What laboratory tests are important for managing a patient with Congenital Adrenal Hyperplasia (CAH)?

Laboratory Monitoring for Congenital Adrenal Hyperplasia (CAH)

Patients with CAH require regular monitoring of 17-hydroxyprogesterone (17-OHP) and androstenedione to assess adequacy of glucocorticoid replacement, along with electrolytes and plasma renin activity to evaluate mineralocorticoid therapy, with annual screening for associated metabolic and autoimmune complications. 1, 2

Core Biochemical Monitoring

Adrenal Androgen Markers

• 17-hydroxyprogesterone (17-OHP) is the primary biomarker for monitoring glucocorticoid replacement adequacy in CAH, though it shows significant temporal variation throughout the day and must be interpreted in relation to medication timing 1, 3
• Androstenedione provides additional assessment of androgen suppression and should be measured alongside 17-OHP, as relying on a single marker can be misleading 1, 3
• Testosterone levels should be monitored in females to assess hyperandrogenism control, particularly when evaluating menstrual irregularities and fertility concerns 4, 1
• Consider measuring 11-oxygenated androgens as they are more disease-specific markers for CAH and may provide better assessment of treatment adequacy than traditional androgens 3

Mineralocorticoid Assessment

• Serum sodium and potassium should be checked at each visit to assess mineralocorticoid replacement adequacy, as hyponatremia and hyperkalemia indicate insufficient fludrocortisone dosing 5, 1
• Plasma renin activity (PRA) is valuable for fine-tuning mineralocorticoid replacement, particularly in patients with features of mineralocorticoid deficiency such as postural hypotension or salt craving 5

ACTH Measurement

• Morning ACTH levels help distinguish between adequate suppression and overtreatment, with elevated ACTH indicating inadequate glucocorticoid dosing 1

Clinical Monitoring Parameters

Vital Signs and Physical Examination

• Blood pressure should be measured in both sitting and standing positions at each visit to detect postural hypotension, which signals insufficient mineralocorticoid therapy or inadequate salt intake 5
• Weight and body mass index (BMI) must be monitored at every visit, as weight loss signals insufficient glucocorticoid dosing while weight gain may indicate overtreatment or development of metabolic complications 5, 1
• Waist circumference should be measured regularly to screen for central obesity and metabolic syndrome, which occur more frequently in CAH patients than the general population 1
• Skin pigmentation assessment is important, as hyperpigmentation indicates inadequate cortisol replacement and excessive ACTH stimulation 5

Growth and Development (Adolescents)

• Height and growth velocity require close monitoring in adolescents to ensure normal growth and bone maturation, as both undertreatment and overtreatment can compromise final height 4
• Bone age assessment helps evaluate the balance between androgen suppression and glucocorticoid exposure 4
• Pubertal staging is essential to ensure normal timing of puberty and detect signs of hyperandrogenism 4

Annual Screening for Complications

Metabolic Monitoring

• Fasting plasma glucose and HbA1c should be measured annually to screen for diabetes mellitus, as CAH patients have increased risk of insulin resistance and metabolic syndrome 5, 1
• Lipid profile requires annual assessment due to increased cardiovascular risk from both the disease and glucocorticoid treatment 1

Bone Health

• Bone mineral density (BMD) by DEXA scan should be performed every 3-5 years to screen for osteoporosis, as long-term glucocorticoid treatment is a known risk factor 6, 1

Autoimmune Screening

• TSH, free T4, and TPO antibodies should be measured every 12 months to screen for autoimmune thyroid disease, which frequently develops in patients with autoimmune adrenal insufficiency 5
• Complete blood count is necessary annually to screen for anemia 5
• Vitamin B12 levels should be checked annually, as autoimmune gastritis causing B12 deficiency is common in autoimmune CAH 5

Reproductive Health Monitoring

• Menstrual history should be documented at each visit in females, as irregular menses indicate inadequate androgen suppression 4, 1
• Fertility assessment should be performed early and regularly in adults desiring pregnancy, as both males and females with CAH have reduced fertility 2, 7

Timing and Frequency of Laboratory Testing

Routine Follow-up

• Annual visits with comprehensive clinical assessment and laboratory monitoring are recommended as the minimum frequency for stable patients 5, 2
• More frequent monitoring (every 3-6 months) may be needed during adolescence due to rapid changes in growth and sex hormone levels that can lead to inadequate androgen suppression 4

Timing of Blood Draws

• Morning samples (ideally 8 AM) should be obtained for 17-OHP, androstenedione, and ACTH to standardize interpretation, though the relationship to medication timing is critical 1, 3
• Consider cortisol day curves when suspecting undertreatment or rapid cortisol clearance, measuring levels at multiple time points throughout the day in relation to medication doses 5

Alternative Monitoring Methods

Non-invasive Sampling

• Salivary steroid measurements are increasingly available and should be considered, especially in children, as they allow for easier collection and multiple time points 3
• Urinary steroid metabolite measurements provide integrated assessment over 24 hours and may better reflect overall androgen exposure 3

Critical Pitfalls to Avoid

• Never rely solely on electrolyte abnormalities to assess mineralocorticoid adequacy, as hyperkalemia is present in only ~50% of primary adrenal insufficiency cases 5
• Do not use serum or urine cortisol levels to guide replacement therapy in patients on hydrocortisone, as they are uninterpretable due to cross-reactivity with the medication 5
• Avoid interpreting 17-OHP or androstenedione in isolation without considering the timing relative to glucocorticoid dosing, as levels vary dramatically throughout the day 3
• When treating concurrent hypothyroidism, always start corticosteroids several days before thyroid hormone replacement to prevent precipitating adrenal crisis 5
• Exogenous steroids including inhaled fluticasone can suppress the HPA axis and confound testing results 5

Treatment Adjustment Based on Monitoring

Signs of Undertreatment

• Elevated 17-OHP and androstenedione levels, increased ACTH, hyperpigmentation, poor appetite, weight loss, and in females: hirsutism, acne, menstrual irregularities 5, 4, 1

Signs of Overtreatment

• Cushingoid features, weight gain, hyperglycemia, hypertension, decreased bone mineral density, growth suppression in children 4, 1

Mineralocorticoid Adjustment

• Inadequate replacement presents with postural hypotension, salt craving, hyponatremia, hyperkalemia, and elevated plasma renin activity 5
• Excessive replacement causes hypertension, peripheral edema, hypokalemia, and suppressed plasma renin activity 5