Adrenal Insufficiency

Overview and Clinical Presentation

first described by Addison in 1855 – hence the term Addison’s Disease

Depending on etiology, it may result in glucocorticoid deficiency or glucocorticoid and mineralocorticoid deficiency

(1) Glucocorticoid Deficiency – decreased cortisol

GI effects – anorexia, nausea, vomiting, abdominal pain, weight loss

Mental effects – diminished vigor, lethargy, apathy, confusion, psychosis

Constitutional Symptoms – fancy way of saying "feels like crap"

Metabolic effects – ß gluconeogenesis Þ fasting hypoglycemia; ß fat mobilization/utilization; liver glycogen depletion

CV/renal – ß ability to excrete free water (cortisol normally suppresses ADH; no cortisol = Ý ADH); hypotension (glucocorticoids are necessary for blood vessels to respond to catacholamines)

Skin – ß cortisol Þ Ý ACTH; ACTH in large amounts can stimulate melanocyte stimulating factor receptors Þ hyperpigmentation (classic sign of Addison’s)

Hematologic – Ý eosinophils, Ý lymphocytes

(2) Mineralocorticoid Deficiency – ß aldosterone (which normally retains Na⁺, excretes K⁺ and H⁺) Þ hyponatremia (no Na⁺ retention), hyperkalemia (no K⁺ excretion), mild acidosis (no H⁺ excretion)

hyponatremia leads to ß ECFV, hypovolemia, ß weight, hypotension, ß renal blood flow, Ý renin production

Primary Adrenal Insufficiency – problem is adrenal gland itself

Presentation depends on rate and absolute degree of adrenal destruction; other factors may precipitate an acute crisis

Acute – sudden destruction of both glands; 80-90% destroyed; usually iatrogenic etiology

Chronic – gradual destruction; more common than acute – three levels of severity:

(1) intercritical phase – destruction is compensated for by Ý ACTH and renin (basal secretion maintained, but adrenal reserve is reduced)

(2) stress (trauma, surgery, infection) – depleted reserve is unable to respond normally

(3) Addisonian Crisis – most advanced stage; same features as chronic insufficiency exaggerated (shock, fever, vomiting, hyponatremia, hyperkalemia, hypoglycemia)

Etiology – before 1920: 60-70% of cases caused by tuberculosis

1950-1980: 80% of non-iatrogenic cases were autoimmune adrenalitis

now: AIDS and malignancies becoming more common

Associated Conditions –50% of idiopathic Addison’s patients have at least one autoimmune disorder; TB Addison’s patients do not

polyglandular autoimmune syndrome type I: adrenal insufficiency, hypoparathyroid, mucocutaneous candidiasis

polyglandular autoimmune syndrome type II: adrenal insufficiency, Hashimoto’s thyroiditis, insulinopenic diabetes mellitus

other autoimmune disorders: pernicious anemia, primary gonadal failure, chronic active hepatitis, celiac disease

Treatment (Give the patient what their adrenals would produce if they were normal!!)

intercritical phase – replacement therapy for glucocorticoids and mineralocorticoids (keep in mind diurnal rhythm)

during stress – increased doses based on level of stress (URI Þ double dose; surgery Þ maximum dose)

Addisonian crisis–medical emergency! max dose of hydocortisone, replace fluids/electrolytes, treat precipitating factor

Secondary Adrenal Insufficiency – result of ACTH deficiency

Etiology – hypothalamic/pituitary suppression from disease (hypopituitarism) or glucocorticoids (prednisone therapy)

Clinical Signs – same as primary disease except no hyperpigmentation (ACTH not Ý ) and no hyponatremia (aldosterone not ß )

recovery takes 6-18 months because reduced ACTH leads to adrenal atrophy – takes time to reverse

Treatment – glucocorticoid therapy with adjustments for stress

Laboratory Diagnosis – rule of thumb for acute adrenal insufficiency: treat first, diagnose later

Basal cortisol may be normal (due to adrenal reserve), so measuring response to stress is more informative

Tests to Establish Diagnosis

(1) ACTH Stimulation Test – give ACTH analog (cosyntropin) and look for cortisol secretion in response

primary adrenal insufficiency – no cortisol will be produced

secondary adrenal insufficiency – impaired short-term cortisol response, but an increasing response over time (>2 days) due to recovery of the glands from atrophy

(2) Metyrapone Test – block 11-b -hydroxylase which catalyzes 11-deoxycortisol Þ cortisol

normally see ß cortisol, Ý ACTH secretion, and Ý 11-deoxycortisol – does not happen with adrenal insufficiency

GI side effects common; can induce an acute crisis

(3) Insulin-induced Hypoglycemia – give insulin; normally resulting hypoglycemia should Ý ACTH and Ý cortisol

hypoglycemia is potentially dangerous
Addison’s patients are particularly sensitive to insulin due to lack of counter-regulation by cortisol

Tests to Determine Etiology

(1) Plasma ACTH – normal is 20-100 pg/ml; levels will be elevated in primary insufficiency but not in secondary

(2) CRH Test – ACTH response to CRH distinguishes pituitary vs.hypothalamic insufficiency in secondary insufficiency

Hyporeninemic Hypoaldosteronism – not true adrenal insufficiency (cortisol function is normal)

Etiology – low plasma renin and aldosterone with no response to [Na⁺] depletion

Clinical Presentation – patients are usually asymptomatic; may have mild renal insufficiency; 50% have diabetes

Treatment – correction of hyperkalemia/acidosis with mineralocorticoid, diuretic, bicarbonate