Endo: Adrenal Insufficiency And Cushing's Syndrome

Front 1

Central steroid nucleus, three major families

Back 1

Cyclopentanoperhydrophenanthrene ring

Families
a) C21 Pregnane (progesterone)
b) C19 Androstane (testosterone)
c) C18 Estrane (estradiol)

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Cholesterol sources

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Precursor to ALL adrenal steroids

1) Diet - from LDLs in blood to be stored as cholesterol esters in cells
2) Release of esters from vacuoles under right conditions
3) De novo synthesis in cells like adrenal steroidogenic cells and liver cells (via acetate)

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Adrenal Steroidogenesis Impt steps

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P450 side chain cleavege enzyme replaces cholesterol side chain with keto-group to make pregnenolone

This converted to 17-hydroxyprogesterone

21- hydroxylase next converts it down cortisol path

Glomerulosa - enzymes for mineralocorticoids (aldosterone)
Fasciculata - enzymes for glucocorticoids (cortisol)

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21-hydroxylase def

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17-hydroxyprogestrone builds up and shunted to androgen path and have no cortisol

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What does ACTH promote

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Glucocorticoid production (cortisol) NOT mineralocorticoids

Also stimulates androgens

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Glucocorticoid Axis

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CRH released from paraventricular nuclei of hypothalamus

Travels down hypophyseal portal tract to activate CRH receptors on ACTH producing cells of anterior pituitary. Releases ACTH (adreno cortico trophic hormone) which stimulates cortex growth and production of enzymes and gene products. Net effect is to produce Cortisol

Cortisol negatively inhibits CRH release and ACTH release

Front 7

Diurnal variation of Cortisol and ACTH

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Both secreted in pulsitile fasion

HIGHEST in EARLY MORNING (5-8AM), Decreases as day proceeds and lowest at midnight

Can be altered in shiftwork

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When to test for ACTH levels

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Looking for deficiency - test in early morning when should be highest

Looking for excess - test at midnight when should be lowest

Front 9

Glucocorticoid Action

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Cortisol binds receptor with a hormone domain, DNA binding domain and regulatory domain in the CYTOPLASM

When cortisol binds, heat shock protein negative regulatory influence is negated, receptor to nucleus and gene transcription

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Glucocorticoid Effect

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All organ systems unlike aldosterone

pharmacologic doses suppresses inflammation

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Mineralocorticoid Regulation

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Axis senses VOLUME not osmolality

JG apparatus (JG cells and macula densa) controls not pituitary

JG cells sample blood of afferent arteriole. Volume sufficiency (high flow) stretches cells to normal level, volume depletion (low flow, hypovolemia) lack of stretch. DCT (macula densea) has filtrate from glomerusus with sodium load reflectin volume status.

JG senses blood flow pressure, macula densa senses Na+ filtered load

Na+ level high - volume sufficencient, Na+ level low then depleted AT MACULA DENSA (post filtration)

Effect is that renin secreted if low volume, Renin catalyzes cleaveage of angiotensinogen to Ag I, goes to lung to be converted to AgII (via ACE)

AgII promotes aldosterone synthesis by increaseing levels of aldose synthase in zona glomerulosa

Aldosterone causes kidney to retain Na+ in CCT and exchange it for potassium to increase blood volume.

RENIN is RATE-LIMITING and controlled by kidney

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Inhibitors of RAAS system

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Renin inhibitors - not used
Competitive antagonists of AgII - ARBs used a lot
ACEi's - used a lot
Aldosterone antagonists - ex spironalactone competes with aldosterone

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Primary vs Secondary Adrenal Insufficiency

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Primary - deficiency in production from organ of interest (mineralcorticoid or glucocoritocid)

Secondary - defect in control of axis from inadequate ACTH

Key Difference - 2dary has NO deficiency of mineralocorticoid (controlled by kidney not pituitary), whereas in primary there is. Glucocorticoid deficiency in both (relies on ACTH)

So primary worse b/c 2 hormones missing

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Primary Hypoadrenalism and Secondary Hypoadernalism and Causes

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Primary Hypoadrenalism - defect in adrenal glands - deficient cortisol and INCREASED ACTH due to lack of feedback. Deficient aldosterone (loss of Na+ follows with K+ preservation = hyponatremia and hyperkalemia with low volume/dehydration). Can lead to CV collapse

Causes - 70% from autoimmune polyglandular syndrome (ADDISON"s DISEASE), Also some from TB or HIV/AIDS

Secondary Hypoadrenalism (pituitary) - (Or tertiary at hypothalamus) - problem in central control leading to dysfunctional cortisol productoin. Aldosterone INTACT b/c regulated by JG apparatus - milder

Causes - exogenous glucocorticoids is main one, high doses in asthma, COPD, autoimmune disease. Axis suppression, cortex atrophy. Can also be due to hypothalamic or pituitary lesions or surgeries in those areas

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Autoimmunity Associated with Idiopathic Addison's Disease

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1) Polyglandular Autoimmune Syndrome Type I/Schmidt's Syndrome - autoimmune thyroid disease, Addison's disease (low cortisol and aldosterone), diabetes, skin depigmentation,/perniscious anemia

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Chronic Primary Adrenal Insufficiency, Treatment

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Gradual (can be rapid) destruction of adrenal tissue leading to increasingly severe symptoms

Treatment: glucocorticoid replacement (not high dose), injectable replacement dose on hand, mineralocorticoid replacement, Medi Alert bracelet

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Symptoms of Adrenal insfficiency/Addisons, labs

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Weakness, fatigue, anorexia, weight loss, GI symptoms, dizziness, orthostatic HTN, hyperpigmentation (MSH)

Labs: HIGH potassium, LOW salt, low volume water

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Cause hyperpigmentation in adrenal insufficiency

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Reflexively increase ACTH levels. From POMC gene with additional products of melanocyte stimulating hormone leading to hyperpigmentation

May only see hyperpigment on gingival areas if dark skinned patient

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Acute Primary Adrenal Insufficiency, Treatment, Cause, Tests

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Adrenal Crisis - dramatically cortisol and aldosterone deficient

At stress exposure no cortisol or aldosterone. Instead of just being light-headed get HYPOTENSION, WEAK, SHOCK, NAUSEA, vomiting, HYPONATREMIA and HYPERKALEMIA - medical emergency

Treatment - HIGH dose glucocorticoids with taper, FULL saline (not half norm or water b/c need salt and water). Minotor. DO NOT need aldosterone replacement acutely b/c pushing fluids and salt but give after stabilized

Cause: usually precipitating event from chronic adrenal insufficiency

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Cosyntropin test

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ACTH stimulation test to measure cortisol response

both primary and secondary have subnormal response so hard to distinguish with just this

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Cushing's Syndrome Classification, Features, Etiology, Eval and Treatment

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HYPERcortisolism

Cushing's Disease - pitutitary tumor making ACTH
Iatrogenic - physician causing (steroids)
Factitious
Endogenous - disruption of axis

Etiology
a) ACTH dependent - unregulated ACTH from pitutitary tumor (Cushing's DISEASE); rarely ectopic
b) ACTH independent - (ACTH LOW) - adenoma, carcinoma or nodular hyperplasia (problem of adrenal gland itself)

Features - OBESITY, weight gain, fat pads, MOON FACIES, HYPERTENSION, violaceous striate, easy bruising, thin skin, HAIRINESS in women, DIABETES, AMENORRHEA, ACNE

Opportunistic infections due to immune suppression, hyperpigmentation if ACTH dependent, growth arrest in children

MAY have feminization if excess adrenal androgen produced from adrenal carcinoma

Evaluation -
1) Document hypercortisolemia via 24hr free urine cortisol or overnight dexamethasone suppression test. show loss of diurnal variation with salivary cortisol level
2) Determine whether ACTH dependent (HIGH) or independent (LOW) via venous petrosal sinus sampling of anterior pitutitary vs peripheral sample

Treatment - Trans-sphenoidal surgery (through nose and sphenoid sinus into sella turcica to remove causative tumor or surgery to remove lesion on adrenals

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Tumors causing Ectopic ACTH syndrome

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OAT cell lung cancer or Carcinoid tumor in foregut

Rarely a pheochromocytoma secreting ACTH