Undiagnosed coeliac disease at age seven: population based prospective birth cohort study
BMJ 2004; 328 doi: https://doi.org/10.1136/bmj.328.7435.322 (Published 05 February 2004) Cite this as: BMJ 2004;328:322
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The remarkable report by Bingley et al (1)assess the prevalence of CD in children as estimated as 1% similar to that in adults in UK. They screened this population according to the two steps fashion, performing TTGA first and subsequently they tested the cases with positive results on EMA. However, we believe that this strategy of screening is inefficient and inaccurate as a screening pathway. Using only a single serological marker or so called two steps screening is not reliable, as use of one serological test will underestimate the real coeliac’s prevalence. This fact has been extensively emphasised as the results of many old and new studies. However this evidence seems to be continuously ignored for some reason in some valuable studies and in clinical practice. Luckily the authors recognise that their strategy may miss some affected children who were not considered as having coeliac disease as they were only positive for TTGA and not for EMA. We know that coeliac patients in different treatable sequent of progression might be positive for an antibody and negative for the other one. Our experiences in assessing the sensitivity of serological tests in different centres show the overall sensitivity of serological tests do not exceed 75% when using the combination test pathway and very disappointed if using only one test (2). We should remember that with only one antibody test (EMA), three of 14 cases with CD would have been missed in Sanders et al study (Lancet. 2001 3;358:1504-8) and as reported by Dickey et al. Reliance on serum endomysial antibody testing underestimates the true prevalence of coeliac disease by one fifth (Scand J Gastroenterol. 2000;35:181-3), keeping in mind that we are dealing with the prevalence of antibodies rather than the real prevalence of CD by such an assessment.
Although a negative result of antibody screening does not exclude the CD diagnosis, a positive result of EMA/tTGA is highly associated with important histological changes. Therefore, we are quiet concern about antibody positive cases, hoping that they have not been left alone with their very likely significant intestinal abnormalities.
References
1. Bingley PJ, Williams AJ, Norcross AJ, Unsworth DJ, Lock RJ, Ness AR, Jones RW; Avon Longitudinal Study of Parents and Children Study Team.Undiagnosed coeliac disease at age seven: population based prospective birth cohort study. BMJ. 2004;328:322-3.
2. Rostami K, Kerckhaert J, Tiemessen R, von Blomberg BM, Meijer JW, Mulder CJ. Sensitivity of antiendomysium and antigliadin antibodies in untreated celiac disease: disappointing in clinical practice. Am J Gastroenterol. 1999 Apr;94(4):888-94
Competing interests: None declared
Competing interests: No competing interests
Sir,
I read with extreme interest the recent paper by Polly Bingley and collegues about the main problem of coeliac disease in clinical practice: this disease is unfortunately still undiagnosed both in childhood and in adult (1). I agree with Bingley’s last statement about the need of searching occult coeliac disease in more cases; however, I would pointed out the attention on two important clinical problems about coeliac disease.
First of all, the epidemiological studies on coeliac disease are nowadays performed by serological tests (2,3). Unfortunately there are many fine papers showing that effectiveness of serological tests in detecting coeliac disease is lower than expected in clinical practice (4,5). In my experience, serological tests (anti-gliadin, anti-endomysium and anti- tissue transglutaminase) show a low prevalence in clinical practice especially in screening patients affected by subclinical/silent form of the disease (6,7). In light of these experiences, there is the concrete risk that several coeliac patients may be missed if screened by serology alone. I think that serological tests should be integrated by other non- invasive tests (i.e. sorbitol or d-xylose H2 breath tests [8,9]) in order to identify correctly the patients undergoing to intestinal biopsy.
The second point has at least the same importance. Bingley and collegues state that “..The benefit of early diagnosis of subclinical coeliac disease remains unproven, but long term follow up of this cohort may help to resolve this…”. I wonder this sentence. It is clear why coeliac disease gets great benefits by an early diagnosis: the length of gluten exposure plays an important role in the appearance of autoimmune disorders (10), may influence the degree of endoscopic and histological damage of the duodenum (11) and may finally influence the mortality of the coeliac patients (12). A late diagnosis may increase these risk especially in patients affected by subclinical/silent form of the disease, in whom the risk are often underestimated (13).
An early diagnosis of coeliac disease should be then increased and, according to Bingley and collegues, the screening should be started in childhood.
REFERENCES
1) Bingley P, Williams AJK, Norcross AJ, Unsworth DJ, Lock RJ, ness Ar et al. Undiagnosed coeliac disease at age seven: population based prospective birth cohort study. BMJ 2004;328: 322-3
2) West J, Logan RF, Hill PG, Lloyd A, Lewis S, Hubbard R et al. Seroprevalence, correlates, and characteristic of indetected coeliac disease in England. Gut 2003;52: 960-5
3) Maki M, Mustalahti K, Kokkonen J, Kulmala P, Haapalahti M, Karttunen T et al. Prevalence of celiac disease among children in Finland. N Engl J Med 2003;348: 2517-24
4) Rostami K, Kerckhaert J, Tiemessen R, von Blomberg ME, Meijer JWR, Mulder CJJ. Sensitivity of antiendomysium and antigliadin antibodies in untreated celiac disease: disappointing in clinical practice. Am J Gastroenterol 1999;94: 888-94
5) Dickey W, Hughes DF, McMillan SA. Reliance on serum endomysial antibody testing underestimates the true prevalence of coeliac disease by one fifth. Scand J Gastroenterol 2000;35: 181-3
6) Tursi A, Brandimarte G, Giorgetti G, Gigliobianco A, Lombardi D, Gasbarrini G. Low prevalence of antigliadin and anti-endomysium antibodies in subclinical/silent coeliac disease. Am J Gastroenterol 2001; 96: 1507- 10
7) Tursi A, Brandimarte G, Giorgetti G. Prevalence of anti-tissue transglutaminase antibodies in different degrees of intestinal damage in celiac disease. J Clin Gastroenterol 2003; 36: 219-221
8) Casellas F, Sardi J, de Torres I, Malagelada J-R. Hydrogen breath test with D-xylose for celiac disease screening is as useful in the elderly as in other age groups. Dig Dis Sci 2001;46: 2201-2205
9) Tursi A, Brandimarte G, Giorgetti GM. Sorbitol H2-breath test versus anti-endomysium antibodies for the diagnosis of subclinical/silent coeliac disease. Scand J Gastroenterol 2001;36: 1170-2
10) Ventura A, Magazzù G, Greco L, for the SIGEP study group for autoimmune disorders in celiac disease. Duration of exposure to gluten and risk of autoimmune disorders in patients with celiac disease. Gastroenterology 1999;117: 297-303
11) Tursi A, Brandimarte G, Giorgetti GM, Gigliobianco A. Endoscopic features of celiac disease in adults and their correlation with age, histological damage and clinical form of the disease. Endoscopy 2002;34: 787-792
12) Corrao G, Corazza GR, Bagnardi V, Brusco G, Ciacci C, Cottone M et al. Mortality in patients with coeliac disease and their relatives: a cohort study. Lancet 2001;358: 356-61
13) Giorgetti GM, Tursi A, Brandimarte G, Anemona L. Small bowel adenocarcinoma as first sign of coeliac disease. Minerva Gastroenterol Dietol 2002;48: 347-350
Competing interests: None declared
Competing interests: No competing interests
To the Editor- In future years we may look back in disbelief at our slowness to institute a national screening programme for coeliac disease (CD). Of course, a better understanding of the natural history of CD, would better enable us to advise the 54 seven year olds with endomysial antibodies in this study [1]. We may find that a low-gluten-containing diet instituted early in life removes the need for a strict life-long gluten free diet. It might be possible to observe whether development of gluten tolerance can occur, causing transient CD, and if so, what factors play a part in the development of this tolerance.
The concepts of silent, latent and potential CD [2] are worth considering. Silent CD is characterised by villous atrophy on a small bowel biopsy in the absence of clinical symptoms. Both latent and potential CD have normal small bowel mucosa whilst on a gluten containing diet. A patient with latent CD has at some in the past had villous atrophy that improved on a gluten free diet. The ability of patients with latent CD to eat gluten may reflect some form of tolerance, or cast doubt on the validity of their original diagnosis.
The conversion of a patient from active to latent CD by the treatment of co-existing giardiasis [3] raises the possibility that infections may be an important co-factor in the development of CD. By increasing levels of pro-inflammatory cytokines in the intestinal mucosa, tolerance to gluten may be prevented.
A child with potential CD has never had villous atrophy but has immunological abnormalities found in CD. These include endomysial antibodies, and high numbers of intraepithelial gamma delta T cells. When comparing the Avon longitudinal study of parents and children (ALSPAC) [1] and the Finnish study [4], age is a crucial factor. The majority of small bowel biopsies in the Finnish study were taken 7 years after the blood samples used for antibody testing. In this time many of the children, initially aged 7-16, may have converted from potential to silent or overt CD, to account for a prevalence of diagnostic small bowel changes of 83 %.
What proportion of these 54 seven year olds [1] have silent or potential CD now, and in the future, might help to answer many of our questions. Any screening programme will probably need to start much younger than 7 to identify potential CD before complications arise.
Undetected CD increases the risk of short stature, weight loss and osteoporosis. They have already lost the equivalent of 9 months' growth and weight [1]. To allow these children to remain untreated may not be ethical.
1 Bingley P, Williams A, Richard W, Jones R et al. Undiagnosed coeliac disease at age seven: population based prospective birth cohort study. BMJ 2004;328:322-323 (7 February).
2 Holmes GK. Potential and latent coeliac disease. Eur J Gastroenterol Hepatol. 2001 Sep;13(9):1057-60.
3 Troncone R, Greco L, Mayer M, Paparo F, Caputo N, Micillo M, Mugione P, Auricchio S. Latent and potential coeliac disease. Acta Paediatr Suppl. 1996 May;412:10-4.
4 Maki M, Mustalahti K, Kokkonen J, Kulmala P, Haapalahti M, Karttunen T, et al. Prevalence of celiac disease among children in Finland. N Engl J Med 2003;348: 2517-24.
Competing interests: None declared
Competing interests: No competing interests
In their study, Polly J Bingley et al find 1% of children positive for IgA antiendomysial antibodies (IgA-EMA) and thus likely to have subclinical coeliac disease, whereas the prevalence of coeliac disease in this agegroup is only 0,1% (1). 20% of children with insulin-dependent diabetes mellitus (IDDM) react to rectal instillation of gliadin(2), up to 12% carry IgA-EMA antibodies (3). Screening of paediatric patients with IDDM will help to effectively identify a subgroup with undiagnosed disease. Close monitoring of these patients is possible with only little additional effort because these children have to be monitored anyway.
Results will yield further data on the benefits of early diagnosis which may prove to significantly improve the further clinical course.
(1) Bingley PJ et al; Undiagnosed coeliac disease at age seven: population based prospective birth cohort study BMJ 2004;328:322-323
(2)Troncone R et al; Gluten sensitivity in a subset of children with insulin dependent diabetes mellitus. Am J Gastroenterol. 2003 Mar;98(3):590-5.
(3)Arato A et al; Frequency of coeliac disease in Hungarian children with type 1 diabetes mellitus. Eur J Pediatr. 2003 Jan;162(1):1-5.
Competing interests: None declared
Competing interests: No competing interests
In commenting on the recent study :
Bingley P, Williams A, Richard W Jones R et al. Undiagnosed coeliac disease at age seven: population based prospective birth cohort study. BMJ 2004;328:322-323
Dr Katona comments:
"we must question whether it is ethical not to inform the 53 patients with IgA endomysial antibodies who are not on a gluten free diet. They have a high risk of developing clinical disease and might choose to start a gluten free diet"
I would add, that in a swift and non comprehensive search of the Pub- Med Database (refs 1-8) it would seem to be unethical not to provide this information. The relationship of previously undiagnosed Coeliac disease, which appears to be of a greater prevalence than previously suspected, to other Auto-Immune diseases has been noted.
MCF
(1)Acta Paediatr. 2003;92(2):165-9. Epidemiological changes in diagnosed coeliac disease in a population of Spanish children.
Lopez-Rodriguez MJ, Canal Macias ML, Lavado Garcia JM, Sanchez Belda M, Robledo Andres P, Pedrera Zamorano JD.
Department of Paediatrics, "San Pedro de Alcantara" Hospital, Caceres, Spain
(2)Mol Psychiatry. 2002;7(4):375-82, 334.
Small intestinal enteropathy with epithelial IgG and complement deposition in children with regressive autism.
Torrente F, Ashwood P, Day R, Machado N, Furlano RI, Anthony A, Davies SE, Wakefield AJ, Thomson MA, Walker-Smith JA, Murch SH.
Centre for Paediatric Gastroenterology, Royal Free & University College Medical School, London, UK.
(3)Hosp Med. 2003 Nov;64(11):684-5. Coeliac disease and Crohn's disease: an association not to be forgotten.
Chakraborty A, Bremner
(4)http://www.ajcn.org/cgi/content/abstract/79/1/148
American Journal of Clinical Nutrition Jan 2004 Longitudinal changes in bone metabolism and bone mineral content in children with celiac disease during consumption of a gluten-free diet1,2,3 Graziano Barera, Sabrina Beccio, Maria Carla Proverbio and Stefano Mora1
(5): Arch Dis Child. 2002 Oct;87(4):293-6. Coeliac disease and liver dysfunction.
Davison S.
Paediatric Liver and GI Unit, St James's University Hospital, Leeds, UK. suzanne.davison@lth.nhs.uk
(6)http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12765303&dopt=Abstract
Lupus. 2003;12(5):394-9. The prevalence of coeliac disease antibodies in patients with the antiphospholipid syndrome.
Shamir R, Shoenfeld Y, Blank M, Eliakim R, Lahat N, Sobel E, Shinar E, Lerner A.
(7)Acta Gastroenterol Belg. 2003 Jul-Sep;66(3):237-40. Related Articles, Links
Coeliac disease in patients with type 1 diabetes mellitus and auto- immune thyroid disorders.
Buysschaert M.
Department of Endocrinology and Nutrition, Cliniques Universitaires St Luc, Universite Catholique de Louvain, B-1200 Brussels, Belgium. buysschaert@diab.uci.ac.be
(8)J Child Neurol. 1999 Jun;14(6):388-94
Familial clustering of autoimmune disorders and evaluation of medical risk factors in autism.
Comi AM, Zimmerman AW, Frye VH, Law PA, Peeden JN.
Johns Hopkins Hospital, Division of Pediatric Neurology, Baltimore, MD 21212, USA. acomimd@aol.com
Competing interests: Parent of Autistic child
Competing interests: No competing interests
Coeliac disease is surely underdiagnosed even in childhood and it could depend by the variety of its clinical features. Moreover patients could have many problembs in the case of a slight simptomatology and isto- pathological findings. In two cases, mother and son, cause of their lwo stature and abdominal symptoms coaliac disease was suspected. IgA-EMA were found positive in both the patients. Mucosal findings at Duodenal biopsies did not show the coeliac classic alterations: it was only slightly flat and so it was defined by the pathologist not sure for diagnosing coeliac disease. The patients by themselves started a gluten free diet and it was observed a rapid improvement of their symptoms. IgA-EMA were non controlled again couse the time of diet was too short. In fact after few months they stopped the diet because of the cost. In Italy gluten free foods are fee-free only in those cases were mucosal changes are strong: flat mucosa. EMA and AGA antibodies are just used for the follow up. So what will these patient do? and what shall we, as gps or specialists, do in tese cases? Is it the case to reclisify this disease? Let's try to answer if Coeliac Disease: one or more types?(1)
(1)Coeliac Disease: one or more types? BMJ;4 December 2003
Competing interests: None declared
Competing interests: No competing interests
To the Editor - This study [1] supports the results of the Finnish study [2] which found IgA transglutaminase and endomysial antibodies in 46 out of 3654 students aged 7-16. However, the prevalence of diagnostic histological changes on small bowel biopsy may not be as high as 83 % at the time of antibody testing. In the Finnish study [2], blood samples for antibody testing were taken in 1994, and the small bowel biopsies performed in 2001, some 7 years later. A prospective, long-term surveillance study [3] re-evaluated relatives of patients with coeliac disease after a median time of 86 months. They found two relatives with IgA endomysial antibodies and flat small bowel mucosa, whom had no antibodies at initial screening. The natural history of coeliac disease may show a significant lag time from the development of these antibodies to changes on small bowel biopsy and clinical disease. This is in common with other autoimmune diseases such as systemic lupus erythematosus (SLE). In a retrospective study of SLE in U.S. Armed Forces personnel [4], autoantibodies were present up to 9.4 years before diagnosis.
Although samples from the Avon longitudinal study of parents and children (ALSPAC) are anonymous, we must question whether it is ethical not to inform the 53 patients with IgA endomysial antibodies who are not on a gluten free diet. They have a high risk of developing clinical disease and might choose to start a gluten free diet. If they have already lost the equivalent of 9 months' growth and weight gain, then can we justify watching as they deteriorate further. The Finnish study has already demonstrated what is likely to be the natural history of the disease from the development of autoantibodies to mucosal changes [2].
1 Bingley P, Williams A, Richard W Jones R et al. Undiagnosed coeliac disease at age seven: population based prospective birth cohort study. BMJ 2004;328:322-323 (7 February).
2 Maki M, Mustalahti K, Kokkonen J, Kulmala P, Haapalahti M, Karttunen T, et al. Prevalence of celiac disease among children in Finland. N Engl J Med 2003;348: 2517-24.
3 Niveloni S, Pedreira S, Bai JC et al. The natural history of gluten sensitivity: report of two new celiac disease patients resulting from a long-term follow-up of nonatrophic, first-degree relatives. Am J Gastroenterol. 2000 Feb;95(2):463-8.
4 Arbuckle MR, McClain MT, Harley JB et al. Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med. 2003 Oct 16;349(16):1526-33.
Competing interests: None declared
Competing interests: No competing interests
I was so pleased to see the results of the Avon Longitudinal Study of parents and children (ALSPAC)which confirm what many people working with adult coeliacs have suspected for a long time - that coeliac disease is likely to be a lifelong condition beginning in childhood. However I was surprised that the authors described the association of short stature and childhood coeliac disease as a "striking observation" suggesting that they were possibly unaware of the well-recognised association of short stature and untreated coeliac disease(1). I am surprised that screening for coeliac disease is rarely included in the work-up for failure to thrive and short stature in children, but hopefully the results of the ALSPAC study may help to change this.
Reference:- 1. Short Stature as the Primary Manifestation of Coeliac Disease JPediatr 1983 Nov 708-711 Groll et al
Competing interests: Mother of 2 coeliac children and former medical adviser for SHS International
Competing interests: No competing interests
IgA antibody testing for coeliac disease has no value in patients with selective IgA deficiency.
Sir:
I enjoyed reading the article by Bingley et al, but am concerned that they have under-estimated the point prevalence of serological results suggestive of hitherto undiagnosed coeliac disease (CD) in this cohort of seven year olds. 1 My concern is based on the sole use of IgA-based antibody tests without any reference to concomitant assessment of the serum IgA concentration among these subjects. (This may have been undertaken in every case, but there is no reference to it in the methods or comment sections of the paper respectively).
Selective IgA deficiency (SIgAD), i.e. a serum concentration of less than 0.05 g/L in the setting of normal IgG and IgM levels, has a reported prevalence of between 0.14% and 0.2% in European subjects. 2 However, two retrospective, case-control studies, (one was in adults only; 3 the other in adults and children 4) revealed that the prevalence of CD among patients with SIgAD is at least 10 times more common than that observed in the general population. Furthermore, both studies demonstrated conclusively that IgA-based antibody testing for suspected or undiagnosed CD is futile.
None of 25 patients who had histological evidence consistent with CD and co-existent SIgAD demonstrated positive IgA anti-reticulin (ARA) or anti- gliadin (AGA) antibody results, whereas IgG-based ARA and AGA results were positive in 94% and 43% respectively of these same patients. By contrast, 91% of the control group (25 patients with CD, but not SIgAD) demonstrated positive IgA ARA and AGA results. 3
In the second study, all 54 patients (eight adults and 46 children) with histological evidence of CD and concomitant SIgAD had negative IgA AGA and anti-endomysial antibody (EMA) results, but 94.4% of the same group had positive IgG AGA results. Among 2044 control subjects (CD, but not SIgAD), 86.6% and 96.6% had positive IgA AGA and EMA results respectively. 4 A subsequent study by the same group found that testing with IgG1 EMA and IgG anti-tissue transglutaminase (tTG) antibodies might be the most sensitive and specific serological means of detecting hitherto undiagnosed CD among patients with SIgAD, albeit the number of patients tested was small. 5
If the prevalence of SIgAD in the current study population was 0.2% then as many as 11 patients might have been affected. Therefore, serological testing for undiagnosed CD using IgA tTG and EMA antibodies would have returned false negative results, thereby underestimating the prevalence of CD by up to 16%.
References
1. Bingley PJ, Williams AJK, Norcross AJ, Unsworth DJ, Lock RJ, Ness AR et al. Undiagnosed coeliac disease at age seven: population based prospective birth cohort study. BMJ 2004;328:322-323.
2. Waldmann TA. Immunodeficiency diseases: primary and acquired. In: Samter M, Talmage DW, Frank MM, Austen KF, Claman HN, eds. Immunological diseases. 4th ed. Boston: Little, Brown and Company, 1998:411-63.
3. Collin P, Maki M, Keyrilainen O, Hallstrom T, Reunala T, Pasternack A. Selective IgA deficiency and coeliac disease. Scand J Gastroenterol 1992;27:367-71.
4. Cataldo F, Marino V, Ventura A, Bottaro G, Corazza GR. Prevalence and clinical features of selective immunoglobulin A deficiency in coeliac disease: an Italian multicentre study. Gut 1998;42:362-65.
5. Cataldo F, Lio D, Marino V, Picarelli A, Ventura A, Corazza GR. IgG1 antiendomysium and IgG antitissue transglutaminase (anti-tTG) antibodies in coeliac patients with selective IgA deficiency. Gut 2000;47:366-69.
Competing interests: None declared
Competing interests: No competing interests