Humoral Hypercalcaemia in Metastatic Gallbladder Cancer Presenting as Delirium: A Case Report.

INTRODUCTION

Hypercalcaemia of malignancy (HCM) is most commonly associated with squamous cell carcinomas of the head and neck, oesophagus and cervix, as well as certain other solid tumours. [ 1 ] Humoral hypercalcaemia of malignancy (HHM) is a major contributor to hypercalcaemia in cancer patients and is caused by paraneoplastic secretion of parathyroid hormone-related protein (PTHrp).

Ever since Albright’s initial description of PTHrp in 1941, its role in mediating the phenomenon of HHM through PTHrp receptors and its numerous paracrine actions has been studied extensively. [ 2 ]

PTHrP increases the expression of receptor activator of nuclear factor-κB ligand (RANKL) on osteoblasts, which binds with RANK receptors on the osteoclast, activating them and promoting bone resorption, causing hypercalcaemia. Hypercalcaemia is defined as a serum calcium concentration >10.5 mg/dL.

It presents with a constellation of symptoms ranging from fatigue, cognitive decline and low mood to severe manifestations such as seizures and coma. Known complications include posterior reversible encephalopathy syndrome, renal failure, pancreatitis, peptic ulcer disease and ventricular arrhythmias. Gall bladder carcinoma (GBC) is known for its aggressive course and late-stage presentation. GBCs are conventionally associated with poor response to treatment and dismal prognosis. HCM in metastatic gall bladder cancer is an exceedingly rare and unsuspected manifestation. HHM is associated with advanced disease and poor prognosis, particularly when severe hypercalcaemia is not promptly recognised and treated.

However, if identified promptly and managed symptomatically, it can improve the patients’ quality of life. This case report highlights the importance of screening for HHM in patients with metastatic gall bladder cancer presenting with delirium.

CASE REPORT

A male in his 50s with metastatic gallbladder adenocarcinoma, who was not receiving cancer-directed therapy, presented to the palliative medicine outpatient department with abdominal pain, constipation, fatigue, behavioural changes and disturbed sleep for 2 days. He additionally reported irritability, low mood, slowing of responses and mild headache, with no associated vomiting or seizures. There was no recent use of opioids or benzodiazepines, and no symptoms suggestive of infection, including fever, cough or urinary complaints.

He had initially presented to the medical oncology department with complaints of abdominal pain, vomiting and weight loss for 20 days. Further evaluation established the diagnosis of gallbladder adenocarcinoma with hepatic and nodal metastases. Following multidisciplinary discussion, the patient was deemed unsuitable for disease-directed therapy and best supportive palliative care was initiated.

On examination, vital signs were stable. The patient was conscious and initially oriented, with a Karnofsky Performance Status (KPS) of 90 and a Richmond Agitation– Sedation Scale score of 0. There was no evidence of dehydration, as indicated by the absence of dry oral mucous membranes, a dry tongue or reduced skin turgor. However, he demonstrated fluctuating attention and cognitive disturbances.

Screening with the Confusion Assessment Method (CAM), followed by application of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria, confirmed the diagnosis of delirium. A systematic work-up was undertaken to evaluate reversible metabolic and infectious causes. Complete blood count, along with renal, liver function tests and serum electrolytes, was performed. The corrected serum calcium was 18.92 mg/dL (reference range 8.5–10.5 mg/dL), with accompanying QT interval and ST-segment shortening on electrocardiography, findings consistent with severe hypercalcaemia. To determine the underlying aetiology, serum PTH and PTHrP levels were measured. PTH was suppressed at 7.83 pg/mL (reference range 15–65 pg/mL), whereas PTHrP was elevated at 701.3 pg/mL (reference range <550 pg/mL, assay dependent). This biochemical profile of suppressed PTH with elevated PTHrP was diagnostic of humoral hypercalcaemia of malignancy. The patient’s laboratory investigations at presentation are summarised in Table 1 .

Based on the history and investigations, a broad differential diagnosis was considered, including metabolic causes such as hypercalcaemia and primary hyperparathyroidism, systemic infections, dehydration, drug-induced causes, cerebrovascular accident and brain metastases. The biochemical profile of severe hypercalcaemia with suppressed PTH and elevated PTHrP confirmed humoral hypercalcaemia of malignancy as the underlying cause of hypoactive delirium.

A collaborative approach with the medical oncology team helped optimise medication selection. We initiated intravenous hydration with 3 L of 0.9% sodium chloride at 250 mL/h. Given the patient’s elevated serum creatinine at presentation, a reduced dose of intravenous zoledronic acid (3.3 mg administered over 15 min in normal saline) was selected after considering the potential risk of renal toxicity, along with subcutaneous calcitonin (200 IU) 3 times daily for 2 days.

Within 12 h of initiating acute care, there was improvement in his attention, orientation and overall alertness. While his KPS remained at 90, he reported feeling better.

Once his symptoms stabilised, we were able to conduct a more comprehensive assessment addressing his psychosocial and spiritual concerns.

Our multidisciplinary team explored his psychological, emotional and spiritual well-being. The patient wished to return home to be with his family. He shared that he had faith in God and believed this episode was a test of his strength. Our medical social worker engaged with him to address financial concerns and provided emotional support.

Goals of care were discussed with the patient and family, and the preferred place of care was determined. We facilitated a smooth transition by providing contacts for local palliative care physicians through our referral network and advised liaison with a general practitioner for ongoing symptomatic support.

As the patient was discharged to his hometown, we followed up with him telephonically.

We did a day 2 telephone follow-up in which he was comfortable and able to carry out self-care activities. At the 2-week follow-up, there was not much deterioration in his performance status, no new onset episodes of delirium and his serum calcium remained within normal limits. At the 1-month follow-up, his KPS had improved to 100. At the 3-month follow-up, the patient contracted a lower respiratory tract infection, for which he was admitted to a local hospital and started on intravenous antibiotics; his serum calcium levels were still within normal limits. He subsequently became oxygen-dependent and died from pneumonia. Furthermore, his son expressed gratitude to the team for compassionate communication, medical management, advice and emotional support. He stated, The patient’s son expressed gratitude to the team, stating that the team’s availability had made a significant difference and increased the family’s confidence in making decisions during a difficult period.

DISCUSSION

Delirium is an acute neuropsychiatric syndrome characterised by a disturbance in attention and awareness, with impairment in cognition, such as memory, orientation, language, visuospatial ability or perception. According to the DSM-5, the disturbance develops over a short period, with a change from baseline, fluctuates during the day and cannot be better explained by another pre-existing neurocognitive disorder.

Delirium remains frequently under-recognised and underdiagnosed, particularly in patients with advanced cancer. The prevalence among patients with advanced metastatic cancer ranges from 35% to 45% in hospitalised palliative care populations and increases markedly in the final days of life, affecting approximately 85% to 90% of actively dying patients. [ 3 ] HCM is a well-recognised oncologic emergency occurring in up to 30% of patients with advanced cancer, most frequently in solid tumours of the lung, kidney, head and neck and breast. Among haematologic malignancies, multiple myeloma shows the highest prevalence (7–10%). [ 4 , 5 ]

Four principal mechanisms underlie malignancy-related hypercalcaemia: secretion of PTHrP in about 80% of cases, osteolytic metastases in around 20%, ectopic calcitriol production and rarely ectopic PTH secretion. HHM is typically characterised by suppressed PTH, elevated PTHrP and the absence of a primary osteolytic mechanism. [ 6 ] At a cellular level, PTHrP stimulates osteoclastic bone resorption via RANKL-RANK signalling, facilitated by down-regulation of osteoprotegerin. The resulting increase in calcium release from bone, augmented by renal reabsorption and intestinal absorption, sustains hypercalcaemia.

Severe hypercalcaemia is uncommon in gastrointestinal malignancies but has been reported in metastatic colorectal, pancreatic and hepatocellular carcinomas. [ 7 , 8 ]

GBC is a rare malignancy, with an incidence of only 1–2 cases/100,000 persons in the United States and a reported overall survival rate below 5%. Paraneoplastic HHM in GBC is exceptionally rare, with only a limited number of biochemically confirmed PTHrP-mediated cases have been reported. [ 9 - 11 ] Our case adds to this limited literature and highlights the importance of considering HHM even in rare tumours when patients present with neuropsychiatric symptoms or unexplained hypercalcaemia.

When evaluating hypercalcaemia, the initial diagnostic step is measurement of serum PTH to distinguish PTH-mediated from non-PTH-mediated causes. A suppressed PTH level excludes primary hyperparathyroidism and directs further evaluation toward HCM. Measurement of PTHrP and calcitriol subsequently helps differentiate humoral hypercalcaemia of malignancy from calcitriol-mediated hypercalcaemia, such as that seen in lymphoma.

Management follows general principles outlined by the Endocrine Society: intravenous hydration to correct volume depletion and enhance renal calcium clearance, transient control with calcitonin in severe cases and longer-term suppression of bone resorption with intravenous bisphosphonates such as zoledronic acid. [ 12 , 13 ]

Denosumab is an effective alternative, particularly in refractory cases or when renal impairment limits bisphosphonate use. The primary goals are correction of hypercalcaemia, relief of symptoms and prevention of acute complications, with treatment decisions guided by prognosis and goals of care. Bisphosphonates remain the cornerstone of therapy. Zoledronic acid begins lowering calcium within 48 h, achieving maximal effect by days 4–7. Calcitonin provides a rapid yet transient response (onset 4–8 h, peak 12–24 h) and is generally used in combination due to tachyphylaxis developing within 48–72 h. Despite therapeutic options, refractory hypercalcaemia usually indicates advanced, treatment-resistant disease. Median survival after onset of malignancy-associated hypercalcaemia is 54 days; persistence despite bisphosphonates is a poor prognostic indicator. In such scenarios, management should align with the goals of care. Correction of hypercalcaemia may provide symptomatic benefit but does not necessarily alter the underlying disease trajectory, particularly in advanced malignancy. [ 13 ]

CONCLUSION

HHM secondary to GBC remains exceptionally rare but clinically important. Early recognition of delirium and appropriate evaluation for reversible metabolic causes, enables timely intervention, symptom relief and improved quality of life even when definitive cancer therapy is not feasible. The case reinforces that in palliative oncology, metabolic emergencies such as hypercalcaemia should be approached with both diagnostic precision and a patient-centred focus on comfort.

Acknowledgement:

We would like to thank our department and colleagues for their support in the management of this case.

Funding Statement

Financial support and sponsorship: Nil.

Footnotes

How to cite this article: Ajithkumar A, Poojary S, Deodhar J, Thota RS. Humoral Hypercalcaemia in Metastatic Gallbladder Cancer Presenting as Delirium: A Case Report. Indian J Palliat Care. 2026;32:328-31. doi: 10.25259/IJPC_150_2026

Ethical approval:

Institutional Review Board approval is not required.

Declaration of patient consent:

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given consent for clinical information to be reported in the journal. The patient understands that the patient’s names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Conflicts of interest:

Dr. Raghu S Thota is the editor of Indian Journal of Palliative Care.

Use of artificial intelligence (AI)-assisted technology for manuscript preparation:

The authors confirm that they have used artificial intelligence (AI)-assisted technology for language refinement and clarity of expression.

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