Hypercalcaemia — causes, evaluation and management, including PTH-independent hypercalcaemia

Definition and thresholds. Hypercalcaemia is defined by an elevation of calcium above 10.6 mg/dL, and values above 11.0 mg/dL should be considered an indication to initiate treatment. This threshold applies only when the albumin level is normal. If there is any doubt about the validity of the total serum calcium, measuring ionised calcium or calculating the albumin-adjusted calcium is essential. Correction: add 0.8 mg/dL to the measured calcium for every 1 g/dL fall in albumin below 4 g/dL — vital in the malnourished older patient, in whom true hypercalcaemia is otherwise missed.

Two causes account for 90%. Primary hyperparathyroidism — the commonest cause in outpatients, typically detected incidentally on routine biochemistry, and PTH-dependent. Malignancy — the commonest cause in hospital inpatients, usually with the cancer already overt, and PTH-independent. Other PTH-dependent causes: tertiary hyperparathyroidism in long-standing CKD, lithium, and familial hypocalciuric hypercalcaemia.

PTH-independent causes — the part of the question most often under-answered. (a) Malignancy by three mechanisms: humoral hypercalcaemia via PTHrP (squamous carcinoma of lung and head and neck, renal, bladder, ovarian), osteolytic metastases and local cytokines (breast cancer, multiple myeloma), and excess 1,25-dihydroxyvitamin D production by lymphoma. (b) Granulomatous disease with extrarenal 1α-hydroxylase activity — sarcoidosis and tuberculosis (the latter of major importance in India), plus fungal infection. (c) Drugs — thiazides, lithium, vitamin D or vitamin A toxicity, calcium-alkali (milk–alkali) syndrome from over-the-counter antacids and supplements, teriparatide, and tamoxifen flare. (d) Endocrine — thyrotoxicosis, adrenal insufficiency, phaeochromocytoma, acromegaly. (e) Immobilisation in a patient with high bone turnover — Paget's disease, myeloma, recent fracture — highly relevant in the bed-bound older patient. (f) Recovery phase of rhabdomyolysis-associated AKI, and parenteral nutrition.

Clinical features and the geriatric presentation. The classical formulation is "bones, stones, abdominal groans and psychic moans" — bone pain and fracture; renal stones, nephrocalcinosis and nephrogenic diabetes insipidus with polyuria, dehydration and prerenal AKI; gastrointestinal anorexia, nausea, vomiting, constipation, peptic ulceration and pancreatitis; neuropsychiatric fatigue, depression, confusion, stupor and coma. In the older adult the presentation is typically delirium, constipation, dehydration and falls, and it is routinely misattributed to dementia, infection or drugs. The ECG shows a short QT interval. Serum calcium belongs in the confusion screen of every older patient.

Evaluation — one measurement decides the whole pathway. Confirm with an albumin-adjusted or ionised calcium, then measure intact PTH. If PTH is high or inappropriately normal, the hypercalcaemia is PTH-dependent — primary or tertiary hyperparathyroidism, lithium, or familial hypocalciuric hypercalcaemia, which is distinguished by a 24-hour urinary calcium and a calcium/creatinine clearance ratio below 0.01. If PTH is suppressed, the hypercalcaemia is PTH-independent — measure PTHrP, 25(OH)D and 1,25(OH)₂D, serum protein electrophoresis and free light chains, TSH, 9 a.m. cortisol, alkaline phosphatase, and image for malignancy or granulomatous disease. Always also review every drug and supplement.

Management by severity. Asymptomatic patients with minimally elevated calcium (below about 12 mg/dL) may be treated as outpatients, with encouragement to adopt oral hydration, mobilisation, and elimination of drugs contributing to hypercalcaemia — thiazides and lithium. Patients who are symptomatic, or whose calcium exceeds about 12 mg/dL, should be considered for inpatient management using volume expansion with saline infusion, corticosteroids and bisphosphonates: (i) Rehydration generally has mild and transient effects on calcium levels; the volume of saline depends on the extent of hypovolaemia, with particular care for the patient's cardiac and renal function. (ii) Bisphosphonates have supplanted all other drugs except calcitonin, which remains useful in severe refractory hypercalcaemia because of its rapid onset — 2 to 4 hours, versus 72 hours for bisphosphonates. Recommended doses: pamidronate 90 mg IV over 2–4 hours or zoledronate 4 mg IV over 15 minutes; in patients with pre-existing renal disease no change in dosage, infusion time or interval is required. (iii) Glucocorticoids are helpful in hypercalcaemia caused by lymphoma, myeloma and breast cancer, and may be of some value in other malignancies, at 10–100 mg per day of prednisone equivalent. Also: stop calcium and vitamin D supplements, mobilise the patient, avoid loop diuretics unless the patient is volume-overloaded, and consider haemodialysis in severe hypercalcaemia with renal or cardiac failure. Raised calcium → confirm with albumin-adjusted or ionised calcium (+0.8 mg/dL per 1 g/dL fall in albumin) ↓ Measure intact PTH — this single test splits the differential ↓ PTH high or inappropriately normal PTH suppressed PTH-DEPENDENT PTH-INDEPENDENT Primary hyperparathyroidism · Tertiary → measure PTHrP · 1,25(OH)₂D · HPT · Lithium · FHH 25(OH)D · SPEP + free light chains · → 24-h urine Ca, Ca/Cr clearance ratio TSH · 9 a.m. cortisol · ALP (<0.01 = FHH) → Sestamibi / neck ultrasound if surgery contemplated ↓ PTHrP high 1,25(OH)₂D high Both normal Humoral hypercalcaemia of Lymphoma · sarcoidosis · Myeloma · osteolytic metastases · malignancy — squamous lung, tuberculosis → glucocorticoids thyrotoxicosis · immobilisation · head & neck, renal drugs · vitamin D toxicity ↓ Treat by severity: <12 mg/dL asymptomatic → oral hydration, mobilise, stop thiazide/lithium · ≥12 mg/dL or symptomatic → IV saline + zoledronate 4 mg / pamidronate 90 mg ± calcitonin (rapid onset) ± steroids (lymphoma, myeloma, granuloma)

dialysis if refractory with renal or cardiac failure LATEST UPDATE (2023–PRESENT) — 1 POINT

Endocrine Society Clinical Practice Guideline on the Treatment of Hypercalcaemia of Malignancy in Adults — the first evidence-based guideline in this area, co-sponsored by ASBMR and the European Society of Endocrinology. Its key positions: all adults with hypercalcaemia of malignancy should be treated with denosumab or an intravenous bisphosphonate rather than left untreated; denosumab is suggested in preference to an intravenous bisphosphonate as first-line therapy; and denosumab is specifically suggested for recurrent or refractory hypercalcaemia in patients previously treated with an intravenous bisphosphonate. In severe or symptomatic disease, calcitonin should be combined with the bisphosphonate or denosumab rather than the antiresorptive used alone. For hypercalcaemia from tumours producing high calcitriol, such as lymphoma, in patients already on glucocorticoids but still severely hypercalcaemic, add an IV bisphosphonate or denosumab. In parathyroid carcinoma, use either a calcimimetic (cinacalcet) or an IV bisphosphonate/denosumab. Two geriatric practice points: denosumab requires no renal dose adjustment and can be used at low eGFR where zoledronate is problematic — a real advantage in the older patient with CKD — but it carries a genuine risk of prolonged, severe hypocalcaemia in advanced CKD, so calcium and vitamin D must be monitored, and its effect cannot be reversed once given.