Rare Causes of Hypercalcemia: 2021 Update

Context: Primary hyperparathyroidism and malignancy are the etiologies in 90% of cases of hypercalcemia. When these entities are not the etiology of hypercalcemia, uncommon conditions need to be considered. In 2005, Jacobs and Bilezikian published a clinical review of rare causes of hypercalcemia, focusing on mechanisms and pathophysiology. This review is an updated synopsis of rare causes of hypercalcemia, extending the observations of the original article. Evidence Acquisition: Articles reporting rare associations between hypercalcemia and unusual conditions were identified through a comprehensive extensive PubMed-based search using the search terms hypercalcemia and etiology, as well as examining the references in the identified case reports. We categorized the reports by adults vs pediatric and further categorized the adult reports based on etiology. Some included reports lacked definitive assessment of etiology and are reported as unknown mechanism with discussion of likely etiology. Evidence Synthesis: There is a growing understanding of the breadth of unusual causes of hypercalcemia. When the cause of hypercalcemia is elusive, a focus on mechanism and review of prior reported cases is key to successful determination of the etiology. Conclusions: The ever-expanding reports of patients with rare and even unknown mechanisms of hypercalcemia illustrate the need for continued investigation into the complexities of human calcium metabolism.

Automated summary

Primary hyperparathyroidism and malignancy account for 90% of cases of hypercalcemia, with uncommon conditions needing to be considered when these are not the etiology. Recent research has led to a better understanding of unusual causes of hypercalcemia, emphasizing the importance of focusing on mechanisms and reviewing prior case reports for successful determination of the etiology. Continued investigation into the complexities of human calcium metabolism is crucial due to an increasing number of reports on rare and unknown mechanisms of hypercalcemia.