Residency · Residency · Medicine Pediatrics

Adrenal Insufficiency: Congenital to Acquired

Overview

Adrenal insufficiency (AI) spans a spectrum from congenital adrenal hyperplasia (CAH) in neonates to autoimmune Addison disease and iatrogenic adrenal suppression in older children and adults. Med-Peds physicians encounter AI across all age groups and must recognize both acute adrenal crisis and chronic insufficiency. The most common cause across all ages is iatrogenic adrenal suppression from exogenous glucocorticoids.

Congenital Adrenal Hyperplasia (CAH)

Pathophysiology

Autosomal recessive deficiency of enzymes in cortisol biosynthesis. 21-hydroxylase deficiency accounts for >90% of cases. Cortisol deficiency leads to loss of negative feedback on ACTH, driving adrenal hyperplasia and shunting of precursors into androgen pathways. 17-hydroxyprogesterone (17-OHP) is the key elevated precursor in 21-hydroxylase deficiency.

Classic CAH

Salt-wasting form (75% of classic CAH): presents in the first 1-2 weeks of life with adrenal crisis — vomiting, dehydration, hyponatremia, hyperkalemia, shock. Simple virilizing form: no salt wasting, but ambiguous genitalia in 46,XX neonates; precocious puberty and accelerated growth in males. Detected on newborn screening via 17-OHP levels (elevated) Newborn screening has dramatically reduced mortality from salt-wasting crises.

Non-Classic CAH

Milder enzyme deficiency; may present in childhood or adulthood. Females: premature adrenarche, hirsutism, acne, menstrual irregularity, infertility. Males: often asymptomatic or incidentally diagnosed. Does NOT cause adrenal crisis under normal conditions but may have insufficient cortisol reserve under severe stress.

Management of CAH

Lifelong glucocorticoid replacement (hydrocortisone in children; hydrocortisone or prednisone/dexamethasone in adults) Mineralocorticoid replacement (fludrocortisone) in salt-wasting forms. Monitoring: 17-OHP, androstenedione, testosterone, renin, growth velocity, bone age. Goal: adequate cortisol replacement without overtreatment causing growth suppression or Cushingoid features. Stress dosing: 2-3x maintenance dose during febrile illness; IV hydrocortisone for surgery or severe illness.

<image>Steroidogenesis pathway showing 21-hydroxylase enzyme block, precursor accumulation, and shunting to androgen synthesis in CAH</image>

Primary Adrenal Insufficiency (Addison Disease)

Etiology

Children: CAH (most common), autoimmune adrenalitis, adrenoleukodystrophy (X-linked, must screen in boys), infections (TB, fungal), adrenal hemorrhage. Adults: autoimmune adrenalitis (most common in developed countries, ~80%), TB (leading cause globally), metastatic disease, bilateral adrenal hemorrhage (Waterhouse-Friderichsen syndrome), medications (ketoconazole, etomidate, checkpoint inhibitors)

Clinical Features

Fatigue, weight loss, anorexia, nausea, abdominal pain. Hyperpigmentation (ACTH-driven melanocyte stimulation) — pathognomonic for primary AI. Hypotension, orthostatic dizziness. Salt craving (mineralocorticoid deficiency) Lab findings: hyponatremia, hyperkalemia, hypoglycemia (especially in children), mild eosinophilia.

Diagnosis

Morning cortisol: <3 mcg/dL strongly suggestive; >18 mcg/dL makes AI unlikely. ACTH stimulation test (cosyntropin test): gold standard — cortisol <18 mcg/dL at 30 or 60 minutes is diagnostic. ACTH level: elevated in primary AI (loss of feedback), low/normal in secondary/tertiary AI. Adrenal antibodies (21-hydroxylase antibodies) for autoimmune etiology. In boys with primary AI: very long chain fatty acids to screen for adrenoleukodystrophy.

<image>Clinical photographs showing hyperpigmentation in primary adrenal insufficiency including palmar creases, buccal mucosa, and skin folds</image>

Secondary and Tertiary Adrenal Insufficiency

Iatrogenic Adrenal Suppression

Most common cause of AI in clinical practice across all ages. Results from chronic exogenous glucocorticoid use suppressing the HPA axis. Risk increases with duration >2-3 weeks, higher doses, and systemic routes. Inhaled corticosteroids can cause suppression, particularly at high doses (fluticasone > budesonide in suppressive potential) Other routes: topical (large surface area in children), intra-articular, intranasal.

Other Causes of Secondary AI

Pituitary adenoma, surgery, or radiation; Traumatic brain injury; Sheehan syndrome (postpartum pituitary necrosis); Hypophysitis (including checkpoint inhibitor-induced); Infiltrative diseases (sarcoidosis, hemochromatosis, Langerhans cell histiocytosis in children).

Key Differences from Primary AI

No hyperpigmentation (ACTH is low, not high) No hyperkalemia (mineralocorticoid axis via renin-angiotensin is intact) Hyponatremia can still occur (cortisol is needed for free water excretion) Hypoglycemia may be prominent, especially in children.

Adrenal Crisis

Recognition

Life-threatening emergency; mortality is high if untreated. Presents with severe hypotension/shock, altered mental status, abdominal pain, fever, hypoglycemia. Precipitants: infection, surgery, trauma, abrupt glucocorticoid withdrawal, failure to stress dose. Children are particularly vulnerable due to limited glycogen reserves and higher metabolic demands.

Emergency Management

Do not delay treatment for diagnostic testing if clinical suspicion is high. IV hydrocortisone: 100 mg bolus in adults; 50 mg/m2 (or 2 mg/kg, max 100 mg) in children. Aggressive IV normal saline resuscitation with dextrose if hypoglycemic. Identify and treat precipitating cause. Continue hydrocortisone 50-100 mg IV every 6-8 hours in adults; 50-100 mg/m2/day divided every 6 hours in children. At stress doses of hydrocortisone (>50 mg/day adult equivalent), additional mineralocorticoid is unnecessary.

<image>Emergency management algorithm for acute adrenal crisis in pediatric and adult patients with stepwise approach to fluid resuscitation and stress dose steroids</image>

Stress Dosing Protocols Across Ages

Pediatric Stress Dosing

Mild-moderate illness (fever, gastroenteritis): 2-3x daily oral hydrocortisone dose. Severe illness, inability to tolerate PO, or surgery: IM/IV hydrocortisone 50 mg/m2 bolus then 50-100 mg/m2/day divided every 6-8 hours. All families must have injectable hydrocortisone at home and be trained in IM administration. Medical alert identification is essential.

Adult Stress Dosing

Minor illness: double oral dose for duration of illness. Moderate stress (e.g., colonoscopy): hydrocortisone 50 mg IV before procedure. Major surgery: hydrocortisone 100 mg IV at induction, then 50 mg every 8 hours for 24-72 hours, then taper. Critical illness: hydrocortisone 50 mg IV every 6-8 hours.

HPA Axis Recovery After Exogenous Steroids

Gradual taper to physiologic dose, then slow withdrawal over weeks-months. Test with morning cortisol or cosyntropin stimulation test to confirm recovery. Recovery can take 6-12 months or longer after prolonged suppression. During taper, stress dosing is still needed for intercurrent illness.

Monitoring and Long-Term Management

Chronic Replacement Therapy

Glucocorticoid: hydrocortisone (preferred in children due to short half-life, easier dose titration); prednisone or dexamethasone may be used in adults for convenience. Typical hydrocortisone doses: 8-12 mg/m2/day in children (divided TID); 15-25 mg/day in adults (divided BID-TID, weight toward morning) Mineralocorticoid: fludrocortisone 0.05-0.2 mg/day; monitor renin and electrolytes. DHEA supplementation: may improve quality of life in adult women with primary AI; not standard in children.

Growth Monitoring in Children

Overtreatment with glucocorticoids suppresses linear growth. Growth velocity is the most sensitive marker of overtreatment. Regular bone age assessments in CAH to monitor skeletal maturation. Balance between adequate cortisol replacement (preventing virilization and growth acceleration) and avoiding growth suppression.

<image>Comparison table of glucocorticoid replacement options showing relative potency, half-life, mineralocorticoid activity, and growth effects for hydrocortisone, prednisone, prednisolone, and dexamethasone</image>

Clinical Pearls

Always consider adrenal insufficiency in any patient with unexplained hypotension, especially if refractory to fluids and vasopressors. A random cortisol drawn during critical illness can be misleading; values <10 mcg/dL in a stressed patient are concerning. Checkpoint inhibitor-induced adrenalitis (primary or hypophysitis-mediated secondary) is increasingly common; onset can be weeks to months after treatment initiation. In neonatal screening for CAH, premature infants have higher baseline 17-OHP levels, leading to false positives; weight-adjusted cutoffs improve specificity. Etomidate (even a single dose for RSI) inhibits 11-beta-hydroxylase and can precipitate adrenal crisis in susceptible patients. Patients with AI should never abruptly discontinue glucocorticoids; this is a common cause of preventable adrenal crisis.

References

• Bornstein SR, Allolio B, Arlt W, et al. Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016;101(2):364-389.
• Speiser PW, Arlt W, Auchus RJ, et al. Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2018;103(11):4043-4088.
• Rushworth RL, Torpy DJ, Falhammar H. Adrenal Crisis. N Engl J Med. 2019;381:852-861.
• El-Maouche D, Arlt W, Merke DP. Congenital Adrenal Hyperplasia. Lancet. 2017;390(10108):2194-2210.

Read this lecture as Markdown