How does lithium therapy affect serum sodium, calcium, potassium, and magnesium, especially in patients presenting with lithium toxicity?

Lithium's Effects on Electrolytes

Lithium therapy primarily disrupts sodium and water homeostasis through nephrogenic diabetes insipidus, while also impairing calcium and magnesium reabsorption, particularly in the setting of lithium toxicity.

Sodium and Water Dysregulation

Lithium causes nephrogenic diabetes insipidus (NDI) in up to 40% of patients, characterized by polyuria and polydipsia that develop within weeks of initiation 1. The mechanism involves lithium entering principal cells of the collecting duct via epithelial sodium channels (ENaC), accumulating to cytotoxic concentrations that inhibit aquaporin-2 (AQP2) expression and function 1. This results in:

• Increased water and sodium diuresis leading to mild dehydration 1
• Hypernatremia risk, particularly in patients with established NDI who develop intercurrent illness 2
• Elevated urinary sodium excretion that persists during chronic therapy 3

The concentrating defect is dose-dependent and can progress to severe polyuria (>4 L/day) with chronic use 4. Amiloride, an ENaC inhibitor, has demonstrated efficacy in treating lithium-induced NDI by blocking lithium entry into collecting duct cells 1.

Calcium Metabolism Disruption

Lithium directly impairs parathyroid hormone (PTH)-mediated renal calcium reabsorption, leading to:

• Increased urinary calcium excretion (fractional excretion rising from 2.2% to 3.5%) 5
• Compensatory hyperparathyroidism developing as a consequence of reduced renal calcium conservation 5
• Dose-dependent inhibition that can be partially overcome with supramaximal PTH concentrations 5

This effect occurs acutely with lithium administration and contributes to the hyperparathyroidism commonly observed in patients on chronic lithium therapy 5.

Magnesium Depletion

Lithium similarly inhibits PTH-mediated magnesium reabsorption in the kidney, resulting in:

• Elevated urinary magnesium losses (fractional excretion increasing from 12% to 18%) 5
• Hypomagnesemia that frequently coexists with other electrolyte disturbances 6, 7
• Impaired response to PTH that parallels the calcium reabsorption defect 5

Hypomagnesemia must be corrected before attempting potassium repletion, as magnesium deficiency makes hypokalemia resistant to treatment 6.

Potassium Disturbances

While lithium itself causes increased urinary potassium excretion 1, 3, the clinical significance depends on concurrent factors:

• Direct lithium effect: Acute administration increases potassium excretion through enhanced distal sodium delivery 1
• Diuretic interaction: Loop and thiazide diuretics markedly amplify potassium wasting when combined with lithium 6, 7
• RAAS activation: The natriuretic effect of lithium triggers secondary aldosterone stimulation, further promoting potassium loss 6

Patients on lithium should have electrolytes and lithium levels monitored every 6 months or more frequently if dose changes or acute illness occurs 8.

Acid-Base Abnormalities

Lithium toxicity produces hyperchloremic metabolic acidosis and renal tubular acidosis through impaired distal tubular function 1. This occurs alongside the concentrating defect and contributes to the overall electrolyte derangement.

Clinical Monitoring Recommendations

Regular monitoring of GFR, electrolytes (sodium, potassium, calcium, magnesium), and lithium levels is mandatory 8. The KDOQI guideline specifically recommends:

• Baseline assessment before initiating therapy 8
• Every 6 months during stable therapy 8
• More frequently with dose adjustments, intercurrent illness, or signs of toxicity 8

Lithium should be temporarily discontinued during serious intercurrent illness in patients with GFR <60 mL/min/1.73 m² due to increased acute kidney injury risk 8.

Critical Drug Interactions

NSAIDs are absolutely contraindicated with lithium therapy, as they reduce renal clearance and dramatically increase lithium toxicity risk 8. Maintain adequate hydration during intercurrent illness to prevent lithium accumulation 8.

Concomitant ACE inhibitors or potassium-sparing diuretics can help prevent electrolyte depletion from lithium's natriuretic effects, though careful monitoring remains essential 6, 7.

Lithium Toxicity Presentation

In the setting of lithium toxicity, expect:

• Severe hypernatremia (>150 mmol/L) with profound polyuria 2
• Hypercalcemia and hypomagnesemia from impaired renal reabsorption 5
• Metabolic acidosis with elevated chloride 1
• Hypokalemia if concurrent diuretic use or volume depletion 6, 7

Lithium toxicity is closely related to serum concentrations and can occur at doses near therapeutic levels, necessitating access to prompt serum lithium determination before initiating therapy 8.