Endocrinology Slides PDF (2022) - Boards & Beyond

Boards & Beyond: Endocrinology Slides Color slides for USMLE Step 1 preparation from the Boards and Beyond Website Jason Ryan, MD, MPH 2022 Edition Boards & Beyond provides a virtual medical school curriculm used by studen...

Boards & Beyond: Endocrinology Slides Color slides for USMLE Step 1 preparation from the Boards and Beyond Website Jason Ryan, MD, MPH 2022 Edition Boards & Beyond provides a virtual medical school curriculm used by students around the globe to supplement their education and prepare for board exams such as USMLE Step 1. This book of slides is intended as a companion to the videos for easy reference and note-taking. Videos are subject to change without notice. PDF versions of all color books are available via the website as part of membership. Visit www.boardsbeyond.com to learn more. Copyright © 2022 Boards and Beyond All rights reserved. i ii  Table of Contents Thyroid Gland........................................................1 Treatment of Diabetes.................................... 59 Thyroid Disorders...............................................9 Reproductive Hormones................................ 65 Thyroid Cancer.................................................. 17 Male Reproductive Hormones..................... 69 Adrenal Glands................................................... 20 Female Reproductive Hormones................ 77 CAH......................................................................... 25 Menstrual Cycle................................................. 81 Adrenal Disorders............................................. 30 Pituitary Gland................................................... 88 Endocrine Pancreas......................................... 39 Parathyroid Gland............................................. 96 Diabetes................................................................ 46 MEN Syndromes..............................................104 Insulin.................................................................... 55 Signaling Pathways.........................................107 iii iv  Thyroid Gland Thyroid Anatomy Two lobes (left, right) Isthmus: thin band of tissue between lobes Sometimes pyramidal lobe above isthmus Thyroid Gland Jason Ryan, MD, MPH Thyroid Anatomy Thyroid Embryology Blood supply: superior and inferior thyroid arteries Forms from floor of pharynx (epithelial cells) Superior thyroid: 1st branch external carotid artery 24-28 Day Old Embryo Inferior thyroid: Thyrocervical trunk (off subclavian) Wikipedia/Public Domain Thyroid Embryology Foramen Cecum Descends into neck Foramen Cecum Initially maintains connection to tongue (end of median sulcus) Thyroglossal duct Disappears later in development Two remnants of duct in child/adult Foramen cecum in tongue Pyramidal lobe of thyroid 1 Thyroglossal Duct Cyst Ectopic Thyroid Persistent remnant of thyroglossal duct Functioning thyroid tissue outside of gland Midline neck mass; usually painless Most common location is base of tongue Usually discovered in childhood Presents as a mass in the tongue Classically, move up with swallowing or tongue Commonly detected during increased demand for hormones protrusion Puberty and pregnancy May contain thyroid cells May be the only functioning thyroid tissue May under-produce thyroid hormone → hypothyroidism ↑ TSH → growth of ectopic tissue Klaus D. Peter, Gummersbach, Germany Thyroid Histology Thyroid Hormones Thyroid gland contains “follicles” Contain the element iodine Filled with colloid (protein material) Iodized salt Single layer of epithelial cells lines each follicle Table salt (NaCl) mixed with small minute amount of iodine “Follicular cells” Done in many countries to prevent iodine deficiency Added to salt in US in 1924 Hormone synthesized by follicular cells Uwe Gille/Wikipedia Thyroid Hormones Thyroglobulin Two hormones: T3 and T4 Large protein Synthesized from tyrosine and iodine Produced by thyroid follicular cells Contains numerous tyrosine molecules Tyrosine Tyrosine Tyrosine Tyrosine Tyrosine Tyrosine Thyroglobulin Triiodothyronine (T3) Thyroxine (T4) 2 Iodine NIS Iodine = I (chemical element, atomic number 53) Na-Iodine Symporter Iodide = iodine bound to another atom Follicular Cell “Iodide salt” with negative charge (I-) Potassium iodide = KI Plasma iodine exists as iodide salt Perchlorate (ClO4-) For thyroid hormone, iodide in our diet needs to be: Pertechnetate (TcO4-) Taken up by follicular cells Na Iodide Oxidized to I2 (undergo “oxidation”) X NIS Added to organic/carbon structures (“organification”) Ty Ty Ty Ty Ty TG Plasma Follicle Lumen Follicular Cell Monoiodotyrosine (MIT) Tyrosine Thyroid Peroxidase (TPO) + Iodide Thyroid Peroxidase (TPO) I2 Ty Ty Ty Ty Ty Iodine (I2) TG Plasma Diiodotyrosine Follicle Lumen (DIT) Hormone Synthesis Coupling Reactions Thyroid Peroxidase Thyroid Peroxidase (TPO) Diiodotyrosine (TPO) Monoiodotyrosine (DIT) (MIT) Triiodothyronine (T3) Thyroxine (T4) Diiodotyrosine Diiodotyrosine (DIT) (DIT) 3 TPO Hormone Synthesis Thyroid Peroxidase Plasma Multifunctional enzyme Follicle Lumen T4 Catalyzes: T3 T3 Follicular Cell T3 T4 T4 T4 Oxidation of iodide T3 T4 T4 Organification of iodine into MIT/DIT TG Proteolysis Coupling of MIT/DIT into T3/T4 TPO antibodies common in autoimmune thyroid TPO disease MIT DIT MIT DIT Iodide Thyroid Peroxidase (TPO) TPO TG I2 Ty Ty Ty Ty Ty TG Thyroid Hormones Hyperthyroid Medications T4 is major hormone produced by thyroid gland Propylthiouracil (PTU) >90% of thyroid hormone produced is T4 Inhibits TPO: ↓ T3/T4 from thyroid gland T3 more potent hormone Inhibits 5’-deiodinase: ↓ T4 to T3 conversion peripherally T4 is a “prohormone” for T3 Methimazole Inhibits TPO PTU and Methimazole are both 5’ deiodinase converts T4 → T3 Propranolol “thioamides” Most conversion occurs in peripheral tissues Beta blocker Iodine Weak inhibitor of 5’-deiodinase Excellent drug in thyrotoxicosis Blocks catecholamines and T4-T3 conversion 5’-deiodinase Thyroxine (T4) Triiodothyronine (T3) Wolff-Chaikoff Effect Amiodarone Excessive iodide in diet could lead to hyperthyroidism Class III antiarrhythmic drug Thyroid protects itself via Wolff-Chaikoff Effect Commonly used in atrial fibrillation Organification inhibited by ↑ iodide Contains iodine Less synthesis of MIT/DIT Can cause hypothyroidism via excess iodine Wolff-Chaikoff Effect 4 Amiodarone Radioactive Iodine Mimics T4 I131 is an isotope of iodine Inhibits 5’-deiodinase Has 53 protons like elemental iodine ↓T3 → ↑TSH from pituitary gland Extra neutrons TSH rises after start of therapy then normalizes Emits radiation (β-decay) Exposure → radioactive iodine in thyroid gland Competes with elemental iodine for uptake Will concentrate in thyroid gland Small dose: Used for imaging Large dose: Destroys thyroid tissue Used as therapy for hyperthyroidism TBG TBG Thyroxine-Binding Globulin Thyroxine-Binding Globulin Most plasma thyroid hormone is T4 Estrogen raises TBG levels Thyroid hormones poorly soluble in water Modifies TBG molecules Slows clearance from plasma Most T4 is bound to TBG Pregnancy, OCP users Some with transthyretin and albumin Will raise total T4 levels TBG present in small amount but has high affinity TBG produced in liver Liver failure lowers TBG levels Less production of protein Key point: Can lower total T4 levels Less TBG → less available T4/T3 to tissues TBG-T4 → T4 TBG Thyroid Hormone Receptor Thyroxine-Binding Globulin Rise in TBG Family of nuclear receptors Hormone-activated transcription factors More bound T4 Modulate gene expression Less free T4 ↑TSH ↑Total T4 ↑ Free T4 (back to normal) ↓TSH (back to normal) 5 Effects of Thyroid Hormone Thyroid Hormone Metabolic Effects Major regulator of metabolic activity and growth ↑ Carbohydrate Metabolism Glucose, lipid metabolism ↑ glycogenolysis, gluconeogenesis Cardiac function ↑ Fat Metabolism ↑ lipolysis Bone growth ↓ concentrations of cholesterol, triglycerides CNS development ↑ low‐density lipoprotein receptors in liver (↓ LDL) ↑ cholesterol secretion in bile Hypothyroid patients: ↑ cholesterol Hyperthyroid patients: hyperglycemia Thyroid Hormone Thyroid Hormone Metabolic Effects Cardiac Effects ↑ basal metabolic rate ↑ CO/HR/SV/contractility Basal rate of energy use per time ↑ β1 receptors in heart Amount of energy burned if you slept all day Hyperthyroid patients: Tachycardia ↑ Na/K ATPase pumps More pumps = more ATP consumed ↑ oxygen demand to replenish ATP ↑ respiratory rate ↑ body temperature Hyperthyroid patients: weight loss McDonough AA, et al. Thyroid hormone coordinately regulates Na+-K+-ATPase alpha- and beta-subunit mRNA levels in kidney. Am J Physiol. 1988 Feb;254(2 Pt 1):C323-9. Thyroid Hormone Thyroid Hormone CNS and Bone effects CNS and Bone effects TH required for normal bone growth/CNS maturation Most common treatable cause intellectual disability Childhood hypothyroidism → cretinism Most babies appear normal Stunted growth Maternal T3/T4 crosses placenta Intellectual disability Newborn screening programs Causes Measure T4 or TSH from heel-stick blood specimens Iodine deficiency Thyroid dysgenesis Inborn errors of hormone synthesis (dyshormonogenesis) TPO most common 6 Thyroid Hormone Thyroid Hormone Regulation CNS and Bone effects Intellectual disability TSH (thyrotropin) released by anterior pituitary Coarse facial features Binds to receptors on follicular cells Short stature Activates cAMP/PKA 2nd messenger system Umbilical hernia ↑ T3/T4 release Enlarged tongue ↑ rate of proteolysis of thyroglobulin Leads to rapid release of more T3/T4 Also stimulates thyroid cell growth, TG synthesis Wellcome Images/Wikipedia Thyroid Hormone Regulation Pregnancy Serum T4/T3 level sensed by hypothalamus Multiple effects on thyroid hormone production Releases thyroid releasing hormone (TRH) Rise in total plasma T4/T3 levels Rise in TBG levels (estrogen) hCG stimulates thyroid (same alpha unit as TSH) Raises free T4 → lower TSH TBG Total T4 Free T4 TSH Mikael Häggström/Wikipedia Weeks of Pregnancy Thyroid Panel Calcitonin Four standard measurements to assess thyroid Hormone produced by thyroid Synthesized by parafollicular cells (C-cells) C cell Andrea Mazza/Wikipedia 7 Calcitonin Lowers serum calcium Suppresses resorption of bone; inhibits osteoclasts Inhibits renal reabsorption of calcium, phosphorus Increased calcium in urine Probably minor role in calcium handling in humans Used as pharmacologic therapy for hypercalcemia 8  Thyroid Disorders Thyroid Disorders Thyroid Disorders Thyroid Disorders Jason Ryan, MD, MPH Hyperthyroid Hypothyroid Thyroiditis Hypothyroidism Hyperlipidemia Metabolism SLOWS DOWN Classic feature of hypothyroidism Lethargy, fatigue ↑ total cholesterol Weakness; dyspnea on exertion ↑ LDL cholesterol Cold intolerance Primary mechanism: ↓ LDL receptor density Weight gain with loss of appetite T3 upregulates LDL receptor gene activation Constipation Hyporeflexia Dry, cool skin Coarse, brittle hair Bradycardia Myxedema Myxedema Thyroid dermopathy Thyroid dermopathy Non-pitting edema of the skin from hypothyroidism Hyaluronic acid deposits in dermis Draws water out → swelling Usually facial/periorbital swelling Pretibial myxedema Special form of myxedema over shin Seen in Graves' disease (hyperthyroidism) Myxedema coma = coma from hypothyroidism Herbert L. Fred, MD and Hendrik A. van Dijk 9 Hypothyroid Myopathy Hyponatremia Muscle symptoms common in hypothyroid Hypothyroidism is a well-described cause ↓Na Weakness, cramps, myalgias High levels of ADH (SIADH) ↑ serum creatine kinase (CK) common (up to 90%) May lead to confusion Wikipedia/Public Domain Thyroid Replacement Hyperthyroidism Levothyroxine (Synthroid): synthetic T4 Metabolism SPEEDS UP Liothyronine (Cytomel): synthetic T3 Hyperactivity Levothyroxine preferred Heat intolerance T3 absorbed from intestines rapidly Weight loss with increased appetite Can cause mild hyperthyroidism symptoms Diarrhea Tachycardia, tremor Hyperreflexia Also, T4 converted to T3 Titrate dose until TSH is normal Warm, moist skin Fine hair Tachycardia (atrial fibrillation) Thyroid Storm Goiter Life-threatening hyperthyroidism (thyrotoxicosis) Enlarged thyroid Usually precipitated by acute event High TSH, inability to produce T3/T4 Patient with pre-existing hyperthyroid disease Thyroid stimulating antibodies (Graves') Graves' or toxic multinodular goiter Surgery, trauma, infection Massive catecholamine surge Fever, delirium Tachycardia with death from arrhythmia Hyperglycemia (catecholamines/thyroid hormone) Hypercalcemia (bone turnover) Wikipedia/Public Domain 10 Lab Findings Lab Findings Best initial test is TSH Most disorders are primary disease Disorder of the thyroid gland TSH is opposite thyroid hormone Hypothyroidism = ↑ TSH with low T3/T4 TSH Hyperthyroidism = ↓ TSH with high T3/T4 Lab Findings Reverse T3 Central hyper/hypo thyroid disease Isomer of T3 also derived from T4 Low TSH and low T3/T4; High TSH and high T3/T4 Rare disorders of the pituitary, hypothalamus Usually hypothalamic-pituitary tumors Tumors block secretion TRH/TSH (hypothyroidism) Rarely a TSHoma can secrete TSH (hyperthyroidism) Reverse T3 Pituitary resistance to thyroid hormone (hyperthyroidism) Thyroxine (T4) Triiodothyronine (T3) Reverse T3 Hyperthyroidism Level usually parallels T4 Graves' disease (#1 cause) Low T4 → Low rT3 Toxic multinodular goiter One special use: Euthyroid sick syndrome Amiodarone Critically ill patients → low TSH → Low T3/T4 Iodine load Can look like central hypothyroidism Early thyroiditis rT3 rises in critical illness (impaired clearance) Critically ill patient with low TSH/T4/T3 Check rT3 Low → central hypothyroidism High → sick euthyroid syndrome 11 Graves' Disease Graves' Disease Autoimmune disease Exophthalmos (bulging eyes) Thyroid stimulating antibodies produced Proptosis (protrusion of eye) and periorbital edema Usually no ocular symptoms Symptoms of hyperthyroidism occur Pretibial myxedema (shins) T-cell lymphocyte activation of fibroblasts Fibroblasts contain TSH receptor Stimulation → secretion of glycosaminoglycans Hydrophilic substances, mostly hyaluronic acid Draws in water → swelling Graves' Disease Graves' Disease Diagnosis: Usually hyperthyroid labs plus exophthalmos Can measure TSH receptor antibodies “Thyroid stimulating immunoglobulins” Treatment Symptoms: beta blockers, thionamides Drugs often started in preparation for definitive therapy Radioactive iodine ablation or surgery Jonathan Trobe, M.D./Wikipedia Herbert L. Fred, MD and Hendrik A. van Dijk Thionamides Thionamides Methimazole Skin rash (common) Inhibits thyroid peroxidase (TPO) Agranulocytosis Organification of iodine Rare drop in WBC Coupling of MIT/DIT May present as fever, infection after starting drug Propylthiouracil (PTU) WBC improves with stopping drug Inhibits TPO Aplastic anemia cases reported Also inhibits 5’-deiodinase Hepatotoxicity Blunts peripheral conversion T4→T3 12 Thionamides Thyroid Storm Treatment Methimazole: teratogen Propranolol Associated with congenital malformations Beta blocker Especially 1st trimester Blocks T4 → T3 conversion PTU often used during early pregnancy Thionamides (PTU, Methimazole) SSKI (saturated solution of potassium iodide) Iodide load → shuts down T4 production Wolff-Chaikoff effect Steroids Reduce T4 → T3 conversion Suppress auto-immune damage Treat possible concomitant adrenal insufficiency Graves' Ophthalmopathy Toxic Adenomas Sometimes worsens despite treating hyperthyroidism Nodules in thyroid that function independently Can cause irritation, excessive tearing , pain Usually contain mutated TSH receptor Do not respond to TSH Symptoms often worse by cold air, wind, bright lights One nodule: Toxic adenoma Severe inflammation treatments: Multiple: Toxic multinodular goiter Steroids Findings: Radiation Palpable nodule Surgery Hyperthyroidism symptoms/labs Treatment: Radioactive iodine or surgery Jonathan Trobe, M.D./Wikipedia Radioactive Iodine Uptake Jod-Basedow Phenomenon Important test for thyroid nodules Iodine-induced hyperthyroidism Administration of I131 (lower dose than ablation) Often occurs in regions of iodine deficiency Contraindicated in pregnancy/breast feeding Introduction of iodine → hyperthyroidism “Hot” nodule Often occurs in patients with toxic adenomas Takes up I131 Drugs administered with high iodine content Not-cancerous Expectorants (potassium iodide) CT contrast dye “Cold” nodule Amiodarone Chance of cancer (~5%) Often biopsied (Fine-needle aspiration) 13 Amiodarone Hypothyroidism Two types of hyperthyroidism Iodine deficiency Type I Iodine excess Occurs in patients with pre-existing thyroid disease Congenital hypothyroidism Graves' or Multi-nodular goiter Amiodarone Amiodarone provides iodine → excess hormone production Thyroiditis Type II Hashimoto’s (#1 cause when dietary iodine is sufficient) Destructive thyroiditis Subacute Excess release T4/ T3 (no ↑ hormone synthesis) Riedel’s Direct toxic effect of drug Can occur in patients without pre-existing thyroid illness Iodine Deficiency Iodine Excess “Endemic goiter” Excessive iodide in diet could lead to hyperthyroidism Goiter in region with widespread iodine deficiency Thyroid protects itself via Wolff-Chaikoff Effect Common in mountainous areas (iodine depleted by run-off) Organification inhibited by ↑ iodide Constant elevation of TSH → enlarged thyroid Less synthesis of MIT/DIT Chronic, high iodine intake → goiter/hypothyroidism Wellcome Images Iodine Goitrogens Substances that inhibit thyroid hormone production Iodine Most common is iodine Lithium (inhibits release of thyroid hormone) Deficiency Excess Load Certain foods (cassava and millet) Hypothyroidism Hypothyroidism Hyperthyroidism Goiter Wolff-Chaikoff 14  Always check TSH Amiodarone Amiodarone before starting amiodarone Can cause hypothyroidism Excess iodine → Wolff-Chaikoff Effect Amiodarone Suppression of thyroid hormone synthesis Normal patients “escape” in few weeks Hypothyroidism Hyperthyroidism Pre-existing subclinical thyroid disease → “failure to escape” Also mimics T4 Inhibits Inhibits 5’-diodinase Iodine Excess Iodine Load Thyroiditis 5’-diodinase Hypothyroidism Hypothyroidism Wolff-Chaikoff ↓T4→T3 Congenital Hypothyroidism Thyroid Hormone CNS and Bone effects TH required for normal bone growth/CNS maturation Most common treatable cause intellectual disability Childhood hypothyroidism → cretinism Newborn screening programs Stunted growth Measure T4 or TSH from heel-stick blood specimens Intellectual impairment Causes Iodine deficiency Thyroid dysgenesis Inborn errors of hormone synthesis (dyshormonogenesis) TPO most common Thyroid Hormone Iatrogenic Hypothyroidism CNS and Bone effects Intellectual impairment Thyroid surgery Coarse facial features Often done for Graves' or malignancy Short stature Radioiodine therapy I131 administered orally as solution or capsule Umbilical hernia Beta-emissions → tissue damage Enlarged tongue Ablation of thyroid function over weeks Done for Graves' or malignancy Neck radiation Hodgkin’s lymphoma Head and neck cancer Wellcome Images/Wikipedia 15 Hashimoto’s Thyroiditis Hashimoto’s Thyroiditis Chronic Autoimmune Thyroiditis Chronic Autoimmune Thyroiditis Most common cause of hypothyroidism (non-diet) Antibodies produced Lymphocytes infiltrate thyroid gland Anti-TPO Autoimmune disorder (T-cell attack thyroid; B cell activation) Anti-thyroglobulin HLA-DR3, HLA-DR5 and others Histology: Massive lymphocytic infiltrate (germinal centers) Hurthle cells (enlarged eosinophilic follicular cells) Hashimoto’s Thyroiditis Subacute Thyroiditis Chronic Autoimmune Thyroiditis de Quervain’s/granulomatous thyroiditis Primarily occurs in women Granulomatous inflammation of thyroid Enlarged non-tender thyroid gland Occurs in young females Gradual loss of thyroid function → symptoms Tender, enlarged thyroid gland Symptoms/labs of hypothyroidism Hyperthyroid → euthyroid → hypothyroid Treatment: thyroid hormone replacement Treatment: Increased risk of Non Hodgkin B cell lymphoma Anti-inflammatories (aspirin, NSAIDs, steroids) Thyroid symptoms usually mild (no treatment) Usually resolves in few weeks Riedel’s Thyroiditis Lymphocytic Thyroiditis Painless Thyroiditis Fibroblast activation/proliferation Variant of Hashimoto’s Fibrous tissue (collagen) deposition in thyroid Lymphocytic infiltration of thyroid gland “Rock hard” thyroid Transient hyperthyroidism Often extends beyond the thyroid Can look like Graves' without eye/skin findings Parathyroid glands → hypoparathyroidism Serum thyroid stimulating immunoglobulins not elevated Recurrent laryngeal nerves → hoarseness Followed sometimes by hypothyroidism Trachea compression → difficulty breathing Can look like Hashimoto’s Associated with IgG4 plasma cells Usually self-limited (weeks) May be an “IgG4-related disease” (autoimmune pancreatitis) IgG4 plasma cells identified in biopsy specimens 16  Thyroid Cancer General Principles Thyroid cancer usually no hyper/hypo symptoms Often presents as nodule Differential is benign adenoma versus cancer Biopsy done by fine needle aspiration Thyroid Cancer Jason Ryan, MD, MPH Thyroid Imaging Radioactive Iodine Uptake Ultrasound Small oral dose I131 given to patient Some characteristics suggest cancer Scintillation camera → image of thyroid Borders, vascularity, calcifications Normal: diffuse, even uptake Diffuse high uptake: Graves' Myohan /Wikipedia Diffuse low uptake: Hashimoto’s Multiple areas of high uptake: nodular goiter Single “hot” nodule: adenoma Single “cold” nodule: Possible cancer Most cancers do not make hormone About 10% cold nodules are malignant Nevit Dilmen/Wikipedia Follicular Adenoma Thyroid Cancer Common cause of thyroid nodules Papillary Benign proliferation of follicles Follicular Normal follicular tissue seen on biopsy Medullary Completely surrounded by fibrous capsule Anaplastic FNA cannot distinguish between adenomas/cancer Cannot see entire capsule Follicular carcinoma has similar histology by FNA FNA follicular pathology followed over time Growth, suspicious new findings → surgery 17 Papillary Carcinoma Papillary Carcinoma Most common form thyroid cancer (~80%) Increased risk with prior radiation exposure Childhood chest radiation for mediastinal malignancy or acne Survivors of atomic bomb detonation (Japan) Nuclear power plant accidents (Chernobyl) Presents as thyroid nodule Sometimes seen on chest/neck imaging (CT/MRI) Diagnosis made after fine needle aspiration (FNA) Excellent prognosis Treated with surgery plus radioactive iodine ablation KGH/Wikipedia Papillary Carcinoma Psammoma Bodies Three key pathology findings: Calcifications with an layered pattern Psammoma bodies Seen in other neoplasms but only papillary for thyroid Nuclear grooves Orphan Annie’s Eye Nuclei Diagnosis made by nuclear findings Wikipedia/Public Domain Nuclear Grooves Orphan Annie's Eyes Empty-appearing nuclei KGH/Wikipedia William Creswell/Flikr KGH/Wikipedia White clearing 18 Follicular Carcinoma Follicular Carcinoma Similar to follicular adenoma Possible hematogenous metastasis Breaks through (“invades”) fibrous capsule Treatment: FNA cannot distinguish between adenomas/cancer Thyroidectomy I131 to ablate any remaining tissue or metastasis Follicular pathology followed over time Growth, suspicious new findings → surgery Yale Rosen/Wikipedia Medullary Carcinoma Medullary Carcinoma Cancer of parafollicular cells (C cells) Malignant cells/Amyloid “stroma” Produces calcitonin Lowers serum calcium Normally minimal effect on calcium levels Used for monitoring Amyloid deposits in thyroid Amyloid = protein deposits Calcitonin = peptide Appearance of amyloid on biopsy Nephron/Wikipedia MEN Syndromes Anaplastic Carcinoma Multiple Endocrine Neoplasia Undifferentiated Carcinoma Gene mutations that run in families Occurs in elderly Cause multiple endocrine tumors Highly malignant - invades local tissues MEN 2A and 2B associated with medullary carcinoma Dysphagia (esophagus) Caused by RET oncogene mutation Hoarseness (recurrent laryngeal nerve) Some patients have elective thyroidectomy Dyspnea (trachea) Don’t confuse with Riedel’s (“rock hard” thyroid/young pt) Poor prognosis Pathology: Undifferentiated cells No papilla, follicles, or amyloid 19  Adrenal Glands Adrenal Glands Located above kidneys Arteries: Suprarenal arteries Left and right Superior, inferior, middle Veins: Adrenal Glands Left adrenal → renal vein → IVC Right adrenal → IVC Jason Ryan, MD, MPH Wikipedia /Public Domain Cortex and Medulla Signal Transmission Cortex: Three groups of hormones Mineralocorticoids (aldosterone) Glucocorticoids (cortisol) Androgens (testosterone) Derived from mesoderm Medulla Epinephrine and norepinephrine Sympathetic nervous system control Derived from neural crest OpenStax College/Wikipedia Use with permission, Katzung BG, Basic and Clinical Pharmacology, 10th ed. New York, McGraw Hill, 2007 Mineralocorticoids Collecting Duct Lumen (Urine) Principal Cell Interstitium/Blood Na+ Most important is aldosterone Na+ Key effects on kidney function Aldosterone Aldosterone ATP K+ Release controlled by RAA system K+ Renin-angiotensin-aldosterone H2O Increase Na+/Water resorption Promote K+/H+ excretion Intercalated Cell Aldosterone Aldosterone Corticosterone 11-deoxycorticosterone H+ 20 Adrenal Androgens Cortisol Cortisol Small contribution to androgen production in males Major glucocorticoid ~50% androgens for females Synthesized by adrenal cortex Clinical relevance: congenital adrenal hyperplasia Binds to intracellular receptors (cytosol) Over/underproduction → abnormal sexual development Glucocorticoid receptor (GR) Production stimulated by ACTH (like cortisol) Translocates to nucleus Activates/suppresses gene transcription Dehydroepiandrosterone Testosterone Androstenedione (DHEA) Pituitary-Adrenal Axis Circadian Rhythms Controls cortisol secretion Serum cortisol highest early morning (about 6 AM) Hypothalamus: CRH 10 to 20 mcg/dL Corticotropin releasing hormone Lowest one hour after sleep onset Paraventricular nucleus (PVN) Less than 5 mcg/dL Anterior pituitary: ACTH Testing rarely done with single blood test Adrenocorticotropic hormone Acts on adrenal gland cAMP/PKA 2nd messenger Adrenal: Cortisol Drosenbach/Wikipedia Cortisol Binding Globulin Cortisol Hormone Effects Cortisol Cortisol poorly soluble in plasma Maintains blood pressure Cortisol Most (>90%) serum cortisol bound to CBG Effects on vascular smooth muscle Increases vascular sensitivity (α1) to norepi/epi Levels ↑ estrogen ↓NO mediated vasodilation ↑ cortisol: hypertension (Cushing’s disease) ↓ cortisol: hypotension (adrenal insufficiency) 21 Cortisol Cortisol Hormone Effects Cortisol Cortisol Suppresses immune system Inactivate NF-KB Sequester lymphocytes in spleen/nodes Key inflammatory transcription factor Reduce T and B cell levels in plasma Mediates response to TNF-α Controls synthesis inflammatory mediators Block neutrophil migration COX-2, PLA2, Lipoxygenase ↑ peripheral neutrophil count Mast cells: blocks histamine release ↓ eosinophil counts Basis for steroids as immunosuppressive drug therapy Corticosteroid Drugs Cortisol Effects Cortisol Cortisol More glucose produced by liver ↑ synthesis of glucose 6-phosphatase, PEPCK ↑ gluconeogenesis Dexamethasone Less glucose taken up peripherally (muscle, fat) Net results: ↑ serum glucose More glycogen storage in liver ↑ synthesis of glycogen synthase Prednisone Methylprednisolone Cortisone Triamcinolone Betamethasone Hydrocortisone Cortisol Cortisol Effects Effects Cortisol Cortisol Activation of lipolysis in adipocytes Enhanced effects of glucagon, epinephrine ↑ free fatty acids Leads to insulin resistance ↑ total cholesterol, ↑ triglycerides Long term steroid use: diabetes Stimulate adipocyte growth Key effect: fat deposition 22 Cortisol Zones of the Adrenal Glands Effects Cortisol Muscle atrophy Skin effects Blunted epidermal cell division in skin ↓ collagen, inhibition of fibroblasts Net effects: Thin skin, easy bruising, striae Bones: Inhibits osteoblasts Steroids → osteopenia and osteoporosis Jpogi/Wikipedia /Public Domain Zones of the Adrenal Glands Zona Glomerulosa 3-β hydroxysteroid Dehydrogenase Pregnenolone Progesterone Cholesterol 21-α hydroxylase 11-β hydroxylase Aldosterone Corticosterone 11-deoxycorticosterone Zona Glomerulosa Zona Glomerulosa 3-β hydroxysteroid ACTH 3-β hydroxysteroid Dehydrogenase Dehydrogenase + Desmolase Pregnenolone Progesterone Pregnenolone Progesterone Cholesterol Cholesterol 21-α hydroxylase 21-α hydroxylase Angiotensin II Angiotensin II + + Aldosterone Aldosterone Synthase 11-β hydroxylase Synthase 11-β hydroxylase Aldosterone Corticosterone 11-deoxycorticosterone Aldosterone Corticosterone 11-deoxycorticosterone 23  Pregnenolone Progesterone Zona Glomerulosa Zona Fasciculata 17-α hydroxylase 3-β hydroxysteroid Dehydrogenase 17-Hydroxypregnenolone 17-Hydroxyprogesterone 21-α hydroxylase 11-β hydroxylase Wikipedia /Public Domain Cortisol 11-Deoxycortisol 17-Hydroxypregnenolone 17-Hydroxyprogesterone Zona Fasciculata Zona Reticularis 17, 20 lyase 3-β hydroxysteroid Dehydrogenase Dehydroepiandrosterone Androstenedione (DHEA) Testosterone Matthew Colo/Wikipedia Ketoconazole Antifungal Blocks ergosterol synthesis in fungi Potent inhibitor of 17,20 lyase ↓ androstenedione/testosterone Key side effect: gynecomastia Also inhibits 17-alpha hydroxylase, desmolase Blocks cortisol synthesis Can be used to treat Cushing’s syndrome 24  CAH CAH Congenital Adrenal Hyperplasia Enzyme deficiency syndrome Loss of one of the four enzymes for cortisol synthesis Congenital 21-α hydroxylase 11-β hydroxylase 17-α hydroxylase Adrenal Hyperplasia 3-β hydroxysteroid dehydrogenase Jason Ryan, MD, MPH CAH Congenital Adrenal Hyperplasia ACTH Cholesterol Aldosterone Cortisol Androgens Matthew Colo/Wikipedia CAH Low Cortisol Congenital Adrenal Hyperplasia Signs/Symptoms All result in low cortisol Hypoglycemia Stimulates ACTH release Nausea/vomiting Can cause ↑ production of other hormones Mineralocorticoids Androgens Adrenal ↑ Non-cortisol ↓ Cortisol ↑ACTH Hyperplasia hormone synthesis 25 Aldosterone Androgens Signs/Symptoms Signs/Symptoms Deficiency Depend on chromosomal sex of child (XX/XY) Na loss → water loss Excess androgens Hypovolemia → shock Female (XX): Ambiguous genitalia Hyperkalemia Male (XY): Precocious (early) puberty ↑ renin Androgen deficiency Excess Female (XX): Normal genitalia Na retention Male (XY): Female or ambiguous genitalia Hypertension Hypokalemia ↓ renin Ambiguous Genitalia ACTH Effects Females (XX) with excess androgen exposure High ACTH can case skin hyperpigmentation Males (XY) with deficient androgen exposure Melanocyte stimulating hormone (MSH) Common precursor protein in pituitary with ACTH ↑ melanin synthesis Proopiomelanocortin ACTH MSH Diabetic fetopathy associated with bilateral adrenal hyperplasia and ambiguous genitalia: a case report. Journal of Medical Case Reports. 2008; 2 : 251. doi:10.1186/1752-1947-2-251 21-α Hydroxylase Deficiency 21-α Hydroxylase Deficiency ACTH ↑ ACTH Cholesterol Cholesterol Aldosterone Cortisol Androgens Aldosterone Cortisol Androgens 26 21-α Hydroxylase Deficiency 21-α Hydroxylase Deficiency Classic cause of CAH (90% of CAH) Low cortisol symptoms Low mineralocorticoid symptoms Excess androgen symptoms Girls (XX): ambiguous genitalia Boys (XY): precocious puberty (early onset) Variable symptoms based on enzyme levels Classic form: 0 to 2% normal enzyme activity Non-classic forms: 20-50% normal enzyme activity 11-β Hydroxylase Deficiency 11-β Hydroxylase Deficiency Similar to 21-α hydroxylase deficiency Low cortisol symptoms ↑ ACTH Girls: ambiguous genitalia Cholesterol Boys: precocious puberty 11- One exception: ↑ mineralocorticoid activity deoxycorticosterone ↑ 11-deoxycorticosterone (weak mineralocorticoid) Hypertension Aldosterone Androgens Cortisol Hypokalemia 17-α Hydroxylase Deficiency 17-α Hydroxylase Deficiency Cytochrome P450c17 enzyme (CYP17A1) Found in adrenal glands and gonads ↑ ACTH Cholesterol Catalyzes two reactions 17-hydroxylase 17,20-lyase Aldosterone Cortisol Androgens 27 17-α Hydroxylase Deficiency 17-α Hydroxylase Deficiency Low cortisol Males (XY): Excess mineralocorticoids: HTN, ↓K+ Female or ambiguous external genitalia Absent uterus/fallopian tubes (Sertoli cells → MIH) Low androgens Undescended testes CYP17A1 : adrenal gland and gonads 3-β Hydroxysteroid 17-α Hydroxylase Deficiency Dehydrogenase Deficiency Females (XX): Normal at birth Primary amenorrhea at puberty ↑ ACTH Cholesterol Theca cells lack of androgens → ↓ estradiol Often diagnosed at puberty XX female fails to develop XY phenotypic female or male fails to develop Aldosterone Cortisol Androgens Hypertension, low K+ identified Disorders of Sex Development CAH Screening Ambiguous Genitalia Some states screen with newborn blood testing Measure level of 17-Hydroxyprogesterone Elevated level in 21-α hydroxylase deficiency (most common) 46, XX 46, XY Excess Androgens Lack of androgens Often CAH Synthesis/Effect Rarely due to CAH 28 CAH Treatment Many forms treated with glucocorticoids Replenishes cortisol Lowers ACTH Stops overproduction of other hormones Can also use mineralocorticoids (fludrocortisone) 29  Adrenal Disorders Adrenal Disorders Excess cortisol Insufficient cortisol Excess mineralocorticoids Tumors Adrenal Disorders Jason Ryan, MD, MPH Cushing’s Syndrome Cushing’s Syndrome Excess Cortisol Effects Syndrome of clinical features due to excess cortisol Hypertension Most common cause: corticosteroid medication Hyperglycemia Often prescribed for inflammatory conditions Diabetes (insulin resistance) e.g., daily prednisone for lupus Immune suppression Cushing’s disease: Pituitary ACTH-secreting tumor Risk of infections, especially opportunistic One cause of Cushing’s syndrome Cushing’s Syndrome Cushing’s Syndrome Excess Cortisol Effects Excess Cortisol Effects Cortisol alters GnRH release → ↓ FSH,LH Stimulation of adipocytes → growth Menstrual irregularities in women Progressive central obesity Abnormal cycles (80%) Face, neck, trunk, abdomen Oligomenorrhea (~30%) “Moon face” SherryC1234 Amenorrhea (~30%) "Buffalo hump" Hirsutism of face in women Fat mound at base of back of neck Males: Erectile dysfunction Homini/Flikr 30 Skin Changes Cushing’s Syndrome Causes Thinning of skin ACTH-independent (↓ACTH) Easy bruising Glucocorticoid therapy Adrenal adenoma Striae: Stretch marks Purple lines on skin ACTH-dependent (↑ACTH) Fragile skin stretches over trunk, breasts, abdomen Cushing’s disease (pituitary ACTH secreting tumor) Thin skin cannot hide venous blood in dermis Ectopic ACTH (small cell lung cancer) Commonly occur on sides and lower abdomen ↑ACTH → adrenal hyperplasia → ↑cortisol Cushing’s Syndrome Cushing’s Syndrome Causes Diagnosis Special note: skin hyperpigmentation Measuring plasma cortisol difficult Can occur in ACTH-dependent Cushing’s syndrome Circadian rhythm → high levels in AM Caused by ↑ ACTH not cortisol Most cortisol bound to CBG ↑ ACTH → ↑ MSH CBG levels can affect serum measurement Wikipedia/Public Domain Cushing’s Syndrome Cushing’s Syndrome Diagnosis Diagnosis 24-hour urine free cortisol Low dose dexamethasone suppression test Integrates cortisol level over time 1mg dexamethasone (“low dose”) administered at bedtime Salivary cortisol Suppresses normal pituitary ACTH release No cortisol binding globulin in saliva Morning blood test Free cortisol level measured at night (should be low) Cortisol level should be low (suppressed) Cortisol remains high in Cushing’s syndrome Adenomas, tumors do not suppress cortisol production 31 Cushing’s Syndrome High Dose Dexamethasone Diagnosis Step 1: Establish Cushing’s syndrome Low dose testing (1mg) Step 2: Establish cause Used to establish diagnosis of Cushing’s syndrome Key test is serum ACTH level High dose dexamethasone test (8mg) Differentiate causes of high ACTH Cushing’s syndrome Will suppress cortisol in pituitary adenomas (↑ set point) Will not suppress cortisol from ACTH tumors AM Cortisol After Dexamethasone Cushing’s Syndrome Ketoconazole Treatment Surgery Antifungal Removal of adenoma (adrenal gland, pituitary) Blocks ergosterol synthesis in fungi Removal of lung tumor Also blocks 1st step in cortisol synthesis Ketoconazole Desmolase (side chain cleavage) Can be used to treat Cushing’s syndrome Also potent inhibitor androgen synthesis Key side effect: gynecomastia Desmolase Cholesterol Pregnenolone Cortisol Adrenal Insufficiency Adrenal Insufficiency Symptoms Insufficient cortisol production Loss of cortisol Primary adrenal insufficiency (Addison’s disease) Weakness, fatigue Failure of adrenal gland Weight loss Cortisol and aldosterone will be low Postural hypotension ACTH will be high Nausea, abdominal pain, diarrhea Hypoglycemia Secondary adrenal insufficiency Failure of pituitary ACTH release Loss of aldosterone Only cortisol will be low Potassium retention → hyperkalemia H+ retention → acidosis Sodium loss in urine → hypovolemia 32 ACTH Effects Addison’s Hyperpigmentation ACTH is high in primary adrenal insufficiency Generalized hyperpigmentation This leads to skin hyperpigmentation Most obvious in sun-exposed areas Melanocyte stimulating hormone (MSH) shares Face, neck, backs of hands common precursor protein in pituitary with ACTH Also areas of friction/pressure ↑ melanin synthesis Elbows, knees, knuckles, May occur is palmar creases Proopiomelanocortin Classic scenario: GI symptoms (nausea, pain) Darkening skin ACTH MSH Wikipedia/Public Domain Adrenal Crisis Addison’s Disease Common Causes Acute adrenal insufficiency Autoimmune adrenalitis Abrupt loss of cortisol and aldosterone Antibody and cell-mediated disorder Antibodies to 21-hydroxylase commonly seen Main manifestation is shock Atrophy of adrenal gland Hypoglycemia Loss of cortex Other symptoms: nausea, vomiting, fatigue, confusion Medulla is spared Often when acute ↑ adrenal function cannot be met Infections Infection, surgery, trauma in patient with adrenal insufficiency Tuberculosis Patients on chronic steroids Fungal (histoplasmosis, cryptococcus) “Stress dose steroids” for prevention CMV Rare: tumor metastasis especially lung Waterhouse-Friderichsen Metastasis from Lung Cancer Syndrome Adrenals Rare cause of acute adrenal insufficiency Usually found on imaging without symptoms Caused by acute hemorrhage into adrenal glands Brain Associated with meningococcemia Headache, neuro deficits, seizures Clinical scenario Bone Patient with bacterial meningitis Pathologic fractures Acute onset of shock Liver Hepatomegaly, jaundice Xishan01/Wikipedia 33 2o Adrenal Insufficiency 2o Adrenal Insufficiency Most common cause: glucocorticoid therapy Basis for “weaning” off steroids Chronic suppression ACTH release Slow discontinuation over time Leads to adrenal atrophy over time Basis for “stress dose steroids” Patients on chronic steroids with infection, trauma, surgery Sudden discontinuation → hypoadrenalism Risk of adrenal crisis High dose of glucocorticoids administered 2o Adrenal Insufficiency Adrenal Insufficiency Important Points Diagnostic Tests No skin findings 8 AM serum cortisol ACTH is not elevated Levels should be highest at this time No hyperkalemia Low level indicates disease Aldosterone not effected Serum ACTH High ACTH with low cortisol = primary disease Low ACTH with low cortisol = secondary disease Adrenal Insufficiency Primary Aldosteronism Diagnostic Tests Mineralocorticoid Excess ACTH stimulation test (“cosyntropin stim test”) Hypertension, classically at a young age Exogenous ACTH administered Hypokalemia Cortisol should rise 30-60 minutes later Weakness, muscle cramps Failure to rise = primary adrenal insufficiency Unreliable finding → many cases with normal K+ Normal rise = secondary disorder Metabolic alkalosis 34 Primary Aldosteronism Primary Aldosteronism Most common causes Diagnosis Bilateral idiopathic hyperaldosteronism (~60%) Plasma aldosterone concentration (PAC) Aldosterone-producing adenoma (~30%) Plasma renin activity (PRA) Sometimes called Conn’s syndrome Plasma incubated Renin cleaves angiotensinogen in plasma Angiotensin I produced → measured by assay ↓ PRA and ↑ PAC = Primary aldosteronism ↑ PRA and ↑ PAC = Secondary aldosteronism Renal artery stenosis, CHF, low volume Primary Aldosteronism Primary Aldosteronism Diagnosis Treatment Abdominal imaging for adrenal nodules/tumors Surgical adrenalectomy Adrenal vein sampling Adenomas Differentiates unilateral vs. bilateral disease Unilateral hyperplasia Measure PAC and PRA in each vein Spironolactone Drug of choice Potassium-sparing diuretic Blocks aldosterone effects Licorice Pheochromocytoma Contains glycyrrhetinic acid (a steroid) Catecholamine-secreting tumor Weak mineralocorticoid effect Pikaluk/Flikr Secrete epinephrine, norepinephrine, dopamine Inhibits renal 11-beta-hydroxysteroid dehydrogenase Chromaffin cells of adrenal medulla Large amounts → Hypertension, hypokalemia Derivatives of neural crest Plasma aldosterone level low 11-beta-hydroxysteroid Cortisol dehydrogenase Cortisone