endocrinology review thyroid, pituitary, adrenal & bone
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Endocrinology Review Thyroid, pituitary, adrenal & bone. Dora Liu, MD FRCPC. Basic thyroid physiology. Hypothalamic-Pituitary- Thyroid Axis. Thyroid hormones. From UpToDate. Thyroid hormone transport. Three major transport proteins: Thyroxine-binding globulin (TBG) - PowerPoint PPT PresentationTRANSCRIPT
Endocrinology Review
Thyroid, pituitary, adrenal & bone
Dora Liu, MD FRCPC
Basic thyroid physiology
Hypothalamic-Pituitary-Thyroid 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 diseaseIncreased 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
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 Medications Pathologic
Pregnancy
Nipple stimulation
Sleep
Stress
Exercise
EstrogenAnti-psychoticsMAOIOpioidsCimetidineLicorice
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
Zone Hormone
Glomerulosa Aldosterone
Fasciculata Cortisol
Reticularis Androgens
Medulla Catecholamines
From Williams Textbook of Endocrinology
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 CushingsDiagnose Cushings
ACTH < 2 ACTH > 2
Adrenal Imaging
Adrenalectomy
High-dose DST
Cushings disease Ectopic Cushingsor Cushings disease
Inferior petrosal sinus sampling
MRI Pituitary
Pituitary surgeryCushings disease Ectopic Cushings
MRI Pituitary
Pituitary surgery
CT Chest/abdoOctreotide scan
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 & actionHypotension Low Na+
Renin
Angiotensinogen Angiotensin I
Angiotensin II
ACE
Blood pressure
Aldosterone
Na+ reabsorption
Assessment of renin-angiotensin-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
XX
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
PTH-Ca2+ feedback loopParathyroid
glands
GI Tract
PTH
ECF Ca2+
1,25 D
-
PTH
-
Ca2+Ca2+ Ca2+
Vitamin D
7-dehydrocholesterol Cholecalciferol
25-OH vitamin D
Calcitriol
PTH
24,25(OH)2 - D
IntestinalCa & PO4
absorption
PTHsecretion
Multiple effectsin bone
Effectsin 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
Bone volume Tissue volume 22% 13% 22%
Normal bone Low BMD Poor quality
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 osteoporosisT-score < -2.5 with
Hx of fragility fracture(s)
Secondary causes of osteoporosis
Endocrine & Metabolic
Nutritional DrugsCollagen disorders
Other
HypogonadismCushingsThyrotoxicosisAnorexia nervosaHyperprolactinemiaPorphyriaHypophosphatemiaDiabetesPregnancyHyperparathyroidismAcromegaly
MalabsorptionMalnutritionChronic cholestatic
liver disease
Gastric operationsVitamin D deficiencyCalcium deficiencyAlcoholism
GlucocorticoidsExcessive thyroid
hormoneHeparinGnRH agonistsPhenytoinPhenobarbitalVitamin D toxicity
Osteogenesis imperfecta
HomocystinuriaEhlers-Danlos
syndromeMarfan
syndrome
Rheumatoid arthritisMyeloma & some
cancersImmobilizationRenal tubular acidosisHypercalciuriaCOPDOrgan transplantationMastocytosisThalassemia
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 DAge < 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
NEJM 2000; 343: 1506
• 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
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!