Can Adrenal Gland Dysfunction Cause Hyponatremia?
Yes, adrenal gland dysfunction is a well-established cause of hyponatremia, with hyponatremia present in 90% of newly diagnosed cases of primary adrenal insufficiency. 1, 2
Mechanism and Clinical Significance
Both primary and secondary adrenal insufficiency cause hyponatremia through distinct but overlapping mechanisms:
Primary Adrenal Insufficiency (Addison's Disease)
Hyponatremia occurs in 90% of newly presenting cases of primary adrenal insufficiency, making it one of the most consistent laboratory findings in this condition. 1, 2
The mechanism involves combined aldosterone and cortisol deficiency, which causes sodium loss in urine and impaired free water clearance due to increased plasma vasopressin and angiotensin II. 1
Primary adrenal insufficiency typically presents with low morning cortisol (<5 µg/dL or <250 nmol/L), markedly elevated ACTH, hyponatremia, and hyperkalemia in approximately 50% of cases—though the absence of hyperkalemia does not exclude the diagnosis. 1, 2, 3
Additional clinical features include hyperpigmentation, salt craving, orthostatic hypotension, fatigue, nausea, vomiting, and weight loss. 1, 4, 5
Secondary Adrenal Insufficiency (Hypopituitarism)
Secondary adrenal insufficiency is a frequently overlooked cause of severe hyponatremia that requires a high index of clinical suspicion, as clinical signs can be quite subtle compared to primary adrenal insufficiency. 6, 5
In a retrospective study of 185 patients with severe hyponatremia, 28 patients had hypopituitarism with secondary adrenal insufficiency, and in 25 of these cases the diagnosis had not been previously recognized despite recurrent hyponatremia during multiple hospital admissions. 6
Secondary adrenal insufficiency presents with low or intermediate morning cortisol levels (5-10 µg/dL) and low or inappropriately normal ACTH levels, distinguishing it from primary adrenal insufficiency. 6, 3
Hyperkalemia is typically absent in secondary adrenal insufficiency because the renin-angiotensin-aldosterone system remains intact, unlike in primary adrenal insufficiency. 2, 7
Clinical clues include missing or scanty pubic and axillary hair, pale and doughy skin, absence of hyperpigmentation (due to low ACTH), and small testicles in men. 6
Critical Diagnostic Pitfalls
Do Not Rely on Electrolyte Patterns Alone
The classic combination of hyponatremia and hyperkalemia is not reliable for diagnosis because serum sodium is often only marginally reduced, and hyperkalemia is present in only approximately 50% of patients at diagnosis. 1, 2
In the presence of severe vomiting, hypokalaemia and alkalosis may be present rather than the expected hyperkalemia, as gastrointestinal losses mask aldosterone deficiency. 1, 8
Distinguish from SIADH
Adrenal insufficiency must be excluded before diagnosing SIADH, as both conditions present with euvolemic hypo-osmolar hyponatremia with inappropriately high urine osmolality and elevated urinary sodium. 7
The cosyntropin stimulation test is medically necessary to rule out adrenal insufficiency in patients with hypo-osmolality and hyponatremia, as the clinical presentations are nearly identical. 7
In most patients with hyponatremic hypopituitarism, plasma antidiuretic hormone levels are inappropriately high, probably due to failure of endogenous cortisol to suppress the hormone in a stressful situation. 6
Diagnostic Approach
Initial Testing
Obtain early-morning (approximately 8 AM) serum cortisol and plasma ACTH as first-line tests when adrenal insufficiency is suspected in a hyponatremic patient. 1, 2, 3
Basal cortisol <250 nmol/L (<9 µg/dL) with elevated ACTH in acute illness is diagnostic of primary adrenal insufficiency. 2, 7
Basal cortisol <400 nmol/L with elevated ACTH in acute illness raises strong suspicion and warrants immediate treatment. 7
In secondary adrenal insufficiency, basal serum cortisol levels in the acutely ill state ranged from 20 to 439 nmol/l (mean 157 nmol/l), which is inappropriately low for the stress of severe illness. 6
Confirmatory Testing
The ACTH stimulation test (cosyntropin/Synacthen test) is the gold standard for confirming adrenal insufficiency when initial values are indeterminate. 2, 7
Administer 0.25 mg cosyntropin intramuscularly or intravenously, with cortisol measurements at baseline and 30 and/or 60 minutes post-administration. 2, 7
**A peak cortisol <500 nmol/L (<18 µg/dL) is diagnostic of adrenal insufficiency**, while >550 nmol/L (>18-20 µg/dL) is considered normal. 2, 7
Emergency Management
Treatment of suspected acute adrenal insufficiency should NEVER be delayed for diagnostic procedures, as mortality is high if untreated. 2, 8, 7
Administer hydrocortisone 100 mg IV immediately in patients with significant hypotension and symptoms of adrenal crisis. 2, 8
Infuse 0.9% saline solution at 1 L in the first hour to address volume depletion. 2, 8
Obtain blood samples for cortisol and ACTH before treatment if possible, but do not delay treatment waiting for results. 2, 8
Treatment and Resolution
All patients with hyponatremic adrenal insufficiency recovered after hydrocortisone substitution, demonstrating that treatment with glucocorticoids is very effective once the diagnosis is made. 6
Hydrocortisone replacement greatly improved both hyponatremia and renal tubular acidosis in documented cases, confirming that cortisol deficiency directly contributes to these electrolyte abnormalities. 9
For primary adrenal insufficiency, add fludrocortisone 0.05-0.3 mg daily for mineralocorticoid replacement in addition to glucocorticoid therapy. 2, 3
Maintenance glucocorticoid therapy typically consists of hydrocortisone 15-25 mg daily or prednisone 3-5 mg daily. 3