J. Clin. Endocrinol. Metab. 2004 89: 544-547, doi: 10.1210/jc.2003-032142  

Simon H. S. Pearce and Nicola J. Leech  

Toward Precise Forecasting of Autoimmune Endocrinopathy

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Editorial: Toward Precise Forecasting of AutoimmuneEndocrinopathy

The practice of medicine is moving from an era of treatingdisease to disease prevention. Thus, it is not surprisingthat the scientific literature is currently filled with studies oforgan-specific autoantibodies as markers of autoimmuneendocrine disease. The association of autoantibodies withautoimmune thyroid disease (AITD) was established morethan 40 yr ago, and yet their role in routine clinical practiceremains ill-defined. Individuals can be identified as being athigh risk of certain autoimmune diseases by virtue of per-sonal or family history. This, combined with the appearanceof autoantibodies long before the development of organ fail-ure, means in principle that the autoimmune endocrinopa-thies have many characteristics suited to prediction and pre-vention. The current practice remains, however, to intervenewith hormone replacement at the point of almost completeorgan failure, leaving little or no scope for disease modifi-cation. This is in contrast to the approach in many otherautoimmune disorders (e.g. rheumatoid arthritis).

To be worthwhile, a screening program must meet severalcriteria: there needs to be an effective intervention that ismore acceptable than the impact of the disease itself. Thepopulation screening approach must have high sensitivityand specificity. The screening methodology must also becost-effective and practical to apply. This article exploreshow far we have traveled in forecasting autoimmune endo-crinopathy in both common endocrine disease and in thecontext of rare but clustering disorders. We refer specificallyto two papers that are being published in this issue of JCEMby Soderbergh et al. (1) and Kifor et al. (2). We review thestrategies for prediction and perhaps targeted prevention byendocrine physicians in the future. Given that physicianswho predict the future are often proven wrong, it is alsouseful to briefly review the scientific basis upon which toadvise individuals or families about their future risk of thecommon, genetically complex, autoimmune diseases.

Prediction of Common Endocrine DisordersType 1 diabetes (T1D)

By virtue of its incidence and the major limitations ofinsulin therapy, it is not surprising that prediction and, morerecently, prevention strategies have been pursued aggres-sively in T1D. Pancreatic autoimmunity is frequently initi-ated in the neonatal period (3), with autoantibodies apparent

by early childhood. In family members (i.e. those with a highbackground risk), screening with serum islet cell antibodies(ICAs) has high sensitivity for predicting diabetes, but onlythose individuals with multiple �-cell autoantibodies appearto progress (4). Several large prospective studies have mea-sured antibodies to the pancreatic �-cell antigens insulin,glutamic acid decarboxylase, and tyrosine phosphatase-related IA-2 protein in at risk individuals. The presenceof serum antibodies to any one of these �-cell antigens isassociated with progression to overt diabetes in 2–15% ofsiblings of a proband with T1D (5–7). However, if antibodiesto all three of these �-cell antigens are present, the 10-yr riskof overt T1D increases markedly to 70–100%, with a sensi-tivity of 80–90%.

Recently, predictive strategies were validated in two land-mark clinical intervention trials. The Diabetes PreventionTrial 1 (DPT-1) screened 84,228 first-degree relatives for ICA(8). Subjects identified as having a 5-yr risk of diabetes of 50%by virtue of ICA and insulin antibody positivity, and withdecreased first phase insulin response were randomized.Although the prevention strategy, prophylactic parenteralinsulin, was ineffective, the screening strategy was accuratewith a rate of development of diabetes of 15% per year (8).The European Nicotinamide Diabetes Intervention Trial(ENDIT) used a similar screening strategy and again con-firmed the feasibility and accuracy of large-scale predictionstrategies (9).

Can prediction strategies be applied to the low-risk generalpopulation?

Less than one in 10 of subjects with T1D has an affectedfamily member. It must, therefore, be established whetherautoantibody screening strategies can be applied to a low-risk unselected population. The prevalence of a single pan-creatic autoantibody in nonrelatives far exceeds those whoprogress to clinical diabetes (3), but as with family studies,combinations of autoantibodies give a high positive predic-tive value for the development of diabetes. In a large pro-spective study screening 4500 healthy schoolchildren, anti-bodies to two or three �-cell antigens were present in 12subjects (0.3%), six of whom developed T1D over an 8-yrobservation period (10). Thus, the presence of antibodies tomore than one �-cell antigen still predicts T1D at least 50%of the time even in the unrelated population.

Does genetic screening aid prediction?

The use of human leukocyte antigen (HLA) genotying, inaddition to assay of antibodies to �-cell antigens alone, hasbeen shown to lead to a small gain in predictive value overantibodies alone. Siblings of a T1D proband who have iden-tical HLA or who carry the most diabetes-susceptible

Abbreviations: ACA, Adrenal cortex antibody; AIRE, autoimmuneregulator; AITD, autoimmune thyroid disease; APS1, autoimmune poly-endocrinopathy syndrome type 1; CaR, calcium-sensing receptor; HLA,human leukocyte antigen; ICA, islet cell antibody; PPT, postpartumthyroiditis; T1D, type 1 diabetes; TPO, thyroid peroxidase.JCEM is published monthly by The Endocrine Society (http://www.endo-society.org), the foremost professional society serving the en-docrine community.

0021-972X/04/$15.00/0 The Journal of Clinical Endocrinology & Metabolism 89(2):544–547Printed in U.S.A. Copyright © 2004 by The Endocrine Society

doi: 10.1210/jc.2003-032142

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DQB*0201/DQB*0302 heterozygous genotype, along withmultiple antibodies have the highest risk of progression toovert diabetes (70–100% over 10 yr) (11). Although geno-typing appears to add little predictive value to autoantibodyscreening, it may provide a once-only method of identifyingthose within the general population who would benefit fromsecond-round screening with autoantibodies. Those individ-uals with the dominantly protective allele DQB1*0602 or whocarry neither the DQB*0201 or DQB*0302 haplotypes (about50% of the Caucasian population) need no further screening.Such an approach has been applied for inclusion in the neo-natal cow’s milk exclusion intervention trial (12).

Prediction of the other common endocrine autoimmunediseases

AITD has been subject to less systematic study because theperceived benefits of early identification of at-risk individ-uals are less clearly defined. In the population-based Whick-ham study (13), serum thyroid peroxidase (TPO; microso-mal) antibody levels measured together with circulating TSHwere shown to predict thyroid failure in healthy unrelatedsubjects. Women with positive microsomal antibodies (butwith normal TSH) had a 2.1% per year risk of developingovert hypothyroidism. Overall, 27% of these euthyroidwomen who initially had serum thyroid antibodies werehypothyroid 20 yr later. Of women with both positive mi-crosomal antibodies and an elevated serum TSH, 55% werehypothyroid at 20 yr, progressing at a rate 4.3% per year (13).This study provides firm evidence on which to advise the10–15% of female subjects in the general population withpositive TPO antibodies about their low future risk of hy-pothyroidism. The data are less robust for men, although itappears that both microsomal antibodies and elevated TSHare, if anything, more predictive of overt hypothyroidism inmen compared with women.

Screening for postpartum thyroiditis (PPT) using TPO au-toantibodies during pregnancy has high sensitivity, correctlyidentifying 90% of women who will develop the problem(14). Specificity is low, however, with only about 50% ofantibody-positive individuals manifesting clinical thyroiddysfunction. PPT is a self-limiting condition in the majorityof cases, and the benefits of early identification are, therefore,not obvious. It has been argued that TPO antibody screeningfor PPT should be pursued, because PPT is associated withpostnatal depression (14). Furthermore, it identifies womenat high risk of progressing to chronic autoimmune hypothy-roidism (about 25% over 5 yr). However, TPO antibody pos-itivity during pregnancy may have no more long-term sig-nificance than that found at other times of life (15).

Predicting a second endocrinopathy

The discussion so far has focused on endocrine diseasesthat are common in the general population in whom pre-diction programs would be applicable to large numbers oflow-risk individuals. For subjects with a first endocrinopathyseeking guidance about their personal risk of a second dis-order, it seems their risk is, to a substantial extent, deter-mined by the nature and prevalence of their first disease. Forinstance, the rare subjects with Addison’s disease as a first

endocrinopathy have about 30% risk of AITD, whereas sub-jects with a more common disorder, childhood T1D, haveonly a 15–20% risk of developing an additional autoimmuneendocrine disorder over a lifetime. Similarly, subjects withAITD, the most common endocrine disease, have the lowestprobability of developing a second disorder (�5%). Is therea role for the application of antibody screening to forecastfurther endocrinopathy?

Addison’s disease

Addison’s disease, although rare, still carries a substantialmortality when unrecognized. This provides a clear rationalefor early detection in at-risk individuals. A large survey ofnearly 9000 adult Italian patients with a first autoimmuneendocrinopathy (predominantly AITD or T1D), assessed therisk of subsequently developing autoimmune adrenocorticalfailure (16). Overall, 0.8% of subjects were positive for ad-renal cortex antibodies (ACAs). However, 9% of the subjectswith autoimmune premature ovarian failure were ACA-positive. Of the 36 subjects who had positive ACA but nor-mal adrenal function at baseline, one third progressed tosymptomatic Addison’s disease or impaired adrenal func-tion on serial ACTH testing (16). The mean time to overtAddison’s disease from a state of normal adrenal functionwas 5.2 yr, with a range of 23 to 71 months. Antibodiesagainst 21 hydroxylase led to a small improvement in pre-dictive value over ACA, but 17 hydroxylase and side-chaincleavage p450 antibodies did not provide additional infor-mation over and above the 21 hydroxylase antibody assay(16). HLA genotyping added little predictive information.

From the complex to a simple monogenic disorder

It is against this background that the study of the mono-genic, autoimmune polyendocrinopathy syndrome type 1(APS1) or autoimmune polyendocrinopathy, candidiasis,and ectodermal dystrophy syndrome is set. This is a raredisorder with onset in childhood and adolescence, but witha relatively predictable course, such that it provides a uniquemodel in which to study the relationship between autoan-tibodies and hormonal failure (17, 18).

APS1 is due to recessive mutations in the autoimmuneregulator (AIRE) gene, which is located on chromosome21q22. The most frequent initial manifestation is chronicmucocutaneous candidiasis with an average onset occurringat 5 yr, which is typically followed by hypoparathyroidism(8 yr) and then Addison’s disease (12 yr) (17, 18). Of note,autoimmune hypoparathyroidism is very rarely seen outsidethe context of APS1. Other less common autoimmune fea-tures are diabetes, primary gonadal failure, pernicious ane-mia, intestinal malabsorption, hepatitis, hypothyroidism, al-opecia, and vitiligo. In comparison to patients with thecommon complex polyendocrinopathy syndrome (type 2 or3), in whom the average number of disease components istwo, subjects with APS1 have an average of four components.Interestingly, APS1 appears to be associated with a uniquespectrum of autoantibodies, some of which are rarely, if ever,found in other disorders.

In this issue of JCEM, Soderbergh et al. (1) present anextensive evaluation of 10 different autoantibodies in a large

Pearce and Leech • Editorial J Clin Endocrinol Metab, February 2004, 89(2):544–547 545

cohort of European APS1 subjects. They make three findingsof note. First, their results suggest that there is redundancyin testing for antibodies to multiple steroidogenic enzymesand that 21 hydroxylase and side-chain cleavage enzyme aresufficient for the prediction of adrenocortical and gonadalfailure, respectively. This extends a similar observation madein adults at risk of Addison’s disease (16).

Second, antibodies against tryptophan hydroxylase, ini-tially identified as being associated with intestinal dysfunc-tion in APS1, are shown in this study to be the strongestpredictor of autoimmune hepatitis. This is an important find-ing, because in one large series up to 5% of APS1 subjects diedof this complication (17). Screening and early detection mayallow timely intervention.

Finally, of 73 APS1 subjects with hypoparathyroidism,none had antibodies against parathyroid calcium-sensingreceptor (CaR). These findings are in contrast to the previousstudy of Li et al. (19) in which about 50% of sera from patientswith autoimmune hypoparathyroidism selectively recog-nized the extracellular domain of the CaR on immunoblot-ting studies. Kifor et al. (2), also in this issue, clearly dem-onstrate that parathyroid antibodies directed against the CaRare present and functionally important in two subjects withhypoparathyroidism, and they have previously demon-strated a comparable biological role for anti-CaR antibodiesin subjects with autoimmune hypercalcemia (20). These dis-crepant findings are likely to relate to differences in antibodyassay technique, highlighting the need for standardization ofsensitive antibody measurements. It is possible that naturallyoccurring autoantibodies to the CaR only recognize a con-formational epitope on the mature glycosylated receptor, butadditional work is needed to clarify this currently contro-versial area.

The study of organ-specific autoantibodies in APS1 hasprovided both a prediction model and a valuable insight intothe pathogenesis of autoimmune endocrinopathy. There iscurrently a flurry of investigation into the mechanism bywhich the defective AIRE gene causes an aberrant immuneresponse. AIRE is expressed in the thymic epithelial antigen-presenting cells, which have a role in educating T cells (neg-ative selection), i.e. eliminating self-reactive T cells. This mayexplain why APS1 subjects have a unique spectrum of au-toantibodies and a high penetrance of certain endocrinopa-thies. As we noted before, hypoparathyroidism is rare insituations other than APS1, suggesting that negative selec-tion of T cells that recognize the CaR and other unknownparathyroid antigens is critical for immune tolerance. Noveltargeted treatments for endocrine autoimmunity may stemfrom a better understanding of this well-characterized dis-ease in the next few years.

What can we hope to achieve from the measurement ofautoantibodies?

Over the last 40 yr, autoantibody assays have been devel-oped to the point of precise disease prediction for certaincommon endocrinopathies such as T1D. This has now set thestage for prevention programs in T1D, as and when appro-priate prevention strategies exist. In individuals with a singleautoimmune endocrinopathy, autoantibody screening can

aid the prediction of a life-threatening second manifestationof autoimmunity. The study of unique autoimmune syn-dromes such as APS-1 will provide many additional insightsinto the pathogenesis of these disorders and will advance thepursuit of targeted immunotherapy for autoimmune endo-crinopathy.

Simon H. S. Pearce and Nicola J. LeechInstitute of Human Genetics (S.H.S.P.) and School of

Clinical Medical Sciences (N.J.L.)University of NewcastleNewcastle upon Tyne, NE1 3BZ United Kingdom

Acknowledgments

We are grateful to Drs. Kate Owen and Tim Cheetham for criticalreading of the manuscript.

Received December 11, 2003. Accepted December 11, 2003.Address all correspondence and requests for reprints to: Dr. Simon

H. S. Pearce, Institute of Human Genetics, Centre for Life, Central Park-way, Newcastle upon Tyne, NE1 3BZ, United Kingdom. E-mail: s.h.s.pearce@ncl.ac.uk.

The work in Dr. Pearce’s laboratory was funded by the WellcomeTrust and Medical Research Council (London, UK).

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JCEM is published monthly by The Endocrine Society (http://www.endo-society.org), the foremost professional society serving theendocrine community.

Pearce and Leech • Editorial J Clin Endocrinol Metab, February 2004, 89(2):544–547 547