26th February 2025

Hypercalcaemia

Overview of hypercalcaemia

Calcium levels are predominantly maintained through: (a) parathyroid hormone’s (PTH) direct effect on bone and the kidneys and (b) activated vitamin D’s indirect effect on the gut.

The list of diagnoses underlying hypercalcaemia range from benign disorders that do not require monitoring to life-threatening illnesses that demand immediate treatment. These conditions can be grouped according to the method through which they raise calcium levels. The degree of derangement can be classified as mild (2.6-3.00 mmol/L), moderate (3.01-3.40 mmol/L), or severe (>3.40 mmol/L).

Table 1 Aetiologies of hypercalcaemia classified by cause. *Most common causes of hypercalcaemia

Increased PTH or PTHrP release

Primary hyperparathyroidism

Hypercalcaemia with an ‘inappropriately normal’ or raised PTH in a patient with normal renal function (i.e., tertiary hyperparathyroidism has been excluded) who does not take lithium points to a probable diagnosis of primary hyperparathyroidism (PHPT). Over 80% of cases are due to a solitary adenoma, with nodular hyperplasia and multiple adenomas forming most of the remainder. Parathyroid malignancy accounts for ≤1% of PHPT, usually with calcium and PTH levels far higher than typical PHPT. Gathering a family history is important as inherited conditions are implicated up to 10% with PHPT, with familial isolated hyperparathyroidism, multiple endocrine neoplasia (MEN), and hyperparathyroidism-jaw tumour syndrome (HPT-JT) the three most notable (all inherited in an autosomal dominant pattern).

Familial hypocalciuric hypercalcaemia

For a diagnosis of PHPT to be confirmed, familial hypocalciuric hypercalcaemia (FHH) must be excluded via urinary tests to rule out hypocalciuria (24-hour urinary calcium excretion, random renal calcium:creatinine excretion ratio, or random calcium:creatinine clearance ratio). In contrast to PHPT, however, FHH is almost always asymptomatic with little clinical significance and so is unlikely in symptomatic hypercalcaemia. This autosomal dominant condition occurs via an inactivating mutation in the calcium-sensing receptor (CaSR) gene, reducing receptor sensitivity to calcium. Higher than normal calcium levels are therefore required to suppress PTH secretion, and defective CaSR in renal tubules leads to increased reabsorption of calcium with subsequent hypocalciuria.

Hypercalcaemia of malignancy

Hypercalcaemia is seen in around 20% of cancer patients, with humoral hypercalcaemia of malignancy accounting for 80% of these. A history highly suspicious of cancer is often the primary concern when hypercalcaemia is incidentally noted. Given the limited physiological role of PTH-related protein (PTHrP), elevated PTHrP warrants urgent investigation for a causative malignancy. These are most often solid tumours, with lung primaries accounting for nearly 30% of cases. Negative feedback on PTH release results in a biochemical picture resembling PHPT except for a normal or low PTH rather than normal or raised.

Management of primary hyperparathyroidism

Referral to an endocrinologist is warranted in patients with PHPT if symptomatic, their serum calcium is ≥2.85 mmol/L, there is concurrent CKD stage ≥III, or they have developed renal stones or are at an increased risk of renal stones (e.g. obesity, gout, diabetes mellitus, Crohn’s disease, structural ureteric abnormalities).

Total or subtotal resection of the parathyroid glands is first-line in primary and tertiary hyperparathyroidism. If surgery is unsuccessful or not possible, calcimimetics such as cinacalcet can be used if serum calcium is >2.85 mmol/L with symptoms or >3.0 mmol/L regardless of symptoms, where it acts to increase CaSR sensitivity and, therefore, decrease PTH levels. Bisphosphonates are considered in moderate or severe hypercalcaemia refractory to IV fluids and in those with an increased risk of fractures.

Increased vitamin D

Vitamin D2 (ergocalciferol; mainly found in plants) or vitamin D3 (cholecalciferol; mainly found in fish & meat) are activated in a two-step process: hepatic hydroxylation creates 25(OH)D (calcifediol), with subsequent renal hydroxylation producing the active metabolite 1,25(OH)2D (calcitriol). Calcitriol increases serum calcium levels through actions on the small intestine and bones. Hypercalcaemia may, therefore, occur with prolonged and excessive ingestion of vitamin D supplements (hypervitaminosis D), granulomatous diseases, e.g. sarcoidosis, TB (as epithelioid histiocytes in granulomas display 1α-hydroxylase activity), or ectopic production of calcitriol in lymphoma. Steroids may be trialled where granulomas or malignancies producing 1α-hydroxylase are implicated.

Increased bone turnover

Osteoclastic bone resorption may be directly promoted by hyperthyroidism, malignancies, e.g. multiple myeloma or metastases to bone, and prolonged immobilisation (e.g. after spinal cord injuries). Osteoblastic bone formation is depressed with prolonged immobilisation, and accounts for the hypercalcaemia seen in immobilised patients with Paget’s disease of bone (whose high bone turnover state otherwise does not cause hypercalcaemia).

Image source: Wikimedia Commons (2020). Emmentalersign, Licensed under a Creative Commons licence. Available for free at: https://commons.wikimedia.org/wiki/File:Emmentalersign_.jpg (Accessed: 24 January 2024). Image source: BioMed Central Ltd (2009). Abdominal radiograph showing osteoblastic changes of spine, pelvic and femoral bones (arrows)., Licensed under a Creative Commons licence. Available for free at: https://casesjournal.biomedcentral.com/articles/10.1186/1757-1626-2-54/figures/2 (Accessed: 24 January 2024).

Decreased renal excretion of calcium

Thiazide diuretics enhance proximal tubular reabsorption of calcium, while glucocorticoid deficiency (as in adrenal insufficiency) also reduces renal excretion of calcium through an unclear mechanism.

Rare causes

Hypervitaminosis A (promotes osteoclastic bone resorption), aluminium intoxication (impairs osteoblastic bone formation), and milk-alkali syndrome (excessive ingestion of calcium-containing antacids or calcium supplements) are rarely seen in clinical practice, particularly as PPIs have replaced aluminium and calcium-containing antacids.

References

• National Institute for Health and Care Excellence. CKS: Hypercalcaemia [Internet]. NICE. 2019 [cited 2023 Feb 20. Available from: https://cks.nice.org.uk/topics/hypercalcaemia/
• Ayuk J, Gittoes N. Primary hyperparathyroidism [Internet]. BMJ Best Practice. 2021 [cited 2023 Feb 20. Available from: https://bestpractice.bmj.com/topics/en-gb/133
• National Institute for Health and Care Excellence. Hyperparathyroidism (primary): diagnosis, assessment and initial management [Internet]. NICE. 2019 [cited 2023 Feb 20. Available from: https://www.nice.org.uk/guidance/ng132
• Donovan PJ, Achong N, Griffin K, Galligan J, Pretorius CJ, McLeod DS. PTHRP-mediated hypercalcemia: causes and survival in 138 patients. J Clin Endocrinol Metab. 2015;100(5):2024–9
• Guise TA, Wysolmerski JJ. Cancer-associated hypercalcemia. N Engl J Med. 2022;386(15):1443–51