Spectrum Of Gluten-related Disorders Research Articles

Celiac Disease and Associated Extraintestinal Manifestations, with Special Reference to Neurological Disorders

Celiac disease (CD), also known as gluten-sensitive enteropathy and nontropical sprue, is one of the most important entities of the wide spectrum of gluten-related disorders (GRDs). It is well known that neurological manifestations can be present either at the onset of CD, or appear during the development of the pathology, and the neurologic findings can show a profound difference. Clinical features show significant variation, ranging from typical manifestations of gastrointestinal involvement to several extraintestinal diseases. The most frequent neurologic signs reported are headaches, epileptic seizures, and migraines. Polyneuritis and the cerebellar ataxias have shown the most frequent association in adults. Headache either in the form of migraine or in nonspecific form represents one of the main clinical presentations in CD. This work aims to provide a narrative review of the current state of CD, highlighting the main extraintestinal disorders associated with CD. Complete compliance to a gluten-free diet (GFD) seems to improve the neurological symptoms even though the underlying pathogenic relationship between CD and the neurologic system remains poorly understood.

Pitfalls in the Diagnosis of Coeliac Disease and Gluten-Related Disorders.

The spectrum of gluten-related disorders (GRD) has emerged as a relevant phenomenon possibly impacting on health care procedures and costs worldwide. Current classification of GRD is mainly based on their pathophysiology, and the following categories can be distinguished: immune-mediated disorders that include coeliac disease (CD), dermatitis herpetiformis (DH), and gluten ataxia (GA); allergic reactions such as wheat allergy (WA); and non-coeliac gluten sensitivity (NCGS), a condition characterized by both gastrointestinal and extra-intestinal symptoms subjectively believed to be induced by the ingestion of gluten/wheat that has recently gained popularity. Although CD, DH, and WA are well-defined clinical entities, whose diagnosis is based on specific diagnostic criteria, a diagnosis of NCGS may on the contrary be considered only after the exclusion of other organic disorders. Neither allergic nor autoimmune mechanisms have been found to be involved in NCGS. Mistakes in the diagnosis of GRD are still a relevant clinical problem that may result in overtreatment of patients being unnecessary started on a gluten-free diet and waste of health-care resources. On the basis of our clinical experience and literature, we aim to identify the main pitfalls in the diagnosis of CD and its complications, DH, and WA. We provide a practical methodological approach to guide clinicians on how to recognize and avoid them.

The impact of gluten ingestion on pathogenesis of neurological disorders

For many years the spectrum of gluten-related disorders had been limited only to celiac disease and its typical gastrointestinal symptoms. In the last few years, not only new disorders like non-celiac gluten sensitivity have been described, but also pathogeneses of celiac disease and wheat allergy have been better understood. It is also known that impaired gluten tolerance in many cases leads to appearance of extraintestinal symptoms that may affect any organ or system of the human body including the nervous system that may be the cause of some neurological disorders such as ataxia, neuropathy, autism spectrum disorder (ASD) or schizophrenia. In this paper we present the spectrum of neurological disorders, whose pathogeneses may depend on gluten ingestion and some proposed mechanisms elucidating those pathogeneses.

Cerebellar Ataxia, Celiac Disease and Non-Celiac Gluten Sensitivity

: Cerebellar ataxia (CA) is one of the most frequent neurological manifestations related to celiac disease (CD). Celiac disease is found in patients with a percentage ranging from 1.9% to 16.7%. Gluten cerebellar ataxia is purely cerebellar and involves the entire cerebellum. The clinical signs of CA are gait ataxia, limb ataxia, dysarthria, pyramidal signs, altered eyes motions, and progressive impairment of stability, and erect position. The patients affected by Gluten CA show an immunological response against a primarily brain expressed TG, such as TG6. The prolonged gluten consumption in patients with gluten ataxia leads to a progressive loss of purkinje cells in the cerebellum. An early diagnosis of CA and gluten related disorders (GRD) increases the possibility to improve the neurological process. Non celiac gluten sensitivity (NCGS) is defined by clinical evidence of improvement of symptoms following the introduction of GFD in the absence of enteropathy. The increased recognition of the whole spectrum of Gluten related disorders (GRD) is the best way to improve the time of the diagnosis and to avoid patients with neurological manifestation remaining untreated if duodenal biopsy does not reveal an enteropathy. Cerebellar Ataxia is equally responsive to GFD in CD and NCGS patients.

World epidemiology of non-celiac gluten sensitivity.

While the term "gluten" has become commonplace, the disorders associated with gluten still remain poorly understood. Non-celiac gluten sensitivity (NCGS), the most recently recognized of the gluten-related disorders, is arguably the most unknown. While celiac disease and wheat allergy have diagnostic algorithm, NCGS remains a diagnosis of exclusion. With no evidence-based objective diagnostic criteria or serological tests, it is difficult to diagnose and even more difficult to study epidemiologically. Studies often use varied definitions of NCGS and are difficult to compare or validate. Further complicating diagnosis, NCGS has variable and wide-ranging symptoms which overlap with a number of other diseases and changes to diet are inherently difficult to study. In fact, some have argued that NCGS does not exist as a distinct entity or that it may not be caused by the gluten portion of foods. In this review, we outline the current knowledge, hypotheses, and debates surrounding the epidemiology of NCGS in the context of the spectrum of gluten-related disorders.

Prospects of Developing Medicinal Therapeutic Strategies and Pharmaceutical Design for Effective Gluten Intolerance Treatment.

Gluten intolerance is an umbrella term for gluten-related disorders manifested in health decline as a result of the gluten ingestion. The spectrum of gluten-related disorders includes three major groups: autoimmune (mainly, Celiac Disease, CD, also known as Celiac Sprue, dermatitis herpetiformis, or gluten-sensitive ataxia), allergic (wheat allergy, WA), and non-autoimmune non-allergic (non-celiac gluten sensitivity, NCGS, or gluten sensitivity, GS). Pathogenesis and diagnostics of CD and WA are well established in contrast to NCGS, pathogenicity of which is still poorly understood and its symptoms are frequently misdiagnosed since most of the NCGS cases are currently identified via the process of CD and WA exclusion. By now, the only one proven effective way for CD treatment is gluten-free diet (GFD). However, such an increasingly gaining popularity diet is apparently unsuitable for NCGS treatment because in this case gluten does not always arise as the major or exclusive culprit of gastrointestinal disorder. Furthermore, it is some physicians' opinion that GFD can be deficient in fiber and in other vitamins and minerals. In many cases, GFD is commercially inaccessible for the most needy, whereas strict adherence to the diet is complicated by the presence of small amounts of the gluten components in some foods and even medicines. In this regard, a number of research groups and pharmaceutical companies are extensively developing alternative medicinal approaches to GFD for effective gluten intolerance treatment. This review summarizes our understanding of gluten-related disorders, possible mechanisms of gluten intolerance activation and advantages of gluten intolerance medicinal treatment using novel drug candidates obtained with a proper pharmaceutical design.

The Overlap between Irritable Bowel Syndrome and Non-Celiac Gluten Sensitivity: A Clinical Dilemma.

The spectrum of gluten-related disorders has widened in recent times and includes celiac disease, non-celiac gluten sensitivity, and wheat allergy. The complex of symptoms associated with these diseases, such as diarrhea, constipation or abdominal pain may overlap for the gluten related diseases, and furthermore they can be similar to those caused by various other intestinal diseases, such as irritable bowel syndrome (IBS). The mechanisms underlying symptom generation are diverse for all these diseases. Some patients with celiac disease may remain asymptomatic or have only mild gastrointestinal symptoms and thus may qualify for the diagnosis of IBS in the general clinical practice. Similarly, the overlap of symptoms between IBS and non-celiac gluten sensitivity (NCGS) often creates a dilemma for clinicians. While the treatment of NCGS is exclusion of gluten from the diet, some, but not all, of the patients with IBS also improve on a gluten-free diet. Both IBS and NCGS are common in the general population and both can coexist with each other independently without necessarily sharing a common pathophysiological basis. Although the pathogenesis of NCGS is not well understood, it is likely to be heterogeneous with possible contributing factors such as low-grade intestinal inflammation, increased intestinal barrier function and changes in the intestinal microbiota. Innate immunity may also play a pivotal role. One possible inducer of innate immune response has recently been reported to be amylase-trypsin inhibitor, a protein present in wheat endosperm and the source of flour, along with the gluten proteins.

Non Celiac Gluten Sensitivity-exploring the New Entity

BackgroundSpectrum of gluten-related disorders got a new entity, represented by gluten sensitivity. Clinical picture is a combination of IBS (irritable bowel syndrome) symptoms and of systemic manifestations. No strict criteria for the diagnosis of NCGS exist, prevalence claimed to be up to 6%.ObjectivesTo study the prevalence of non-celiac gluten sensitivity (NCGS) and response to dietary intervention in IBS.Subjects and Methods90 patients between 18 to 65 years, with a diagnosis of IBS as per Rome III criteria, were included. Celiac disease and wheat allergy were excluded appropriately. Patients fulfilling the inclusion criteria were given gluten free diet for 4 weeks and patients followed weekly. The patients were interviewed for symptoms at baseline and weekly for 4 weeks, and compared on 100 mm visual analogue scale. Study population was again given normal gluten containing diet to look for reappearance of the symptoms. Analysis of quantitative data measured 3 times (baseline, 1 month after GFD after re-challenge) was done using Friedman RM ANOVA on Ranks and Appropriate Post Hoc test was used.ResultsMales outnumbered the females in the study. On a visual analogue scale, 3 patients showed significant improvement with gluten free diet for overall symptoms (P < .05), pain (P < .05), bloating P < .05), satisfaction with stool consistency (P < .05). On gluten rechallenge after completion of 4 weeks, patient symptom deterioration occurred in days to week duration.ConclusionsOur data identifies a patient population suffering from non-celiac gluten sensitivity.LimitationsRandomized double-blind placebo controlled study would have been better approach. The present study is limited with low sample size. BackgroundSpectrum of gluten-related disorders got a new entity, represented by gluten sensitivity. Clinical picture is a combination of IBS (irritable bowel syndrome) symptoms and of systemic manifestations. No strict criteria for the diagnosis of NCGS exist, prevalence claimed to be up to 6%. Spectrum of gluten-related disorders got a new entity, represented by gluten sensitivity. Clinical picture is a combination of IBS (irritable bowel syndrome) symptoms and of systemic manifestations. No strict criteria for the diagnosis of NCGS exist, prevalence claimed to be up to 6%. ObjectivesTo study the prevalence of non-celiac gluten sensitivity (NCGS) and response to dietary intervention in IBS. To study the prevalence of non-celiac gluten sensitivity (NCGS) and response to dietary intervention in IBS. Subjects and Methods90 patients between 18 to 65 years, with a diagnosis of IBS as per Rome III criteria, were included. Celiac disease and wheat allergy were excluded appropriately. Patients fulfilling the inclusion criteria were given gluten free diet for 4 weeks and patients followed weekly. The patients were interviewed for symptoms at baseline and weekly for 4 weeks, and compared on 100 mm visual analogue scale. Study population was again given normal gluten containing diet to look for reappearance of the symptoms. Analysis of quantitative data measured 3 times (baseline, 1 month after GFD after re-challenge) was done using Friedman RM ANOVA on Ranks and Appropriate Post Hoc test was used. 90 patients between 18 to 65 years, with a diagnosis of IBS as per Rome III criteria, were included. Celiac disease and wheat allergy were excluded appropriately. Patients fulfilling the inclusion criteria were given gluten free diet for 4 weeks and patients followed weekly. The patients were interviewed for symptoms at baseline and weekly for 4 weeks, and compared on 100 mm visual analogue scale. Study population was again given normal gluten containing diet to look for reappearance of the symptoms. Analysis of quantitative data measured 3 times (baseline, 1 month after GFD after re-challenge) was done using Friedman RM ANOVA on Ranks and Appropriate Post Hoc test was used. ResultsMales outnumbered the females in the study. On a visual analogue scale, 3 patients showed significant improvement with gluten free diet for overall symptoms (P < .05), pain (P < .05), bloating P < .05), satisfaction with stool consistency (P < .05). On gluten rechallenge after completion of 4 weeks, patient symptom deterioration occurred in days to week duration. Males outnumbered the females in the study. On a visual analogue scale, 3 patients showed significant improvement with gluten free diet for overall symptoms (P < .05), pain (P < .05), bloating P < .05), satisfaction with stool consistency (P < .05). On gluten rechallenge after completion of 4 weeks, patient symptom deterioration occurred in days to week duration. ConclusionsOur data identifies a patient population suffering from non-celiac gluten sensitivity. Our data identifies a patient population suffering from non-celiac gluten sensitivity.

Coeliac Disease and Noncoeliac Gluten Sensitivity

The spectrum of gluten-related disorders was restricted to coeliac disease and wheat allergy, but the new contemporary entity referred to as noncoeliac gluten sensitivity has gained recognition mainly in adults but also in children. Noncoeliac gluten sensitivity is defined as the presence of a variety of symptoms related to gluten ingestion in patients in whom coeliac disease and wheat allergy have been excluded. The pathophysiology and biomarkers of coeliac disease and wheat allergy are well known, but this is not the case for noncoeliac gluten sensitivity. It is also not clear whether noncoeliac gluten sensitivity is caused by consumption of gluten or by consumption of fermentable oligosaccharides, disaccharides, monosaccharides, and polyols. Randomized trials on noncoeliac gluten sensitivity in children are lacking and are hardly needed to evaluate its role in paediatric patients with gastroenterology to avoid the use of unnecessary restrictive diets in children and interference with proper diagnosis of coeliac disease.

Risk of low bone mineral density and low body mass index in patients with non-celiac wheat-sensitivity: a prospective observation study.

BackgroundNon-celiac gluten sensitivity (NCGS) or ‘wheat sensitivity’ (NCWS) is included in the spectrum of gluten-related disorders. No data are available on the prevalence of low bone mass density (BMD) in NCWS. Our study aims to evaluate the prevalence of low BMD in NCWS patients and search for correlations with other clinical characteristics.MethodsThis prospective observation study included 75 NCWS patients (63 women; median age 36 years) with irritable bowel syndrome (IBS)-like symptoms, 65 IBS and 50 celiac controls. Patients were recruited at two Internal Medicine Departments. Elimination diet and double-blind placebo controlled (DBPC) wheat challenge proved the NCWS diagnosis. All subjects underwent BMD assessment by Dual Energy X-Ray Absorptiometry (DXA), duodenal histology, HLA DQ typing, body mass index (BMI) evaluation and assessment for daily calcium intake.ResultsDBPC cow's milk proteins challenge showed that 30 of the 75 NCWS patients suffered from multiple food sensitivity. Osteopenia and osteoporosis frequency increased from IBS to NCWS and to celiac disease (CD) (P <0.0001). Thirty-five NCWS patients (46.6%) showed osteopenia or osteoporosis. Low BMD was related to low BMI and multiple food sensitivity. Values of daily dietary calcium intake in NCWS patients were significantly lower than in IBS controls.ConclusionsAn elevated frequency of bone mass loss in NCWS patients was found; this was related to low BMI and was more frequent in patients with NCWS associated with other food sensitivity. A low daily intake of dietary calcium was observed in patients with NCWS.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-014-0230-2) contains supplementary material, which is available to authorized users.

Risk of low bone mineral density and low body mass index in patients with non-celiac wheat-sensitivity: a prospective observation study

Non-celiac gluten sensitivity (NCGS) or ‘wheat sensitivity’ (NCWS) is included in the spectrum of gluten-related disorders. No data are available on the prevalence of low bone mass density (BMD) in NCWS. Our study aims to evaluate the prevalence of low BMD in NCWS patients and search for correlations with other clinical characteristics. This prospective observation study included 75 NCWS patients (63 women; median age 36 years) with irritable bowel syndrome (IBS)-like symptoms, 65 IBS and 50 celiac controls. Patients were recruited at two Internal Medicine Departments. Elimination diet and double-blind placebo controlled (DBPC) wheat challenge proved the NCWS diagnosis. All subjects underwent BMD assessment by Dual Energy X-Ray Absorptiometry (DXA), duodenal histology, HLA DQ typing, body mass index (BMI) evaluation and assessment for daily calcium intake. DBPC cow's milk proteins challenge showed that 30 of the 75 NCWS patients suffered from multiple food sensitivity. Osteopenia and osteoporosis frequency increased from IBS to NCWS and to celiac disease (CD) (P <0.0001). Thirty-five NCWS patients (46.6%) showed osteopenia or osteoporosis. Low BMD was related to low BMI and multiple food sensitivity. Values of daily dietary calcium intake in NCWS patients were significantly lower than in IBS controls. An elevated frequency of bone mass loss in NCWS patients was found; this was related to low BMI and was more frequent in patients with NCWS associated with other food sensitivity. A low daily intake of dietary calcium was observed in patients with NCWS.

Gluten, Celiac Disease, and Gluten Intolerance and the Impact of Gluten Minimization Treatments with Prolylendopeptidase on the Measurement of Gluten in Beer

There is an increase in the number of people adopting a gluten-free diet, with one-fifth of Australian consumers avoiding certain food or drinks for allergy or intolerance reasons. For most consumers, the belief that a gluten-free diet is healthier than a gluten containing diet is unsupported by a formal diagnosis. However, for a small group of subjects who have gluten sensitive disorder, a lifelong, gluten-free diet is required, including avoidance of beer. Prolylendopeptidase enzymes (PEP) cleave gluten proteins after the abundant proline residues and have the potential to destroy gluten proteins and remove or minimize immunoreactive peptides from food. However, PEP treatment may also confound measurement of gluten concentration in food and beverages by destroying epitopes that are used to enumerate gluten peptides – we ask, “does PEP treatment destroy celiac reactive epitopes or merely disguise them from ELISA enumeration?” There is now sufficient data to show that treatment of gluten peptides with bacterial PEP in combination with other proteases, or the fungal Aspergillus niger PEP alone, reduces the immunoreactivity of gluten peptides, with celiac T-cells to near zero. This is also accompanied by destruction of key epitopes that are used by antibodies to enumerate gluten peptides during ELISA reactions. Thus, both immunoreactivity and ELISA measurements are reduced to near zero by PEP treatment. However, definitive evidence of the safety of treated beer for celiacs ideally requires a double-blind crossover, dietary challenge. Consuming sufficient beer to present a suitable load of hordein peptides is not possible, and presenting hordeins in the same form as encountered in treated beer is difficult. The effect of protease treatments on the safety of treated gluten for the remainder the celiac-like diseases, including gluten ataxia and dermatitis herpetiformis, and the larger spectrum of gluten-related disorders, including gluten intolerance and the IgE-mediated allergic responses Bakers asthma, gluten allergy, WDEIA, and urticaria, cannot be definitively assessed until the epitopes involved have been defined. The gluten sensitive disorders and the gluten proteins are reviewed, and the effects of proteolysis on several archetypal gluten peptides are examined.

The Spectrum of Gluten-Related Disorders

Gluten is a rubbery mass consisting of water insoluble proteins from wheat, rye and barley. It is well known that dietary gluten may trigger an abnormal immune response in genetically susceptible individuals, causing a number of disorders whose clinical spectrum ranges from celiac disease to dermatitis herpetiformis and wheat allergy. In the last few years, other conditions that are supposed to be pathogenetically linked with gluten have emerged, such as gluten ataxia and non-celiac gluten sensitivity. In this review, we critically evaluate clinical and diagnostic aspects of gluten-related disorders.

Emerging concepts: from coeliac disease to non-coeliac gluten sensitivity

The rise in gluten consumption over time has led to the increasing recognition of coeliac disease (CD) with associated complications. However, only recently has there been an appreciation that the spectrum of gluten-related disorders is greater than just CD, which may explain the growing global popularity in gluten-free products. Current literature suggests that a newly recognised clinical entity in the form of non-coeliac gluten sensitivity (NCGS) may be the most common gluten-related disorder encountered by healthcare professionals, although its exact prevalence is as yet unknown. This article will review the historical relationship between mankind and gluten as well as the progressive recognition that it is possible for gluten to have a deleterious effect on our health. To this effect we discuss the prevalence, diagnosis and complications of CD including the benefits derived from a gluten-free diet (GFD). Finally, we discuss our current understanding of NCGS, in addition to highlighting the need for further research to determine the extent, clinicopathological features and serological biomarkers to help recognise this emerging condition in clinical practice.

Serological Tests in Gluten Sensitivity (Nonceliac Gluten Intolerance)

To characterize the serological pattern of gluten sensitivity (GS) and to compare it with that found in celiac disease. 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. 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). 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. 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.

Spectrum of gluten-related disorders: consensus on new nomenclature and classification

A decade ago celiac disease was considered extremely rare outside Europe and, therefore, was almost completely ignored by health care professionals. In only 10 years, key milestones have moved celiac disease from obscurity into the popular spotlight worldwide. Now we are observing another interesting phenomenon that is generating great confusion among health care professionals. The number of individuals embracing a gluten-free diet (GFD) appears much higher than the projected number of celiac disease patients, fueling a global market of gluten-free products approaching $2.5 billion (US) in global sales in 2010. This trend is supported by the notion that, along with celiac disease, other conditions related to the ingestion of gluten have emerged as health care concerns. This review will summarize our current knowledge about the three main forms of gluten reactions: allergic (wheat allergy), autoimmune (celiac disease, dermatitis herpetiformis and gluten ataxia) and possibly immune-mediated (gluten sensitivity), and also outline pathogenic, clinical and epidemiological differences and propose new nomenclature and classifications.

Coeliac disease: changing diagnostic criteria?

Coeliac disease: changing diagnostic criteria?