What is the appropriate work‑up for mild hypercalcemia with elevated aspartate aminotransferase and alanine aminotransferase and a high albumin level?

Work-Up for Mild Hypercalcemia with Elevated Transaminases and High Albumin

The first step is to confirm true hypercalcemia by correcting for the elevated albumin (5.5 g/dL), which will likely reveal a normal or only minimally elevated calcium level, making extensive hypercalcemia work-up potentially unnecessary. 1

Correct the Calcium for Albumin

Using the standard correction formula: Corrected calcium (mg/dL) = Total calcium (mg/dL) + 0.8 × [4 – Serum albumin (g/dL)], your patient's corrected calcium = 10.4 + 0.8 × [4 – 5.5] = 9.2 mg/dL, which is normal. 1

• The albumin of 5.5 g/dL is significantly elevated and suggests hemoconcentration, dehydration, or a paraproteinemia rather than true hypercalcemia. 1
• If the corrected calcium is normal (<10.5 mg/dL), no hypercalcemia work-up is needed; instead, focus on the elevated transaminases and high albumin. 2, 3

If Corrected Calcium Remains Elevated (>10.5 mg/dL)

Measure Intact PTH Immediately

• PTH is the single most important test to distinguish PTH-dependent (primary hyperparathyroidism) from PTH-independent causes (malignancy, granulomatous disease, medications). 2, 3
• Elevated or normal PTH (≥20 pg/mL) indicates primary hyperparathyroidism. 2, 3
• Suppressed PTH (<20 pg/mL) points to malignancy, granulomatous disease (sarcoidosis), vitamin D intoxication, or medications. 2, 4, 3

Additional Initial Laboratory Tests

• 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D: Elevated 1,25-OH vitamin D with suppressed PTH suggests granulomatous disease (sarcoidosis, tuberculosis) or lymphoma. 4
• Serum protein electrophoresis (SPEP) with immunofixation: The high albumin (5.5 g/dL) raises concern for a paraproteinemia; SPEP screens for multiple myeloma, which causes 10–15% of malignancy-related hypercalcemia. 2, 3
• Phosphate level: Hypophosphatemia occurs in primary hyperparathyroidism; normal or elevated phosphate suggests malignancy or vitamin D intoxication. 2
• Alkaline phosphatase: Can be elevated in bone metastases, Paget's disease, or primary hyperparathyroidism with bone involvement. 2

Imaging Studies

• Chest X-ray: Essential to screen for sarcoidosis (hilar lymphadenopathy), lung malignancy, or tuberculosis if PTH is suppressed. 4
• Abdominal ultrasound or CT: Evaluate for renal calculi (common in primary hyperparathyroidism) and assess liver parenchyma given the elevated transaminases. 2

Evaluate the Elevated Transaminases (AST 65, ALT 98)

Calculate the AST/ALT Ratio and Assess Severity

• AST/ALT ratio = 65/98 = 0.66, which is **<1** and suggests nonalcoholic fatty liver disease (NAFLD), viral hepatitis, or medication-induced liver injury rather than alcoholic liver disease (which typically shows AST/ALT >2). 5
• ALT 98 U/L is approximately 2–3× the upper limit of normal for women (ULN ≈25 IU/L) or 2× ULN for men (ULN ≈33 IU/L), representing mild elevation (<5× ULN). 5

Obtain a Complete Liver Panel

• AST, ALT, alkaline phosphatase, GGT, total and direct bilirubin, albumin, PT/INR: Your patient's albumin is already known to be elevated (5.5 g/dL), which is atypical for chronic liver disease and suggests hemoconcentration or paraproteinemia. 5
• Viral hepatitis serologies (HBsAg, anti-HBc IgM, anti-HCV): Essential to exclude chronic viral hepatitis as a cause of transaminase elevation. 5

Assess for Metabolic Syndrome and NAFLD

• Fasting glucose or HbA1c, fasting lipid panel: NAFLD is the most common cause of elevated transaminases in patients with metabolic risk factors (obesity, diabetes, hypertension, dyslipidemia). 5
• Calculate the FIB-4 score using age, ALT, AST, and platelet count to stratify risk for advanced fibrosis; a score >2.67 warrants hepatology referral. 5

Medication Review

• Review all prescription drugs, over-the-counter medications, and herbal supplements for hepatotoxic potential; medication-induced liver injury causes 8–11% of cases with mildly elevated transaminases. 5

Abdominal Ultrasound

• First-line imaging to detect hepatic steatosis (sensitivity 84.8%, specificity 93.6% for moderate-to-severe steatosis), biliary obstruction, or focal liver lesions. 5

Investigate the High Albumin (5.5 g/dL)

Causes of Elevated Albumin

• Dehydration/hemoconcentration: The most common cause; check for clinical signs of volume depletion. 1
• Paraproteinemia: Multiple myeloma or monoclonal gammopathy can falsely elevate total protein and albumin; SPEP with immunofixation is mandatory. 2, 3

Repeat Albumin After Rehydration

• If dehydration is present, rehydrate the patient and repeat calcium, albumin, and liver enzymes in 2–4 weeks to determine if abnormalities persist. 5

Common Pitfalls to Avoid

• Do not pursue extensive hypercalcemia work-up without first correcting calcium for albumin; failure to do so leads to unnecessary testing and misdiagnosis. 1, 2
• Do not assume mild transaminase elevations are benign; even modest increases can reflect significant pathology, especially in women whose normal ALT range is lower. 5
• Do not overlook multiple myeloma in a patient with "hypercalcemia" and high albumin; SPEP is essential. 2, 3
• Do not delay PTH measurement if corrected calcium is truly elevated; PTH is the single most important test to guide further evaluation. 2, 3

Monitoring and Follow-Up

• If corrected calcium is normal: Repeat liver enzymes in 2–4 weeks to establish a trend; if ALT increases to ≥3× ULN or doubles from baseline, intensify the diagnostic evaluation. 5
• If corrected calcium remains elevated: Proceed with PTH-guided work-up as outlined above; refer to endocrinology if primary hyperparathyroidism is confirmed or if PTH-independent hypercalcemia remains unexplained after initial testing. 2, 3
• If SPEP reveals a monoclonal protein: Refer to hematology for evaluation of multiple myeloma or monoclonal gammopathy of undetermined significance (MGUS). 2, 3