Kalle Kurppa

Diagnosing Mild Enteropathy Celiac Disease: A Randomized, Controlled Clinical Study

BACKGROUND & AIMS The diagnostic criteria for celiac disease require small-bowel mucosal villous atrophy with crypt hyperplasia (Marsh III). However, mucosal damage develops gradually and patients may evince clinical symptoms before histologic changes appear. Endomysial antibodies are specific in predicting forthcoming villous atrophy. We hypothesized that patients with mild enteropathy but positive endomysial antibodies benefit from a gluten-free diet (GFD) similarly to patients with more severe enteropathy. METHODS Small-bowel endoscopy together with clinical evaluations was performed in all together 70 consecutive adults with positive endomysial antibodies. Of these, 23 had only mild enteropathy (Marsh I-II) and they were randomized either to continue on a gluten-containing diet or start a GFD. After 1 year, clinical, serologic, and histologic evaluations were repeated. A total of 47 participants had small-bowel mucosal lesions compatible with celiac disease (Marsh III), and these served as disease controls. RESULTS In the gluten-containing diet group (Marsh I-II) the small-bowel mucosal villous architecture deteriorated in all participants, and the symptoms and abnormal antibody titers persisted. In contrast, in the GFD group (Marsh I-II) the symptoms were alleviated, antibody titers decreased, and mucosal inflammation diminished equally to celiac controls (Marsh III). When the trial was completed, all participants chose to continue on a life-long GFD. CONCLUSIONS Patients with endomysial antibodies benefit from a GFD regardless of the degree of enteropathy. The diagnostic criteria for celiac disease need re-evaluation: endomysial antibody positivity without atrophy belongs to the spectrum of genetic gluten intolerance, and warrants dietary treatment.

Celiac disease without villous atrophy in children: a prospective study.

OBJECTIVE To establish whether children who are endomysial antibody (EmA) positive and have normal small-bowel mucosal villous morphology are truly gluten-sensitive and may benefit from early treatment with a gluten-free diet. STUDY DESIGN Children who were EmA positive with normal small-bowel mucosal villi were compared with children who were seropositive with villous atrophy by using several markers of untreated celiac disease. Thereafter, children with normal villous structure either continued on a normal diet or were placed on a gluten-free diet and re-investigated after 1 year. Seventeen children who were seronegative served as control subjects for baseline investigations. RESULTS Normal villous morphology was noted in 17 children who were EmA positive, and villous atrophy was noted in 42 children who were EmA positive. These children were comparable in all measured variables regardless of the degree of enteropathy, but differed significantly from the seronegative control subjects. During the dietary intervention, in children who were EmA positive with normal villi, the disease was exacerbated in children who continued gluten consumption, whereas in all children who started the gluten-free diet, both the gastrointestinal symptoms and abnormal antibodies disappeared. CONCLUSIONS The study provided evidence that children who are EmA positive have a celiac-type disorder and benefit from early treatment despite normal mucosal structure, indicating that the diagnostic criteria for celiac disease should be re-evaluated.

Altered Duodenal Microbiota Composition in Celiac Disease Patients Suffering From Persistent Symptoms on a Long-Term Gluten-Free Diet

Objectives:A significant fraction of celiac disease patients suffer from persistent symptoms despite a long-term gluten-free diet (GFD) and normalized small bowel mucosa. The commonly suggested reasons, such as inadvertent gluten-intake or presence of other gastrointestinal disease, do not explain the symptoms in all these patients. Recently, alterations in intestinal microbiota have been associated with autoimmune disorders, including celiac disease. This led us to test a hypothesis that abnormal intestinal microbiota may be associated with persisting gastrointestinal symptoms in treated celiac disease patients.Methods:Duodenal microbiota was analyzed in 18 GFD-treated patients suffering from persistent symptoms and 18 treated patients without symptoms by 16S rRNA gene pyrosequencing. The celiac disease patients had been following a strict GFD for several years and had restored small bowel mucosa and negative celiac autoantibodies. Their symptoms on GFD were assessed with Gastrointestinal Symptom Rating Scale.Results:The results of several clustering methods showed that the treated celiac disease patients with persistent symptoms were colonized by different duodenal microbiota in comparison with patients without symptoms. The treated patients with persistent symptoms had a higher relative abundance of Proteobacteria (P=0.04) and a lower abundance of Bacteroidetes (P=0.01) and Firmicutes (P=0.05). Moreover, their microbial richness was reduced. The results indicated intestinal dysbiosis in patients with persistent symptoms even while adhering to a strict GFD.Conclusions:Our findings indicate that dysbiosis of microbiota is associated with persistent gastrointestinal symptoms in treated celiac disease patients and open new possibilities to treat this subgroup of patients.

Diet Improves Perception of Health and Well-being in Symptomatic, but Not Asymptomatic, Patients With Celiac Disease

BACKGROUND & AIMS The benefits of serologic screening and early diagnosis of celiac disease in asymptomatic patients are not known. We investigated the impact of a gluten-free diet on self-perceived health and well-being in symptomatic and asymptomatic patients with celiac disease. METHODS We performed a prospective study of 698 consecutive adults newly diagnosed with celiac disease because of classic (n = 490) or extraintestinal (n = 62) symptoms or through screening of at-risk groups (n = 146; 23 were asymptomatic and analyzed separately). The survey included questions on health and well-being; quality of life was evaluated by the psychological general well-being (PGWB) questionnaire. Patients were followed for 1 year of treatment; 110 healthy subjects served as controls. RESULTS On a gluten-free diet, self-perceived health improved significantly among patients with classic symptoms and those detected by screening. Patients in all groups were equally concerned about their health before the diagnosis, but anxiety was alleviated by the gluten-free diet. At diagnosis, the quality of life reduced among all 3 groups but improved significantly among patients on the diet. Among the 23 asymptomatic patients, perception of health worsened and concern about health increased while they were on the diet. CONCLUSIONS Self-perceived health and well-being were low among patients at the time they were diagnosed with celiac disease. Most patients benefited from a gluten-free diet, so it is important to identify patients with celiac disease. Perception of health decreased among asymptomatic cases, which discourages population-based screening.

IL23R in the Swedish, Finnish, Hungarian and Italian populations: association with IBD and psoriasis, and linkage to celiac disease

BackgroundAssociation of the interleukin-23 receptor (IL23R) with inflammatory bowel disease (IBD) has been confirmed in several populations. IL23R also associates with psoriasis, suggesting that the gene may be an important candidate for many chronic inflammatory diseases.MethodsWe studied association of single-nucleotide variants in IL23R with IBD in Swedish patients, in both Crohns disease (CD) and ulcerative colitis (UC) subsets. The same genetic variants were also studied in Finnish patients with psoriasis or celiac disease, and in Hungarian and Italian patients with celiac disease.ResultsAssociation of IL23R with IBD was replicated in our Swedish patients, and linkage and association of the IL23R region with psoriasis was found in the Finnish population. The IL23R region was also linked to celiac disease in Finnish families, but no association of IL23R variants with celiac disease was found in the Finnish, Hungarian or Italian samples.ConclusionOur study is the first to demonstrate association of IL23R with CD and UC in Swedish patients with IBD. It is also the first study to report linkage and association of the IL23R region with psoriasis in the Finnish population. Importantly, this is the first report of linkage of the IL23R region to celiac disease, a chronic inflammatory condition in which IL23R has not been previously implicated.

Validation of Morphometric Analyses of Small-Intestinal Biopsy Readouts in Celiac Disease

Background Assessment of the gluten-induced small-intestinal mucosal injury remains the cornerstone of celiac disease diagnosis. Usually the injury is evaluated using grouped classifications (e.g. Marsh groups), but this is often too imprecise and ignores minor but significant changes in the mucosa. Consequently, there is a need for validated continuous variables in everyday practice and in academic and pharmacological research. Methods We studied the performance of our standard operating procedure (SOP) on 93 selected biopsy specimens from adult celiac disease patients and non-celiac disease controls. The specimens, which comprised different grades of gluten-induced mucosal injury, were evaluated by morphometric measurements. Specimens with tangential cutting resulting from poorly oriented biopsies were included. Two accredited evaluators performed the measurements in blinded fashion. The intraobserver and interobserver variations for villus height and crypt depth ratio (VH:CrD) and densities of intraepithelial lymphocytes (IELs) were analyzed by the Bland-Altman method and intraclass correlation. Results Unevaluable biopsies according to our SOP were correctly identified. The intraobserver analysis of VH:CrD showed a mean difference of 0.087 with limits of agreement from −0.398 to 0.224; the standard deviation (SD) was 0.159. The mean difference in interobserver analysis was 0.070, limits of agreement −0.516 to 0.375, and SD 0.227. The intraclass correlation coefficient in intraobserver variation was 0.983 and that in interobserver variation 0.978. CD3+ IEL density countings in the paraffin-embedded and frozen biopsies showed SDs of 17.1% and 16.5%; the intraclass correlation coefficients were 0.961 and 0.956, respectively. Conclusions Using our SOP, quantitative, reliable and reproducible morphometric results can be obtained on duodenal biopsy specimens with different grades of gluten-induced injury. Clinically significant changes were defined according to the error margins (2SD) of the analyses in VH:CrD as 0.4 and in CD3+-stained IELs as 30%.

Gastrointestinal symptoms, quality of life and bone mineral density in mild enteropathic coeliac disease: a prospective clinical trial.

Abstract Objective. The diagnosis of coeliac disease requires small-bowel mucosal villous atrophy with crypt hyperplasia. However, patients with endomysial antibodies but structurally normal villi may suffer from a disorder similar to those with villous atrophy. The aim of this study was to evaluate gastrointestinal symptoms, quality of life and bone mineral density in patients with mild enteropathy, and the effect of a gluten-free diet. Material and methods. A prospective trial was carried out in 73 adults having endomysial antibodies with normal villous morphology (Marsh I–II; mild enteropathy) or villous atrophy (Marsh III). Gastrointestinal symptoms and quality of life were surveyed by means of structured questionnaires and bone mineral density by means of X-ray absorptiometry. Altogether, 110 subjects served as non-coeliac controls. Results. At baseline, patients with mild enteropathy evinced more gastrointestinal symptoms than non-coeliac controls, but there were no significant differences in quality of life between the groups. After 1 year on a gluten-free diet, indigestion and depression were significantly alleviated in the mild enteropathy group. Osteoporosis or osteopenia was detected in 58% of subjects in the mild enteropathy group and there was a trend towards improved bone mineral density after the treatment. Conclusions. Endomysial antibody-positive patients with normal villous structure may suffer from gastrointestinal symptoms and have poor bone health. Furthermore, they benefit from a gluten-free diet similar to those with overt villous atrophy.

Factors Associated with Dietary Adherence in Celiac Disease: A Nationwide Study

Aims: Diagnostics and follow-up of celiac disease have gradually shifted from tertiary centers to secondary and primary health care. In order to establish whether this has affected the success of treatment, and to identify predictors for dietary non-adherence, we carried out a study in a nationwide cohort of treated celiac patients. Patients and Methods: 843 biopsy-proven patients, 94 children and 749 adults, were enrolled and interviewed. Adherence to a gluten-free diet was determined by means of an interview and serological testing. Results: Altogether, 88% were on a strict gluten-free diet; the rest had occasional dietary transgressions. Younger age at diagnosis, being currently a teenager, and current symptoms were associated with non-adherence. There was no association between non-adherence and place of diagnosis, gender, disease phenotype or severity of symptoms before diagnosis, presence of comorbidities, family history of celiac disease, smoking, duration of diet, use of oats, self-efficacy for the diet or lack of follow-up. Conclusions: Good dietary adherence can be achieved also in patients diagnosed and followed in primary health care. In a country with a high prevalence and good general knowledge of celiac disease, only age at diagnosis and age at present would appear to be major determinants for adherence.

Association study of FUT2 (rs601338) with celiac disease and inflammatory bowel disease in the Finnish population

Homozygosity for a nonsense mutation in the fucosyltransferase 2 (FUT2) gene (rs601338G>A) leads to the absence of ABH blood groups (FUT2 non-secretor status) in body fluids. As the secretor status has been shown to be a major determinant for the gut microbial spectrum, assumed to be important in the gut immune homeostasis, we studied the association of rs601338-FUT2 with celiac disease (CelD) and inflammatory bowel disease (IBD) in the Finnish population. Rs601338 was genotyped in CelD (n = 909), dermatitis herpetiformis (DH) (n = 116), ulcerative colitis (UC) (n = 496) and Crohns disease (CD) (n = 280) patients and healthy controls (n = 2738). CelD showed significant genotypic [P = 0.0074, odds ratio (OR): 1.28] and recessive (P = 0.015, OR: 1.28) association with the rs601338-AA genotype. This was also found in the combined CelD+DH dataset (genotype association: P = 0.0060, OR: 1.28; recessive association: P < 0.011, OR: 1.28). The A allele of rs601338 showed nominal association with dominant protection from UC (P = 0.044, OR: 0.82) and UC+CD (P = 0.035, OR: 0.84). The frequency of non-secretors (rs601338-GG) in controls, CelD, DH, UC and CD datasets was 14.7%, 18%, 18.1%, 14.3% and 16.1%, respectively. No association was evident in the DH or CD datasets alone. In conclusion, FUT2 non-secretor status is associated with CelD susceptibility and FUT2 secretor status may also play a role in IBD in the Finnish population.

Predictors of persistent symptoms and reduced quality of life in treated coeliac disease patients: a large cross-sectional study

BackgroundEvidence suggests that many coeliac disease patients suffer from persistent clinical symptoms and reduced health-related quality of life despite a strict gluten-free diet. We aimed to find predictors for these continuous health concerns in long-term treated adult coeliac patients.MethodsIn a nationwide study, 596 patients filled validated Gastrointestinal Symptom Rating Scale and Psychological General Well-Being questionnaires and were interviewed regarding demographic data, clinical presentation and treatment of coeliac disease, time and place of diagnosis and presence of coeliac disease-associated or other co-morbidities. Dietary adherence was assessed by a combination of self-reported adherence and serological tests. Odds ratios and 95% confidence intervals were calculated by binary logistic regression.ResultsDiagnosis at working age, long duration and severity of symptoms before diagnosis and presence of thyroidal disease, non-coeliac food intolerance or gastrointestinal co-morbidity increased the risk of persistent symptoms. Patients with extraintestinal presentation at diagnosis had fewer current symptoms than subjects with gastrointestinal manifestations. Impaired quality of life was seen in patients with long duration of symptoms before diagnosis and in those with psychiatric, neurologic or gastrointestinal co-morbidities. Patients with persistent symptoms were more likely to have reduced quality of life.ConclusionsThere were a variety of factors predisposing to increased symptoms and impaired quality of life in coeliac disease. Based on our results, early diagnosis of the condition and consideration of co-morbidities may help in resolving long-lasting health problems in coeliac disease.