Hypercalcemia in Children Using the Ketogenic Diet: A Multicenter Study

Abstract

Context: The ketogenic diet is associated with progressive skeletal demineralization, hypercalciuria, and nephrolithiasis. Acute hypercalcemia has been described as a newly recognized complication of this treatment.

Objective: To describe the clinical characteristics of acute hypercalcemia in children on the ketogenic diet through analysis of the presentation, response to treatment, and natural history in a large cohort of patients.

Design: A multicenter case series was performed including children who developed acute hypercalcemia while treated with the ketogenic diet. Information on clinical presentation, treatment, and course of this complication was collated centrally.

Results: There were 14 patients (median (range) age 6.3 (0.9 to 18) years) who developed hypercalcemia 2.1 (range, 0.2-12) years after starting the ketogenic diet. All had low levels of parathyroid hormone and levels of 1,25-dihydroxyvitamin D were low in all except one. Seven (50%) had impaired renal function at presentation. All except the 2 oldest had low alkaline phosphatase levels for age. Once normocalcemia was achieved, hypercalcemia recurred in only 2 of these patients over observation of up to 9.8 years. One patient discontinued the ketogenic diet prior to achieving normocalcemia while 4 more stopped the diet during follow-up after resolution of hypercalcemia.

Conclusions: Ketotic hypercalcemia can occur years after starting the ketogenic diet, especially in the setting of renal impairment. The mechanism is unknown but appears to be due to reduced osteoblast activity and impaired bone formation. We recommend close attention to optimizing bone health in these children, and screening for the development of ketotic hypercalcemia.

Keywords: hypercalcemia; hypercalciuria; ketogenic diet; nephrocalcinosis.

Figure 1.

Laboratory results seen in all children using the ketogenic diet at the time of developing hypercalcemia. Reference ranges are highlighted in gray, with multiple reference ranges shown where age-specific ranges are applicable.

Figure 2.

Adenosine has a short serum half-life and undergoes phosphorylation or deamination soon after secretion. The ketogenic diet reduces adenosine kinase activity, prolonging the serum half-life and increasing interaction with adenosine receptors (A1, A2A, A2B, and A3). The net effect of this may reduce osteoblast differentiation.