How to manage lithium-induced hypercalcemia?

Management of Lithium-Induced Hypercalcemia

Initial Assessment and Diagnosis

The first step is to confirm true hypercalcemia by measuring ionized calcium or correcting for albumin, and simultaneously measure intact parathyroid hormone (iPTH) to establish the diagnosis of lithium-induced hyperparathyroidism. 1

• Lithium-induced hypercalcemia occurs in 10-60% of patients on long-term lithium therapy and is frequently associated with elevated PTH levels 2
• Measure serum calcium, albumin, phosphorus, iPTH, and 25-hydroxyvitamin D to characterize the hypercalcemia 1
• Assess for symptoms including polyuria, polydipsia, nausea, confusion, fatigue, and abdominal pain 1
• Note that urinary calcium excretion is typically low (hypocalciuria) in lithium-induced hyperparathyroidism, distinguishing it from typical primary hyperparathyroidism 3

Treatment Algorithm

Step 1: Discontinue Lithium (First-Line Approach)

For patients with lithium-induced hypercalcemia, discontinuation of lithium should be attempted first, as this may reverse the hypercalcemia in some cases. 4

• Work with psychiatry to transition to alternative mood stabilizers, preferably anticonvulsants such as valproate or carbamazepine 5
• Monitor serum calcium and iPTH levels at 2-4 weeks and 2-3 months after lithium discontinuation 4
• Be aware that hypercalcemia may not resolve after lithium cessation in many patients, particularly those with established parathyroid adenomas 4, 5

Step 2: Acute Hypercalcemia Management (If Symptomatic or Severe)

If calcium is >12 mg/dL or patient is symptomatic, initiate acute treatment while addressing the underlying cause:

• Hydration: Administer IV normal saline to correct hypovolemia and promote calciuresis, maintaining urine output of at least 100 mL/hour 1
• Loop diuretics: Use furosemide in patients with renal or cardiac insufficiency to prevent fluid overload 1
• Bisphosphonates: Administer IV zoledronic acid 4 mg as first-line therapy for moderate to severe hypercalcemia 1
• Calcitonin: Consider calcitonin-salmon 100 IU subcutaneously or intramuscularly as a bridge until bisphosphonates take effect 1

Step 3: Medical Management with Cinacalcet (If Lithium Cannot Be Stopped)

For patients who cannot discontinue lithium due to psychiatric necessity, cinacalcet hydrochloride provides an effective nonsurgical alternative to normalize calcium and reduce PTH secretion. 3

• Start cinacalcet 30 mg daily and titrate up to 60 mg daily based on response 3
• This approach successfully normalized serum calcium (from 10.8-11.0 mg/dL to 9.9-10.3 mg/dL) and reduced iPTH levels in patients with 15-30 years of lithium therapy 3
• Monitor serum calcium and iPTH every 2-4 weeks during dose titration 3
• Continue lithium therapy with close monitoring if psychiatric condition requires it 3

Step 4: Surgical Management (Parathyroidectomy)

Parathyroidectomy is indicated when hypercalcemia persists despite lithium discontinuation or when medical management fails. 4, 5

• Consider surgery for persistent hypercalcemia (>10.5 mg/dL) 2-3 months after lithium cessation 4, 5
• Pre-operative imaging with sestamibi scan is recommended to localize adenomas 5
• Be aware that multiple parathyroid adenomas occur more commonly in lithium-induced hyperparathyroidism than in typical primary hyperparathyroidism 6
• Parathyroidectomy is definitive treatment, with normalization of calcium levels post-operatively 5

Ongoing Monitoring

• All patients on lithium should have serum calcium checked every 15 months along with creatinine and TSH 2
• For patients continuing lithium after hypercalcemia diagnosis, monitor calcium and iPTH every 3-6 months 4
• Monitor for recurrence of hypercalcemia even after parathyroidectomy if lithium is restarted 6

Critical Clinical Pitfalls

• Do not assume hypercalcemia will resolve with lithium discontinuation alone—many patients develop irreversible hyperparathyroidism requiring surgery 4, 5
• Avoid delaying treatment in symptomatic patients while waiting for lithium cessation to take effect 1
• Do not overlook the possibility of multiple parathyroid adenomas, which are more common in lithium-induced disease 6
• The decision to continue lithium must balance psychiatric stability against metabolic complications, requiring close collaboration with psychiatry 4