First_Aid_for_the_USMLE_Step_1_2023_Compressed_-1-450

["330 SEC TION III Endocrine\u2003 \uf07d\u2009endocrine\u2014Embryology ` \u2009ENDOCRINE \u2014 EMBRYOLOGY Thyroid development Thyroid diverticulum arises from floor of primitive pharynx and descends into neck. Connected to A tongue by thyroglossal duct, which normally disappears but may persist as cysts or the pyramidal lobe of thyroid. Foramen cecum is normal remnant of thyroglossal duct. Most common ectopic thyroid tissue site is the tongue (lingual thyroid). Removal may result in hypothyroidism if it is the only thyroid tissue present. Thyroglossal duct cyst A presents as an anterior midline neck mass that moves with swallowing or protrusion of the tongue (vs persistent cervical sinus leading to pharyngeal cleft cyst in lateral neck). Thyroid follicular cells derived from endoderm. Parafollicular cells arise from 4th pharyngeal pouch. Foramen cecum Internal carotid artery Hyoid bone External carotid artery Superior thyroid artery Thyrohyoid membrane Inferior thyroid artery Thyroglossal duct Thyroid cartilage Thyrocervical trunk Left subclavian artery Thyroid Trachea Brachiocephalic artery","Endocrine\u2003 \uf07d\u2009endocrine\u2014Anatomy SEC TION III 331 ` \u2009ENDOCRINE \u2014 A N ATOMY Pituitary gland Secretes FSH, LH, ACTH, TSH, prolactin, Proopiomelanocortin derivatives\u2014\u03b2-endorphin, Anterior pituitary GH, and \u03b2-endorphin. Melanotropin (MSH) ACTH, and MSH. Go pro with a BAM! (adenohypophysis) secreted from intermediate lobe of pituitary. Derived from oral ectoderm (Rathke pouch). FLAT PiG: FSH, LH, ACTH, TSH, PRL, GH. Posterior pituitary \u0083\t \u03b1 subunit\u2014hormone subunit common to B-FLAT: Basophils\u2014FSH, LH, ACTH, TSH. (neurohypophysis) TSH, LH, FSH, and hCG. Acid PiG: Acidophils \u2014 PRL, GH. \u0083\t \u03b2 subunit\u2014determines hormone specificity. Stores and releases vasopressin (antidiuretic hormone, or ADH) and oxytocin, both made in the hypothalamus (supraoptic and paraventricular nuclei) and transported to posterior pituitary via neurophysins (carrier proteins). Derived from neuroectoderm. Adrenal cortex and Adrenal cortex (derived from mesoderm) and medulla (derived from neural crest). medulla HISTOLOGY 1\u00b0 REGULATION BY HORMONE 1\u00b0 HORMONE ANATOMY Zona Glomerulosa CLASS PRODUCED Adrenal gland Angiotensin II Mineralocorticoids Aldosterone CORTEX Zona Fasciculata ACTH, CRH Glucocorticoids Cortisol Capsule Superior surface MEDULLA Zona Reticularis ACTH, CRH Androgens DHEA of kidney Chroma n cells Catecholamines Epi, NE Preganglionic sympathetic \ufb01bers GFR corresponds with salt (mineralocorticoids), sugar (glucocorticoids), and sex (androgens). Endocrine pancreas Islets of Langerhans are collections of \u03b1, \u03b2, and Capillary cell types \u03b4 endocrine cells. Islets arise from pancreatic \u02dc cell buds. \u00b0 cell \u03b1 = gluc\u03b1gon (peripheral) \u02db cell \u03b2 = insulin (central) \u03b4 = somatostatin (interspersed) uploaded by medbooksvn","332 SEC TION III Endocrine\u2003 \uf07d\u2009endocrine\u2014physiology ` \u2009ENDOCRINE \u2014 PHYSIOLOGY Hypothalamic-pituitary hormones HORMONE FUNCTION CLINICAL NOTES ADH \u008f water permeability of distal convoluted tubule Alcohol consumption \u008e \u0090 ADH secretion and collecting duct cells in kidney to \u008f water \u008e\u00a0polyuria and dehydration reabsorption \u0090 in chronic glucocorticoid use CRH \u008f ACTH, \u008f MSH, \u008f \u03b2-endorphin Dopamine \u0090 prolactin, \u0090 TSH Also called prolactin-inhibiting factor Dopamine antagonists (eg, antipsychotics) can GHRH \u008f GH GnRH \u008f FSH, \u008f LH cause galactorrhea due to hyperprolactinemia MSH \u008f\u00a0melanogenesis by melanocytes Analog (tesamorelin) used to treat Oxytocin HIV\u2011associated lipodystrophy Prolactin Causes uterine contractions during labor. Responsible for milk letdown reflex in response Suppressed by hyperprolactinemia Tonic GnRH analog (eg, leuprolide) suppresses to suckling. \u0090 GnRH hypothalamic\u2013pituitary\u2013gonadal axis. Stimulates lactogenesis. Pulsatile GnRH leads to puberty, fertility Somatostatin \u0090 GH, \u0090 TSH Causes hyperpigmentation in Cushing disease, TRH \u008f TSH, \u008f prolactin as MSH and ACTH share the same precursor molecule, proopiomelanocortin Modulates fear, anxiety, social bonding, mood, and depression Pituitary prolactinoma \u008e amenorrhea, osteoporosis, hypogonadism, galactorrhea Breastfeeding \u008e \u008f prolactin \u008e \u0090 GnRH \u008e\u00a0delayed postpartum ovulation (natural contraception) Also called growth hormone inhibiting hormone (GHIH) \u008f\u00a0TRH (eg, in 1\u00b0\/2\u00b0 hypothyroidism) may increase prolactin secretion \u008e\u00a0galactorrhea Hypothalamus CRH GnRH TRH GHRH DA Anterior ACTH LH FSH TSH GH Prolactin pituitary Acidophils (eosinophilic) Basophils (basophilic) Somatostatin","Endocrine\u2003 \uf07d\u2009endocrine\u2014physiology SEC TION III 333 Growth hormone GHRH Aging, obesity, Also called somatotropin. Secreted by anterior Somatostatin hyperglycemia pituitary. Sleep, hypoglycemia, stress, puberty, exercise Stimulates linear growth and muscle mass through IGF-1 (somatomedin C) secretion by Anterior Posterior liver. \u008f\u00ad insulin resistance (diabetogenic). pituitary pituitary Released in pulses in response to growth Growth hormone\u2013releasing hormone (GHRH). hormone Secretion \u008f during sleep, hypoglycemia, stress, puberty, exercise. Secretion \u0090 with aging, obesity, hyperglycemia, somatostatin, somatomedin (regulatory molecule secreted by liver in response to GH acting on target tissues). Excess secretion of GH (eg, pituitary adenoma) may cause acromegaly (adults) or gigantism (children). Treatment: somatostatin analogs (eg, octreotide) or surgery. Amino acid uptake IGF-1 Amino acid uptake Glucose uptake Protein synthesis Protein synthesis Lipolysis DNA and RNA synthesis Chondroitin sulfate Collagen Cell size and number Antidiuretic hormone Also called vasopressin. ADH level is \u0090 in central diabetes insipidus\u00a0(DI), Synthesized in hypothalamus (supraoptic and normal or \u008f in nephrogenic DI. SOURCE FUNCTION paraventricular nuclei), stored and secreted by Nephrogenic DI can be caused by mutation in posterior pituitary. V2-receptor. REGULATION Regulates b1ood pressure (V1-receptors) and serum osmolality (V2-receptors). Primary Desmopressin (ADH analog) is a treatment for function is serum osmolality regulation (ADH central DI and nocturnal enuresis. \u0090 serum osmolality, \u008f urine osmolality) via regulation of aquaporin channel insertion in Vasopressin is also a potent vasopressor that can principal cells of renal collecting duct. be used to increase organ perfusion in septic shock. Plasma osmolality (1\u00b0); hypovolemia. uploaded by medbooksvn","334 SEC TION III Endocrine\u2003 \uf07d\u2009endocrine\u2014physiology Prolactin Secreted mainly by anterior pituitary. Structurally homologous to growth hormone. Excessive amounts of prolactin associated with SOURCE Stimulates milk production in breast; inhibits FUNCTION ovulation in females and spermatogenesis \u0090\u00a0libido. in males by inhibiting GnRH synthesis and REGULATION release. Dopamine agonists (eg, bromocriptine, cabergoline) inhibit prolactin secretion and Prolactin secretion from anterior pituitary can be used in treatment of prolactinoma. is tonically inhibited by dopamine from tuberoinfundibular pathway of hypothalamus. Dopamine antagonists (eg, most antipsychotics, Prolactin in turn inhibits its own secretion metoclopramide) and estrogens (eg, OCPs, by \u008f dopamine synthesis and secretion from pregnancy) stimulate prolactin secretion. hypothalamus. TRH \u008f\u00a0prolactin secretion (eg, in 1\u00b0 or 2\u00b0 hypothyroidism). Dopamine has stronger effect on prolactin regulation than TRH does. Sight\/cry of baby Higher cortical centers Hypothalamus Medications Dopamine TRH 1\u00b0\/2\u00b0 hypothyroidism Chest wall injury (via ANS) Nipple stimulation Anterior Posterior pituitary pituitary Reduced prolactin Prolactin Estrogen Pregnancy elimination GnRH FSH Renal failure Ovulation Spermatogenesis LH Milk production","Endocrine\u2003 \uf07d\u2009endocrine\u2014physiology SEC TION III 335 Thyroid hormones Thyroid produces triiodothyronine (T3) and thyroxine (T4), iodine-containing hormones that control the body\u2019s metabolic rate. SOURCE Follicles of thyroid. 5\u2032-deiodinase converts T4 (the major thyroid product) to T3 in peripheral tissue (5, FUNCTION 4, 3). Peripheral conversion is inhibited by glucocorticoids, \u03b2-blockers, and propylthiouracil (PTU). Reverse T3 (rT3) is a metabolically inactive byproduct of the peripheral conversion of T4 and its REGULATION production is increased by growth hormone and glucocorticoids. Functions of thyroid peroxidase include oxidation, organification of iodine, and coupling of monoiodotyrosine (MIT) and diiodotyrosine (DIT). Inhibited by PTU and methimazole. DIT + DIT = T4. DIT + MIT\u00a0= T3. Wolff-Chaikoff effect\u2014protective autoregulation; sudden exposure to excess iodine temporarily turns off thyroid peroxidase \u008e\u00a0\u0090\u00a0T3\/T4 production. Only free hormone is active. T3 binds nuclear receptor with greater affinity than T4. T3 functions \u20147 B\u2019s: \u0083\t Brain maturation \u0083\t Bone growth (synergism with GH and IGF-1) \u0083\t \u03b2-adrenergic effects. \u008f\u00a0\u03b21 receptors in heart \u008e\u00a0\u008f\u00a0CO, HR, SV, contractility; \u03b2-blockers alleviate adrenergic symptoms in thyrotoxicosis \u0083\t Basal metabolic rate \u008f\u00a0(via \u008f\u00a0Na+\/K+-ATPase \u008e\u00a0\u008f\u00a0O2 consumption, RR, body temperature) \u0083\t Blood sugar (\u008f\u00a0glycogenolysis, gluconeogenesis) \u0083\t Break down lipids (\u008f\u00a0lipolysis) \u0083\t Stimulates surfactant synthesis in Babies TRH \u008e\u00a0\u2295 TSH release \u008e\u00a0\u2295 follicular cells. Thyroid-stimulating immunoglobulin (TSI) may \u2295 follicular cells in Graves disease. Negative feedback primarily by free T3\/T4: \u0083\t Anterior pituitary \u008e\u00a0\u0090\u00a0sensitivity to TRH \u0083\t Hypothalamus \u008e\u00a0\u0090\u00a0TRH secretion Thyroxine-binding globulin (TBG) binds most T3\/T4 in blood. Bound T3\/T4 = inactive. \u0083\t \u008f\u00a0TBG in pregnancy, OCP use (estrogen \u008e\u00a0\u008f\u00a0TBG) \u008e\u00a0\u008f total T3\/T4 \u0083\t \u0090\u00a0TBG in steroid use, nephrotic syndrome T3 and T4 are the only lipophilic hormones with charged amino acids and require specific transporters to diffuse into the cell (facilitated diffusion). Follicular lumen Thyroid follicular epithelial cell Blood E ector organs Hypothalamus TG + I\u2082 TG I- Downstream thyroid I- Na+ function Thyroid Organi\ufb01cation, T\u2083 Anterior peroxidase coupling pituitary TG Endocytosis TG Proteases T\u2083 << T\u2084 T\u2083 TSI (to circulation) T\u2084 rT\u2083 Thyroid gland (follicular cells) 5\u2019-deiodinase T\u2083 T\u2084 E ector organs uploaded by medbooksvn","336 SEC TION III Endocrine\u2003 \uf07d\u2009endocrine\u2014physiology Parathyroid hormone Chief cells of parathyroid PTH \u008f serum Ca2+, \u0090 serum PO43\u2013, \u008f urine \u008f\u00a0free Ca2+ in the blood (1\u00b0 function) PO43\u2013 , \u008f\u00a0urine cAMP SOURCE \u008f\u00a0Ca2+ and PO43\u2013 absorption in GI system FUNCTION \u008f\u00a0Ca2+ and PO43\u2013 from bone resorption \u008f\u00a0RANK-L (receptor activator of NF-\u03baB ligand) \u008f\u00a0Ca2+ reabsorption from DCT secreted by osteoblasts and osteocytes; binds REGULATION \u0090 PO43\u2013 reabsorption in PCT RANK (receptor) on osteoclasts and their \u008f\u00a01,25-(OH)2D3 (calcitriol) production by precursors to stimulate osteoclasts and \u008f\u00a0Ca2+ \u008e\u00a0bone resorption (intermittent PTH release activating 1\u03b1-hydroxylase in PCT (tri to make can also stimulate bone formation) D3 in the PCT) PTH = Phosphate-Trashing Hormone \u0090 serum Ca2+ \u008e \u008f PTH secretion PTH-related peptide (PTHrP) functions \u008f serum PO43\u2212 \u008e \u008f PTH secretion \u0090 serum Mg2+ \u008e \u008f PTH secretion like PTH and is commonly increased in \u0090\u0090 serum Mg2+ \u008e \u0090 PTH secretion malignancies (eg, squamous cell carcinoma of Common causes of \u0090 Mg2+ include diarrhea, the lung, renal cell carcinoma) aminoglycosides, diuretics, alcohol use Ca2+ is the major regulator of PTH release disorder PTH activity \u2193 ionized Ca2+, \u2191 PO43\u2013 , or 1,25-(OH)2 D3 \u2191 Feedback Four \u2191 Vitamin D activity \u2191 PO43\u2013 inhibition para- 25-OH D3 of PTH thyroid \u2191 synthesis glands 1\u03b1-hydroxylase \u2191 1,25-(OH)2 D3 \u2191 1,25-(OH)2 D3 PTH released Bone Intestines into circulation Renal tubular cells \u2191 1,25-(OH)2 D3 synthesis re\u2191leCaas2e+danfrdo\u2191mPbOo43n\u2013e \u2191 absorption of Reabsorption: \u2191 Ca2+, PO43\u2013 Ca2+ and PO43\u2013 Urine Ca2+, \u2191 PO43\u2013 \u2191 Ca2+ and \u2191 PO43\u2013 \u2191 Ca2+ and PO43\u2013","Endocrine\u2003 \uf07d\u2009endocrine\u2014physiology SEC TION III 337 Calcium homeostasis Plasma Ca2+ exists in three forms: Ca2+ competes with H+ to bind to albumin \u0083\t Ionized\/free (~ 45%, active form) \u0083\t Bound to albumin (\u223c 40%) \u008f pH (less H+) \u008e albumin binds more \u0083\t Bound to anions (\u223c 15%) Ca2+ \u008e\u00a0\u0090\u00a0ionized Ca2+ (eg, cramps, pain, Ionized\/free Ca2+ is 1\u00b0 regulator of PTH; paresthesias, carpopedal spasm) \u008e\u00a0\u008f\u00a0PTH changes in pH alter PTH secretion, whereas \uf090 pH (more H+) \u008e\u00a0albumin binds less Ca2+ changes in albumin concentration do not \u008e\u00a0\u008f\u00a0ionized Ca2+ \u008e\u00a0\uf090 PTH Calcitonin Parafollicular cells (C cells) of thyroid. Calcitonin opposes actions of PTH. Not \u0090 bone resorption. important in normal Ca2+ homeostasis SOURCE \u008f serum Ca2+ \u008e\u00a0\u008f\u00a0calcitonin secretion. FUNCTION Calcitonin tones down serum Ca2+ levels and REGULATION Parafollicular cells (C cells) of thyroid keeps it in bones Ca2+ serum Ca2+ Ca2+ Peripheral blood Ca2+ calcitonin Osteoclast Decreased resorption Calcitonin lowers serum Ca2+ by inhibiting osteoclastic bone resorption Glucagon Made by \u03b1 cells of pancreas. SOURCE Promotes glycogenolysis, gluconeogenesis, lipolysis, ketogenesis. Elevates blood sugar levels to FUNCTION maintain homeostasis when bloodstream glucose levels fall too low (ie, fasting state). REGULATION Secreted in response to hypoglycemia. Inhibited by insulin, amylin, somatostatin, hyperglycemia. uploaded by medbooksvn","338 SEC TION III Endocrine\u2003 \uf07d\u2009endocrine\u2014physiology Insulin Preproinsulin (synthesized in RER of pancreatic \u03b2 cells) \u008e\u00a0cleavage of \u201cpresignal\u201d \u008e\u00a0proinsulin (stored in secretory granules) \u008e\u00a0cleavage of proinsulin \u008e\u00a0exocytosis of insulin and C-peptide SYNTHESIS equally. Both insulin and C-peptide are \u008f in endogenous insulin secretion (eg, type 2 DM, insulin SS secretagogues, insulinoma), whereas exogenous insulin lacks C-peptide. Insulin C-peptide Insulin is synthesized in pancreas and cleared by both liver and kidneys. Proinsulin Binds insulin receptors (tyrosine kinase Insulin-dependent glucose transporters: FUNCTION activity ), inducing glucose uptake (carrier- \u0083\t GLUT4: adipose tissue, striated muscle mediated transport) into insulin-dependent (exercise can also \u008f\u00a0GLUT4 expression) REGULATION tissue and gene transcription. Insulin-independent transporters: Anabolic effects of insulin: \u0083\t GLUT1: RBCs, brain, cornea, placenta \u0083\t \u008f glucose transport in skeletal muscle and \u0083\t GLUT2 (bidirectional): \u03b2 islet cells, liver, adipose tissue kidney, GI tract (think 2-way street) \u0083\t \u008f glycogen synthesis and storage \u0083\t GLUT3: brain, placenta \u0083\t \u008f triglyceride synthesis \u0083\t GLUT5 (fructose): spermatocytes, GI tract \u0083\t \u008f Na+ retention (kidneys) \u0083\t SGLT1\/SGLT2 (Na+-glucose cotransporters): \u0083\t \u008f protein synthesis (muscles) kidney, small intestine \u0083\t \u008f cellular uptake of K+ and amino acids \u0083\t \u0090 glucagon release Brain prefers glucose, but may use ketone bodies \u0083\t \u0090 lipolysis in adipose tissue during starvation. RBCs utilize only glucose, as they lack mitochondria for aerobic metabolism. Unlike glucose, insulin does not cross placenta. In mothers with diabetes, excess glucose can BRICK LIPS (insulin-independent glucose cross placenta and \u008f\u008f\u00a0fetal insulin. uptake): Brain, RBCs, Intestine, Cornea, Kidney, Liver, Islet (\u03b2) cells, Placenta, Spermatocytes. Glucose is the major regulator of insulin release. \u008f\u00a0insulin response with oral vs IV glucose due to incretins (eg, glucagonlike peptide 1 [GLP-1], glucose-dependent insulinotropic polypeptide [GIP]), which are released after meals and \u008f\u00a0\u03b2 cell sensitivity to glucose. Release \u0090\u00a0 by \u03b12, \u008f\u00a0by \u03b22 stimulation (2 = regulates insulin). Glucose enters \u03b2 cells \u008e \u008f ATP generated from glucose metabolism closes K+ channels (target of sulfonylureas) and depolarizes \u03b2 cell membrane . Voltage-gated Ca2+ channels open \u008e\u00a0Ca2+ influx and stimulation of insulin exocytosis . Insulin ATP-sensitive K+ Voltage-gated K+ channels close Ca2+ channels Tyrosine Depolarization open phosphorylation ATP Intracellular Insulin Vesicles Cell growth, Ca2+ containing DNA Exocytosis GLUT4 synthesis of insulin granules Glucose Glycogen, Glucose ATP\/ADP ratio GLUT4 lipid, protein GLUT2 Glycolysis Glucose synthesis Blood vessel Insulin-dependent glucose uptake Insulin secretion by pancreatic cells","Endocrine\u2003 \uf07d\u2009endocrine\u2014physiology SEC TION III 339 Adrenal steroids and congenital adrenal hyperplasias ACTH Cholesterol (via StARa) Ketoconazole, Anastrozole, spironolactone, abiraterone letrozole, exemestane Cholesterol desmolase 3\u03b2-hydroxysteroid Pregnenolone 17\u03b1-hydroxylase A 17-hydroxypregnenolone 17,20-lyase Dehydroepiandrosterone (DHEA) dehydrogenase Progesterone 17\u03b1-hydroxylase 17-hydroxyprogesterone 17,20-lyase Androstenedione Aromatase Estrone B 21-hydroxylation 11-deoxycorticosterone 11-deoxycortisol Testosterone Aromatase Estradiol C 11\u03b2-hydroxylation Metyrapone Cortisol Corticosterone 5\u03b1-reductase Dihydrotestosterone Glycyrrhetinic acid (DHT) Aldosterone synthase Angiotensin II Aldosterone Cortisone Finasteride Estrogens, DHT ZONA GLOMERULOSA ZONA FASCICULATA ZONA RETICULARIS Mineralocorticoids Glucocorticoids Androgens Adrenal cortex Peripheral tissue aRate-limiting step. ENZYME DEFICIENCY MINERALO\u00adCORTICOIDS [K+] BP CORTISOL SEX LABS PRESENTATION HORMONES \u000717\u03b1-hydroxylasea \u008f \u0090\u008f \u0090 \u0090 \u0090 androstenedione XY: atypical genitalia, undescended testes XX: lacks 2\u00b0 sexual development \u000721-hydroxylasea \u0090 \u008f\u0090 \u0090 \u008f \u008f renin activity Most common \u008f 17-hydroxy\u00ad Presents in infancy (salt progesterone wasting) or childhood (precocious puberty) XX: virilization \u000711\u03b2-hydroxylasea \u0090 aldosterone \u0090 \u008f \u0090 \u008f \u0090 renin activity Presents in infancy \u008f 11-deoxycorti\u00ad (severe hypertension) costerone or childhood (results in (precocious puberty) \u008f\u00a0BP) XX: virilization aAll congenital adrenal enzyme deficiencies are autosomal recessive disorders and most are characterized by skin hyperpigmentation (due to \u008f\u00a0MSH production, which is coproduced and secreted with ACTH) and bilateral adrenal gland enlargement (due to \u008f\u00a0ACTH stimulation). If deficient enzyme starts with 1, it causes hypertension; if deficient enzyme ends with 1, it causes virilization in females. uploaded by medbooksvn","340 SEC TION III Endocrine\u2003 \uf07d\u2009endocrine\u2014physiology Cortisol Adrenal zona fasciculata. Bound to corticosteroid-binding globulin. SOURCE \u008f Appetite Cortisol is A BIG FIB. FUNCTION \u008f Blood pressure: Exogenous glucocorticoids can cause REGULATION \u0083\t Upregulates \u03b11-receptors on arterioles reactivation of TB and candidiasis (blocks IL-2 \u008e\u00a0\u008f\u00a0sensitivity to norepinephrine and production). epinephrine (permissive action) Stress Hypothalamus \u0083\t At high concentrations, can bind to Circadian rhythm mineralocorticoid (aldosterone) receptors CRH \u008f Insulin resistance (diabetogenic) \u008f Gluconeogenesis, lipolysis, and proteolysis Anterior pituitary (\u0090\u00a0glucose utilization) \u0090 Fibroblast activity (poor wound healing, Endorphins MSH \u0090\u00a0collagen synthesis, \u008f\u00a0striae) Proopiomelanocortin ACTH \u0090 Inflammatory and Immune responses: Cortisol \u0083\t Inhibits production of leukotrienes and prostaglandins Downstream cortisol function \u0083\t Inhibits WBC adhesion \u008e neutrophilia \u0083\t Blocks histamine release from mast cells Chronic stress may induce prolonged cortisol \u0083\t Eosinopenia, lymphopenia secretion, cortisol resistance, impaired \u0083\t Blocks IL-2 production immunocompetency, and dysregulation of \u0090 Bone formation (\u0090 osteoblast activity) HPA axis. CRH (hypothalamus) stimulates ACTH release (pituitary) \u008e\u00a0cortisol production in adrenal zona fasciculata. Excess cortisol \u0090 CRH, ACTH, and cortisol secretion. Appetite regulation Stimulates hunger (orexigenic effect) and GH release (via GH secretagog receptor). Produced by Ghrelin stomach. Sleep deprivation, fasting, or Prader-Willi syndrome \u008e\u00a0\u008f\u00a0ghrelin production. Leptin Ghrelin makes you ghrow hunghry. Acts on lateral area of hypothalamus (hunger center) to \u008f\u00a0appetite. Endocannabinoids Satiety hormone. Produced by adipose tissue. Mutation of leptin gene \u008e\u00a0severe obesity. Obese people have \u008f\u00a0leptin due to \u008f\u00a0adipose tissue but are tolerant or resistant to leptin\u2019s anorexigenic effect. Sleep deprivation or starvation \u008e\u00a0\u0090\u00a0leptin production. Leptin keeps you thin. Acts on ventromedial area of hypothalamus (satiety center) to \u0090 appetite. Act at cannabinoid receptors in hypothalamus and nucleus accumbens, two key brain areas for the homeostatic and hedonic control of food intake \u008e\u00a0\u008f\u00a0appetite. Exogenous cannabinoids cause \u201cthe munchies.\u201d","Endocrine\u2003 \uf07d\u2009endocrine\u2014physiology SEC TION III 341 Signaling pathways of endocrine hormones cAMP FSH, LH, ACTH, TSH, CRH, hCG, ADH (V2- FLAT ChAMPs CHuGG cGMP receptor), MSH, PTH, Calcitonin, Histamine (H2-receptor), Glucagon, GHRH BAD GraMPa Think vasodilation and diuresis BNP, ANP, EDRF (NO) GOAT HAG IP3 GnRH, Oxytocin, ADH (V1-receptor), TRH, PET CAT in TV Histamine (H1-receptor), Angiotensin II, Intracellular receptor Gastrin MAP kinase pathway Get Found In the MAP Receptor tyrosine Progesterone, Estrogen, Testosterone, Cortisol, JAK\/STAT pathway kinase Aldosterone, T3\/T4, Vitamin D Think acidophils and cytokines Nonreceptor tyrosine GET a JAKed PIG kinase IGF-1, FGF, PDGF, EGF, Insulin G-CSF, Erythropoietin, Thrombopoietin Prolactin, Immunomodulators (eg, cytokines IL-2, IL-6, IFN), GH Signaling pathways of steroid hormones Binding to receptor Steroid hormones are lipophilic and therefore must circulate bound to specific binding located in nucleus H Hormone globulins, which \u008f their solubility. or in cytoplasm In males, \u008f sex hormone\u2013binding Transformation of R Receptor globulin (SHBG) lowers free testosterone receptor to expose \u008e gynecomastia. DNA-binding protein In females, \u0090 SHBG raises free testosterone Binding to Cytoplasm \u008e hirsutism. enhancer-like H element in DNA R Gene \u008f estrogen (eg, OCPs, pregnancy) \u008e\u00a0\u008f SHBG. Intron Exon Ribosome Pre-mRNA mRNA Nucleus Protein Response uploaded by medbooksvn","342 SEC TION III Endocrine\u2003 \uf07d\u2009endocrine\u2014Pathology ` \u2009ENDOCRINE \u2014 PATHOLOGY Characterized by excessive free water retention, euvolemic hyponatremia with continued Syndrome of inappropriate urinary Na+ excretion, urine osmolality > antidiuretic hormone secretion serum osmolality. \uf069 Body responds to water retention with \uf069 \u0090\u00a0aldosterone and \u008f\u00a0ANP and BNP \u008e\u00a0\u008f\u00a0urinary serum Hypothalamus \uf069 serum osmolality Na+ secretion \u008e\u00a0normalization of extracellular osmolality serum volume fluid volume \u008e\u00a0euvolemic hyponatremia. Central DI ADH \uf069 urine osmolality Treatment: fluid restriction (first line), salt \uf069urine volume tablets, IV hypertonic saline, diuretics, ADH antagonists (eg, conivaptan, tolvaptan, Posterior SIADH Medullary collecting duct demeclocycline). pituitary Aquaporin channels (storage) ADH SIADH causes include (HEELD-up water): \u0083\t Head trauma\/CNS disorders ADH antagonists \u0083\t Ectopic ADH (eg, small cell lung cancer) Lithium \u0083\t Exogenous hormones (eg, vasopressin, desmopressin, oxytocin) Nephrogenic DI \u0083\t Lung disease \u0083\t Drugs (eg, SSRIs, carbamazepine, cyclophosphamide) Primary polydipsia and Characterized by the production of large amounts of dilute urine +\/\u2013 thirst. Urine specific gravity diabetes insipidus < 1.006. Urine osmolality usually < 300 mOsm\/kg. Central DI may be transient if damage is below hypothalamic median eminence or in the posterior pituitary (ADH in hypothalamus can still be secreted systemically via portal capillaries in median eminence). Primary polydipsia Central DI Nephrogenic DI DEFINITION Excessive water intake \u0090\u00a0ADH release ADH resistance CAUSES Psychiatric illnesses, Idiopathic, brain injury Hereditary (ADH receptor hypothalamic lesions (trauma, hypoxia, tumor, mutation), drugs (eg, affecting thirst center surgery, infiltrative diseases) lithium, demeclocycline), hypercalcemia, hypokalemia SERUM OSMOLALITY \u0090 \u008f \u008f ADH LEVEL \u0090\u00a0or normal \u0090 Normal or \u008f WATER RESTRICTIONa Significant \u008f in urine No change or slight \u008f in urine No change or slight \u008f in urine osmolality (> 700 mOsm\/kg) osmolality osmolality DESMOPRESSIN ADMINISTRATIONb \u2014 Significant \u008f in urine Minimal change in urine osmolality (> 50%) osmolality TREATMENT Water restriction Desmopressin (DDAVP) Manage the underlying cause; low-solute diet, HCTZ, amiloride, indomethacin aNo water intake for 2\u20133 hours followed by hourly measurements of urine volume and osmolality as well as plasma Na+ concentration and osmolality. bDesmopressin (ADH analog) is administered if serum osmolality > 295\u2013300 mOsm\/kg, plasma Na+\u00a0\u2265\u00a0145 mEq\/L, or urine osmolality does not increase despite \u008f\u00a0plasma osmolality.","Endocrine\u2003 \uf07d\u2009endocrine\u2014Pathology SEC TION III 343 Hypopituitarism Undersecretion of pituitary hormones due to \u0083\t Nonsecreting pituitary adenoma, craniopharyngioma Acromegaly \u0083\t Sheehan syndrome\u2014ischemic infarct of pituitary following severe postpartum hemorrhage; pregnancy-induced pituitary growth \u008e\u00a0\u008f\u00a0susceptibility to hypoperfusion. Usually presents with FINDINGS failure to lactate, amenorrhea, cold intolerance (anterior pituitary hormones mainly affected). DIAGNOSIS \u0083\t Empty sella syndrome\u2014atrophy or compression of pituitary (which lies in the sella turcica), TREATMENT often idiopathic, common in obese females; associated with idiopathic intracranial hypertension \u0083\t Pituitary apoplexy\u2014sudden hemorrhage of pituitary gland, often in the presence of an existing pituitary adenoma. Usually presents with sudden onset severe headache, visual impairment (eg, bitemporal hemianopia, diplopia due to CN III palsy), and features of hypopituitarism \u0083\t Brain injury \u0083\t Radiation Treatment: hormone replacement therapy (glucocorticoids, thyroxine, sex steroids, human growth hormone) Excess GH in adults. Typically caused by pituitary adenoma. Large tongue with deep furrows, frontal \u008f GH in children \u008e gigantism (\u008f linear bone bossing, coarsening of facial features with growth due to unfused epiphysis). aging A , deep voice, diaphoresis (excessive sweating), hypertrophic arthropathy, impaired A glucose tolerance (insulin resistance), HTN, LVH, HFpEF (most common cause of death). \u008f serum IGF-1; failure to suppress serum GH following oral glucose tolerance test; pituitary mass seen on brain MRI. Pituitary adenoma resection. If not cured, Baseline treat with octreotide (somatostatin analog), pegvisomant (GH receptor antagonist), or dopamine agonists (eg, cabergoline). uploaded by medbooksvn","344 SEC TION III Endocrine\u2003 \uf07d\u2009endocrine\u2014Pathology Hypothyroidism vs hyperthyroidism Hypothyroidism Hyperthyroidism METABOLIC Cold intolerance, \u0090\u00a0sweating, weight gain Heat intolerance, \u008f\u00a0sweating, weight loss (\u0090\u00a0basal metabolic rate \u008e\u00a0\u0090\u00a0calorigenesis), (\u008f\u00a0synthesis of Na+\/K+-ATPase \u008e\u00a0\u008f\u00a0basal hyponatremia (\u0090\u00a0free water clearance) metabolic rate \u008e\u00a0\u008f\u00a0calorigenesis) SKIN\/HAIR Dry, cool skin (due to \u0090\u00a0blood flow); coarse, Warm, moist skin (due to vasodilation); fine hair; brittle hair; diffuse alopecia; brittle nails; onycholysis ( A ); pretibial myxedema in Graves puffy facies and generalized nonpitting edema disease B (myxedema) due to \u008f\u00a0GAGs in interstitial spaces \u008e\u00a0\u008f\u00a0osmotic pressure \u008e\u00a0water retention Ophthalmopathy in Graves disease (including periorbital edema, exophthalmos), lid lag\/ OCULAR Periorbital edema C retraction (\u008f\u00a0sympathetic stimulation of superior tarsal muscle) GASTROINTESTINAL Constipation (\u0090\u00a0GI motility), \u0090\u00a0appetite MUSCULOSKELETAL Hyperdefecation\/diarrhea (\u008f\u00a0GI motility), Hypothyroid myopathy (proximal weakness, \u008f\u00a0appetite REPRODUCTIVE \u008f\u00a0CK), carpal tunnel syndrome, myoedema NEUROPSYCHIATRIC (small lump rising on the surface of a muscle Thyrotoxic myopathy (proximal weakness, CARDIOVASCULAR when struck with a hammer) normal CK), osteoporosis\/\u008f\u00a0fracture rate (T3 directly stimulates bone resorption) Abnormal uterine bleeding, \u0090\u00a0libido, infertility Abnormal uterine bleeding, gynecomastia, Hypoactivity, lethargy, fatigue, weakness, \u0090\u00a0libido, infertility depressed mood, \u0090\u00a0reflexes (delayed\/slow relaxing) Hyperactivity, restlessness, anxiety, insomnia, fine tremors (due to \u008f\u00a0\u03b2-adrenergic activity), Bradycardia, dyspnea on exertion (\u0090\u00a0cardiac \u008f\u00a0reflexes (brisk) output) Tachycardia, palpitations, dyspnea, arrhythmias LABS \u008f\u00a0TSH (if 1\u00b0) (eg, atrial fibrillation), chest pain and systolic \u0090\u00a0free T3 and T4 HTN due to \u008f\u00a0number and sensitivity of Hypercholesterolemia (due to \u0090\u00a0LDL receptor \u03b2-adrenergic receptors, \u008f\u00a0expression of cardiac expression) sarcolemmal ATPase and \u0090\u00a0expression of phospholamban AB \u0090\u00a0TSH (if 1\u00b0) \u008f\u00a0free T3 and T4 \u0090\u00a0LDL, HDL, and total cholesterol C","Endocrine\u2003 \uf07d\u2009endocrine\u2014Pathology SEC TION III 345 Hypothyroidism Also called chronic autoimmune thyroiditis. Most common cause of hypothyroidism in iodine- Hashimoto thyroiditis sufficient regions. Associated with HLA-DR3 (differs by ethnicity), \u008f\u00a0risk of primary thyroid lymphoma (typically diffuse large B-cell lymphoma). Subacute granulomatous Findings: moderately enlarged, nontender thyroid. May be preceded by transient hyperthyroid thyroiditis state (\u201cHashitoxicosis\u201d) due to follicular rupture and thyroid hormone release. Riedel thyroiditis Serology: \u2295 antithyroid peroxidase (antimicrosomal) and antithyroglobulin antibodies. Congenital Histology: H\u00fcrthle cells A , lymphoid aggregates with germinal centers B . hypothyroidism Postpartum thyroiditis\u2014mild, self-limited variant of Hashimoto thyroiditis arising < 1 year after Other causes delivery. Also called de Quervain thyroiditis. Usually, a self-limited disease. Natural history: transient hyperthyroidism \u008e\u00a0euthyroid state \u008e\u00a0hypothyroidism \u008e\u00a0euthyroid state. Often preceded by viral infection. Findings: \u008f\u00a0ESR, jaw pain, very tender thyroid (de Quervain is associated with pain). Histology: granulomatous inflammation C . Also called invasive fibrous thyroiditis. May occur as part of IgG4-related disease spectrum (eg, autoimmune pancreatitis, retroperitoneal fibrosis, noninfectious aortitis). Hypothyroidism occurs in 1\u20443 of patients. Fibrosis may extend to local structures (eg, trachea, esophagus), mimicking anaplastic carcinoma. Findings: slowly enlarging, hard (rocklike), fixed, nontender thyroid. Histology: thyroid replaced by fibrous tissue and inflammatory infiltrate D . Formerly called cretinism. Most commonly caused by thyroid dysgenesis (abnormal thyroid gland development; eg, agenesis, hypoplasia, ectopy) or dyshormonogenesis (abnormal thyroid hormone synthesis; eg, mutations in thyroid peroxidase) in iodine-sufficient regions. Findings (6 P\u2019s): pot-bellied, pale, puffy-faced child E with protruding umbilicus, protuberant tongue F , and poor brain development. Iodine deficiency (most common cause worldwide; typically presents with goiter G ), iodine excess (Wolff-Chaikoff effect), drugs (eg, amiodarone, lithium), nonthyroidal illness syndrome (also called euthyroid sick syndrome; \u0090\u00a0T3 with normal\/\u0090\u00a0T4 and TSH in critically ill patients). ABCD EF G Before treatment After treatment uploaded by medbooksvn","346 SEC TION III Endocrine\u2003 \uf07d\u2009endocrine\u2014Pathology Hyperthyroidism Most common cause of hyperthyroidism. Thyroid-stimulating immunoglobulin (IgG, can cause Graves disease transient neonatal hyperthyroidism; type II hypersensitivity) stimulates TSH receptors on thyroid A (hyperthyroidism, diffuse goiter), dermal fibroblasts (pretibial myxedema), and orbital fibroblasts (Graves orbitopathy). Activation of T-cells \u008e lymphocytic infiltration of retroorbital space \u008e\u00a0\u008f\u00a0cytokines (eg, TNF-\u03b1, IFN-\u03b3) \u008e\u00a0\u008f\u00a0fibroblast secretion of hydrophilic GAGs \u008e \u008f osmotic muscle swelling, muscle inflammation, and adipocyte count \u008e exophthalmos A . Often presents during stress (eg, pregnancy). Associated with HLA-DR3 and HLA-B8. Histology: tall, crowded follicular epithelial cells; scalloped colloid. Toxic multinodular Focal patches of hyperfunctioning follicular cells distended with colloid working independently goiter of TSH (due to TSH receptor mutations in 60% of cases). \u008f release of T3 and T4. Hot nodules Thyroid storm (hyperfunctioning nodules visualized on radioactive iodine scan) are rarely malignant. Jod-Basedow Uncommon but serious complication that occurs when hyperthyroidism is incompletely treated\/ phenomenon untreated and then significantly worsens in the setting of acute stress such as infection, trauma, Causes of goiter surgery. Presents with agitation, delirium, fever, diarrhea, coma, and tachyarrhythmia (cause of death). May see \u008f LFTs. Treat with the 4 P\u2019s: \u03b2-blockers (eg, propranolol), propylthiouracil, glucocorticoids (eg, prednisolone), potassium iodide (Lugol iodine). Iodide load \u008e\u00a0\u0090\u00a0T4 synthesis \u008e\u00a0Wolff-Chaikoff effect. Iodine-induced hyperthyroidism. Occurs when a patient with iodine deficiency and partially autonomous thyroid tissue (eg, autonomous nodule) is made iodine replete. Can happen after iodine IV contrast or amiodarone use. Opposite to Wolff-Chaikoff effect. Smooth\/diffuse: Graves disease, Hashimoto thyroiditis, iodine deficiency, TSH-secreting pituitary adenoma. Nodular: toxic multinodular goiter, thyroid adenoma, thyroid cancer, thyroid cyst. Thyroid adenoma Benign solitary growth of the thyroid. Most are nonfunctional (\u201ccold\u201d on radioactive iodine scan), A can rarely cause hyperthyroidism via autonomous thyroid hormone production (\u201chot\u201d or \u201ctoxic\u201d). Most common histology is follicular (arrows in A ); absence of capsular or vascular invasion (unlike follicular carcinoma).","Endocrine\u2003 \uf07d\u2009endocrine\u2014Pathology SEC TION III 347 Thyroid cancer Typically diagnosed with fine needle aspiration; treated with thyroidectomy. Complications of surgery include hypocalcemia (due to removal of parathyroid glands), transection of recurrent Papillary carcinoma laryngeal nerve during ligation of inferior thyroid artery (leads to dysphagia and dysphonia A [hoarseness]), and injury to the external branch of the superior laryngeal nerve during ligation of superior thyroid vascular pedicle (may lead to loss of tenor usually noticeable in professional voice users). Most common. Empty-appearing nuclei with central clearing (\u201cOrphan Annie\u201d eyes) A , psamMoma bodies, nuclear grooves (Papi and Moma adopted Orphan Annie). \u008f risk with RET\/ PTC rearrangements and BRAF mutations, childhood irradiation. Papillary carcinoma: most prevalent, palpable lymph nodes. Good prognosis. Follicular carcinoma Good prognosis. Invades thyroid capsule and vasculature (unlike follicular adenoma), uniform follicles; hematogenous spread is common. Associated with RAS mutation and PAX8-PPAR-\u03b3 Medullary carcinoma translocations. Fine needle aspiration cytology may not be able to distinguish between follicular B adenoma and carcinoma. From parafollicular \u201cC cells\u201d; produces calcitonin, sheets of polygonal cells in an amyloid stroma B (stains with Congo red). Associated with MEN 2A and 2B (RET mutations). Undifferentiated\/ Older patients; presents with rapidly enlarging neck mass \u008e compressive symptoms (eg, dyspnea, anaplastic carcinoma dysphagia, hoarseness); very poor prognosis. Associated with TP53 mutation. uploaded by medbooksvn","348 SEC TION III Endocrine\u2003 \uf07d\u2009endocrine\u2014Pathology Diagnosing 250 parathyroid disease 2\u00b0 hyperparathyroidism PTH (pg\/mL) (vitamin D de\ufb01ciency, \u2193 Ca2+ intake, 3\u00b0 hyperparathyroidism chronic kidney disease) (chronic kidney disease) 50 1\u00b0 hyperparathyroidism (hyperplasia, adenoma, Normal carcinoma) 10 Hypoparathyroidism PTH-independent 20 (surgical resection, hypercalcemia autoimmune) (excess Ca2+ intake, cancer, \u2191 vitamin D) 2 4 6 8 10 12 14 16 18 Ca2+ (mg\/dL) Hypoparathyroidism Due to injury to parathyroid glands or their blood supply (usually during thyroid surgery), A autoimmune destruction, or DiGeorge syndrome. Findings: tetany, hypocalcemia, hyperphosphatemia. Chvostek sign\u2014tapping of facial nerve (tap the Cheek) \u008e contraction of facial muscles. Trousseau sign\u2014occlusion of brachial artery with BP cuff (cuff the Triceps) \u008e carpal spasm. Pseudohypoparathyroidism type 1A\u2014autosomal dominant, maternally transmitted mutations (imprinted GNAS gene). GNAS1-inactivating mutation (coupled to PTH receptor) that encodes the Gs protein \u03b1 subunit \u008e\u00a0inactivation of adenylate cyclase when PTH binds to its receptor \u008e\u00a0end-organ resistance (kidney and bone) to PTH. Physical findings: Albright hereditary osteodystrophy (shortened 4th\/5th digits A , short stature, round face, subcutaneous calcifications, developmental delay). Labs: \u008f PTH, \u0090\u00a0Ca2+, \u008f PO43\u2013. Pseudopseudohypoparathyroidism\u2014autosomal dominant, paternally transmitted mutations (imprinted GNAS gene) but without end-organ resistance to PTH due to normal maternal allele maintaining renal responsiveness to PTH. Physical findings: same as Albright hereditary osteodystrophy. Labs: normal PTH, Ca2+, PO43\u2013. Lab values in hypocalcemic disorders DISORDER Ca2+ PO43\u2013 PTH ALP 25(OH) VITAMIN D 1,25(OH)2 VITAMIN D Vitamin D deficiency \u2014\/\u0090 \u2014\/\u0090 \u008f \u008f \u0090 \u2014\/\u008f 2\u00b0 hyperpara- \u0090 \u008f \u008f \u008f \u2014\u0090 thyroidism (CKD) Hypoparathyroidism \u0090 \u008f \u0090 \u2014 \u2014 \u2014\/\u0090 Pseudohypo- \u0090 \u008f \u008f \u008f \u2014 \u2014\/\u0090 parathyroidism","Endocrine\u2003 \uf07d\u2009endocrine\u2014Pathology SEC TION III 349 Hyperparathyroidism Usually due to parathyroid adenoma or Osteitis fibrosa cystica\u2014cystic bone spaces Primary hyperplasia. Hypercalcemia, hypercalciuria filled with brown fibrous tissue A (\u201cbrown hyperparathyroidism (renal stones), polyuria (thrones), tumor\u201d consisting of osteoclasts and deposited hypophosphatemia, \u008f PTH, \u008f ALP, \u008f urinary hemosiderin from hemorrhages; causes A cAMP. Most often asymptomatic. May present bone pain). Due to \u008f\u00a0PTH, classically with bone pain, weakness, constipation associated with 1\u00b0 (but also seen with 2\u00b0) (\u201cgroans\u201d), abdominal\/flank pain (kidney hyperparathyroidism. stones, acute pancreatitis), neuropsychiatric disturbances (\u201cpsychiatric overtones\u201d). \u201cStones, thrones, bones, groans, and psychiatric overtones.\u201d Secondary 2\u00b0 hyperplasia due to \u0090 Ca2+ absorption Renal osteodystrophy\u2014renal disease \u008e\u00a02\u00b0 and hyperparathyroidism and\/or \u008f PO43\u2212, most often in chronic 3\u00b0 hyperparathyroidism \u008e\u00a0bone lesions. kidney disease (causes hypovitaminosis\u00a0D Tertiary and hyperphosphatemia \u008e\u00a0\u0090\u00a0Ca2+). hyperparathyroidism Hypocalcemia, hyperphosphatemia in chronic kidney disease (vs\u00a0hypophosphatemia with most other causes), \u008f\u00a0ALP, \u008f PTH. Refractory (autonomous) hyperparathyroidism resulting from chronic kidney disease. \u008f\u008f\u00a0PTH, \u008f Ca2+. Familial hypocalciuric Autosomal dominant. Defective G-coupled Ca2+-sensing receptors in multiple tissues (eg, hypercalcemia parathyroids, kidneys). Higher than normal Ca2+ levels required to suppress PTH. Excessive renal Ca2+ reabsorption \u008e\u00a0mild hypercalcemia and hypocalciuria with normal to \u008f\u00a0PTH levels. uploaded by medbooksvn","350 SEC TION III Endocrine\u2003 \uf07d\u2009endocrine\u2014Pathology Diabetes mellitus Polydipsia, polyuria, polyphagia (3 P\u2019s), weight loss, DKA (type 1), hyperosmolar hyperglycemic state (type\u00a02). ACUTE MANIFESTATIONS CHRONIC COMPLICATIONS Rarely, can be caused by unopposed secretion of GH and epinephrine. Also seen in patients on glucocorticoid therapy (steroid diabetes). DIAGNOSIS Nonenzymatic glycation: \u0083\t Small vessel disease (hyaline arteriolosclerosis) \u008e retinopathy, neuropathy, nephropathy. \u0083\t Large vessel disease (atherosclerosis) \u008e CAD, cerebrovascular disease, peripheral vascular disease. MI is the most common cause of death. Osmotic damage (sorbitol accumulation in organs with aldose reductase and \u0090 or absent sorbitol dehydrogenase): \u0083\t Neuropathy: motor, sensory (glove and stocking distribution), autonomic degeneration (eg, GERD, gastroparesis, diabetic diarrhea). \u0083\t Cataracts. TEST\tDIAGNOSTIC CUTOFF\tNOTES HbA1c\t \u2265 6.5%\t Reflects average blood glucose \t\t\u2002\u2002 over prior 3 months (influenced \t\t\u2002\u2002 by RBC turnover) Fasting plasma glucose\t \u2265 126 mg\/dL\t Fasting for > 8 hours 2-hour oral glucose tolerance test\t \u2265 200 mg\/dL\t 2 hours after consumption of 75 g \t\t\u2002\u2002 of glucose in water Random plasma glucose\t \u2265 200 mg\/dL\t Presence of hyperglycemic \t\t\u2002\u2002 symptoms is required available insulin lipolysis proteolysis gluconeogenesis glycogenolysis tissue glucose uptake plasma muscle mass, free fatty acids weight loss Hypoglycemia, glycosuria ketogenesis, Vomiting Osmotic diuresis plasma osmolality ketonemia, ketonuria thirst Hyperventilation, Loss of water, Anion gap Kussmaul respiration Na, and K metabolic acidosis Hypovolemia Circulation failure, tissue perfusion","Endocrine\u2003 \uf07d\u2009endocrine\u2014Pathology SEC TION III 351 Type 1 vs type 2 diabetes mellitus Type 1 Type 2 \u008f resistance to insulin, progressive pancreatic 1\u00b0 DEFECT Autoimmune T-cell\u2013mediated destruction of \u03b2 cells \u03b2-cell failure Sometimes INSULIN NECESSARY IN TREATMENT Always > 40 yr Yes AGE (EXCEPTIONS COMMON) < 30 yr Relatively strong (90% concordance in identical ASSOCIATION WITH OBESITY No twins), polygenic No GENETIC PREDISPOSITION Relatively weak (50% concordance in identical Mild to moderate twins), polygenic Low Rare ASSOCIATION WITH HLA SYSTEM Yes, HLA-DR4 and -DR3 (4 \u2013 3 = type 1) Variable (with amyloid deposits) \u008f initially, but \u0090 in advanced disease GLUCOSE INTOLERANCE Severe Sometimes INSULIN SENSITIVITY High Islet amyloid polypeptide deposits KETOACIDOSIS Common \u03b2-CELL NUMBERS IN THE ISLETS \u0090 SERUM INSULIN LEVEL \u0090 CLASSIC SYMPTOMS OF POLYURIA, Common POLYDIPSIA, POLYPHAGIA, WEIGHT Islet leukocytic infiltrate LOSS HISTOLOGY Hyperglycemic emergencies Diabetic ketoacidosis Hyperosmolar hyperglycemic state PATHOGENESIS Insulin noncompliance or \u008f\u00a0requirements Profound hyperglycemia \u008e\u00a0excessive osmotic due to \u008f\u00a0stress (eg, infection) \u008e\u00a0lipolysis and diuresis \u008e\u00a0dehydration and \u008f\u00a0serum osmolality oxidation of free fatty acids \u008e\u00a0\u008f\u00a0ketone bodies \u008e\u00a0HHS. Classically seen in older patients with (\u03b2-hydroxybutyrate > acetoacetate). type 2 DM and limited ability to drink. Insulin deficient, ketones present. Insulin present, ketones deficient. SIGNS\/SYMPTOMS DKA is Deadly: Delirium\/psychosis, Kussmaul Thirst, polyuria, lethargy, focal neurologic respirations (rapid, deep breathing), Abdominal deficits, seizures. pain\/nausea\/vomiting, Dehydration. Fruity breath odor due to exhaled acetone. LABS Hyperglycemia, \u008f\u00a0H+, \u0090\u00a0HCO3\u2013 (\u008f\u00a0anion gap Hyperglycemia (often > 600 mg\/dL), \u008f\u00a0serum metabolic acidosis), \u008f\u00a0urine and blood ketone osmolality (> 320 mOsm\/kg), normal pH (no levels, leukocytosis. Normal\/\u008f\u00a0serum K+, but acidosis), no ketones. Normal\/\u008f\u00a0serum K+, depleted intracellular K+ due to transcellular \u0090\u00a0intracellular K+. shift from \u0090\u00a0insulin and acidosis. Osmotic diuresis \u008e\u00a0\u008f\u00a0K+ loss in urine \u008e\u00a0total body K+\u00a0depletion. COMPLICATIONS Life-threatening mucormycosis, cerebral Can progress to coma and death if untreated. edema, cardiac arrhythmias. TREATMENT IV fluids, IV insulin, and K+ (to replete intracellular stores). Glucose may be required to prevent hypoglycemia from insulin therapy. uploaded by medbooksvn","352 SEC TION III Endocrine\u2003 \uf07d\u2009endocrine\u2014Pathology Hypoglycemia in Usually occurs in patients treated with insulin or insulin secretagogues (eg, sulfonylureas, diabetes mellitus meglitinides) in the setting of high-dose treatment, inadequate food intake, and\/or exercise. \u0083\t Neurogenic (autonomic) symptoms: diaphoresis, tachycardia, tremor, anxiety, hunger. Allow perception of \u0090 glucose (hypoglycemia awareness). \u0083\t Neuroglycopenic symptoms: altered mental status, seizures, death due to insufficient glucose in CNS. May occur in the absence of preceding neurogenic symptoms in patients with attenuated autonomic response (hypoglycemia unawareness). Treatment: simple carbohydrates (eg, glucose tablets, fruit juice), IM glucagon, IV dextrose. Cushing syndrome \u008f cortisol due to a variety of causes: \u0083\t Exogenous glucocorticoids \u008e \u0090 ACTH \u008e bilateral adrenal atrophy. Most common cause. ETIOLOGY \u0083\t Primary adrenal adenoma, hyperplasia, or carcinoma \u008e\u00a0\u0090 ACTH \u008e\u00a0atrophy of uninvolved adrenal gland. FINDINGS \u0083\t ACTH-secreting pituitary adenoma (Cushing disease); paraneoplastic ACTH secretion (eg, DIAGNOSIS small cell lung cancer, bronchial carcinoids) \u008e bilateral adrenal hyperplasia. Cushing disease is A responsible for the majority of endogenous cases of Cushing syndrome. B MOON FACIES: Metabolic syndrome (hypertension, hyperglycemia, hyperlipidemia), Obesity (truncal weight gain with wasting of extremities, round \u201cmoon\u201d facies A , dorsocervical fat pad \u201cbuffalo hump\u201d), Osteoporosis, Neuropsychiatric (depression, anxiety, irritability), Facial plethora, Androgen excess (acne, hirsutism), Cataract, Immunosuppression, Ecchymoses (easy bruising), Skin changes (thinning, striae B , hyperpigmentation). Screening tests include: \u008f free cortisol on 24-hr urinalysis, \u008f late night salivary cortisol, and no suppression with overnight low-dose dexamethasone test. 24-hr urine free cortisol, late night salivary cortisol, and\/or inadequate suppression on 1 mg overnight dexamethasone test Measure serum ACTH Suppressed Elevated ACTH-independent ACTH-dependent Cushing syndrome Cushing syndrome Exogenous glucocorticoids High-dose dexamethasone CRH stimulation test or adrenal tumor suppression test ACTH, cortisol No Consider adrenal CT No ACTH, cortisol to con\ufb01rm Ectopic ACTH Cushing disease Ectopic ACTH secretion secretion MRI of the pituitary (to identify adenoma) CT of the chest\/abdomen\/pelvis (to identify tumor)","Endocrine\u2003 \uf07d\u2009endocrine\u2014Pathology SEC TION III 353 Nelson syndrome Enlargement of pre-existing ACTH\u2013secreting pituitary adenoma after bilateral adrenalectomy for refractory Cushing disease \u008e\u00a0\u008f\u00a0ACTH (hyperpigmentation), mass effect (headaches, bitemporal hemianopia). Treatment: transsphenoidal resection, postoperative pituitary irradiation for residual tumor. Adrenal insufficie y Inability of adrenal glands to generate enough glucocorticoids +\/\u2212 mineralocorticoids for the body\u2019s needs. Can be acute or chronic. Symptoms include weakness, fatigue, orthostatic hypotension, Primary adrenal muscle aches, weight loss, GI disturbances, sugar and\/or salt cravings. insufficiency A Treatment: glucocorticoid +\/\u2212 mineralocorticoid replacement. \u0090\u00a0gland function \u008e\u00a0\u0090\u00a0cortisol, \u0090\u00a0aldosterone \u008e\u00a0hypotension (hyponatremic volume contraction), hyperkalemia, metabolic acidosis, skin\/mucosal hyperpigmentation A (\u008f\u00a0melanin synthesis due to \u008f\u00a0MSH, a byproduct of POMC cleavage). Primary pigments the skin\/mucosa. Addison disease\u2014chronic 1\u00b0 adrenal insufficiency; caused by adrenal atrophy or destruction. Most commonly due to autoimmune adrenalitis (high-income countries) or TB (low-income countries). Secondary and \u0090\u00a0pituitary ACTH secretion (secondary) or \u0090\u00a0hypothalamic CRH secretion (tertiary). No tertiary adrenal hyperkalemia (aldosterone synthesis preserved due to functioning adrenal gland, intact RAAS), no insufficiency hyperpigmentation. Acute adrenal 2\u00b0 adrenal insufficiency is due to pituitary pathologies, 3\u00b0 adrenal insufficiency is most commonly insufficiency due to abrupt cessation of chronic glucocorticoid therapy (HPA suppression). Tertiary from treatment. Also called adrenal (addisonian) crisis; often precipitated by acute stressors that \u008f\u00a0glucocorticoid requirements (eg, infection) in patients with pre-existing adrenal insufficiency or on glucocorticoid therapy. May present with acute abdominal pain, nausea, vomiting, altered mental status, shock. Waterhouse-Friderichsen syndrome\u2014bilateral adrenal hemorrhage in the setting of sepsis (eg,\u00a0meningococcemia) \u008e\u00a0acute 1\u00b0 adrenal insufficiency. Concern for adrenal insu ciency Check AM cortisol or ACTH stimulation \u2193 AM cortisol and\/or \u2193 peak cortisol on stimulation test Measure random serum ACTH \u2193 or inappropriately \u2191 ACTH normal ACTH 2\u00b0\/3\u00b0 adrenal 1\u00b0 adrenal insu ciency insu ciency uploaded by medbooksvn","354 SEC TION III Endocrine\u2003 \uf07d\u2009endocrine\u2014Pathology Hyperaldosteronism Increased secretion of aldosterone from adrenal gland. Clinical features include hypertension, \u0090\u00a0or normal K+, metabolic alkalosis. 1\u00b0 hyperaldosteronism does not directly cause edema due Primary to aldosterone escape mechanism. However, certain 2\u00b0 causes of hyperaldosteronism (eg, heart hyperaldosteronism failure) impair the aldosterone escape mechanism, leading to worsening of edema. Secondary hyperaldosteronism Seen in patients with bilateral adrenal hyperplasia or adrenal adenoma (Conn syndrome). \u008f\u00a0aldosterone, \u0090\u00a0renin. Leads to treatment-resistant hypertension. Seen in patients with renovascular hypertension, juxtaglomerular cell tumors (renin-producing), and edema (eg, cirrhosis, heart failure, nephrotic syndrome). Neuroendocrine Heterogeneous group of neoplasms originating from neuroendocrine cells (which have traits similar tumors to nerve cells and hormone-producing cells). Most neoplasms occur in the GI system (eg, carcinoid, gastrinoma), pancreas (eg, insulinoma, glucagonoma), and lungs (eg, small cell carcinoma). Also in thyroid (eg, medullary carcinoma) and adrenals (eg, pheochromocytoma). Neuroendocrine cells (eg, pancreatic \u03b2 cells, enterochromaffin cells) share a common biologic function through amine precursor uptake decarboxylase (APUD) despite differences in embryologic origin, anatomic site, and secretory products (eg, chromogranin A, neuron-specific enolase [NSE], synaptophysin, serotonin, histamine, calcitonin). Treatment: surgical resection, somatostatin analogs. Neuroblastoma Most common tumor of the adrenal medulla in children, usually < 4 years old. Originates from A neural crest cells. Occurs anywhere along the sympathetic chain. Most common presentation is abdominal distension and a firm, irregular mass that can cross the midline (vs Wilms tumor, which is smooth and unilateral). Less likely to develop hypertension than with pheochromocytoma (neuroblastoma is normotensive). Can also present with opsoclonus-myoclonus syndrome (\u201cdancing eyes-dancing feet\u201d). \u008f\u00a0HVA and VMA (catecholamine metabolites) in urine. Homer-Wright rosettes (neuroblasts surrounding a central area of neuropil A ) characteristic of neuroblastoma and medulloblastoma. Bombesin and NSE\u00a0\u2295. Associated with amplification of N-myc oncogene.","Endocrine\u2003 \uf07d\u2009endocrine\u2014Pathology SEC TION III 355 Pheochromocytoma Most common tumor of the adrenal medulla Rule of 10\u2019s: in adults (black arrow in A ; red arrow points 10% malignant ETIOLOGY to bone metastases). Derived from chromaffin 10% bilateral A cells (arise from neural crest). 10% extra-adrenal (eg, bladder wall, organ of Zuckerkandl) SYMPTOMS May be associated with germline mutations (eg, 10% calcify NF-1, VHL, RET [MEN 2A, 2B]). 10% kids FINDINGS TREATMENT Most tumors secrete epinephrine, Episodic hyperadrenergic symptoms (5 P\u2019s): norepinephrine, and dopamine, which can Pressure (\u008f BP) cause episodic hypertension. May also secrete Pain (headache) EPO \u008e\u00a0polycythemia. Perspiration Palpitations (tachycardia) Symptoms occur in \u201cspells\u201d\u2014relapse and remit. Pallor \u008f\u00a0catecholamines and metanephrines (eg, Chromogranin, synaptophysin and NSE \u2295. homovanillic acid, vanillylmandelic acid) in urine and plasma. Phenoxybenzamine for pheochromocytoma. Irreversible \u03b1-antagonists (eg, phenoxybenzamine) followed by \u03b2-blockers prior to tumor resection. \u03b1-blockade must be achieved before giving \u03b2-blockers to avoid a hypertensive crisis. A before B. uploaded by medbooksvn","356 SEC TION III Endocrine\u2003 \uf07d\u2009endocrine\u2014Pathology Multiple endocrine All MEN syndromes have autosomal dominant inheritance. neoplasias The X-MEN are dominant over villains. SUBTYPE CHARACTERISTICS MEN1 Pituitary tumors (prolactin or GH) Pancreatic endocrine tumors\u2014Zollinger-Ellison syndrome, insulinomas, VIPomas, glucagonomas MEN2A (rare) MEN2B Parathyroid adenomas A Associated with mutation of MEN1 (tumor suppressor, codes for menin, chromosome 11), angiofibromas, collagenomas, meningiomas Parathyroid hyperplasia Medullary thyroid carcinoma\u2014neoplasm of parafollicular C cells; secretes calcitonin; prophylactic thyroidectomy required Pheochromocytoma (secretes catecholamines) Associated with mutation in RET (protooncogene, codes for receptor tyrosine kinase, chromosome 10) Medullary thyroid carcinoma Pheochromocytoma Mucosal neuromas A (oral\/intestinal ganglioneuromatosis) Associated with marfanoid habitus; mutation in RET gene MEN1 = 3 P\u2019s MEN2A = 2 P\u2019s, 1 M MEN2B = 1 P, 2 M\u2019s Pituitary Parathyroid Medullary Mucosal thyroid carcinoma neuromas Pheochromocytoma Pancreas","Endocrine\u2003 \uf07d\u2009endocrine\u2014Pathology SEC TION III 357 Pancreatic islet cell tumors Insulinoma Tumor of pancreatic \u03b2 cells \u008e\u00a0overproduction of insulin \u008e\u00a0hypoglycemia. May see Whipple triad: low blood glucose, symptoms of hypoglycemia (eg, lethargy, syncope, diplopia), and resolution of symptoms after normalization of plasma glucose levels. Symptomatic patients have \u0090\u00a0blood glucose and \u008f\u00a0C-peptide levels (vs exogenous insulin use). \u223c\u00a010% of cases associated with MEN1 syndrome. Treatment: surgical resection. Glucagonoma Tumor of pancreatic \u03b1 cells \u008e overproduction of glucagon. Presents with 6 D\u2019s: dermatitis (necrolytic migratory erythema), diabetes (hyperglycemia), DVT, declining weight, depression, diarrhea. Treatment: octreotide, surgical resection. Somatostatinoma Tumor of pancreatic \u03b4 cells \u008e overproduction of somatostatin \u008e\u00a0\u0090\u00a0secretion of secretin, cholecystokinin, glucagon, insulin, gastrin, gastric inhibitory peptide (GIP). May present with diabetes\/glucose intolerance, steatorrhea, gallstones, achlorhydria. Treatment: surgical resection; somatostatin analogs (eg, octreotide) for symptom control. Carcinoid tumors Carcinoid tumors arise from neuroendocrine cells, most commonly in the intestine or lung. A Neuroendocrine cells secrete 5-HT, which undergoes hepatic first-pass metabolism and enzymatic breakdown by MAO in the lung. If 5-HT reaches the systemic circulation (eg, after liver metastasis), carcinoid tumor may present with carcinoid syndrome\u2014episodic flushing, diarrhea, wheezing, right-sided valvular heart disease (eg, tricuspid regurgitation, pulmonic stenosis), niacin deficiency (pellagra), \u008f\u00a0urinary 5-HIAA. Histology: rosettes A , chromogranin A \u2295, synaptophysin \u2295. Treatment: surgical resection, somatostatin analog (eg, octreotide) or tryptophan hydroxylase inhibitor (eg, telotristat) for symptom control. Rule of thirds: 1\/3 metastasize 1\/3 present with 2nd malignancy 1\/3 are multiple Zollinger-Ellison Gastrin-secreting tumor (gastrinoma) of duodenum or pancreas. Acid hypersecretion causes syndrome recurrent ulcers in duodenum and jejunum. Presents with abdominal pain (peptic ulcer disease, distal ulcers), diarrhea (malabsorption). Positive secretin stimulation test: \u008f\u00a0gastrin levels after administration of secretin, which normally inhibits gastrin release. May be associated with MEN1. uploaded by medbooksvn","358 SEC TION III Endocrine\u2003 \uf07d\u2009endocrine\u2014Pharmacology ` \u2009ENDOCRINE \u2014 PH A RM A COLOGY Diabetes mellitus All patients with diabetes mellitus should receive education on diet, exercise, blood glucose therapy monitoring, and complication management. Treatment differs based on the type of diabetes and glycemic control: \u0083\t Type 1 DM\u2014insulin replacement \u0083\t Type 2 DM\u2014oral agents (metformin is first line), non-insulin injectables, insulin replacement; weight loss particularly helpful in lowering blood glucose \u0083\t Gestational DM\u2014insulin replacement if nutrition therapy and exercise alone fail Regular (short-acting) insulin is preferred for DKA (IV), hyperkalemia (+ glucose), stress hyperglycemia. Metformin, GLP-1 analogs, DPP-4 pioglitazone inhibitors, amylin analogs insulin sensitivity glucagon release Adipose tissue Pancreas (\u02dc c ells) Skeletal muscle gastric emptying glucose production Stomach Liver Sulfonylureas, meglitinides, SGLT2 inhibitors GLP-1 analogs, DPP-4 glucose reabsorption inhibitors Kidney insulin secretion Pancreas (\u00b0 c ells) \u02dc -Glucosidase inhibitors glucose absorption Intestine DRUG MECHANISM ADVERSE EFFECTS Insulin preparations Bind insulin receptor (tyrosine kinase activity) Hypoglycemia, lipodystrophy, hypersensitivity Liver: \u008f\u00a0glucose storage as glycogen reactions (rare), weight gain Rapid acting (no lag): Muscle: \u008f\u00a0glycogen, protein synthesis lispro, aspart, glulisine Fat: \u008f\u00a0TG storage Plasma insulin level Lispro, aspart, glulisine Short acting: Cell membrane: \u008f\u00a0K+ uptake Regular regular NPH Intermediate acting: NPH Detemir Glargine Long acting: detemir, glargine 0 2 4 6 8 10 12 14 16 18 Very long acting: Hours degludec","Endocrine\u2003 \uf07d\u2009endocrine\u2014Pharmacology SEC TION III 359 Diabetes mellitus therapy (continued) DRUG MECHANISM ADVERSE EFFECTS Increase insulin sensitivity GI upset, lactic acidosis (use with caution in renal insufficiency), vitamin B12 deficiency. Metformin Inhibits mitochondrial glycerol-3-phosphate dehydrogenase (mGPD) \u008e\u00a0inhibition of Weight loss (often desired). hepatic gluconeogenesis and the action of glucagon. Weight gain, edema, HF, \u008f\u00a0risk of fractures. Delayed onset of action (several weeks). \u008f\u00a0glycolysis, peripheral glucose uptake (\u008f\u00a0insulin sensitivity). Disulfiram-like reaction with first-generation sulfonylureas only (rarely used). Pioglitazone Activate PPAR-\u03b3 (a nuclear receptor) \u008e\u00a0\u008f\u00a0insulin sensitivity and levels of adiponectin Hypoglycemia (\u008f\u00a0risk in renal insufficiency), \u008e\u00a0regulation of glucose metabolism and fatty weight gain. acid storage. Increase insulin secretion Sulfonylureas (1st gen) Close K+ channels in pancreatic B cell Chlorpropamide, tolbutamide membrane \u008e\u00a0cell depolarizes \u008e\u00a0insulin Sulfonylureas (2nd gen) release via \u008f\u00a0Ca2+ influx. Glipizide, glyburide Meglitinides Nateglinide, repaglinide Increase glucose-induced insulin secretion GLP-1 analogs \u0090\u00a0glucagon release, \u0090\u00a0gastric emptying, Nausea, vomiting, pancreatitis. Weight loss Exenatide, liraglutide, \u008f\u00a0glucose-dependent insulin release. (often desired). semaglutide \u008f\u00a0satiety (often desired). DPP-4 inhibitors Inhibit DPP-4 enzyme that deactivates GLP-1 Respiratory and urinary infections, weight Linagliptin, saxagliptin, \u008e\u00a0\u0090\u00a0glucagon release, \u0090\u00a0gastric emptying. sitagliptin neutral. \u008f\u00a0glucose-dependent insulin release. \u008f\u00a0satiety (often desired). Decrease glucose absorption Glucosuria (UTIs, vulvovaginal candidiasis), dehydration (orthostatic hypotension), weight Sodium-glucose Block reabsorption of glucose in proximal loss. Glucose flows in urine. co-transporter 2 convoluted tubule. inhibitors Use with caution in renal insufficiency Canagliflozin, (\u0090\u00a0efficacy with \u0090\u00a0GFR). dapagliflozin, empagliflozin GI upset, bloating. Not recommended in renal insufficiency. \u03b1-glucosidase Inhibit intestinal brush-border \u03b1-glucosidases inhibitors \u008e\u00a0delayed carbohydrate hydrolysis and glucose Hypoglycemia, nausea. \u008f\u00a0satiety (often desired). absorption \u008e\u00a0\u0090\u00a0postprandial hyperglycemia. Acarbose, miglitol Others Amylin analogs \u0090\u00a0glucagon release, \u0090\u00a0gastric emptying. Pramlintide uploaded by medbooksvn","360 SEC TION III Endocrine\u2003 \uf07d\u2009endocrine\u2014Pharmacology Thionamides Propylthiouracil, methimazole. MECHANISM Block thyroid peroxidase, inhibiting the oxidation of iodide as well as the organification and CLINICAL USE coupling of iodine \u008e inhibition of thyroid hormone synthesis. PTU also blocks 5\u2032-deiodinase \u008e\u00a0\u0090\u00a0Peripheral conversion of T4 to T3. ADVERSE EFFECTS Hyperthyroidism. PTU used in Primary (first) trimester of pregnancy (due to methimazole teratogenicity); methimazole used in second and third trimesters of pregnancy (due to risk of PTU-induced hepatotoxicity). Not used to treat Graves ophthalmopathy (treated with glucocorticoids). Skin rash, agranulocytosis (rare), aplastic anemia, hepatotoxicity. PTU use has been associated with ANCA-positive vasculitis. Methimazole is a possible teratogen (can cause aplasia cutis). Levothyroxine, liothyronine MECHANISM Hormone replacement for T4 (levothyroxine; levo = 4 letters) or T3 (liothyronine; lio = 3 letters). Avoid levothyroxine with antacids, bile acid resins, or ferrous sulfate (\u0090\u00a0absorption). CLINICAL USE Hypothyroidism, myxedema. May be misused for weight loss. Distinguish exogenous hyperthyroidism from endogenous hyperthyroidism by using a combination of TSH receptor antibodies, radioactive iodine uptake, and\/or measurement of thyroid blood flow on ultrasound. ADVERSE EFFECTS Tachycardia, heat intolerance, tremors, arrhythmias. Hypothalamic\/pituitary drugs DRUG CLINICAL USE Conivaptan, tolvaptan ADH antagonists Demeclocycline SIADH (block action of ADH at V2-receptor) ADH antagonist, a tetracycline SIADH (interferes with ADH signaling) Desmopressin ADH analog Central DI, von Willebrand disease, sleep enuresis, hemophilia A GH GH deficiency, Turner syndrome Oxytocin Induction of labor (stimulates uterine contractions), control uterine hemorrhage Somatostatin Acromegaly, carcinoid syndrome, gastrinoma, glucagonoma, esophageal varices (octreotide) Fludrocortisone Synthetic analog of aldosterone with glucocorticoid effects. Fluidrocortisone retains fluid. Mineralocorticoid replacement in 1\u00b0 adrenal insufficiency. MECHANISM Similar to glucocorticoids; also edema, exacerbation of heart failure, hyperpigmentation. CLINICAL USE ADVERSE EFFECTS","Endocrine\u2003 \uf07d\u2009endocrine\u2014Pharmacology SEC TION III 361 Cinacalcet Sensitizes calcium-sensing receptor (CaSR) in parathyroid gland to circulating Ca2+ \u008e\u00a0\u0090\u00a0PTH. Pronounce \u201cSenacalcet.\u201d MECHANISM 2\u00b0 hyperparathyroidism in patients with CKD receiving hemodialysis, hypercalcemia in 1\u00b0 CLINICAL USE hyperparathyroidism (if parathyroidectomy fails), or in parathyroid carcinoma. ADVERSE EFFECTS Hypocalcemia. Sevelamer Nonabsorbable phosphate binder that prevents phosphate absorption from the GI tract. Hyperphosphatemia in CKD. MECHANISM Hypophosphatemia, GI upset. CLINICAL USE ADVERSE EFFECTS Cation exchange resins Patiromer, sodium polystyrene sulfonate, zirconium cyclosilicate. MECHANISM Bind K+ in colon in exchange for other cations (eg, Na+, Ca2+) \u008e\u00a0K+ excreted in feces. CLINICAL USE Hyperkalemia. ADVERSE EFFECTS Hypokalemia, GI upset. uploaded by medbooksvn","362 SEC TION III ENDOCRINE\u2003 \uf07d\u2009ENDOCRINE\u2014PHARMACOLOGY ` \u2009N O T E S","HIGH-YIELD SYSTEMS Gastrointestinal \u201cA good set of bowels is worth more to a man than any quantity of brains.\u201d\u00ad\u00ad `\tEmbryology\t 364 \u2014Josh Billings `\tAnatomy\t 367 `\tPhysiology\t 378 \u201cMan should strive to have his intestines relaxed all the days of his life.\u201d `\tPathology\t 383 \u2014Moses Maimonides `\tPharmacology\t 405 \u201cAll right, let\u2019s not panic. I\u2019ll make the money by selling one of my livers. I can get by with one.\u201d \u2014Homer Simpson, The Simpsons \u201cThe truth does not change according to our ability to stomach it emotionally.\u201d \u2014Flannery O\u2019Connor When studying the gastrointestinal system, be sure to understand the normal embryology, anatomy, and physiology and how the system is affected by various pathologies. Study not only disease pathophysiology, but also its specific findings, so that you can differentiate between two similar diseases. For example, what specifically makes ulcerative colitis different from Crohn disease? Also, be comfortable with basic interpretation of abdominal x-rays, CT scans, and endoscopic images. 363 uploaded by medbooksvn","364 SEC TION III Gastrointestinal\u2003 \uf07d\u2009gastrointestinal\u2014Embryology ` \u2009GASTROINTESTINAL \u2014 EMBRYOLOGY Normal Foregut\u2014esophagus to duodenum at level of pancreatic duct and common bile duct insertion gastrointestinal (ampulla of Vater). embryology \u0083\t 4th-6th week of development\u2014stomach rotates 90\u00b0 clockwise. \u0083\t Left vagus becomes anteriorly positioned, and right vagus becomes posteriorly positioned. Midgut\u2014lower duodenum to proximal 2\/3 of transverse colon. \u0083\t 6th week of development\u2014physiologic herniation of midgut through umbilical ring. \u0083\t 10th week of development\u2014returns to abdominal cavity rotating around superior mesenteric artery (SMA), 270\u00b0 counterclockwise (~180\u00b0 before 10th week, remaining ~90\u00b0 in 10th week). Hindgut\u2014distal 1\/3 of transverse colon to anal canal above pectinate line. Pharyngeal origin Foregut Midgut Hindgut Celiac trunk Aorta Superior mesenteric artery Inferior mesenteric artery","Gastrointestinal\u2003 \uf07d\u2009gastrointestinal\u2014Embryology SEC TION III 365 Ventral wall defects Developmental defects due to failure of rostral fold closure (eg, sternal defects [ectopia cordis]), lateral fold closure (eg, omphalocele, gastroschisis), or caudal fold closure (eg, bladder exstrophy). PRESENTATION COVERAGE Gastroschisis Omphalocele ASSOCIATIONS Paraumbilical herniation of abdominal contents Herniation of abdominal contents through through abdominal wall defect umbilicus Not covered by peritoneum or amnion A ; Covered by peritoneum and amnion B (light \u201cthe guts come out of the gap (schism) in the gray shiny sac); \u201cabdominal contents are sealed letter\u00a0G\u201d in the letter O\u201d Not associated with chromosome abnormalities; Associated with congenital \u201cOnomalies\u201d (eg, good prognosis trisomies 13 and 18, Beckwith-Wiedemann syndrome) and other structural abnormalities (eg, cardiac, GU, neural tube) AB Congenital umbilical Failure of umbilical ring to close after physiologic herniation of midgut. Covered by skin C . hernia Protrudes with \u008f intra-abdominal pressure (eg, crying). May be associated with congenital disorders (eg, Down syndrome, congenital hypothyroidism). Small defects usually close C spontaneously. uploaded by medbooksvn","366 SEC TION III Gastrointestinal\u2003 \uf07d\u2009gastrointestinal\u2014Embryology Tracheoesophageal Esophageal atresia (EA) with distal tracheoesophageal fistula (TEF) is the most common (85%) anomalies and often presents as polyhydramnios in utero (due to inability of fetus to swallow amniotic fluid). Neonates drool, choke, and vomit with first feeding. TEFs allow air to enter stomach (visible on CXR). Cyanosis is 2\u00b0 to laryngospasm (to avoid reflux-related aspiration). Clinical test: failure to pass nasogastric tube into stomach. In H-type, the fistula resembles the letter H. In pure EA, CXR shows gasless abdomen. Trachea Esophagus Tracheoesophageal \ufb01stula Esophageal atresia Normal anatomy Pure EA Pure TEF EA with distal TEF (atresia or stenosis) (H-type) (most common) Gastric bubble Gasless stomach Prominent gastric bubble Normal Intestinal atresia Presents with bilious vomiting and abdominal distension within first 1\u20132 days of life. A Duodenal atresia\u2014failure to recanalize. X-ray A shows \u201cdouble bubble\u201d (dilated stomach, proximal duodenum). Associated with Down syndrome. Jejunal and ileal atresia\u2014disruption of mesenteric vessels (typically SMA) \u008e ischemic necrosis of fetal intestine \u008e segmental resorption: bowel becomes discontinuous. X-ray may show \u201ctriple bubble\u201d (dilated stomach, duodenum, proximal jejunum) and gasless colon. Associated with cystic fibrosis and gastroschisis. May be caused by tobacco smoking or use of vasoconstrictive drugs (eg,\u00a0cocaine) during pregnancy. Hypertrophic pyloric Most common cause of gastric outlet obstruction in infants. Palpable olive-shaped mass (due to stenosis hypertrophy and hyperplasia of pyloric sphincter muscle) in epigastric region, visible peristaltic waves, and nonbilious projectile vomiting at \u223c 2\u20136 weeks old. More common in firstborn males; Narrow associated with exposure to macrolides. pyloric channel Results in hypokalemic hypochloremic metabolic alkalosis (2\u00b0 to vomiting of gastric acid and subsequent volume contraction). Thickened and lengthened Ultrasound shows thickened and lengthened pylorus. pylorus Treatment: surgical incision of pyloric muscles (pyloromyotomy).","Gastrointestinal\u2003 \uf07d\u2009gastrointestinal\u2014Anatomy SEC TION III 367 Pancreas and spleen Pancreas\u2014derived from foregut. Ventral pancreatic bud contributes to uncinate process. Both embryology ventral and dorsal buds contribute to pancreatic head and main pancreatic duct. A Annular pancreas\u2014abnormal rotation of ventral pancreatic bud forms a ring of pancreatic tissue stomach \u008e\u00a0encircles 2nd part of duodenum; may cause duodenal narrowing (arrows in A ) and vomiting. Associated with Down syndrome. Pancreas divisum\u2014ventral and dorsal parts fail to fuse at 7 weeks of development. Common anomaly; mostly asymptomatic, but may cause chronic abdominal pain and\/or pancreatitis. Spleen\u2014arises in mesentery of the stomach (dorsal mesogastrium, hence, mesodermal), but has foregut supply (celiac trunk \u008e\u00a0splenic artery). ` \u2009GASTROINTESTINAL \u2014 ANATOMY Retroperitoneal Retroperitoneal structures A are posterior to SAD PUCKER: structures (and outside of) the peritoneal cavity. Injuries Suprarenal (adrenal) glands [not shown] Duodenum Ascending to retroperitoneal structures can cause blood Aorta and IVC colon or gas accumulation in retroperitoneal space. Duodenum (2nd through 4th parts) Right Pancreas (except tail) Liver Ureters [not shown] Colon (descending and ascending) Kidneys Esophagus (thoracic portion) [not shown] Duodenum\/jejunum Rectum (partially) [not shown] Peritoneum Descending A colon Left Pancreas IVC Kidney Asc Desc Aorta Colon Colon IVC Ao R. Kid L. Kid uploaded by medbooksvn","368 SEC TION III Gastrointestinal\u2003 \uf07d\u2009gastrointestinal\u2014Anatomy Important gastrointestinal ligaments Liver Falciform Diaphragm ligament Liver Stomach Hepatogastric Stomach Portal triad ligament Spleen Hepatoduodenal Spleen ligament Transverse Kidney Gastrosplenic colon ligament Splenorenal ligament Gastrocolic ligament LIGAMENT CONNECTS STRUCTURES CONTAINED NOTES Falciform ligament Liver to anterior abdominal Ligamentum teres hepatis Derivative of ventral mesentery wall (derivative of fetal umbilical vein), patent paraumbilical Derivative of ventral mesentery Hepatoduodenal Liver to duodenum veins Pringle maneuver\u2014ligament is ligament Portal triad: proper hepatic compressed manually or with Hepatogastric Liver to lesser curvature of artery, portal vein, common a vascular clamp in omental ligament stomach bile duct foramen to control bleeding from hepatic inflow source Gastrocolic ligament Greater curvature and Gastric vessels (portal vein, hepatic artery) vs transverse colon outflow (hepatic veins, IVC) Gastrosplenic Gastroepiploic arteries Borders the omental foramen, ligament Greater curvature and spleen Short gastrics, left which connects the greater and lesser sacs Splenorenal ligament Spleen to left pararenal space gastroepiploic vessels Part of lesser omentum Splenic artery and vein, tail of Derivative of ventral mesentery pancreas Separates greater and lesser sacs on the right May be cut during surgery to access lesser sac Part of lesser omentum Derivative of dorsal mesentery Part of greater omentum Derivative of dorsal mesentery Separates greater and lesser sacs on the left Part of greater omentum Derivative of dorsal mesentery","Gastrointestinal\u2003 \uf07d\u2009gastrointestinal\u2014Anatomy SEC TION III 369 Digestive tract Layers of gut wall A (inside to outside\u2014MSMS): anatomy \u0083\t Mucosa\u2014epithelium, lamina propria, muscularis mucosa \u0083\t Submucosa\u2014includes submucosal nerve plexus (Meissner), secretes fluid Mesentery \u0083\t Muscularis externa\u2014includes myenteric nerve plexus (Auerbach), motility Vein \u0083\t Serosa (when intraperitoneal), adventitia (when retroperitoneal) Lymph vAertsesreyl Ulcers can extend into submucosa, inner or outer muscular layer. Erosions are in mucosa only. Lumen Frequency of basal electric rhythm (slow waves), which originate in the interstitial cells of Cajal: duodenum > ileum > stomach. A Mucosa Tunica mucosa Epithelium Lamina propria Muscularis mucosa Submucosa Tunica submucosa Submucosal gland Submucosal nerve plexus (Meissner) Serosa Muscularis Tunica muscularis Inner circular layer Tunica serosa Myenteric nerve plexus (peritoneum) (Auerbach) Outer longitudinal layer Digestive tract histology Esophagus Nonkeratinized stratified squamous epithelium. Upper 1\/3, striated muscle; middle and lower 2\/3 smooth muscle, with some overlap at the transition. Stomach Gastric glands A . Parietal cells are eosinophilic (pink), chief cells are basophilic. Duodenum Villi B and microvilli \u008f absorptive surface. Brunner glands (bicarbonate-secreting cells of submucosa), crypts of Lieberk\u00fchn (contain stem cells that replace enterocytes\/goblet cells and Paneth cells that secrete defensins, lysozyme, and TNF), and plicae circulares (distal duodenum). Jejunum Villi, crypts of Lieberk\u00fchn, and plicae circulares (taller, more prominent, numerous [vs ileum]) \u008e feathered appearance with oral contrast and \u008f surface area. Ileum Villi, Peyer patches (arrow in C ; lymphoid aggregates in lamina propria, submucosa), plicae circulares (proximal ileum), crypts of Lieberk\u00fchn. Largest number of goblet cells in small intestine. Colon Crypts of Lieberk\u00fchn with abundant goblet cells, but no villi D . ABCD uploaded by medbooksvn","370 SEC TION III Gastrointestinal\u2003 \uf07d\u2009gastrointestinal\u2014Anatomy Abdominal aorta and branches Superior and inferior Arteries supplying GI structures are single and mesenteric artery branch anteriorly. Abdominal watershed aorta Splenic \ufb02exure Arteries supplying non-GI structures are paired and branch laterally and posteriorly. Superior Inferior mesenteric mesenteric artery Two areas of the colon have dual blood supply from distal arterial branches (\u201cwatershed artery Inferior mesenteric areas\u201d) \u008e\u00a0susceptible in colonic ischemia: and hypogastric \u0083\t Splenic flexure\u2014SMA and IMA Hypogastric artery artery watershed \u0083\t Rectosigmoid junction\u2014IMA branches (last (internal iliac artery) Rectosigmoid junction sigmoid arterial branch and superior rectal artery) Duodenum Aorta Nutcracker syndrome\u2014compression of left renal vein between superior mesenteric artery and aorta. May cause abdominal (flank) pain, gross hematuria (from rupture of thin-walled renal varicosities), left-sided varicocele. Superior mesenteric artery syndrome\u2014 characterized by intermittent intestinal obstruction symptoms (primarily postprandial pain) when SMA and aorta compress transverse (third) portion of duodenum. Typically occurs in conditions associated with diminished mesenteric fat (eg, rapid weight loss, low body weight, malnutrition, gastric bypass surgeries). SMA","Gastrointestinal\u2003 \uf07d\u2009gastrointestinal\u2014Anatomy SEC TION III 371 Gastrointestinal blood supply and innervation EMBRYONIC ARTERY PARASYMPATHETIC VERTEBRAL STRUCTURES SUPPLIED GUT REGION INNERVATION LEVEL Celiac Pharynx (vagus nerve only) and lower esophagus Foregut Vagus T12\/L1 (celiac artery only) to proximal duodenum; liver, gallbladder, pancreas, spleen (mesoderm) Midgut SMA Vagus L1 Distal duodenum to proximal 2\/3 of transverse colon Hindgut IMA Pelvic L3 Distal 1\/3 of transverse colon to upper portion of anal canal Sympathetic innervation arises from abdominal prevertebral ganglia: celiac, superior mesenteric, and inferior mesenteric. Celiac trunk Branches of celiac trunk: common hepatic, splenic, and left gastric. These constitute the main blood supply of the foregut. Strong anastomoses exist between: \u0083\t Left and right gastroepiploics \u0083\t Left and right gastrics Celiac trunk Abdominal aorta Common hepatic Esophageal branches Left hepatic Right hepatic Left gastric Splenic Cystic Short gastric Left gastroepiploic Proper hepatic Gastroduodenal Areas supplied by: Posterior superior Left gastric artery pancreaticoduodenal Splenic artery Anterior superior Common hepatic artery pancreaticoduodenal Anastomosis Right gastric Right gastroepiploic uploaded by medbooksvn","372 SEC TION III Gastrointestinal\u2003 \uf07d\u2009gastrointestinal\u2014Anatomy Portosystemic anastomoses Azygos vein Pathologic blood in portal hypertension Flow through TIPS, reestablishing IVC Esophageal veins normal \ufb02ow direction Left gastric vein Normal venous drainage Hepatic vein Portosystemic Systemic venous system shunt Portal venous system Portal vein Paraumbilical Splenic vein vein Inferior mesenteric vein Umbilicus Epigastric Superior rectal veins vein Middle rectal veins Inferior rectal veins SITE OF ANASTOMOSIS CLINICAL SIGN PORTAL \u2194 SYSTEMIC Esophagus Esophageal varices Left gastric \u2194 esophageal (drains into azygos) Umbilicus Caput medusae Paraumbilical \u2194 small epigastric veins (branches of inferior and superficial epigastric veins) of the anterior abdominal wall Rectum Anorectal varices Superior rectal \u2194 middle and inferior rectal Varices of gut, butt, and caput (medusae) are commonly seen with portal hypertension. T\u0007 reatment with a Transjugular Intrahepatic Portosystemic Shunt (TIPS) between the portal vein and hepatic vein relieves portal hypertension by shunting blood to the systemic circulation, bypassing the liver. TIPS can precipitate hepatic encephalopathy due to \u0090\u00a0clearance of ammonia from shunting.","Gastrointestinal\u2003 \uf07d\u2009gastrointestinal\u2014Anatomy SEC TION III 373 Pectinate line Also called dentate line. Formed where endoderm (hindgut) meets ectoderm. Nerves Arteries Veins Lymphatics Above pectinate line: internal hemorrhoids, Visceral innervation Superior rectal Superior rectal vein Drain to internal adenocarcinoma. (inferior hypogastric artery (branch \u2192 IMV \u2192 splenic vein \u2192 portal vein iliac LN Internal hemorrhoids\u2014abnormal distention of plexus [T12\u2013L3]) of IMA) anal venous plexus A . Risk factors include older age and chronic constipation. Receive visceral innervation and are therefore not painful. A Pectinate line Somatic innervation Inferior rectal artery Inferior rectal vein Drain to super\ufb01cial Below pectinate line: external hemorrhoids, (pudendal nerve (branch of internal \u2192 internal pudendal inguinal LN anal fissures, squamous cell carcinoma. [S2\u2013S4]) pudendal artery) vein \u2192 internal iliac vein \u2192 common iliac External hemorrhoids\u2014receive somatic innervation (inferior rectal branch of vein \u2192 IVC pudendal nerve) and are therefore painful if thrombosed. Anal fissure\u2014tear in anoderm below pectinate line. Pain while pooping; blood on toilet paper. Located in the posterior midline because this area is poorly perfused. Associated with low-fiber diets and constipation. uploaded by medbooksvn","374 SEC TION III Gastrointestinal\u2003 \uf07d\u2009gastrointestinal\u2014Anatomy Liver tissue The functional unit of the liver is made up of Dual blood supply to liver: portal vein (~80%) architecture hexagonally arranged lobules surrounding the and hepatic artery (~20%). central vein with portal triads on the edges A (consisting of a portal vein, hepatic artery, bile Zone I\u2014periportal zone: ducts, as well as lymphatics) A . \u0083\t Affected 1st by viral hepatitis \u0083\t Best oxygenated, most resistant to circulatory Apical surface of hepatocytes faces bile compromise canaliculi. Basolateral surface faces sinusoids. \u0083\t Ingested toxins (eg, cocaine) Kupffer cells (specialized macrophages) located Zone II\u2014intermediate zone: in sinusoids clear bacteria and damaged or \u0083\t Yellow fever senescent RBCs. Zone III\u2014pericentral (centrilobular) zone: Hepatic stellate (Ito) cells in space of Disse \u0083\t Affected 1st by ischemia (least oxygenated) store vitamin A (when quiescent) and produce \u0083\t High concentration of cytochrome P-450 extracellular matrix (when activated). \u0083\t Most sensitive to metabolic toxins (eg, Responsible for hepatic fibrosis. ethanol, CCl4, rifampin, acetaminophen) \u0083\t Site of alcoholic hepatitis Central vein (drains into hepatic vein) Sinusoids Stellate cell Space of Disse Zone 1 Branch of Kup er cell Zone 2 hepatic artery Zone 3 Blood \ufb02ow Branch of Bile \ufb02ow portal vein Bile ductule","Gastrointestinal\u2003 \uf07d\u2009gastrointestinal\u2014Anatomy SEC TION III 375 Biliary structures Cholangiography shows filling defects in gallbladder (blue arrow in A ) and common bile (red A arrow in A ). Femoral region Gallstones that reach the confluence of the common bile and pancreatic ducts at the ampulla of Vater can block both the common bile and pancreatic ducts (double duct sign), causing both ORGANIZATION cholangitis and pancreatitis, respectively. Femoral triangle Tumors that arise in head of pancreas (usually ductal adenocarcinoma) can cause obstruction of Femoral sheath common bile duct \u008e\u00a0enlarged gallbladder with painless jaundice (Courvoisier sign). Cystic duct Liver Gallbladder Common hepatic duct Common bile duct Accessory Neck Tail pancreatic duct Head Body Sphincter of Oddi Duodenum Pancreas Ampulla of Vater Main pancreatic duct Lateral to medial: nerve-artery-vein-lymphatics. You go from lateral to medial to find your navel. Contains femoral nerve, artery, vein. Fascial tube 3\u20134 cm below inguinal ligament. Venous near the penis. Contains femoral vein, artery, and canal (deep inguinal lymph nodes) but not femoral nerve. External iliac vessels Inferior epigastric Iliopsoas vessels Rectus abdominis Anterior superior Inguinal (Hesselbach) iliac spine triangle Femoral artery Femoral nerve Femoral vein Inguinal ligament Femoral ring Lymphatics Fascia lata Femoral triangle Saphenous opening Femoral sheath Satorius Adductor longus uploaded by medbooksvn","376 SEC TION III Gastrointestinal\u2003 \uf07d\u2009gastrointestinal\u2014Anatomy Inguinal canal Deep (internal) Inferior epigastric inguinal ring vessels ANTEROLATERAL ABDOMINAL WALL LAYERS site of protrusion of Abdominal wall site of protrusion of Parietal peritoneum indirect hernia direct hernia Extraperitoneal tissue Transversalis fascia Super\ufb01cial (external) Medial umbilical ligament Transversus abdominis muscle inguinal ring Median umbilical ligament Internal oblique muscle Rectus abdominis muscle Aponeurosis of external Pyramidalis muscle oblique muscle Conjoint tendon Linea alba Inguinal ligament SPERMATIC CORD LAYERS (ICE tie) External spermatic fascia (external oblique) Cremasteric muscle and fascia (internal oblique) Internal spermatic fascia (transversalis fascia) Myopectineal orifi e Anterior superior iliac spine Evagination of INGUINAL CANAL CONTENTS transversalis fascia Internal (deep) inguinal ring Female: round ligament of uterus Male: ductus (vas) deferens INGUINAL (HESSELBACH) TRIANGLE Ilioinguinal nerve Internal spermatic vessels Pubic tubercle Pubis symphysis Femoral nerve External iliac vessels Femoral ring Anterior abdominal wall (viewed from inside) Hernias Protrusion of peritoneum through an opening, usually at a site of weakness. Contents may be at Spigelian hernia risk for incarceration (not reducible back into abdomen\/pelvis) and strangulation (ischemia and necrosis). Complicated hernias can present with tenderness, erythema, fever. Also called spontaneous lateral ventral hernia or hernia of semilunar line. Occurs through defects between the rectus abdominis and the semilunar line in the Spigelian aponeurosis. Most occur in the lower abdomen due to lack of the posterior rectus sheath. Presentation is variable but may include abdominal pain and a palpable lump along the Spigelian fascia. Diagnosis: ultrasound and CT scan.","Gastrointestinal\u2003 \uf07d\u2009gastrointestinal\u2014Anatomy SEC TION III 377 Hernias (continued) Abdominal structures enter the thorax. Bowel sounds may be heard on chest auscultation. Most Diaphragmatic hernia common causes: A \u0083\t Infants\u2014congenital defect of pleuroperitoneal membrane \u008e\u00a0left-sided herniation (right hemidiaphragm is relatively protected by liver) A . Indirect inguinal \u0083\t Adults\u2014laxity\/defect of phrenoesophageal membrane \u008e\u00a0hiatal hernia (herniation of stomach hernia through esophageal hiatus). B Sliding hiatal hernia\u2014gastroesophageal Herniated Herniated junction is displaced upward as gastric cardia gastric cardia gastric fundus slides into hiatus; \u201chourglass stomach.\u201d Most common type. Associated with GERD. Sliding hiatal hernia Paraesophageal hiatal hernia Paraesophageal hiatal hernia\u2014 gastroesophageal junction is usually normal but gastric fundus protrudes into the thorax. Goes through the internal (deep) inguinal Peritoneum ring, external (superficial) inguinal ring, and Deep into the groin. Enters internal inguinal ring inguinal ring lateral to inferior epigastric vessels. Caused Inguinal canal by failure of processus vaginalis to close (can form hydrocele). May be noticed in infants or Super\ufb01cial discovered in adulthood. Much more common inguinal ring in males B . Intestinal loop within spermatic Follows the pathway of testicular descent. cord Covered by all 3 layers of spermatic fascia. Testis Direct inguinal hernia Protrudes through inguinal (Hesselbach) Peritoneum Deep Femoral hernia triangle. Bulges directly through parietal inguinal peritoneum medial to the inferior epigastric Intestinal ring vessels but lateral to the rectus abdominis. loop Super\ufb01cial Goes through external (superficial) inguinal inguinal ring ring only. Covered by external spermatic fascia. Usually occurs in older males due to Spermatic cord acquired weakness of transversalis fascia. Testis MDs don\u2019t lie: Medial to inferior epigastric vessels = Intestinal loop Direct\u00a0hernia. beneath inguinal Lateral to inferior epigastric vessels = indirect ligament hernia. Protrudes below inguinal ligament through femoral canal below and lateral to pubic tubercle. More common in females, but overall inguinal hernias are the most common. More likely to present with incarceration or strangulation (vs inguinal hernia). uploaded by medbooksvn","378 SEC TION III Gastrointestinal\u2003 \uf07d\u2009gastrointestinal\u2014Physiology ` \u2009GASTROINTESTINAL \u2014 P H YSIOLOGY Gastrointestinal regulatory substances REGULATORY SUBSTANCE SOURCE ACTION REGULATION NOTES Gastrin G cells (antrum \u008f\u2002\u0007\u0007gastric H+ secretion \u008f\u2002\u0007by stomach \u008f by chronic PPI use of stomach, \u008f\u2002\u0007growth of gastric mucosa distention\/ \u008f in chronic atrophic gastritis duodenum) \u008f\u2002\u0007gastric motility alkalinization, amino acids, (eg, H pylori) peptides, vagal \u008f\u008f in Zollinger-Ellison stimulation via gastrin-releasing syndrome (gastrinoma) peptide (GRP) Somatostatin D cells \u0090\u2002\u0007gastric acid and Inhibits secretion of various (pancreatic islets, pepsinogen secretion \u0090\u2002\u0007by pH < 1.5 hormones (encourages Cholecystokinin GI mucosa) \u008f\u2002\u0007by acid somato-stasis) \u0090\u2002\u0007pancreatic and small \u0090\u2002\u0007by vagal Secretin I cells (duodenum, intestine fluid secretion Octreotide is an analog used jejunum) stimulation to treat acromegaly, carcinoid Glucose- \u0090\u2002\u0007gallbladder contraction syndrome, VIPoma, and dependent S cells \u0090\u2002\u0007insulin and glucagon \u008f\u2002\u0007by fatty acids, variceal bleeding insulinotropic (duodenum) amino acids peptide release Acts on neural muscarinic Motilin K cells \u008f\u2002\u0007by acid, fatty pathways to cause pancreatic (duodenum, \u008f\u2002\u0007pancreatic secretion acids in lumen secretion jejunum) \u008f\u2002\u0007gallbladder contraction of duodenum \u0090\u2002\u0007gastric emptying \u008f\u2002\u0007sphincter of Oddi \u008f\u2002\u0007by fatty acids, amino acids, relaxation oral glucose \u008f\u2002\u0007pancreatic HCO3\u2013 \u008f\u2002 in fasting state \u008f aHciCdOin3\u2013dnueoudteranluizmes, gastric secretion allowing \u0090\u2002\u0007gastric acid secretion \u008f\u2002\u0007by distention pancreatic enzymes to and vagal function \u008f\u2002\u0007bile secretion stimulation Exocrine: \u0090\u2002\u0007by adrenergic Also called gastric inhibitory \u0090\u2002 gastric H+ secretion input peptide (GIP) Endocrine: \u008f\u2002 in fasting state Oral glucose load \u008f\u00a0insulin \u008f\u2002 insulin release \u0090\u2002 by food compared to IV equivalent due to GIP secretion Small intestine Produces migrating motor Motilin receptor agonists (eg, complexes (MMCs) erythromycin) are used to stimulate intestinal peristalsis. Vasoactive Parasympathetic \u008f\u2002\u0007intestinal water and VIPoma\u2014non-\u03b1, non-\u03b2 islet intestinal ganglia in electrolyte secretion cell pancreatic tumor that sphincters, secretes VIP; associated polypeptide gallbladder, \u008f\u2002\u0007relaxation of intestinal with Watery Diarrhea, small intestine smooth muscle and Hypokalemia, Achlorhydria sphincters (WDHA syndrome) Nitric oxide \u008f\u2002\u0007smooth muscle Loss of NO secretion is relaxation, including implicated in \u008f LES tone of lower esophageal achalasia sphincter (LES) Ghrelin Stomach \u008f in Prader-Willi syndrome \u008f\u2002appetite (\u201cghrowlin\u2019 \u0090 after gastric bypass surgery stomach\u201d)","Gastrointestinal\u2003 \uf07d\u2009gastrointestinal\u2014Physiology SEC TION III 379 Gastrointestinal secretory products PRODUCT SOURCE ACTION REGULATION NOTES Gastric acid Parietal cells \u0090 stomach pH \u008f\u2002\u0007by histamine, Autoimmune destruction (stomach A ) Vitamin B12\u2013binding vagal of parietal cells \u008e chronic stimulation gastritis and pernicious Intrinsic factor Parietal cells protein (required for B12 (ACh), gastrin anemia (stomach) uptake in terminal ileum) \u0090\u2002\u0007by somatostatin, Pepsinogen (inactive) is Pepsin Chief cells Protein digestion GIP, converted to pepsin (active) in Bicarbonate (stomach) prostaglandin, the presence of H+ Neutralizes acid secretin Mucosal cells Trapped in mucus that covers (stomach, \u008f\u2002\u0007by vagal the gastric epithelium duodenum, stimulation salivary glands, (ACh), local pancreas) and acid Brunner glands (duodenum) \u008f\u2002\u0007by pancreatic and biliary secretion with secretin A Gastric pit Surface epithelium Upper glandular Mucous cell layer Parietal cell Deeper glandular Chief cell layer Enterochroma n-like Muscularis mucosa cell Submucosa uploaded by medbooksvn"]