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Summary Table

Feature	Detail
Risk Factors	Autoimmune disease (most common in developed countries), tuberculosis (most common worldwide), HIV/AIDS, adrenal hemorrhage (Waterhouse-Friderichsen syndrome in meningococcemia), metastatic cancer to adrenals, chronic anticoagulation, antiphospholipid syndrome
Etiology	Destruction of the adrenal cortex leading to deficiency of cortisol, aldosterone, and adrenal androgens. Autoimmune adrenalitis accounts for roughly 80% of cases in industrialized nations.
Patient Presentation	Chronic fatigue, weight loss, anorexia, nausea, vomiting, abdominal pain, salt craving, postural dizziness
Classic Physical Exam	Hyperpigmentation (skin creases, buccal mucosa, scars, nipples), hypotension/orthostatic hypotension, vitiligo (if autoimmune)
Key Diagnostic Results	Low morning cortisol, elevated ACTH, failed cortisol response on cosyntropin stimulation test, hyperkalemia, hyponatremia, non-anion gap metabolic acidosis, possible hypercalcemia and eosinophilia
Management	Hydrocortisone (glucocorticoid replacement) + Fludrocortisone (mineralocorticoid replacement); stress-dose steroids during illness or surgery
Keywords	Hyperpigmentation + hypotension, salt craving, hyperkalemia with hyponatremia, "bronze skin," Waterhouse-Friderichsen

1. Pathophysiology

Addison's disease results from the progressive destruction of the adrenal cortex, which must lose approximately 90% of its functional tissue before clinical insufficiency becomes apparent. The cortex is responsible for producing three classes of hormones: glucocorticoids (cortisol) from the zona fasciculata, mineralocorticoids (aldosterone) from the zona glomerulosa, and adrenal androgens (DHEA) from the zona reticularis.

When cortisol production falls, the hypothalamic-pituitary axis loses its negative feedback. The anterior pituitary responds by increasing secretion of ACTH, which is co-cleaved from the precursor molecule proopiomelanocortin (POMC). POMC also gives rise to melanocyte-stimulating hormone (MSH), and the excess MSH is what drives the characteristic hyperpigmentation. This is the single most important pathophysiologic link to understand for exam purposes: hyperpigmentation occurs because ACTH is elevated, and ACTH elevation only happens in primary adrenal failure, not secondary (pituitary) or tertiary (hypothalamic) insufficiency.

The loss of aldosterone is what distinguishes primary from secondary adrenal insufficiency at the metabolic level. Aldosterone normally acts on the distal tubule and collecting duct to reabsorb sodium and excrete potassium and hydrogen ions. Without aldosterone, the patient develops hyponatremia, hyperkalemia, and a non-anion gap metabolic acidosis (type IV renal tubular acidosis). The sodium wasting also causes volume depletion, contributing to the hypotension and salt craving. In secondary adrenal insufficiency, aldosterone is preserved because it is regulated primarily by the renin-angiotensin-aldosterone system (RAAS), not ACTH. This is why secondary insufficiency does not cause hyperkalemia.

Cortisol deficiency itself impairs vascular tone and the body's ability to mount a stress response. During physiologic stress (infection, surgery, trauma), the adrenal glands normally increase cortisol output several-fold. A patient with Addison's disease cannot do this, which is why they are at risk for adrenal crisis, a life-threatening emergency characterized by profound hypotension, shock, fever, and altered mental status.

2. Classification and Clinical Manifestation

Type	Mechanism	Cortisol	Aldosterone	ACTH	Hyperpigmentation	Hyperkalemia
Primary (Addison's)	Adrenal cortex destruction	Low	Low	High	Yes	Yes
Secondary	Pituitary ACTH deficiency (tumor, surgery, Sheehan syndrome)	Low	Normal	Low	No	No
Tertiary	Chronic exogenous steroid use causing hypothalamic-pituitary suppression	Low	Normal	Low	No	No

Clinical Manifestation

Hormone	Clinical Manifestations
Cortisol deficiency	Fatigue, weakness, weight loss, anorexia, nausea, vomiting, abdominal pain, hypoglycemia (especially in children), inability to mount stress response, hypotension
Aldosterone deficiency	Salt craving, orthostatic hypotension, hyponatremia, hyperkalemia, metabolic acidosis, volume depletion
Androgen deficiency	Decreased axillary and pubic hair (more noticeable in women), reduced libido
Elevated ACTH/MSH	Hyperpigmentation of palmar creases, buccal mucosa, scars, areolae, pressure points

Adrenal crisis deserves special attention. It presents acutely with cardiovascular collapse, severe hypotension refractory to fluids and vasopressors, fever, abdominal pain mimicking an acute abdomen, altered consciousness, and severe electrolyte derangements. The most common precipitant is an intercurrent illness in a patient with undiagnosed Addison's disease, or a patient who fails to increase their steroid dose during physiologic stress.

3. Diagnostic Workup

Test	Role	Expected Finding
Morning serum cortisol	Screening / initial test	Low (< 3 mcg/dL is highly suggestive; > 18 mcg/dL essentially rules it out)
Serum ACTH	Differentiate primary vs. secondary	Elevated in primary, low/normal in secondary
Cosyntropin (ACTH) stimulation test	Best initial diagnostic test	Cortisol fails to rise above 18-20 mcg/dL at 30 or 60 minutes
Basic metabolic panel	Supportive	Hyperkalemia, hyponatremia, possible hypercalcemia, non-anion gap metabolic acidosis
CBC	Supportive	Eosinophilia (cortisol normally suppresses eosinophils)
21-hydroxylase antibodies	Confirm autoimmune etiology	Positive in autoimmune adrenalitis
CT abdomen (adrenals)	Determine structural cause	Small/atrophied adrenals (autoimmune) vs. enlarged/calcified (TB, hemorrhage, infiltration)

The cosyntropin stimulation test is the best initial diagnostic test and the most commonly tested step. Synthetic ACTH (cosyntropin, 250 mcg IV) is administered, and serum cortisol is measured at baseline, 30 minutes, and 60 minutes. In a healthy individual, cortisol should rise to at least 18-20 mcg/dL. In primary adrenal insufficiency, the adrenal glands are destroyed and cannot respond, so cortisol remains low regardless of ACTH stimulation.

Once the cosyntropin test confirms adrenal insufficiency, you need to determine whether it is primary or secondary. This is where the plasma ACTH level becomes critical. A high ACTH with a failed cosyntropin test confirms primary disease. A low ACTH with a failed cosyntropin test points to secondary insufficiency (pituitary problem), and you would then pursue pituitary MRI.

For identifying the underlying cause in primary disease, 21-hydroxylase antibodies help confirm autoimmune adrenalitis. If antibodies are negative, CT imaging of the adrenals is warranted to look for tuberculosis (bilateral adrenal calcification is classic), hemorrhage, or infiltrative disease.

An important lab pattern to recognize on the exam: hyponatremia + hyperkalemia + metabolic acidosis + eosinophilia in a patient with hypotension and hyperpigmentation. This combination should immediately trigger consideration of Addison's disease.

4. Management and Treatment

Setting	Treatment	Details
Chronic glucocorticoid replacement	Hydrocortisone	15-25 mg/day divided into 2-3 doses (typical: 10 mg morning, 5 mg afternoon, 5 mg evening; the largest dose is given in the morning to mimic physiologic diurnal rhythm)
Chronic mineralocorticoid replacement	Fludrocortisone	0.05-0.2 mg once daily
Adrenal crisis	IV hydrocortisone	100 mg IV bolus, then 50 mg IV every 6-8 hours; aggressive IV normal saline; dextrose if hypoglycemic
Stress dosing (minor illness)	Double or triple oral hydrocortisone	2-3x the daily dose for the duration of the illness
Stress dosing (major surgery)	IV hydrocortisone	100 mg IV before induction, then 50 mg every 8 hours for 24-72 hours, then taper to maintenance

Chronic management requires lifelong replacement of both cortisol and aldosterone. Hydrocortisone is preferred over other glucocorticoids because its short half-life allows dosing that mimics the normal diurnal cortisol curve. Prednisolone or dexamethasone can be used as alternatives, but dexamethasone has no mineralocorticoid activity and its long half-life makes physiologic dosing difficult.

Fludrocortisone replaces aldosterone. Its adequacy is monitored by checking blood pressure, serum potassium, and plasma renin activity. The goal is to normalize potassium and keep renin in the upper-normal range. Patients should be advised to maintain a liberal salt intake.

Adrenal crisis is a medical emergency. The single most important step is immediate IV hydrocortisone 100 mg before any diagnostic workup. Do not wait for lab confirmation. If the diagnosis is uncertain, dexamethasone 4 mg IV can be given instead because it does not interfere with the cosyntropin stimulation test (hydrocortisone cross-reacts with the cortisol assay, making subsequent testing uninterpretable). Aggressive volume resuscitation with isotonic saline is critical. Once the patient stabilizes, transition to oral replacement and taper to maintenance doses.

Stress dosing is a concept frequently tested. Patients must be educated to increase their glucocorticoid dose during febrile illness, trauma, or surgical procedures. Failure to stress-dose is the most common cause of adrenal crisis in a known Addison's patient. All patients should wear a medical alert bracelet and carry an emergency injectable hydrocortisone kit.

One key point: at high doses (> 50 mg/day), hydrocortisone provides adequate mineralocorticoid effect. Therefore, fludrocortisone is unnecessary during acute crisis management and can be added back once the patient is on maintenance doses.

5. Differential Diagnosis and Distractors

Differential Diagnosis	Why It Is Similar	Key Discriminator
Secondary adrenal insufficiency (pituitary failure)	Fatigue, hypotension, low cortisol, weight loss	No hyperpigmentation (ACTH is low, not high), no hyperkalemia (aldosterone is intact), history of pituitary surgery/radiation or chronic steroid use
Hypothyroidism	Fatigue, weight changes, weakness	No hyperpigmentation, no hyperkalemia, TSH is elevated, different metabolic profile
Hemochromatosis	Skin darkening ("bronze diabetes")	Darkening is generalized and gray-bronze (iron deposition), not in creases/mucosa; ferritin and transferrin saturation are elevated; associated with diabetes and hepatomegaly
Pheochromocytoma	Episodic symptoms, adrenal pathology	Causes hypertension (not hypotension), episodic headaches/palpitations/diaphoresis, elevated catecholamines
Anorexia nervosa	Weight loss, fatigue, amenorrhea, electrolyte abnormalities	Hypokalemia (not hyperkalemia), body image distortion, no hyperpigmentation
Chronic fatigue syndrome	Persistent fatigue, weakness	Normal cortisol, normal electrolytes, no hyperpigmentation, diagnosis of exclusion
Celiac disease / malabsorption	Weight loss, fatigue, possible autoimmune overlap	Diarrhea and steatorrhea are prominent, anti-tTG antibodies positive, no hyperkalemia or hyperpigmentation
Nelson syndrome	Hyperpigmentation with elevated ACTH	Occurs after bilateral adrenalectomy, pituitary macroadenoma with very high ACTH, visual field defects

The two most commonly confused entities on exams are primary vs. secondary adrenal insufficiency. The table below reinforces the distinction:

Feature	Primary (Addison's)	Secondary (Pituitary)
ACTH	High	Low
Aldosterone	Low	Normal
Hyperpigmentation	Present	Absent
Hyperkalemia	Present	Absent
Most common cause	Autoimmune / TB	Abrupt steroid withdrawal

6. Traps and High-Yield Pearls

The most common trap with Addison's disease questions is confusing primary with secondary adrenal insufficiency. Test-writers will present a patient on chronic prednisone who abruptly stops the medication and develops fatigue, hypotension, and hyponatremia. Students see "adrenal insufficiency" and jump to Addison's, but the absence of hyperkalemia and hyperpigmentation should redirect you to tertiary/secondary insufficiency from HPA axis suppression. Always check the potassium: if it is normal, this is not primary adrenal failure.

Another classic trap is the adrenal crisis scenario where the vignette buries the adrenal history and focuses on the acute presentation of shock, abdominal pain, and fever. Students anchor on sepsis, acute abdomen, or meningitis. The key trigger is unexplained hypotension refractory to fluids and vasopressors, especially with hyperkalemia and hyponatremia. In a patient with a history of autoimmune disease, tuberculosis, or steroid use, this should raise immediate concern.

The Waterhouse-Friderichsen syndrome vignette is high-yield: a child or young adult with meningococcal meningitis who develops purpura fulminans, DIC, and acute adrenal hemorrhage. This is acute primary adrenal insufficiency from bilateral adrenal hemorrhage, and the treatment is immediate IV hydrocortisone along with antibiotics and supportive care.

Remember that fludrocortisone is not needed in secondary insufficiency because aldosterone production is governed by the RAAS, which is independent of ACTH. This is tested frequently as an "unnecessary treatment" option.

Finally, the concept being tested is almost always one of three things: the ability to recognize the classic presentation (hyperpigmentation + hyperkalemia + hyponatremia + hypotension), the ability to distinguish primary from secondary causes using ACTH and potassium, or the knowledge that stress dosing is required and that failure to provide it is the most common precipitant of adrenal crisis.

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