Thyroid and Adrenal Gland PDF
Document Details
Uploaded by CourtlyJadeite821
Alte University
Jason Ryan
Tags
Summary
This PDF document provides information about the thyroid and adrenal glands, including their anatomy, embryology, and hormone-related functions. It details the synthesis and effects of various hormones, and potential disorders.
Full Transcript
Jason Ryan, MD, MPH Two lobes (left, right) Isthmus: thin band of tissue between lobes Sometimes pyramidal lobe above isthmus Blood supply: superior and inferior thyroid arteries Superior thyroid: 1st branch external carotid artery Inferior thyroid: Thyrocervical trunk (off subclavian)...
Jason Ryan, MD, MPH Two lobes (left, right) Isthmus: thin band of tissue between lobes Sometimes pyramidal lobe above isthmus Blood supply: superior and inferior thyroid arteries Superior thyroid: 1st branch external carotid artery Inferior thyroid: Thyrocervical trunk (off subclavian) Forms from floor of pharynx (epithelial cells) 24-28 Day Old Embryo Wikipedia/Public Domain Descends into neck Initially maintains connection to tongue Thyroglossal duct Disappears later in development Two remnants of duct in child/adult Foramen cecum in tongue Pyramidal lobe of thyroid Foramen Cecum (end of median sulcus) Persistent remnant of thyroglossal duct Midline neck mass; usually painless Usually discovered in childhood Classically, move up with swallowing or tongue protrusion May contain thyroid cells Klaus D. Peter, Gummersbach, Germany Functioning thyroid tissue outside of gland Most common location is base of tongue Presents as a mass in the tongue Commonly detected during increased demand for hormones Puberty and pregnancy May be the only functioning thyroid tissue May under-produce thyroid hormone hypothyroidism ↑ TSH growth of ectopic tissue Thyroid gland contains “follicles” Filled with colloid (protein material) Single layer of epithelial cells lines each follicle “Follicular cells” Hormone synthesized by follicular cells Uwe Gille/Wikipedia Contain the element iodine Iodized salt Table salt (NaCl) mixed with small minute amount of iodine Done in many countries to prevent iodine deficiency Added to salt in US in 1924 Two hormones: T3 and T4 Synthesized from tyrosine and iodine Tyrosine Triiodothyronine (T3) Thyroxine (T4) Large protein Produced by thyroid follicular cells Contains numerous tyrosine molecules Tyrosine Tyrosine Tyrosine Tyrosine Tyrosine Thyroglobulin Iodine = I (chemical element, atomic number 53) Iodide = iodine bound to another atom “Iodide salt” with negative charge (I-) Potassium iodide = KI Plasma iodine exists as iodide salt For thyroid hormone, iodide in our diet needs to be: Taken up by follicular cells Oxidized to I2 (undergo “oxidation”) Added to organic/carbon structures (“organification”) NIS Na-Iodine Symporter Follicular Cell Perchlorate (ClO4-) Pertechnetate (TcO4-) Na Iodide X NIS Ty Ty Ty Ty Ty TG Plasma Follicle Lumen Follicular Cell Iodide Thyroid Peroxidase (TPO) Ty Ty Ty Ty Ty I2 TG Plasma Follicle Lumen Monoiodotyrosine (MIT) Tyrosine Thyroid Peroxidase (TPO) + Iodine (I2) Diiodotyrosine (DIT) Thyroid Peroxidase (TPO) Monoiodotyrosine (MIT) Triiodothyronine (T3) Diiodotyrosine (DIT) Coupling Reactions Thyroid Peroxidase Diiodotyrosine (TPO) (DIT) Thyroxine (T4) Diiodotyrosine (DIT) Thyroid Peroxidase Multifunctional enzyme Catalyzes: Oxidation of iodide Organification of iodine into MIT/DIT Coupling of MIT/DIT into T3/T4 TPO antibodies common in autoimmune thyroid disease Plasma Follicle Lumen T4 T3 T3 Follicular Cell T3 T4 T4 T4 T3 T4 T4 Proteolysis TG TPO MIT DIT Iodide MIT DIT Thyroid Peroxidase (TPO) TPO TG I2 Ty Ty Ty Ty Ty TG T4 is major hormone produced by thyroid gland >90% of thyroid hormone produced is T4 T3 more potent hormone T4 is a “prohormone” for T3 5’ deiodinase converts T4 T3 Most conversion occurs in peripheral tissues Iodine 5’-deiodinase Thyroxine (T4) Triiodothyronine (T3) Propylthiouracil (PTU) Inhibits TPO: ↓ T3/T4 from thyroid gland Inhibits 5’-deiodinase: ↓ T4 to T3 conversion peripherally Methimazole Inhibits TPO PTU and Methimazole are both Propranolol “thioamides” Beta blocker Weak inhibitor of 5’-deiodinase Excellent drug in thyrotoxicosis Blocks catecholamines and T4-T3 conversion Excessive iodide in diet could lead to hyperthyroidism Thyroid protects itself via Wolff-Chaikoff Effect Organification inhibited by ↑ iodide Less synthesis of MIT/DIT Class III antiarrhythmic drug Commonly used in atrial fibrillation Contains iodine Can cause hypothyroidism via excess iodine Wolff-Chaikoff Effect Mimics T4 Inhibits 5’-deiodinase ↓T3 ↑TSH from pituitary gland TSH rises after start of therapy then normalizes I131 is an isotope of iodine Has 53 protons like elemental iodine Extra neutrons 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 Thyroxine-Binding Globulin Most plasma thyroid hormone is T4 Thyroid hormones poorly soluble in water Most T4 is bound to TBG Some with transthyretin and albumin TBG present in small amount but has high affinity TBG produced in liver Key point: Less TBG less available T4/T3 to tissues TBG-T4 T4 Thyroxine-Binding Globulin Estrogen raises TBG levels Modifies TBG molecules Slows clearance from plasma Pregnancy, OCP users Will raise total T4 levels Liver failure lowers TBG levels Less production of protein Can lower total T4 levels Thyroxine-Binding Globulin Rise in TBG More bound T4 Less free T4 ↑TSH ↑Total T4 ↑ Free T4 (back to normal) ↓TSH (back to normal) Family of nuclear receptors Hormone-activated transcription factors Modulate gene expression Major regulator of metabolic activity and growth Glucose, lipid metabolism Cardiac function Bone growth CNS development Metabolic Effects ↑ Carbohydrate Metabolism ↑ glycogenolysis, gluconeogenesis ↑ Fat Metabolism ↑ lipolysis ↓ concentrations of cholesterol, triglycerides ↑ low-density lipoprotein receptors in liver (↓ LDL) ↑ cholesterol secretion in bile Hypothyroid patients: ↑ cholesterol Hyperthyroid patients: hyperglycemia Metabolic Effects ↑ basal metabolic rate Basal rate of energy use per time Amount of energy burned if you slept all day ↑ 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. Cardiac Effects ↑ CO/HR/SV/contractility ↑ β1 receptors in heart Hyperthyroid patients: Tachycardia CNS and Bone effects TH required for normal bone growth/CNS maturation Childhood hypothyroidism cretinism Stunted growth Mental retardation Causes Iodine deficiency (3rd world) Thyroid dysgenesis Inborn errors of hormone synthesis (dyshormonogenesis) TPO most common CNS and Bone effects Most common treatable cause of mental retardation Most babies appear normal Maternal T3/T4 crosses placenta Newborn screening programs Measure T4 or TSH from heel-stick blood specimens CNS and Bone effects Mental retardation Coarse facial features Short stature Umbilical hernia Enlarged tongue Wellcome Images/Wikipedia TSH (thyrotropin) released by anterior pituitary Binds to receptors on follicular cells Activates cAMP/PKA 2nd messenger system ↑ T3/T4 release ↑ rate of proteolysis of thyroglobulin Leads to rapid release of more T3/T4 Also stimulates thyroid cell growth, TG synthesis Serum T4/T3 level sensed by hypothalamus Releases thyroid releasing hormone (TRH) Mikael Häggström/Wikipedia Multiple effects on thyroid hormone production 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 Weeks of Pregnancy Four standard measurements to assess thyroid Hormone produced by thyroid Synthesized by parafollicular cells (C-cells) C cell Andrea Mazza/Wikipedia 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 Jason Ryan, MD, MPH Thyroid Disorders Hyperthyroid Hypothyroid Thyroiditis Metabolism SLOWS DOWN Lethargy, fatigue Weakness; dyspnea on exertion Cold intolerance Weight gain with loss of appetite Constipation Hyporeflexia Dry, cool skin Coarse, brittle hair Bradycardia Classic feature of hypothyroidism ↑ total cholesterol ↑ LDL cholesterol Primary mechanism: ↓ LDL receptor density T3 upregulates LDL receptor gene activation 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 Grave’s disease (hyperthyroidism) Myxedema coma = coma from hypothyroidism Thyroid dermopathy Herbert L. Fred, MD and Hendrik A. van Dijk Muscle symptoms common in hypothyroid Weakness, cramps, myalgias ↑ serum creatine kinase (CK) common (up to 90%) Wikipedia/Public Domain Hypothyroidism is a well-described cause ↓Na High levels of ADH (SIADH) May lead to confusion Levothyroxine (Synthroid): synthetic T4 Liothyronine (Cytomel): synthetic T3 Levothyroxine preferred T3 absorbed from intestines rapidly Can cause mild hyperthyroidism symptoms Tachycardia, tremor Also, T4 converted to T3 Titrate dose until TSH is normal Metabolism SPEEDS UP Hyperactivity Heat intolerance Weight loss with increased appetite Diarrhea Hyperreflexia Warm, moist skin Fine hair Tachycardia (atrial fibrillation) Life-threatening hyperthyroidism (thyrotoxicosis) Usually precipitated by acute event Patient with pre-existing hyperthyroid disease Grave’s or toxic multinodular goiter Surgery, trauma, infection Massive catecholamine surge Fever, delirium Tachycardia with death from arrhythmia Hyperglycemia (catecholamines/thyroid hormone) Hypercalcemia (bone turnover) Enlarged thyroid High TSH, inability to produce T3/T4 Thyroid stimulating antibodies (Grave’s) Wikipedia/Public Domain 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 Hyperthyroidism = ↓ TSH with high T3/T4 Central hyper/hypo thyroid disease 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) Pituitary resistance to thyroid hormone (hyperthyroidism) Isomer of T3 also derived from T4 Revere T3 Thyroxine (T4) Triiodothyronine (T3) Level usually parallels T4 Low T4 Low rT3 One special use: Euthyroid sick syndrome Critically ill patients low TSH Low T3/T4 Can look like central hypothyroidism rT3 rises in critical illness (impaired clearance) Critically ill patient with low TSH/T4/T3 Check rT3 Low central hypothyroidism High sick euthyroid syndrome Grave’s disease (#1 cause) Toxic multinodular goiter Amiodarone Iodine load Early thyroiditis Autoimmune disease Thyroid stimulating antibodies produced Symptoms of hyperthyroidism occur Exophthalmos (bulging eyes) Proptosis (protrusion of eye) and periorbital edema Usually no ocular symptoms 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 Jonathan Trobe, M.D./Wikipedia Herbert L. Fred, MD and Hendrik A. van Dijk 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 Methimazole Inhibits thyroid peroxidase (TPO) Organification of iodine Coupling of MIT/DIT Propylthiouracil (PTU) Inhibits TPO Also inhibits 5’-deiodinase Blunts peripheral conversion T4T3 Skin rash (common) Agranulocytosis Rare drop in WBC May present as fever, infection after starting drug WBC improves with stopping drug Aplastic anemia cases reported Hepatotoxicity Methimazole: teratogen Associated with congenital malformations Especially 1st trimester PTU often used during early pregnancy Treatment Propranolol Beta blocker Blocks T4 T3 conversion 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 Sometimes worsens despite treating hyperthyroidism Can cause irritation, excessive tearing , pain Symptoms often worse by cold air, wind, bright lights Severe inflammation treatments: Steroids Radiation Surgery Jonathan Trobe, M.D./Wikipedia Nodules in thyroid that function independently Usually contain mutated TSH receptor Do not respond to TSH One nodule: Toxic adenoma Multiple: Toxic multinodular goiter Findings: Palpable nodule Hyperthyroidism symptoms/labs Treatment: Radioactive iodine or surgery Important test for thyroid nodules Administration of I131 (lower dose than ablation) Contraindicated in pregnancy/breast feeding “Hot” nodule Takes up I131 Not-cancerous “Cold” nodule Chance of cancer (~5%) Often biopsied (Fine-needle aspiration) Iodine-induced hyperthyroidism Often occurs in regions of iodine deficiency Introduction of iodine hyperthyroidism Often occurs in patients with toxic adenomas Drugs administered with high iodine content Expectorants (potassium iodide) CT contrast dye Amiodarone Two types of hyperthyroidism Type I Occurs in patients with pre-existing thyroid disease Grave’s or Multi-nodular goiter Amiodarone provides iodine excess hormone production Type II Destructive thyroiditis Excess release T4/ T3 (no ↑ hormone synthesis) Direct toxic effect of drug Can occur in patients without pre-existing thyroid illness Iodine deficiency Iodine excess Congenital hypothyroidism Amiodarone Thyroiditis Hashimoto’s (#1 cause when dietary iodine is sufficient) Subacute Riedel’s “Endemic goiter” Goiter in region with widespread iodine deficiency Common in mountainous areas (iodine depleted by run-off) Constant elevation of TSH enlarged thyroid Wellcome Images Excessive iodide in diet could lead to hyperthyroidism Thyroid protects itself via Wolff-Chaikoff Effect Organification inhibited by ↑ iodide Less synthesis of MIT/DIT Chronic, high iodine intake goiter/hypothyroidism Iodine Deficiency Excess Load Hypothyroidism Hypothyroidism Hyperthyroidism Goiter Wolff-Chaikoff Substances that inhibit thyroid hormone production Most common is iodine Lithium (inhibits release of thyroid hormone) Certain foods (cassava and millet) Can cause hypothyroidism Excess iodine Wolff-Chaikoff Effect Suppression of thyroid hormone synthesis Normal patients “escape” in few weeks Pre-existing subclinical thyroid disease “failure to escape” Also mimics T4 Inhibits 5’-diodinase Always check TSH before starting amiodarone Amiodarone Hypothyroidism Hyperthyroidism Inhibits Iodine Excess Iodine Load Thyroiditis 5’-diodinase Hypothyroidism Hypothyroidism Wolff-Chaikoff ↓T4T3 TH required for normal bone growth/CNS maturation Childhood hypothyroidism cretinism Stunted growth Mental retardation Causes Iodine deficiency (3rd world) Thyroid dysgenesis Inborn errors of hormone synthesis (dyshormonogenesis) TPO most common CNS and Bone effects Most common treatable cause of mental retardation Newborn screening programs Measure T4 or TSH from heel-stick blood specimens CNS and Bone effects Mental retardation Coarse facial features Short stature Umbilical hernia Enlarged tongue Wellcome Images/Wikipedia Thyroid surgery Often done for Grave’s or malignancy Radioiodine therapy I131 administered orally as solution or capsule Beta-emissions tissue damage Ablation of thyroid function over weeks Done for Grave’s or malignancy Neck radiation Hodgkin’s lymphoma Head and neck cancer Chronic Autoimmune Thyroiditis Most common cause of hypothyroidism (non-diet) Lymphocytes infiltrate thyroid gland Autoimmune disorder (T-cell attack thyroid; B cell activation) HLA-DR5 Chronic Autoimmune Thyroiditis Antibodies produced Anti-TPO Anti-thyroglobulin Histology: Massive lymphocytic infiltrate (germinal centers) Hurthle cells (enlarged eosinophilic follicular cells) Chronic Autoimmune Thyroiditis Primarily occurs in women Enlarged non-tender thyroid gland Gradual loss of thyroid function symptoms Symptoms/labs of hypothyroidism Treatment: thyroid hormone replacement Increased risk of Non Hodgkin B cell lymphoma de Quervain’s/granulomatous thyroiditis Granulomatous inflammation of thyroid Occurs in young females Tender, enlarged thyroid gland Hyperthyroid euthyroid hypothyroid Treatment: Anti-inflammatories (aspirin, NSAIDs, steroids) Thyroid symptoms usually mild (no treatment) Usually resolves in few weeks Fibroblast activation/proliferation Fibrous tissue (collagen) deposition in thyroid “Rock hard” thyroid Often extends beyond the thyroid Parathyroid glands hypoparathyroidism Recurrent laryngeal nerves hoarseness Trachea compression difficulty breathing Associated with IgG4 plasma cells May be an “IgG4-related disease” (autoimmune pancreatitis) IgG4 plasma cells identified in biopsy specimens Painless Thyroiditis Variant of Hashimoto’s Lymphocytic infiltration of thyroid gland Transient hyperthyroidism Can look like Grave’s without eye/skin findings Serum thyroid stimulating immunoglobulins not elevated Followed sometimes by hypothyroidism Can look like Hashimoto’s Usually self-limited (weeks) Jason Ryan, MD, MPH Thyroid cancer usually no hyper/hypo symptoms Often presents as nodule Differential is benign adenoma versus cancer Biopsy done by fine needle aspiration Ultrasound Some characteristics suggest cancer Borders, vascularity, calcifications Nevit Dilmen/Wikipedia Small oral dose I131 given to patient Scintillation camera image of thyroid Normal: diffuse, even uptake Diffuse high uptake: Grave’s 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 Common cause of thyroid nodules Benign proliferation of follicles Normal follicular tissue seen on biopsy Completely surrounded by fibrous capsule 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 Papillary Follicular Medullary Anaplastic 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 Three key pathology findings: Psammoma bodies Nuclear grooves Orphan Annie’s Eye Nuclei Diagnosis made by nuclear findings Calcifications with an layered pattern Seen in other neoplasms but only papillary for thyroid Wikipedia/Public Domain KGH/Wikipedia Empty-appearing nuclei KGH/Wikipedia William Creswell/Flikr White clearing Similar to follicular adenoma Breaks through (“invades”) fibrous capsule FNA cannot distinguish between adenomas/cancer Follicular pathology followed over time Growth, suspicious new findings surgery Yale Rosen/Wikipedia Possible hematogenous metastasis Treatment: Thyroidectomy I131 to ablate any remaining tissue or metastasis Cancer of parafollicular cells (C cells) Produces calcitonin Lowers serum calcium Normally minimal effect on calcium levels With malignancy hypocalcemia Amyloid deposits in thyroid Amyloid = protein deposits Calcitonin = peptide Appearance of amyloid on biopsy Malignant cells/Amyloid “stroma” Nephron/Wikipedia Multiple Endocrine Neoplasia Gene mutations that run in families Cause multiple endocrine tumors MEN 2A and 2B associated with medullary carcinoma Caused by RET oncogene mutation Some patients have elective thyroidectomy Undifferentiated Carcinoma Occurs in elderly Highly malignant - invades local tissues Dysphagia (esophagus) Hoarseness (recurrent laryngeal nerve) Dyspnea (trachea) Don’t confuse with Riedel’s (“rock hard” thyroid/young pt) Poor prognosis Pathology: Undifferentiated cells No papilla, follicles, or amyloid Jason Ryan, MD, MPH Located above kidneys Arteries: Suprarenal arteries Left and right Superior, inferior, middle Veins: Left adrenal renal vein IVC Right adrenal IVC Wikipedia /Public Domain 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 Most important is aldosterone Key effects on kidney function Release controlled by RAA system Renin-angiotensin-aldosterone Increase Na+/Water resorption Promote K+/H+ excretion Aldosterone Corticosterone 11-deoxycorticosterone Lumen (Urine) Principal Cell Interstitium/Blood Na+ Na+ Aldosterone ATP K+ Aldosterone K+ H2O Intercalated Cell Aldosterone H+ Small contribution to androgen production in males ~50% androgens for females Clinical relevance: congenital adrenal hyperplasia Over/underproduction abnormal sexual development Production stimulated by ACTH (like cortisol) Dehydroepiandrosterone Testosterone Androstenedione (DHEA) Cortisol Major glucocorticoid Synthesized by adrenal cortex Binds to intracellular receptors (cytosol) Glucocorticoid receptor (GR) Translocates to nucleus Activates/suppresses gene transcription Controls cortisol secretion Hypothalamus: CRH Corticotropin releasing hormone Paraventricular nucleus (PVN) Anterior pituitary: ACTH Adrenocorticotropic hormone Acts on adrenal gland cAMP/PKA 2nd messenger Adrenal: Cortisol Drosenbach/Wikipedia Serum cortisol highest early morning (about 6 AM) 10 to 20 mcg/dL Lowest one hour after sleep onset Less than 5 mcg/dL Testing rarely done with single blood test Cortisol poorly soluble in plasma Cortisol Most (>90%) serum cortisol bound to CBG Levels ↑ estrogen Hormone Effects Cortisol Maintains blood pressure Effects on vascular smooth muscle Increases vascular sensitivity (α1) to norepi/epi ↓NO mediated vasodilation ↑ cortisol: hypertension (Cushing’s disease) ↓ cortisol: hypotension (adrenal insuf iciency) Hormone Effects Cortisol Suppresses immune system Sequester lymphocytes in spleen/nodes Reduce T and B cell levels in plasma Block neutrophil migration ↑ peripheral neutrophil count Mast cells: blocks histamine release ↓ eosinophil counts Basis for steroids as immunosuppressive drug therapy Cortisol Inactivate NF-KB Key inflammatory transcription factor Mediates response to TNF-α Controls synthesis inflammatory mediators COX-2, PLA2, Lipoxygenase Cortisol Dexamethasone Prednisone Methylprednisolone Cortisone Triamcinolone Betamethasone Hydrocortiosne Effects Cortisol More glucose produced by liver ↑ synthesis of glucose 6-phosphatase, PEPCK ↑ gluconeogenesis Less glucose taken up peripherally (muscle, fat) Net results: ↑ serum glucose More glycogen storage in liver ↑ synthesis of glycogen synthase Effects Cortisol Activation of lipolysis in adipocytes ↑ free fatty acids ↑ total cholesterol, ↑ triglycerides Stimulate adipocyte growth Key effect: fat deposition Effects Cortisol Enhanced effects of glucagon, epinephrine Leads to insulin resistance Long term steroid use: diabetes Effects Cortisol Muscle atrophy Skin effects Blunted epidermal cell division in skin ↓ collagen, inhibition of ibroblasts Net effects: Thin skin, easy bruising, striae Bones: Inhibits osteoblasts Steroids osteopenia and osteoporosis Jpogi/Wikipedia /Public Domain 3-β hydroxysteroid Dehydrogenase Pregnenolone Progesterone Cholesterol 21-α hydroxylase 11-β hydroxylase Aldosterone Corticosterone 11-deoxycorticosterone 3-β hydroxysteroid Dehydrogenase Pregnenolone Progesterone Cholesterol 21-α hydroxylase Angiotensin II + Aldosterone Synthase 11-β hydroxylase Aldosterone Corticosterone 11-deoxycorticosterone ACTH 3-β hydroxysteroid Dehydrogenase + Desmolase Pregnenolone Progesterone Cholesterol 21-α hydroxylase Angiotensin II + Aldosterone Synthase 11-β hydroxylase Aldosterone Corticosterone 11-deoxycorticosterone Wikipedia /Public Domain Pregnenolone Progesterone Zona Glomerulosa Zona Fasciculata 17-α hydroxylase 3-β hydroxysteroid Dehydrogenase 17-Hydroxypregnenolone 17-Hydroxyprogesterone 21-α hydroxylase 11-β hydroxylase 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 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 Jason Ryan, MD, MPH Congenital Adrenal Hyperplasia Enzyme deficiency syndrome Loss of one of the four enzymes for cortisol synthesis 21-α hydroxylase 11-β hydroxylase 17-α hydroxylase 3-β hydroxysteroid dehydrogenase Matthew Colo/Wikipedia Congenital Adrenal Hyperplasia ACTH Cholesterol Aldosterone Cortisol Androgens Congenital Adrenal Hyperplasia All result in low cortisol Stimulates ACTH release Can cause ↑ production of other hormones Mineralocorticoids Androgens Adrenal ↑ Non-cortisol ↓ Cortisol ↑ACTH Hyperplasia hormone synthesis Signs/Symptoms Hypoglycemia Nausea/vomiting Signs/Symptoms Deficiency Na loss water loss Hypovolemia shock Hyperkalemia ↑ renin Excess Na retention Hypertension Hypokalemia ↓ renin Signs/Symptoms Depend on chromosomal sex of child (XX/XY) Excess androgens Female (XX): Ambiguous genitalia Male (XY): Precocious (early) puberty Androgen deficiency Female (XX): Normal genitalia Male (XY): Female or ambiguous genitalia Females (XX) with excess androgen exposure Males (XY) with deficient androgen exposure 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 High ACTH can case skin hyperpigmentation Melanocyte stimulating hormone (MSH) Common precursor protein in pituitary with ACTH ↑ melanin synthesis Proopiomelanocortin ACTH MSH ACTH Cholesterol Aldosterone Cortisol Androgens ↑ ACTH Cholesterol Aldosterone Cortisol Androgens 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 ↑ ACTH Cholesterol 11-deoxycorticosterone Aldosterone Cortisol Androgens Similar to 21-α hydroxylase deficiency Low cortisol symptoms Girls: ambiguous genitalia Boys: precocious puberty One exception: ↑ mineralocorticoid activity ↑ 11-deoxycorticosterone (weak mineralocorticoid) Hypertension Hypokalemia ↑ ACTH Cholesterol Aldosterone Cortisol Androgens Cytochrome P450c17 enzyme (CYP17A1) Found in adrenal glands and gonads Catalyzes two reactions 17-hydroxylase 17,20-lyase Low cortisol Excess mineralocorticoids: HTN, ↓K+ Low androgens CYP17A1 : adrenal gland and gonads Males (XY): Female or ambiguous external genitalia Absent uterus/fallopian tubes (Sertoli cells MIH) Undescended testes Females (XX): Normal at birth Primary amenorrhea at puberty Theca cells lack of androgens ↓ estradiol Often diagnosed at puberty XX female fails to develop XY phenotypic female or male fails to develop Hypertension, low K+ identified ↑ ACTH Cholesterol Aldosterone Cortisol Androgens Ambiguous Genitalia 46, XX 46, XY Excess Androgens Lack of androgens Often CAH Synthesis/Effect Rarely due to CAH Some states screen with newborn blood testing Measure level of 17-Hydroxyprogesterone Elevated level in 21-α hydroxylase deficiency (most common) Many forms treated with glucocorticoids Replenishes cortisol Lowers ACTH Stops overproduction of other hormones Can also use mineralocorticoids (fludrocortisone) Jason Ryan, MD, MPH Excess cortisol Insufficient cortisol Excess mineralocorticoids Tumors Syndrome of clinical features due to excess cortisol Most common cause: corticosteroid medication Often prescribed for inflammatory conditions i.e. daily prednisone for lupus Cushing’s disease: Pituitary ACTH-secreting tumor One cause of Cushing’s syndrome Excess Cortisol Effects Hypertension Hyperglycemia Diabetes (insulin resistance) Immune suppression Risk of infections, especially opportunistic Excess Cortisol Effects Cortisol alters GnRH release ↓ FSH,LH Menstrual irregularities in women Abnormal cycles (80%) Oligomenorrhea (~30%) Amenorrhea (~30%) Hirsutism of face in women Males: Erectile dysfunction Excess Cortisol Effects Stimulation of adipocytes growth Progressive central obesity Face, neck, trunk, abdomen “Moon face” SherryC1234 "Buffalo hump" Fat mound at base of back of neck Homini/Flikr Thinning of skin Easy bruising Striae: Stretch marks Purple lines on skin Fragile skin stretches over trunk, breasts, abdomen Thin skin cannot hide venous blood in dermis Commonly occur on sides and lower abdomen Causes ACTH-independent (↓ACTH) Glucocorticoid therapy Adrenal adenoma ACTH-dependent (↑ACTH) Cushing’s disease (pituitary ACTH secreting tumor) Ectopic ACTH (small cell lung cancer) ↑ACTH adrenal hyperplasia ↑cortisol Causes Special note: skin hyperpigmentation Can occur in ACTH-dependent Cushing’s syndrome Caused by ↑ ACTH not cortisol ↑ ACTH ↑ MSH Wikipedia/Public Domain Diagnosis Measuring plasma cortisol difficult Circadian rhythm high levels in AM Most cortisol bound to CBG CBG levels can affect serum measurement Diagnosis 24-hour urine free cortisol Integrates cortisol level over time Salivary cortisol No cortisol binding globulin in saliva Free cortisol level measured at night (should be low) Diagnosis Low dose dexamethasone suppression test 1mg dexamethasone (“low dose”) administered at bedtime Suppresses normal pituitary ACTH release Morning blood test Cortisol level should be low (suppressed) Cortisol remains high in Cushing’s syndrome Adenomas, tumors do not suppress cortisol production Diagnosis Step 1: Establish Cushing’s syndrome Step 2: Establish cause Key test is serum ACTH level Low dose testing (1mg) Used to establish diagnosis of Cushing’s syndrome High dose dexamethasone test (3mg) 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 Treatment Surgery Removal of adenoma (adrenal gland, pituitary) Removal of lung tumor Ketoconazole Antifungal Blocks ergosterol synthesis in fungi Also blocks 1st step in cortisol synthesis 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 Insufficient cortisol production Primary adrenal insufficiency (Addison’s disease) Failure of adrenal gland Cortisol and aldosterone will be low ACTH will be high Secondary adrenal insufficiency Failure of pituitary ACTH release Only cortisol will be low Symptoms Loss of cortisol Weakness, fatigue Weight loss Postural hypotension Nausea, abdominal pain, diarrhea Hypoglycemia Loss of aldosterone Potassium retention hyperkalemia H+ retention acidosis Sodium loss in urine hypovolemia ACTH is high in primary adrenal insufficiency This leads to skin hyperpigmentation Melanocyte stimulating hormone (MSH) shares common precursor protein in pituitary with ACTH ↑ melanin synthesis Proopiomelanocortin ACTH MSH Generalized hyperpigmentation Most obvious in sun-exposed areas Face, neck, backs of hands Also areas of friction/pressure Elbows, knees, knuckles, May occur is palmar creases Classic scenario: GI symptoms (nausea, pain) Darkening skin Wikipedia/Public Domain Acute adrenal insufficiency Abrupt loss of cortisol and aldosterone Main manifestation is shock Hypoglycemia Other symptoms: nausea, vomiting, fatigue, confusion Often when acute ↑ adrenal function cannot be met Infection, surgery, trauma in patient with adrenal insufficiency Patients on chronic steroids “Stress dose steroids” for prevention Common Causes Autoimmune adrenalitis Antibody and cell-mediated disorder Antibodies to 21-hydroxylase commonly seen Atrophy of adrenal gland Loss of cortex Medulla is spared Infections Tuberculosis Fungal (histoplasmosis, cryptococcus) CMV Rare: tumor metastasis especially lung Adrenals Usually found on imaging without symptoms Brain Headache, neuro deficits, seizures Bone Pathologic fractures Liver Hepatomegaly, jaundice Rare cause of acute adrenal insufficiency Caused by acute hemorrhage into adrenal glands Associated with meningococcemia Clinical scenario Patient with bacterial meningitis Acute onset of shock Xishan01/Wikipedia o Most common cause: glucocorticoid therapy Chronic suppression ACTH release Leads to adrenal atrophy over time Sudden discontinuation hypoadrenalism o Basis for “weaning” off steroids Slow discontinuation over time Basis for “stress dose steroids” Patients on chronic steroids with infection, trauma, surgery Risk of adrenal crisis High dose of glucocorticoids administered o Important Points No skin findings ACTH is not elevated No hyperkalemia Aldosterone not effected Diagnostic Tests 8 AM serum cortisol Levels should be highest at this time Low level indicates disease Serum ACTH High ACTH with low cortisol = primary disease Low ACTH with low cortisol = secondary disease Diagnostic Tests ACTH stimulation test (“cosyntropin stim test”) Exogenous ACTH administered Cortisol should rise 30-60 minutes later Failure to rise = primary adrenal insufficiency Normal rise = secondary disorder Mineralocorticoid Excess Hypertension, classically at a young age Hypokalemia Weakness, muscle cramps Unreliable finding many cases with normal K+ Metabolic alkalosis Most common causes Bilateral idiopathic hyperaldosteronism (~60%) Aldosterone-producing adenoma (~30%) Sometimes called Conn’s syndrome Diagnosis Plasma aldosterone concentration (PAC) Plasma renin activity (PRA) 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 Diagnosis Abdominal imaging for adrenal nodules/tumors Adrenal vein sampling Differentiates unilateral vs. bilateral disease Measure PAC and PRA in each vein Treatment Surgical adrenalectomy Adenomas Unilateral hyperplasia Spironolactone Drug of choice Potassium-sparing diuretic Blocks aldosterone effects Contains glycyrrhetinic acid (a steroid) Weak mineralocorticoid effect Pikaluk/Flikr Inhibits renal 11-beta-hydroxysteroid dehydrogenase Large amounts Hypertension, hypokalemia Plasma aldosterone level low 11-beta-hydroxysteroid Cortisol dehydrogenase Cortisone Catecholamine-secreting tumor Secrete epinephrine, norepinephrine, dopamine Chromaffin cells of adrenal medulla Derivatives of neural crest Clinical presentation Classically episodic symptoms Hypertension Headaches Palpitations Sweating Pallor (pale skin) Diagnosis Serum catecholamine levels not routinely used Levels fluctuate Some metabolism intratumoral Breakdown products of catecholamines measured Usually via 24 hour urine collection Diagnosis COMT MAO COMT MAO Dopamine Homovanillic Acid (HVA) Monoamine Oxidase (MAO) Catechol-O-methyltransferase (COMT) Diagnosis COMT Norepinephrine Normetanephrine MAO MAO Dihydroxymandelic COMT Vanillylmandelic Acid acid (VMA) MAO MAO COMT Epinephrine Metanephrine Diagnosis Metanephrines often measured for diagnosis Metanephrine and normetanephrine 24hour urine collection or plasma Older test: 24 hour collection of VMA Treatment Definitive therapy: Surgery Pre-operative management: Phenoxybenzamine (irreversible α blocker) Non-selective beta blockers (propranolol) Catecholamine-secreting tumor Arise from sympathetic ganglia (extraadrenal) Similar clinical presentation to pheochromocytoma Tumor of primitive sympathetic ganglion cells Also derived from neural crest cells Can arise anywhere in sympathetic nervous system Adrenal gland most common (40 percent) Abdominal (25 percent) Thoracic (15 percent) Almost always occurs in children 3rd most common childhood cancer (leukemia, brain tumors) Most common extracranial tumor Symptoms related to tumor mass effect Commonly present as abdominal pain Can synthesize catecholamines Rarely cause symptoms like pheochromocytoma Urinary HVA/VMA levels used for diagnosis Rare feature: Opsoclonus-myoclonus-ataxia (OMA) Rare paraneoplastic syndrome Rapid eye movements, rhythmic jerking, ataxia Half of OMA patients have a neuroblastoma Diverse range of disease progression Key risk factor: Age at diagnosis Infants with disseminated disease often cured Children over 18 months often die despite therapy Younger age = better prognosis N-myc Proto-oncogene Amplified/overexpressed in some tumors Associated with poor prognosis 131 Metaiodobenzylguanidine MIBG Chemical analog of norepinephrine Diagnosis of pheochromocytoma & neuroblastoma Concentrated in sympathetic tissues Labeled with radioactive iodine (I131) Will concentrate in tumors emit radiation Special note: thyroid gland must be protected Simultaneous administration of potassium iodide Non-radioactive iodine Will be taken up by thyroid instead Norepinephrine Often discovered on abdominal imaging “Adrenal incidentaloma” Concern for malignancy and/or functioning adenoma May secrete cortisol or aldosterone Common functional tests 24 hour urine metanephrines (pheochromocytoma) 24 hour urine free cortisol (Cushing’s) Low dose dexamethasone suppression (Cushing’s) Serum PRA/aldosterone (aldosteronism) Often followed for growth over time (non-functional) Large (>5cm) often removed