Lithium's Effect on Calcium Metabolism
Lithium therapy increases serum calcium levels and parathyroid hormone (PTH) secretion, leading to hypercalcemia in 10-24% of patients on long-term treatment. 1, 2
Mechanism of Action
Lithium alters the calcium-sensing mechanism of parathyroid cells, making them less sensitive to calcium's normal inhibitory feedback. 3 This results in:
- Shift in the set-point for PTH secretion toward higher calcium values, meaning the parathyroid glands continue secreting PTH despite elevated calcium levels 4
- Decreased urinary calcium excretion through enhanced renal tubular reabsorption 3
- Increased serum calcium concentrations within weeks to months of therapy initiation 3
Time Course of Effects
Short-term exposure (< 6 months):
- Serum ionized calcium increases by 0.03-0.04 mmol/L above normal 4
- 80% of patients show increases in calcium and PTH within the first 4 weeks, though often remaining within normal range 3
Long-term exposure (> 3 years):
- Both intact PTH and midregion PTH levels become significantly elevated 4
- Parathyroid gland volume increases 3-fold compared to non-lithium users 4
- Hypercalcemia develops in 10-24% of patients 1, 3, 2
- Hyperparathyroidism occurs in 8.6% of exposed patients 2
Clinical Monitoring Requirements
Baseline assessment before initiating lithium should include serum calcium levels along with complete blood count, thyroid function tests, urinalysis, blood urea nitrogen, creatinine, and pregnancy testing in females. 5
During maintenance therapy, calcium levels should be monitored every 12-15 months alongside lithium levels, renal function, and thyroid function. 5, 1 This monitoring frequency is critical because:
- Only 12% of lithium patients have calcium checked by their general practitioners in a 15-month period, compared to nearly 100% monitoring rates for TSH and creatinine 1
- A linear relationship exists between duration of lithium exposure and ionized calcium levels 2
Management of Lithium-Associated Hypercalcemia
When hypercalcemia develops in lithium-treated patients, the approach differs from standard hypercalcemia management:
- Do not automatically discontinue lithium if the patient's bipolar disorder is well-controlled and calcium elevation is mild 3
- Investigate for parathyroid adenoma formation through imaging and additional PTH measurements, as lithium may unmask or contribute to adenoma development 6, 3
- Consider parathyroidectomy if parathyroid adenoma is confirmed and hypercalcemia is persistent or symptomatic 6
Important Caveats
The relationship between lithium and parathyroid adenomas remains controversial. While several case reports describe adenomas in lithium-treated patients, it remains unclear whether lithium directly stimulates adenoma formation or simply unmasks pre-existing sporadic adenomas through its effects on calcium homeostasis. 3 However, the documented 3-fold increase in parathyroid volume with long-term therapy suggests a genuine proliferative effect. 4
The biological consequences of chronically elevated PTH in lithium-treated patients include lower serum phosphate, higher serum chloride, and elevated 1,25-dihydroxyvitamin D levels, all consistent with PTH's known biological actions. 4 The long-term skeletal effects and potential acceleration of osteopenia remain areas requiring further investigation. 4