Refractory hypercalcaemia of malignancy in hepatocellular carcinoma: A dual humoral mechanism — ASN Events
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Refractory hypercalcaemia of malignancy in hepatocellular carcinoma: A dual humoral mechanism (#443)

Amelia Nielssen 1 2 , Dr Marjy Grealish 1 , Katherine Wright 3 , Ricci Barel 2 4 , Stephanie H. Lim 3 5 6 , Brian Tran 1 7 8
  1. Department of Endocrinology, Macarthur Diabetes Endocrinology Metabolism Services , Campbelltown, NSW, Australia
  2. Department of Medicine, St Vincent's Hospital, Darlinghurst, NSW, Australia
  3. Department of Medical Oncology, Macarthur Cancer Therapy Centre, Campbelltown, NSW, Australia
  4. Macarthur Diabetes Endocrinology Metabolism Services, Campbelltown Hospital, Campbelltown, NSW, Australia
  5. School of Medicine, Western Sydney University, Liverpool Hospital Clinical school, Liverpool, NSW, Australia
  6. Ingham Institute for Applied Medical Research, Liverpool, NSW, Australia
  7. Department of Endocrinology, Nepean Hospital, Sydney, NSW, Australia
  8. Sydney Medical School, University of Sydney, Sydney, NSW, Australia

Hypercalcaemia of malignancy (HCM) affects 10–20% of oncology patients and carries a median survival of 30 days. Parathyroid hormone-related protein (PTHrP)-mediated humoral HCM accounts for most cases, while calcitriol-mediated HCM is rare (1%) and infrequently reported in hepatocellular carcinoma (HCC). A 2025 systematic review identified 17 cases of PTHrP-calcitriol co-mediated HCM, none with HCC. We present a case of refractory HCM with concurrent calcitriol excess and PTHrP secretion.

A 63-year-old male presented with new severe PTH-independent (PTH 1.2 pmol/L) hypercalcaemia (corrected calcium 4.35 mmol/L). CT identified multiple hepatic lesions up to 70mm with portal vein tumour thrombus, osseous metastases, supraclavicular and portacaval lymphadenopathy, consistent with metastatic HCC. AFP was elevated (706 IU/mL). Biopsy was not pursued given classical imaging, AFP and urgent need to initiate treatment with lenvatinib.

Initial management of hypercalcaemia included intravenous fluids and 90mg of pamidronate, alongside a short course of high-dose dexamethasone for liver capsular pain, with calcium rapidly improving and normalising over 6 days. Hypercalcaemia recurred within 2 weeks, requiring zoledronic acid, followed by monthly denosumab for refractory hypercalcaemia. Cinacalcet 30mg was trialled for a suspected PTHrP-mediated component, with significant response, but ceased after 4 days due to gastrointestinal intolerance. Further biochemical workup revealed elevated calcitriol (290 pmol/L; ref 48–190) and PTHrP (34.4 pmol/L; ref <2.5), suggesting possible dual humoral mechanisms. Partial control (corrected calcium 2.8–2.92 mmol/L) was achieved only when prednisolone 30mg daily was added to ongoing aggressive antiresorptive therapy, targeting the calcitriol-mediated component.

This case illustrates a possible dual mechanism of HCM in HCC, with ectopic calcitriol production and PTHrP secretion driving refractory hypercalcaemia. The calcitriol-mediated component was only identified on further workup for bisphosphonate refractory disease, highlighting the value of early comprehensive biochemical phenotyping. Dual mechanisms may coexist and should be a consideration in cases of refractory HCM.