What causes hypercalcemia with elevated amylase and normal lipase levels?

Hypercalcemia with Mildly Elevated Amylase and Normal Lipase

Your patient's calcium of 10.5 mg/dL represents mild hypercalcemia that requires diagnostic workup to identify the underlying cause, while the amylase elevation of 85 U/L (assuming upper limit of normal is ~85) with normal lipase of 24 U/L suggests a non-pancreatic source of amylase elevation rather than acute pancreatitis. 1

Understanding the Clinical Picture

Calcium Level Interpretation

• Calcium 10.5 mg/dL is mildly elevated (normal range typically 8.5-10.2 mg/dL), which is usually asymptomatic but may cause constitutional symptoms like fatigue and constipation in approximately 20% of patients 1
• This level does not require emergency intervention but demands investigation of the underlying cause 1
• You must correct the calcium for albumin using the formula: Corrected calcium (mg/dL) = Total calcium + 0.8 × [4.0 - Serum albumin (g/dL)] to determine the true calcium level 2, 3

Amylase and Lipase Discordance

• Normal lipase with borderline amylase essentially rules out acute pancreatitis as the cause of symptoms, since lipase is more specific for pancreatic injury 4
• Amylase can be elevated from non-pancreatic sources including salivary glands, intestines, fallopian tubes, and certain malignancies 1
• The mild hypercalcemia itself is unlikely to cause pancreatitis at this level—hypercalcemia-induced pancreatitis typically occurs with calcium levels >12-14 mg/dL 5, 4, 6

Diagnostic Workup Algorithm

Step 1: Measure Intact PTH Immediately

• PTH is the single most important test to distinguish PTH-dependent from PTH-independent causes 1
• Elevated or inappropriately normal PTH (>20 pg/mL) indicates primary hyperparathyroidism, which accounts for approximately 45% of all hypercalcemia cases 1, 3
• Suppressed PTH (<20 pg/mL) indicates malignancy, granulomatous disease, vitamin D intoxication, or medication-related causes 1, 3

Step 2: Additional Laboratory Tests

• Measure 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D together—their relationship provides critical diagnostic information 3
• Check PTHrP if PTH is suppressed, as this suggests malignancy-associated hypercalcemia 3
• Obtain phosphorus level: high-normal or elevated suggests primary hyperparathyroidism, while low suggests malignancy 1
• Assess renal function (creatinine, BUN) as hypercalcemia can cause renal impairment 7

Step 3: Medication and Supplement Review

• Specifically ask about thiazide diuretics, lithium, calcium supplements (>500 mg/day), vitamin D supplements (>400 IU/day), and vitamin A intake 3
• Inquire about over-the-counter supplements, as vitamin D intoxication can cause hypercalcemia with elevated amylase 5
• Review for SGLT2 inhibitors, immune checkpoint inhibitors, or recent denosumab discontinuation 1

Most Likely Etiologies in This Context

Primary Hyperparathyroidism (Most Common)

• Accounts for ~90% of outpatient hypercalcemia cases when combined with malignancy 1
• Characterized by elevated or inappropriately normal PTH with hypercalcemia 3
• Typically presents with mild, asymptomatic hypercalcemia discovered incidentally 1
• The amylase elevation is coincidental or from a non-pancreatic source 1

Malignancy (Second Most Common)

• More likely if PTH is suppressed and PTHrP is elevated 3
• Associated with poor prognosis (median survival ~1 month if symptomatic) 7, 3
• Usually presents with more severe hypercalcemia (>12 mg/dL) 1

Vitamin D Intoxication

• Can cause both hypercalcemia and elevated amylase through recurrent subclinical pancreatic inflammation 5
• Diagnosed by markedly elevated 25-hydroxyvitamin D (>150 ng/mL, often >300 ng/mL) 5
• Requires specific questioning about supplement use, as patients may not volunteer this information 5

Critical Pitfalls to Avoid

• Do not assume pancreatitis based on amylase alone—lipase is far more specific and is normal in this case 4
• Do not order parathyroid imaging before confirming biochemical diagnosis with PTH—imaging is for surgical planning, not diagnosis 3
• Do not rely on corrected calcium formulas if albumin is abnormal—measure ionized calcium directly to avoid pseudo-hypercalcemia 7, 3
• Do not miss medication-induced causes—thiazides and excessive calcium/vitamin D supplementation are easily reversible 3, 1

Management Based on Etiology

If Primary Hyperparathyroidism is Confirmed

• Refer to endocrinology and experienced parathyroid surgeon for evaluation 3
• Surgical indications include: corrected calcium >1 mg/dL above upper limit of normal, age <50 years, impaired kidney function (GFR <60 mL/min), osteoporosis, or history of nephrolithiasis 3, 1
• If patient is >50 years with calcium <1 mg/dL above normal and no end-organ damage, observation with monitoring every 3 months is appropriate 1, 3

If PTH-Independent Cause

• Immediately discontinue all calcium supplements, vitamin D, and thiazide diuretics 3
• Ensure adequate oral hydration (2-3 liters daily if tolerated) 7
• Treat underlying cause: glucocorticoids for granulomatous disease or vitamin D intoxication, oncologic treatment for malignancy 7, 1