What are the differential diagnoses and management options for a patient presenting with salt cravings, considering potential underlying conditions such as adrenal insufficiency, dehydration, and psychiatric disorders?

Salt Craving: Differential Diagnoses and Management

Salt craving is a cardinal symptom of primary adrenal insufficiency (Addison's disease) and should trigger immediate evaluation with morning cortisol and ACTH levels, followed by cosyntropin stimulation testing if initial results are indeterminate. 1, 2

Primary Differential Diagnoses

Adrenal Insufficiency (Most Critical to Rule Out)

Primary adrenal insufficiency must be excluded first because it is life-threatening and presents with salt craving as a pathognomonic feature alongside fatigue, weight loss, hyperpigmentation, nausea, and orthostatic hypotension. 1, 3

Diagnostic Approach:

• Obtain morning (8 AM) serum cortisol and plasma ACTH simultaneously as first-line testing. 1, 2
• Basal cortisol <250 nmol/L (<9 μg/dL) with elevated ACTH in acute illness is diagnostic of primary adrenal insufficiency. 1, 2
• Basal cortisol <400 nmol/L (<14.5 μg/dL) with elevated ACTH raises strong suspicion and warrants empiric treatment if clinically unstable. 1, 2
• If cortisol is indeterminate (250-400 nmol/L), perform cosyntropin stimulation test: administer 0.25 mg IV or IM, measure cortisol at 30 and 60 minutes—peak <500 nmol/L (<18 μg/dL) confirms adrenal insufficiency. 1, 2

Critical Pitfall:

• Hyponatremia is present in 90% of adrenal insufficiency cases, but hyperkalemia occurs in only ~50%—absence of hyperkalemia cannot exclude the diagnosis. 1, 2, 4
• Vomiting causes hypokalemia that masks the expected hyperkalemia from aldosterone deficiency. 4

Etiologic Workup After Diagnosis:

• Measure 21-hydroxylase (anti-adrenal) autoantibodies—positive in ~85% of autoimmune Addison's disease in Western populations. 1, 2
• If antibodies negative, obtain adrenal CT imaging to evaluate for hemorrhage, tuberculosis, metastatic disease, or adrenoleukodystrophy. 1, 2
• In males with negative antibodies, assay very long-chain fatty acids (VLCFA) to screen for adrenoleukodystrophy. 1

Treatment:

• If clinically unstable with suspected adrenal crisis: give 100 mg IV hydrocortisone immediately plus 0.9% saline at 1 L/hour—never delay treatment for diagnostic testing. 1, 2
• Maintenance therapy: 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) plus fludrocortisone 50-200 µg daily. 1, 2
• Patients should take salt and salty foods ad libitum and avoid liquorice and grapefruit juice. 1

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Bartter Syndrome

Bartter syndrome presents with renal salt wasting, polyuria, dehydration, and prominent salt craving beyond infancy, distinguished by hypokalemia, metabolic alkalosis, and elevated urinary chloride (>20 mEq/L). 1, 5

Diagnostic Features:

• Hypokalemia with metabolic alkalosis and inappropriately elevated urinary chloride (>20 mEq/L) despite volume depletion. 1, 5
• Elevated plasma renin activity with normal to low blood pressure (distinguishes from hyperaldosteronism). 1
• Hypercalciuria is common in Bartter syndrome (unlike Gitelman syndrome which has hypocalciuria). 5

Confirmatory Testing:

• Genetic testing for genes underlying Bartter syndrome (SLC12A1, KCNJ1, CLCNKB, BSND, CASR). 5

Treatment:

• Pharmacologic sodium chloride supplementation at 5-10 mmol/kg/day. 1, 5
• Potassium chloride supplementation (not potassium citrate, which worsens alkalosis). 1, 5
• NSAIDs (indomethacin or ibuprofen) in symptomatic patients, especially in early childhood, with gastric acid inhibitors for gastroprotection. 1, 5
• Do not supplement salt in patients with secondary nephrogenic diabetes insipidus and hypernatremic dehydration. 1

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Gitelman Syndrome

Gitelman syndrome is characterized by the triad of hypokalemia, hypomagnesemia, and hypocalciuria (urinary calcium-to-creatinine ratio <0.2), with salt craving, muscle weakness, and fatigue. 5

Diagnostic Features:

• Hypokalemia with metabolic alkalosis, hypomagnesemia, and hypocalciuria distinguish it from Bartter syndrome. 5
• Often presents later in childhood or adolescence with milder symptoms than Bartter syndrome. 5

Confirmatory Testing:

• Genetic testing for SLC12A3 mutations. 5

Treatment:

• Magnesium supplementation is the cornerstone of therapy—use organic magnesium salts (citrate, lactate) for better bioavailability. 1, 5
• Potassium chloride supplementation with target serum potassium of 3.0 mmol/L. 1, 5
• Liberal salt intake. 5

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Cerebral Salt Wasting (CSW)

CSW presents with hyponatremia, extracellular volume depletion, and inappropriately high renal sodium loss (>20 mmol/L), typically in the context of intracranial pathology (subarachnoid hemorrhage, traumatic brain injury, neurosurgery). 5

Critical Distinction from SIADH:

• CSW requires sodium and volume replacement, while SIADH requires fluid restriction—treatments are diametrically opposed. 5
• CSW shows clinical signs of volume depletion (orthostasis, skin tenting), while SIADH is euvolemic. 5
• Both have high urine osmolality and high urine sodium, but volume status differs. 5

Diagnostic Approach:

• Assess volume status clinically (orthostatic vital signs, skin turgor, mucous membranes). 5
• Measure serum and urine osmolality, urine sodium simultaneously. 5
• Adrenal insufficiency must be excluded before diagnosing SIADH, as both present with euvolemic hypo-osmolar hyponatremia. 2

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Secondary Considerations

Psychiatric Disorders and Eating Disorders

Salt craving can occur in patients with psychiatric conditions, but adrenal insufficiency must be ruled out first as psychiatric symptoms (anxiety, depression, anorexia) can be manifestations of undiagnosed adrenal insufficiency. 1, 6, 7

• Adrenal insufficiency can present with anorexia, nausea, vomiting, and anxiety that mimic eating disorders. 6
• Patients with mental illness who complain of postprandial symptoms plus fatigue warrant HPA axis evaluation. 7
• Anchoring bias can lead to misdiagnosis—symptoms attributed to psychiatric illness may actually represent adrenal insufficiency. 6

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Medication-Induced (Corticosteroid Withdrawal)

Patients with chronic corticosteroid use (≥20 mg/day prednisone equivalent for ≥3 weeks) who develop salt craving, hypotension, and gastrointestinal symptoms should be presumed to have iatrogenic secondary adrenal insufficiency. 4

• Draw morning cortisol and ACTH before any steroid administration. 4
• Cortisol <250 nmol/L with low/normal ACTH confirms secondary adrenal insufficiency. 4
• If clinically unstable, give 100 mg IV hydrocortisone immediately without waiting for test results. 4

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Aldosterone-Secreting Adrenal Tumors (Primary Hyperaldosteronism)

While typically presenting with hypertension rather than salt craving, primary hyperaldosteronism can occasionally present with weakness and hypokalemia. 5

• Plasma aldosterone-to-renin ratio >30 suggests primary hyperaldosteronism. 5
• Confirmatory testing with saline suppression test or salt loading test. 5

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Systematic Diagnostic Algorithm

1. Obtain simultaneous measurements: serum sodium, potassium, chloride, bicarbonate, creatinine, glucose, morning cortisol, ACTH, and spot urine sodium, chloride, osmolality. 2, 5

2. If cortisol <250 nmol/L with high ACTH: diagnose primary adrenal insufficiency and initiate treatment immediately. 1, 2

3. If cortisol 250-400 nmol/L: perform cosyntropin stimulation test—peak <500 nmol/L confirms adrenal insufficiency. 1, 2

4. If hypokalemia with metabolic alkalosis and elevated urinary chloride: consider Bartter or Gitelman syndrome—check urinary calcium-to-creatinine ratio and magnesium levels. 1, 5

5. If hyponatremia with volume depletion and high urine sodium: consider cerebral salt wasting in context of CNS pathology. 5

6. Screen for associated conditions: thyroid function (TSH, free T4, TPO antibodies), plasma glucose, HbA1c, complete blood count, vitamin B12, and tissue transglutaminase antibodies annually in confirmed adrenal insufficiency. 1

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Key Clinical Pearls

• All patients with confirmed adrenal insufficiency must wear medical alert identification, carry emergency injectable hydrocortisone 100 mg IM kit, and receive stress-dose education. 1, 2
• Postural hypotension reflects insufficient mineralocorticoid therapy and/or low salt intake in treated adrenal insufficiency. 1
• Never rely on electrolyte abnormalities alone—10-20% of adrenal insufficiency patients have normal electrolytes at presentation. 2
• Exogenous steroids (including inhaled fluticasone) suppress the HPA axis and confound diagnostic testing. 1, 2