Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Endocrinology Review Thyroid, pituitary, adrenal & bone Dora Liu, MD FRCPC Basic thyroid physiology Hypothalamic-PituitaryThyroid Axis Thyroid hormones From UpToDate Thyroid hormone transport • Three major transport proteins: – Thyroxine-binding globulin (TBG) – Thyroxine-binding prealbumin (TBPA) – Albumin • Free (unbound) hormones are active • Proportion of “free” hormones: – 0.04% of T4 – 0.4% of T3 Thyrotoxicosis Clinical features of thyrotoxicosis • • • • • • • • Weight loss Increased appetite Heat intolerance Anxiety, irritability Fine tremor Fatigue Thyroid stare Systolic HTN • • • • • • • • Tachycardia Palpitations Atrial fibrillation Frequent BM’s Proximal weakness Diaphoresis Moist skin Fine hair Thyrotoxicosis - Investigations • Primary: – Low TSH – Increased fT3 and/or fT4 – Thyroid uptake and scan to determine etiology of 1o hyperthyroidism • Secondary: – TSH elevated or not suppressed – Increased fT3 and/or fT4 Causes of 1o thyrotoxicosis • • • • • • Graves’ disease Toxic adenoma or toxic multinodular goitre Thyroiditis Jod-Basedow (iodine-induced) Exogenous thyroid hormone Gestational hyperthyroidism (hCG-induced) Graves’ disease • Autoimmune disorder • Thyroid stimulating immunoglobulin binds TSH receptor • F>M • Any age with peak in 3rd-4th decade • Diffusely enlarged “meaty” goitre Graves Hyperthyroidism Graves ophthalmopathy Pretibial myxedema Graves disease Increased homogeneous uptake Treatment of Graves disease • • • • Methimazole or propylthiouracil (PTU) Radioactive iodine therapy Thyroidectomy Temporary measures: -blockade until hyperthyroidism improves – Steroids (decrease T4 to T3 conversion) – Iodine (Wolff-Chaikoff effect) Toxic adenoma • Solitary thyroid nodule produces excess hormone • Accounts for < 5% of hyperthyroidism • Frequency increases with age • F>M • Treatment of choice: radioactive iodine therapy Toxic adenoma Toxic multinodular goitre 2 nodules producing excess hormone • In Canada, most patients are > 50 yrs old • Younger patients in areas of iodine deficiency • Compressive symptoms can occur • Treatment of choice: I-131 Toxic multinodular goitre Toxic multinodular goitre Thyroiditis • Destruction of thyroid cells causes release of hormones • Autoimmune, infectious and toxic causes • Can occur in post-partum period • Can be associated with fever, painful & tender gland Diagnosis & treatment of thyroiditis • • • • • Low uptake on thyroid scan NSAIDs for painful inflammation -blockers to control symptoms Steroids for severe cases Often followed by hypothyroid phase Gestational hyperthyroidism • hCG mimics TSH and stimulates thyroid hormone production • Associated with hyperemesis gradvidarum, multiple gestation • Improves by 2nd trimester • Must differentiate from Graves disease -blocker & PTU can be used during pregnancy Extrathyroidal sources of thyroid hormone • Exogenous sources: – Exogenous thyroid hormone – Hamburger thyrotoxicosis • Endogenous sources: – Struma ovarii – Functioning thyroid cancer Other causes of hyperthyroidism • TSH-secreting tumour • Iodine load (Jod-Basedow phenomenon) • Pituitary resistance to thyroid hormone Hypothyroidism Hypothyroidism • 2-3% of population • F:M = 10:1 • 1o hypothyroidism (90%) – – – – Autoimmune (e.g., Hashimoto’s) Iatrogenic (surgery, RAI, drugs, iodine) Congenital, intrinsic defect of hormone synthesis Infiltrative (amyloid, progressive systemic sclerosis) • 2o hypothyroidism - TSH deficiency • 3o hypothyroidism - TRH deficiency Clinical features of hypothyroidism • Fatigue • Cold intolerance • Slow mental & physical performance • Hoarse voice • Bradycardia • Diastolic hypertension • Edema • • • • • • • • Weight gain Constipation Menorrhagia Dry skin Macroglossia Muscle cramps Delayed DTR Dyslipidemia Hypothyroidism - Lab tests • 1o hypothyroidism – Elevated TSH – Low fT4 and/or fT3 • Central hypothyroidism – Low fT4 and/or fT3 – TSH not reliable Treatment of hypothyroidism • Typical L-T4 dose 50 - 200 mcg • Start low dose (25 mcg) and titrate up slowly in elderly • R/O adrenal insufficiency • Check TSH 6-8 wk after dose change & titrate to normalize TSH for 1o hypothyroidism • Titrate to normalize fT3 for central hypothyroidism Myxedema coma • Severe hypothyroidism • Precipitating event (e.g., trauma, sepsis, cold exposure, MI, narcotics) • Clinical features: Hypothermia, hypoglycemia, hypotension, bradycardia, hypoventilation • Mortality up to 60% • Treatment: – ABCs – Stress-dose steroids – L-T4 0.2-0.5 mg IV then 0.1 mg daily Non-thyroidal illness “Sick euthyroid syndrome” Non-thyroidal illness • Change in thyroid hormone levels related to serious illness • Abnormalities in TSH secretion, hormone binding & metabolism • Decreased T4 to T3 conversion • Typically see low fT3 & high rT3 • More severe illness: fT3, fT4 & TSH can all be low • Rx: Treat underlying illness Thyroid nodules and malignancies Thyroid nodules • ~ 4% prevalence • ~ 5% malignant • If nodule is identified, check TSH – Low TSH Thyroid scan • Low probability of malignancy with hot nodules • FNAB if cold nodule is present (15-20% malignant) – Normal or high TSH FNAB if palpable or > 1 cm in diameter Thyroid malignancies • Well-differentiated thyroid carcinomas: – Papillary – Follicular • Medullary thyroid carcinoma – Familial forms: MEN IIa & IIb, familial medullary carcinoma – Calcitonin is a tumour marker • Anaplastic thyroid carcinoma – Very poor prognosis Well-differentiated thyroid carcinoma • Total thyroidectomy • I-131 therapy if higher risk – – – – Multifocal Large tumour Capsular invasion Lymph node or distant metastases • TSH suppression • Follow thyroglobulin level Medullary thyroid CA • Look for other features of MEN IIa & IIb – R/O pheochromocytoma – R/O 1o hyperparathyroidism – RET protooncogene mutation • Treatment – Surgical resection for cure – Some respond to MIBG or octreotide • Prophylactic thyroidectomy in affected relatives MEN syndromes MEN 1 •Parathyroid adenoma •Enteropancreatic tumour •Foregut carcinoid •Anterior pituitary tumour •Adrenal cortex MEN 2A •Medullary thyroid cancer •Pheochromocytoma •Parathyroid tumours •Cutaneous lichen amyloidosis MEN 2B •Medullary thyroid cancer •Pheochromocytoma •Marfanoid habitus •Mucosal neuromas Medullary thyroid CA • Look for other features of MEN IIa & IIb – R/O pheochromocytoma – R/O 1o hyperparathyroidism – RET proto-oncogene mutation • Treatment – Surgical resection for cure – Some respond to MIBG or octreotide • Prophylactic thyroidectomy in affected relatives Pituitary - Adrenal Disorders Basic pituitary & adrenal physiology Hypothalamic & anterior pituitary hormones • • • • • • • GHRH Growth hormone (GH) TRH TSH Somatostatin GH & TSH TRH & Prolactin-releasing factors Prolactin Dopamine Prolactin CRH ACTH GnRH LH & FSH Pituitary hormones • Anterior – Growth hormone – ACTH – LH – FSH – TSH – Prolactin • Posterior – ADH (arginine vasopressin) – Oxytocin Hyperprolactinemia Causes of hyperprolactinemia Physiologic Pregnancy Nipple stimulation Sleep Stress Exercise Medications Pathologic Estrogen Anti-psychotics MAOI Opioids Cimetidine Licorice Pituitary tumours Stalk compression Chest wall lesions Hypothyroidism Renal failure Severe liver disease Hyperprolactinemia • Clinical features: – Galactorrhea, gynecomastia, infertility, low bone density – Headaches, bitemporal hemianopsia (if macroadenoma affects optic chiasm) • Treat underlying cause, if present • 1o Rx for prolactinoma: – Dopamine agonist (e.g., bromocriptine or cabergoline) Acromegaly Clinical features of acromegaly • • • • • • • • Coarse facial features Acral enlargement Hyperhidrosis Heat intolerance Oily skin Fatigue Weight gain HTN • • • • • • • Goitre Cardiomegaly Insulin resistance Arthralgias Parasthesias Hypogonadism Headaches Acromegaly • Diagnostic tests: – Glucose suppression test – IGF-1 level • Treatment: – – – – Surgery Somatostatin analogues (Octreotide) Radiotherapy GH receptor antagonist (Pegvisomant) Posterior pituitary disorders SIADH Diagnostic criteria • Plasma osmolality < 275 mOsm/kg H2O, excluding pseudohyponatremia or hyperglycemia • Inappropriate urine concentration (UOsm > 100 with normal renal function) • Clinical euvolemia • Elevated urine sodium excretion with normal salt and water intake • Absence of other potential causes of euvolemic hypo-osmolality (hypothyroidism, adrenal insufficiency, diuretic use) Treating SIADH • Fluid restriction • Loop diuretics • Hypertonic saline if urgent correction needed • Demeclocycline, lithium (rarely used) • Do not correct Na+ too quickly • Treat underlying cause Diabetes insipidus • Clinical features: – Polyuria, polydispsia – Hypernatremia, dehydration – Low urine Na+ & osmolality • Treatments: – Oral & IV fluids – ddAVP – For nephrogenic DI: • Na+ restriction, thiazides & PG inhibitors Hypothalamic Pituitary Adrenal Axis From Williams Textbook of Endocrinology POMC synthesis and cleavage From Williams Textbook of Endocrinology Microscopic anatomy From Williams Textbook of Endocrinology Zone Hormone Glomerulosa Aldosterone Fasciculata Cortisol Reticularis Androgens Medulla Catecholamines Adrenal steroid function • Glucocorticoids – Affects fuel metabolism, responses to injury and general cell function • Mineralocorticoids – Control body Na+ and K+ content • Androgens – Similar function to male gonadal hormones Adrenal steroidogenesis From Williams Textbook of Endocrinology Sites of glucocorticoid action From Williams Textbook of Endocrinology Cushing’s syndrome Features of Cushing’s • Moon facies • Facial plethora • Dorsal & supraclavicular fat pads • Mental status change • HTN • Visceral adiposity • • • • • • • Muscle wasting Ecchymoses Thin skin Purple striae Osteoporosis Avascular necrosis Insulin resistance Screening tests for Cushing’s syndrome • 24 hr urinary free cortisol • Low-dose dexamethasone suppression test • Evening cortisol • Salivary cortisol (23:00) Working up Cushings Diagnose Cushings ACTH > 2 ACTH < 2 High-dose DST Adrenal Imaging Cushings disease Ectopic Cushings or Cushings disease MRI Pituitary Inferior petrosal sinus sampling Adrenalectomy Pituitary surgery Cushings disease Ectopic Cushings MRI Pituitary CT Chest/abdo Octreotide scan Pituitary surgery Adrenal insufficiency Clinical features of adrenal insufficiency • • • • • • Weight loss Fatigue Weakness Hypoglycemia Hyponatremia Anemia • Addison’s – – – – Hyperpigmentation Volume depletion N/V, abdo pain Hyperkalemia Adrenal insufficiency • Treatment – IV fluids – Glucocorticoid therapy – Mineralocorticoid therapy for Addison’s • Diagnosis – ACTH stimulation test – Insulin tolerance test for central disease Primary hyperaldosteronism Aldosterone secretion & action Hypotension Low Na+ Renin Angiotensinogen Angiotensin I Aldosterone ACE Angiotensin II Na+ reabsorption Blood pressure Assessment of reninangiotensin-aldosterone axis • • • • Random plasma renin activity not reliable Plasma aldosterone > 695 pmol/L Aldosterone:renin ratio 24 hr urinary aldosterone – Normal 14-56 nmol – Aldosterone-producing adenoma 125 9 nmol – Idiopathic hyperaldosteronism 75 5 nmol • Adrenal vein sampling From UpToDate Adrenal androgens Adrenal androgen secretion • > 50% of circulating androgens in premenopausal females • Relative contribution smaller in males • Stimulated by ACTH • DHEA and androstenedione levels demonstrate circadian rhythm (but not DHEAS) Congenital adrenal hyperplasia X X Congenital adrenal hyperplasia • Autosomal recessive disorder • Presentations of CAH: – Female neonates: Ambiguous genitalia – Male neonates: Adrenal crisis – Non-classic: Hirsutism & infertility in females • Treatment: – Glucocorticoid therapy – Mineralocorticoid for salt-wasting varieties Pheochromocytoma Clinical features of pheochromocytoma • Paroxysmal or sustained HTN • Triad: H/A, palpitation/tachycardia, diaphoreseis • Postural drop in BP • Dilated cardiomyopathy • Tremor, anxiety • Chest pain • Papilledema, blurry vision Pheochromocytoma • Diagnosis – Urine metanephrines or plasma catecholamines – MIBG, octreotide scan • Treatment -blockade or CCB (not -blocker 1st!) – Volume restoration – Adrenalectomy Bone & calcium disorders 2+ PTH-Ca feedback loop Parathyroid glands - PTH PTH GI Tract 1,25 D Ca2+ Ca2+ Ca2+ ECF Ca2+ - Vitamin D 7-dehydrocholesterol Cholecalciferol 25-OH vitamin D PTH Calcitriol Intestinal Ca & PO4 absorption PTH secretion Multiple effects in bone 24,25(OH)2 - D Effects in muscle Hypercalcemia Clinical manifestations of hypercalcemia • • • • General: Weakness CVS: HTN, valve & arterial calcification GI: Constipation, anorexia, N/V, pancreatitis Renal: Stones, DI (polyuria), renal insufficiency • MSK: Bone pain • CNS: Altered mental status Mechanisms for hypercalcemia • Increased bone resorption • Increased gastrointestinal absorption of calcium • Decreased renal excretion of calcium Increased bone resorption • Hyperparathyroidism (usually 1o) • Malignancies – – – – • • • • • PTHrP (solid tumours, leukemia) 1,25(OH)2D (lymphomas) Ectopic PTH (rare) Osteolytic lesions Hyperthyroidism Immobilization Paget’s disease (usually with immobilization) Estrogen, tamoxifen Hypervitaminosis A More causes of hypercalcemia • Increased calcium absorption – Increased calcium intake – Hypervitaminosis D • • • • • • • Lithium Thiazide diuretics Pheochromocytoma Adrenal insufficiency Rhabdomyolysis Theophylline Familial hypocalciuric hypercalcemia Ways to lower calcium • • • • • • IV fluids Furosemide Calcitonin Steroids Bisphosphonates Dialysis Hypocalcemia Clinical features of hypocalcemia • • • • • • • • Paresthesia Laryngospasm Seizures Carpopedal spasm Chvostek’s sign (CN VII) Trousseau’s sign (carpal spasm) Hyperreflexia Mental status changes Causes of hypocalcemia • Low PTH – Hypoparathyroidism – Hypomagnesemia • Vitamin D related – Vitamin D deficiency – 1 -hydroxylase activity (renal failure, vit D dependent rickets) – Vitamin D resistant rickets • Pseudohypoparathyroidism (PTH resistance) • Drugs (calcitonin, furosemide) Treatment of hypocalcemia • ABC’s • Replace calcium – Calcium gluconate IV – Oral calcium • Treat hypomagnesemia, if present • May require vitamin D • Correct underlying cause Osteoporosis What is osteoporosis? • Systemic skeletal disorder • Characterized by compromised bone strength • Leads to enhanced bone fragility and a consequent increase in fracture risk What determines bone strength? • Bone density – Expressed in grams of bone mass over area or volume of bone – Determined by peak bone mass & amount of bone loss • Bone quality – Refers to architecture, damage accumulation (e.g., microfractures) & mineralization NIH Consensus Statement 2000 Bone density & quality determine bone strength Normal bone Low BMD Poor quality 22% 13% 22% Bone volume Tissue volume Osteoporosis & fractures • Osteoporosis is a significant risk factor for fractures • Fractures occur when a failure-inducing force is applied to osteoporotic bone Who is at risk for fractures? • Major risk factors: – – – – – – – – – – – Age ≥ 65 years Vertebral compression fracture Fragility fracture after age 40 FHx of osteoporotic fracture Systemic glucocorticoid therapy 3 mos Malabsorption syndrome Primary hyperparathyroidism Propensity to fall Osteopenia apparent on X-ray film Hypogonadism Early menopause (before age 45) CMAJ 2002; 167(10 Suppl) Who is at risk for fractures? • Minor risk factors: – – – – – – – – – – Rheumatoid arthritis Past history of clinical hyperthyroidism Chronic anticonvulsant therapy Low dietary calcium intake Smoker Excessive alcohol intake Excessive caffeine intake Weight < 57 kg Weight loss 10% of weight at age 25 Chronic heparin therapy CMAJ 2002; 167(10 Suppl) DEXA is used to measure BMD • The PROS of DEXA scanning – Quick, non-invasive – 1/10 radiation of CXR (background radiation exposure over 1 day) – Most accurate estimator of fracture risk • The CONS of DEXA scanning – Not a measure of bone strength (only accounts for ~70% of strength) – Inter-operator variability, lack of standardization Who should be screened? • Indications for BMD scan: – Patients with 1 major or 2 minor risk factors for osteoporosis – Age ≥ 65 years regardless of risk factors • Contraindications for BMD scan: – Pregnancy – Recent GI study or nuclear medicine test (wait at least 72 hr; up to 7 d for long-lived isotopes like gallium) Interpretation of BMD measurements • T-score: # of SD’s from average person of same gender at peak bone mass • Z-score: # of SD’s compared to average person of same gender, age & race WHO diagnostic categories Classification Criterion Normal T-score ≥ - 1.0 Osteopenia T-score between -1.0 and -2.5 Osteoporosis T-score < -2.5 Severe osteoporosis T-score < -2.5 with Hx of fragility fracture(s) Secondary causes of osteoporosis Endocrine & Metabolic Hypogonadism Cushings Thyrotoxicosis Anorexia nervosa Hyperprolactinemia Porphyria Hypophosphatemia Diabetes Pregnancy Hyperparathyroidism Acromegaly Nutritional Drugs Malabsorption Malnutrition Chronic cholestatic liver disease Gastric operations Vitamin D deficiency Calcium deficiency Alcoholism Glucocorticoids Excessive thyroid hormone Heparin GnRH agonists Phenytoin Phenobarbital Vitamin D toxicity Collagen disorders Osteogenesis imperfecta Homocystinuria Ehlers-Danlos syndrome Marfan syndrome Other Rheumatoid arthritis Myeloma & some cancers Immobilization Renal tubular acidosis Hypercalciuria COPD Organ transplantation Mastocytosis Thalassemia Calcium & vitamin D intake Calcium Children (4-8) 800 mg Adolescents (9-18) 1300 mg Premenopausal women 1000 mg Men <50 1000 mg Menopausal women 1500 mg Men > 50 1500 mg Pregnant or lactating women 1000 mg Vitamin D Age < 50 400 IU Age > 50 800 IU Fall Prevention • Risk Factors – – – – – – – Sedatives Previous fall Cognitive impairment Visual impairment Foot problems Gait abnormalities Lower extremity disability • Prevention measures – – – – – Bathroom lights on Install grab bars Avoid loose rugs Remove clutter Keep wires behind furniture Who should receive pharmacotherapy? • Patients with osteoporosis • Patients with T-score < -1.5 with 1 major or 2 minor risk factors • Some argue 10-yr risk for fracture should be used instead Bisphosphonates • Similar in structure to pyrophosphate in bone • Attaches to bone surface and inhibits osteoclastic resorption • Poorly absorbed orally • GI side effects common Calcitonin • • • • • Inhibits bone resorption Analgesic effect No drug-drug interactions Well-tolerated Evidence for reduction in vertebral fractures, but not non-vertebral fractures Hormone replacement therapy • The benefits: – – – – Decreases osteoclastic activity Increases BMD & lowers fracture risk Treats symptoms of estrogen deficiency Decreases colon cancer risk • The down side: – Increased CVD, VTE & PE risk – Increased breast cancer risk – Adverse effect on cognition Selective Estrogen Receptor Modulator (SERM) • Binds to estrogen receptors • Produces an estrogen agonist effect in some tissues • Produces an estrogen antagonist effect in others • Examples: Tamoxifen, raloxifene Guidelines for Teriparatide • 1st line Rx for women ≥ 65 yrs with T < -2.5 and Hx of vertebral fracture • Preferable to treat bisphosphonate naïve patients • Consider treating post-menopausal women with T < -3.5 who continue to fracture despite adequate (2 yr) trial of therapy • Discontinue bisphosphonate prior to PTH • Limit PTH Rx to maximum 18 mos • Administer bisphosphonate therapy after PTH course CMAJ 2006; 175:48 Hip protectors • 1801 frail but ambulatory elderly adults, mean age 82 yrs • Hip protector : control = 1 : 2 • 1 month F/U • Relative hazard of hip fracture = 0.4; P=0.008 NEJM 2000; 343: 1506 Vertebroplasty & kyphoplasty • Vertebroplasty = minimally invasive surgical procedure to relieve the pain of compression fractures • Kyphoplasty = proprietary derivative procedure using polymethylmethacrylate (PMMA) to fix a vertebral body in place after balloon inflation of the body Good luck!