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
11-hydroxylase def diagnosis
increased 11-deoxycortisol
11-hydroxylase deficiency tx
GCs
patients are not hypotensive, not at risk for Addisonian crisis
Adrenal incidentaloma pathogenesis
abdominal CT - 2% of population
80% non-functional
masses may be due to adenoma, carcinoma, pheochromocytoma, cyst, myelipoma, metastases
small lesions ( followup CT in 6 months
Large tumours/symptomatic –> biochemical investigation
Non-malignant adrenal incidentalomas
Hemorrhage
Cyst
Abscess
Chronic granulomatous disease (TB, histoplasmosis)
Adrenal incidentalomas - benign neoplasms
myelolipoma ganglioneuroma adrenocortical adneoma hemangioma pheochromocytoma leiomyoma
Adrenal incidentalomas - malignant neoplasms
neuroblastoma (most commonly: extracranial neural tumour in kids)
Adrenocortical adenoma (most commonly found incidentaloma)
pheochromocytoma (10% disease - 10% extra adrenal, 10% metastasize, 10% bilateral)
Adrenal incidentalomas - bilateral masses
pituitary adenoma (Cushing's) adrenal nodular hyperplasia ectopic ACTH/CRH production metastases pheochromocytoma lymphoma hemorrhage
Adrenal cortical adenoma
2/3 women, detected at 30-40 years
benign appearance, Conn’s
- zona fasciculata –> Cushing’s
- Zona reticularis –> adrenogenital syndrome
If non-functional, adjacent adrenal has normal cortical thickness
If functional then adjacent adrenal will be atrophic
Neuroblastoma
Most common extra-cranial solid tumour in infancy
- most common before 8 yo
- 80% before 4
- responsible for 15% of childhood cancer deaths
- early metastases: bone marrow, bone , lymph, meninges, liver, ovary, paratesticular
SNS malignancy from neuroblasts
Pattern of distribution follows sites of primary disease
- 25% adrenal medulla
- sympathetic chain
Many chromosomal and molecular abnormalities identified
- MYCN-verexpressed oncogene (25% cases, poor prognosis)
- H-RAS: lower disease state
Schmida histopathologic classification
degree of neuroblast differnetiation presence/absence of schwannianor stromal development (stromal-rich, stromal-poor) index of cellular proliferation nodular pattern age
Metastasis to adrenal
common at autopsy
usually bilateral
most common primary tumours are breast/lung
usually does not affect adrenal function unless extensive (>80%)
gross pathology: single or multiple firm masses replacing some/all adrenal gland
- larger mets –> hemorrhage, necrosis
Natural catecholamines
NE
E
dopamine
Norepinephrine souces, fxn, adrenergic receptors
SNS-major
adrenal medulla
CNS
fxn: neurotransmitter, vasoactive
alpha 1, 2 and beta 1
Epinephrine sources, fxn, adrenergic receptors
Adrenal medulla - major
SNS, CNS
Metabolic (carb metabolism), vasoactive
beta2
Dopamine sources, fxn, adrenergic receptors
CNS (hypothalamus)
inhibit prolactin
dopamine receptors
alpha stimulation effects
v/c insulin secretino sweating piloerection glycogenolysis
beta stimulation effects
vasodilation insulin release cardiac contraction rate increases (1) relaxation of smooth muscle in GI brochondilation (2) stimulation of renin release lipolysis
Catecholamine formation pathway
Phenylalanine/diet –> tyrosine –> tyrosine hydroxylase RDS –> DOPA –> dopamine granules in CNS –> dopamine beta hydroxylase –> NE (SNS) –> PNMT (induced by cortisol) –> Epi
Stimulation of catecholamine release
hypotension hypoxia cold MI angina hemorrhage surgery pain emotion anoxia (NE) hypoglycemia(E)
Catecholamine metabolism
once relapsed, rapidly degraded by COMT & MAO, only 2% excreted as free CA
MAO COMT –> VMA, metanpehrine/normetanephrine
2% as unaltered CA, 20% metanephrine, rest as VMA
Pathogenesis pheochromocytoma
rare, usually benign tumour of the adrenal medulla and SNS
90% in adrenal, 10% malignant, 10% bilateral
Curable
can cause serious hypertensive crisis
Familial: MEN 2A, MEN2B, neurofibromatosis, von Hippel Lindau disease
Paragangliomas: neuroendocrime tumours, 1-3% can secrete catecholamines, associated with succinate dehydrogenase mutations
Pheochromocytoma clinical features
Key: persistent orepisodic hypertension sweating headache palpitations tachycardia anxiety/fear of impedingdeath
Others: weight loss nausea and vomiting cold hands and feet chest pain visual disturbances
Pheochromocytoma symptom triggers
compression of tumour
change in position
exercise
emotional distress
Pheochromocytoma investigations
24 hour urine metanephrins (met and normet), catecholamines (epi and norepi) and VMA
Radiology: CT and MRI
Nuclear medicine: I-131/I-123 MIBG (taken up by tissues that make catecholamines)
Tumour marker: chromogranin A
MEN1 pathology
3P triad: parathyroid (90%), pancreatic islet cell (75% - insulin/gastrin), anterior pituitary (25% - most prolactin, but may be others/nonfunctional)
Most rarely associated with carcinoid, adrenal cortical and lipoid tumours
200 / million
Auosomal dominant with high penetrance, genetic cause linked to nuclear protein MENIN
MEN1 clinical presentation
dependent on hormone being secreted
clinically evident 40 yo
MEN1 testing
Biochemical abnormality detetable <20 DNA mnutation Annual screening for high risk patients Biochemical tests: - fasting glucose and insulin - calcium and PTH - Gastrinn - Prolactin, IGF1
MEN2A pathology
90% of MEN2
Triad: medullary carcinoma of thyroid (MCT)
pheochromocytoma
hyperparathyroidism
MEN2 clinical presentation
mass in neck
less commonly: present with hyperparathyroidism/pheochromocytoma
2B recognized earlier because of facial appearance and ganglioneuromas causing GI problems
MEN2B pathology
MCT and pheochromocytoma common
hyperparathyroid rare
Penetrance high, presentation earlier than 2A
Developmental abnormalities: ganglioneuromas, neuromas of lips/tongue, marfinoid features, skeletal anomalies
MEN2 investigations
Dx: fine needle biopsy, elevated calcitonin
Screening: early DNA testing for all 1st degree relatives
MCT can be lethal befoer age 6, some advocate prophylactic thyroidectomy early in life
RET Proto-oncogene (receptor TK in neural crest cells) responsible for MEN2
activating mutation of tyrosine kinase
Use of natural/synthetic adrenal steroids
Treatment of endocrine disorders - replacement therapy
Treatment of endocrine disorders
Use of steroids in endocrine disorders
Chronic adrenal insufficiency - mimic endogenous rhythm, increase dose during stress
Acute adrenal insufficiency, bolus
Congenital adrenal hyperplasia
Use of steroids in non-endocrine disorders
RA, SLE, temporal arteritis, polymyalgia rheumatica, poly/dermatomyositis, etc Anaphylaxis: epinephrine Bronchial asthma IBD Minimal change glomerulonephritis Dermatologic Cerebral edema, increased intracranial pressure, spinal cord injury, MS Ophthalmologic organ transplantation Lymphoma, ALL Prenatal lung maturation Postoperative nausea/vomiting prophylaxis
Inhibitors of glucocorticoid synthesis
P450 inhibitors: aminoglutethimide, metyrapone, ketoconazole, etomidate
5-alpha reductase inhibitors: finasteride
Inhibitors of GC action
Mifepristone (“anti-progesterone”)
Progesterone receptor blocker, used for termination of early pregnanices
Acts as a glucocorticoid receptor blocker at high doses
Cell types in adrenal medulla
Neural crest cells
Chromaffin
Sustentacular
Ganglion
Chromaffin cells
small nests and cords of cells large polygonal, poorly-defined borders granular basophilic cytoplasma variation in cell size secretes catecholamines
Sustentacular cells
supporting spindle cells at the pierphery of nests of chromafifin cells, rich vasculature
Ganglion cells
occasional single cell associated with myelinated nerve bundles
GC acting as MC
Kidney has enzyme which converts cortisol to cortisone (inactive)
But if high level of cortisol –> overwhelm enzyme, acts as a MC (aldosterone)
2-day high dose dexamethasone test
used in differential diagnosis of Cushing syndrome (pituitary vs ectopic) but not that useful
30-40% of ectopic sources still suppressed
BIPSS
most definitive means of accurately distinguishing pituitary from non-pituitary ACTH-dependent CUshing syndrome
but MUST establish diagnosis for Cushing first - gradient still seen in normal patients!
Cushing’s disease treatment
surgery of pituitary lesion
pharmacological inhibition of ACTH secretion
Ectopic ACTH treatment
surgical possible if tumour benign, but metastatic difficult
steroid synthesis blockers (metyrapone, ketoconazole)
Adrenal tumour treatment
Unilateral adrenalectomy is excellent
Supplement with GC until axis back to normal
Urine free cortisol
50% sens 100% spec
Midnight serum cortisol
more specific than urine
Midnight salivary cortisol
Now recommended - highest sensitivity and specificity
may still have false positives due to abnormal sleep/wake cycles and stress
RET proto oncogene
activating mutations –> MEN 2A MEN 2B familial MCT
inactivating - associated with Hirschsprung’s disease
Cortisol in serum
bound to CBG or albumin
Cortisol secretion per day
10 mg / day
can go up to 100x during stress
Cortisol PK
effect prolonged even after elimination (half life not useful)
