Search

Objective: Our previous coeliac disease genome-wide association study (GWAS) implicated risk variants in the human leucocyte antigen (HLA) region and eight novel risk regions. To identify more coeliac disease loci, we selected 458 single nucleotide polymorphisms (SNPs) that showed more modest association in the GWAS for genotyping and analysis in four independent cohorts., Design: 458 SNPs were assayed in 1682 cases and 3258 controls from three populations (UK, Irish and Dutch). We combined the results with the original GWAS cohort (767 UK cases and 1422 controls); six SNPs showed association with p<1 x 10(-04) and were then genotyped in an independent Italian coeliac cohort (538 cases and 593 controls)., Results: We identified two novel coeliac disease risk regions: 6q23.3 (OLIG3-TNFAIP3) and 2p16.1 (REL), both of which reached genome-wide significance in the combined analysis of all 2987 cases and 5273 controls (rs2327832 p = 1.3 x 10(-08), and rs842647 p = 5.2 x 10(-07)). We investigated the expression of these genes in the RNA isolated from biopsies and from whole blood RNA. We did not observe any changes in gene expression, nor in the correlation of genotype with gene expression., Conclusions: Both TNFAIP3 (A20, at the protein level) and REL are key mediators in the nuclear factor kappa B (NF-kappaB) inflammatory signalling pathway. For the first time, a role for primary heritable variation in this important biological pathway predisposing to coeliac disease has been identified. Currently, the HLA risk factors and the 10 established non-HLA risk factors explain approximately 40% of the heritability of coeliac disease.

Chromosomal region 2q33 encodes the immune regulatory genes, CTLA4, ICOS and CD28, which are involved in regulation of T-cell activity and has been studied as a candidate gene locus in autoimmune diseases, including coeliac disease (CD). We have investigated whether an association exists between this region and CD in the Irish population using a comprehensive analysis for genetic variation. Using a haplotype-tagging approach, this gene cluster was investigated for disease association in a case-control study comprising 394 CD patients and 421 ethnically matched healthy controls. Several SNPs, including CTLA4&#95;CT60, showed association with disease; however, after correction for multiple-testing, CTLA4-658C/T was the only polymorphism found to show significant association with disease when allele, genotype, or carrier status frequency were analysed (carrier status (Allele C), P = 0.0016). Haplotype analysis revealed a haplotype incorporating the CD28/CTLA4 and two 5' ICOS polymorphisms to be significantly associated with disease (patients 24.1%; controls 31.5%; P = 0.035), as was a shorter haplotype composed of the CTLA4 markers only (30.9 vs 34.9%; P = 0.042). The extended haplotype incorporating CD28/CTLA4 and 5' ICOS is more strongly associated with disease than haplotypes of individual genes. This suggests a causal variant associated with this haplotype may be associated with disease in this population.

Genetic predisposition to coeliac disease (CD) is determined primarily by alleles at the HLA-DQB locus, and evidence exists implicating other major histocompatibility complex-linked genes (6p21) and the CTLA4 locus on chromosome 2q33. In addition, extensive family studies have provided strong, reproducible evidence for a susceptibility locus on chromosome 5q (CELIAC2). However, the gene responsible has not been identified. We have assayed genetic variation at the IL4, IL5, IL9, IL13, IL17B and NR3C1 (GR) loci, all of which are present on chromosome 5q and have potential or demonstrated involvement in autoimmune and/or inflammatory disease, in a sample of 409 CD cases and 355 controls. Thirteen single nucleotide polymorphisms were chosen on the basis of functional relevance, prior disease association and, where possible, prior knowledge of the haplotype variation present in European populations. There were no statistically significant allele or haplotype frequency differences between cases and controls. Therefore, these results provide no evidence that these loci are associated with CD in this sample population.

Objective: Susceptibility to sarcoidosis and coeliac disease has been linked to the class II haplotype HLA-DR3, DQ2, and an association between the two disorders has been suggested. As a pilot study, we have sought to determine the prevalence of coeliac disease in a cohort of Irish patients with sarcoidosis., Design: Prospective, case-controlled study., Methods: One hundred and two sarcoid patients (47 males, 55 females) from the west of Ireland and 105 (52 males, 53 females) healthy, ethnically matched, controls underwent interview and screening for coeliac disease and human leucocyte antigen typing by serology. Those with elevated anti-gliadin IgA (AGA) and/or positive endomysial antibody (EMA) were offered small intestinal biopsy., Results: Three (3%) sarcoid patients had a prior diagnosis of coeliac disease. A further 12 (12%) patients and four (4%) controls had elevated AGA (P = 0.047), of whom three and one, respectively, had positive EMA. Small intestinal biopsy in 11 patients and three controls confirmed coeliac disease in one individual each, giving a prevalence of coeliac disease in patients compared with controls of 4/102 (4%) versus 1/105 (1%) (P = 0.21). Sensitivity and specificity of EMA and elevated AGA in sarcoid patients was 100% and 50%, and 50% and 9%, respectively. Of the four affected sarcoid patients, three carried HLA-DR3, DQ2 and one carried DR5 (12), DR7, DQ2., Conclusion: We have demonstrated a moderately increased prevalence of coeliac disease in Irish patients with sarcoidosis, which we feel justifies future screening of our sarcoid population. Estimation of EMA is recommended and should be restricted to those with susceptible haplotypes.

In addition to the well-established association of coeliac disease (CD) with HLA-DQ (6p21) and possibly CTLA4 (2q33), there is considerable evidence for a susceptibility locus on chromosome 5q, which contains many potential candidates for inflammatory disease, including a cluster of cytokine genes in 5q31. CD cases and controls were genotyped for four single-nucleotide polymorphism (SNP) markers that together characterize >90% of the haplotype variation at the IBD5 locus encoding, among others, the SLC22A4 gene. IBD5 and SLC22A4 map to 5q31 and have recently been associated with Crohn's disease and rheumatoid arthritis. Haplotype frequencies do not differ significantly between CD cases and controls in the Irish population, and therefore the chromosome 5 CD susceptibility locus most likely lies elsewhere on 5q.

Levels of secretory IgA1 (SIgA1) in the saliva have not been measured previously in either coeliac disease (CD) or inflammatory bowel disease (IBD). Saliva was collected from coeliacs, IBD patients and controls. The concentration of total SIgA in saliva was measured by enzyme linked immunosorbent assay (ELISA) with an anti-human SIgA antibody as the bound phase and human SIgA isolated from colostrum as the standard. The concentration of SIgA1 was determined using an ELISA with a lectin with a high affinity for human SIgA1. The IBD patients have a significantly higher concentration of SIgA1 than the controls. The rate of secretion of saliva and %SIgA1 was significantly lower in coeliacs than in the control and IBD groups. The rate of secretion of SIgA1 was significantly higher in the IBD than in the coeliacs. We describe hitherto unreported levels of SIgA1 in CD and IBD.

Aims: To investigate the prevalence of lymphocytic gastritis in patients with coeliac disease., Methods: Gastric biopsies from 70 patients with coeliac disease were examined by light microscopy for the presence of lymphocytic gastritis, defined as 25 or more intraepithelial lymphocytes/100 gastric columnar epithelial cells., Results: Lymphocytic gastritis was found in seven cases. Positive cases had a mean of 32.1 intraepithelial lymphocytes/100 columnar cells, compared with a mean of 13.9 in negative cases, and 5.15 in noncoeliac controls. No differences were found for age, sex, gastric corpus or antrum, or degree of inflammation in the gastric lamina propria. All intraepithelial lymphocytes were of T cell lineage. Cases not showing lymphocytic gastritis did however show significantly increased gastric intraepithelial lymphocytes compared with non-coeliac controls. Eighteen of 70 cases were positive for Helicobacter pylori, and four of seven cases of lymphocytic gastritis were H pylori positive; no significant difference was observed between H pylori positive and negative patients. Three cases had concomitant ulcerative enteritis, of which none showed lymphocytic gastritis, while five cases had concomitant enteropathy associated T cell lymphoma, of which one showed lymphocytic gastritis., Conclusions: Lymphocytic gastritis occurred in 10% of patients with coeliac disease. Cases without lymphocytic gastritis nevertheless showed increased gastric intraepithelial lymphocytes. Coeliac disease may on occasion be a diffuse lymphocytic enteropathy occurring in response to gluten. Lymphocytic gastritis outside coeliac disease may involve an immune response to luminal antigens, such as H pylori, not unlike the response to gluten in patients with coeliac disease.

Aims: To determine the frequency of abnormal pancreolauryl tests in untreated and treated adults with coeliac disease and to see whether abnormalities in treated coeliac patients correlate with the degree of recovery of intestinal morphology or brush border enzyme activity., Methods: Pancreolauryl tests were performed in a study population of 57 adult coeliac patients (25 on gluten containing diets and 32 on gluten free diets), 59 symptomatic controls, and eight patients with pancreatic disease. Brush border enzyme activity and morphological assessment were performed on small intestinal biopsies in 27 of the treated coeliac patients., Results: Forty per cent of untreated coeliac patients and 18% of treated coeliac patients had abnormal tests. In treated coeliac patients, no significant correlation was detected between the pancreolauryl test result and either brush border enzyme activity or morphological parameters., Conclusion: Abnormal pancreolauryl test results are common in untreated and treated adult coeliac disease patients. Abnormalities in treated coeliac patients do not correlate with the degree of recovery of small intestinal morphology or brush border enzymes.

Immunoglobulin deficiency, especially deficiency of IgA, has been described in patients with celiac sprue (CS). Our study was performed in an area of high prevalence of CS to determine the prevalence of immunodeficiency states in patients with CS, to examine their clinical characteristics, response to treatment, and HLA phenotypes compared with a group of age- and sex-matched persons with CS but without immunoglobulin deficiency. Fourteen of 604 patients with CS were identified as being selectively deficient in IgA, whereas one had common variable immunodeficiency. At diagnosis, anemia was present in 8 of 14 IgA-deficient patients compared with 10 of 42 controls (p = 0.047), whereas abdominal pain was more common in controls with CS. Autoimmunity and recurrent infection were more prevalent in the IgA-deficient group. Response to gluten-free diet was similar in both groups in terms of histologic structure and recovery of intestinal brush-border enzyme activity. IgA-deficient participants with CS had no increased risk of associated malignancy or lymphoma. HLA phenotypes were similar in both groups. The prevalences of selective IgA deficiency and common variable immunodeficiency in this series of patients with CS are 2.31 in 100 and 0.16 in 100, respectively. Although this group is unique in character, close follow-up coupled with conscientious compliance with a gluten-free diet, remains the mainstay of treatment for these patients.

Coeliac disease is associated with selective IgA deficiency and various autoimmune disorders. An association between Addison's disease and coeliac disease has been documented previously in the literature but never heretofore in coeliac patients with selective IgA deficiency. From a coeliac registry of over 700 biopsy-proven coeliac patients, studied closely over a 25-year period at University College Hospital, Galway, we now report the finding of Addison's disease and selective IgA deficiency in two patients with established coeliac disease. Previous reports of Addison's disease in coeliac patients were sporadic, and it was felt that the association between the two conditions was fortuitous. We now believe that coeliac patients, especially those who are selectively deficient in serum IgA, should be followed up with increased vigilance, as the association between IgA-deficient coeliac patients and Addison's disease is greater than can be explained by chance. Furthermore, we suggest that patients with established Addison's disease may have subclinical coeliac disease and should be screened with anti-reticulin or anti-endomyseal antibodies.

Celiac disease is a strongly heritable gastrointestinal illness that is an especially important model of the genetically complex multifactorial immune mediated diseases. The HLA component of celiac disease (a specific HLA-DQ heterodimer)is largely established and is relatively uncomplicated, and the environmental component (gluten and related grain storage proteins in the diet) is remarkably well understood. Previous family studies of celiac disease suggested that there is at least one important non-HLA locus. This locus may be a stronger genetic factor than HLA, and it apparently has a recessive mode of inheritance. We used a three step genome screening protocol to identify loci that contribute to celiac disease in the western counties of ireland, a region with the highest prevalence of celiac disease in the world. The most significant of several possible non-HLA loci that we found was on chromosome 6p about 30 cM telomeric from HLA. It has a multipoint maximum lod score of 4.66 (compared with 4.44 for HLA-DQ) and appears to have a recessive mode of inheritance. Our study localizes and provides strong evidence for linkage of at least one non-HLA locus to celiac disease and may serve as a prototype for an efficient approach to screening the human genome for loci that contribute to complex diseases.

Background: The ability to secrete blood group antigens into body fluids and secretions is controlled by a single gene on chromosome 19. By means of erythrocyte Lewis (Le) antigen phenotype secretor status can be inferred. An increase prevalence of non-secretors of blood group antigens among coeliac patients has recently been described., Methods: Blood was collected from 112 coeliac patients and 103 controls and tested for secretor status. Secretor status was correlated with human leucocyte antigens (HLA) in coeliac patients, thus evaluating a proposed interaction of susceptibility genes--that is, the secretor gene on chromosome 19 and HLA-linked genes on chromosome 6. Case notes for coeliacs were reviewed with regard to clinical outcome., Results: Of 112 coeliacs who had either Le(a) or Le(b) antigens, 36 (32%) were non-secretors Le(a+, b-), compared with 27% (28) of 103 disease-free controls (P = 0.313). Recessive Lewis phenotype Le(a-, b-) was found in 9% of coeliacs versus 2% of controls. Prevalence of HLA-A1, B8, DR3, and DQ2 was unrelated to secretor status in coeliac versus patients. An increased prevalence of complications and coeliac-associated abnormalities was found in the non-secreting and recessive coeliac groups., Conclusions: This study shows no firm relationship between the non-secretor state and coeliac disease, nor any difference in the distribution of HLA markers among secretor and non-secretor coeliacs. It is unlikely, therefore, that the secretor gene is the much sought-after second coeliac gene.

Celiac disease (CD) has one of the strongest class II HLA associations of any human illness. We used DNA-RFLP typing to study the class II HLA genotypes of celiac disease patients from the West of Ireland, the geographic area with the highest rate of celiac disease in the world. We confirmed the high frequency of HLA-DR3 in this population, and we were also able to demonstrate the additional risk of developing celiac disease imparted by HLA-DR7. This was done by clearly distinguishing DR7,DQ2 haplotypes from DR7,DQ9 haplotypes, and by "subtraction analysis" of haplotype frequencies. As reported in other populations, most of the patients without DR3 were heterozygous for DR7 and DR11 or 12 (DR5), or had DR4. We used PCR-RFLP and direct sequencing of amplified DNA to examine HLA-DR4 subtypes. The frequency of HLA-DR4 was markedly decreased in patients compared with controls (p = 0.000001) and there was a significant alteration of DR4 subtypes of the patients compared with controls (p = 0.0227). Moreover, all of the CD patients (5 of 5) with DR4 had a haplotype associated with the DQB1*0302 allele compared with only 11 of 23 control subjects with DR4. Our results in this population with exceptionally high risk of CD strongly support the DQ heterodimer hypothesis and suggest that the recently described sequence difference between the DQB1*02 alleles of DR3 and DR7 may contribute to a synergistic increased risk when these haplotypes are inherited together. In addition, our findings suggest a role for HLA-DQ in DR4-associated CD.

The Epstein-Barr virus has been implicated in the etiology of endemic Burkitt's lymphoma, post-transplant lymphoma, large-cell anaplastic CD30 (Ki-1)-positive lymphoma, and in many T-cell lymphomas. A recent report has found Epstein-Barr virus genome in association with 4 of 11 cases (36%) of enteropathy-associated T-cell lymphoma. In a retrospective study, we have characterized 22 consecutive cases of enteropathy-associated T-cell lymphoma from the West of Ireland where celiac disease is endemic. All cases were immunophenotyped with T- and B-cell markers including the anaplastic large-cell lymphoma marker CD30 or Ki-1. Nineteen cases were studied for latent membrane protein expression and 16 for Epstein-Barr virus small RNAs by in situ hybridization using EBER oligonucleotides on routinely processed sections. Only 1 of 16 cases (6%) showed Epstein-Barr virus in tumor cells and no cases stained with latent membrane protein. Eight of 22 cases (36%) including the EBER-positive case were positive for CD30. These results suggest that the Epstein-Barr virus does not commonly play a role in the pathogenesis of enteropathy-associated T-cell lymphoma from this area.

Celiac sprue (CS) is frequently complicated by malignancy, most commonly small intestinal lymphoma. Our study was performed in an area with a high prevalence of CS to define the clinical features, response to treatment, and outcome of this tumor. Of a total of 31 lymphomas complicating CS identified, 30 case records and 24 tumor specimens were reviewed. Overall 1-year survival was 9 of 29 (31%) and 5-year survival 3 of 27 (11%). Seven previously diagnosed celiac patients developed lymphoma; length on gluten-free diet ranged from 12 to 252 months (median 44 months). In this group, presentation was nonspecific, diagnosis difficult, and survival poor (lymphoma diagnosed in life in four of seven, mean survival 2.25 months). Twenty-three patients had CS and lymphoma diagnosed during the same illness. In this group, 14 of 23 presented with a surgical emergency and were treated with tumor resection and chemotherapy. Nine are disease-free and alive or died of another cause after 10-196 months (mean 74 follow-up). Celiac-associated lymphoma is a frequent, difficult to diagnose, and commonly fatal complication of CS. An aggressive diagnostic approach, including laparoscopy, is recommended. Long-term survival can be expected in a significant number of these patients and in our series was almost exclusively confined to those treated with chemotherapy.

Although celiac disease has one of the strongest human lymphocyte antigen (HLA) class II associations of any human illness, it is clear that at least one gene that is not linked to the HLA region also is required for its pathogenesis. The occurrence of large numbers of gamma delta T cells in the bowel mucosa of patients and the recent description of T cell receptor (TCR) gamma chain polymorphic variants identified by restriction fragment length polymorphism analysis led the authors to examine TCR gamma genotypes in relation to HLA-DR, DQ genotypes in 89 patients with celiac disease and 55 control subjects from the West of Ireland. The overall frequency of TCR gamma genotypes in patients and control subjects was comparable. However, most of the patients had 1 of 3 HLA-DR3 genotypes (DR3/15, 3/7, or 3/3), and there was a significant alteration of the expected frequency of TCR gamma genotypes among patients with these three genotypes. The major differences were an increased association of HLA-DR3 homozygosity, with TCR gamma genotypes having a 16.0 kb fragment and an increased frequency of DR3/7 heterozygosity and decreased frequency of DR3/15 heterozygosity, respectively, in association with the TCR gamma 13.0/11.3 kb genotype. Based on their results, there is the possibility that an interaction between the products of two polymorphic and unlinked gene regions contributes to the pathogenesis of celiac disease.

Brown bowel syndrome is the name applied to a brown discoloration of the intestine. This is due to lipofuscin deposition in intestinal smooth muscle and occurs in association with malabsorption. Three cases occurring in a coeliac registry of 559 patients are described. One patient presented with acute massive bleeding per rectum, and two were diagnosed at autopsy. The syndrome may be accompanied by vitamin E deficiency and neurologic dysfunction. Two patients had evidence of peripheral neuropathy, and one had low vitamin E levels. Concomitant vitamin D deficiency was present. Fat-soluble vitamin malabsorption, especially if there is a poor response to a gluten-free diet or neuropathy, might alert the clinician to the possibility of brown-bowel syndrome and suggests careful search for lipofuscin in biopsy material, using special histologic techniques.

alpha 1 antitrypsin or protease inhibitor (Pi) phenotyping was carried out on 111 coeliac disease patients (CD) and 250 controls. The Pi MM phenotype was present in 95 (85.6%) of the coeliacs and 225 (90%) of the controls. The groups did not differ significantly with regard to Pi phenotypes. In the CD group the Pi Phenotype did not relate to HLA B8 or DR3 status. Associated diseases in the CD patients did not correlate with Pi phenotype.

The highest reported prevalence of celiac disease (gluten-sensitive enteropathy) is found in the West of Ireland. Recent genetic data have suggested that major histocompatibility complex-linked loci may have a dominant genetic effect for disease susceptibility in this population compared with a recessive effect in other groups. To further understand the role of the MHC in celiac disease in the West of Ireland, we analyzed markers for 22 MHC haplotypes from celiac patients and compared them with 18 nontransmitted haplotypes found in the parents of celiac children, and with reported haplotypes from other populations. An extended MHC haplotype including [HLA-B8, DR3, DQw2, Bf*S, C4A*Q0, and C4B*1] accounted for 50% of celiac haplotypes but only 27% of nontransmitted parental haplotypes. Compared with other reported haplotypes in celiacs, patients from the West of Ireland show a higher prevalence of HLA-A1 as a component of this extended haplotype, suggesting that although the core haplotype is similar between Irish patients and others, the celiac population in the West of Ireland differs at other HLA loci. We did not observe any other common haplotypes among our patients unlike the situation in other populations. These differences may underlie the possible dominant effect of HLA-linked loci and the unusually high prevalence of celiac disease in the Irish population. We also found that the serum levels of complement components C3c, C4, and factor B were significantly lower among celiac patients than nonceliacs. The lower serum level of C4 appears to be related to the presence of deletions and null alleles at the C4A and C4B loci in celiacs.

Restriction fragment length polymorphism analysis, using a single restriction enzyme TaqI-multiple-probe system for HLA-DRB1-DQB1 and -DQA1, was used to determine HLA-DR and -DQ frequencies in 56 unrelated celiac patients and 47 unrelated controls from the west of Ireland. In addition, HLA-DPB1 allelic frequencies were determined in the same group of patients and controls by using the technique of enzymatic DNA amplification of the polymorphic second exon of HLA-DPB1 genes in conjunction with sequence-specific oligonucleotide probing. The results suggest that HLA-DQ rather than HLA-DR is more important in conferring susceptibility to celiac disease. Furthermore, no association between HLA-DP and celiac disease was found in this study.

A two gene model has been proposed to explain the inheritance of coeliac disease (CD). One gene is on chromosome 6 in the MHC complex (HLA associated). It has been suggested the second gene is located on chromosome 14, in or near the region encoding for immunoglobulin heavy chain allotypes (Gm types). In a study of 102 unrelated Irish coeliacs and a group of ethnic controls, we have failed to show an association of CD with any particular Gm type or types. There is no evidence to confirm that a gene on chromosome 14 is implicated in the inheritance of CD.

Although coeliac disease (CD) is strongly associated with the HLA alleles B8 and DR3, the genetic basis of this illness remains obscure. Recent studies show that at least two unlinked loci are involved. Most studies agree on recessivity at the HLA-unlinked locus but differ with respect to dominance or recessivity at the HLA-linked disease susceptibility locus. To address this controversy, we examined the association of CD with HLA in 39 families from the West of Ireland. Previous studies have shown that the prevalence of CD and the frequencies of the HLA antigens associated with it are higher in this population than in most others. Analysis of the data revealed a significant excess of concordant sib-pairs with two HLA haplotypes in common and an excess of discordant pairs with no haplotype in common. Chi-square tests confirmed a highly significant association between HLA-B8 and CD. Both heterozygotes and homozygotes for B8 had a significantly increased risk of CD. The risk for homozygotes was slightly higher than for heterozygotes, although not significantly so. The segregation ratio for disease occurrence among sibs of probands was estimated to be 0.185 when neither parent is affected. We estimated a gene frequency of 0.003 for the disease allele (C) at the HLA-linked locus and of 0.648 for the disease allele (d) at the HLA-unlinked locus. Assuming that CCdd homozygotes are always affected and that only carriers of C who are homozygous dd can be affected, the disease was found to be completely penetrant in Ccdd heterozygotes. These results support dominance at the HLA-linked locus conferring susceptibility to CD. Possible reasons for the discrepancy between the West of Ireland and other populations are discussed.

The clinical, radiological and pathological features of 7 patients with coeliac disease (CD) who developed lung abscesses or cavities are described. These patients were seen during a 20-year period during which time approximately 600 coeliacs were seen and 50 died. Six of the coeliac patients with lung abscess died. The patients were middle aged. Staphylococcal infection, Klebsiella pneumoniae, bronchial carcinoma and previous pulmonary tuberculosis accounted for the cavities in 4 patients. In the 3 other patients a definite cause could not be identified. Hyposplenism and malnutrition were common. Next to malignancy pulmonary abscess was the commonest cause of death in the coeliac population. The development of respiratory symptoms should be regarded as a potentially serious and a life-threatening event in the middle-aged coeliac patients. Lung abscess should be added to the list of respiratory diseases associated with coeliac disease.

HLA, A, B, and DR typing was done on seven of 10 patients with lymphoma, and six patients with carcinoma, all of whom had a flat small intestinal mucosa. Sixty-nine per cent (nine of 13) had HLA B8 and 71% (five of seven) had DR3. The corresponding levels for the local coeliac population are 76% and 84% respectively and the local non-coeliac population 43% and 44%. Two of the patients with lymphoma had a child with coeliac disease. The histological type of the lymphoma was malignant histiocytosis of the intestine in seven, histiocytic lymphoma in two, and was not classifiable in one. The similarity of the HLA type suggests that the flat mucosa in both groups is due to coeliac disease.

The first part of the duodenum has been studied endoscopically in treated and untreated coeliac patients. Biopsies taken from the duodenal cap during endoscopic examination, show villous atrophy similar to that found in the distal duodenum and jejunum. Using the indigocarmine scattering method, severe atrophy of the mucosal surface can be demonstrated throughout the duodenal cap, in vivo, in untreated coeliac disease.

The sera of 69 index coeliac patients, 121 of their first-degree relatives, and 104 controls were screened for the presence of reticulin antibodies. Among the untreated coeliac patients 75% of adults and 93% of children had reticulin antibody in their serum. Reticulin antibody was not present in any adequately treated coeliac patient. Of the first-degree relatives, 21 were reticulin antibody positive; 17 of these were biopsied and 12 were shown to have coeliac disease. Sixty-five of the coeliac relatives who did not have reticulin antibodies in their sera were biopsied and two had coeliac disease. Of the 68 relatives and 63 controls with normal biopsies, five of the relatives and four of the controls were reticulin antibody positive.

Between 1960 and 1974 the incidence of coeliac disease in children under 12 years in County Galway remained fairly constant, but since 1975 it has fallen by 62% and the lowered incidence seems well established. The number of those who were breast fed and the age at which first gluten feeding took place during the 22 years both increased significantly and from the mid-70s total protein content and osmolarity of proprietary cow's milk formulas were reduced. All three factors may be relevant. A negative correlation with the incidence of gastroenteritis was found.

Lactase, sucrase, and alkaline phosphatase activities were measured in 833 peroral small intestinal biopsies from 373 patients with coeliac disease. Enzyme activities decreased with increasing degrees of mucosal damage. Enzyme activities in mucosae of patients with coeliac disease in remission were lower than in control groups matched for age, sex, and site of biopsy. Enzyme activities were measured in 81 patients when the mucosa was severely damaged and later when considerable improvement had occurred. Lactase activity remained low in 13% of patients under the age of 18 and in 33% of those over 18 years. Sucrase activity usually improved with histological recovery, but alkaline phosphatase activity tended to remain depressed in patients in whom lactase activity failed to improve.

An increased association of ulcerative colitis and coeliac disease has been reported, as have the results of several small-bowel biopsy studies in ulcerative colitis. Forty-two patients from a population of 438 patients with coeliac disease had rectal biopsies. Fourteen of these showed inflammation of various degrees of severity, including three compatible with a diagnosis of ulcerative colitis. The presenting complaint in 34 of these patients was diarrhoea or steatorrhoea. Twenty-seven patients had coeliac disease diagnosed at the same time or after their rectal biopsy. The other 15 were previously diagnosed coeliacs. Twelve of the 14 patients with abnormal rectal biopsy specimens were known to have subtotal/total villous atrophy at the time of rectal biopsy. Proctitis as seen in these coeliac patients had no unique features to differentiate it from proctitis caused by other disorders. The diarrhoea/steatorrhoea stopped in all patients on commencement of a gluten-free diet, except in those with ulcerative colitis. Proctitis is common in patients with coeliac disease presenting with diarrhoea/steatorrhoea. This study supports the finding of an increased association of coeliac disease and ulcerative colitis and is, to our knowledge, the first rectal biopsy study of a coeliac population.

Tissue typing (HLA-A, -B and -DR) was carried out on 92 patients with coeliac disease (CD) and on a further 71 first degree relatives of 13 of these patients. Results of antigen frequencies in unrelated patients and segregation analysis in families shows that HLA-DR3 but not HLA-DR7 is positively associated with CD. Haplotype and sib-pair data from these coeliac families suggest that with all of them, genetic susceptibility to CD lies in the HLA region of the sixth chromosome. In families where the coeliac proband has HLA-DR3, the relative risk to siblings who also have this antigen is increased 35 times.

Splenic size and function was assessed in eight patients with celiac disease and coexisting malignancy (six had small bowel lymphoma and two gastric adenocarcinoma). The size of the spleen was reduced in four of seven patients as seen at autopsy or radionucleotide scanning. Splenic function was studied using "pitted" erythrocyte counts, platelet counts, and Howell-Jolly bodies and was impaired in five of eight patients. Malignant disease developed in some celiacs with normal splenic size and function. Splenic function as measured by pitted erythrocyte counts was similar in the celiac patients with malignancy and appropriately matched nonmalignant celiacs. We conclude that hyposplenism in celiac disease does not influence the development of malignant disease.

Splenic function was assessed using 'pitted' erythrocyte counts in 61 first degree relatives of patients with coeliac disease. 'Pitted' erythrocyte counts were normal in 12 parents, but were raised in 20% of 49 siblings and/or children of coeliac patients. First degree relatives had higher 'pitted' erythrocyte counts than normal controls (p = 0.002). The counts were lower in coeliac relatives than in age matched coeliacs (p = 0.0001), but no difference was present between the relatives and coeliac patients whose small bowel mucosa was morphologically normal. Considerable interfamily variation was found in 'pitted' erythrocyte counts, both in the coeliac patients and first degree relatives, and the pattern tended to 'run true' within families. The genetic factor influencing splenic function in coeliac disease is not HLA-linked but seems to be associated with a second, probably recessive, gene influencing the inheritance of coeliac disease.

Platelet count and volume were measured in 84 splenectomised subjects, 142 patients with coeliac disease and 77 healthy subjects. An inverse, non-linear correlation between platelet count and volume was found in healthy subjects and coeliac patients, but was not present in splenectomised subjects who had higher platelet counts (P = 0.0001) and mean platelet volumes (P = 0.0001) than healthy subjects. Platelet counts correlated with splenic function in patients with coeliac disease and were higher in patients with severe hyposplenism than in normosplenic coeliacs (P = 0.0001). Splenic function did not influence the mean platelet volume (MPV) in coeliac disease but normosplenic coeliacs had higher MPV than normal subjects (P = 0.05). Serum iron and red cell folate were not correlated to MPV in coeliac disease. We conclude that splenic function effects platelet count and volume in non-coeliac subjects and platelet count in coeliac disease. However, other unidentified factor(s) influence the MPV in coeliac disease.

Follow-up studies on 36 children, in whom celiac disease (gluten-sensitive enteropathy) was established by gluten challenge, were carried out after management on gluten-free diets for a mean of six years. Evaluations included measurement of height and weight, which for the group approximated normal distributions, and histologic examination of the duodenal or jejunal mucosa. Mucosal morphology was regarded as normal in 16, and there were minimal changes in 20. Epithelial cell height was within the normal range in all the children. Interepithelial lymphocytes were within normal range in the majority and lymphoid cells in the lamina propria were not different from those in control subjects. Mucosal lactase was significantly lower in patients than in control subjects in the duodenum and the jejunum, whereas sucrase and alkaline phosphatase values were significantly lower in the jejunum but not in the duodenum. Low content of mucosal lactase and increased numbers of interepithelial lymphocytes may be sensitive indicators of persisting ingestion of gluten in mucosa that is otherwise normal or approximately so in appearance.

Splenic function was quantitatively assessed using "pitted" erythrocyte counts in 177 patients with gluten-sensitive enteropathy. Hyposplenism was found to be a common, but not inevitable, complication of gluten-sensitive enteropathy that fluctuated with disease activity. Splenic function improved after withdrawal of gluten from the diet and a close relationship was demonstrated between hyposplenism and the morphology of the small intestine. The severity of the hyposplenism increased with advancing age and prolongation of exposure to dietary gluten. Splenic function did not vary with the HLA-A, -B, and -DR antigens, but, due to the presence of HLA-B8 and -DR3 in the vast majority of patients, a role for this haplotype in the causation of the hyposplenism cannot be excluded.