STEPTRACKERENDOCRINE | PATHOLOGY + BIOCHEMISTRY + GENETICS | HIGH-YIELD REVIEW

Adrenal Insufficiency & CAH

When the cortex makes too little — destroyed glands, a silent pituitary, a crisis — and the enzyme defects that reroute steroid synthesis.

FOCUS ON
Primary (Addison): cortisol + aldosterone lost, ACTH high → hyperpigmentation, hypotension, hyponatremia, hyperkalemia. Secondary/tertiary: only cortisol lost, no pigment, no hyperkalemia (chronic steroids). Waterhouse-Friderichsen: meningococcal adrenal hemorrhage. CAH: 21-OH (salt wasting, virilization, ↑ 17-OH-progesterone) vs 11β-OH and 17α-OH (hypertension, hypokalemia).
DISORDER
MECHANISM · CAUSE
FEATURES · LABS
CLUE · TREATMENT
Primary adrenal insufficiency (Addison)
Autoimmune (21-hydroxylase antibodies; developed world), TB (worldwide), metastases, hemorrhage, HIV/CMV, APS-1/2, adrenoleukodystrophy
Fatigue, weight loss, salt craving, GI upset, hypotension; ↓ Na⁺, ↑ K⁺, acidosis, hypoglycemia, eosinophilia
Hyperpigmentation (↑ ACTH/MSH from POMC)
Diagnosis
Low reserve
Low morning cortisol; cosyntropin (ACTH) stimulation → no cortisol rise; ACTH high (primary) or low (central)
Hydrocortisone + fludrocortisone (primary)
Secondary / tertiary insufficiency
↓ ACTH (pituitary) or ↓ CRH (hypothalamus); chronic exogenous steroids most common
Cortisol low, aldosterone preserved (RAAS) → no hyperkalemia; no hyperpigmentation
Hydrocortisone only
Adrenal crisis
Acute stress or steroid withdrawal without enough cortisol
Shock refractory to pressors, vomiting, abdominal pain, fever, confusion
IV hydrocortisone + saline now; test later
Waterhouse-Friderichsen syndrome
Bilateral adrenal hemorrhage in sepsis (N meningitidis), DIC
Petechial/purpuric rash, shock, adrenal failure
Also anticoagulation, antiphospholipid syndrome
Adrenoleukodystrophy
X-linked ABCD1 → very-long-chain fatty acids accumulate (peroxisome)
Boys: adrenal insufficiency + progressive demyelination, behavior change
↑ VLCFA
21-hydroxylase deficiency
~90% of CAH
↓ cortisol and aldosterone; precursors shunted to androgens; ↑ ACTH → hyperplasia
Neonatal salt-wasting crisis (↓ Na⁺, ↑ K⁺, hypotension); virilized 46,XX girls; early puberty in boys
↑ 17-hydroxyprogesterone, ↑ renin · newborn screen
Nonclassic 21-hydroxylase deficiency
Partial enzyme activity
Later hirsutism, acne, irregular menses — mimics PCOS
↑ 17-OH-progesterone after ACTH
11β-hydroxylase deficiency
↓ cortisol; 11-deoxycorticosterone (a mineralocorticoid) accumulates; androgens ↑
Hypertension, hypokalemia, ↓ renin; virilization of 46,XX
Aldosterone itself ↓
17α-hydroxylase deficiency
↓ cortisol and ↓ sex steroids; mineralocorticoids (DOC) ↑
Hypertension, hypokalemia; 46,XX: no puberty, primary amenorrhea · 46,XY: female external genitalia, undescended testes, no uterus
Undervirilized males
CAH — treatment
Replace cortisol to suppress ACTH drive
Glucocorticoids (± fludrocortisone in salt wasters); surgery for genital ambiguity
Testicular adrenal rests in men

Mechanism — steroid synthesis branches

CholesterolStAR, desmolase
→
Pregnenolone
→
Mineralocorticoids21-OH → 11β-OH → aldosterone
17α-OH → cortisol (21-OH, 11β-OH)
17α-OH + 17,20-lyase → androgens

A block shunts precursors to the open branches: 21-OH block → androgens up; 17α-OH block → mineralocorticoids up. ACTH rises in all forms, enlarging both adrenals.

CAH at a glance

ENZYME
BP / K⁺
ANDROGENS
KEY LAB
21-hydroxylase
↓ BP, ↑ K⁺
↑
↑ 17-OH-progesterone, ↑ renin
11β-hydroxylase
↑ BP, ↓ K⁺
↑
↑ 11-deoxycorticosterone, ↓ renin
17α-hydroxylase
↑ BP, ↓ K⁺
↓
↓ 17-OH steroids, ↓ renin
Primary vs central
Primary: ↑ ACTH, pigment, ↑ K⁺ (aldosterone lost) · central: ↓ ACTH, no pigment, normal K⁺.

How it's tested

COMMON CONFUSIONAll three CAH forms raise ACTH and cause adrenal hyperplasia. Blood pressure and virilization pattern separate them: low BP + virilization (21), high BP + virilization (11β), high BP + undervirilization (17α).
THE TRAPHyperkalemia and hyperpigmentation are absent in secondary adrenal insufficiency — their absence doesn't rule out adrenal insufficiency in a patient who stopped long-term prednisone.
YOUR APPROACHLow cortisol? → ACTH (high = primary) → aldosterone effects (K⁺) → cause. In infants/teens: genitalia + BP + K⁺ → enzyme.

If you see… think…

Fatigue, dark skin creases, Na⁺ 128, K⁺ 5.9 → primary adrenal insufficiency
Most common cause of Addison in the US → autoimmune adrenalitis
Shock unresponsive to pressors after stopping prednisone → adrenal crisis — IV hydrocortisone
Child with petechial rash, meningococcemia and shock → Waterhouse-Friderichsen
Boy with Addison disease and new behavioral decline → adrenoleukodystrophy (VLCFA)
Newborn girl with ambiguous genitalia, vomiting, ↓ Na⁺, ↑ K⁺ → 21-hydroxylase deficiency
Lab that confirms 21-hydroxylase deficiency → ↑ 17-hydroxyprogesterone
Virilized girl with hypertension and hypokalemia → 11β-hydroxylase deficiency
46,XY teen with female genitalia, no puberty, hypertension → 17α-hydroxylase deficiency
Young woman with PCOS-like picture and ↑ 17-OH-progesterone after ACTH → nonclassic CAH