Toward Precise Forecasting of Autoimmune Endocrinopathy

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Toward Precise Forecasting of Autoimmune Endocrinopathy

  1. 1. Toward Precise Forecasting of Autoimmune Endocrinopathy Simon H. S. Pearce and Nicola J. Leech J. Clin. Endocrinol. Metab. 2004 89: 544-547, doi: 10.1210/jc.2003-032142 To subscribe to Journal of Clinical Endocrinology & Metabolism or any of the other journals published by The Endocrine Society please go to: http://jcem.endojournals.org//subscriptions/ Copyright © The Endocrine Society. All rights reserved. Print ISSN: 0021-972X. Online
  2. 2. 0021-972X/04/$15.00/0 The Journal of Clinical Endocrinology & Metabolism 89(2):544 –547 Printed in U.S.A. Copyright © 2004 by The Endocrine Society doi: 10.1210/jc.2003-032142 Editorial: Toward Precise Forecasting of Autoimmune Endocrinopathy The practice of medicine is moving from an era of treating by early childhood. In family members (i.e. those with a high disease to disease prevention. Thus, it is not surprising background risk), screening with serum islet cell antibodies that the scientific literature is currently filled with studies of (ICAs) has high sensitivity for predicting diabetes, but only organ-specific autoantibodies as markers of autoimmune those individuals with multiple -cell autoantibodies appear endocrine disease. The association of autoantibodies with to progress (4). Several large prospective studies have mea- autoimmune thyroid disease (AITD) was established more sured antibodies to the pancreatic -cell antigens insulin, than 40 yr ago, and yet their role in routine clinical practice glutamic acid decarboxylase, and tyrosine phosphatase- remains ill-defined. Individuals can be identified as being at related IA-2 protein in at risk individuals. The presence high risk of certain autoimmune diseases by virtue of per- of serum antibodies to any one of these -cell antigens is sonal or family history. This, combined with the appearance associated with progression to overt diabetes in 2–15% of of autoantibodies long before the development of organ fail- siblings of a proband with T1D (5–7). However, if antibodies ure, means in principle that the autoimmune endocrinopa- to all three of these -cell antigens are present, the 10-yr risk thies have many characteristics suited to prediction and pre- of overt T1D increases markedly to 70 –100%, with a sensi- vention. The current practice remains, however, to intervene tivity of 80 –90%. with hormone replacement at the point of almost complete Recently, predictive strategies were validated in two land- organ failure, leaving little or no scope for disease modifi- mark clinical intervention trials. The Diabetes Prevention cation. This is in contrast to the approach in many other Trial 1 (DPT-1) screened 84,228 first-degree relatives for ICA autoimmune disorders (e.g. rheumatoid arthritis). (8). Subjects identified as having a 5-yr risk of diabetes of 50% To be worthwhile, a screening program must meet several by virtue of ICA and insulin antibody positivity, and with criteria: there needs to be an effective intervention that is decreased first phase insulin response were randomized. more acceptable than the impact of the disease itself. The Although the prevention strategy, prophylactic parenteral population screening approach must have high sensitivity insulin, was ineffective, the screening strategy was accurate and specificity. The screening methodology must also be with a rate of development of diabetes of 15% per year (8). cost-effective and practical to apply. This article explores The European Nicotinamide Diabetes Intervention Trial how far we have traveled in forecasting autoimmune endo- (ENDIT) used a similar screening strategy and again con- crinopathy in both common endocrine disease and in the firmed the feasibility and accuracy of large-scale prediction context of rare but clustering disorders. We refer specifically strategies (9). to two papers that are being published in this issue of JCEM by Soderbergh et al. (1) and Kifor et al. (2). We review the ¨ Can prediction strategies be applied to the low-risk general strategies for prediction and perhaps targeted prevention by population? endocrine physicians in the future. Given that physicians who predict the future are often proven wrong, it is also Less than one in 10 of subjects with T1D has an affected useful to briefly review the scientific basis upon which to family member. It must, therefore, be established whether advise individuals or families about their future risk of the autoantibody screening strategies can be applied to a low- common, genetically complex, autoimmune diseases. risk unselected population. The prevalence of a single pan- creatic autoantibody in nonrelatives far exceeds those who progress to clinical diabetes (3), but as with family studies, Prediction of Common Endocrine Disorders combinations of autoantibodies give a high positive predic- Type 1 diabetes (T1D) tive value for the development of diabetes. In a large pro- By virtue of its incidence and the major limitations of spective study screening 4500 healthy schoolchildren, anti- insulin therapy, it is not surprising that prediction and, more bodies to two or three -cell antigens were present in 12 recently, prevention strategies have been pursued aggres- subjects (0.3%), six of whom developed T1D over an 8-yr sively in T1D. Pancreatic autoimmunity is frequently initi- observation period (10). Thus, the presence of antibodies to ated in the neonatal period (3), with autoantibodies apparent more than one -cell antigen still predicts T1D at least 50% of the time even in the unrelated population. Abbreviations: ACA, Adrenal cortex antibody; AIRE, autoimmune regulator; AITD, autoimmune thyroid disease; APS1, autoimmune poly- Does genetic screening aid prediction? endocrinopathy syndrome type 1; CaR, calcium-sensing receptor; HLA, The use of human leukocyte antigen (HLA) genotying, in human leukocyte antigen; ICA, islet cell antibody; PPT, postpartum thyroiditis; T1D, type 1 diabetes; TPO, thyroid peroxidase. addition to assay of antibodies to -cell antigens alone, has JCEM is published monthly by The Endocrine Society (http://www. been shown to lead to a small gain in predictive value over endo-society.org), the foremost professional society serving the en- antibodies alone. Siblings of a T1D proband who have iden- docrine community. tical HLA or who carry the most diabetes-susceptible 544
  3. 3. Pearce and Leech • Editorial J Clin Endocrinol Metab, February 2004, 89(2):544 –547 545 DQB*0201/DQB*0302 heterozygous genotype, along with endocrinopathy have about 30% risk of AITD, whereas sub- multiple antibodies have the highest risk of progression to jects with a more common disorder, childhood T1D, have overt diabetes (70 –100% over 10 yr) (11). Although geno- only a 15–20% risk of developing an additional autoimmune typing appears to add little predictive value to autoantibody endocrine disorder over a lifetime. Similarly, subjects with screening, it may provide a once-only method of identifying AITD, the most common endocrine disease, have the lowest those within the general population who would benefit from probability of developing a second disorder ( 5%). Is there second-round screening with autoantibodies. Those individ- a role for the application of antibody screening to forecast uals with the dominantly protective allele DQB1*0602 or who further endocrinopathy? carry neither the DQB*0201 or DQB*0302 haplotypes (about 50% of the Caucasian population) need no further screening. Addison’s disease Such an approach has been applied for inclusion in the neo- Addison’s disease, although rare, still carries a substantial natal cow’s milk exclusion intervention trial (12). mortality when unrecognized. This provides a clear rationale for early detection in at-risk individuals. A large survey of Prediction of the other common endocrine autoimmune nearly 9000 adult Italian patients with a first autoimmune diseases endocrinopathy (predominantly AITD or T1D), assessed the AITD has been subject to less systematic study because the risk of subsequently developing autoimmune adrenocortical perceived benefits of early identification of at-risk individ- failure (16). Overall, 0.8% of subjects were positive for ad- uals are less clearly defined. In the population-based Whick- renal cortex antibodies (ACAs). However, 9% of the subjects ham study (13), serum thyroid peroxidase (TPO; microso- with autoimmune premature ovarian failure were ACA- mal) antibody levels measured together with circulating TSH positive. Of the 36 subjects who had positive ACA but nor- were shown to predict thyroid failure in healthy unrelated mal adrenal function at baseline, one third progressed to subjects. Women with positive microsomal antibodies (but symptomatic Addison’s disease or impaired adrenal func- with normal TSH) had a 2.1% per year risk of developing tion on serial ACTH testing (16). The mean time to overt overt hypothyroidism. Overall, 27% of these euthyroid Addison’s disease from a state of normal adrenal function women who initially had serum thyroid antibodies were was 5.2 yr, with a range of 23 to 71 months. Antibodies hypothyroid 20 yr later. Of women with both positive mi- against 21 hydroxylase led to a small improvement in pre- crosomal antibodies and an elevated serum TSH, 55% were dictive value over ACA, but 17 hydroxylase and side-chain hypothyroid at 20 yr, progressing at a rate 4.3% per year (13). cleavage p450 antibodies did not provide additional infor- This study provides firm evidence on which to advise the mation over and above the 21 hydroxylase antibody assay 10 –15% of female subjects in the general population with (16). HLA genotyping added little predictive information. positive TPO antibodies about their low future risk of hy- pothyroidism. The data are less robust for men, although it From the complex to a simple monogenic disorder appears that both microsomal antibodies and elevated TSH It is against this background that the study of the mono- are, if anything, more predictive of overt hypothyroidism in genic, autoimmune polyendocrinopathy syndrome type 1 men compared with women. (APS1) or autoimmune polyendocrinopathy, candidiasis, Screening for postpartum thyroiditis (PPT) using TPO au- and ectodermal dystrophy syndrome is set. This is a rare toantibodies during pregnancy has high sensitivity, correctly disorder with onset in childhood and adolescence, but with identifying 90% of women who will develop the problem a relatively predictable course, such that it provides a unique (14). Specificity is low, however, with only about 50% of model in which to study the relationship between autoan- antibody-positive individuals manifesting clinical thyroid tibodies and hormonal failure (17, 18). dysfunction. PPT is a self-limiting condition in the majority APS1 is due to recessive mutations in the autoimmune of cases, and the benefits of early identification are, therefore, regulator (AIRE) gene, which is located on chromosome not obvious. It has been argued that TPO antibody screening 21q22. The most frequent initial manifestation is chronic for PPT should be pursued, because PPT is associated with mucocutaneous candidiasis with an average onset occurring postnatal depression (14). Furthermore, it identifies women at 5 yr, which is typically followed by hypoparathyroidism at high risk of progressing to chronic autoimmune hypothy- (8 yr) and then Addison’s disease (12 yr) (17, 18). Of note, roidism (about 25% over 5 yr). However, TPO antibody pos- autoimmune hypoparathyroidism is very rarely seen outside itivity during pregnancy may have no more long-term sig- the context of APS1. Other less common autoimmune fea- nificance than that found at other times of life (15). tures are diabetes, primary gonadal failure, pernicious ane- mia, intestinal malabsorption, hepatitis, hypothyroidism, al- Predicting a second endocrinopathy opecia, and vitiligo. In comparison to patients with the The discussion so far has focused on endocrine diseases common complex polyendocrinopathy syndrome (type 2 or that are common in the general population in whom pre- 3), in whom the average number of disease components is diction programs would be applicable to large numbers of two, subjects with APS1 have an average of four components. low-risk individuals. For subjects with a first endocrinopathy Interestingly, APS1 appears to be associated with a unique seeking guidance about their personal risk of a second dis- spectrum of autoantibodies, some of which are rarely, if ever, order, it seems their risk is, to a substantial extent, deter- found in other disorders. mined by the nature and prevalence of their first disease. For In this issue of JCEM, Soderbergh et al. (1) present an ¨ instance, the rare subjects with Addison’s disease as a first extensive evaluation of 10 different autoantibodies in a large
  4. 4. 546 J Clin Endocrinol Metab, February 2004, 89(2):544 –547 Pearce and Leech • Editorial cohort of European APS1 subjects. They make three findings aid the prediction of a life-threatening second manifestation of note. First, their results suggest that there is redundancy of autoimmunity. The study of unique autoimmune syn- in testing for antibodies to multiple steroidogenic enzymes dromes such as APS-1 will provide many additional insights and that 21 hydroxylase and side-chain cleavage enzyme are into the pathogenesis of these disorders and will advance the sufficient for the prediction of adrenocortical and gonadal pursuit of targeted immunotherapy for autoimmune endo- failure, respectively. This extends a similar observation made crinopathy. in adults at risk of Addison’s disease (16). Simon H. S. Pearce and Nicola J. Leech Second, antibodies against tryptophan hydroxylase, ini- Institute of Human Genetics (S.H.S.P.) and School of tially identified as being associated with intestinal dysfunc- Clinical Medical Sciences (N.J.L.) tion in APS1, are shown in this study to be the strongest University of Newcastle predictor of autoimmune hepatitis. This is an important find- Newcastle upon Tyne, NE1 3BZ United Kingdom ing, because in one large series up to 5% of APS1 subjects died of this complication (17). Screening and early detection may Acknowledgments allow timely intervention. We are grateful to Drs. Kate Owen and Tim Cheetham for critical Finally, of 73 APS1 subjects with hypoparathyroidism, reading of the manuscript. none had antibodies against parathyroid calcium-sensing receptor (CaR). These findings are in contrast to the previous Received December 11, 2003. Accepted December 11, 2003. study of Li et al. (19) in which about 50% of sera from patients Address all correspondence and requests for reprints to: Dr. Simon with autoimmune hypoparathyroidism selectively recog- H. S. Pearce, Institute of Human Genetics, Centre for Life, Central Park- nized the extracellular domain of the CaR on immunoblot- way, Newcastle upon Tyne, NE1 3BZ, United Kingdom. E-mail: s.h.s. pearce@ncl.ac.uk. ting studies. Kifor et al. (2), also in this issue, clearly dem- The work in Dr. Pearce’s laboratory was funded by the Wellcome onstrate that parathyroid antibodies directed against the CaR Trust and Medical Research Council (London, UK). are present and functionally important in two subjects with hypoparathyroidism, and they have previously demon- References strated a comparable biological role for anti-CaR antibodies in subjects with autoimmune hypercalcemia (20). These dis- 1. Soderbergh A, Myhre AG, Ekwall O, Gebre-Medhin G, Hedstrand H, Land- ¨ gren E, Miettinen A, Eskelin P, Halonen M, Tuomi T, Gustafsson J, Husebye crepant findings are likely to relate to differences in antibody ES, Perheentupa J, Gylling M, Manns MP, Rorsman F, Kampe O, Nilsson T ¨ assay technique, highlighting the need for standardization of 2004 Prevalence and clinical associations of 10 defined autoantibodies in au- sensitive antibody measurements. It is possible that naturally toimmune polyendocrine syndrome type I. J Clin Endocrinol Metab 89:557–562 2. Kifor O, McElduff A, LeBoff MS, Moore Jr FD, Butters R, Gao P, Cantor TL, occurring autoantibodies to the CaR only recognize a con- Kifor I, Brown EM 2004 Activating antibodies to the calcium-sensing receptor formational epitope on the mature glycosylated receptor, but in two patients with autoimmune hypoparathyroidism. J Clin Endocrinol Metab 89:548 –556 additional work is needed to clarify this currently contro- 3. Ziegler AG, Hummel M, Schenker M, Bonifacio E 1999 Autoantibody ap- versial area. pearance and risk for development of childhood diabetes in offspring of The study of organ-specific autoantibodies in APS1 has parents with type 1 diabetes: the 2-year analysis of the German BABYDIAB Study. Diabetes 48:460 – 468 provided both a prediction model and a valuable insight into 4. Gardner SG, Gale EA, Williams AJ, Gillespie KM, Lawrence KE, Bottazzo the pathogenesis of autoimmune endocrinopathy. There is GF, Bingley PJ 1999 Progression to diabetes in relatives with islet autoanti- currently a flurry of investigation into the mechanism by bodies. Is it inevitable? Diabetes Care 22:2049 –2053 5. Verge CF, Gianani R, Kawasaki E, Yu L, Pietropaolo M, Jackson RA, Chase which the defective AIRE gene causes an aberrant immune HP, Eisenbarth GS 1996 Prediction of type I diabetes in first-degree relatives response. AIRE is expressed in the thymic epithelial antigen- using a combination of insulin, GAD, and ICA512bdc/IA-2 autoantibodies. Diabetes 45:926 –933 presenting cells, which have a role in educating T cells (neg- 6. Kulmala P, Savola K, Petersen JS, Vahasalo P, Karjalainen J, Lopponen T, ative selection), i.e. eliminating self-reactive T cells. This may Dyrberg T, Akerblom HK, Knip M 1998 Prediction of insulin-dependent explain why APS1 subjects have a unique spectrum of au- diabetes mellitus in siblings of children with diabetes. A population-based study. The Childhood Diabetes in Finland Study Group. J Clin Invest 101: toantibodies and a high penetrance of certain endocrinopa- 327–336 thies. As we noted before, hypoparathyroidism is rare in 7. Bingley PJ, Christie MR, Bonifacio E, Bonfanti R, Shattock M, Fonte MT, situations other than APS1, suggesting that negative selec- Bottazzo GF, Gale EA 1994 Combined analysis of autoantibodies improves prediction of IDDM in islet cell antibody-positive relatives. Diabetes 43:1304 – tion of T cells that recognize the CaR and other unknown 1310 parathyroid antigens is critical for immune tolerance. Novel 8. Diabetes Prevention Trial–Type 1 Diabetes Study Group 2002 Effects of insulin in relatives of patients with type 1 diabetes mellitus. N Engl J Med targeted treatments for endocrine autoimmunity may stem 346:1685–1691 from a better understanding of this well-characterized dis- 9. Gale EA; European Nicotinamide Diabetes Intervention Trial Group 2003 ease in the next few years. Intervening before the onset of type 1 diabetes: baseline data from the Euro- pean Nicotinamide Diabetes Intervention Trial (ENDIT). Diabetologia 46:339 – 346 10. LaGasse JM, Brantley MS, Leech NJ, Rowe RE, Monks S, Palmer JP, Nepom What can we hope to achieve from the measurement of GT, McCulloch DK, Hagopian WA; Washington State Diabetes Prediction autoantibodies? Study 2002 Successful prospective prediction of type 1 diabetes in schoolchil- dren through multiple defined autoantibodies: an 8-year follow-up of the Over the last 40 yr, autoantibody assays have been devel- Washington State Diabetes Prediction Study. Diabetes Care 25:505–511 11. Kulmala P, Savola K, Reijonen H, Veijola R, Vahasalo P, Karjalainen J, oped to the point of precise disease prediction for certain Tuomilehto-Wolf E, Ilonen J, Tuomilehto J, Akerblom HK, Knip M 2000 common endocrinopathies such as T1D. This has now set the Genetic markers, humoral autoimmunity, and prediction of type 1 diabetes in stage for prevention programs in T1D, as and when appro- siblings of affected children. Childhood Diabetes in Finland Study Group. 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  5. 5. Pearce and Leech • Editorial J Clin Endocrinol Metab, February 2004, 89(2):544 –547 547 terovirus infections as a risk factor for type I diabetes: virus analyses in a and steroid 21-hydroxylase autoantibodies in adult patients with organ- dietary intervention trial. Clin Exp Immunol 132:271–277 specific autoimmune diseases: markers of low progression to clinical Addi- 13. Vanderpump MP, Tunbridge WM, French JM, Appleton D, Bates D, Clark son’s disease. J Clin Endocrinol Metab 82:932–938 F, Grimley Evans J, Hasan DM, Rodgers H, Tunbridge F, Young ET 1995 The 17. Perheentupa J 2002 APS1/APECED: the clinical disease and therapy. Endo- incidence of thyroid disorders in the community: a twenty-year follow-up of crinol Metab Clin North Am 31:295–320 the Whickham Survey. Clin Endocrinol (Oxf) 43:55– 68 18. Pearce SH, Cheetham TD 2001 Autoimmune polyendocrinopathy syndrome 14. Harris B, Othman S, Davies JA, Weppner GJ, Richards CJ, Newcombe RG, type 1: treat with kid gloves. Clin Endocrinol (Oxf) 54:433– 435 Lazarus JH, Parkes AB, Hall R, Phillips DI 1992 Association between postpartum 19. Li Y, Song YH, Rais N, Connor E, Schatz D, Muir A, Maclaren N 1996 thyroid dysfunction and thyroid antibodies and depression. BMJ 305:152–156 Autoantibodies to the extracellular domain of the calcium sensing receptor in 15. Amino N, Tada H, Hidaka Y, Crapo LM, Stagnaro-Green A 1999 Therapeutic patients with acquired hypoparathyroidism. J Clin Invest 97:910 –914 controversy: screening for postpartum thyroiditis. J Clin Endocrinol Metab 20. Kifor O, Moore Jr FD, Delaney M, Garber J, Hendy GN, Butters R, Gao P, 84:1813–1821 Cantor TL, Kifor I, Brown EM, Wysolmerski J 2003 A syndrome of hypocal- 16. Betterle C, Volpato M, Rees Smith B, Furmaniak J, Chen S, Greggio NA, ciuric hypercalcemia caused by autoantibodies directed at the calcium-sensing Sanzari M, Tedesco F, Pedini B, Boscaro M, Presotto F 1997 I. Adrenal cortex receptor. J Clin Endocrinol Metab 88:60 –72 JCEM is published monthly by The Endocrine Society (http://www.endo-society.org), the foremost professional society serving the endocrine community.

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