Giacomo Caio

Serological tests in gluten sensitivity (nonceliac gluten intolerance).

Goals: To characterize the serological pattern of gluten sensitivity (GS) and to compare it with that found in celiac disease. Background: GS has recently been identified as a new clinical entity included in the spectrum of gluten-related disorders, but it is still lacking of diagnostic markers. Study: Sera from 78 patients with GS and 80 patients with celiac disease were retrospectively assessed for immunoglobulin (Ig)G/IgA antigliadin antibodies (AGA), IgG deamidated gliadin peptide antibodies (DGP-AGA), IgA tissue transglutaminase antibodies (tTGA), and IgA endomysial antibodies (EmA). Results: IgG AGA were positive in 56.4% of GS patients and in 81.2% of celiac patients, with high antibody titers in both groups. IgA AGA were detected in 7.7% of GS patients and in 75% of celiac patients, showing lower enzyme-linked immunosorbent assay activities in GS than those found in celiac disease. Only 1 of the 78 patients with GS was positive for IgG DGP-AGA (detected in 88.7% of patients with celiac disease). IgA tTGA and IgA EmA were negative in all GS patients, whereas their positivity in celiac patients was 98.7% and 95%, respectively. Patients with GS displayed a variegated clinical picture with intestinal and extraintestinal symptoms (abdominal pain, bloating, diarrhea, constipation, foggy mind, tiredness, eczema/skin rash, headache, joint/muscle pain, numbness of legs/arms, depression, and anemia) together with normal or mildly abnormal small intestinal mucosa. Conclusions: The serological pattern of GS is characterized by IgG AGA positivity in more than half of cases associated to IgA AGA in a few patients, but without EmA, tTGA, and DGP-AGA, which are the specific markers of celiac disease.

Intestinal cell damage and systemic immune activation in individuals reporting sensitivity to wheat in the absence of coeliac disease.

Objective Wheat gluten and related proteins can trigger an autoimmune enteropathy, known as coeliac disease, in people with genetic susceptibility. However, some individuals experience a range of symptoms in response to wheat ingestion, without the characteristic serological or histological evidence of coeliac disease. The aetiology and mechanism of these symptoms are unknown, and no biomarkers have been identified. We aimed to determine if sensitivity to wheat in the absence of coeliac disease is associated with systemic immune activation that may be linked to an enteropathy. Design Study participants included individuals who reported symptoms in response to wheat intake and in whom coeliac disease and wheat allergy were ruled out, patients with coeliac disease and healthy controls. Sera were analysed for markers of intestinal cell damage and systemic immune response to microbial components. Results Individuals with wheat sensitivity had significantly increased serum levels of soluble CD14 and lipopolysaccharide (LPS)-binding protein, as well as antibody reactivity to bacterial LPS and flagellin. Circulating levels of fatty acid-binding protein 2 (FABP2), a marker of intestinal epithelial cell damage, were significantly elevated in the affected individuals and correlated with the immune responses to microbial products. There was a significant change towards normalisation of the levels of FABP2 and immune activation markers in a subgroup of individuals with wheat sensitivity who observed a diet excluding wheat and related cereals. Conclusions These findings reveal a state of systemic immune activation in conjunction with a compromised intestinal epithelium affecting a subset of individuals who experience sensitivity to wheat in the absence of coeliac disease.

Non-celiac gluten sensitivity： questions still to be answered despite increasing awareness

Recently, the increasing number of patients worldwide who are sensitive to dietary gluten without evidence of celiac disease or wheat allergy has contributed to the identification of a new gluten-related syndrome defined as non-celiac gluten sensitivity. Our knowledge regarding this syndrome is still lacking, and many aspects of this syndrome remain unknown. Its pathogenesis is heterogeneous, with a recognized pivotal role for innate immunity; many other factors also contribute, including low-grade intestinal inflammation, increased intestinal barrier function and changes in the intestinal microbiota. Gluten and other wheat proteins, such as amylase trypsin inhibitors, are the primary triggers of this syndrome, but it has also been hypothesized that a diet rich in fermentable monosaccharides and polyols may elicit its functional gastrointestinal symptoms. The epidemiology of this condition is far from established; its prevalence in the general population is highly variable, ranging from 0.63% to 6%. From a clinical point of view, non-celiac gluten sensitivity is characterized by a wide array of gastrointestinal and extraintestinal symptoms that occur shortly after the ingestion of gluten and improve or disappear when gluten is withdrawn from the diet. These symptoms recur when gluten is reintroduced. Because diagnostic biomarkers have not yet been identified, a double-blind placebo-controlled gluten challenge is currently the diagnostic method with the highest accuracy. Future research is needed to generate more knowledge regarding non-celiac gluten sensitivity, a condition that has global acceptance but has only a few certainties and many unresolved issues.

Clinical and immunological features of celiac disease in patients with Type 1 diabetes mellitus.

Celiac disease (CD) is one of the most frequent autoimmune disorders occurring in Type 1 diabetes mellitus (T1DM). The prevalence of CD in T1DM varies from 3 to 16%, with a mean prevalence of 8%. The clinical presentation of CD in T1DM is classified as symptomless in approximately half of cases, but a more accurate analysis often discloses a wide array of symptoms suggestive of CD. Both T1DM and CD show the same genetic background and an abnormal small intestinal immune response with inflammation and a variable grade of enteropathy. Serological screening for CD should be performed in all T1DM patients by means of antibodies to tissue transglutaminase at T1DM onset. T1DM patients found to be celiacs must be treated by a gluten-free diet. Potential CD cases (especially when asymptomatic) should be kept on a gluten-containing diet with a careful clinical and antibody follow-up, since many of them will not develop villous atrophy.

The changing clinical profile of celiac disease: a 15-year experience (1998-2012) in an Italian referral center

BackgroundCeliac disease is a multiform, challenging condition characterized by extremely variable features. Our goal was to define clinical, serological and histopathological findings in a large cohort of celiacs diagnosed in a single referral center.MethodsFrom January 1998 to December 2012, 770 patients (599 females, median age 36 years, range 18-78 years) were diagnosed as celiacs at St.Orsola-Malpighi Hospital (Bologna, Italy). The clinical phenotypes were classified as: 1) classical (malabsorption syndrome); 2) non-classical (extraintestinal and/or gastrointestinal symptoms other than diarrhea); 3) subclinical. Serology, duodenal histology, comorbidities, response to gluten-free diet and complications were evaluated.ResultsDisease onset was symptomatic in 610 patients (79%), while 160 celiacs showed a subclinical phenotype. In the symptomatic group the non-classical prevailed over the classical phenotype (66% vs 34%). Diarrhea was found in 27%, while other gastrointestinal manifestations were bloating (20%), aphthous stomatitis (18%), alternating bowel habit (15%), constipation (13%) and gastroesophageal reflux disease (12%). Extraintestinal manifestations included osteopenia/osteoporosis (52%), anemia (34%), cryptogenic hypertransaminasemia (29%) and recurrent miscarriages (12%). Positivity for IgA tissue transglutaminase antibodies was detected in 97%. Villous atrophy was found in 87%, while 13% had minor lesions consistent with potential celiac disease. A large proportion of patients showed autoimmune disorders, i.e. autoimmune thyroiditis (26.3%), dermatitis herpetiformis (4%) and diabetes mellitus type 1 (3%). Complicated celiac disease was very rare.ConclusionsOur study demonstrates that the clinical profile of celiac disease changed over time with an increasing rate of non-classical and subclinical phenotypes.

Non-celiac gluten sensitivity: A work-in-progress entity in the spectrum of wheat-related disorders

Non-celiac gluten sensitivity is an undefined syndrome with gastrointestinal and extra-intestinal manifestations triggered by gluten in patients without celiac disease and wheat allergy. The pathogenesis involves immune-mediated mechanisms requiring further research. Symptoms disappear in a few hours or days after gluten withdrawal and recur rapidly after gluten ingestion. Besides gluten, other wheat proteins as well as fermentable oligo-, di-, mono-saccharides and polyols (FODMAPs) may contribute to this syndrome. This syndrome occurs mainly in young women, being rare in children. Its prevalence ranges from 0.6% to 6%, based on primary or tertiary care center estimates. No biomarker is available, but half of patients tests positive for IgG anti-gliadin antibodies, which disappear quickly after gluten-free diet together with symptoms. Also, genetic markers are still undefined. Although currently limited to a research setting, double-blind, placebo-controlled, cross-over trial strategy is recommended to confirm the diagnosis. Treatment is based on dietary restriction with special care to nutrient intake.

Old and new serological tests for celiac disease screening

Evaluation of: Lewis NR, Scott BB. Meta-analysis: deamidated gliadin peptide (DGP) antibody and tissue transglutaminase (tTG) antibody compared as screening test for celiac disease. Aliment. Pharmacol. Ther. 31(1), 73–81 (2010). In celiac disease (CD), deamidation of gliadin peptides, induced by tissue transglutaminase (tTG), generates novel antigenic epitopes evoking a specific immune response. Serological tests based on the detection of antibodies to deamidated gliadin peptides (DGP) have been developed with very promising results in terms of sensitivity and specificity for CD screening. In the present study, a meta-analysis of studies published from 1998 to 2008 was designed to compare the performance of DGP antibodies with that of tTG antibodies, the validated and routinely employed test for CD screening. The authors have limited their analysis to IgA class antibodies underlining that most of the considered studies had methodological imperfections, especially ascertainment bias. The results of this meta-analysis indicated that the pooled sensitivities for DGP and tTG antibodies were 87.8% (95% CI: 85.6–89.9) and 93% (95% CI: 91.2–94.5), respectively, and the pooled specificities were 94.1% (95%CI: 92.5–95.5) and 96.5% (95% CI: 95.2–97.5), respectively. In summary, although both tests represent a very good tool for identifying celiac patients, tTG antibodies display a higher predictive value than DGP antibodies, and must still be considered the best serological test for CD screening.

Low incidence but poor prognosis of complicated coeliac disease: A retrospective multicentre study

BACKGROUND Coeliac disease is a chronic enteropathy characterized by an increased mortality caused by its complications, mainly refractory coeliac disease, small bowel carcinoma and abdominal lymphoma. Aim of the study was to study the epidemiology of complications in patients with coeliac disease. METHODS Retrospective multicenter case-control study based on collection of clinical and laboratory data. The incidence of complicated coeliac disease was studied among coeliac patients directly diagnosed in four Italian centres. Patients referred to these centres after a diagnosis of coeliac disease and/or complicated coeliac disease in other hospitals were therefore excluded. RESULTS Between 1/1999 and 10/2011, 1840 adult coeliac patients were followed up for 7364.3 person-years. Fourteen developed complications. Since five patients died, at the end of the observation period (10/2011), the prevalence of complicated coeliac disease was 9/1835 (1/204, 0.49%, 95% CI 0.2-0.9%). The annual incidence of complicated coeliac disease in the study period was 14/7364 (0.2%, 95% CI 0.1-0.31%). Although complications tend to occur soon after the diagnosis of coeliac disease, Kaplan-Meier curve analysis showed that they can actually occur at any time after the diagnosis of coeliac disease. CONCLUSIONS Complications of coeliac disease in our cohort were quite rare, though characterised by a very high mortality.

Gut-liver axis: an immune link between celiac disease and primary biliary cirrhosis.

The association between celiac disease and primary biliary cirrhosis is well established. The breakdown of gut–liver axis equilibrium plays a central role in the development of immune disorders involving the small bowel and liver. In celiac disease, immunologically active molecules generated from the cross-linking between tissue transglutaminase and food/bacterial antigens reach the liver through the portal circulation owing to the increased intestinal permeability. A molecular mimicry between bacterial antigens and the pyruvate dehydrogenase E2 component, recognized by antimitochondrial autoantibodies, may have a role in primary biliary cirrhosis pathogenesis. An aberrant intestinal T lymphocyte homing to the liver may contribute to trigger immune hepatic damage. Both celiac disease and primary biliary cirrhosis share several features, including a higher prevalence in females, autoimmune comorbidities and specific autoantibodies. Reciprocal screening for both diseases is recommended, as an early diagnosis with the appropriate treatment can improve the outcome of these patients.

Non-coeliac gluten/wheat sensitivity: advances in knowledge and relevant questions

ABSTRACT Introduction: Non-coeliac gluten/wheat sensitivity (NCG/WS) is a syndrome characterized by intestinal and extra-intestinal symptoms occurring a few hours or days after the ingestion of gluten and wheat proteins in patients testing negative for coeliac disease and wheat allergy. Areas covered: The present review deals with recent scientific acquisitions of this gluten-related syndrome, including pathogenetic mechanisms, clinical picture, symptom score, biomarkers and double-blind placebo-controlled trial for diagnosis, and treatment. The methodology used was a literature search on NCG/WS using Medline and Premedline from 1970 to August 2016. Expert commentary: We discussed the pathogenesis of symptom generation and altered gut physiology in NCG/WS. Possible mechanisms include innate and adaptive immune activation, impaired intestinal epithelial barrier and changes in gut microbiome. These interlinked factors may be exploited for their clinical relevance as possible biomarkers. A systemic immune response to microbial and wheat antigens, together with intestinal cell damage, occurs in patients with NCG/WS. Due to the lack of established biomarkers, it is mandatory to validate the diagnosis of the syndrome by means of a well-defined work-up involving dietary challenge. Finally, dietary and other therapeutic indications have been thoroughly reviewed.