Autoimmune hypoparathyroidism (AH) is characterized by hypocalcemia, hyperphosphatemia, and inappropriately low intact parathyroid hormone (PTH) levels. Activating autoantibodies against the calcium-sensing receptor (CaSR) have been implicated in its pathogenesis by suppressing PTH secretion. We report three patients with AH and describe the clinical significance and functional characteristics of anti-CaSR antibodies.

Case 1 was an 87-year-old man who presented with numbness in his hands and fingertips. He was diagnosed with hypoparathyroidism based on corrected calcium (cCa) of 6.8 mg/dL, phosphate of 4.3 mg/dL, and intact PTH of 15 pg/mL. Following the introduction of prednisolone for polymyalgia rheumatica, his hypoparathyroidism unexpectedly remitted. Case 2 was an 83-year-old man who developed numbness in his extremities following COVID-19 and was diagnosed with hypoparathyroidism. After initiation of intranasal corticosteroid therapy for nasal obstruction, his cCa levels fluctuated markedly, ranging from 6.7 to 10.7 mg/dL. Case 3 was a 75-year-old man diagnosed with hypoparathyroidism during evaluation for amyotrophic lateral sclerosis, and serum calcium levels were managed conservatively because of the possibility of fluctuations in autoantibody titers after the transition to home medical care.

Anti-CaSR antibodies were detected in all three patients by ELISA. Purified antibodies were subjected to functional analyses using HEK293 cells stably expressing CaSR. Both Gq- and Gi-mediated signaling pathways were enhanced in the presence of patient-derived antibodies, confirming their activating properties.

These findings indicate that anti-CaSR antibodies contribute directly to disease pathogenesis through activation of multiple downstream signaling pathways. Moreover, the clinical activity of AH may fluctuate or even remit during immunosuppressive therapy. Identification of anti-CaSR antibodies may provide clinically useful information for disease monitoring and management. To our knowledge, this is the first study to demonstrate that anti-CaSR antibodies isolated from patients with AH activate both Gq and Gi signaling pathways, underscoring the importance of understanding the underlying pathophysiology in clinical practice.