The ingestion of wheat gliadin (alcohol-soluble proteins, an integral part of wheat gluten) and related proteins induce, in genetically predisposed individuals, celiac disease (CD), which is characterized by immune-mediated impairment of the small intestinal mucosa. The lifelong omission of gluten and related grain proteins, i.e., a gluten-free diet (GFD), is at present the only therapy for CD. Although a GFD usually reduces CD symptoms, it does not entirely restore the small intestinal mucosa to a fully healthy state. Recently, the participation of microbial components in pathogenetic mechanisms of celiac disease was suggested. The present review provides information on infectious diseases associated with CD and the putative role of infections in CD development. Moreover, the involvement of the microbiota as a factor contributing to pathological changes in the intestine is discussed. Attention is paid to the mechanisms by which microbes and their components affect mucosal immunity, including tolerance to food antigens. Modulation of microbiota composition and function and the potential beneficial effects of probiotics in celiac disease are discussed.

• Keywords
• celiac disease, gluten-free diet, immune response, infections, microbiota, parasites,
• Publication type
• Journal Article MeSH
• Review MeSH

Immunologically mediated liver diseases belong to the common extraintestinal manifestations of celiac disease. We have reviewed the current literature that addresses the association between celiac disease and liver disorders. We searched relevant articles on MEDLINE/PubMed up to 15 June 2018. The objective of the article is to provide a comprehensive and up-to-date review on the latest hypotheses explaining the pathogenetic relationship between celiac disease and liver injury. Besides the involvement of gut⁻liver axis, tissue transglutaminase antibodies, and impairment of intestinal barrier, we integrate the latest achievements made in elucidation of the role of gut microbiota in celiac disease and liver disorders, that has not yet been sufficiently discussed in the literature in this context. The further objective is to provide a complete clinical overview on the types of liver diseases frequently found in celiac disease. In conclusion, the review highlights the clinical implication, recommend a rational approach for managing elevated transaminases in celiac patients, and underscore the importance of screening for celiac disease in patients with associated liver disease.

• Keywords
• autoimmunity, celiac hepatitis, gut–liver axis, intestinal barrier, liver immunity, non-alcoholic fatty liver disease, tolerance,
• MeSH
• Autoimmunity * MeSH
• Hepatitis, Autoimmune diet therapy   epidemiology   immunology   microbiology   MeSH
• Autoantibodies immunology   MeSH
• Diet, Gluten-Free MeSH
• Celiac Disease diet therapy   epidemiology   immunology   microbiology   MeSH
• Dysbiosis MeSH
• Liver immunology   microbiology   MeSH
• Humans MeSH
• Non-alcoholic Fatty Liver Disease diet therapy   epidemiology   immunology   microbiology   MeSH
• Vitamin D Deficiency epidemiology   immunology   MeSH
• Permeability MeSH
• Prognosis MeSH
• Protein Glutamine gamma Glutamyltransferase 2 MeSH
• GTP-Binding Proteins immunology   MeSH
• Risk Factors MeSH
• Intestines immunology   MeSH
• Gastrointestinal Microbiome MeSH
• Intestinal Mucosa metabolism   MeSH
• Transglutaminases immunology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Autoantibodies MeSH
• Protein Glutamine gamma Glutamyltransferase 2 MeSH
• GTP-Binding Proteins MeSH
• Transglutaminases MeSH

AIM: To study the coincidence of celiac disease, we tested its serological markers in patients with various liver diseases. METHODS: Large-scale screening of serum antibodies against tissue transglutaminase (tTG), and deamidated gliadin using enzyme-linked immunosorbent assay and serum antibodies against endomysium using immunohistochemistry, in patients with various liver diseases (n = 962) and patients who underwent liver transplantation (OLTx, n = 523) was performed. The expression of tTG in liver tissue samples of patients simultaneously suffering from celiac disease and from various liver diseases using immunohistochemistry was carried out. The final diagnosis of celiac disease was confirmed by histological analysis of small-intestinal biopsy. RESULTS: We found that 29 of 962 patients (3%) with liver diseases and 5 of 523 patients (0.8%) who underwent OLTx were seropositive for IgA and IgG anti-tTG antibodies. However, celiac disease was biopsy-diagnosed in 16 patients: 4 with autoimmune hepatitis type I, 3 with Wilson's disease, 3 with celiac hepatitis, 2 with primary sclerosing cholangitis, 1 with primary biliary cirrhosis, 1 with Budd-Chiari syndrome, 1 with toxic hepatitis, and 1 with non-alcoholic steatohepatitis. Unexpectedly, the highest prevalence of celiac disease was found in patients with Wilson's disease (9.7%), with which it is only rarely associated. On the other hand, no OLTx patients were diagnosed with celiac disease in our study. A pilot study of the expression of tTG in liver tissue using immunohistochemistry documented the overexpression of this molecule in endothelial cells and periportal hepatocytes of patients simultaneously suffering from celiac disease and toxic hepatitis, primary sclerosing cholangitis or autoimmune hepatitis type I. CONCLUSION: We suggest that screening for celiac disease may be beneficial not only in patients with associated liver diseases, but also in patients with Wilson's disease.

• Keywords
• Anti-tissue transglutaminase antibodies, Autoimmune liver diseases, Celiac disease, Liver transplantation, Tissue transglutaminase, Wilson's disease,
• MeSH
• Autoantibodies blood   MeSH
• Biopsy MeSH
• Celiac Disease blood   diagnosis   epidemiology   immunology   MeSH
• Adult MeSH
• Gliadin immunology   MeSH
• Immunoglobulin A blood   MeSH
• Immunoglobulin G blood   MeSH
• Immunohistochemistry MeSH
• Liver enzymology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Liver Diseases diagnosis   epidemiology   surgery   MeSH
• Mass Screening * methods   MeSH
• Predictive Value of Tests MeSH
• Prevalence MeSH
• Protein Glutamine gamma Glutamyltransferase 2 MeSH
• GTP-Binding Proteins MeSH
• Aged MeSH
• Transglutaminases immunology   MeSH
• Liver Transplantation MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Geographicals
• Czech Republic epidemiology   MeSH
• Names of Substances
• Autoantibodies MeSH
• Gliadin MeSH
• Immunoglobulin A MeSH
• Immunoglobulin G MeSH
• Protein Glutamine gamma Glutamyltransferase 2 MeSH
• GTP-Binding Proteins MeSH
• Transglutaminases MeSH

Calreticulin, upon translocation to the cell surface, plays a critical role in the recognition of tumour cells and in experimentally induced cellular anti-tumour immunity. However, less is known about anti-calreticulin antibodies and their role in malignancies. Using enzyme-linked immunosorbent assay (ELISA), we found immunoglobulin (Ig)A and/or IgG anti-calreticulin antibodies in sera of approximately 63% of patients with hepatocellular carcinoma (HCC), 57% of patients with colorectal adenocarcinoma (CRA) and 47% of patients with pancreatic adenocarcinoma (PACA), while healthy controls, patients with viral hepatitis C and with chronic pancreatitis reached only 2%, 20% and 31% seropositivity, respectively. We found significantly elevated mean levels of IgA anti-calreticulin antibodies (P < 0.001) in patients with HCC (78.7 +/- 52.3 AU, mean +/- standard deviation), PACA (66.5 +/- 30.9 AU) and CRA (61.8 +/- 25.8 AU) when compared to healthy controls (41.4 +/- 19.2 AU). Significantly elevated mean levels of IgG anti-calreticulin antibodies (P < 0.001) were detected in patients with HCC (121.9 +/- 94.2 AU), gall bladder adenocarcinoma (118.4 +/- 80.0 AU) and PACA (88.7 +/- 55.6 AU) when compared to healthy controls (56.7 +/- 22.9 AU). Pepscan analysis revealed a large number of antigenic epitopes of calreticulin recognized by both IgA and IgG antibodies of patients with HCC and PACA, indicating robust systemic immune response. Moreover, significantly elevated levels of antibodies against peptide KGEWKPRQIDNP (P < 0.001) in these patients, tested by ELISA, confirmed the distinct character of antibody reactivity against calreticulin. The high occurrence and specificity of serum anti-calreticulin autoantibodies in the majority of patients with some gastrointestinal malignancies provide the evidence for their possible clinical relevance.

• MeSH
• Adenocarcinoma blood   immunology   MeSH
• Autoantigens immunology   MeSH
• Autoantibodies blood   immunology   MeSH
• B-Lymphocytes immunology   MeSH
• Hepatitis C, Chronic blood   immunology   MeSH
• Adult MeSH
• Enzyme-Linked Immunosorbent Assay MeSH
• Epitopes immunology   MeSH
• Carcinoma, Hepatocellular blood   immunology   MeSH
• Immunoglobulin A blood   immunology   MeSH
• Immunoglobulin G blood   immunology   MeSH
• Calreticulin immunology   MeSH
• Colorectal Neoplasms blood   immunology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Neoplasm Proteins immunology   MeSH
• Liver Neoplasms blood   immunology   MeSH
• Pancreatic Neoplasms blood   immunology   MeSH
• Gallbladder Neoplasms blood   immunology   MeSH
• Pancreatitis blood   immunology   MeSH
• Antibodies, Neoplasm blood   immunology   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Antibody Specificity MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Comparative Study MeSH
• Names of Substances
• Autoantigens MeSH
• Autoantibodies MeSH
• Epitopes MeSH
• Immunoglobulin A MeSH
• Immunoglobulin G MeSH
• Calreticulin MeSH
• Neoplasm Proteins MeSH
• Antibodies, Neoplasm MeSH

Refractory coeliac disease (RCD) is a very rare and dangerous form of CD, in which gluten-free diet loses its therapeutic effect and the damage of intestinal mucosa persists. Because of the adherence to the diet, serological markers of CD [immunoglobulin A (IgA) antibodies against gliadin, tissue transglutaminase (tTG) and endomysium] are often missing in RCD patients. We found substantially elevated levels of IgA anti-calreticulin (CRT) antibodies in the sera of almost all RCD patients tested. These sera were negative for IgA antibodies to gliadin and tTG and only some of them showed IgA antibodies to enterocytes. Analysis of patients' IgA reactivity to CRT fragments (quarters and halves) by Western blotting revealed differences in the specificity of IgA antibodies between RCD and CD patients. We therefore used the Pepscan technique with synthetic overlapping decapeptides of CRT to characterize antigenic epitopes recognized by serum IgA antibodies of RCD patients. Employing this method we demonstrated several dominant antigenic epitopes recognized by IgA antibodies of RCD patients on the CRT molecule. Epitope GVTKAAEKQMKD was recognized predominantly by serum IgA of RCD patients. Our results suggest that testing for serum IgA antibodies against CRT and its selected peptide could be a very useful tool in RCD differential diagnosis.

• MeSH
• Diet, Gluten-Free adverse effects   MeSH
• Celiac Disease blood   diagnosis   immunology   MeSH
• Enzyme-Linked Immunosorbent Assay MeSH
• Enterocytes chemistry   immunology   MeSH
• Gliadin blood   immunology   MeSH
• Immunoglobulin A blood   immunology   MeSH
• Calreticulin blood   immunology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Antibodies, Anti-Idiotypic blood   immunology   MeSH
• Aged MeSH
• Sensitivity and Specificity MeSH
• Transglutaminases blood   immunology   MeSH
• Blotting, Western MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Gliadin MeSH
• Immunoglobulin A MeSH
• Calreticulin MeSH
• Antibodies, Anti-Idiotypic MeSH
• Transglutaminases MeSH

The prevalence of celiac disease (CD) was determined in healthy blood donors and in high-risk groups of adults (a total of 1835 adults--randomly selected 1312 healthy blood donors, 102 patients with primary osteoporosis, 58 patients with autoimmune diseases and 365 infertile women). It was calculated on the basis of a two-step serologic screening method--in the first step IgA and IgG antigliadin antibodies (AGA) and IgA anti-gamma-glutamyltransferase ('transglutaminase') antibodies (ATG) were estimated, in the second step sera positive for IgA AGA and/or IgA ATG were examined for antiendomysial IgA (AEA) antibodies. Immunoenzymic assay (ELISA) was used for determining of AGA and ATG antibodies; immunofluorescence method, performed on human umbilical cord tissue, was used for assaying of AEA antibodies. Total serum IgA level in only IgG AGA positive subjects was measured by routine turbidimetric method. 0.45% of healthy blood donors, 0.98% of osteoporotic patients, 2.7% of patients suffering from autoimmune disease and 1.13% of women with infertility considered as immunologically mediated were found to be positive in both steps of serologic screening (AGA and/or ATG and antiendomysium positive). The presumed high prevalence of seropositivity for CD in apparently healthy Czech adult population was confirmed. In the high-risk groups, the prevalence of seropositivity for CD was approximately 2-4 times higher than in healthy blood donors. The real prevalence of CD in the tested groups, however, can be estimated after performing small intestinal biopsy in the seropositive patients.

• MeSH
• Autoimmune Diseases complications   MeSH
• Celiac Disease complications   diagnosis   epidemiology   immunology   MeSH
• Adult MeSH
• Enzyme-Linked Immunosorbent Assay MeSH
• gamma-Glutamyltransferase immunology   MeSH
• Gliadin immunology   MeSH
• Immunoglobulin A blood   MeSH
• Immunoglobulin G blood   MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Osteoporosis complications   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Seroepidemiologic Studies MeSH
• Infertility, Female complications   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Geographicals
• Czech Republic epidemiology   MeSH
• Names of Substances
• gamma-Glutamyltransferase MeSH
• Gliadin MeSH
• Immunoglobulin A MeSH
• Immunoglobulin G MeSH