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Idiopathic Hypercalcemia: Looking Beyond the Obvious

Primary hyperparathyroidism (PHPT) is the most common cause of parathyroid mediated hypercalcemia (high normal or high PTH) while hypercalcemia of malignancy (HCM) is the leading cause of non PTH mediated hypercalcemia (low PTH levels). These together account for up to 90% of all causes of hypercalcemia (1). In the remaining 10% of the cases, other etiologies such as familial hypocalciuric hypercalcemia, vitamin D toxicity, milk alkali syndrome, medications, and immobilization are often diagnosed. However, in a subset of cases, the etiology of hypercalcemia remains undiagnosed and is often labeled as idiopathic hypercalcemia. As nephrologists, we see a fair share of these non CKD patients who present with non PTH mediated hypercalcemia and hypercalciuria that persist despite discontinuation of calcium and vitamin D supplementation along with other offending medications. Such cases may compel you to look beyond the obvious.

A recent case series identified 7 family members in 3 different generations with intermittent non PTH mediated hypercalcemia, hypercalciuria, nephrolithiasis and nephrocalcinosis who were found to have elevated 1,25 di hydroxy vitamin D3 levels (calcitriol) due to mutations involving the CYP24A1 gene (2).  This gene encodes the enzyme, 24-hydroxylase which is responsible for the degradation of the vitamin D metabolites (Figure 1). In healthy individuals, the circulating levels of 24,25 di hydroxy vitamin D3 is 10-25% of the total 25 hydroxy vitamin D. Inactivating mutation of CYP24A1 encoding 24-hydroxylase causes elevation of 1,25 di hydroxy  vitamin D3 levels that enhance the absorption of calcium in the intestine and kidneys along with bone resorption causing hypercalcemia and hypercalciuria.  24,25 di hydroxy vitamin D3 levels are low or undetectable.

Figure 1. A schematic representation of altered vitamin D metabolism in patients with CYP24A1   mutations

Several recent reports involving heterozygous mutations of CYP24A1 gene have been reported in adults and commonly involve a biochemical picture of varying severity of hypercalcemia, hypercalciuria and nephrolithiasis, variable 25 hydroxy vitamin D levels and high normal or high 1,25 di hydroxy vitamin D3 levels and are indistinguishable from other causes of vitamin D mediated hypercalcemia such as sarcoidosis, granulomatous diseases, lymphomas etc (3;4). In such cases, a family history of hypercalcemia or nephrolithiasis and measurement of 24,25 di hydroxy vitamin D3 may offer a clue for identifying patients with CYP24A1 mutations. 

Impaired 24-hydroxylase activity due to CYP24A1 mutations results in relative deficiency of the metabolite, 24,25(OH)2D, but its levels may be affected by the amount of vitamin D intake and other factors affecting 25 hydroxy vitamin D3 levels. Therefore,measuring the ratio of 25 OH Vit D3 /24,25 OH D3 would reliably identify patients with CYP24A1 mutation (Figure 2). A ratio <25  excludes patients with impaired CYP24A1 activity, whereas a ratio  >99 is highly suggestive of CYP24A1 homozygous mutation (5). Patients with non PTH mediated hypercalcemia, whose 25 OH Vit D /24,25 OH D ratio is >25 and <99, may have heterozygous mutation of CYP24A1 and benefit from confirmation with genetic testing (6)

Figure 2. Correlation between 25(OH)D/24,25(OH)2D in healthy individuals (●) and patients with CYP24A1 mutations (▴). Blue dotted line represents the cut off in healthy individuals and red dotted line represents the cut off in patients with CYP24A1 mutations (modified from Tebben PJ, et al)

Patients with hypercalcemia due to CYP24A1 mutations should avoid vitamin D supplementation and limit calcium intake. In certain cases with moderate to severe hypercalcemia, patients may need treatment with glucocorticoids or drugs such as ketoconazole that promote degradation of vitamin D(4,5).

In conclusion, evaluating and diagnosing patients with non PTH mediated hypercalcemia due to CYP24A1 mutations improves patient management and helps avoid misdiagnosis, unnecessary investigations and inappropriate treatments.


  1. A. Vakiti, C. Anastasopoulou, and P. Mewawalla, Malignancy-Related Hypercalcemia. StatPearls Publishing, 2023.

  2. P. J. Tebben et al., “Hypercalcemia, hypercalciuria, and elevated calcitriol concentrations with autosomal dominant transmission due to CYP24A1 mutations: effects of ketoconazole therapy,” J. Clin. Endocrinol. Metab., vol. 97, no. 3, pp. E423–7, Mar. 2012.

  3. T. O. Carpenter, “Take another CYP: confirming a novel mechanism for . ‘idiopathic’ hypercalcemia,” The Journal of clinical endocrinology and metabolism, vol. 97, no. 3. pp. 768–771, Mar. 2012.

  4. T. O. Carpenter, “CYP24A1 loss of function: Clinical phenotype of monoallelic and biallelic mutations,” J. Steroid Biochem. Mol. Biol., vol. 173, pp. 337–340, Oct. 2017.

  5. P. J. Tebben, R. J. Singh, and R. Kumar, “Vitamin D-Mediated Hypercalcemia: Mechanisms, Diagnosis, and Treatment,” Endocr. Rev., vol. 37, no. 5, pp. 521–547, Oct. 2016.

  6. “Ratio of 25(OH)D-to-24,25(OH)2D: A new test to confirm 24-hydroxylase (CYP24A1) deficiency as the cause of hypercalcemia - Mayo Clinic.” Accessed: May 31, 2024. [Online]. Available: 


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