Is hyperpigmentation a symptom of hypercortisolism (elevated cortisol levels) or hypocortisolism (decreased cortisol levels)?

Hyperpigmentation is a Symptom of Hypocortisolism, Not Hypercortisolism

Hyperpigmentation is a characteristic symptom of hypocortisolism (adrenal insufficiency) and is not associated with hypercortisolism (Cushing syndrome). 1

Pathophysiology of Hyperpigmentation in Hypocortisolism

Hyperpigmentation in adrenal insufficiency occurs through the following mechanism:

• When cortisol levels are low, the negative feedback inhibition on the hypothalamic-pituitary axis is reduced
• This leads to increased production of ACTH (adrenocorticotropic hormone) from the pituitary
• High ACTH levels stimulate melanocytes in the skin, causing increased melanin production
• The result is generalized hyperpigmentation of the skin 1, 2

This is particularly evident in:

• Primary adrenal insufficiency (Addison's disease) where ACTH levels are markedly elevated
• Cases of familial glucocorticoid deficiency where there is insensitivity to ACTH 3, 4

Diagnostic Differentiation Between Hypocortisolism and Hypercortisolism

The following table highlights key differences between primary adrenal insufficiency and Cushing syndrome:

Feature	Primary Adrenal Insufficiency	Cushing Syndrome (Hypercortisolism)
Cortisol	Low	High
ACTH	High	Low (adrenal cause) or High (pituitary/ectopic cause)
Electrolytes	↓Na, ↑K	↑Na, ↓K
Skin	Hyperpigmentation	Thinning, striae, easy bruising
Weight	Weight loss	Weight gain, central obesity
Blood pressure	Hypotension	Hypertension

1

Clinical Evidence Supporting Hyperpigmentation in Hypocortisolism

Several case reports and clinical guidelines confirm the association between hyperpigmentation and hypocortisolism:

• A 33-year-old female presented with striking pigmentation typical of Addison's disease, with high plasma ACTH levels maintaining normal cortisol levels (compensated hypoadrenalism) 2

• An infant with familial glucocorticoid deficiency (a form of hypocortisolism) presented with generalized hyperpigmentation, which faded after corticosteroid treatment normalized ACTH levels 3

• Nelson syndrome, characterized by pituitary hyperplasia and cutaneous hyperpigmentation, occurs following bilateral adrenalectomy due to lowered plasma cortisol levels 5

• A 10-month-old baby with familial glucocorticoid deficiency presented with generalized hyperpigmentation, low serum cortisol, and high ACTH levels 4

Clinical Implications

The presence of hyperpigmentation should prompt evaluation for adrenal insufficiency:

• Morning serum cortisol and ACTH levels should be measured
• Cortisol levels <110 nmol/L (<4 μg/dL) suggest adrenal insufficiency
• ACTH stimulation test may be needed for confirmation 1

Treatment Considerations

For patients with confirmed adrenal insufficiency:

• Lifelong hormone replacement therapy with glucocorticoids (hydrocortisone 15-25 mg daily in divided doses)
• Mineralocorticoid replacement (fludrocortisone 0.05-0.2 mg daily) if needed
• Patient education on stress dosing to prevent adrenal crisis
• Medical alert identification and emergency hydrocortisone injection kit 1

Common Pitfalls

1. Mistaking hyperpigmentation as a symptom of hypercortisolism can lead to inappropriate treatment
2. Failing to recognize compensated hypoadrenalism where cortisol levels may be normal but ACTH levels are elevated
3. Not considering familial glucocorticoid deficiency in infants with hyperpigmentation
4. Overlooking the need for stress dosing of glucocorticoids during illness or procedures in patients with adrenal insufficiency

Remember that hyperpigmentation typically improves with appropriate glucocorticoid replacement therapy as ACTH levels normalize.