensitivity.
Congenital hypothyroidism (cretinism)
Severe fetal hypothyroidism due to maternal hypothyroidism, thyroid agenesis, thyroid dysgenesis ( most common cause in US), iodine deficiency, dyshormonogenetic goiter. Findings include (6 Ps): Pot0bellied, Pale, Puffy face child with Protruding umbilicus, Protuberant tongue, and Poor brain development.
Subacute thyroiditis (de Quervain)
It is a self-limited disease often following a flue like illness. It may be hyperthyroid early in course, followed by hypothyroidism. Histology includes granulomatous inflammation. Findings include an increase ESR, jaw pain, early inflammation, very tender thyroid. de Quervain is associated with pain.
Thyroid is replaced by fibrous tissue (hypothyroid). Fibrosis may extend to local structures (eg airway), mimicking anaplastic carcinoma. It is considered a manifestation of IgG4 related systemic disease (eg autoimmune pancreatitis, retroperitoneal fibrosis, noninfectious aortitis). Findings include a fixed hard (rock hard) painless goiter.
Other causes of hypothyroidism
Iodine deficiency, goitrogens, Wolff-Chaikoff effect (thyroid gland downregulation in response to an increase in iodide).
It is the most common cause of hyperthyroidism. Autoantibodies (IgG) stimulate TSH receptors on thyroid (hyperthyroidism, diffuse goiter), retro-orbital fibroblasts (exophthalmos involvers proptosis and extraocular muscle swelling) and dermal fibroblasts (pretibial myxedema). It often presents during stress (eg childbirth).
Toxic multinodular goiter
Focal patches of hyperfunctioning follicular cells working independently of TSH due to a mutation in the TSH receptor. This causes an increase release T3 and T4. Follicles are distended with colloid and lined by flattened epithelium with areas of fibrosis and hemorrhage. Hot nodules are rarely malignant.
A stress-induced catecholamine surge, which is a serious complication of thyrotoxicosis due to disease and other hyperthyroid disorders. It presents with agitation, delirium, fever,diarrhea, coma, and tachyarrhythmia (cause of death). There may be an increase in ALP due to an increase in bone turnover. Treat with the 3 Ps: beta blockers (eg Propranolol), Propylthiouracil, corticosteroids (eg Prednisolone).
Thyrotoxicosis if a patient with iodine deficiency goiter is made iodine replete.
Thyroidectomy is an option for thyroid cancers and hyperthyroidism. Complications of surgery include hoarsness (due to recurrent laryngeal nerve damage), hypocalcemia (due to removal of parathyroid glands), and transection of recurrent and superior laryngeal nerves (during ligation of inferior thyroid artery and superior laryngeal artery, respectively).
Papillary thyroid carcinoma
It is the most thyroid cancer and has excellent prognosis. It is empty appearing nuclei with central clearing (Orphan Annie eyes), psammoma bodies, nuclear grooves. Lymphatic invasion is common. There is an increase risk with RET and BRAF mutations and childhood irradiation.
Follicular thyroid carcinoma
It has a good prognosis. It invades thyroid capsule (unlike follicular adenoma) with uniform follicles.
Medullary thyroid carcinoma
It is from parafollicular C cells. It produces calcitonin. There are also solid sheets of cells in an amyloid stroma. Hematogenous spread is common. It is associated with MEN 2A and 2B (RET mutations)
Undifferentiated/ anaplastic thyroid carcinoma
It occurs in older patients and invades local structures. It has a very poor prognosis.
It is associated with Hashimoto thyroiditis.
Causes include accidental surgical excision of parathyroid glands, autoimmune destruction, or DiGeorge syndrome. Findings include hypocalcemia and tetany. There is a positive Chvostek sign (tap the CHeek) where when tapping the facial nerve causes contraction of facial muscles. Trousseau sign is also positive (cuff the TRicep); when occluding the brachial artery with a BP cuff, there is carpal spasm. Both PTH and Ca will be low.
Pseudohypoparathyroidism (Albright hereditary osteodystrophy)
Unresponsivenss of kidney to PTH. Findings include hypocalcemia and shortened 4th/5th digits, and short stature. It is autosomal dominant.
Familial hypocalciuric hypercalcemia
It is due to defective Ca sensing receptor on parathyroid cells. PTH cannot be suppressed by an increase in Ca level leads to mild hypercalcemia with normal to increased PTH levels.
Secondary hyperplasia due to a decrease in Ca and/or increase in PO4, most often due to chronic renal disease, which causes hypovitaminosis D leading to a decrease in Ca absorption. PTH is high, Ca is low, ALP is high. There is also hyperphosphatemia in chronic renal failure (vs hypophosphatemia with most other causes).
Causes include hyperplasia and adenoma carcinoma. PTH and Ca are high. There is also hypercalciuria (renal stones), hypophosphatemia, high ALP, high cAMP in urine. It is most often asymptomatic. It may present with weakness and constipation (groans), abdominal/flank pain (kidney stone, acute pancreatitis), and depression (psychiatric overtones). Chronic primary hyperparathyroidism can result in osteitis fibrosa cystica.
PTH independent hypercalcemia
Due to excess Ca ingestion or cancer. PTH is low, Ca is high.
Osteitis fibrosa cystica
Cystic bone spaces filled with frown fibrous tissue (brown tumor consisting of deposited hemosiderin from hemorrhages, causes bone pain). Stones, bones, groans, and psychiatric overtones. It is caused by primary hyperparathyroidism.
Bone lesions due to primary or tertiary hyperparathyroidism due in turn to renal disease.
Refractory (autonomous) hyperparathyroidism resulting from chronic renal disease. PTH is very high and Ca is high.
It is most commonly prolactinoma (benign). Adenoma may be functional (hormone producing) or nonfunctional (silent). Nonfunctional tumors present with mass effect (bitemporal hemianopia, hypopituitarism, headache). Functional tumor presentation is base on the hormone produced. For example, prolactinoma presents with amenorrhea, galactorrhea, low libido, and infertility. A somatotropic adenoma presents with acromegaly. Treatment for prolactinoma is a dopamine agonists (bromocriptine or cabergoline), transsphenoidal resection.
Excess GH in adults. Typically caused by pituitary adenoma.
Excess GH in children causes gigantism (an increase in linear bone growth). Heart failure is the most common cause of death.
Findings with acromegaly
Large tongue with deep furrows, deep voice, large hands and feet, coarse facial features, impaired glucose tolerance (insulin resistance). There is an increase risk of colorectal polyps and cancer.
Diagnosis of acromegaly
There is an increase serum IGF-1. Failure to suppress serum GH following oral glucose tolerance test. A pituitary mass is seen on brain MRI.
Treatment of acromegaly
Pituitary adenoma resection. If not cured, treat with octreotide (somatostatin analog) or pegvisomant (growth hormone receptor antagonist).
It is characterized by intense thirst and polyuria with inability to concentrate urine due to a lack of ADH (central) or failure of response to circulating ADH (nephrogenic).
Etiology of central DI
Causes include pituitary tumor, autoimmune, trauma, surgery, ischemic encephalopathy, idiopathic.
Etiology of nephrogenic DI
It can be hereditary (ADH receptor mutation), secondary to hypercalcemia, lithium, demeclocycline (ADH antagonist).
Findings in central DI
There is a decrease in ADH, urine specific gravity is less than 1.006, serum osmolality is over 290 mOsm/kg, hyperosmotic volume contraction.
Finding in nephrogenic DI
There is normal levels of ADH, urine specific gravity is less than 1.006, serum osmolality is over 290 mOsm/kg, hyperosmotic volume contraction.
Water deprivation test with DI
No water intake for 2-3 hours followed by hourly measurements of urine volume and osmolarity and plasma Na concentration and osmolarity. ADH analog (desmopressin acetate) is administered if normal values are not clearly reached. With central DI, there is over a 50% increase in urine osmolality only after administration of ADH analog. With nephrogenic DI, there is minimal change in urine osmolality, even after administration of ADH analog.
Treatment of central DI
Intranasal desmopressin acetate and hydration
Treatment of nephrogenic DI
hydrochlorothiazide, indomethacin, amiloride, and hydration.
Syndrome on inappropriate antidiuretic hormone (SIADH)
There is excessive free water retention, euvolemic hyponatremia with continued urinary Na extretion. Urine osmolality is greater than serum osmolality. The body responds to water retention with a decrease in aldosterone (hyponatremia) to maintain near normal volume status. There is very low serum Na levels that can lead to cerebral edema seizures. Correct Na levels slowly to prevent osmotic demyelination syndrome (formerly known as central pontine myelinolysis). Causes include extopic ADH (eg small cell lung cancer), CNS disorders/ head trauma, pulmonary disease, and drugs (cyclophosphamide). Treatment includes fluid restriction, IV hypertonic saline, conivaptan (inhibitor of ADH), tolvaptan (a competitive vasopressin receptor 2 antagonist), demeclocycline (an antibiotic that induces nephrogenic diabetes insipidus).
Causes of undersecretion of pituitary hormones include nonsecreting pituitary adenoma, craniopharyngioma, sheehan syndrome, empty sella syndrome, pituitary apoplexy, brain injury, radiation. Treatment includes hormone replacement therapy (corticosteroids, thyroxine, sex steroids, human growth hormone).
Ischemic infarct of pituitary following postpartum bleeding. It usually presents with failure to lactate, absent menstruation, or cold intolerance. It can cause hypopituitarism.
Empty sella syndrome
Atrophy or compression of pituitary gland, often idiopathic, common in obese women. It can cause hypopituitarism.
Sudden hemorrhage of the pituitary gland, often in the presence of an existing pituitary adenoma. It can cause hypopituitarism.
It causes polydipsia, polyuria, polyphagia, weight loss, DKA (type 1), hyperosmolar coma (type 2). Rarely, it can be caused by unopposed secretion of GH and epinephrine. It can also be seen in patients on glucocorticoid therapy (steroid diabetes).
Acute manifestations of insulin deficiency or insensitivity
It causes a decrease serum glucose uptake, which leads to hyperglycemia, glycosuria, osmotic diuresis, and electrolyte depletion. This can cause dehydration with or without acidosis, which leads to coma and death. An increase in protein catabolism increases plasma amino acids, and nitrogen loss in the urine. Increased lipolysis (insulin deficiency only) causes increased plasma FFAs, ketogenesis, ketonuria, ketonemia.
Chronic complications of DM
Non enzymatic glycation causes small vessel disease (diffuse thickening of basement membrane), which causes retinopathy (hemorrhage, exudates, microaneurysms, vessel proliferation), glaucoma, neuropathy, nephropathy (nodular glomerulosclerosis, aka Kimmelstiel-Wilson nodules causes progressive proteinuria and arteriolosclerosis, leading to hypertension. This leads to chronic renal failure). Non enzymatic glycation also causes large vessel atherosclerosis, CAD, peripheral vascular occlusive disease, gangrene, which leads to limb loss and cerebrovascular disease. MI is the most common cause of death. Osmotic damage (sorbitol accumulation in organs with aldose reductase and decreased or absent sorbitol dehydrogenase) causes neuropathy (motor, sensory, and autonomic degeneration) and cataracts.
Diagnosis of diabetes mellitus
A fasting serum glucose level over 126 mg/dL (7.0 mmol/l) that is measured on two separate occasions, is diagnostic for DM. Fasting is defined as 8 hours without caloric intake. An oral glucose tolerance test measures postprandial plasma glucose levels, 2 hours following a 75-gram glucose bolus. Plasma glucose levels over 200 mg/dl (11.1 mmol/l) are diagnostic for DM. HbA1c is a measure of non-enzymatic glycation that occurs on the beta chain of the hemoglobin molecule upon exposure to glucose in the plasma. HbA1c ≥ 6.5% is part of the diagnostic criteria for DM. The goal for long term management of diabetes is to maintain HbA1c levels between 6-7%. In addition to the above tests, if a random plasma glucose (RPG) test measures 200 mg/dL or higher, and the patient is showing symptoms of diabetes (polyphagia, polydipsia, polyuria), diabetes may be diagnosed.
Type 1 diabetes mellitus
It is due to autoimmune destruction of beta cells. Insulin is always necessary in treatment. It often presents in those under the age of 30. It is not associated with obesity. Genetic predisposition is relatively weak (50% concordance in identical twins); it is also polygenic. It is associated with HLA-DR3 and DR4. Glucose intolerance is severe and insulin sensitivity is high. Ketoacidosis is common. There is a decrease in beta cell numbers in the islets. Serum insulin level is low. The classic symptoms of polydipsia, polyuria, polyphagia, weight loss is common. Histology will show Islet leukocytic infiltrate.
Type 2 diabetes mellitus
It is due to an increase in resistance to insulin, progressive pancreatic beta cell failure. Insulin is sometimes necessary in treatment. It often presents in those over the age of 40. It is associated with obesity. Genetic predisposition is relatively strong (90% concordance in identical twins); it is also polygenic. Glucose intolerance is mild to moderate and insulin sensitivity is low. Ketoacidosis is rare. There is a variable number of beta cell numbers in the islets with amyloid deposits. Serum insulin level is variable. The classic symptoms of polydipsia, polyuria, polyphagia, weight loss is sometimes seen. Histology will show Islet amyloid polypeptide (IAPP) deposits.
Diabetic ketoacidosis is a hyperglycemic crisis characterized by the presence of ketones and metabolic acidosis. DKA is a complication of diabetes mellitus (most commonly type 1). Physiologic stress (e.g., infection, intoxication, lack of medication) leads to increased blood glucose and therefore increased insulin demand. In the setting of severe insulin deficiency, as seen in type 1 diabetes, the increased glucose cannot be used as energy. As a result, lipolysis occurs, leading to increased circulating free fatty acids that eventually breakdown to ketones. In the setting of insulin deficiency, the free fatty acids undergo hepatic conversion into ketones (β-hydroxybutyrate, acetoacetate), which causes the ketonuria seen in DKA. The ketones are converted into ketoacids (β-hydroxybutyric acid, acetoacetic acid), which contributes to the metabolic acidosis seen in DKA.
Signs and symptoms of DKA
Patients classically present with abdominal pain, vomiting, fruity breath odor, and profound dehydration (even though they may not look like it). Acetoacetic acid is converted to acetone, which causes the fruity odor on the patient’s breath. Hyperglycemia leads to glucosuria, which causes osmotic diuresis and subsequent dehydration. Patients may even have mental status changes secondary to dehydration. Kussmaul respirations, which are rapid/deep breathing
Lab findings with diabetic ketoacidosis
Kussmaul respirations are a respiratory compensation for the metabolic acidosis in DKA. Carbonic acid in blood is converted to CO2, causing deep, rapid breathing in an attempt to expel the excess CO2. Diagnosis of DKA is based on elevated glucose (>300 mg/dL), anion gapped metabolic acidosis (bicarbonate 17), and urine strongly positive for glucose and ketones. Initial electrolyte panel commonly shows normal or high potassium and low sodium. Glucose and ketones in the blood pass into the urine, causing osmotic diuresis, (loss of water and electrolytes in the urine). Potassium moves from intracellular fluid to extracellular fluid to compensate for electrolyte loss, so patients with DKA, who actually have low total-body potassium stores, generally have normal or high potassium on labs. When potassium moves from intracellular fluid to extracellular fluid, water follows. Sodium gets diluted out by the increased water, so patients with DKA, who actually have normal total-body sodium stores, generally have low sodium on labs.
Complications with diabetic ketoacidosis
life threatening mucormycosis (usually caused by Rhizopus infection), cerebral edema, cardia arrhythmias, and heart failure.
Treatment of diabetic ketoacidosis
Treatment of DKA includes normal saline, potassium, insulin, glucose (to prevent hypoglycemia). Treatment of the precipitating event as appropriate is also necessary.
A tumor of pancreatic alpha cells leading to an overproduction of glucagon. It presents with dermatitis (necrolytic migratory erythema), diabetes (hyperglycemia), DVT, an depression (four D's).
Tumor of pancreatic beta cells leads to an overproduction of insulin, which causes hypoglycemia. The Whipple triad, low blood glucose, symptoms of hypoglycemia (eg lethargy, syncope, diplopia), and resolution of symptoms after normalization of glucose levels, may be present. Symptomatic patients have a decrease in blood glucose and an increase in C-peptide levels (vs exogenous insulin use). Treatment is surgical resection.
An ileal carcinoid tumor is the most common malignancy of the small intestine, and the most common cause of carcinoid syndrome (occurs in less that 10% of patients). Carcinoid tumors are comprised of neuroendocrine cells, which produce serotonin (5-HT). Carcinoid syndrome is strongly associated with metastatic disease, in order to avoid first pass by the liver. The rule of 1/3s for carcinoid syndrome states that: 1/3 metastasize, 1/3 present with a 2nd malignancy, 1/3 are multiple.
Symptoms and diagnosis of carcinoid syndrome
Symptoms of carcinoid syndrome include: Flushing of the skin, Secretory (watery, voluminous) diarrhea, Abdominal cramps with nausea and vomiting, Wheezing, caused by bronchoconstriction and/or bronchospasm, Tricuspid insufficiency or pulmonic valve stenosis (TIPS). Carcinoid heart disease is characterized by pathognomonic plaque-like deposits of fibrous tissue, commonly on the endocardium of valvular cusps and leaflets. The right side of the heart is affected because the lungs (like the liver) contain MAO, which inactivates humoral substances before they are returned to the left heart. Diagnosis of carcinoid syndrome is made by increased urinary secretion of 5-hydroxyindoleacetic acid (5-HIAA), a degradation product of serotonin.
Treatment of carcinoid syndrome
Carcinoid syndrome is treated with octreotide, a somatostatin analogue that, among other things, inhibits the release of serotonin. Surgical resection and chemotherapy with 5-fluorouracil and doxorubicin are other treatment options. Niacin (B3) may be deficient in carcinoid syndrome as a result of increased tryptophan metabolism into serotonin. Tryptophan is a common precursor to both serotonin and niacin.
Zollinger Ellison syndrome
Zollinger Ellison Syndrome (ZES) is caused by gastrin-secreting tumors (gastrinoma) that are most commonly found in the pancreas or the small intestine near the pancreas (e.g. duodenum). Excess production of HCl will cause recalcitrant gastric ulcers, duodenal ulcers, and chronic watery diarrhea. Other symptoms of ZES include epigastric pain, steatorrhea, and vomiting. Gastrin activates stomach parietal cells (which secrete HCl) and enterochromaffin-like cells (which secrete histamine). A positive secretin stimulation test indicates that gastrin levels remain elevated after the administration of secretin (normally inhibits gastrin release). ZES is associated with Multiple Endocrine Neoplasia 1 (MEN-1).
Multiple endocrine neoplasias (MEN)
Multiple endocrine neoplasias (MEN) are a group of genetically inherited diseases that result in proliferative lesions of multiple endocrine organs. All three MEN syndromes are associated with autosomal dominant inheritance.
MEN-1, aka Wermer syndrome, is characterized by abnormalities involving the parathyroid, pancreas and pituitary. The involvement of these endocrine organs can be remembered as the "3 Ps" or the mnemonic “Para-Pan-Pit”: The most common parathyroid manifestation of MEN-1 is primary hyperparathyroidism. Parathyroid abnormalities include hyperplasia (monocolonal) and adenomas. Pancreatic endocrine tumors include gastrinomas and insulinomas. Pituitary adenomas are most frequently prolactinomas, although some patients develop growth hormone-secreting tumors. MEN-1 syndrome is caused by mutations in the MEN-1 tumor suppressor gene, which encodes a poorly-understood product called menin, involved in transcription regulation. This gene is found on chromosome 11.
MEN-2A, or Sipple syndrome, is characterized by medullary carcinoma, pheochromocytoma, and hyperplasia of the parathyroid glands. These can be remembered using the mnemonic “MPH”. Medullary thyroid carcinomas are seen in almost 100% of patients. Pheochromocytomas in patients with MEN-2A are often bilateral, and occur in 40-50% of patients. Hyperplasia of parathyroid, with evidence of hypercalcemia or renal stones, occurs in 10-20% of patients. MEN-2A has been linked to mutations in the RET proto-oncogene, which encodes a receptor tyrosine kinase. This proto-oncogene is found on chromosome 10.
MEN-2B has significant clinical overlap with MEN-2A (medullary thyroid carcinoma and pheochromocytoma), but is accompanied by neuromas and a marfanoid habitus. Medullary thyroid carcinomas are typically multifocal and more aggressive than those found in MEN-2A. Multiple neuromas (neoplasias of nerve tissue) of the skin and mucosa, called oral and intestinal ganglioneuromatosis, accompany MEN-2B. A marfanoid habitus is seen in MEN-2B. MEN-2B is associated with a single amino acid change in the RET proto-oncogene, affecting a critical region of the tyrosine kinase catalytic domain. This is distinct from the mutations seen in MEN-2A.
Treatment strategies for diabetes mellitus
For type 1 DM, low carbohydrate diet and insulin replacement. For type 2 DM, dietary modification and exercise for weight loss, oral agents, non insulin injectables, and insulin replacement. For gestational DM, dietary modifications, exercise, insulin replacement if lifestyle modification fails.
Rapid acting insulin
Rapid acting insulin
Rapid acting insulin
Rapid acting insulin
Rapid-acting insulins have a rapid onset and an early peak of activity, permitting control of postprandial glucose. Examples of rapid-acting insulins include: Insulin lispro, Insulin aspart, Insulin glulisine. To remember the rapid-acting insulins, use the mnemonic, "there's no LAG with rapid-acting insulins". The onset of rapid-acting insulin is 15 minutes. Its peak effect is 30-90 minutes after administration, and its duration is between 3-5 hours.
Short acting insulin
Short-acting insulin is the same as the normal insulin secreted in our bodies. Short-acting insulin is different from rapid-acting insulin, such as glulisine, lispro and aspart. Short-acting insulin has an onset of 30 to 60 minutes. Its peak effect is 2-4 hours after administration, and it has a duration of 5-8 hours. In addition to prophylactic/ maintenance therapy of types 1 and 2 DM, short-acting (regular) insulin is also used to treat: Diabetic ketoacidosis (administered intravenously), Hyperkalemia (administered with glucose to prevent hypokalemia), Stress hyperglycemia
Intermediate acting insulin
An example of intermediate-acting insulin is NPH. NPH is often combined with rapid-acting and short-acting (regular) insulin. NPH has an onset of 1-3 hours, and a peak effect at 8 hours. Intermediate-acting insulin has a duration of 12-16 hours.
Long acting insulin
Long acting insulin
Long-acting insulins include insulin glargine and insulin detemir. These insulins are used to help control basal levels of glucose. In other words, long-acting insulins ensure a small amount of insulin is in the blood stream to assist in the movement of glucose into cells around the clock. Long-acting insulins all have an onset of 1 hour, and a duration of 20-26 hours (glargine has a longer duration than detemir). Note that long-acting insulins are "peakless".
oral antidiabetic agents
There are nine major classes of oral antidiabetic agents, which can be remembered with the mnemonic STαB Mellitus with DAGS: Sulfonylureas, Thiazolidinediones, α-glucosidase inhibitors, Biguanides, Meglitinides, Dipeptidyl peptidase-4 (DPP-4) inhibitors , Amylin analogues, Glucagon-like polypeptide-1 (GLP-1) analogs (subcutaneous administration), SGLT-2 inhibitors.
Sulfonylureas (chlorpropamide, tolbutamide, glyburide, glipizide) increase insulin secretion by closure of ATP-gated K+ channel in the pancreatic β-cell membrane. Remember that GLUT-2 transporters bring glucose into pancreatic β-cells, where it is metabolized to produce ATP via aerobic respiration. The rise in ATP closes ATP-gated K+ channels. When K+ channels are closed, the cell depolarizes causing voltage-gated Ca2+ channels to open. This release of Ca2+ triggers the release of insulin. There are two generations of sulfonylureas. First generation sulfonylureas have longer half-lives and include chlorpropamide and tolbutamide. Second generation sulfonylureas are more potent and have shorter half-lives. They include glyburide (the dose of which must be decreased with renal failure) and glipizide (the dose of which must be decreased with liver failure). It is first line therapy in type 2 DM.
Overadministration of sulfonylureas can lead to hypoglycemia, the risk of which is increased in renal failure. Additionally, first generation sulfonylureas can have disulfiram-like effects (ethanol intolerance). Second generation can cause hypoglycemia.
First generation sulfonylureas
First generation sulfonylureas
Second generation sulfonylureas
Second generation sulfonylureas
Second generation sulfonylureas
Thiazolidinediones (rosiglitazone, pioglitazone) improve insulin sensitivity in peripheral tissues. These agents bind to PPAR-γ (peroxisome proliferator activating receptor-gamma), causing increased insulin receptor number and sensitivity, as well as decreased hepatic gluconeogenesis. Activation of PPARγ by thiazolidinediones induces adipocyte hyperplasia, which in turn: Promotes the uptake of serum fatty acids into new adipocytes and shifts the balance of lipid stores from extra-adipose to adipose tissue. These responses increase tissue sensitivity to insulin. Commonly used thiazolidinedione medications include rosiglitazone and pioglitazone.
Side effects of thiazolidinediones
Side effects of thiazolidinediones include hepatotoxicity and cardiovascular toxicity, with absolute contraindication in patients with liver failure or CHF. Additionally, they can cause weight gain, edema, and increased risk of fractures.
α-glucosidase inhibitors (acarbose, miglitol) prevent disaccharides in the gut from their final degradation into monosaccharides by brush border enzymes, prior to absorption. This class of drugs is poorly tolerated by patients. In effect, they are simulating a disaccharidase deficiency (e.g. lactose intolerance), causing osmotic diarrhea and presenting more sugars to the colonic flora. The colonic flora digests these sugars, releasing gas and causing flatulence. Two commonly used α-glucosidase inhibitors are acarbose and miglitol.
Biguanides (metformin) repress hepatic gluconeogenesis and increase peripheral insulin sensitivity and utilization of glucose. (Although unclear, the proposed mechanism of biguanides (metformin) is that they activate AMP-activated protein kinase (AMPK), which increase expression of a small heterodimer partner (SHP). SHP inhibits expression of liver phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase, thus repressing hepatic gluconeogenesis). Metformin is the most important example of a biguanide, and is the first line agent for T2DM.
Side effects of biguanides
Side effects of metformin include: GI distress (e.g., diarrhea), Weight loss, Lactic acidosis (rare, but has a 50% mortality when it occurs; most commonly seen in patients with underlying renal disease).
Meglitinides (repaglinide, nateglinide) increase insulin secretion, and thus are also known as non-sulfonylurea secretagogues. The major side effect of meglitinides is hypoglycemia (just like sulfonylureas). Two important meglitinides are repaglinide and nateglinide.
Dipeptidyl peptidase-4 (DPP-4) inhibitors
Dipeptidyl peptidase-4 (DPP-4) inhibitors (sitagliptin, saxagliptin, and linagliptin) inhibit the degradation of incretins by DPP-4. This increases insulin and decreases glucagon. Toxicities include mild urinary or respiratory infections.
Incretins include glucagon-like peptide (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). The role of GLP-1 and GIP (increased by DPP-4 inhibitors) is to increase insulin and decrease glucagon levels.
Dipeptidyl peptidase-4 (DPP-4) inhibitors
Dipeptidyl peptidase-4 (DPP-4) inhibitors
Dipeptidyl peptidase-4 (DPP-4) inhibitors
Amylin analogues (pramlintide) slow gastric emptying and suppress glucagon release, thus helping to regulate postprandial blood glucose. Amylin also suppresses appetite. Side effects include hypoglycemia, nausea, diarrhea.
Glucagon-like polypeptide 1 (GLP-1) analogs
Glucagon-like polypeptide 1 (GLP-1) analogs (exenatide, liraglutide) increase insulin and decrease glucagon release. Excess hepatic glucose output is often seen in diabetes due to the suppression of GLP-1 release. Toxicities include nausea, vomiting and pancreatitis.
SGLT-2 inhibitors (canagliflozin, dapagliflozin) block the reabsorption of glucose in the proximal convoluted tubule by inhibiting the SGLT-2 sodium-glucose cotransporter (responsible for ~90% of glucose absorption in the nephron). Side effects of SGLT-2 inhibitors include glucosuria and increased incidence of UTIs and vaginal yeast infections.
Blocks thyroid peroxidase, inhibiting the oxidation of iodide and the organification (coupling) of iodine, thus inhibiting thyroid hormone synthesis. Propluthiouracil also blocks 5' deiodanase leading to a decrease in T3 and T4. Clinical use is for hyperthyroidism. PTU blocks Peripheral conversion, used in pregnancy. Toxicities include skin rash, agranulocytosis (rare), aplastic anemia, hepatoxicity.
Blocks thyroid peroxidase, inhibiting the oxidation of iodide and the organification (coupling) of iodine, thus inhibiting thyroid hormone synthesis. Clinical use is for hyperthyroidism. Toxicities include skin rash, agranulocytosis (rare), aplastic anemia. Methimazole is a possible teratogen (can cause aplasia cutis).
Levothyroxine (T4) and triiodothyronine (T3)
It is a thyroid hormone analog. It is used to treat hypothyroidism and myxedema. It is used off label as a weight loss supplement. Toxicities include tachycardia, heat tolerance, tremors, arrhythmia.
An ADH antagonist. It is used to treat SIADH by blocking the action of ADH at V2 receptor.
An ADH antagonist. It is used to treat SIADH by blocking the action of ADH at V2 receptor.
Used to treat central (not nephrogenic) DI.
Used to treat GH deficiency and Turner syndrome
It is used to stimulate labor, uterine contractions, milk let down. It is also used to control uterine hemorrhage.
It is used to treat acromegaly, carcinoid syndrome, gastrinoma, glucagonoma, esophageal varices.
It is an ADH antagonist (member of tetracycline family). It is used to treat SIADH. Toxicities include nephrogenic DI, photosensitivity, abnormalities of bone and teeth.
Fludrocortisone is the only widely used synthetic mineralocorticoid (although it also has glucocorticoid activity). It is predominantly used clinically as an aldosterone replacement.
Mechanism of glucocorticoids
The metabolic, catabolic, anti inflammatory, and immunosuppressive effects are mediated by the interactions with glucocorticoid response elements, inhibition of phospholipase A2, and inhibition of transcription factors such as NF-kB.
Clinical uses of glucocorticoids
It is used to treat Addison disease, inflammation, immunosuppression, and asthma.
Side effects of glucocorticoids
Taken in total, the long-term side effects of corticosteroid therapy can lead to or exacerbate metabolic syndrome, which describes the constellation of: Elevated fasting glucose, Dyslipidemia (elevated fasting triglycerides and/or decreased HDL cholesterol), Central obesity, Hypertension. Cortisol is a catabolic hormone, increasing nutrient breakdown. Glucocorticoid therapy may lead to increased plasma levels of: Glucose (diabetogenic), Fatty acids, Ketones, Blood urea nitrogen (BUN). The catabolic effects of cortisol can also lead to the redistribution of body mass. The “Cushingoid” appearance includes: Moon facies (rounded face due to fatty deposition), Buffalo hump (fatty tissue deposition between the shoulders, also called dorsocervical fat pad), Central obesity (fat deposited around abdomen), Abdominal striae (due to inhibition of fibroblast activity by cortisol). Synthetic corticosteroids have varying degrees of mineralocorticoid cross reactivity, which leads to water retention and hypertension. Glucocorticoids cause a neutrophilic leukocytosis on CBC due to the fact that they facilitate the demargination of neutrophils (loss of adhesion to vessel walls).