Addison disease (primary adrenal insufficiency) is one of those Step 1 favorites because it ties together endocrine physiology, autoimmunity, electrolytes, and hemodynamics—and it shows up in both classic vignettes and “don’t-miss” emergencies (adrenal crisis). If you can explain why patients get hyperpigmentation, hyponatremia, hyperkalemia, and hypotension, you can answer most questions on it.
Where Addison Disease Fits (Big Picture)
Adrenal insufficiency = not enough adrenal cortex hormones.
Types (know the distinctions)
| Condition | Problem location | Cortisol | Aldosterone | ACTH | Hyperpigmentation? | Potassium |
|---|---|---|---|---|---|---|
| Primary adrenal insufficiency (Addison) | Adrenal cortex failure | ↓ | ↓ | ↑ | Yes | ↑ |
| Secondary adrenal insufficiency | Pituitary ACTH low | ↓ | ~Normal (usually) | ↓ | No | Normal |
| Tertiary adrenal insufficiency | Hypothalamus/withdrawal of exogenous steroids | ↓ | ~Normal | ↓ | No | Normal |
High-yield takeaway: Hyperkalemia + hyperpigmentation = primary adrenal insufficiency until proven otherwise.
Definition (Step-Style)
Addison disease is primary adrenal insufficiency due to destruction/dysfunction of the adrenal cortex → low cortisol and low aldosterone (often also ↓ adrenal androgens, especially relevant in women).
Pathophysiology (Make It Mechanistic)
1) Cortisol deficiency: “can’t respond to stress”
Cortisol normally:
- Supports vascular tone (permissive effect on catecholamines)
- Promotes gluconeogenesis
- Helps maintain normal blood pressure
So cortisol deficiency causes:
- Hypotension
- Fatigue, weakness
- Hypoglycemia (more common in children; still testable in adults)
- Poor stress tolerance → adrenal crisis under illness/surgery
2) Aldosterone deficiency: “salt wasting”
Aldosterone normally increases:
- Na⁺ reabsorption (via ENaC) in collecting duct principal cells
- K⁺ and H⁺ secretion (principal + alpha-intercalated cells)
Loss of aldosterone →:
- Hyponatremia
- Hyperkalemia
- Metabolic acidosis (type 4 RTA physiology—impaired H⁺ secretion and hyperkalemia)
3) ACTH elevation: “why hyperpigmentation?”
In primary adrenal failure:
- Low cortisol → loss of negative feedback → ↑ ACTH
- ACTH comes from POMC, which also produces MSH-like peptides
- More melanocyte stimulation → hyperpigmentation, often in:
- Palmar creases
- Buccal mucosa
- Areas exposed to friction/pressure
Step pearl: Hyperpigmentation is not expected in secondary/tertiary adrenal insufficiency (ACTH low).
Etiologies You Must Know (with “classic clues”)
Most common in the US: Autoimmune adrenalitis
- Often part of autoimmune polyglandular syndromes
- APS-2: Addison + autoimmune thyroid disease ± type 1 DM (classic Step combo)
Infectious/destructive causes (classic boards list)
- TB (granulomatous destruction; think immigrants, cavitary lung disease)
- Disseminated fungal infection (e.g., Histoplasma)
- Metastatic cancer to adrenal glands
- Adrenal hemorrhage
- Waterhouse-Friderichsen syndrome (classically meningococcemia)
- Anticoagulation/trauma/sepsis
Medication-related “mimics”
- Ketoconazole, etomidate: inhibit steroid synthesis → adrenal insufficiency picture
Clinical Presentation (Recognize the Vignette)
Chronic Addison (typical Step stem)
- Weakness, fatigue, weight loss
- Anorexia, abdominal pain, nausea/vomiting
- Orthostatic hypotension
- Salt craving
- Hyperpigmentation (primary only)
- Possible amenorrhea/decreased libido (↓ adrenal androgens; especially women)
Labs (memorize the pattern)
- ↓ Cortisol
- ↑ ACTH
- ↓ Aldosterone
- ↑ Renin (volume depletion stimulates RAAS upstream)
- Hyponatremia
- Hyperkalemia
- Non-anion gap metabolic acidosis (can show up as ↓ HCO₃⁻)
Diagnosis (How Questions Want You to Confirm It)
Stepwise approach (high-yield)
- Morning serum cortisol
- Low AM cortisol supports adrenal insufficiency (but not definitive alone)
- ACTH (cosyntropin) stimulation test = classic confirmation
- Give cosyntropin → measure cortisol response
Interpretation
| Condition | Baseline ACTH | Cortisol after cosyntropin |
|---|---|---|
| Primary adrenal insufficiency | High | No/insufficient rise |
| Secondary/tertiary insufficiency (early) | Low | Blunted rise |
| Secondary/tertiary insufficiency (chronic) | Low | Often blunted/no rise (adrenal atrophy over time) |
Practical Step framing: In Addison, the adrenal gland is damaged—so it can’t respond to ACTH stimulation.
Additional tests sometimes tested
- 21-hydroxylase antibodies (autoimmune adrenalitis)
- Electrolytes: hyponatremia/hyperkalemia
- Plasma renin activity: elevated
Treatment (Chronic vs Crisis)
Chronic management
Replace what’s missing:
- Glucocorticoid: hydrocortisone (common), or prednisone
- Mineralocorticoid: fludrocortisone (key for primary insufficiency)
Counseling is testable:
- Stress-dose steroids for illness/surgery (“sick day rules”)
- Medical alert identification
Adrenal crisis (medical emergency)
Trigger: infection, trauma, surgery, stopping steroids, severe stress.
Presentation:
- Severe hypotension/shock
- Vomiting, abdominal pain
- Fever
- Hyponatremia, hyperkalemia, hypoglycemia
Management (don’t overthink)
- Immediate IV hydrocortisone
- Aggressive IV fluids (normal saline; add dextrose if hypoglycemic)
- Treat the precipitating cause (e.g., infection)
Step pearl: In crisis, don’t wait for confirmatory testing if unstable—treat first.
High-Yield Associations & “Classic Traps”
Autoimmune clustering (very testable)
- Addison + Hashimoto or Graves
- Addison + type 1 diabetes
- Addison + pernicious anemia, vitiligo
Hyperpigmentation clues
- Oral mucosa discoloration is a strong hint
- Present in primary adrenal insufficiency due to high ACTH (POMC)
Electrolyte signature
- Primary: hyponatremia + hyperkalemia + acidosis
- Secondary: hyponatremia can occur (↑ ADH from low cortisol), but hyperkalemia is NOT typical (aldosterone preserved)
“Primary vs secondary” shortcut
- Hyperkalemia = primary
- Hyperpigmentation = primary
- History of chronic steroid use with abrupt cessation = secondary/tertiary (ACTH low)
Rapid Review Table (Exam-Day Memory)
| Feature | Addison (Primary) |
|---|---|
| Cortisol | ↓ |
| Aldosterone | ↓ |
| ACTH | ↑ |
| Renin | ↑ |
| Na⁺ | ↓ |
| K⁺ | ↑ |
| Blood pressure | ↓ (often orthostatic) |
| Skin | Hyperpigmentation |
| Confirmatory test | Cosyntropin: little/no cortisol rise |
| Treatment | Hydrocortisone + fludrocortisone |
First Aid Cross-References (for quick flipping)
In First Aid for the USMLE Step 1 (Endocrine section), connect Addison disease with:
- Adrenal insufficiency and cosyntropin stimulation test
- Autoimmune polyglandular syndromes (Addison + thyroid disease ± T1DM)
- Steroid physiology: cortisol’s permissive effect on catecholamines (helps explain hypotension)
- Electrolyte changes from mineralocorticoid deficiency (hyponatremia, hyperkalemia)
(Edition layouts vary, so use these as topic cross-links rather than strict page numbers.)
Mini-Vignette Practice (How It’s Usually Asked)
A patient with months of fatigue, weight loss, salt craving, and orthostatic hypotension has diffuse hyperpigmentation and labs showing Na⁺ 128, K⁺ 5.8. Morning cortisol is low and ACTH is high. Next step to confirm?
→ Cosyntropin stimulation test (expect no rise in cortisol).
If the same patient arrives septic-looking with vomiting and profound hypotension:
→ IV hydrocortisone + IV fluids immediately.