# Clinical Cases: Adrenal Cortex Anatomy and Physiology

## Case 1: Congenital Adrenal Hyperplasia (21-Hydroxylase Deficiency)

### Patient Demographics
- **Age:** 5 days
- **Sex:** Female (46,XX)
- **Occupation:** N/A (neonate)

### Chief Complaint
"The baby has ambiguous genitalia."

### History of Present Illness
A 5-day-old infant, born at term via uncomplicated vaginal delivery, is referred for evaluation of ambiguous genitalia noted at birth. The parents are non-consanguineous with no family history of adrenal disorders or infant deaths. The pregnancy was uncomplicated with no exposure to androgens. The newborn screening test is pending. The infant has been breastfeeding well but the mother notes the baby seems more sleepy over the past day and has not been feeding as vigorously.

### Physical Examination
- **Vital Signs:** HR 160 bpm, BP 58/35 mmHg (low), Temp 36.2°C
- **General:** Sleepy, mildly dehydrated appearing
- **Genitalia:**
  - Clitoromegaly (phallus-like structure ~2 cm)
  - Single urogenital opening
  - Fused, rugated labioscrotal folds with hyperpigmentation
  - No palpable gonads
  - Prader stage IV virilization
- **Skin:** Hyperpigmentation of areolae and genitalia
- **Abdomen:** No palpable masses

### Workup
- **Laboratory Studies:**
  - Sodium: 126 mEq/L (low)
  - Potassium: 6.8 mEq/L (high)
  - Glucose: 52 mg/dL (low)
  - 17-hydroxyprogesterone: 15,000 ng/dL (markedly elevated, normal <100)
  - Cortisol: 2.1 μg/dL (low)
  - ACTH: 520 pg/mL (markedly elevated)
  - Aldosterone: Low
  - Plasma renin activity: Markedly elevated
  - Testosterone: Elevated for female infant
  - Androstenedione: Elevated
- **Karyotype:** 46,XX
- **Pelvic ultrasound:** Normal uterus and ovaries present
- **Genetic testing:** Homozygous mutation in CYP21A2 gene

### Diagnosis
**Classic congenital adrenal hyperplasia (CAH)** due to 21-hydroxylase deficiency - salt-wasting form

### Treatment
**ACUTE (adrenal crisis):**
1. IV normal saline bolus for volume resuscitation
2. IV dextrose for hypoglycemia
3. IV hydrocortisone 25 mg/m² bolus, then 50-100 mg/m²/day divided every 6 hours
4. Calcium gluconate and insulin/glucose for hyperkalemia if severe
5. Fludrocortisone 0.05-0.2 mg daily once oral intake established

**LONG-TERM:**
1. Glucocorticoid replacement: Hydrocortisone 10-15 mg/m²/day divided TID
2. Mineralocorticoid replacement: Fludrocortisone 0.05-0.2 mg daily
3. Sodium chloride supplementation in infancy
4. Stress dosing education (2-3x maintenance during illness)
5. Surgical: Feminizing genitoplasty (timing and extent controversial)
6. Psychology/endocrinology multidisciplinary follow-up
7. Monitor: Growth, bone age, 17-OHP levels, androstenedione

### Clinical Pearl
21-hydroxylase deficiency accounts for ~95% of CAH cases. The enzyme block prevents cortisol and aldosterone synthesis while accumulating precursors that are shunted to androgen production. In classic salt-wasting CAH, both glucocorticoid and mineralocorticoid deficiency occur, leading to adrenal crisis (hyponatremia, hyperkalemia, hypotension, hypoglycemia) typically in the first 2 weeks of life. Excess adrenal androgens cause virilization of 46,XX females in utero. ACTH elevation (due to lack of cortisol negative feedback) causes hyperpigmentation via melanocyte-stimulating hormone effects. Newborn screening for 17-hydroxyprogesterone can detect CAH before adrenal crisis occurs.

### Clinical Image
![CAH Steroidogenesis Pathway](case_01_image.jpg)

*Adrenal steroidogenesis pathway showing the block at 21-hydroxylase and resulting accumulation of 17-hydroxyprogesterone with shunting to androgen synthesis.*

**Image Source:** Wikimedia Commons - "Steroidogenesis pathway"
**License:** CC BY-SA 3.0
**URL:** https://commons.wikimedia.org/wiki/File:Steroidogenesis.svg

---

## Case 2: Adrenal Incidentaloma - Subclinical Cortisol Secretion

### Patient Demographics
- **Age:** 58 years
- **Sex:** Female
- **Occupation:** Real estate agent

### Chief Complaint
"A mass was found on my adrenal gland during a CT scan."

### History of Present Illness
A 58-year-old woman had a CT scan of her abdomen performed for evaluation of kidney stones, which incidentally revealed a 2.5 cm left adrenal mass. She is asymptomatic with no classic features of Cushing syndrome. However, on detailed questioning, she reports mild weight gain over the past 2 years, poorly controlled type 2 diabetes despite multiple medications, and recently diagnosed hypertension. She bruises more easily than before. She has no symptoms of pheochromocytoma (headaches, palpitations, sweating episodes).

### Physical Examination
- **Vital Signs:** BP 152/92 mmHg, HR 78 bpm
- **General:** Mildly overweight, no buffalo hump or moon facies
- **Skin:** A few bruises on arms, no striae, no hyperpigmentation
- **Abdomen:** No masses palpable
- **Extremities:** Mild proximal weakness if tested carefully

### Workup
- **Imaging:**
  - CT Abdomen: 2.5 cm left adrenal mass, 8 Hounsfield units (lipid-rich, benign appearance), homogeneous, well-circumscribed
  - Washout characteristics: >50% (consistent with adenoma)
- **Biochemical Evaluation:**
  - 1 mg overnight dexamethasone suppression test (DST): Cortisol 3.8 μg/dL (fails to suppress <1.8)
  - Repeat DST: Cortisol 2.9 μg/dL (confirms non-suppression)
  - ACTH: 4 pg/mL (suppressed, indicating autonomous cortisol)
  - 24-hour urine free cortisol: 42 μg (normal <50)
  - DHEA-S: Low-normal
  - Late-night salivary cortisol: 0.12 μg/dL (borderline elevated)
  - Plasma metanephrines: Normal
  - Aldosterone/renin ratio: Normal

### Diagnosis
**Adrenal adenoma with autonomous cortisol secretion** (previously "subclinical Cushing syndrome," now termed "mild autonomous cortisol secretion" - MACS)

### Treatment Options
1. **Adrenalectomy (laparoscopic):**
   - Indicated given: diabetes poorly controlled, hypertension, autonomous cortisol secretion
   - May improve metabolic parameters
   - Will need peri-operative glucocorticoid coverage (suppressed contralateral adrenal)
   - Taper steroids post-operatively as HPA axis recovers
2. **Conservative management (if surgery declined):**
   - Aggressive management of cardiometabolic risk factors
   - Annual reassessment of hormonal status and imaging
   - Consider bone density screening
3. **Post-surgical monitoring:**
   - Morning cortisol to assess adrenal recovery
   - Taper hydrocortisone replacement over months
   - Monitor glucose and blood pressure (may improve)

### Clinical Pearl
Adrenal incidentalomas are found in ~5% of abdominal CT scans. All require biochemical evaluation for hormone excess: (1) 1 mg overnight DST for cortisol, (2) plasma or urine metanephrines for pheochromocytoma, and (3) aldosterone/renin ratio if hypertensive. MACS (mild autonomous cortisol secretion) is present in 5-30% of adrenal incidentalomas and is associated with increased cardiovascular risk, diabetes, and osteoporosis even without classic Cushing features. CT characteristics help distinguish benign from malignant lesions: <10 HU (lipid-rich adenoma), >50% washout (adenoma), while >4 cm size, irregular borders, or high density raise concern for carcinoma.

### Clinical Image
![Adrenal Incidentaloma CT](case_02_image.jpg)

*CT scan showing a well-circumscribed, homogeneous left adrenal mass with low Hounsfield units consistent with a lipid-rich adrenal adenoma.*

**Image Source:** Radiopaedia - "Adrenal adenoma"
**License:** CC BY-NC-SA 3.0
**URL:** https://radiopaedia.org/cases/adrenal-adenoma-3

---

## Case 3: Understanding Adrenal Zones - Zona Glomerulosa Physiology

### Patient Demographics
- **Age:** 45 years
- **Sex:** Male
- **Occupation:** Long-haul truck driver

### Chief Complaint
"I've had high blood pressure that won't come down despite taking 4 medications."

### History of Present Illness
A 45-year-old man is referred for evaluation of resistant hypertension. Despite taking lisinopril 40 mg, amlodipine 10 mg, hydrochlorothiazide 25 mg, and metoprolol 100 mg daily with good adherence, his blood pressure remains consistently elevated at 165-175/100-105 mmHg. He reports muscle cramps, weakness, frequent urination (nocturia), and excessive thirst. He has no family history of early hypertension. His potassium has been consistently low (2.8-3.2 mEq/L) despite potassium supplementation.

### Physical Examination
- **Vital Signs:** BP 172/104 mmHg, HR 68 bpm
- **General:** Well-appearing man
- **Cardiovascular:** Regular rate, no murmurs, PMI slightly displaced
- **Neurologic:** Mild proximal muscle weakness (4+/5), reflexes normal
- **Fundoscopic:** Grade II hypertensive changes

### Workup
- **Laboratory Studies (off interfering medications x 4 weeks):**
  - Potassium: 2.9 mEq/L (low)
  - Sodium: 144 mEq/L (high-normal)
  - Bicarbonate: 31 mEq/L (elevated - metabolic alkalosis)
  - Aldosterone: 28 ng/dL (elevated)
  - Plasma renin activity (PRA): 0.3 ng/mL/hr (suppressed)
  - Aldosterone-to-renin ratio (ARR): 93 (elevated, >30 suggestive)
- **Confirmatory Testing:**
  - Oral sodium loading test: Aldosterone remains >10 ng/dL (confirms autonomous secretion)
- **CT Adrenal:** 1.8 cm left adrenal nodule, low density
- **Adrenal Vein Sampling:** Left adrenal aldosterone:cortisol ratio markedly higher than right (lateralization confirmed)

### Diagnosis
**Primary aldosteronism (Conn syndrome)** due to unilateral aldosterone-producing adenoma (APA) arising from the zona glomerulosa

### Treatment
1. **Pre-operative:**
   - Mineralocorticoid receptor antagonist (spironolactone 25-50 mg daily or eplerenone)
   - Normalize potassium
   - Blood pressure control
2. **Definitive treatment:**
   - Laparoscopic left adrenalectomy (unilateral disease confirmed by AVS)
3. **Post-operative:**
   - Monitor for hyperkalemia (suppressed contralateral zona glomerulosa)
   - Temporary mineralocorticoid supplementation rarely needed
   - Blood pressure often normalizes or significantly improves
4. **If bilateral disease or surgery declined:**
   - Long-term mineralocorticoid receptor antagonist therapy

### Clinical Pearl
The adrenal cortex has three functional zones: zona glomerulosa (mineralocorticoids - aldosterone), zona fasciculata (glucocorticoids - cortisol), and zona reticularis (androgens - DHEA). Each zone has distinct enzymatic machinery: the zona glomerulosa uniquely expresses aldosterone synthase (CYP11B2). Primary aldosteronism is now recognized as the most common cause of secondary hypertension (5-10% of hypertensives), and screening with the aldosterone-to-renin ratio is recommended for resistant hypertension, hypokalemia with hypertension, adrenal incidentaloma with hypertension, and family history of early stroke or primary aldosteronism.

### Clinical Image
![Adrenal Zones Diagram](case_03_image.jpg)

*Diagram of adrenal cortex showing the three zones (glomerulosa, fasciculata, reticularis) with their respective hormones and key synthetic enzymes.*

**Image Source:** Wikimedia Commons - "Adrenal cortex zones"
**License:** CC BY-SA 3.0
**URL:** https://commons.wikimedia.org/wiki/File:Adrenal_gland_(cortex).jpg