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Journal of Pediatric Gastroenterology & Nutrition:
doi: 10.1097/MPG.0b013e31821c974f
Case Reports

Spontaneous Negative Seroconversion of Endomysial Antibodies Does Not Exclude Subsequent Celiac Disease

Kurppa, Kalle*; Collin, Pekka; Lindfors, Katri*; Mäki, Markku*; Kaukinen, Katri

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*Pediatric Research Centre, University of Tampere and Tampere University Hospital

Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital and Medical School, University of Tampere, Tampere, Finland.

Address correspondence and reprint requests to Katri Kaukinen, MD, PhD, University of Tampere, Medical School, FIN-33014 University of Tampere, Finland (e-mail: katri.kaukinen@uta.fi).

Received 27 December, 2010

Accepted 19 March, 2011

This study and the Celiac Disease Study Group were supported by the Academy of Finland Research Council for Health, the Competitive Research Funding of the Pirkanmaa Hospital District, the Sigrid Juselius Foundation, the Foundation for Paediatric Research, the National Graduate School of Clinical Investigation, the Ehrnrooth Foundation and the Finnish Celiac Society, the Finnish Foundation for Gastroenterological Research, the Yrjö Jahnsson Foundation, Duodecim, and the Finnish Medical Foundation.

The authors report no conflicts of interest.

According to current criteria, detection of small-bowel mucosal villous atrophy and crypt hyperplasia is required for the final diagnosis of celiac disease (1); however, some individuals may evince positive serum transglutaminase and endomysial antibodies while still having normal villous morphology (2). These subjects are considered to have so-called potential celiac disease and may later develop mucosal atrophy or experience clinical symptoms and benefit from early treatment while the villous morphology is still normal (3–8). Particularly subjects who have low antibody titers may remain in clinical latency or undergo negative seroconversion despite taking a gluten-containing diet, however (9–12). Such cases are often considered to be false-positive for celiac antibodies, but at present their natural history remains unclear.

We describe 4 individuals who had clinical suspicion of celiac disease and positive serum endomysium antibodies but normal small-bowel mucosal villous morphology. In all of the patients, a temporary negative seroconversion was seen despite a regular gluten-containing diet; however, after variable periods they developed small-bowel mucosal villous atrophy and crypt hyperplasia diagnostic for celiac disease.

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PATIENT 1

A 2-year-old boy was screened for serum celiac antibodies as his sister was found to have celiac disease. He showed no signs of malabsorption, but endomysial antibodies were positive (titer 1:5). Several small-bowel mucosal biopsies were taken upon gastrointestinal endoscopy, but there were no signs of villous atrophy and crypt hyperplasia. The child continued on a gluten-containing diet and later became seronegative. Thereafter, no regular follow-up was maintained; however, at age 19 years he developed gastrointestinal symptoms suggestive of celiac disease, and the endomysial antibodies had seroconverted to positive (1:500). He also had the HLA-DQ2 genotype characteristic for celiac disease. A new endoscopy was performed and revealed total villous atrophy with crypt hyperplasia diagnostic for celiac disease. The subject started a gluten-free diet, which resulted in good clinical and histological response and disappearance of the serum autoantibodies.

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PATIENT 2

A 30-year-old normal-weight woman had slightly elevated serum alanine aminotransferase levels (82 U/L, reference value ≤45) and a fatty liver disease. In subsequent investigations she was found to have positive endomysial antibodies (1:50) and an HLA-DQ2 genotype suggestive of celiac disease. Upper gastrointestinal endoscopy was carried out, but no morphological damage was detected in the small-bowel mucosa. In frozen mucosal samples there was an increased density of mucosal CD3+, αβ+, and γδ+ intraepithelial lymphocytes, and mucosal transglutaminase 2-specific autoantibody deposits with normal villi indicating potential celiac disease (14) (Fig. 1). Nevertheless, the official criteria for celiac disease were not fulfilled and the subject remained undiagnosed. After 1 year she became seronegative despite a regular gluten-containing diet. Two years later she complained of abdominal pain and her endomysial antibodies were again positive (1:500). Small-bowel mucosal biopsy showed total villous atrophy and crypt hyperplasia (Fig. 1). In addition, both of the density of the intraepithelial lymphocytes and the intensity of the autoantibody deposits were increased. Celiac disease was diagnosed and she was placed on a gluten-free diet, during which her clinical symptoms and endomysial antibodies disappeared.

Figure 1
Figure 1
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PATIENT 3

A 4-year-old girl was investigated in view of poor growth. There were no clinical symptoms or signs of malabsorption, but her serum endomysial antibodies were positive (1:5). Nonetheless, because the small-bowel mucosal biopsy specimens showed normal villous structure, celiac disease was excluded and she continued on a gluten-containing diet. Her height remained significantly below that expected, but subsequently she was seroconverted to negative and regular follow-up was discontinued. At age 16 years, however, she underwent serological reinvestigations and was again found to have positive endomysial (1:50) and transglutaminase antibodies (26.0 U/L, reference value <5.0). She also had the HLA-DQ2 genotype. A new endoscopy was carried out and the mucosal biopsies revealed subtotal villous atrophy with crypt hyperplasia diagnostic for celiac disease (Fig. 1). A gluten-free diet was initiated, and after 1 year of receiving treatment she had converted to seronegative.

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PATIENT 4

A 32-year-old normal-weight man was investigated by reason of increased liver enzymes and mild abdominal complaints. No specific explanation was found and later the transaminases normalized and the symptoms were alleviated without medical intervention. Five years later he participated in a celiac disease family study because his mother had celiac disease. Positive endomysial antibodies (1:5) were detected and gastrointestinal endoscopy was carried out, but the mucosal samples showed normal villous morphology and he remained on a normal diet. After another 5 years he became seronegative and follow-up was discontinued. Seventeen years later, at age 54, he participated in another family study of celiac disease. This time he had loose stools and the endomysial and transglutaminase antibodies had seroconverted to positive (1:500 and 32.4 U/L, respectively). He also had the HLA-DQ2 genotype, and a new small-bowel biopsy showed total villous atrophy with crypt hyperplasia diagnostic for celiac disease. After 1 year of receiving a gluten-free diet, the symptoms had disappeared, histological changes were ameliorated, and the serum antibody titers decreased.

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DISCUSSION

The present study showed that antibody-positive patients with celiac disease may temporarily become seronegative on a normal gluten-containing diet (ie, approximately 10–15 g/day gluten), and that celiac disease with small-bowel mucosal damage may still occur later in life. It was also demonstrated that not even low antibody titers can be automatically considered a false-positive finding. Furthermore, it must be borne in mind that the small-bowel mucosal lesion can always be patchy, predisposing to false-negative results. These observations highlight the need for a lifelong and careful follow-up of such endomysial antibody-positive individuals despite the initially normal villous morphology. Also, as in 2 of our cases, celiac disease had been ruled out in childhood, adult gastroenterologists should be aware that, even if once excluded, the disease may still manifest later in adulthood. Interestingly, we have recently shown that even the phenotype of celiac disease may change from the classical intestinal form to extraintestinal dermatitis herpetiformis, further demonstrating that clinicians’ alertness to recognizing the heterogeneous presentation is essential (16).

Here, we also showed, in accord with some previous studies, that the development of small-bowel mucosal villous atrophy in seropositive individuals may take decades despite continuous exposure to dietary gluten (9,15). We should therefore be cautious in making the diagnosis of transient celiac disease. This notwithstanding, there are also examples of long-term disease latency even on a normal diet (10,13). Hopman et al (13) observed 2 patients with apparent celiac disease latency after 20 years without treatment. Matysiak-Budnik et al (9) found that 13 of 61 patients with celiac disease diagnosed in childhood showed no significant clinical or histological signs of the disease despite being on an unrestricted diet for up to 21 years. Some of these cases, however, yielded abnormal laboratory values, positive celiac autoantibodies, and signs of mucosal inflammation, and 2 of them later had clinical and histological relapse (9). Although it is possible that some patients with celiac disease will develop temporary or even permanent tolerance for gluten, at the same time there is evidence that some seropositive cases may benefit from early treatment before villous atrophy develops (5–8). In our opinion, a gluten-free diet may be considered in such symptomatic cases, particularly if there are also signs of celiac disease–associated complications. The determination of celiac-type genetics in these subjects is also helpful, because if results prove negative, celiac disease is unlikely.

By contrast, at present it remains debatable whether asymptomatic subjects detected by mass screening would gain similar profit from the treatment. In fact, recent results indicate that not even those asymptomatic patients who already have villous atrophy will gain significant health benefits from dietary treatment (17). In addition, whereas in most symptomatic seropositive individuals the mucosal damage will progress while on a gluten-containing diet (7,8), this may not be the case in those having no symptoms (8,13,18,19). Nevertheless, although it remained uncertain whether the poor growth in patient 2 and increased serum transaminases in patients 3 and 4 were caused by gluten consumption, both complications are associated with untreated celiac disease (1,20). It may even be hypothesized that earlier diagnosis and treatment would have prevented the female patients’ permanent growth restriction. In any case, the potential risk of such problems in an otherwise asymptomatic subject gives cause for concern, and more prospective and controlled studies in such subjects should be carried out. Also, because the tranglutaminase antibodies were not available at the time of our first investigations, whether they behave similarly to the endomysial antibodies remains to be studied.

In conclusion, the present study showed that the natural history of endomysial-antibody–positive celiac disease is highly variable and that a temporary negative seroconversion does not exclude subsequent overt celiac disease. The possible progression of the mucosal damage after an extended period warrants lifelong monitoring of such cases. In addition, there is increasing evidence to suggest that at least symptomatic seropositive individuals may benefit from early treatment even before small-bowel mucosal atrophy develops.

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REFERENCES

1. Hill ID, Dirks MH, Liptak GS, et al. Guideline for the diagnosis and treatment of celiac disease in children: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2005; 40:1–19.

2. Fasano A, Berti I, Gerarduzzi T, et al. Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a large multicenter study. Arch Intern Med 2003; 163:286–292.

3. Ferguson A, Arranz E, O’Mahony S. Clinical and pathological spectrum of coeliac disease-active, silent, latent, potential. Gut 1993; 34:150–151.

4. Mäki M, Holm K, Koskimies S, et al. Normal small bowel biopsy followed by coeliac disease. Arch Dis Child 1990; 65:1137–1141.

5. Kaukinen K, Mäki M, Partanen J, et al. Celiac disease without villous atrophy: revision of criteria called for. Dig Dis Sci 2001; 46:879–887.

6. Paparo F, Petrone E, Tosco A, et al. Clinical, HLA, and small bowel immunohistochemical features of children with positive serum antiendomysium antibodies and architecturally normal small intestinal mucosa. Am J Gastroenterol 2005; 100:2294–2298.

7. Kurppa K, Collin P, Viljamaa M, et al. Diagnosing mild enteropathy celiac disease: a randomized, controlled clinical study. Gastroenterology 2009; 136:816–823.

8. Kurppa K, Ashorn M, Iltanen S, et al. Celiac disease without villous atrophy in children: a prospective study. J Pediatr 2010; 157:373–380.

9. Matysiak-Budnik T, Malamut G, de Serre NP, et al. Long-term follow-up of 61 coeliac patients diagnosed in childhood: evolution toward latency is possible on a normal diet. Gut 2007; 56:1379–1386.

10. Simell S, Hoppu S, Hekkala A, et al. Fate of five celiac disease-associated antibodies during normal diet in genetically at-risk children observed from birth in a natural history study. Am J Gastroenterol 2007; 102:2026–2035.

11. Simell S, Hoppu S, Simell T, et al. Age at development of type 1 diabetes- and celiac disease-associated antibodies and clinical disease in genetically susceptible children observed from birth. Diabetes Care 2010; 33:774–779.

12. Hogen Esch C, Csizmadia G, van Hoogstraten I, et al. Childhood coeliac disease: towards an improved serological mass screening strategy. Aliment Pharmacol Ther 2010; 31:760–766.

13. Hopman EG, von Blomberg ME, Batstra MR, et al. Gluten tolerance in adult patients with celiac disease 20 years after diagnosis? Eur J Gastroenterol Hepatol 2008; 20:423–429.

14. Salmi TT, Collin P, Reunala T, et al. Diagnostic methods beyond conventional histology in coeliac disease diagnosis. Dig Liver Dis 2010; 42:28–32.

15. Mäki M, Lähdeaho ML, Hällström O, et al. Postpubertal gluten challenge in coeliac disease. Arch Dis Child 1989; 64:1604–1607.

16. Kurppa K, Koskinen O, Collin P, et al. Changing phenotype of celiac disease after long-term gluten exposure. J Pediatr Gastroenterol Nutr 2008; 47:500–503.

17. Ukkola A, Mäki M, Kurppa K, et al. Diet improves perception of health and well-being in symptomatic, but not asymptomatic, patients with celiac disease. Clin Gastroenterol Hepatol 2011;9:118–23.

18. van Koppen EJ, Schweizer JJ, Csizmadia CG, et al. Long-term health and quality-of-life consequences of mass screening for childhood celiac disease: a 10-year follow-up study. Pediatrics 2009; 123:e582–e588.

19. Tosco A, Salvati VM, Auricchio R, et al. Natural history of potential celiac disease in children. Clin Gastroenterol Hepatol 2011;9:320–5.

20. Troncone R, Kosova R. Short stature and catch-up growth in celiac disease. J Pediatr Gastroenterol Nutr 2010; 51:S137–S138.

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