Hypoparathyroidism and Autoimmune Polyendocrine Syndromes
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《新英格兰医药杂志》
To the Editor: In their review of autoimmune polyendocrine syndromes, Eisenbarth and Gottlieb (May 13 issue)1 do not, in our view, sufficiently discuss autoimmune hypoparathyroidism and recent advances in its understanding. Autoimmune hypoparathyroidism is present in 80 to 85 percent of patients with autoimmune polyendocrine syndrome type I and up to 5 percent of patients with autoimmune polyendocrine syndrome type II. The autoantigens were unknown until the extracellular domain of the calcium-sensing receptor was identified as a potential target.2 The calcium-sensing receptor is a cell-surface, G protein–coupled receptor through which parathyroid cells, thyroidal C cells, and various kidney cells recognize and respond to changes in ionized calcium in order to maintain calcium homeostasis.
Antibodies to the calcium-sensing receptor have been reported in 49 to 56 percent of patients with hypoparathyroidism.2,3,4 In contrast, Soderbergh et al. were unable to detect antibodies to the receptor in 73 patients with autoimmune polyendocrine syndromes and hypoparathyroidism.5 Aside from technical problems related to the assays, the differences between their findings and others' might be explained by the specific isoforms used to detect the antibodies to the calcium-sensing receptor. Some authors use the 151-kD isoform, which is incompletely glycosylated, whereas others use the fully mature, completely glycosylated, 168-kD form. Thus, how the antibodies are sought may be quite important in diagnosing autoimmune hypoparathyroidism in autoimmune polyendocrine syndrome type I.
Matthias Schott, M.D.
Werner A. Scherbaum, M.D.
Heinrich Heine University
40225 Düsseldorf, Germany
schottmt@uni-duesseldorf.de
References
Eisenbarth GS, Gottlieb PA. Autoimmune polyendocrine syndromes. N Engl J Med 2004;350:2068-2079.
Li Y, Song YH, Rais N, et al. Autoantibodies to the extracellular domain of the calcium sensing receptor in patients with acquired hypoparathyroidism. J Clin Invest 1996;97:910-914.
Goswami R, Brown EM, Kochupillai N, et al. Prevalence of calcium sensing receptor autoantibodies in patients with sporadic idiopathic hypoparathyroidism. Eur J Endocrinol 2004;150:9-18.
Kifor O, McElduff A, LeBoff MS, et al. Activating antibodies to the calcium-sensing receptor in two patients with autoimmune hypoparathyroidism. J Clin Endocrinol Metab 2005;89:548-556.
Soderbergh A, Myhre AG, Ekwall O, et al. Prevalence and clinical associations of 10 defined autoantibodies in autoimmune polyendocrine syndrome type I. J Clin Endocrinol Metab 2004;89:557-562.
The authors reply: Our review highlights autoantibody assays with high specificity and sensitivity and a clear consensus with regard to the target autoantigen. In their article, Soderbergh and coworkers1 call into question the association of autoantibodies to the calcium-sensing receptor and the hypoparathyroidism of autoimmune polyendocrine syndrome type I, stating, "It is not likely that the results are explained by the lack of posttranslational modifications of the CASR [calcium-sensing receptor] because glycosylation was not required for antibody reactivity" in the study by Li et al.2 Goswami and coworkers used Western blot techniques to detect antibodies and found an unacceptable fraction of the normal controls (13.3 percent) to be positive.3 Western blot assays in the field of organ-specific autoimmunity are usually much inferior to fluid-phase radioassays, such as those used by Soderbergh and coworkers, and our current assessment of the literature is that the prominence of autoantibodies to the calcium-sensing receptor in hypoparathyroidism remains unproven and, furthermore, that the assay method is not at the standard needed for clinical decision making. It is hoped that autoantibody workshops and improved assay methods will one day provide an autoantibody assay (for which there is a consensus) to aid in the diagnosis and prediction of hypoparathyroidism.
George S. Eisenbarth, M.D., Ph.D.
Peter Gottlieb, M.D.
University of Colorado Health Sciences Center
Denver, CO 80262
george.eisenbarth@uchsc.edu
References
Soderbergh A, Myhre AG, Ekwall O, et al. Prevalence and clinical associations of 10 defined autoantibodies in autoimmune polyendocrine syndrome type I. J Clin Endocrinol Metab 2004;89:557-562.
Li Y, Song YH, Rais N, et al. Autoantibodies to the extracellular domain of the calcium sensing receptor in patients with acquired hypoparathyroidism. J Clin Invest 1996;97:910-914.
Goswami R, Brown EM, Kochupillai N, et al. Prevalence of calcium sensing receptor autoantibodies in patients with sporadic idiopathic hypoparathyroidism. Eur J Endocrinol 2004;150:9-18.
Antibodies to the calcium-sensing receptor have been reported in 49 to 56 percent of patients with hypoparathyroidism.2,3,4 In contrast, Soderbergh et al. were unable to detect antibodies to the receptor in 73 patients with autoimmune polyendocrine syndromes and hypoparathyroidism.5 Aside from technical problems related to the assays, the differences between their findings and others' might be explained by the specific isoforms used to detect the antibodies to the calcium-sensing receptor. Some authors use the 151-kD isoform, which is incompletely glycosylated, whereas others use the fully mature, completely glycosylated, 168-kD form. Thus, how the antibodies are sought may be quite important in diagnosing autoimmune hypoparathyroidism in autoimmune polyendocrine syndrome type I.
Matthias Schott, M.D.
Werner A. Scherbaum, M.D.
Heinrich Heine University
40225 Düsseldorf, Germany
schottmt@uni-duesseldorf.de
References
Eisenbarth GS, Gottlieb PA. Autoimmune polyendocrine syndromes. N Engl J Med 2004;350:2068-2079.
Li Y, Song YH, Rais N, et al. Autoantibodies to the extracellular domain of the calcium sensing receptor in patients with acquired hypoparathyroidism. J Clin Invest 1996;97:910-914.
Goswami R, Brown EM, Kochupillai N, et al. Prevalence of calcium sensing receptor autoantibodies in patients with sporadic idiopathic hypoparathyroidism. Eur J Endocrinol 2004;150:9-18.
Kifor O, McElduff A, LeBoff MS, et al. Activating antibodies to the calcium-sensing receptor in two patients with autoimmune hypoparathyroidism. J Clin Endocrinol Metab 2005;89:548-556.
Soderbergh A, Myhre AG, Ekwall O, et al. Prevalence and clinical associations of 10 defined autoantibodies in autoimmune polyendocrine syndrome type I. J Clin Endocrinol Metab 2004;89:557-562.
The authors reply: Our review highlights autoantibody assays with high specificity and sensitivity and a clear consensus with regard to the target autoantigen. In their article, Soderbergh and coworkers1 call into question the association of autoantibodies to the calcium-sensing receptor and the hypoparathyroidism of autoimmune polyendocrine syndrome type I, stating, "It is not likely that the results are explained by the lack of posttranslational modifications of the CASR [calcium-sensing receptor] because glycosylation was not required for antibody reactivity" in the study by Li et al.2 Goswami and coworkers used Western blot techniques to detect antibodies and found an unacceptable fraction of the normal controls (13.3 percent) to be positive.3 Western blot assays in the field of organ-specific autoimmunity are usually much inferior to fluid-phase radioassays, such as those used by Soderbergh and coworkers, and our current assessment of the literature is that the prominence of autoantibodies to the calcium-sensing receptor in hypoparathyroidism remains unproven and, furthermore, that the assay method is not at the standard needed for clinical decision making. It is hoped that autoantibody workshops and improved assay methods will one day provide an autoantibody assay (for which there is a consensus) to aid in the diagnosis and prediction of hypoparathyroidism.
George S. Eisenbarth, M.D., Ph.D.
Peter Gottlieb, M.D.
University of Colorado Health Sciences Center
Denver, CO 80262
george.eisenbarth@uchsc.edu
References
Soderbergh A, Myhre AG, Ekwall O, et al. Prevalence and clinical associations of 10 defined autoantibodies in autoimmune polyendocrine syndrome type I. J Clin Endocrinol Metab 2004;89:557-562.
Li Y, Song YH, Rais N, et al. Autoantibodies to the extracellular domain of the calcium sensing receptor in patients with acquired hypoparathyroidism. J Clin Invest 1996;97:910-914.
Goswami R, Brown EM, Kochupillai N, et al. Prevalence of calcium sensing receptor autoantibodies in patients with sporadic idiopathic hypoparathyroidism. Eur J Endocrinol 2004;150:9-18.