Disorders of the Adrenal Cortex¶
Chapter 398 | Harrison's 22e · Part 12 – Endocrinology & Metabolism · Chapter 398
Key Clinical Points¶
- Cushing's syndrome is categorized as ACTH-dependent (pituitary or ectopic) or ACTH-independent (adrenal).
- Mineralocorticoid excess (e.g., Conn's syndrome) is identified by an Aldosterone-to-Renin Ratio (ARR) ≥ 750 pmol/L.
- Adrenal incidentalomas require a dual assessment for malignancy (based on size and Hounsfield Units [HU]) and hormone excess.
- Primary adrenal insufficiency (Addison's disease) is characterized by high ACTH, high renin, and low aldosterone.
- Secondary adrenal insufficiency involves low-normal ACTH with normal renin and normal aldosterone levels.
- Congenital Adrenal Hyperplasia (CAH) presents as various enzymatic deficiencies (e.g., 21-hydroxylase, 11β-hydroxylase).
- The HPA axis follows a distinct circadian rhythm, peaking in the morning; dexamethasone suppression tests are used to evaluate its integrity.
- The Renin-Angiotensin-Aldosterone (RAA) system is the primary regulator of mineralocorticoid levels and blood pressure.
- Adrenal steroidogenesis involves three main pathways: glucocorticoids, mineralocorticoids, and androgen precursors.
- HSD11B2 acts as a gatekeeper to prevent cortisol from activating the mineralocorticoid receptor (MR).
DEFINITION & CLASSIFICATION¶
• Adrenal Cortex: Produces three classes of hormones: ◦ Glucocorticoids (e.g., cortisol) ◦ Mineralocorticoids (e.g., aldosterone) ◦ Adrenal androgen precursors (e.g., dehydroepiandrosterone [DHEA]) • Cushing's Syndrome: Result of excess glucocorticoids. ◦ ACTH-dependent: Pituitary adenoma or ectopic ACTH source. ◦ ACTH-independent: Adrenal nodule/hyperplasia. • Mineralocorticoid Excess: Excess of mineralocorticoids (e.g., Conn's syndrome, Liddle's syndrome). • Adrenal Insufficiency: Deficiency of one or more corticosteroid classes. ◦ Primary (Addison's): Destruction of the adrenal gland. ◦ Secondary: Pituitary or hypothalamic failure.
ETIOLOGY & PATHOPHYSIOLOGY¶
• Steroidogenesis: ◦ Process involves conversion of cholesterol to pregnenolone via CYP11A1. ◦ Glucocorticoid synthesis requires 17α-hydroxylase (CYP17A1) and 11β-hydroxylase (CYP11B1). ◦ Mineralocorticoid production is regulated by the RAA system and involves CYP11B2. • HPA Axis Regulation: ◦ Cortisol synthesis is under negative feedback control from the hypothalamus and pituitary. ◦ ACTH acts as the pivotal regulator of cortisol synthesis, with additional effects on mineralocorticoid and androgen synthesis. ◦ Circadian Rhythm: Cortisol levels peak in the morning (approx. 8:30 AM) and are low in the evening. • RAA System: ◦ Renin → Angiotensin I → Angiotensin II → Aldosterone. ◦ Aldosterone promotes renal sodium retention and potassium excretion. • Gatekeeper Mechanism: ◦ 11β-HSD2 converts cortisol to inactive cortisone in specific tissues (e.g., kidneys) to prevent mineralocorticoid receptor (MR) activation by cortisol.
CLINICAL FEATURES¶
• Cushing's Syndrome: ◦ Body Fat: Weight gain, central obesity, rounded face, fat pad on back of neck ("buffalo hump"). ◦ Bone: Osteopenia, osteoporosis (vertebral fractures), decreased linear growth in children. ◦ Cardiovascular: Hypertension, hypokalemia, edema, atherosclerosis. ◦ Reproductive: Decreased libido; in women, amenorrhea (due to cortisol-mediated inhibition of gonadotropin release). ◦ Blood and Immune: Increased susceptibility to infections, increased white blood cell count, eosinopenia, hypercoagulable state. ◦ Skin: Broad, purple stretch marks (striae) (Fig. 398-11). • Addison's Disease (Primary Adrenal Insufficiency): ◦ Glucocorticoid Deficiency: Fatigue, weight loss, myalgia, fever, normochromic anemia, lymphocytosis, eosinophilia, hypoglycemia. ◦ Mineralocorticoid Deficiency: Abdominal pain, nausea, vomiting, dizziness, salt craving, hyperkalemia, hyponatremia. ◦ Androgen Deficiency: Dry/itchy skin (women), loss of libido, loss of axillary/pubic hair (women). ◦ Hyperpigmentation: Seen in primary insufficiency due to ACTH/POMC excess; prominent in palms, soles, and oral mucosa (Fig. 398-17).
DIFFERENTIAL DIAGNOSIS¶
• Cushing's Syndrome: ◦ Pituitary source (Cushing's disease) vs. Ectopic ACTH production vs. Adrenal-driven excess. • Mineralocorticoid Excess: ◦ Primary Hyperaldosteronism (Conn's) vs. Secondary (e.g., Renal Artery Stenosis) vs. Apparent Mineralocorticoid Excess (AME). • Adrenal Insufficiency: ◦ Primary (Addison's) vs. Secondary (Pituitary/Hypothalamic).
DIAGNOSTIC APPROACH¶
- Cushing's Syndrome Management:
- Identify source (Pituitary, Ectopic, or Adrenal) via ACTH and imaging.
- Surgical intervention for pituitary adenomas or ectopic tumors.
-
Medical management for patients not amenable to surgery.
-
Mineralocorticoid Excess Management:
- Primary Hyperaldosteronism (Conn's): Surgery if unilateral adenoma is confirmed via AVS.
- Secondary causes: Treat underlying cause (e.g., renal artery stenosis).
-
Liddle's Syndrome: Manage with appropriate medications (e.g., Amiloride/Eplerenone) as it is a genetic mutation of ENaC.
-
Adrenal Insufficiency Management:
- Primary Adrenal Insufficiency: Glucocorticoid + Mineralocorticoid replacement.
- Secondary Adrenal Insufficiency: Glucocorticoid replacement only.
- Emergency management for acute adrenal crisis (hypotension, hyperkalemia).
SPECIAL POPULATIONS¶
• Congenital Adrenal Hyperplasia (CAH): - 21-Hydroxylase deficiency (CYP21A2): Glucocorticoid/Mineralocorticoid deficiency, androgen excess. Marker: 17-OHP. - 11β-Hydroxylase deficiency (CYP11B1): Glucocorticoid deficiency, mineralocorticoid excess, androgen excess. - 17α-Hydroxylase deficiency (CYP17A1): Glucocorticoid deficiency, mineralocorticoid excess, androgen deficiency. - P450 oxidoreductase deficiency (POR): Glucocorticoid deficiency, prenatal androgen excess and postnatal androgen deficiency, skeletal malformations.
KEY PEARLS & HIGH-YIELD POINTS¶
• Cushing's Diagnosis: ACTH ≥ 15 pg/mL is the threshold for ACTH-dependent disease. CRH test requires ≥ 40% ACTH increase or >20\% cortisol increase. • Mineralocorticoid Diagnosis: ARR ≥ 750 pmol/L is the primary screening tool; be aware of medications (e.g., diuretics, ACE inhibitors) that cause false negatives. • Adrenal Incidentaloma: HU <10 and size <40 mm are key markers for benignity. • Addison's Disease: Characterized by hyperpigmentation due to ACTH/POMC excess; primary insufficiency only shows hyperkalemia and hyperpigmentation. • CAH Variants: 21-OHD is the most common form of CAH, leading to androgen excess and virilization.
Reference Tables¶
TABLE 398-2 Signs and Symptoms of Cushing’s Syndrome¶
Harrison's 22e, p.3056
| FEMALE:MALE RATIO |
% | |
|---|---|---|
| ACTH-Dependent Cushing’s Syndrome | 90 | |
| Cushing’s disease (= ACTH-producing pituitary adenoma) |
4:1 | 75 |
| Ectopic ACTH syndrome (due to ACTH secretion by bronchial or pancreatic carcinoid tumors, small- cell lung cancer, medullary thyroid carcinoma, pheochromocytoma, and others) |
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 AND SYMPTOMS |
|---|---|
| Body fat | Weight gain, central obesity, rounded face, fat pad on back of neck (“buffalo hump”) |
| Bone | Osteopenia, osteoporosis (vertebral fractures), decreased linear growth in children |
| Cardiovascular system | Hypertension, hypokalemia, edema, atherosclerosis |
| Reproductive system | Decreased libido; in women, amenorrhea (due to cortisol-mediated inhibition of gonadotropin release) |
| Blood and immune system |
Increased susceptibility to infections, increased white blood cell count, eosinopenia, hypercoagulation with increased risk of deep vein thrombosis and pulmonary embolism |
TABLE 398-3 Causes of Primary Mineralocorticoid Excess¶
Harrison's 22e, p.3060
| CAUSES OF PRIMARY MINERALOCORTICOID EXCESS |
MECHANISM | % |
|---|---|---|
| Sporadic Primary Aldosteronism | 94–99 | |
| Adrenal (Conn’s) adenoma | Autonomous aldosterone excess can be caused by somatic (intratumor) mutations in the potassium channel GIRK4 (encoded by KCNJ5; identified as cause of disease in 40–70% of aldosterone-producing adenomas and associated with overproduction of hybrid steroids). Further causes include somatic mutations affecting the α-subunit of the Na+/K+-ATPase (encoded by ATP1A1), the plasma membrane calcium-transporting ATPase 3 (encoded by ATP2B3), the voltage-gated calcium channel CaV1.3 and CaV3.2 (encoded by CACNA1D and CACNA1H, respectively), and the ClC-2 chloride channel (encoded by CLCN2). All mutations result in the upregulation of CYP11B2 and hence aldosterone synthesis. Rarely, somatic mutations affecting β-catenin (encoded by CTNNB1) have been observed alone or in combination with CACNA1D mutations and are presumed to promote an increase in the number of aldosterone-producing cells. |
30–40 |
| Bilateral adrenal hyperplasia | Bilateral autonomous aldosterone excess due to aldosterone-producing diffuse hyperplasia and/or multiple aldosterone- producing micronodules. CACNA1D somatic mutations have been described in 58% of aldosterone-producing micronodules of patients with bilateral aldosterone excess who underwent unilateral adrenalectomy as a nonstandard treatment. |
60–70 |
| Familial Primary Aldosteronism | 1–6 | |
| Autosomal dominant. Crossover between the CYP11B1 and CYP11B2 genes results in ACTH-driven aldosterone production. Characterized by severe hypertension in childhood or young adults (often <20 years), with a high risk of cardiovascular events including hemorrhagic stroke at a young age due to ruptured intracranial aneurysm. Analysis of adrenal steroidogenesis shows overproduction of hybrid steroids. |
||
| Autosomal dominant. The most common form (1–6% of adults with primary aldosteronism). Due to germline CLCN2 mutations. Variable phenotypic presentation, which typically includes early-onset hypertension. |
||
| Autosomal dominant. Germline KCNJ5 mutations. Characterized by severe early-onset hypertension (<20 years) with massive bilateral macronodular adrenal hyperplasia. Analysis of adrenal steroidogenesis shows overproduction of hybrid steroids. |
||
| Autosomal dominant. Germline CACNA1H mutations. Characterized by severe early-onset hypertension (<20 years), which can be associated with developmental disorders in some cases. |
||
| De novo CACNA1D mutations. Characterized by childhood-onset hypertension, seizures, neurologic abnormalities, congenital hyperinsulinism, and cardiac abnormalities. |
||
| Other Causes (Rare) | <1 | |
| Syndrome of apparent mineralocorticoid excess (SAME) |
Mutations in HSD11B2 result in lack of renal inactivation of cortisol to cortisone, leading to excess activation of the MR by cortisol (inhibition of 11β-hydroxysteroid dehydrogenase type 2 by excess licorice ingestion can have similar effects). |
|
| Cushing’s syndrome | Cortisol excess overcomes the capacity of HSD11B2 to inactivate cortisol to cortisone, consequently flooding the MR. | |
| Glucocorticoid resistance | Upregulation of cortisol production due to GR mutations results in flooding of the MR by cortisol. | |
| Adrenocortical carcinoma | Autonomous aldosterone and/or DOC excess. | |
| Congenital adrenal hyperplasia | Accumulation of DOC due to mutations in CYP11B1 or CYP17A1. | |
| Progesterone-induced hypertension |
Progesterone acts as an abnormal ligand due to mutations in the MR gene. | |
| Liddle’s syndrome | Mutant ENaC β or γ subunits resulting in reduced degradation of ENaC keeping the membrane channel in open conformation for longer, enhancing mineralocorticoid action. |
TABLE 398-4 Effects of Medications and Other Conditions on the Aldosterone-Renin Ratio¶
Harrison's 22e, p.3062
| EFFECT ON THE ARR | ANTIHYPERTENSIVE DRUGS | OTHER MEDICATIONS | OTHER CONDITIONS |
|---|---|---|---|
| Possible false-negative results (due to increase of renin and/or aldosterone) |
MR antagonists; diuretics; DHP- calcium antagonists; ACE inhibitors; AT1R blockers; aliskirena |
SGLT2 inhibitors; SSRIs | Hypokalemia; dietary salt restriction; malignant hypertension; renovascular hypertension; pregnancy |
| β-Blockers; clonidine; α-methyldopa; aliskirena |
NSAIDs; estrogen-containing oral contraceptives |
||
| Negligible effect | Non-DHP-calcium antagonists; α- 1 adrenergic receptor antagonists; hydralazine |
/ | / |
TABLE 398-5 Classification of Unilateral Adrenal Masses MASS Benign Adrenocortical adenoma¶
Harrison's 22e, p.3063
| MASS | APPROXIMATE PREVALENCE (%) |
|---|---|
| Benign | |
| Adrenocortical adenoma | |
| Endocrine-inactive | 40–70 |
| Cortisol-producing (mild autonomous cortisol secretion) | 20–50 |
| Aldosterone-producing | 2–5 |
| Cortisol-producing (overt Cushing’s syndrome) | 1–4 |
| Pheochromocytoma | 1–5 |
| Adrenal myelolipoma | 3-6 |
| Adrenal ganglioneuroma | 1 |
| Adrenal cyst and pseudocyst | 1 |
| Adrenal hematoma/hemorrhagic infarction | <1 |
| Adrenal hemangioma | <0.1 |
| Indeterminate | |
| Malignant | |
| Metastases (most frequent: breast, lung) | 3–7 |
| Adrenocortical carcinoma | 0.4–4 |
| Malignant pheochromocytoma | <1 |
| Adrenal neuroblastoma | <0.1 |
| Lymphomas (including primary adrenal lymphoma) | <0.1 |
TABLE 398-6 Classification System for Staging of Adrenocortical Carcinoma¶
Harrison's 22e, p.3065
| ENSAT STAGE | TNM STAGE | TNM DEFINITIONS |
|---|---|---|
| I | T1,N0,M0 | T1, tumor ≤5 cm |
| N0, no positive lymph node | ||
| M0, no distant metastases | ||
| T2,N0,M0 | ||
| III | T1–T2,N1,M0 | N1, positive lymph node(s) |
| T3–T4,N0–N1,M0 | M0, no distant metastases | |
| T3, tumor infiltration into surrounding tissue |
||
| T4, tumor invasion into adjacent organs or venous tumor thrombus in vena cava or renal vein |
||
| T1–T4,N0–N1,M1 |
TABLE 398-7 Causes of Primary Adrenal Insufficiency DIAGNOSIS Autoimmune polyglandular syndrome 1 (APS1) Autoimmune…¶
Harrison's 22e, p.3067
| DIAGNOSIS | GENE | ASSOCIATED FEATURES |
|---|---|---|
| Autoimmune polyglandular syndrome 1 (APS1) | AIRE | Hypoparathyroidism, chronic mucocutaneous candidiasis, other autoimmune disorders, rarely lymphomas |
| Associations with HLA-DR3, CTLA-4 | ||
| Isolated autoimmune adrenalitis | Associations with HLA-DR3, CTLA-4 | |
| CYP21A2, CYP11B1, CYP17A1, HSD3B2, POR |
||
| Congenital lipoid adrenal hyperplasia (CLAH) | STAR, CYP11A1 | 46,XY DSD, gonadal failure (see also Chap. 402) |
| NR0B1 (DAX-1), NR5A1 (SF-1) | ||
| Adrenoleukodystrophy (ALD), adrenomyeloneuropathy (AMN) |
ABCD1 | Demyelination of central nervous system (ALD) or spinal cord and peripheral nerves (AMN) |
| MC2R MRAP STAR NNT TXNRD2 MCM4 |
||
| Triple A syndrome | AAAS | Alacrima, achalasia, neurologic impairment |
| SLOS | ||
| Kearns-Sayre syndrome | Mitochondrial DNA deletions | Progressive external ophthalmoplegia, pigmentary retinal degeneration, cardiac conduction defects, gonadal failure, hypoparathyroidism, type 1 diabetes, |
| CDKN1C | ||
| MIRAGE syndrome | SAMD9 | Myelodysplasia, infection, restriction of growth, genital phenotypes, and enteropathy |
| SGPL1 | ||
| Adrenal infections | Tuberculosis, HIV, CMV, cryptococcosis, histoplasmosis, coccidioidomycosis | |
| Adrenal hemorrhage | Meningococcal sepsis (Waterhouse-Friderichsen syndrome), primary antiphospholipid syndrome |
|
| Bilateral adrenalectomy | E.g., in the management of Cushing’s syndrome or after bilateral nephrectomy |
TABLE 398-8 Causes of Secondary Adrenal Insufficiency DIAGNOSIS Pituitary tumors (endocrine active and inactive…¶
Harrison's 22e, p.3068
| DIAGNOSIS | GENE | ASSOCIATED FEATURES |
|---|---|---|
| Pituitary tumors (endocrine active and inactive adenomas, very rare: carcinoma) |
Depending on tumor size and location: visual field impairment (bilateral hemianopia), hyperprolactinemia, secondary hypothyroidism, hypogonadism, growth hormone deficiency |
|
| Pituitary irradiation | Radiotherapy administered for pituitary tumors, brain tumors, or craniospinal irradiation in leukemia |
|
| Pituitary apoplexy/ hemorrhage |
Hemorrhagic infarction of large pituitary adenomas or pituitary infarction consequent to traumatic major blood loss (e.g., surgery or pregnancy: Sheehan’s syndrome) |
|
| Drug-induced | Chronic glucocorticoid excess (endogenous or exogenous), immune check point inhibitors, opioids, interferon alpha, ribavirin, megestrol acetate |
|
| TBX19 (Tpit) |
||
| Combined pituitary hormone deficiency (CPHD) |
PROP-1 | Progressive development of CPHD in the order GH, PRL, TSH, LH/FSH, ACTH |
| HESX1 | CPHD and septo-optic dysplasia | |
| LHX3 | CPHD and limited neck rotation, sensorineural deafness |
|
| LHX4 | CPHD and cerebellar abnormalities | |
| SOX3 | CPHD and variable mental retardation | |
| POMC |
TABLE 398-9 Signs and Symptoms of Adrenal Insufficiency
- Signs and Symptoms Caused by Glucocorticoid Deficiency
- Fatigue, lack of energy
- Weight loss, anorexia
- Myalgia, joint pain
- Fever
- Normochromic anemia, lymphocytosis, eosinophilia
- Slightly increased TSH (due to loss of feedback inhibition of TSH release)
- Hypoglycemia (more frequent in children)
- Low blood pressure, postural hypotension
- Hyponatremia (due to loss of feedback inhibition of AVP release)
- Signs and Symptoms Caused by Mineralocorticoid Deficiency (Primary
Adrenal Insufficiency Only) - Signs and Symptoms Caused by Adrenal Androgen Deficiency
- Lack of energy
- Dry and itchy skin (in women)
- Loss of libido (in women)
- Loss of axillary and pubic hair (in women)
- Other Signs and Symptoms
TABLE 398-10 Variants of Congenital Adrenal Hyperplasia VARIANT 21-Hydroxylase deficiency (21OHD) 11 β -Hydroxylase…¶
Harrison's 22e, p.3071
| VARIANT | GENE | IMPACT ON STEROID SYNTHESIS | DIAGNOSTIC MARKER STEROIDS IN SERUM (AND URINE) |
|---|---|---|---|
| 21-Hydroxylase deficiency (21OHD) | CYP21A2 | Glucocorticoid deficiency, mineralocorticoid deficiency, adrenal androgen excess |
17-Hydroxyprogesterone, 21-deoxycortisol (pregnanetriol, 17-hydroxypregnanolone, pregnanetriolone) |
| CYP11B1 | Glucocorticoid deficiency, mineralocorticoid excess, adrenal androgen excess |
||
| 17α-Hydroxylase deficiency (17OHD) | CYP17A1 | (Glucocorticoid deficiency), mineralocorticoid excess, androgen deficiency |
11-Deoxycorticosterone, corticosterone, pregnenolone, progesterone (tetrahydro-11-deoxycorticosterone, tetrahydrocorticosterone, pregnenediol, pregnanediol) |
| HSD3B2 | Glucocorticoid deficiency, (mineralocorticoid deficiency), adrenal androgen excess (females and males), gonadal androgen deficiency (males) |
||
| P450 oxidoreductase deficiency (PORD) | POR | Glucocorticoid deficiency, (mineralocorticoid excess), prenatal androgen excess and postnatal androgen deficiency, skeletal malformations |
Pregnenolone, progesterone, 17-hydroxyprogesterone (pregnanediol, pregnanetriol) |