Endocrine Abstracts

The extracellular calcium-sensing receptor (CaR) plays a key role in the body's capacity to maintain a nearly constant level of the extracellular ionized calcium concentration. The parathyroid glands play an especially important role in calcium homeostasis through their capacity to sense even minute perturbations in the extracellular calcium concentration and to respond in ways that will normalize the level of extracellular calcium. In response to hypocalcemia, for example, increased PTH secretion enhances distal tubular calcium reabsorption, thereby resetting the kidney to sustain a higher extracellular calcium concentration. Greater renal synthesis of 1,25-dihydroxyvitamin D in response to elevated PTH levels, in turn, promotes intestinal calcium absorption and, in concert with PTH, increases skeletal calcium release. Enhanced calcium influx from intestine and bone, coupled with decreased loss of calcium in the urine, raises the extracellular ionized calcium concentration back toward its normal level, thereby restoring calcium homeostasis. There are several clinical disorders in which alterations in the structure and/or function of the CaR cause defective sensing of extracellular calcium and, in turn, deranged calcium homoeostasis. These disorders can be inherited, as in familial hypocalciuric hypercalcemia (FHH), which results from inactivating mutations in the CaR, or autosomal dominant hypocalcemia, which is caused by activating mutations in the receptor, or they may be acquired, as in primary hyperparathyroidism. Recently, we identified novel, acquired, immune-mediated abnormalities in the sensing of extracellular calcium. Patients with inactivating anti-CaR antibodies have a clinical picture that resembles FHH or primary hyperparathyroidism, while those with activating antibodies have a clinical presentation resembling hypoparathyroidism. This talk will compare and contrast the clinical features and pathophyiological mechanisms underlying these inherited and acquired abnormalities in the sensing of extracellular calcium.