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Endocrine Pathology Endocrine pathology in a nutshell problem up here problem down here Endocrine pathology in a nutshell Problem: too much too little Endocrine Pathology Organs Diseases • • • • Non-neoplastic Pituitary Thyroid Adrenals Pancreas too much hormone too little hormone Neoplastic benign malignant Pituitary Introduction Hyperpituitarism Hypopituitarism Pituitary gland Anterior and posterior pituitary Anterior pituitary Posterior pituitary Pituitary Introduction Anterior pituitary (adenohypophysis) • GH, ACTH, TSH, LH, FSH, and prolactin. • Controlled by hypothalamus. • Most problems happen here. Pituitary Introduction Posterior pituitary (neurohypophysis) • oxytocin, ADH (vasopressin) • hypothalamus makes them • posterior pituitary stores them Pituitary Introduction Oxytocin • labor • milk let-down • cuddling (after orgasm) • monogamy (vole studies) • trust (investment experiment) • female bonding (UCLA study) www.verolabs.com Hyperpituitarism • Definition: too much anterior pituitary hormone(s) • Most common cause: pituitary adenoma • Pituitary adenoma symptoms: • None, for a while • Endocrine abnormalities • Mass effects • Many types Pituitary adenoma Hyperpituitarism Growth Hormone Adenoma • Produces gigantism or acromegaly • Other findings • • • • diabetes mellitus hypertension arthritis gastrointestinal carcinoma • Lab findings • GH (spurts) • IGF-I (better) • GH unresponsive to glucose Adult male with gigantism 12 year old male with gigantism Tallest man in the world in 2008 Tallest man in the world in 2009 Tallest man in the world for 2010 Guinness Book Fezzik, Inigo Montoya, and Vizzini Andre the Giant Andre the Giant Acromegalic facial features Acromegaly: development over time Hyperpituitarism Other Pituitary Adenomas • Prolactinoma • ACTH-producing • FSH-LH-producing • TSH-producing • Non-functioning Surgical removal of pituitary adenoma Hypopituitarism • Definition: too little anterior pituitary hormone(s) • Causes • Pituitary destruction • Ischemic necrosis • Pituitary apoplexy • Symptoms usually insidious • • • • Dwarfism Loss of libido, menstrual abnormalities Hypothyroidism Adrenal insufficiency Thyroid Pathology Thyroid Introduction Hyperthyroidism Hypothyroidism Non-neoplastic diseases Neoplasms Normal thyroid follicles thyroid growth TRH 3° TSH 2° hormone synthesis 1° Thyroid Hormone • Most thyroid hormone is bound. • Only the free form is active! • Thyroid hormone • • • • binds to nuclear receptors changes gene expression increases carb and fat breakdown stimulates protein synthesis • Result: increased basal metabolic rate. Thyroid Lab Tests Thyroid Lab Tests TSH T4 Endocrine pathology in a nutshell problem up here problem down here Endocrine pathology in a nutshell problem up here problem down here Thyroid Lab Tests TSH low low T4 2° or 3° hypothyroidism subclinical normal hyperthyroidism high primary hyperthyroidism normal * euthyroidism * high primary hypothyroidism subclinical hypothyroidism 2° or 3° hyperthyroidism Thyroid Lab Tests TSH low low T4 2° or 3° hypothyroidism subclinical normal hyperthyroidism high primary hyperthyroidism normal * euthyroidism * high primary hypothyroidism subclinical hypothyroidism 2° or 3° hyperthyroidism Thyroid Lab Tests TSH low low T4 2° or 3° hypothyroidism subclinical normal hyperthyroidism high primary hyperthyroidism normal * euthyroidism * high primary hypothyroidism subclinical hypothyroidism 2° or 3° hyperthyroidism Thyroid Lab Tests TSH low low T4 2° or 3° hypothyroidism subclinical normal hyperthyroidism high primary hyperthyroidism normal * euthyroidism * high primary hypothyroidism subclinical hypothyroidism 2° or 3° hyperthyroidism Thyroid Lab Tests TSH low low T4 2° or 3° hypothyroidism subclinical normal hyperthyroidism high primary hyperthyroidism normal * euthyroidism * high primary hypothyroidism subclinical hypothyroidism 2° or 3° hyperthyroidism Thyroid Lab Tests TSH low low T4 2° or 3° hypothyroidism subclinical normal hyperthyroidism high primary hyperthyroidism normal * euthyroidism * high primary hypothyroidism subclinical hypothyroidism 2° or 3° hyperthyroidism Hyperthyroidism A hypermetabolic state caused by thyroid hormones. cardiac: rapid pulse, arrythmias neuromuscular: tremor, emotional lability eye: lid lag skin: warm, moist gastrointestinal: diarrhea skeletal: osteoporosis thyroid storm: thyroid hormone Lid lag Hypothyroidism A hypometabolic state caused by ↓ thyroid hormones. slowing of mind and body myxedema: deepened voice cardiac: slow pulse gastrointestinal: constipation skin: dry, cool, pale cold intolerance delayed reflexes myxedema coma Hypothyroidism with myxedema: before and after treatment Congenital Hypothyroidism • iodine deficiency or genetic problems. • symptoms are mild to severe • treatment: thyroid hormone replacement • prevention better Thyroiditis Definition: Inflammation of the thyroid • Hashimoto thyroiditis • Lymphocytic thyroiditis • DeQuervain thyroiditis • Fibrosing thyroiditis Thyroiditis Definition: Inflammation of the thyroid • Hashimoto thyroiditis • Commonest cause of hypothyroidism in US! • F>>M • Autoimmune destruction of gland Hashimoto Thyroiditis • Female • Myxedema •TPO Antibodies Hashimoto thyroiditis: Hϋrthle cells Thyroiditis Definition: Inflammation of the thyroid • Hashimoto thyroiditis • DeQuervain thyroiditis • Recent URI • Self-limiting DeQuervain Thyroiditis • Looks scary • Really harmless • Goes away by itself Rex De Quervain thyroiditis: Multinucleated giant cell Thyroiditis Definition: Inflammation of the thyroid • Hashimoto thyroiditis • DeQuervain thyroiditis • Silent thyroiditis • Post-partum or middle age • Mild symptoms Silent Thyroiditis • Swelling of the thyroid gland •Person alternates between hyper and hypothyroidism Silent thyroiditis: lymphoid infiltrate Thyroiditis Definition: Inflammation of the thyroid • Hashimoto thyroiditis • DeQuervain thyroiditis • Lymphocytic thyroiditis • Fibrosing thyroiditis • Rock-hard neck mass • Can compress trachea Riedel’s Fibrosing Thyroiditis •Rarest form of thyroiditis •Dense fibrosis invades thyroid parenchyma and even beyond the capsule Woody •Woody Reidel thyroiditis Graves Disease • Common autoimmune disease! • Triad • Hyperthyroidism • Ophthalmopathy • Dermopathy • Anti-TSH receptor antibodies • Stimulate thyroid growth • Causes T4 release • Reacts with retro-orbital tissues, skin of legs Graves Dermopathy Marty Feldman as Igor in Young Frankenstein Exophthalmos Pretibial myxedema Goiter • Goiter: general term for a big thyroid gland • Latin “guttar” (throat) • Cause: defective T4 synthesis. • iodine deficiency (endemic) • other defects (sporadic) Goiter Goiter Goiter no iodine T4 enzyme defects TSH Thyroid Neoplasms Most neoplasms present as nodules. • Nodules are common! • Most are benign. • Thyroid carcinoma is uncommon. Incidence of thyroid carcinoma vs. adenoma carcinoma adenoma Thyroid Neoplasms biopsy or FNA cancer follicles take it out! thyroiditis treat it! • http://www.youtube.com/watch?v=CN5yFGa MDCs Thyroid Adenoma • Common! • Most patients are euthyroid (some are hyperthyroid) • Radioactive iodine uptake: most adenomas are “cold” Thyroid adenoma Thyroid adenoma Thyroid adenoma Thyroid Adenoma • Take it out! • Why, if it’s benign? • Need to see the whole tumor (including capsule ) to make sure it’s not carcinoma Thyroid Carcinoma • Papillary thyroid carcinoma • Follicular thyroid carcinoma • Medullary thyroid carcinoma • Anaplastic thyroid carcinoma Incidence of different types of thyroid carcinoma medullary (5%) anaplastic (<5%) follicular (10%) papillary (80%) Thyroid Carcinoma • Papillary thyroid carcinoma • Most common • Best prognosis • “Orphan Annie” tumor Papillary thyroid carcinoma Papillary thyroid carcinoma Papillary thyroid carcinoma Papillary thyroid carcinoma Papillary Carcinoma: The Little Orphan Annie Tumor • often affects younger women • tends to stay around for years without getting any bigger • is usually well-behaved; seldom kills people • has nuclei that resemble Orphan Annie’s eyes • has psammoma bodies (from the greek psammos, or sand) Annie’s dog is named Sandy Thyroid Carcinoma • Papillary thyroid carcinoma • Follicular thyroid carcinoma • 2nd most common • Good prognosis Papillary/Follicular Carinoma Which one is follicular carcinoma? Thyroid Carcinoma • Papillary thyroid carcinoma • Follicular thyroid carcinoma • Medullary thyroid carcinoma • Rare • Endocrine tumor • Bad prognosis Medullary thyroid carcinoma Thyroid Carcinoma • Papillary thyroid carcinoma • Follicular thyroid carcinoma • Medullary thyroid carcinoma • Anaplastic thyroid carcinoma • • • • Rare Bulky, fast-growing, metastatic at diagnosis Invades surrounding tissue Very bad prognosis Medullary thyroid carcinoma Adrenal Pathology Adrenal Pathology • Introduction • Too much stuff • Too little stuff • Tumors Introduction • two glands • upper pole of kidneys • 4 g each • cortex (three zones) • medulla Adrenal gland anatomy Capsule Zona glomerulosa Zona fasiculata Medulla Zona reticularis Adrenal gland histology Salt, sugar, sex. The deeper you go, the sweeter it gets. Glomerulosa, fasiculata, reticularis = GFR (glomerular filtration rate) Cushing Syndrome • Too much glucocorticoids • Causes • Ingested steroids • Adrenal adenoma • Pituitary adenoma • Paraneoplastic syndrome • Symptoms • Hypertension, weight gain • Glucose intolerance • Bone aches • Buffalo hump • Moon face Cushing syndrome Addison Disease • Too little cortisol and mineralocorticoids • Low Aldosterone • Primary chronic adrenal insufficiency • Cause: usually autoimmune • Symptoms • Slow onset (need to destroy 90% of cortex!) • Weakness, fatigue, GI complaints • Hypotension • Skin hyperpigmentation M.J. 33 y/o female Previously healthy 33 y/o female, who began having symptoms: fatigue, weight loss, craving potato chips Wednesday • Headache Thursday • Very fatigued, vomiting Saturday • Husband brought to ER • Vision loss right eye • IV fluids unhelpful Sunday • Right side paralyzed • Oxygen levels dropping • CT: brain swelling • Coma • BP 70/33 • Given IV fluids, respirator • 40 pound weight gain Tuesday • No brain activity, kidneys shutting down • “Nothing else can be done” Thursday • Different doctor • IV Na+, hydrocortisone, dextrose Saturday • Opened eyes Sunday • Started removing IVs Next weeks • Removed feeding tube • Speech, physical, occupational therapy Two months later • Back to work • Feeling normal • Cortisol and prednisone daily, for life • Carry crisis kit (hydrocortisone) M.J. 33 y/o female Previously healthy 33 y/o female, who began having symptoms: fatigue, weight loss, craving potato chips Wednesday • Headache Thursday • Very fatigued, vomiting Saturday • Husband brought to ER • Vision loss right eye • IV fluids unhelpful Sunday • Right side paralyzed • Oxygen levels dropping • CT: brain swelling • Coma • BP 70/33 • Given IV fluids, respirator • 40 pound weight gain Tuesday • No brain activity, kidneys shutting down • “Nothing else can be done” Thursday • Different doctor • IV Na+, hydrocortisone, dextrose Saturday • Opened eyes Sunday • Started removing IVs Next weeks • Removed feeding tube • Speech, physical, occupational therapy Waterhouse-Friderichsen Syndrome • Bacterial infection (N. meningitidis) • Hypotension, shock • Massive, bilateral adrenal hemorrhage • Rapidly progressive Pheochromocytoma • Neoplasm of catecholamine-producing cells • Rare cause of hypertension! • Urine: catecholamines, VMA and metanephrines • The 10% tumor! • • • • 10% extra-adrenal (“paraganglioma”) 10% bilateral 10% familial (MEN) 10% bad (malignant) Pheochromocytoma Pheochromocytoma Pheochromocytoma Neuroblastoma • Derived from neural crest cells • Relatively common childhood tumor • Prognosis better in: • Children < 18 months • Lower stage tumors • Lower grade tumors • Hyperdiploid tumors • Fewer copies of N-myc Neuroblastoma Neuroblastoma Diabetes Diabetes Common, common, common! • 100 million worldwide have it (3% of the world)! • 13 million in US have it (only half diagnosed)! • 54,000 die in US each year (#7 cause of death)! • Lifetime risk of getting diabetes: up to 5%! Diabetes • A disease in which the body does not produce or properly use insulin • Primary vs. secondary • Primary: type 1 vs. type 2 • Pathogenesis different, but end result same Diabetes All have in common: not enough insulin. Type I Diabetes • Problem: not enough β cells • Lots of susceptibility genes, one in MHC II region • MHC II antigen abnormal • T cells attack islets • Slow, persistent attack Type II Diabetes • Problem: can’t make enough insulin, and tissues can’t use insulin properly • Probably lots of contributory genes • Deranged insulin secretion • Insulin resistance Diabetes pathophysiology Non-enzymatic glycosylation • glucose attaches itself to proteins, forming AGEs * • AGEs crosslink, trap stuff • AGEs bind to receptors, do nasty stuff Intracellular hyperglycemia • some cells take up the glucose without insulin • glucose activates protein kinase C • …which induces production of pro-angiogenic and pro-fibroblastic molecules * advanced glycosylation end-products Hemoglobin A1C Diabetes complications • Increased infections • Microangiopathy • Retinopathy • Nephropathy • Neuropathy Diabetes complications • Increased infections • Oral (and other) candidiasis • “Malignant” otitis externa Oral candidiasis Malignant otitis externa Diabetes complications • Increased infections • Microangiopathy • accelerated, severe atherosclerosis • increased permeability Atherosclerosis: aorta Atherosclerosis: coronary vessels Peripheral vascular disease Diabetes complications • Increased infections • Microangiopathy • Retinopathy • retinopathy • cataracts • glaucoma Diabetes complications • Increased infections • Microangiopathy • Retinopathy • Neuropathy • peripheral neuropathy • motor, sensory Diabetes complications • Increased infections • Microangiopathy • Retinopathy • Neuropathy • Nephropathy • glomerular lesions • vascular lesions • pyelonephritis Glomerular lesions Fungal bladder infection MEN Syndromes Brad Pitt vs. John Cleese No contest! MEN Syndromes • genetic disorders • predispose to endocrine tumors • MEN-1 and MEN-2 MEN Syndromes MEN tumors are worse! • younger • multiple organs • multifocal • hyperplasia • aggressive MEN Syndromes ORGAN MEN-1 medullary carcinoma thyroid other endocrine organs MEN-2 hyperplasia, adenoma, carcinoma MEN Syndromes ORGAN MEN-1 medullary carcinoma thyroid other endocrine organs MEN-2 hyperplasia, adenoma, carcinoma MEN-1 Lesions • Parathyroid hyperplasia • Pancreatic carcinoma • Pituitary adenoma • Other stuff MEN-1 Genetics • mutation in MEN1 gene • MEN1 encodes menin • classic tumor suppressor gene MEN-1 • Pit • MEN gene • Run-of-the-mill • Inactive MEN Syndromes ORGAN MEN-1 medullary carcinoma thyroid other endocrine organs MEN-2 hyperplasia, adenoma, carcinoma MEN-2 Lesions • Medullary thyroid carcinoma • Pheochromocytoma • Parathyroid hyperplasia • Other stuff Parafollicular C cells and medullary thyroid carcinoma MEN-2 Genetics • RET mutation • • • • Proto-oncogene → oncogene Tyrosine kinase receptor Constitutively activated Unusual! • Genetic testing required MEN-2 • Cleese-cell hyperplasia • bRETon gene • one-of-a-kind • always turned on
