Chapter 398: Disorders of the Adrenal Cortex¶
Chapter 398 | Part 12: Endocrinology and Metabolism
KEY CLINICAL POINTS¶
- Cushing's syndrome is characterized by cortisol excess with clinical features like central obesity, hypertension, and hyperpigmentation.
- Primary mineralocorticoid excess (e.g., Conn's syndrome) is caused by aldosterone overproduction, leading to hypokalemia and hypertension.
- Adrenal insufficiency (Addison's disease) presents with hyperpigmentation, hyponatremia, and hypoglycemia, requiring glucocorticoid and mineralocorticoid replacement.
- Congenital adrenal hyperplasia (CAH) is caused by enzyme defects in steroidogenesis, with 21-hydroxylase deficiency being the most common cause.
- Diagnosis of adrenal tumors involves imaging (CT/MRI), biochemical tests (ARR, UFC), and functional tests (cosyntropin stimulation).
1. DEFINITION & OVERVIEW¶
The adrenal cortex produces glucocorticoids (cortisol), mineralocorticoids (aldosterone), and androgens. Disorders include Cushing's syndrome (cortisol excess), primary mineralocorticoid excess (aldosterone excess), adrenal insufficiency (glucocorticoid/mineralocorticoid deficiency), and congenital adrenal hyperplasia (CAH).
Table 398-1: Causes of Endogenous Cushing’s Syndrome¶
| CAUSE | RATIO | % |
|---|---|---|
| ACTH-Dependent Cushing’s Syndrome | 4:1 | 75 |
| Ectopic ACTH Syndrome | 1:1 | 15 |
| ACTH-Independent Cushing’s Syndrome | 4:1 | 10 |
Table 398-2: Signs and Symptoms of Cushing’s Syndrome¶
| BODY COMPARTMENT/SYSTEM | SIGNS/SYMPTOMS |
|---|---|
| Body Fat | Weight gain, central obesity, buffalo hump |
| Skin | Thin skin, striae, acne, hirsutism |
| Bones | Osteoporosis, vertebral fractures |
| Muscles | Proximal myopathy |
1.1 Anatomy and Development¶
Adrenal glands weigh 6–11 g each, located above kidneys. Adrenal cortex has three zones: zona glomerulosa (mineralocorticoids), zona fasciculata (glucocorticoids), and zona reticularis (androgens). Development begins from urogenital ridge, with steroidogenesis regulated by HPA and RAA axes.
1.2 Regulatory Control¶
Glucocorticoid synthesis is regulated by HPA axis (CRH → ACTH → cortisol). Mineralocorticoid synthesis is controlled by RAA system (renin-angiotensin-aldosterone pathway). 11 β -HSD2 inactivates cortisol to cortisone, preventing MR overactivation.
2. EPIDEMIOLOGY¶
Cushing’s syndrome incidence: 1.8–3.2 per million/year. Endogenous Cushing’s is rare (<1% of population), while iatrogenic Cushing’s is common (1% of population using chronic glucocorticoids). Adrenal insufficiency prevalence: 5/10,000.
2.1 Cushing’s Syndrome¶
ACTH-dependent (Cushing’s disease, 75% of cases) vs. ACTH-independent (adenoma, 10%). Ectopic ACTH (15% of cases) includes carcinoid tumors, pheochromocytoma, and thymic tumors.
2.2 Adrenal Insufficiency¶
Autoimmune (30–40% of cases), infections (tuberculosis), or iatrogenic (exogenous glucocorticoid suppression). Prevalence: 5/10,000 in general population.
3. ETIOLOGY & PATHOPHYSIOLOGY¶
Cushing’s syndrome: ACTH-dependent (pituitary tumors, ectopic ACTH) or ACTH-independent (adrenal tumors, exogenous steroids). Primary mineralocorticoid excess: aldosterone overproduction (adenoma, hyperplasia). Adrenal insufficiency: autoimmune (80%), infections, or iatrogenic.
Table 398-3: Causes of Primary Mineralocorticoid Excess¶
| CAUSE | MECHANISM | % |
|---|---|---|
| Adrenal Adenoma | Autonomous aldosterone excess | 30–40 |
| Bilateral Hyperplasia | Diffuse aldosterone overproduction | 60–70 |
| Familial Forms | Genetic mutations | 1–6 |
3.1 Cushing’s Syndrome¶
ACTH-dependent: pituitary corticotroph adenoma (Cushing’s disease). ACTH-independent: adrenal adenoma, carcinoma, or exogenous steroids. Ectopic ACTH: carcinoid tumors, pheochromocytoma.
3.2 Primary Aldosteronism¶
Bilateral hyperplasia (60–70%) or unilateral adenoma (30–40%). Genetic causes: KCNJ5 mutations (adenoma), CACNA1D (hyperplasia), or CLCN2 (familial forms).
3.3 Adrenal Insufficiency¶
Autoimmune (80%), infections (tuberculosis), or iatrogenic (exogenous steroids). Congenital causes: CAH (CYP21A2 deficiency), or adrenoleukodystrophy (ABCD1 mutations).
4. CLINICAL FEATURES¶
Cushing’s syndrome: central obesity, hypertension, hyperglycemia, striae, and hyperpigmentation. Primary aldosteronism: hypertension, hypokalemia, and metabolic alkalosis. Adrenal insufficiency: fatigue, hypotension, hyperpigmentation, and hypoglycemia.
Table 398-4: Effects of Medications on ARR¶
| EFFECT ON ARR | ANTIHYPER TENSIVE DRUGS | OTHER MEDICATIONS | OTHER CONDITIONS |
|---|---|---|---|
| False-negative | MR antagonists, diuretics | SGLT2 inhibitors, SSRIs | Hypokalemia, dietary salt restriction |
| False-positive | b-blockers, clonidine | NSAIDs, estrogen-containing contraceptives | Renovascular hypertension, pregnancy |
4.1 Cushing’s Syndrome¶
Central obesity, buffalo hump, moon face, striae, acne, hirsutism, and hypertension. Late features: osteoporosis, diabetes, and psychiatric symptoms.
4.2 Primary Aldosteronism¶
Hypertension, hypokalemia, metabolic alkalosis, and hyperpigmentation. May present with pseudohypoaldosteronism (SAME) or hyperaldosteronism (Conn’s syndrome).
4.3 Adrenal Insufficiency¶
Fatigue, weight loss, hypotension, hyperpigmentation, and hypoglycemia. Severe cases: adrenal crisis with hypovolemic shock and electrolyte imbalances.
5. DIFFERENTIAL DIAGNOSIS¶
Cushing’s syndrome: ACTH-dependent vs. independent. Primary aldosteronism: Conn’s syndrome vs. Liddle’s syndrome. Adrenal insufficiency: autoimmune vs. iatrogenic.
5.1 Cushing’s Syndrome¶
Distinguish ACTH-dependent (pituitary, ectopic) vs. ACTH-independent (adrenal). Use ARR, dexamethasone suppression, and imaging.
5.2 Primary Aldosteronism¶
Differentiate Conn’s syndrome (adenoma) vs. bilateral hyperplasia. Use ARR, plasma aldosterone/renin ratio, and imaging.
5.3 Adrenal Insufficiency¶
Autoimmune vs. iatrogenic. Use cosyntropin stimulation test and ACTH levels to differentiate.
6. INVESTIGATIONS & DIAGNOSIS¶
Cushing’s: dexamethasone suppression, ACTH stimulation, and imaging. Primary aldosteronism: ARR, plasma aldosterone/renin, and CT/MRI. Adrenal insufficiency: cosyntropin stimulation and ACTH measurement.
Table 398-5: Classification of Unilateral Adrenal Masses¶
| MASS | APPROXIMATE PREVALENCE (%) |
|---|---|
| Adrenocortical Adenoma | 40–70 |
| Cortisol-Producing (MACS) | 20–50 |
| Aldosterone-Producing | 2–5 |
| Pheochromocytoma | 1–5 |
6.1 Cushing’s Syndrome¶
24-h UFC, dexamethasone suppression test, and midnight salivary cortisol. Use cosyntropin stimulation to confirm.
6.2 Primary Aldosteronism¶
Plasma aldosterone/renin ratio, 24-h urinary aldosterone, and CT/MRI for adrenal masses.
6.3 Adrenal Insufficiency¶
Cosyntropin stimulation test (cortisol <450 nmol/L) and ACTH measurement to differentiate primary vs. secondary.
7. MANAGEMENT & TREATMENT¶
Cushing’s: surgery (adrenalectomy), radiation, or medications (ketoconazole, metyrapone). Primary aldosteronism: spironolactone or mineralocorticoid receptor antagonists. Adrenal insufficiency: hydrocortisone, fludrocortisone, and stress-dose adjustments.
Table 398-6: Staging of Adrenocortical Carcinoma¶
| ENSAT STAGE | TNM STAGE | DEFINITIONS |
|---|---|---|
| I | T1,N0,M0 | Tumor £5 cm |
| II | T2,N0,M0 | Tumor >5 cm |
| III | T1–T2,N1,M0 | Positive lymph nodes |
| IV | T1–T4,N0–N1,M1 | Distant metastases |
7.1 Cushing’s Syndrome¶
Surgical removal of adrenal tumor or pituitary tumor. Medical management with ketoconazole, metyrapone, or pasireotide for inoperable cases.
7.2 Primary Aldosteronism¶
Spironolactone (12.5–100 mg/day) or eplerenone (25–100 mg/day). Laparoscopic adrenalectomy for unilateral adenoma.
7.3 Adrenal Insufficiency¶
Hydrocortisone (15–25 mg/day) and fludrocortisone (0.1–0.2 mg/day). Stress-dose adjustments (double dose for surgery/illness).
8. PROGNOSIS & COMPLICATIONS¶
Cushing’s: mortality 10–20% if untreated. Adrenal insufficiency: mortality 5–10% in adrenal crisis. CAH: complications include infertility, hypertension, and osteoporosis.
8.1 Cushing’s Syndrome¶
Complications: diabetes, hypertension, osteoporosis, and infections. Mortality 10–20% without treatment.
8.2 Adrenal Insufficiency¶
Adrenal crisis: hypovolemic shock, electrolyte imbalances, and death if untreated. Long-term: osteoporosis and metabolic syndrome.
8.3 Congenital Adrenal Hyperplasia¶
Classic CAH: salt-wasting crisis in neonates. Nonclassic CAH: hirsutism, infertility, and metabolic complications.
9. SPECIAL CONSIDERATIONS¶
Pregnancy: increase hydrocortisone dose by 50% in third trimester. Genetic counseling for CAH. Avoid NSAIDs in adrenal insufficiency. Monitor bone density in glucocorticoid users.
9.1 Pregnancy¶
Hydrocortisone dose increased by 50% in third trimester. Monitor for gestational hypertension and preterm labor.
9.2 Genetic Counseling¶
CAH is autosomal recessive. Genetic testing for CYP21A2 mutations in families with history.
9.3 Medication Use¶
Avoid NSAIDs in adrenal insufficiency. Monitor bone density in long-term glucocorticoid users.
10. KEY POINTS & CLINICAL PEARLS¶
- Dexamethasone suppression test is critical for diagnosing Cushing’s syndrome. 2. ARR (plasma aldosterone/renin ratio) differentiates primary vs. secondary aldosteronism. 3. Cosyntropin stimulation test confirms adrenal insufficiency. 4. Spironolactone is first-line for primary aldosteronism. 5. Hydrocortisone and fludrocortisone are essential for adrenal insufficiency management.