Adrenal Insufficiency in Wilson Disease: Diagnosis and Management
Direct Answer
Yes, adrenal insufficiency can occur in Wilson disease and should be immediately suspected and treated in this patient. The constellation of fatigue, weight loss, hypotension, hyponatremia, hyperkalemia, and nausea/vomiting is classic for adrenal crisis, and Wilson disease can cause hypopituitarism leading to secondary adrenal insufficiency through copper deposition in the hypothalamic-pituitary axis 1, 2.
Immediate Emergency Management
Do not delay treatment for diagnostic testing if the patient is hemodynamically unstable.
- Administer 100 mg IV hydrocortisone immediately plus 0.9% saline infusion at 1 L/hour if the patient shows signs of adrenal crisis (hypotension, altered mental status, severe vomiting) 3, 4.
- Draw baseline serum cortisol and plasma ACTH before hydrocortisone administration if feasible, but treatment must never be delayed 3, 4.
- If you need to treat empirically but still want diagnostic testing later, use dexamethasone 4 mg IV instead of hydrocortisone, as dexamethasone does not interfere with cortisol assays 3, 4.
Why Wilson Disease Causes Adrenal Insufficiency
Wilson disease can cause hypopituitarism through copper deposition or secondary neuronal damage in the hypothalamic-pituitary axis, leading to secondary adrenal insufficiency.
- Case reports document complete resolution of hypopituitarism (including corticotroph deficiency) after copper-chelating therapy with D-penicillamine and zinc 1.
- The mechanism involves copper accumulation in the pituitary gland or secondary neuronal damage, even when pituitary MRI appears normal 1, 2.
- This is a secondary (central) adrenal insufficiency pattern: low cortisol with low or inappropriately normal ACTH 3, 2.
Diagnostic Approach
Step 1: Baseline Hormone Assessment
Obtain early-morning (8 AM) serum cortisol and plasma ACTH immediately.
- Morning cortisol <250 nmol/L (<9 µg/dL) with low or inappropriately normal ACTH confirms secondary adrenal insufficiency 3, 4, 5.
- Morning cortisol 250–400 nmol/L (9–14 µg/dL) with low ACTH raises strong suspicion and warrants confirmatory testing 3, 4.
- Morning cortisol >550 nmol/L (>18–20 µg/dL) effectively rules out adrenal insufficiency 3.
Step 2: Confirmatory Testing (If Baseline Indeterminate)
Perform the cosyntropin stimulation test when morning cortisol is 5–18 µg/dL or clinical suspicion remains high.
- Protocol: Administer 0.25 mg (250 µg) cosyntropin IV or IM, then measure serum cortisol at baseline, 30 minutes, and optionally 60 minutes 3, 4, 5.
- Interpretation:
Step 3: Distinguish Primary vs. Secondary Adrenal Insufficiency
The electrolyte pattern helps differentiate:
- Hyponatremia + hyperkalemia strongly suggests primary adrenal insufficiency (both glucocorticoid and mineralocorticoid deficiency) 3, 4.
- Hyponatremia without hyperkalemia suggests secondary adrenal insufficiency (glucocorticoid deficiency only, intact mineralocorticoid axis) 3.
- Critical caveat: Hyperkalemia is present in only ~50% of primary adrenal insufficiency cases, so its absence does not exclude the diagnosis 3, 4, 6.
In Wilson disease, expect secondary adrenal insufficiency with:
- Low cortisol + low/normal ACTH 3, 2
- Hyponatremia without hyperkalemia (unless primary adrenal involvement) 3
- Normal skin pigmentation (no hyperpigmentation, since ACTH is low) 3
Critical Pitfalls to Avoid
Pitfall 1: Relying on Hyperkalemia to Make the Diagnosis
- Hyperkalemia occurs in only ~50% of adrenal insufficiency cases 3, 4, 6.
- If the patient has vomiting, hypokalemia may mask the expected hyperkalemia from aldosterone deficiency 6.
- Never exclude adrenal insufficiency based on normal potassium alone 3, 4.
Pitfall 2: Confusing Adrenal Insufficiency with SIADH
- Both conditions present with euvolemic hyponatremia, low serum osmolality, inappropriately high urine osmolality, and elevated urinary sodium 3.
- Adrenal insufficiency must be excluded before diagnosing SIADH 3.
- The cosyntropin stimulation test is medically necessary to differentiate these conditions 3.
- Treatment differs critically: adrenal insufficiency requires glucocorticoid replacement, while SIADH requires fluid restriction 3.
Pitfall 3: Delaying Treatment for Diagnostic Testing
- Mortality is high if adrenal crisis is untreated 3, 4.
- In unstable patients, give 100 mg IV hydrocortisone immediately—do not wait for cortisol results 3, 4.
- Use dexamethasone 4 mg IV if you need to preserve diagnostic accuracy for later testing 3, 4.
Long-Term Management
Glucocorticoid Replacement
All patients with confirmed secondary adrenal insufficiency require lifelong glucocorticoid replacement.
- Hydrocortisone 15–25 mg daily in divided doses (typically 10 mg at 7 AM, 5 mg at noon, 2.5–5 mg at 4 PM) 3, 5.
- Alternative: Prednisone 3–5 mg daily 3, 5.
- Do not use dexamethasone for chronic replacement 3.
Mineralocorticoid Replacement (Only for Primary Adrenal Insufficiency)
- Fludrocortisone 50–200 µg daily is required only if the patient has primary adrenal insufficiency 3, 5.
- Secondary adrenal insufficiency does not require mineralocorticoid replacement because the renin-angiotensin-aldosterone system remains intact 3.
Stress Dosing Education
All patients must be educated on stress dosing to prevent adrenal crisis.
- Double or triple the usual dose during illness, fever, or physical stress 3, 5.
- Prescribe an emergency injectable hydrocortisone 100 mg IM kit with self-injection training 3, 5.
- Patients must wear a medical alert bracelet indicating adrenal insufficiency 3, 5.
Wilson Disease-Specific Considerations
Initiate copper-chelating therapy immediately, as hypopituitarism may resolve with treatment.
- Start D-penicillamine and zinc for copper chelation 1.
- Hypopituitarism can resolve when urinary copper excretion normalizes under copper chelation 1.
- Reassess pituitary function after 3 months of copper-chelating therapy to determine if glucocorticoid replacement can be discontinued 1.
Monitoring and Follow-Up
- Annual endocrine follow-up to assess for HPA axis recovery 3.
- Screen for other autoimmune conditions (thyroid function, diabetes, celiac disease) if primary adrenal insufficiency is found 3.
- Monitor for signs of over-replacement (weight gain, insomnia, edema) or under-replacement (fatigue, nausea, weight loss) 3.
Drug Interactions Affecting Hydrocortisone Requirements
CYP3A4 inducers increase hydrocortisone clearance and may require higher doses:
- Anticonvulsants (phenytoin, carbamazepine, phenobarbital), rifampin, barbiturates 3.
CYP3A4 inhibitors decrease hydrocortisone clearance and may require lower doses:
- Grapefruit juice, licorice 3.
When to Suspect Concurrent Hypothyroidism
If the patient has both adrenal insufficiency and hypothyroidism, start corticosteroids several days before initiating thyroid hormone replacement to prevent precipitating adrenal crisis 3, 6.