Introduction: Humoral hypercalcemia of malignancy driven by PTHrP is a syndrome frequently associated with squamous cell carcinoma. We present a case of humoral hypercalcemia as a rare manifestation of hepatocellular carcinoma and describe the impact of early diagnosis on patient care.
Case Description/Methods: A 67-year-old male with HCC presented to the emergency department with subacute confusion, constipation, and lower extremity weakness. Physical exam revealed tangential thinking and no asterixis. Serum calcium was 14.8 (corrected to 15.3), creatinine 1.36 (baseline 0.8), AST 141, ALT 32, and AFP 135 (all previously normal). Imaging revealed new liver lesions in multiple segments, enlarged lymph nodes in the porta hepatis, widespread lytic lesions in the spine, calvarium, and facial bones with a 3.4 cm x 2.4 cm left orbital wall mass consistent with metastatic disease. Serum calcium levels normalized with IV fluids, calcitonin, and zolendronic acid. The PTHrP was elevated at 79. Vitamin D levels, SPEP and UPEP were normal. He returned one week later with recurrent severe hypercalcemia. No further cancer treatment options were available so the patient elected for hospice services and died at home.
Discussion: Malignancy is the most common cause of hypercalcemia in the inpatient setting. Malignancy-associated hypercalcemia occurs through three distinct mechanisms – humoral (PTHrP mediated), lytic bone lesions, and increased absorption due to excess 1,25 vitamin D production by the cancer.
Most cases of HCC-associated hypercalcemia are due to metastatic lytic bone lesions. Less than 10% of cases are attributable to PTHrP, which is severe and often refractory. The mechanism for this is unknown but may be related to an underlying paraneoplastic syndrome and downstream metabolic derangements.
Humoral hypercalcemia in patients with HCC is associated with a more advanced TNM stage and higher tumor burden. In a study of 534 patients with HCC, 6.3% had humoral hypercalcemia and had worse prognoses by Child-Pugh scores. Another study of 165 patients with HCC and PTHrP-mediated hypercalcemia found a median survival time of 15 days. Early recognition of humoral hypercalcemia in patients with HCC is essential given its association with higher mortality. Doing so can help providers expedite locoregional therapy or guide goals of care discussions with their patients.
