Autoimmune hypercalcemia due to autoantibodies against the calcium-sensing receptor.

CONTEXT: Autoimmune hypocalciuric hypercalcemia (AHH) is an acquired disorder caused by the presence of blocking autoantibodies against the calcium-sensing receptor (CaSR). Few cases of this condition have been described to date in the literature. OBJECTIVE: The objectives of this study were to describe two patients in whom the presence of AHH was suspected and to assess the patients for the presence of CaSR antibodies. METHODS: CaSR antibodies were detected and characterised by immunoprecipitation assays, CaSR peptide ELISAs, and functional assays based on the calcium-stimulated accumulation of inositol-1-phosphate in a mammalian cell line expressing the CaSR. RESULTS: Both patients presented with an acquired form of hypocalciuric hypercalcemia. Mutational analyses of CASR, GNA11 and AP2S1 for familial hypocalciuric hypercalcemia, were negative. According to the presence of Hashimoto's disease in one patient and latent autoimmune diabetes of adulthood and thyroid autoimmunity in the other, AHH was suspected. Immunoprecipitation assays detected CaSR antibodies in both patients. Analysis of the antibody binding sites revealed two main epitopes at amino acids 41-69 and 114-126. Preincubation with purified CaSR antibodies against epitope 114-126 resulted in a significant decrease in inositol-1-phophate accumulation upon calcium-stimulation of mammalian cells expressing the CaSR, suggesting that the antibodies had receptor-blocking activity. CONCLUSIONS: AHH is to be suspected in patients with an acquired biochemical pattern of PTH-dependant hypocalciuric hypercalcemia, especially in those with other concomitant autoimmune diseases. Diagnosis by means of detecting CaSR antibodies may help to better characterise this probably under-reported condition.