Transcript Endocrinology Review: Adrenal, thyroid & bone

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
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Weight loss
Increased appetite
Heat intolerance
Anxiety, irritability
Fine tremor
Fatigue
Thyroid stare
Systolic HTN
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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
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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
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Methimazole or propylthiouracil (PTU)
Radioactive iodine therapy
Thyroidectomy
Temporary measures:
– -blockade
– 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
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
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
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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 gravidarum,
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%)
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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
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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 levothyroxine (LT4) 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 > 11.5 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
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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
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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,
cabergoline, quinagolide)
Acromegaly
Clinical features of acromegaly
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Coarse facial features
Acral enlargement
Hyperhidrosis
Heat intolerance
Oily skin
Fatigue
Weight gain
HTN
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Goitre
Cardiomegaly
Insulin resistance
Arthralgias
Parasthesias
Hypogonadism
Headaches
Acromegaly
• Diagnostic tests:
– Glucose suppression test
– IGF-1 level
• Treatment:
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Surgery
Somatostatin analogues (Octreotide)
Dopamine agonist (less effective)
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
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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
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Weight loss
Fatigue
Weakness
Hypoglycemia
Hyponatremia
Anemia
• Addison’s
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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
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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
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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
Congenital adrenal hyperplasia
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Pheochromocytoma
Clinical features of
pheochromocytoma
• Paroxysmal or sustained HTN
• Triad: H/A, palpitations/tachycardia,
diaphoresis
• 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
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PTH
PTH
GI Tract
1,25 D
Ca2+
Ca2+
Ca2+
ECF Ca2+
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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
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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
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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
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Lithium
Thiazide diuretics
Pheochromocytoma
Adrenal insufficiency
Rhabdomyolysis
Theophylline
Familial hypocalciuric hypercalcemia
Ways to lower calcium
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IV fluids
Furosemide
Calcitonin
Steroids
Bisphosphonates
Dialysis
Hypocalcemia
Clinical features of hypocalcemia
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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
Indications for BMD ≥ 50 yrs
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Age ≥ 65 yrs
Fragility fracture after age 40 yr
Prolonged glucocorticoid use
Use of other high-risk medications
Parental hip fracture
Vertebral # or osteopenia on X-ray
Current smoking or high EtOH intake
Low weight (< 60kg) or wt loss (>10% of weight at age 25 yr)
Rheumatoid arthritis
Other disorder strongly associated with osteoporosis
CMAJ 2010
Indications for BMD < 50 yrs
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Fragility fracture
Prolonged use of glucocorticoid
Use of other high-risk medication
Hypogonadism or premature ovarian failure
Malabsorption syndrome
Primary hyperparathyroidism
Disorder strongly associated with rapid bone loss
and/or fracture
CMAJ 2010
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
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 per day
Children (4-8)
1000 mg
Adolescents (9-18)
1300 mg
Premenopausal women
1000 mg
Men <50
1000 mg
Menopausal women
1200 mg
Men > 50
1200 mg
Pregnant or lactating women
1300 mg
Vitamin D per day
Age < 50
400-1000 IU
Age > 50
800-2000 IU
Fall Prevention
• Risk Factors
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Sedatives
Previous fall
Cognitive impairment
Visual impairment
Foot problems
Gait abnormalities
Lower extremity
disability
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Bathroom lights on
Install grab bars
Avoid loose rugs
Remove clutter
Keep wires behind
furniture
Who should receive
pharmacotherapy?
Probability (%)
10-yr fracture probability
T-score
Age (yrs)
Osteoporos Int 2001; 12: 989
FRAX™ Calculation tool
FRAX™ Calculation tool
CAROC
Fragility fracture after 40 yr or prolonged systemic
glucocorticoid use increase basal risk by one category
Treat high risk patients
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> 20% 10-yr fracture risk
Prior fragility # of hip
Fragility # of spine
> 1 fragility #
CMAJ 2010
Moderate risk (10-20% 10-yr risk)
Consider treatment if:
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Prior wrist # and age > 65 yr
L-spine T-score << femoral neck
Rapid bone loss
Androgen deprivation therapy or aromatase inhibitor
Long-term or repeated glucocorticoid use
Recurrent falls (> 2 in 12 mos)
Disorder strongly associated with osteoporosis or
rapid bone loss
CMAJ 2010
Bisphosphonates
• Similar in structure to pyrophosphate in bone
• Attaches to bone surface and inhibits
osteoclastic resorption
• PO: Alendronate, risedronate
• IV: Pamidronate, zoledronic acid
• Possible adverse effects: Reflux, ONJ, atrial
fibrillation, low-energy subtrochanteric
fractures
Denosumab (Prolia)
• Human monoclonal RANKL antibody
• Inhibits osteoclastic activity
• Pros:
– Convenient, 60 mg SC q6 mos
– Reduces vertebral & non-vertebral #’s
– Well-tolerated
• Cons:
– ONJ, atypical subtrochanteric fractures
– Infection, hypocalcemia
Hormone replacement therapy
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Decreases osteoclastic activity
Increases BMD & lowers fracture risk
Treats symptoms of estrogen deficiency
Decreases colon cancer risk
• Cons:
– 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 24 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!