Can hydrochlorothiazide cause hypercalcemia?

Can Hydrochlorothiazide Cause Hypercalcemia?

Yes, hydrochlorothiazide (HCTZ) can cause hypercalcemia, primarily by increasing renal calcium reabsorption in the proximal tubule, and this effect is particularly pronounced in patients with underlying primary hyperparathyroidism or elevated parathyroid hormone (PTH) levels. 1, 2

Mechanism of Thiazide-Induced Hypercalcemia

HCTZ increases serum calcium through enhanced renal proximal tubular calcium reabsorption, reducing urinary calcium excretion (hypocalciuria). 1, 2 This mechanism operates independently of kidney function—even anuric patients on hemodialysis demonstrate increased serum calcium after HCTZ administration, confirming an extra-renal effect. 3

The calcium-elevating effect appears highly dependent on PTH levels:

• In anuric hemodialysis patients with PTH ≥300 pg/mL, 80% (8 of 10) developed hypercalcemia after HCTZ administration. 3
• In those with PTH <300 pg/mL, only 22% (2 of 9) showed increased calcium (relative risk 3.9, p=0.012). 3
• This suggests PTH acts as a permissive factor for thiazide's calcium-elevating effect. 3

Clinical Significance and Unmasking of Hyperparathyroidism

The most clinically important consequence is that thiazides can unmask or exacerbate underlying primary hyperparathyroidism, converting asymptomatic normocalcemic or intermittently hypercalcemic disease into overt symptomatic hypercalcemia. 2, 4

A case report illustrates this danger: a 68-year-old woman on HCTZ 12.5 mg daily (along with vitamin A 11,000 IU and calcium/vitamin D supplements) presented with severe hypercalcemia (calcium 15.8 mg/dL) and altered mental status, ultimately diagnosed with primary hyperparathyroidism requiring parathyroidectomy. 5 While vitamin A and supplements contributed, HCTZ was a key factor in precipitating the crisis. 5

Prevalence and Pattern of Hypercalcemia

In hypertensive patients on chronic thiazide therapy:

• 36% developed transient, self-limited asymptomatic hypercalcemia at varying periods during 2-12 years of treatment. 6
• These episodes resolved spontaneously within 2-4 weeks despite continued thiazide use. 6
• The hypercalcemia correlated positively with increases in total protein, albumin, and globulin, suggesting a component related to extracellular fluid depletion and hemoconcentration. 6
• Mean total serum calcium was higher in thiazide-treated patients compared to controls, primarily due to increased protein-bound calcium. 6

Monitoring Requirements

The FDA label for hydrochlorothiazide explicitly states that periodic determination of serum electrolytes should be performed, and that calcium excretion is decreased by thiazides. 1 Pathologic changes in the parathyroid glands with hypercalcemia and hypophosphatemia have been observed in patients on prolonged thiazide therapy. 1

Guidelines recommend monitoring serum potassium and calcium levels in patients on thiazide therapy. 7

Diagnostic Considerations

When evaluating hypercalcemia in a patient taking thiazides, distinguishing primary hyperparathyroidism from thiazide effect alone can be challenging. 4 Key considerations:

• Thiazides may make it harder to establish the etiology of hypercalcemia by masking the typical hypercalciuria seen in primary hyperparathyroidism. 4
• Paradoxically, thiazides may help distinguish secondary hyperparathyroidism caused by hypercalciuria from normocalcemic primary hyperparathyroidism in patients with concomitant hyperparathyroidism and hypercalciuria. 4
• Thiazides should be discontinued before performing parathyroid function tests. 1

Therapeutic Use of Thiazide's Calcium Effect

While thiazides can cause hypercalcemia, this same mechanism is therapeutically exploited to reduce urinary calcium excretion in conditions such as idiopathic hypercalciuria, Dent disease, and hypocalcemic hypercalciuria from calcium-sensing receptor mutations. 7 This demonstrates that the calcium-retaining effect is dose-dependent and context-dependent.

Common Pitfalls

• Assuming mild hypercalcemia in a thiazide-treated patient is benign without ruling out underlying hyperparathyroidism. 4, 6 While transient elevations are common, persistent or marked hypercalcemia warrants investigation. 6
• Failing to recognize that even low-dose HCTZ (12.5 mg daily) can precipitate severe hypercalcemia in susceptible patients, particularly those with undiagnosed hyperparathyroidism or on calcium/vitamin D supplements. 5
• Not appreciating that the hypercalcemic effect can occur at any time during chronic therapy, not just at initiation. 6
• Overlooking the contribution of hemoconcentration to measured total calcium—ionized calcium should be checked if there is concern about true hypercalcemia versus protein-bound elevation. 6