I-20. Adrenocortical insufficiency (acute/chronic); congenital adrenal hyperplasia

急性・慢性副腰皮質機能低下症；先天性副腰過形成

HPA Axis & Cortisol

CRH (hypothalamus) → ACTH (pituitary) → cortisol (adrenal cortex) → metabolic effects. High cortisol from zona fasciculata also facilitates epinephrine synthesis.
Excess ACTH binds melanocortin-1 receptor (MC1R, low affinity) due to high concentration → skin pigmentation. ACTH also drives zona reticularis androgens, which exert no negative feedback → if cortisol is absent, androgens overproduced → adrenal hyperplasia.

Glucocorticoid & Mineralocorticoid Effects

Glucocorticoids (zona fasciculata)

Anti-inflammatory/immunosuppressive; needed in stress.
Liver: ↑gluconeogenesis, glycogenolysis. Muscle: ↑glucose uptake/glycogenesis, ↑protein catabolism. Adipose: ↓glucose uptake, ↑lipolysis.
↑Insulin resistance → ↑blood glucose (stress fuel). Permissive on SNS tone → maintains CO/BP. ↑GFR. Inhibits bone formation/↑resorption. CNS arousal. Fetal maturation + surfactant.

Mineralocorticoids

↑Na⁺/water reabsorption, ↑K⁺/H⁺ secretion. Aldosterone regulated by renin (low BP/SYM) and hyperkalemia (negative feedback). ACTH maintains (but is not essential for) aldosterone production.

Adrenocortical Insufficiency

Primary (problem in the gland)

Chronic (Addison’s disease): autoimmune inflammation, infections (TB, HIV), congenital adrenal hypoplasia, metastasis.
Acute (Addisonian crisis): adrenal hemorrhage (e.g. meningococcal → Waterhouse-Friedrichsen), trauma/surgery, GI infection.
The cortex has good reserve → symptoms appear only when ~90% destroyed.

Secondary

Glucocorticoid therapy: chronic use suppresses CRH/ACTH → zona fasciculata + reticularis atrophy; sudden withdrawal → fatal crisis.
Pituitary damage (hemorrhage, tumor) → ↓ACTH.

Addison’s Disease — Symptoms

Chronic glucocorticoid (G) + mineralocorticoid (M) deficiency:

Weight loss, weakness, fatigue: fluid loss (M), hyperkalemia (M → chronic depolarization → ↓muscle excitability), ↓appetite (G), hypoglycemia (G), ↓CNS activity (depression, confusion from acidosis, poor stress tolerance).
Nausea/vomiting/diarrhea (acidosis, M) — diarrhea can provoke crisis.
Dehydration, hypotension, orthostatic hypotension, collapse (fluid loss M; ↓vascular tone/CO G).
Hyperpigmentation of skin/oral mucosa (↑ACTH in primary).
Hormones: ↓aldosterone, ↓cortisol, ↑ACTH, ↑renin activity. Treatment: mineralocorticoid + glucocorticoid replacement.

Acute Adrenal Crisis (Addisonian)

Causes: adrenal hemorrhage (Waterhouse-Friedrichsen), trauma/surgery, GI infection.
Symptoms: acute salt-water/circulatory failure — vomiting, dehydration, hypotension, shock, hypoglycemia, coma.

Congenital Adrenal Hyperplasia (adrenogenital syndrome)

Inherited enzyme defect in cortisol synthesis → glucocorticoid deficiency → intermediates shunted to androgen overproduction (zona reticularis) → no negative feedback on ACTH → adrenal hyperplasia. Mineralocorticoid effect depends on the defect:
- 21β-hydroxylase deficiency (>95%): no cortisol or mineralocorticoid; excess androgens; weight loss, vomiting, dehydration, hyperkalemia, shock; salt-losing crisis at 2–4 weeks.
- 11β-hydroxylase deficiency (~4%): androgen excess, cortisol deficiency, ↑mineralocorticoid activity → Na⁺/water retention (hypertension), hypokalemia.
- 3β-HSD defect (rare): cortisol + mineralocorticoid deficiency, androgen excess → dehydration, hyperkalemia.
Androgen hypersecretion → virilization, early adrenarche, hirsutism, amenorrhea, infertility, ↓spermatogenesis (excess androgens ↓GnRH/LH/FSH).

一問一答

▶Why does excess ACTH cause skin pigmentation?

At high concentrations ACTH binds the low-affinity melanocortin-1 receptor (MC1R) on melanocytes, stimulating pigmentation.

▶What is the HPA axis controlling cortisol?

CRH (hypothalamus) → ACTH (pituitary) → cortisol (adrenal cortex); high cortisol from the zona fasciculata also facilitates epinephrine synthesis.

▶What are the actions and regulation of mineralocorticoids?

↑Na+/water reabsorption, ↑K+/H+ secretion; aldosterone is regulated by renin (low BP/sympathetic activation) and by hyperkalemia (negative feedback). ACTH maintains but is not essential for its production.

▶Why does cortisol deficiency lead to adrenal androgen overproduction and hyperplasia?

ACTH drives zona reticularis androgens, which exert no negative feedback; without cortisol, ACTH stays high → androgen overproduction and adrenal hyperplasia.

▶What are the main metabolic effects of glucocorticoids?

Anti-inflammatory/immunosuppressive; ↑hepatic gluconeogenesis/glycogenolysis, ↑muscle protein catabolism, ↑adipose lipolysis, ↑insulin resistance → ↑blood glucose; permissive on SNS tone (maintains CO/BP), ↑GFR, inhibits bone formation, CNS arousal, and fetal lung maturation.

▶What causes chronic primary adrenocortical insufficiency (Addison's disease)?

Autoimmune inflammation (most common), infections (TB, HIV), congenital adrenal hypoplasia, and metastasis.

▶What causes secondary adrenocortical insufficiency?

Chronic glucocorticoid therapy suppressing CRH/ACTH (→ zona fasciculata + reticularis atrophy; sudden withdrawal is fatal) and pituitary damage (hemorrhage, tumor) reducing ACTH.

▶At what point do symptoms of primary adrenal insufficiency appear?

Only when about 90% of the cortex is destroyed, because the gland has good functional reserve.

▶What is Waterhouse-Friderichsen syndrome?

Acute primary adrenal insufficiency from adrenal hemorrhage, classically due to meningococcal infection.

▶Why does hyperkalemia develop in Addison's disease and what does it cause?

Mineralocorticoid deficiency reduces K+ secretion → hyperkalemia → chronic depolarization → reduced muscle excitability (weakness).

▶Why do hypotension and dehydration occur in Addison's disease?

Mineralocorticoid deficiency causes salt-water loss, and glucocorticoid deficiency reduces vascular tone and cardiac output → hypotension, orthostatic hypotension, and collapse.

▶What is the hormone profile of Addison's disease?

↓Aldosterone, ↓cortisol, ↑ACTH, and ↑renin activity.

▶Why does hyperpigmentation occur in primary but not secondary adrenal insufficiency?

In primary disease ACTH is elevated (loss of cortisol feedback) and stimulates skin/oral mucosa pigmentation; in secondary disease ACTH is low.

▶What is the treatment of Addison's disease?

Mineralocorticoid plus glucocorticoid replacement.

▶What are the symptoms of an acute adrenal (Addisonian) crisis?

Acute salt-water/circulatory failure — vomiting, dehydration, hypotension, shock, hypoglycemia, and coma.

▶What is the basic mechanism of congenital adrenal hyperplasia?

An inherited enzyme defect in cortisol synthesis → glucocorticoid deficiency → intermediates shunted to androgen overproduction → no ACTH feedback → adrenal hyperplasia.

▶What characterizes 21β-hydroxylase deficiency (>95% of CAH)?

No cortisol or mineralocorticoid with excess androgens; weight loss, vomiting, dehydration, hyperkalemia, and shock — a salt-losing crisis at 2–4 weeks of age.

▶How does 11β-hydroxylase deficiency CAH present?

Androgen excess and cortisol deficiency with increased mineralocorticoid activity → Na+/water retention (hypertension) and hypokalemia.

▶What are the effects of androgen hypersecretion in CAH?

Virilization, early adrenarche, hirsutism, amenorrhea, infertility, and decreased spermatogenesis (excess androgens suppress GnRH/LH/FSH).

▶Why does glucocorticoid deficiency cause hypoglycemia?

Loss of cortisol-driven gluconeogenesis and glycogenolysis reduces blood glucose, with poor tolerance of fasting/stress.