- Email: [email protected]
Coeliac disease
THE LANCET
Seminar
Coeliac disease
Diagnostic criteria The diagnostic criteria, as stated by the European Society for Paediatric Gastroenterology and Nutrition (ESPGAN) in 1970, are: small-bowel mucosal atrophy with improvement or normalisation on a gluten-free diet and a deterioration of the villous morphology during intake of a gluten-containing diet. In 1990, these criteria were modified.3 The findings of characteristic small-bowel mucosal atrophy and clinical remission on a gluten-free diet are essential. In symptom-free patients, a second biopsy sample is needed to show mucosal recovery on treatment with a gluten-free diet. The presence of circulating antibodies and their disappearance on a glutenfree diet support the diagnosis. The old ESPGAN criteria, including gluten challenge, may be used when needed—eg, in children younger than 2 years who live in countries where intolerance to protein in cow’s milk is common, or in patients for whom the findings from their first biopsy sample was equivocal. Gluten challenge after mucosal healing in children who are initially negative for serum reticulin or endomysial antibodies is also advisable (the challenge should not be done in children younger than 6 years).3 In developed countries, coeliac disease is generally indicated by a manifest mucosal lesion with typical villous atrophy and crypt hyperplasia in adults and in children older than 2 years with or without symptoms or signs of malabsorption (figure 1). Small-bowel biopsy sampling is essential, and the diagnosis should not be based on symptoms or serological tests alone. By definition, coeliac disease is excluded in patients who have a normal small-bowel mucosal morphology when they are on a normal gluten-containing diet. However, gluten sensitivity is no longer restricted to villous atrophy. Smallbowel mucosal damage develops gradually from normal mucosal morphology to overt atrophy with hyperplasia of Lancet 1997; 349: 1755–59 Departments of Paediatrics (M Mäki MD) and Medicine (P Collin MD), Tampere University Hospital and University of Tampere, PO Box 607, FIN-33101 Tampere, Finland Correspondence to: Dr Markku Mäki (e-mail: [email protected])
Vol 349 • June 14, 1997
DR3-DQ2 DR5/7-DQ2 DR4-DQ8
Manifest mucosal lesion
Clinical coeliac disease Silent coeliac disease Coeliac disease latency
Healthy individuals
Jejunal morphology
Coeliac disease was described with great accuracy by Samuel Gee more than a century ago.1 However, the harmful effect of ingested wheat gluten was not recognised until the late 1940s by Dicke.2 Soon after this discovery peroral small-bowel biopsy, the cornerstone for making an accurate diagnosis, was introduced. Life-long glutensensitive disorder, characterised by malabsorption in its classical form, and the typical small-bowel histological lesion are well understood. However, during the 1980s and 1990s, it has become apparent that coeliac disease is underdiagnosed and that the clinical features of the disease have changed in both children and adults. Genetic and immunobiological reseach has taken a leap forward. This seminar focuses on the established facts of coeliac disease and introduces advances in clinical and basic research.
Genetic susceptibility
Markku Mäki, Pekka Collin
Normal mucosal morphology
Figure 1: The coeliac disease iceberg and spectrum of gluten sensitivity
crypts.4 The early lesion comprises lymphocyte infiltration into the epithelium and lamina propria. Individuals who are on normal amounts of gluten and have normal smallbowel villous architecture can still be gluten-sensitive; they may have a latent coeliac disease and small-bowel villous atrophy and crypt hyperplasia is contracted later in the disease process.5 The definition of coeliac-type gluten sensitivity (coeliac trait) should also include the susceptibility genes for coeliac disease (figure 1). Latent coeliac disease may be suspected in individuals: positive for reticulin and endomysial tissue autoantibodies with a high density of ␥␦ T-cell-receptorbearing intraepithelial lymphocytes, or with positive coeliac-like intestinal antibody pattern. Diagnostic difficulties emerge when minor mucosal changes are found such as partial small-bowel villous atrophy, or an increased density of intraepithelial lymphocytes in otherwise normal mucosa. Patients may be advised to go on a gluten-free diet to show clinical response as a sign of gluten sensitivity. We recommend that these patients should be followed up while on a normal glutencontaining diet. A new biopsy sample should be taken if symptoms appear or worsen or if a clear increase in antibody titres is found. In any case a follow-up biopsy sample should be done within 2 years if latent coeliac disease is suspected. Alternatively, an aggressive gluten challenge can be done to show mucosal deterioration. Dermatitis herpetiformis, a skin disease characterised by blistering, is the classical non-gastrointestinal manifestation of coeliac disease along with granular IgA deposits in unaffected skin. About 75% of patients with dermatitis herpetiformis have small-bowel villous atrophy with crypt hyperplasia, and in the remainder, minor mucosal changes can be seen.6 Both the mucosal lesion and rash respond to the gluten-free diet and a life-long diet is the treatment of choice. Dermatitis herpetiformis and coeliac disease share the HLA-DQ2 haplotype, and both diseases may exist within one family. Dermatitis herpetiformis can be seen as one manifestation of coeliac disease rather than an associated disease. 1755
THE LANCET
Clinical suspicion of coeliac disease Strong
Screening for coeliac disease
oesophageal cancer has also been found in coeliac disease. Again the risk of malignancy seems to be significantly lower when the coeliac iceberg is explored.16,19
Weak
Role of cereals Small-bowel biopsy
Gastroscopy for other reasons
Serum antibodies • IgA-class and IgG-class gliadin AB • IgA-class reticulin and endomysial AB
Figure 2: Algorithm for diagnosis of coeliac disease
Changing symptom pattern and associated disorders Diarrhoea, weight loss, and weakness have been the classic signs of coeliac disease in adults. A severe malabsorption syndrome has been common as well. In the early 1980s, British investigators showed that the clinical features of coeliac disease have changed.7,8 There had been by this time a shift towards milder symptoms such as indigestion in adults and recurrent abdominal pain in children. The classic symptoms and signs had become rare. Sometimes isolated iron deficiency is the only manifestation of coeliac disease. And, despite manifest mucosal lesion the disease can be even symptom-free, clinically silent. Silent coeliac disease has been reported in relatives of coeliac patients, and in other risk groups screened for coeliac disease. In children, it has become evident that the disease exists or appears late even though classical forms with malabsorption are not apparent.9 Patients with coeliac disease may suffer from neurological symptoms such as peripheral neuropathy, ataxia, intellectual deterioration and brain atrophy, and epilepsy with posterior cerebral calcifications.10–12 Dentists can suspect coeliac disease by finding characteristic dental enamel defects of permanent teeth.13 Infertility or miscarriages have been described in women, and reversible infertility in men.14 Low bone-mineral density is a common feature in untreated coeliac disease;15 the density improves on a gluten-free diet, but not always completely. Aphthosis of the mouth mucosa, arthritis or other joint symptoms, and elevated liver-enzyme concentrations sometimes lead to the diagnosis of coeliac disease. The prevalence of coeliac disease has increased due to better recognition of the disease and associated diseases. Some autoimmune diseases which have the HLA DR3DQ2 haplotype seem to be associated with coeliac disease. About 2–4% of patients with insulin-dependent diabetes mellitus or autoimmune thyroid diseases have coeliac disease. Patients with selective IgA deficiency have a tenfold increased risk of coeliac disease. Sjögren’s syndrome, alopecia areata, or Addison’s disease are other disorders in which an association with coeliac disease is possible.16 The occurrence of small-bowel lymphoma, the outcome of which is poor, is estimated to be 50–100-fold greater in patients with coeliac disease and dermatitis herpetiformis, when compared with the general population.17,18 The risk of lymphoma is greatest when coeliac disease is diagnosed in the elderly. Lymphoma should be suspected when a patient with coeliac disease has new symptoms despite being on a gluten-free diet. A gluten-free diet seems to reduce the risk of lymphoma. An increase in small-bowel, pharyngeal, or 1756
It is generally accepted that the cereals: wheat, rye, barley or their prolamines gliadin, secalin, and hordein, respectively, are the major triggering factors in coeliac disease and dermatitis herpetiformis. There is no scientific evidence that oats and its prolamin avenin is harmful to patients with coeliac disease. It has been shown that adults with coeliac disease tolerate 50 g of oats a day without clinical relapse or adverse effects on the small-bowel mucosa, and ingestion of oats does not prevent mucosal recovery in patients newly diagnosed with coeliac disease if they maintained an otherwise gluten-free diet.20,21 The prolamin content of oats is five times less than that in wheat, rye, and barley, and this may be the reason for the absence of oat toxicity. Rice and maize do not initiate the disease processes. A milestone in the chemisty of cereal proteins was the determination of the complete aminoacid sequence of an ␣-type gliadin.22 In-vitro organ-culture methods showed two short aminoacid sequences, QQQP and PSQQ, to be common to the active peptides found in A-gliadin domain I. Later both in-vivo installation testing and in-vitro organculture testing established the disease-inducing capacity of the gliadin peptides. The peptide corresponding to residues 206–217, containing the motif PSQQ and being homologous to the adenovirus type 12 E1B protein has given conflicting results.
Management Patients with coeliac disease and dermatitis herpetiformis must adhere to the gluten-free diet permanently. In all such diets wheat starch, containing trace amounts of gliadin, is not permitted. A new issue is whether oats could be allowed. According to follow-up studies, only 50–70% of patients with coeliac disease maintain a strict gluten-free diet later in life, and poor compliance is the main reason for a poor response. Corticosteroids are rarely necessary in the treatment of coeliac disease . Oats clearly diversifies the diet of patients with coeliac disease but some aspects of oats in the diet should be taken into account. Ingested oats should not be contaminated by wheat gliadins at harvesting, in mills, during storage, or during packing. Moreover, oat prolamines were able in vitro to activate an immune response in intestinal biopsy specimens.23 However, it is doubtful whether in-vitro organ-culture test results should be the gold standard instead of clinical and histological long-term assessment. The Codex Alimentarius standard 118–1981 defines a diet as gluten-free when “the total nitrogen content of the gluten containing cereal grains used in the product does not exceed 0·05 g/100 g of these grains on a dry matter basis”.24 Wheat-starch based gluten-free flours, meeting the Codex standard, may contain up to 40–60 mg gluten per 100 g (200–300 ppm gliadin). Wheat starch probably contains significantly less gliadin than that allowed. Again, if the gliadin found in trace amounts in wheat starch is tested in an in-vitro organ-culture system, a positive reaction is seen. On the other hand, patients with coeliac disease from many European countries have followed a gluten-free yet wheat-starch containing diet, and their small-bowel mucosa has healed. On such an otherwise
Vol 349 • June 14, 1997
THE LANCET
strict gluten-free diet, no excess mortality16 nor over representation of malignancies18 have been noticed. The definition of gluten-free diet needs to be reconsidered, if trace amounts of gliadin are shown to cause ill health.
Epidemiology The prevalence of coeliac disease has been about one in 1000 individuals. However, there are great differences between European countries.25 Recent screening studies have found a prevalence of one in 300,26,27 and it has been suggested that the prevalence might be as high as one in 100 individuals;28 however, this finding is on the basis of the occurrence of endomysial antibodies and not on biopsy-proven cases. Nevertheless, it is clear that diagnosing symptomatic coeliac disease reveals only the tip of the iceberg. In the late 1970s it was thought that childhood coeliac disease was disappearing. However, more cases were detected in older people and so the prevalence remained unchanged at about one in 1000. In contrast to other countries, the incidence of coeliac disease in children in Sweden has increased during the past 15 years to a figure of more than one in 300. This is probably due to a large amount of gluten in the diet of young infants.
Screening policy and diagnosis A plan of action for screening and case finding for coeliac disease is shown in figure 2. Small-bowel biopsy should be the first diagnostic procedure, when clinical suspicion of coeliac disease is strong. Coeliac disease can also be detected or excluded by upper gastrointestinal endoscopy provided that biopsy specimens from distal duodenum are taken routinely. Screening for coeliac disease is recommended when the clinical symptoms are subtle, but still indicative for the disease. Screening can further be applied to individuals who are at increased risk of coeliac disease; either because of heredity, extraintestinal symptoms, or associated disorders. Intestinal permeability tests are not widely used as screening methods. Now the focus is on non-invasive simple serological tests. Serum gliadin antibody tests, by enzyme-linked immunosorbent assays, are most widely used to diagnose coeliac disease.29 These antibodies have been found frequently in individuals with untreated coeliac disease, and they are suitable for screening. The use of both IgA and IgG antibodies are recommended. The sensitivity and specificity of the tests are good, 70–100%; however, in some studies the sensitivity and especially the specificity has been significantly lower; this probably depends on the selection of the study group. False positive gliadin antibodies are frequently found in other diseases and in healthy individuals.30 Serum reticulin antibodies are detectable by a standard indirect immunofluorescence method with rat tissues as antigens. Earlier studies suggested a low sensitivity. However, when IgA class R1 type reticulin antibodies have been looked for, the sensitivity and specificity of the test have been over 90%.30 Serum from patients with coeliac disease reacts not only with rodent, but also with primate and human tissues. An endomysial antibody test is both sensitive and specific for untreated coeliac disease and is highly predictive in clinical practice. However, the disadvantage of this test is a high cost and poor availability of the substrate, which is monkey oesophagus. An endomysial antibody test with human umbilical cord as antigen31 has given comparable results
Vol 349 • June 14, 1997
and may replace reticulin and conventional endomysial tests in the near future. The selection of a serological test depends on the population to be screened and on laboratory resources. Combining the gliadin antibody test with the reticulin or endomysial antibody test results in the best sensitivity. On the other hand, the specificity of the gliadin antibody test may be poor in cases where the probability of coeliac disease is low, and in these cases tissue antibody tests alone may be suitable due to their high specificity.30 Is it justified to screen for silent coeliac disease? Holmes and colleagues18 and Lewis and colleagues32 have shown that the gluten-free diet may in both coeliac disease and dermatitis herpetiformis protect from the development of small-bowel lymphoma. However, taking into account the high prevalence of coeliac disease, it can be said that lymphoma is a rare complication nowadays. However, bone-mineral density is decreased in patients with untreated coeliac disease, and this is an obvious indication for early detection of the disease. There is some evidence that osteopenia occurs even in individuals with silent coeliac disease. Another point is whether the quality of life in silent coeliac disease improves during a gluten-free diet. Cost-benefit analyses regarding early diagnosis and treatment are warranted.
Genetic, immunological, and pathogenetic aspects The tendency of coeliac disease to run in families is well recognised.33 The disease prevalence among healthy firstdegree relatives has varied from 1 to 18%. Figure 3 shows a family where the proband was diagnosed to have coeliac disease on clinical grounds, and where biopsy samples of the healthy individuals revealed two cases of silent coeliac disease. Twin studies have also shown that the genetic component is clear. Concordance between identical twins is 70%, and may even be higher because individuals found to be discordant have later been shown to be concordant (individuals excluded for coeliac disease on biopsy sampling who later developed the disease—ie, latent coeliac disease).
A DQA1 DQB1 DPB1
B
0101/2 0103 0602 0603 0402 0101
C
D
0501 0201 0101
0501 0201 0401
C B A C A C A D DQA1 0103 0501 0101/2 0501 0101/2 0501 0101/2 0501 DQB1 0603 0201 0602 0201 0602 0201 0602 0201 DPB1 0101 0101 0402 0101 0402 0101 0402 0401 Bold face = alleles encoding HLA DQ2 = biopsy-sample proven healthy = index case (with coeliac disease) = silent coeliac disease Figure 3: Family tree and HLA-II haplotypes of one family with three members with coeliac disease
1757
THE LANCET
Coeliac disease is associated with the HLA class II extended haplotypes DR3-DQ2 or DR5/7-DQ2 (figures 1 and 3). The DQ2 molecule, an ␣/ heterodimer, is situated on the surfaces of cells involved in immune responses and is encoded by the alleles DQA1*0501 and DQB1*0201.34 A small minority of the coeliac disease patients have the haplotype DR4-DQ8 (DQA1*0301, DQB1*0302). Most coeliac disease patients carry the risk alleles encoding the DQ2, but this is also the case in about 20% of the general population. Therefore it is probable that other genes outside the HLA region are involved in coeliac disease susceptibility. There is now evidence, through autosomal genomic screening, that there is linkage of at least one nonHLA locus to coeliac disease.35 One of the future targets for coeliac research is to identify other susceptibility genes and their function. Several major hypotheses regarding the nature of the primary host defect in coeliac disease have been proposed during the past decades, namely: the missing enzyme theory, the immunological hypothesis, the membrane glycoprotein defect, and the mucosal permeability defect. When the pathogenetic mechanisms are known it may turn out that all these mechanisms are operative. The immunological theory is the one most widely accepted. HLA class II molecules on antigen presenting cells expose processed peptides to immunocompetent T cells thus
initiating the disease mechanisms. The major environmental trigger is ingested gluten but adenovirus infection has also been suggested to play some part. Gliadin-specific, DQ2-restricted T cells have been isolated from the intestinal mucosa of patients. More important than the aminoacid sequences in the disease-inducing gliadins seem to be the critical aminoacids in the processed peptide that anchor the peptide to the groove of the DQ2 molecule.36,37 Also gliadin-triggered autoimmune mechanisms might be operative in the pathogenesis of coeliac disease.38,39 Details of coeliac disease even in the most current textbooks are out of date. Clinical features have changed, symptoms are often minor or atypical, and the disease can even be clinically silent, also the spectrum of gluten sensitivity has widened during the past two decades. All these factors add to the underdiagnosis of coeliac disease. Underdiagnosis must be tackled so early treatment can prevent ill health—non-invasive serological screening tests are already proving to be a useful tool in clinical practice.
References
19 Collin P, Pukkala E, Reunala T. Malignancy and survival in dermatitis herpetiformis: a comparison with coeliac disease. Gut 1996; 38: 528–30. 20 Janatuinen EK, Pikkarainen PH, Kemppainen TA, et al. A comparison of diets with and without oats in adults with celiac disease. N Engl J Med 1995; 333: 1033–37. 21 Srinivasan U, Leonard N, Jones E, et al. Absence of oats toxicity in adult coeliac disease. BMJ 1996; 313: 1300–01. 22 Kasarda DD, Okita TW, Bernardin JE. Nucleic acid (cDNA) and amino acid sequences of ␣-type gliadins from wheat (Triticum aestivum). Proc Natl Acad Sci USA 1984; 1981: 4712–16. 23 Leone NA, Mazzarella G, Ciacci C, et al. Oats prolamines in vitro activate intestinal cell-mediated immunity in coeliac disease. In: Collin P, Màki M, eds. Seventh International Symposium on Coeliac Disease, September 5–7, 1996,Tampere, Finland.Tampere: Lege Artis, 1996: 69. 24 Joint FAO/WHO Food Standards Programme. Codex Alimentarius Commission. Codex Stan, 1981: 118. 25 Greco L, Mäki M, Di Donato F,Visakorpi JK. Epidemiology of coeliac disease in Europe and the Mediterranean area: In: Auricchio S, Visakorpi JK, eds. Common food intolerances 1: Epidemiology of coeliac disease. Dynamic Nutrition Research. Basel: S Karger AG, 1992: 25–44. 26 Grodzinsky E, Franzen L, Hed J, Ström M. High prevalence of celiac disease in healthy adults revealed by antigliadin antibodies. Ann Allergy 1992; 69: 66–70. 27 Catassi C, Rätsch IM, Fabiani E , et al. Coeliac disease in the year 2000: exploring the iceberg. Lancet 1994; 343: 200–03. 28 McMillan SA,Watson RPG, McCrum EE, Evans AE. Factors associated with serum antibodies to reticulin, endomysium, and gliadin in an adult population. Gut 1996; 39: 43–47. 29 Savilahti E,Viander M, Perkkio M,Vainio E, Kalimo K, Reunala T. IgA antigliadin antibodies: a marker of mucosal damage in childhood coeliac disease. Lancet 1983; 1: 320–22. 30 Mäki M.The humoral immune system in coeliac disease. Baillieres Clin Gastroenterol 1995; 9: 231–49. 31 Ladinser B, Rossipal E, Pittschieler K. Endomysium antibodies in coeliac disease: an improved method. Gut 1994; 35: 776–78. 32 Lewis HM, Reunala TL, Garioch JJ, et al. Protective effect of gluten-free diet against development of lymphoma in dermatitis herpetiformis. Br J Dermatol 1996; 135: 363–67. 33 MacDonald WC, Dobbins WO, Rubin CE. Studies on the familial nature of coeliac sprue using biopsy of the small intestine. N Engl J Med 1965; 272: 448–56. 34 Sollid LM,Thorsby E. HLA susceptibility genes in celiac disease: genetic mapping and role in pathogenesis. Gastroenterology 1993; 105: 910–22. 35 Zhong F, McCombs CC, Olson JM, et al. An autosomal screen for genes that predispose to celiac disease in the western counties of Ireland.
1 2 3
4
5
6
7 8
9
10 11 12
13 14
15
16 17 18
Gee S. On the coeliac disease. St Bart Hosp Rep 1888; 24: 17–20. Dicke WK. Coeliakie. MD Thesis, Utrecht 1950. Walker-Smith JA, Guandalini S, Schmitz J, Shmerling DH, Visakorpi JK. Revised criteria for diagnosis of coeliac disease. Arch Dis Child 1990; 65: 909–11. Marsh MN. Gluten, major histocompatibility complex, and the small intestine. A molecular and immunobiologic approach to the spectrum of gluten sensitivity (‘celiac sprue’). Gastroenterology 1992; 102: 330–54. Mäki M, Holm K, Koskimies S, Hällström O,Visakorpi JK. Normal small bowel biopsy followed by coeliac disease. Arch Dis Child 1990; 65: 1137–41. Reunala T, Kosnai I, Karpati S, Kuitunen P,Török E, Savilahti E. Dermatitis herpetiformis: jejunal findings and skin response to glutenfree diet. Arch Dis Child 1984; 59: 517–22. Swinson CM, Levi AJ. Is coeliac disease underdiagnosed? BMJ 1980; 281: 1258–60. Logan RFA,Tucker G, Rifkind EA, Heading RC, Ferguson A. Changes in clinical features of coeliac disease in adults in Edinburgh and the Lothians 1960-79. BMJ 1983; 286: 95–97. Mäki M, Kallonen K, Lähdeaho ML, Visakorpi JK. Changing pattern of childhood coeliac disease in Finland. Acta Paediatr Scand 1988; 77: 408–12. Gobbi G, Bouquet F, Greco L, et al. Coeliac disease, epilepsy and cerebral calcifications. Lancet 1990; 340: 439–43. Collin P, Pirttilä T, Nurmikko T, Somer H, Erilä T, Keyriläinen O. Celiac disease, brain atrophy and dementia. Neurology 1991; 41; 372–75. Hadjivassiliou M, Gibson A, Davies-Jones GAB, Lobo AJ, Stephenson TJ, Milford-Wars A. Does cryptic gluten sensitivity play a part in neurological illness? Lancet 1996; 347: 369–71. Aine L, Mäki M, Collin P, Keyriläinen O. Dental enamel defects in celiac disease. J Oral Pathol Med 1990; 19: 241–45. Sher KS, Jayanthi V, Probert CS, Stewart CR, Mayberry JF. Infertility, obstetric and gynaecological problems in coeliac sprue. Dig Dis 1994; 12: 186–90. Molteni N, Caraceni MP, Bardella MT, Ortolani S, Gandolini GG, Bianchi P. Bone mineral density in adult celiac patients and the effect of gluten-free diet from childhood. Am J Gastroenterol 1990; 85: 51–53. Collin P, Mäki M. Associated disorders in coeliac disease: clinical aspects. Scand J Gastroenterol 1994; 29: 769–75. Leonard JN, Tucker WF, Fry JS, et al. Increased incidence of malignancy in dermatitis herpetiformis. BMJ 1983; 286: 16–18. Holmes GKT, Prior P, Lane MR, Pope D, Allan RN. Malignancy in coeliac disease—effect of a gluten free diet. Gut 1989; 30: 333–38.
1758
We thank Tuula Halttunen for preparing the figures. Coeliac Disease Study Group is supported by grants from the Medical Research Council, the Academy of Finland; the Sigrid Juselius Foundation; the Medical Research Fund of Tampere University Hospital; the Emil Aaltonen Foundation; the Foundation for Paediatric Research; and the Yrjö Jahnsson Foundation.
Vol 349 • June 14, 1997
THE LANCET Nat Genet 1996; 14: 329–33. 36 van de Wal Y, Kooy YMC, Drijfhout JW, Amons R, Koning F. Peptide binding characteristics of the coeliac disease-associated DQ(␣1*0501, 1*0201) molecule. Immunogenetics 1996; 44: 246–53. 37 Johansen BH, Gjertsen HA,Vartdal F, et al. Binding of peptides from the N-terminal region of alpha-gliadin to the celiac disease-associated HLA-
DQ2 molecule assessed in biochemical and T cell assays. Clin Immunol Immunopathol 1996; 79: 288–93. 38 Picarelli A, Maiuri L, Mazzilli MC, et al. Gluten-sensitive disease with mild enteropathy. Gastroenterology 1996; 111: 608–16. 39 Mäki M. Coeliac disease and autoimmunity due to unmasking cryptic epitopes. Lancet 1996; 348: 1046-47.
Further reading General
de Ritis G, Auricchio S, Jones HW, Lew EJ, Bernardin JE, Kasarda DD. In vitro (organ culture) studies of the toxicity of specific A-gliadin peptides in celiac disease. Gastroenterology 1988; 94: 41–49. Mantzaris G, Jewell DP. In vivo toxicity of a synthetic dodecapeptide from A gliadin in patients with coeliac disease. Scand J Gastroenterol 1991; 26; 392–98. Sturgess R, Day P, Ellis HJ, et al. Wheat peptide challenge in coeliac disease. Lancet 1994; 343: 758–61. Maiuri L, Picarelli A, Boirivant M, et al. Definition of the initial immunologic modifications upon in vitro gliadin challenge in the small intestine of celiac patients. Gastroenterology 1996; 110: 1368–78.
Coeliac disease (Howdle PD, ed). Baillieres Clin Gastroenterol 1995; 9: 1–416.
Latency Holm K, Mäki M, Savilahti E, Lipsanen V, Laippala P, Koskimies S. Intraepithelial gamma/delta T-cell-receptor lymphocytes and genetic susceptibility to coeliac disease. Lancet 1992; 339: 1500–03. Arranz E, Ferguson A. Intestinal antibody pattern of celiac disease: occurrence in patients with normal jejunal histology. Gastroenterology 1993; 104: 1263–72. Ferguson A, Arranz E , O’Mahony S. Clinical and pathological spectrum of coeliac disease—active, silent, latent, potential. Gut 1993; 34: 150–51. Collin P, Helin H, Mäki M, Mällström O, Karvonen A-L. Follow-up of patients positive in reticulin and gliadin antibody tests with normal small bowel biopsy findings. Scand J Gastroenterol 1993; 28: 595–98. Troncone R. Latent coeliac disease in Italy. Acta Paediatr 1995; 84: 1252–57.
Changing pattern Collin P, Hällström O, Mäki M, Viander M, Keyriläinen O. Atypical coeliac disease found with serologic screening. Scand J Gastroenterol 1990; 25: 245–50. Corazza G R, Frisoni M, Treggiari EA, et al. Subclinical celiac sprue. Increasing occurrence and clues to its diagnosis. J Clin Gastroenterol 1993; 16: 16–21. Hankey GL, Holmes GKT. Coeliac disease in the elderly. Gut 1994; 35: 65–67. Visakorpi JK, Mäki M. Changing clinical features of coeliac disease. Acta Paediatr Suppl 1994; 83: 10–13. Marsh MN. The natural history of gluten sensitivity: defining, refining and redefining. QJM 1995; 88: 9–13. Troncone R, Greco L, Auricchio S. Gluten-sensitive enteropathy. Pediatr Clin North Am 1996; 43: 355–73.
Extraintestinal symptoms and associated diseases Savilahti E, Pelkonen P, Visakorpi JK, IgA deficiency in children. A clinical study with special reference to intestinal findings. Arch Dis Child 1971; 46: 665–70. Pare P, Douville P, Caron D, Lagace R. Adult celiac sprue: changes in the pattern of clinical recognition. J Clin Gastroenterol 1988; 10: 395–400. Collin P, Reunala T, Pukkala E, Laippala P, Keyriläinen O, Pasternack A. Coeliac disease—associated disorders and survival. Gut 1994; 35: 1215–18. Marsh MN. Bone disease and gluten sensitivity: time to act, to treat, and to prevent. Am J Gastroenterol 1994; 89: 2105–07. Corazza FR, Di Sario A, Cecchetti L, et al. Bone mass and metabolism in patients with celiac disease. Gastroenterology 1995; 109: 122–28. Corazza GR, Andreani ML, Venturo N, Bernardi M, Tosti A, Gasbarrini G. Celiac disease and alopecia areata: report of a new association. Gastroenterology 1995; 109: 1333–37. McFarlane XA, Bhalla AK, Reeves DE, Morgan LM, Robertson DA. Osteoporosis in treated adult coeliac disease. Gut 1995; 36: 710–14. Mäki M, Huupponen T, Holm K, Hällstrom O. Seroconversion of reticulin autoantibodies predicts coeliac disease in insulin dependent diabetes mellitus. Gut 1995; 36: 239–42. Aine L. Coeliac-type permanent tooth enamel defects. Ann Med 1996; 28: 9–12. Valdimarsson T, Löfman O, Toss G, Ström M. Reversal of osteopenia with diet in adult coeliac disease. Gut 1996; 38: 322–27.
Malignancy Holmes GKT, Stokes PL, Sorahan TM, Prior P, Waterhouse JAH, Cooke WT. Coeliac disease, gluten-free diet and malignancy. Gut 1976; 17: 612–19. Swinson CM, Slavin G, Coles EC, Booth CC. Coeliac disease and malignancy. Lancet 1983; i: 11–15.
The role of cereals and precipitating factors Kagnoff MF, Austin RK, Hubert JJ, Bernardin JE, Kasarda DD. Possible role for a human adenovirus in the pathogenesis of celiac disease. J Exp Med 1984; 160; 1544–57.
Vol 349 • June 14, 1997
Epidemiology Hallert C, Gotthard R, Norrby K, Walan A. On the prevalence of adult coeliac disease in Sweden. Scand J Gastroenterol 1981; 16: 257–61. Logan RFA, Rifkind EA, Busuttil A, Gilmour HM, Ferguson A. Prevalence and “incidence” of celiac disease in Edinburgh and the Lothian region of Scotland. Gastroenterology 1986; 90: 334–42. Mäki M, Holm K. Incidence ad prevalence of coeliac disease in Tampere. Coeliac disease is not disappearing. Acta Paediatr Scand 1990; 78: 739–42. Ascher H, Krantz I, Kristiansson B. Increasing incidence of coeliac disease in Sweden. Arch Dis Child 1991; 66: 608–11. Talley NJ, Valdovinos M, Petterson TM, Carpenter HA, Melton L Jr. Epidemiology of celiac sprue: a community-based study. Am J Gastroenterol 1994; 89: 843–46.
Screening Karpati S, Burgin-Wolff A, Krieg T, Meurer M, Stolz W, Braun-Falco O. Binding to human jejunum of serum IgA antibody from children with coeliac disease. Lancet 1990; 336: 1335–38. McMillan SA, Haughton DJ, Biggart JD, Edgar JD, Porter KG, McNeill TA. Predictive value for coeliac disease of antibodies to gliadin, endomysium, and jejunum in patients attending for jejunal biopsy. BMJ 1991; 303: 1163–65. Troncone R, Ferguson A. Anti-gliadin antibodies. J Pediatr Gastroenterol Nutr 1991; 12: 150–58. Mäki M, Hällström O, Marttinen A. Reaction of human non-collagenous polypeptides with coeliac disease autoantibodies. Lancet 1991; 338: 724–25. Mäki M, Holm K, Lipsanen V, et al. Serological markers and HLA genes among healthy first-degree relatives of patients with coeliac disease. Lancet 1991; 338: 1350–53. Ferreira M, Davies SL, Butler M, Scott D, Clark M, Kumar P. Endomysial antibody: is it the best screening test for coeliac disease? Gut 1992; 33: 1633–37. Unsworth DJ, Brown DL. Serological screening suggests that adult coeliac disease is underdiagnosed in the UK and increases the incidence by up to 12%. Gut 1994; 35: 61–64. Volta U, Molinaro N, De Franceschi L, Fratangelo DS, Bianchi FB. IgA antiendomysial antibodies on human umbilical cord tissue for celiac disease screening. Save both money and monkeys. Dig Dis Sci 1995; 40: 1902–05.
Genetics, immunology and pathogenesis Brandtzaeg P, Halstensen TS, Kett K, et al. Immunobiology and immunopathology of human gut mucosa: humoral immunity and intraepithelial lymphocytes. Gastroenterology 1989; 97: 1562–84. Sollid LM, Markussen G, Ek J, Gjerde H, Vartdal F, Thorsby E. Evidence for a primary association of celiac disease to a particular HLA-DQ ␣/ heterodimer. J Exp Med 1989; 169: 345–50. Reunala T, Mäki M. Dermatitis herpetiformis: a genetic disease. Eur J Dermatol 1993; 3: 519–26. Lundin K, Scott H, Hansen T, et al. Gliadin-specific, HLA-DQ(␣1*0501, 1*0291) restricted T cells isolated from the small intestinal mucosa of celiac disease patients. J Exp Med 1993; 178: 87–96. Tighe MR, Ciclitira PJ. The gluten-host interaction. Baillieres Clin Gastroenterol 1995; 9: 211–30. Ferguson A. New perspectives of the pathogenesis of coeliac disease: evolution of a working clinical definition. J Intern Med 1997; 240: 315–18.
1759
Seminar
Coeliac disease
Diagnostic criteria The diagnostic criteria, as stated by the European Society for Paediatric Gastroenterology and Nutrition (ESPGAN) in 1970, are: small-bowel mucosal atrophy with improvement or normalisation on a gluten-free diet and a deterioration of the villous morphology during intake of a gluten-containing diet. In 1990, these criteria were modified.3 The findings of characteristic small-bowel mucosal atrophy and clinical remission on a gluten-free diet are essential. In symptom-free patients, a second biopsy sample is needed to show mucosal recovery on treatment with a gluten-free diet. The presence of circulating antibodies and their disappearance on a glutenfree diet support the diagnosis. The old ESPGAN criteria, including gluten challenge, may be used when needed—eg, in children younger than 2 years who live in countries where intolerance to protein in cow’s milk is common, or in patients for whom the findings from their first biopsy sample was equivocal. Gluten challenge after mucosal healing in children who are initially negative for serum reticulin or endomysial antibodies is also advisable (the challenge should not be done in children younger than 6 years).3 In developed countries, coeliac disease is generally indicated by a manifest mucosal lesion with typical villous atrophy and crypt hyperplasia in adults and in children older than 2 years with or without symptoms or signs of malabsorption (figure 1). Small-bowel biopsy sampling is essential, and the diagnosis should not be based on symptoms or serological tests alone. By definition, coeliac disease is excluded in patients who have a normal small-bowel mucosal morphology when they are on a normal gluten-containing diet. However, gluten sensitivity is no longer restricted to villous atrophy. Smallbowel mucosal damage develops gradually from normal mucosal morphology to overt atrophy with hyperplasia of Lancet 1997; 349: 1755–59 Departments of Paediatrics (M Mäki MD) and Medicine (P Collin MD), Tampere University Hospital and University of Tampere, PO Box 607, FIN-33101 Tampere, Finland Correspondence to: Dr Markku Mäki (e-mail: [email protected])
Vol 349 • June 14, 1997
DR3-DQ2 DR5/7-DQ2 DR4-DQ8
Manifest mucosal lesion
Clinical coeliac disease Silent coeliac disease Coeliac disease latency
Healthy individuals
Jejunal morphology
Coeliac disease was described with great accuracy by Samuel Gee more than a century ago.1 However, the harmful effect of ingested wheat gluten was not recognised until the late 1940s by Dicke.2 Soon after this discovery peroral small-bowel biopsy, the cornerstone for making an accurate diagnosis, was introduced. Life-long glutensensitive disorder, characterised by malabsorption in its classical form, and the typical small-bowel histological lesion are well understood. However, during the 1980s and 1990s, it has become apparent that coeliac disease is underdiagnosed and that the clinical features of the disease have changed in both children and adults. Genetic and immunobiological reseach has taken a leap forward. This seminar focuses on the established facts of coeliac disease and introduces advances in clinical and basic research.
Genetic susceptibility
Markku Mäki, Pekka Collin
Normal mucosal morphology
Figure 1: The coeliac disease iceberg and spectrum of gluten sensitivity
crypts.4 The early lesion comprises lymphocyte infiltration into the epithelium and lamina propria. Individuals who are on normal amounts of gluten and have normal smallbowel villous architecture can still be gluten-sensitive; they may have a latent coeliac disease and small-bowel villous atrophy and crypt hyperplasia is contracted later in the disease process.5 The definition of coeliac-type gluten sensitivity (coeliac trait) should also include the susceptibility genes for coeliac disease (figure 1). Latent coeliac disease may be suspected in individuals: positive for reticulin and endomysial tissue autoantibodies with a high density of ␥␦ T-cell-receptorbearing intraepithelial lymphocytes, or with positive coeliac-like intestinal antibody pattern. Diagnostic difficulties emerge when minor mucosal changes are found such as partial small-bowel villous atrophy, or an increased density of intraepithelial lymphocytes in otherwise normal mucosa. Patients may be advised to go on a gluten-free diet to show clinical response as a sign of gluten sensitivity. We recommend that these patients should be followed up while on a normal glutencontaining diet. A new biopsy sample should be taken if symptoms appear or worsen or if a clear increase in antibody titres is found. In any case a follow-up biopsy sample should be done within 2 years if latent coeliac disease is suspected. Alternatively, an aggressive gluten challenge can be done to show mucosal deterioration. Dermatitis herpetiformis, a skin disease characterised by blistering, is the classical non-gastrointestinal manifestation of coeliac disease along with granular IgA deposits in unaffected skin. About 75% of patients with dermatitis herpetiformis have small-bowel villous atrophy with crypt hyperplasia, and in the remainder, minor mucosal changes can be seen.6 Both the mucosal lesion and rash respond to the gluten-free diet and a life-long diet is the treatment of choice. Dermatitis herpetiformis and coeliac disease share the HLA-DQ2 haplotype, and both diseases may exist within one family. Dermatitis herpetiformis can be seen as one manifestation of coeliac disease rather than an associated disease. 1755
THE LANCET
Clinical suspicion of coeliac disease Strong
Screening for coeliac disease
oesophageal cancer has also been found in coeliac disease. Again the risk of malignancy seems to be significantly lower when the coeliac iceberg is explored.16,19
Weak
Role of cereals Small-bowel biopsy
Gastroscopy for other reasons
Serum antibodies • IgA-class and IgG-class gliadin AB • IgA-class reticulin and endomysial AB
Figure 2: Algorithm for diagnosis of coeliac disease
Changing symptom pattern and associated disorders Diarrhoea, weight loss, and weakness have been the classic signs of coeliac disease in adults. A severe malabsorption syndrome has been common as well. In the early 1980s, British investigators showed that the clinical features of coeliac disease have changed.7,8 There had been by this time a shift towards milder symptoms such as indigestion in adults and recurrent abdominal pain in children. The classic symptoms and signs had become rare. Sometimes isolated iron deficiency is the only manifestation of coeliac disease. And, despite manifest mucosal lesion the disease can be even symptom-free, clinically silent. Silent coeliac disease has been reported in relatives of coeliac patients, and in other risk groups screened for coeliac disease. In children, it has become evident that the disease exists or appears late even though classical forms with malabsorption are not apparent.9 Patients with coeliac disease may suffer from neurological symptoms such as peripheral neuropathy, ataxia, intellectual deterioration and brain atrophy, and epilepsy with posterior cerebral calcifications.10–12 Dentists can suspect coeliac disease by finding characteristic dental enamel defects of permanent teeth.13 Infertility or miscarriages have been described in women, and reversible infertility in men.14 Low bone-mineral density is a common feature in untreated coeliac disease;15 the density improves on a gluten-free diet, but not always completely. Aphthosis of the mouth mucosa, arthritis or other joint symptoms, and elevated liver-enzyme concentrations sometimes lead to the diagnosis of coeliac disease. The prevalence of coeliac disease has increased due to better recognition of the disease and associated diseases. Some autoimmune diseases which have the HLA DR3DQ2 haplotype seem to be associated with coeliac disease. About 2–4% of patients with insulin-dependent diabetes mellitus or autoimmune thyroid diseases have coeliac disease. Patients with selective IgA deficiency have a tenfold increased risk of coeliac disease. Sjögren’s syndrome, alopecia areata, or Addison’s disease are other disorders in which an association with coeliac disease is possible.16 The occurrence of small-bowel lymphoma, the outcome of which is poor, is estimated to be 50–100-fold greater in patients with coeliac disease and dermatitis herpetiformis, when compared with the general population.17,18 The risk of lymphoma is greatest when coeliac disease is diagnosed in the elderly. Lymphoma should be suspected when a patient with coeliac disease has new symptoms despite being on a gluten-free diet. A gluten-free diet seems to reduce the risk of lymphoma. An increase in small-bowel, pharyngeal, or 1756
It is generally accepted that the cereals: wheat, rye, barley or their prolamines gliadin, secalin, and hordein, respectively, are the major triggering factors in coeliac disease and dermatitis herpetiformis. There is no scientific evidence that oats and its prolamin avenin is harmful to patients with coeliac disease. It has been shown that adults with coeliac disease tolerate 50 g of oats a day without clinical relapse or adverse effects on the small-bowel mucosa, and ingestion of oats does not prevent mucosal recovery in patients newly diagnosed with coeliac disease if they maintained an otherwise gluten-free diet.20,21 The prolamin content of oats is five times less than that in wheat, rye, and barley, and this may be the reason for the absence of oat toxicity. Rice and maize do not initiate the disease processes. A milestone in the chemisty of cereal proteins was the determination of the complete aminoacid sequence of an ␣-type gliadin.22 In-vitro organ-culture methods showed two short aminoacid sequences, QQQP and PSQQ, to be common to the active peptides found in A-gliadin domain I. Later both in-vivo installation testing and in-vitro organculture testing established the disease-inducing capacity of the gliadin peptides. The peptide corresponding to residues 206–217, containing the motif PSQQ and being homologous to the adenovirus type 12 E1B protein has given conflicting results.
Management Patients with coeliac disease and dermatitis herpetiformis must adhere to the gluten-free diet permanently. In all such diets wheat starch, containing trace amounts of gliadin, is not permitted. A new issue is whether oats could be allowed. According to follow-up studies, only 50–70% of patients with coeliac disease maintain a strict gluten-free diet later in life, and poor compliance is the main reason for a poor response. Corticosteroids are rarely necessary in the treatment of coeliac disease . Oats clearly diversifies the diet of patients with coeliac disease but some aspects of oats in the diet should be taken into account. Ingested oats should not be contaminated by wheat gliadins at harvesting, in mills, during storage, or during packing. Moreover, oat prolamines were able in vitro to activate an immune response in intestinal biopsy specimens.23 However, it is doubtful whether in-vitro organ-culture test results should be the gold standard instead of clinical and histological long-term assessment. The Codex Alimentarius standard 118–1981 defines a diet as gluten-free when “the total nitrogen content of the gluten containing cereal grains used in the product does not exceed 0·05 g/100 g of these grains on a dry matter basis”.24 Wheat-starch based gluten-free flours, meeting the Codex standard, may contain up to 40–60 mg gluten per 100 g (200–300 ppm gliadin). Wheat starch probably contains significantly less gliadin than that allowed. Again, if the gliadin found in trace amounts in wheat starch is tested in an in-vitro organ-culture system, a positive reaction is seen. On the other hand, patients with coeliac disease from many European countries have followed a gluten-free yet wheat-starch containing diet, and their small-bowel mucosa has healed. On such an otherwise
Vol 349 • June 14, 1997
THE LANCET
strict gluten-free diet, no excess mortality16 nor over representation of malignancies18 have been noticed. The definition of gluten-free diet needs to be reconsidered, if trace amounts of gliadin are shown to cause ill health.
Epidemiology The prevalence of coeliac disease has been about one in 1000 individuals. However, there are great differences between European countries.25 Recent screening studies have found a prevalence of one in 300,26,27 and it has been suggested that the prevalence might be as high as one in 100 individuals;28 however, this finding is on the basis of the occurrence of endomysial antibodies and not on biopsy-proven cases. Nevertheless, it is clear that diagnosing symptomatic coeliac disease reveals only the tip of the iceberg. In the late 1970s it was thought that childhood coeliac disease was disappearing. However, more cases were detected in older people and so the prevalence remained unchanged at about one in 1000. In contrast to other countries, the incidence of coeliac disease in children in Sweden has increased during the past 15 years to a figure of more than one in 300. This is probably due to a large amount of gluten in the diet of young infants.
Screening policy and diagnosis A plan of action for screening and case finding for coeliac disease is shown in figure 2. Small-bowel biopsy should be the first diagnostic procedure, when clinical suspicion of coeliac disease is strong. Coeliac disease can also be detected or excluded by upper gastrointestinal endoscopy provided that biopsy specimens from distal duodenum are taken routinely. Screening for coeliac disease is recommended when the clinical symptoms are subtle, but still indicative for the disease. Screening can further be applied to individuals who are at increased risk of coeliac disease; either because of heredity, extraintestinal symptoms, or associated disorders. Intestinal permeability tests are not widely used as screening methods. Now the focus is on non-invasive simple serological tests. Serum gliadin antibody tests, by enzyme-linked immunosorbent assays, are most widely used to diagnose coeliac disease.29 These antibodies have been found frequently in individuals with untreated coeliac disease, and they are suitable for screening. The use of both IgA and IgG antibodies are recommended. The sensitivity and specificity of the tests are good, 70–100%; however, in some studies the sensitivity and especially the specificity has been significantly lower; this probably depends on the selection of the study group. False positive gliadin antibodies are frequently found in other diseases and in healthy individuals.30 Serum reticulin antibodies are detectable by a standard indirect immunofluorescence method with rat tissues as antigens. Earlier studies suggested a low sensitivity. However, when IgA class R1 type reticulin antibodies have been looked for, the sensitivity and specificity of the test have been over 90%.30 Serum from patients with coeliac disease reacts not only with rodent, but also with primate and human tissues. An endomysial antibody test is both sensitive and specific for untreated coeliac disease and is highly predictive in clinical practice. However, the disadvantage of this test is a high cost and poor availability of the substrate, which is monkey oesophagus. An endomysial antibody test with human umbilical cord as antigen31 has given comparable results
Vol 349 • June 14, 1997
and may replace reticulin and conventional endomysial tests in the near future. The selection of a serological test depends on the population to be screened and on laboratory resources. Combining the gliadin antibody test with the reticulin or endomysial antibody test results in the best sensitivity. On the other hand, the specificity of the gliadin antibody test may be poor in cases where the probability of coeliac disease is low, and in these cases tissue antibody tests alone may be suitable due to their high specificity.30 Is it justified to screen for silent coeliac disease? Holmes and colleagues18 and Lewis and colleagues32 have shown that the gluten-free diet may in both coeliac disease and dermatitis herpetiformis protect from the development of small-bowel lymphoma. However, taking into account the high prevalence of coeliac disease, it can be said that lymphoma is a rare complication nowadays. However, bone-mineral density is decreased in patients with untreated coeliac disease, and this is an obvious indication for early detection of the disease. There is some evidence that osteopenia occurs even in individuals with silent coeliac disease. Another point is whether the quality of life in silent coeliac disease improves during a gluten-free diet. Cost-benefit analyses regarding early diagnosis and treatment are warranted.
Genetic, immunological, and pathogenetic aspects The tendency of coeliac disease to run in families is well recognised.33 The disease prevalence among healthy firstdegree relatives has varied from 1 to 18%. Figure 3 shows a family where the proband was diagnosed to have coeliac disease on clinical grounds, and where biopsy samples of the healthy individuals revealed two cases of silent coeliac disease. Twin studies have also shown that the genetic component is clear. Concordance between identical twins is 70%, and may even be higher because individuals found to be discordant have later been shown to be concordant (individuals excluded for coeliac disease on biopsy sampling who later developed the disease—ie, latent coeliac disease).
A DQA1 DQB1 DPB1
B
0101/2 0103 0602 0603 0402 0101
C
D
0501 0201 0101
0501 0201 0401
C B A C A C A D DQA1 0103 0501 0101/2 0501 0101/2 0501 0101/2 0501 DQB1 0603 0201 0602 0201 0602 0201 0602 0201 DPB1 0101 0101 0402 0101 0402 0101 0402 0401 Bold face = alleles encoding HLA DQ2 = biopsy-sample proven healthy = index case (with coeliac disease) = silent coeliac disease Figure 3: Family tree and HLA-II haplotypes of one family with three members with coeliac disease
1757
THE LANCET
Coeliac disease is associated with the HLA class II extended haplotypes DR3-DQ2 or DR5/7-DQ2 (figures 1 and 3). The DQ2 molecule, an ␣/ heterodimer, is situated on the surfaces of cells involved in immune responses and is encoded by the alleles DQA1*0501 and DQB1*0201.34 A small minority of the coeliac disease patients have the haplotype DR4-DQ8 (DQA1*0301, DQB1*0302). Most coeliac disease patients carry the risk alleles encoding the DQ2, but this is also the case in about 20% of the general population. Therefore it is probable that other genes outside the HLA region are involved in coeliac disease susceptibility. There is now evidence, through autosomal genomic screening, that there is linkage of at least one nonHLA locus to coeliac disease.35 One of the future targets for coeliac research is to identify other susceptibility genes and their function. Several major hypotheses regarding the nature of the primary host defect in coeliac disease have been proposed during the past decades, namely: the missing enzyme theory, the immunological hypothesis, the membrane glycoprotein defect, and the mucosal permeability defect. When the pathogenetic mechanisms are known it may turn out that all these mechanisms are operative. The immunological theory is the one most widely accepted. HLA class II molecules on antigen presenting cells expose processed peptides to immunocompetent T cells thus
initiating the disease mechanisms. The major environmental trigger is ingested gluten but adenovirus infection has also been suggested to play some part. Gliadin-specific, DQ2-restricted T cells have been isolated from the intestinal mucosa of patients. More important than the aminoacid sequences in the disease-inducing gliadins seem to be the critical aminoacids in the processed peptide that anchor the peptide to the groove of the DQ2 molecule.36,37 Also gliadin-triggered autoimmune mechanisms might be operative in the pathogenesis of coeliac disease.38,39 Details of coeliac disease even in the most current textbooks are out of date. Clinical features have changed, symptoms are often minor or atypical, and the disease can even be clinically silent, also the spectrum of gluten sensitivity has widened during the past two decades. All these factors add to the underdiagnosis of coeliac disease. Underdiagnosis must be tackled so early treatment can prevent ill health—non-invasive serological screening tests are already proving to be a useful tool in clinical practice.
References
19 Collin P, Pukkala E, Reunala T. Malignancy and survival in dermatitis herpetiformis: a comparison with coeliac disease. Gut 1996; 38: 528–30. 20 Janatuinen EK, Pikkarainen PH, Kemppainen TA, et al. A comparison of diets with and without oats in adults with celiac disease. N Engl J Med 1995; 333: 1033–37. 21 Srinivasan U, Leonard N, Jones E, et al. Absence of oats toxicity in adult coeliac disease. BMJ 1996; 313: 1300–01. 22 Kasarda DD, Okita TW, Bernardin JE. Nucleic acid (cDNA) and amino acid sequences of ␣-type gliadins from wheat (Triticum aestivum). Proc Natl Acad Sci USA 1984; 1981: 4712–16. 23 Leone NA, Mazzarella G, Ciacci C, et al. Oats prolamines in vitro activate intestinal cell-mediated immunity in coeliac disease. In: Collin P, Màki M, eds. Seventh International Symposium on Coeliac Disease, September 5–7, 1996,Tampere, Finland.Tampere: Lege Artis, 1996: 69. 24 Joint FAO/WHO Food Standards Programme. Codex Alimentarius Commission. Codex Stan, 1981: 118. 25 Greco L, Mäki M, Di Donato F,Visakorpi JK. Epidemiology of coeliac disease in Europe and the Mediterranean area: In: Auricchio S, Visakorpi JK, eds. Common food intolerances 1: Epidemiology of coeliac disease. Dynamic Nutrition Research. Basel: S Karger AG, 1992: 25–44. 26 Grodzinsky E, Franzen L, Hed J, Ström M. High prevalence of celiac disease in healthy adults revealed by antigliadin antibodies. Ann Allergy 1992; 69: 66–70. 27 Catassi C, Rätsch IM, Fabiani E , et al. Coeliac disease in the year 2000: exploring the iceberg. Lancet 1994; 343: 200–03. 28 McMillan SA,Watson RPG, McCrum EE, Evans AE. Factors associated with serum antibodies to reticulin, endomysium, and gliadin in an adult population. Gut 1996; 39: 43–47. 29 Savilahti E,Viander M, Perkkio M,Vainio E, Kalimo K, Reunala T. IgA antigliadin antibodies: a marker of mucosal damage in childhood coeliac disease. Lancet 1983; 1: 320–22. 30 Mäki M.The humoral immune system in coeliac disease. Baillieres Clin Gastroenterol 1995; 9: 231–49. 31 Ladinser B, Rossipal E, Pittschieler K. Endomysium antibodies in coeliac disease: an improved method. Gut 1994; 35: 776–78. 32 Lewis HM, Reunala TL, Garioch JJ, et al. Protective effect of gluten-free diet against development of lymphoma in dermatitis herpetiformis. Br J Dermatol 1996; 135: 363–67. 33 MacDonald WC, Dobbins WO, Rubin CE. Studies on the familial nature of coeliac sprue using biopsy of the small intestine. N Engl J Med 1965; 272: 448–56. 34 Sollid LM,Thorsby E. HLA susceptibility genes in celiac disease: genetic mapping and role in pathogenesis. Gastroenterology 1993; 105: 910–22. 35 Zhong F, McCombs CC, Olson JM, et al. An autosomal screen for genes that predispose to celiac disease in the western counties of Ireland.
1 2 3
4
5
6
7 8
9
10 11 12
13 14
15
16 17 18
Gee S. On the coeliac disease. St Bart Hosp Rep 1888; 24: 17–20. Dicke WK. Coeliakie. MD Thesis, Utrecht 1950. Walker-Smith JA, Guandalini S, Schmitz J, Shmerling DH, Visakorpi JK. Revised criteria for diagnosis of coeliac disease. Arch Dis Child 1990; 65: 909–11. Marsh MN. Gluten, major histocompatibility complex, and the small intestine. A molecular and immunobiologic approach to the spectrum of gluten sensitivity (‘celiac sprue’). Gastroenterology 1992; 102: 330–54. Mäki M, Holm K, Koskimies S, Hällström O,Visakorpi JK. Normal small bowel biopsy followed by coeliac disease. Arch Dis Child 1990; 65: 1137–41. Reunala T, Kosnai I, Karpati S, Kuitunen P,Török E, Savilahti E. Dermatitis herpetiformis: jejunal findings and skin response to glutenfree diet. Arch Dis Child 1984; 59: 517–22. Swinson CM, Levi AJ. Is coeliac disease underdiagnosed? BMJ 1980; 281: 1258–60. Logan RFA,Tucker G, Rifkind EA, Heading RC, Ferguson A. Changes in clinical features of coeliac disease in adults in Edinburgh and the Lothians 1960-79. BMJ 1983; 286: 95–97. Mäki M, Kallonen K, Lähdeaho ML, Visakorpi JK. Changing pattern of childhood coeliac disease in Finland. Acta Paediatr Scand 1988; 77: 408–12. Gobbi G, Bouquet F, Greco L, et al. Coeliac disease, epilepsy and cerebral calcifications. Lancet 1990; 340: 439–43. Collin P, Pirttilä T, Nurmikko T, Somer H, Erilä T, Keyriläinen O. Celiac disease, brain atrophy and dementia. Neurology 1991; 41; 372–75. Hadjivassiliou M, Gibson A, Davies-Jones GAB, Lobo AJ, Stephenson TJ, Milford-Wars A. Does cryptic gluten sensitivity play a part in neurological illness? Lancet 1996; 347: 369–71. Aine L, Mäki M, Collin P, Keyriläinen O. Dental enamel defects in celiac disease. J Oral Pathol Med 1990; 19: 241–45. Sher KS, Jayanthi V, Probert CS, Stewart CR, Mayberry JF. Infertility, obstetric and gynaecological problems in coeliac sprue. Dig Dis 1994; 12: 186–90. Molteni N, Caraceni MP, Bardella MT, Ortolani S, Gandolini GG, Bianchi P. Bone mineral density in adult celiac patients and the effect of gluten-free diet from childhood. Am J Gastroenterol 1990; 85: 51–53. Collin P, Mäki M. Associated disorders in coeliac disease: clinical aspects. Scand J Gastroenterol 1994; 29: 769–75. Leonard JN, Tucker WF, Fry JS, et al. Increased incidence of malignancy in dermatitis herpetiformis. BMJ 1983; 286: 16–18. Holmes GKT, Prior P, Lane MR, Pope D, Allan RN. Malignancy in coeliac disease—effect of a gluten free diet. Gut 1989; 30: 333–38.
1758
We thank Tuula Halttunen for preparing the figures. Coeliac Disease Study Group is supported by grants from the Medical Research Council, the Academy of Finland; the Sigrid Juselius Foundation; the Medical Research Fund of Tampere University Hospital; the Emil Aaltonen Foundation; the Foundation for Paediatric Research; and the Yrjö Jahnsson Foundation.
Vol 349 • June 14, 1997
THE LANCET Nat Genet 1996; 14: 329–33. 36 van de Wal Y, Kooy YMC, Drijfhout JW, Amons R, Koning F. Peptide binding characteristics of the coeliac disease-associated DQ(␣1*0501, 1*0201) molecule. Immunogenetics 1996; 44: 246–53. 37 Johansen BH, Gjertsen HA,Vartdal F, et al. Binding of peptides from the N-terminal region of alpha-gliadin to the celiac disease-associated HLA-
DQ2 molecule assessed in biochemical and T cell assays. Clin Immunol Immunopathol 1996; 79: 288–93. 38 Picarelli A, Maiuri L, Mazzilli MC, et al. Gluten-sensitive disease with mild enteropathy. Gastroenterology 1996; 111: 608–16. 39 Mäki M. Coeliac disease and autoimmunity due to unmasking cryptic epitopes. Lancet 1996; 348: 1046-47.
Further reading General
de Ritis G, Auricchio S, Jones HW, Lew EJ, Bernardin JE, Kasarda DD. In vitro (organ culture) studies of the toxicity of specific A-gliadin peptides in celiac disease. Gastroenterology 1988; 94: 41–49. Mantzaris G, Jewell DP. In vivo toxicity of a synthetic dodecapeptide from A gliadin in patients with coeliac disease. Scand J Gastroenterol 1991; 26; 392–98. Sturgess R, Day P, Ellis HJ, et al. Wheat peptide challenge in coeliac disease. Lancet 1994; 343: 758–61. Maiuri L, Picarelli A, Boirivant M, et al. Definition of the initial immunologic modifications upon in vitro gliadin challenge in the small intestine of celiac patients. Gastroenterology 1996; 110: 1368–78.
Coeliac disease (Howdle PD, ed). Baillieres Clin Gastroenterol 1995; 9: 1–416.
Latency Holm K, Mäki M, Savilahti E, Lipsanen V, Laippala P, Koskimies S. Intraepithelial gamma/delta T-cell-receptor lymphocytes and genetic susceptibility to coeliac disease. Lancet 1992; 339: 1500–03. Arranz E, Ferguson A. Intestinal antibody pattern of celiac disease: occurrence in patients with normal jejunal histology. Gastroenterology 1993; 104: 1263–72. Ferguson A, Arranz E , O’Mahony S. Clinical and pathological spectrum of coeliac disease—active, silent, latent, potential. Gut 1993; 34: 150–51. Collin P, Helin H, Mäki M, Mällström O, Karvonen A-L. Follow-up of patients positive in reticulin and gliadin antibody tests with normal small bowel biopsy findings. Scand J Gastroenterol 1993; 28: 595–98. Troncone R. Latent coeliac disease in Italy. Acta Paediatr 1995; 84: 1252–57.
Changing pattern Collin P, Hällström O, Mäki M, Viander M, Keyriläinen O. Atypical coeliac disease found with serologic screening. Scand J Gastroenterol 1990; 25: 245–50. Corazza G R, Frisoni M, Treggiari EA, et al. Subclinical celiac sprue. Increasing occurrence and clues to its diagnosis. J Clin Gastroenterol 1993; 16: 16–21. Hankey GL, Holmes GKT. Coeliac disease in the elderly. Gut 1994; 35: 65–67. Visakorpi JK, Mäki M. Changing clinical features of coeliac disease. Acta Paediatr Suppl 1994; 83: 10–13. Marsh MN. The natural history of gluten sensitivity: defining, refining and redefining. QJM 1995; 88: 9–13. Troncone R, Greco L, Auricchio S. Gluten-sensitive enteropathy. Pediatr Clin North Am 1996; 43: 355–73.
Extraintestinal symptoms and associated diseases Savilahti E, Pelkonen P, Visakorpi JK, IgA deficiency in children. A clinical study with special reference to intestinal findings. Arch Dis Child 1971; 46: 665–70. Pare P, Douville P, Caron D, Lagace R. Adult celiac sprue: changes in the pattern of clinical recognition. J Clin Gastroenterol 1988; 10: 395–400. Collin P, Reunala T, Pukkala E, Laippala P, Keyriläinen O, Pasternack A. Coeliac disease—associated disorders and survival. Gut 1994; 35: 1215–18. Marsh MN. Bone disease and gluten sensitivity: time to act, to treat, and to prevent. Am J Gastroenterol 1994; 89: 2105–07. Corazza FR, Di Sario A, Cecchetti L, et al. Bone mass and metabolism in patients with celiac disease. Gastroenterology 1995; 109: 122–28. Corazza GR, Andreani ML, Venturo N, Bernardi M, Tosti A, Gasbarrini G. Celiac disease and alopecia areata: report of a new association. Gastroenterology 1995; 109: 1333–37. McFarlane XA, Bhalla AK, Reeves DE, Morgan LM, Robertson DA. Osteoporosis in treated adult coeliac disease. Gut 1995; 36: 710–14. Mäki M, Huupponen T, Holm K, Hällstrom O. Seroconversion of reticulin autoantibodies predicts coeliac disease in insulin dependent diabetes mellitus. Gut 1995; 36: 239–42. Aine L. Coeliac-type permanent tooth enamel defects. Ann Med 1996; 28: 9–12. Valdimarsson T, Löfman O, Toss G, Ström M. Reversal of osteopenia with diet in adult coeliac disease. Gut 1996; 38: 322–27.
Malignancy Holmes GKT, Stokes PL, Sorahan TM, Prior P, Waterhouse JAH, Cooke WT. Coeliac disease, gluten-free diet and malignancy. Gut 1976; 17: 612–19. Swinson CM, Slavin G, Coles EC, Booth CC. Coeliac disease and malignancy. Lancet 1983; i: 11–15.
The role of cereals and precipitating factors Kagnoff MF, Austin RK, Hubert JJ, Bernardin JE, Kasarda DD. Possible role for a human adenovirus in the pathogenesis of celiac disease. J Exp Med 1984; 160; 1544–57.
Vol 349 • June 14, 1997
Epidemiology Hallert C, Gotthard R, Norrby K, Walan A. On the prevalence of adult coeliac disease in Sweden. Scand J Gastroenterol 1981; 16: 257–61. Logan RFA, Rifkind EA, Busuttil A, Gilmour HM, Ferguson A. Prevalence and “incidence” of celiac disease in Edinburgh and the Lothian region of Scotland. Gastroenterology 1986; 90: 334–42. Mäki M, Holm K. Incidence ad prevalence of coeliac disease in Tampere. Coeliac disease is not disappearing. Acta Paediatr Scand 1990; 78: 739–42. Ascher H, Krantz I, Kristiansson B. Increasing incidence of coeliac disease in Sweden. Arch Dis Child 1991; 66: 608–11. Talley NJ, Valdovinos M, Petterson TM, Carpenter HA, Melton L Jr. Epidemiology of celiac sprue: a community-based study. Am J Gastroenterol 1994; 89: 843–46.
Screening Karpati S, Burgin-Wolff A, Krieg T, Meurer M, Stolz W, Braun-Falco O. Binding to human jejunum of serum IgA antibody from children with coeliac disease. Lancet 1990; 336: 1335–38. McMillan SA, Haughton DJ, Biggart JD, Edgar JD, Porter KG, McNeill TA. Predictive value for coeliac disease of antibodies to gliadin, endomysium, and jejunum in patients attending for jejunal biopsy. BMJ 1991; 303: 1163–65. Troncone R, Ferguson A. Anti-gliadin antibodies. J Pediatr Gastroenterol Nutr 1991; 12: 150–58. Mäki M, Hällström O, Marttinen A. Reaction of human non-collagenous polypeptides with coeliac disease autoantibodies. Lancet 1991; 338: 724–25. Mäki M, Holm K, Lipsanen V, et al. Serological markers and HLA genes among healthy first-degree relatives of patients with coeliac disease. Lancet 1991; 338: 1350–53. Ferreira M, Davies SL, Butler M, Scott D, Clark M, Kumar P. Endomysial antibody: is it the best screening test for coeliac disease? Gut 1992; 33: 1633–37. Unsworth DJ, Brown DL. Serological screening suggests that adult coeliac disease is underdiagnosed in the UK and increases the incidence by up to 12%. Gut 1994; 35: 61–64. Volta U, Molinaro N, De Franceschi L, Fratangelo DS, Bianchi FB. IgA antiendomysial antibodies on human umbilical cord tissue for celiac disease screening. Save both money and monkeys. Dig Dis Sci 1995; 40: 1902–05.
Genetics, immunology and pathogenesis Brandtzaeg P, Halstensen TS, Kett K, et al. Immunobiology and immunopathology of human gut mucosa: humoral immunity and intraepithelial lymphocytes. Gastroenterology 1989; 97: 1562–84. Sollid LM, Markussen G, Ek J, Gjerde H, Vartdal F, Thorsby E. Evidence for a primary association of celiac disease to a particular HLA-DQ ␣/ heterodimer. J Exp Med 1989; 169: 345–50. Reunala T, Mäki M. Dermatitis herpetiformis: a genetic disease. Eur J Dermatol 1993; 3: 519–26. Lundin K, Scott H, Hansen T, et al. Gliadin-specific, HLA-DQ(␣1*0501, 1*0291) restricted T cells isolated from the small intestinal mucosa of celiac disease patients. J Exp Med 1993; 178: 87–96. Tighe MR, Ciclitira PJ. The gluten-host interaction. Baillieres Clin Gastroenterol 1995; 9: 211–30. Ferguson A. New perspectives of the pathogenesis of coeliac disease: evolution of a working clinical definition. J Intern Med 1997; 240: 315–18.
1759