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Case studies identify new autoimmune form of parathyroid hormone impairment

A recent case study has identified how a misguided autoimmune reaction to the parathyroid hormone type 1 receptor (abbreviated PTHR or PTH1R) can cause parathyroid hormone (PTH) resistance, a condition that can cause serious disruptions of the body’s mineral levels. Normally, PTH helps control calcium and phosphorus levels. PTH resistance occurs when the body fails to respond to PTH, causing high calcium levels and low phosphorus levels in the blood.

Most cases of PTH resistance are congenital, due to genetic mutations or gene-related effects on one of the signaling proteins that mediates PTH activity. However, the PTH resistance of two women referred to the National Institutes of Health Clinical Center did not fit this pattern, prompting researchers, including those with the NIDDK Intramural Research Program, to dig deeper into the cause of their symptoms. Though these two women demonstrated classic signs of PTH resistance— high calcium levels, low phosphorus levels, and other common symptoms such as muscle cramps, tingling, and numbness—these symptoms had started later in life, and the women did not have genetic traits known to cause PTH resistance. Additionally, the women had elevated PTH levels that were difficult to correct with standard medication regimens. The scientists tested the women’s blood to look for autoimmune irregularities and found that both women had high levels of antibodies directed against PTH1R, which were impairing the receptor’s ability to bind PTH. Further tests also found that the women had higher-than-usual levels of an immune cell type sometimes seen in other autoimmune diseases.

Together, these results identified how autoimmunity against PTH1R can lead to PTH resistance. Further research will be needed to determine how common this cause of PTH resistance is, and, since both people in this case study were Black women, whether it is affected by ancestry or biological sex. These findings could also have important implications for PTH resistance treatment, suggesting that people with an autoimmune-associated form of the condition may benefit from immune-suppressing therapies.

Mandl A, Burbelo PD, Di Pasquale G, …Weinstein LS. Parathyroid hormone resistance and autoantibodies to the PTH1 receptor. N Engl J Med 385: 1974-1980, 2021.

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