Unexplained Weight Loss and Hypercalcaemia
A 60-year-old woman presents with a 6-month history of fatigue, constipation, and 8 kg weight loss. She has a history of hypertension and takes hydrochlorothiazide. Physical examination is unremarkable. Laboratory results: corrected calcium 3.1 mmol/L (reference 2.2–2.6), phosphate 0.7 mmol/L (reference 0.8–1.4), alkaline phosphatase 150 U/L (reference 30–130), creatinine 110 µmol/L (reference 60–110), and parathyroid hormone (PTH) 2.0 pmol/L (reference 1.6–6.9). A 24-hour urinary calcium is 8 mmol (reference 2.5–7.5). Serum protein electrophoresis shows a small IgG lambda paraprotein, and free light chain ratio is normal. A chest X-ray is normal. The patient is anxious about a diagnosis of cancer.
1. Interpret the calcium, phosphate, PTH, and urinary calcium results, and generate a differential diagnosis.
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The patient has hypercalcaemia with low phosphate, low-normal PTH, and elevated urinary calcium. In primary hyperparathyroidism, PTH would be elevated or inappropriately normal, and urinary calcium is usually normal or high. Here PTH is low, which points to a non-parathyroid cause. The low phosphate suggests increased renal phosphate wasting, which can occur in malignancy-associated hypercalcaemia due to PTHrP or in vitamin D-mediated hypercalcaemia. However, vitamin D intoxication usually causes high phosphate. Malignancy is a strong consideration: PTHrP secretion by a solid tumour (e.g., squamous cell lung cancer, renal cell carcinoma, or head and neck cancer) causes hypercalcaemia, low phosphate, and suppressed PTH. Multiple myeloma can cause hypercalcaemia, but the paraprotein is small and the free light chain ratio is normal, making myeloma less likely, though a bone marrow biopsy could be considered. Other causes include granulomatous disease (e.g., sarcoidosis) and thiazide use, which reduces urinary calcium excretion and can unmask hypercalcaemia. The judgement is to recognise that the combination of low PTH and low phosphate strongly suggests a PTHrP-mediated process, and that malignancy must be excluded even with a normal chest X-ray.
2. What further investigations would you order, and how would you manage the hypercalcaemia acutely?
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Further investigations should include a CT scan of the chest, abdomen, and pelvis to look for occult malignancy; measurement of PTHrP; serum angiotensin-converting enzyme and a chest CT for sarcoidosis; and a bone marrow biopsy if myeloma remains a concern despite the normal light chain ratio. A 24-hour urinary calcium is already elevated, which argues against familial hypocalciuric hypercalcaemia. Acutely, the patient should be rehydrated with intravenous normal saline (e.g., 2–4 L over 24 hours) to restore volume and promote calcium excretion. Loop diuretics should be avoided unless there is volume overload after rehydration, because they can worsen dehydration. Bisphosphonates (e.g., zoledronic acid) are the mainstay for malignancy-associated hypercalcaemia; they inhibit osteoclast activity and take 2–4 days to work. Calcitonin can be used for rapid but transient reduction. Glucocorticoids are useful if the cause is granulomatous disease or lymphoma. The judgement is to prioritise volume repletion and bisphosphonate therapy while investigating the underlying cause, and to avoid thiazides, which worsen hypercalcaemia.