Adrenal Flashcards
Cortisol metabolic functions
provide glucose for the brain
provide substrates for gluconeogenesis
increases: gluconeogenesis, lipolysis, protein catabolism, serum glucose, glycogen synthesis
decreasesL peripheral glucose utilization, protein synthesis
Cortisol BP functions
generally increases BP
Increases: Angiotensinogen synthesis, vasucular reactivity to v/cers, epinephrine synthesis, sodium out of cells
decreases: kinins, prostaglandins
At high concentrations, may bind MC receptors in kidneys
ALso increases GFR, decreases water absorption
Cortisol immune function
Immunosuppression
leukocytosis via decrease diapedesis of PMNs, increase release from bm
suppresses inflammatory response - stabilizing lysosomes, inhibiting leukocyte igration and phagocytosis
-inhibits proinflammatory actions of ILs and interferons
Cortisol miscellaneous action
bone: inhibit bone formation, increase bone resorption
growth: inhibit growth
gonads: inhibit response of pituitary to GnRH – decreased gonadotropins and gonadal steroids
CNS: initially causes euphoria, eventually causes irritability, depression, decreased libido
thyroid: may inhibit TSH secretion from pituitary
Aldosterone functions
Increases ECF
Increases Na resorption and K excretion at DCT
water follows Na
Adrenal androgen functions
DHEA, androstenedione, DHEA
functions not well defined, peripherally converted to testosterone, DHT, estradiol
Constitutes 50% circulating testosterone in women, 5% in men
MOA of steroid hormones in cells
CLASS1 nuclear receptors: steroid receptor family
Causes of hypoadrenalism
primary: Addison’s
secondary: low CRH, ATH, pituitary
Exogenous - long term GCs –> adrenal atrophy
Key treatment of adrenal insufficiency
If vomiting –> absolutely must have fluid iv administration
should always increase medications if ill/surgery/stress
Dx of adrena linsufficiency
1) patient with postural hypotension, hyponatremia, hyperkalemia +/- pigmentation
2) measure ACTH and baseline control, then do a rapid ACTH stimulation test –> measure cortisol
3) Low ACTH + blunted cortisol response to ACTH –> exogenous GC or secondary adrenal insufficiency
4) insulin induced hypoglycemia test
5) increased ACTH –> atrophy
no change in ACTH –> secondary pituitary/hypothalamic disease
Addison’s pathophysiology
AI adrenalitis - most common cause, associated with other AI disorders (40%)
Granulomatous disease (TB, histoplasmosis, coccidiodes)
Neoplasm: malignant mets, lymphoma, space-occupying in the gland
Hemochromatosis
Amyloidosis
Adrenalectomy
Adrenal hemorrhage
AIDS
Drugs (metyrapone, mitotane, ketoconazole)
Adrenoleukodystrophy
Congenital adrenal hyperplasia
Clinical features of Addison’s
Non-specific until 90% gland destroyed Muscle weakness/fatigue weight loss/anoexia orthostatic Hypotension Hyponatremia and hyperkalemia due to hypoaldosteronism Hypoglycemia Hyperpigmentation (increase in ACTH --> increase in alpha-MSH) GI disturbances Amenorrhea
Addisonian crisis
acute deficiency of aldosterone and cortisol, caused by partial adrenal insufficiency
may be expressed folowing severe illness oro ther stress - patient has insufficient adrenal reserve
symptoms: fever, dehydration, nausea, vomiting, hypotension, shock, abdominal pain, coma, and death
- aldosterone/cortisol deficiency –> circulatory collapse
- hyperkalemia –> cardiac arrhythmia or arrest
- low BP –> pre-renal acute renal failure
Adrenal leukodystrophy pathogenesis
Cause of Addison’s in up to 40% of patients
X-linked deficiency of peroxisomal enzyme involved in catabolism of very long chain fatty acids
- cholesterol esters of VLCFAs accumulate in adrneal, testes, CNS white matter, and peripheral nervous system
- males with ALD may present with severe neurological and/or adrenal problems
Early or late onset
ALD symptoms
Neurological: emotional liability, learning disorders, seizures, demyelination, death
adrenal symptoms
neurological + adrenal symptoms
Dx of ALD
high concentration of VLCFAs in plasma or blood cells in male with adrenal and CNS problems
MRI - characteristic white matter changes
2ndary adrenal insufficiency pathogenesis
secondary to long-term GC therapy (most common)
less commonly due to hypothalamic/pituitary dysfunction
2ndary adrenal insufficiency symptoms
No hyperpigmentation (decreased ACTH)
Mineralocorticoid function normal: RAAS does not rely on ACTH –> no volume depletion/hyperkalemia
Decreased cortisol, increased water –> delusional hyponatremia
Main problems: weakness, fatigue, anorexia, nausea, hypoglycemia, arthalgias/myalgias
secondary may be associated with other features of hypo-/hyperpituitarism
Assessment of patients on long-term steroids
leads to atrophy of the adrenal axis
may take up to 2 years after withdrawal to recover normal response in some cases, depending on dose, duration and individual
Rapid ACTH stimulation test may be useful to assess recovery
or simply skip a dose of GC -> assess morning cortisol
Cushing’s syndrome pathogenesis
Exogenous GCs (most common)
small ACTH producing pituitary adenoma/hyperplasia - most common endogenous case
Ectopic ACTH by non-adrenal neoplasm
- tumours secrete ACTH-like substance
- adults usually due to SCC of lung cancer/ carcinoid
- grossly enlarged adrenal glands with tan brown, diffusely hyperplastic cortex
Bilateral adrenal hyperplasia, adrenal adenoma or adrenal carcinoma
- 25% of endogenous cases
- 80% women
- high cortisol but low ACTH
- opposite adrenal gland is atrophic
Cushing’s syndrome symptoms
sudden weight gain central obesit hypertension facial plethora proximal muscle weakness glucose intolerance/diabetes mellitus decreased libido, impotence depression/psychosis osteopenia/osteoporosis easy bruising hyperlipidemia menstrual disorders Violaceous striae, wider than 1 cm recurrent opportunistic or bacterial infections acne hirsutism
Cushing’s tests
dexamethasone suppression test and ACTH, urine catecholamines and metanephrines, aldo:renin ratio
if any positive –> surgery
6-12% secrete cortisol (subclinical CUshing’s), 2-3% are pheochromocytomas, smaller percent secretes aldosterone
Dexamethasone suppression test
exogenous steroid, provides negative feedback to the pituitary to suppress the secretion of ACTH
unable to pass BBB
Binds to GC receptors in the pituitary gland (outside the BBB)
Low dose: should suppress cortisol without pathology
High dose: exerts negative control on the pituitary ACTH producing cells, but not on ectopic ACTH producing cells or adrenal adenoma
Conn’s syndrome pathogenesis
primary hyperaldosteronism due to adrneal pathology
Now thought to be common - up to 10% of hypertensives
Adrenal adenoma secreting aldosternoe (APA): approx 30%
Idiopathic hyperaldosteronism (IHA) :approx 70%
other rare causes
Conn’s syndrome clinical features
main feature: elevated aldosterone + suppressed plasma renin/plasma renin activity in pateint with HTN and hypokalemia
HTN secondary to sodium and water retention
sodium concentration usually normal (water follows)
Volume expansion –> stretch myocytes of heart –> ANP –> increased Na retention by RAAS inhibition
Spontaneous hypokalemia in most
- muscle weakness, abnormal glucose tolerance, nephrogenic diabetes insipidus, ECG changes
- sodium administration may provoke hypokalemia
Conn’s syndrome diagnosis
Patient with hypertension with unexplained hypokalemia, resistant hypertension or adrenal incidentaloma
1) Increased aldosterone:renin ratio
2) confirmatory saline infusion (suppression test)
3) failure to suppress aldosterone –> primary aldosteronism, test to differentiate APA from IHA
Conn’s syndrome treatment
APA: surgery
IHA: medical - spironolactone
Conn’s syndrome radiologic diagnosis
CT
bilateral adrenal venous sampling - most definitive
if different between sides –> adenoma
same - IHA
Secondary hyperaldosteronism causes
decreased renal perfusion renal artery stenosis volume depletion Renin-secreting tumour aortic coarctation
Congenital adrenal hyperplasia causes
hereditary deficiency of enzymes in steroid biosynthetic pathway
Most common: 21-hydroxylase deficiency (95%) - newborn screening in BC
21-hydroxylase def physical findings
severe:
- decreased aldosterone and cortisol
- Addisonian crisis at early age
- excess androgen causes virilization in enwborn females and precocious puberty in males
Less severe:
- cortisol/aldosterone output compensated
- main problem: excess androgens - may only become apparently after puberty
- complications include: virilization, primary amenorrhea, rapid growth initially with premature epiphyseal closure, acne, precocious puberty, development of early sex drive, hirsutism
Non-classic: >1/100, carriers 1/7
- may be a common cause of hirsutism in females in some populatiosn
21-hydroxylase def diagnosis
presentation (severe): child with adrenal insufficiency (hypotension, electrolyte abnormalities) and females with signs of virilization (ambiguous genitalia)
Definitive test: 17 hydroxyprogesterone (built up metabolite)
Other abnormalities: low cortisol, increased androgens, including testosterone
21-hydroxylase deficiency treatment
Glucocorticoid +/- mineralocorticoid
Flutamide to block androgen effects
11-hydroxylase def pathogenesis
cortisol level may/may not be adequate
excess androgen production problematic
Increased level of 11-hydroxycorticosterone –> MC activity –> hypertension
