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Extraintestinal Manifestations of Coeliac Disease
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Extraintestinal Manifestations of Coeliac Disease

A special issue of Nutrients (ISSN 2072-6643).

Deadline for manuscript submissions: closed (30 September 2018) | Viewed by 180507

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editors

Prof. Dr. Marios Hadjivassiliou

E-Mail Website
Guest Editor
Academic Department of Neurosciences, University of Sheffield, Sheffield S10 2JF, UK
Interests: ataxias; neurological manifestations of coeliac disease and gluten sensitivity
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. David S Sanders

E-Mail Website
Guest Editor
Academic Unit of Gastroenterology, Royal Hallamshire Hospital & University of Sheffield, UK
Interests: Coeliac Disease
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Coeliac Disease (CD) affects at least 1% of the population. “Classical” CD refers to gastrointestinal presentations with anaemia and gastrointestinal symptoms. CD can, however, present with extraintestinal manifestations, the commonest of which are dermatitis herpetiformis and neurological presentations (e.g., ataxia, neuropathy, encephalopathy). Recognition and research into the pathophysiology of such manifestations is likely to enhance our understanding of this complex autoimmune disorder. This Special Issue will concentrate on the latest research into such manifestations, both in clinical terms and also in the pathophysiology of such manifestations, aiming to cover the following areas:

  • Dermatitis Herpetiformis
  • CD and other autoimmune disorders
  • Neurological manifestations (ataxia, peripheral neuropathy, encephalopathy)
  • Pathophysiology
  • The role of antibodies in the pathophysiology (antigliadin antibodies)
  • Transglutaminases (in particular TG3 and TG6)
Prof. Marios Hadjivassiliou
Prof. David Sanders
Guest Editors

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Keywords

  • Coeliac disease
  • Gluten sensitivity
  • Non-coeliac gluten sensitivity
  • Gluten ataxia
  • Gluten Neuropathy
  • Neurological manifestations of gluten sensitivity
  • Dermatitis Herpetiformis

Published Papers (20 papers)

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Research

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7 pages, 656 KiB  
Article
The Significance of Low Titre Antigliadin Antibodies in the Diagnosis of Gluten Ataxia
by Marios Hadjivassiliou, Richard A Grünewald, David S Sanders, Panagiotis Zis, Iain Croall, Priya D Shanmugarajah, Ptolemaios G Sarrigiannis, Nick Trott, Graeme Wild and Nigel Hoggard
Nutrients 2018, 10(10), 1444; https://doi.org/10.3390/nu10101444 - 05 Oct 2018
Cited by 20 | Viewed by 5021
Abstract
Background: Patients with gluten ataxia (GA) without enteropathy have lower levels of antigliadin antibodies (AGA) compared to patients with coeliac disease (CD). Magnetic Resonance Spectroscopy (NAA/Cr area ratio) of the cerebellum improves in patients with GA following a strict gluten-free diet (GFD). This [...] Read more.
Background: Patients with gluten ataxia (GA) without enteropathy have lower levels of antigliadin antibodies (AGA) compared to patients with coeliac disease (CD). Magnetic Resonance Spectroscopy (NAA/Cr area ratio) of the cerebellum improves in patients with GA following a strict gluten-free diet (GFD). This is associated with clinical improvement. We present our experience of the effect of a GFD in patients with ataxia and low levels of AGA antibodies measured by a commercial assay. Methods: Consecutive patients with ataxia and serum AGA levels below the positive cut-off for CD but above a re-defined cut-off in the context of GA underwent MR spectroscopy at baseline and after a GFD. Results: Twenty-one consecutive patients with GA were included. Ten were on a strict GFD with elimination of AGA, 5 were on a GFD but continued to have AGA, and 6 patients did not go on a GFD. The NAA/Cr area ratio from the cerebellar vermis increased in all patients on a strict GFD, increased in only 1 out of 5 (20%) patients on a GFD with persisting circulating AGA, and decreased in all patients not on a GFD. Conclusion: Patients with ataxia and low titres of AGA benefit from a strict GFD. The results suggest an urgent need to redefine the serological cut-off for circulating AGA in diagnosing GA. Full article
(This article belongs to the Special Issue Extraintestinal Manifestations of Coeliac Disease)
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11 pages, 1732 KiB  
Article
There Is No Association between Coeliac Disease and Autoimmune Pancreatitis
by Giulia De Marchi, Giovanna Zanoni, Maria Cristina Conti Bellocchi, Elena Betti, Monica Brentegani, Paola Capelli, Valeria Zuliani, Luca Frulloni, Catherine Klersy and Rachele Ciccocioppo
Nutrients 2018, 10(9), 1157; https://doi.org/10.3390/nu10091157 - 24 Aug 2018
Cited by 3 | Viewed by 3455
Abstract
Autoimmune pancreatitis (AIP) is a rare disorder whose association with coeliac disease (CD) has never been investigated, although CD patients display a high prevalence of both endocrine and exocrine pancreatic affections. Therefore, we sought to evaluate the frequency of CD in patients with [...] Read more.
Autoimmune pancreatitis (AIP) is a rare disorder whose association with coeliac disease (CD) has never been investigated, although CD patients display a high prevalence of both endocrine and exocrine pancreatic affections. Therefore, we sought to evaluate the frequency of CD in patients with AIP and in further medical pancreatic disorders. The screening for CD was carried out through the detection of tissue transglutaminase (tTG) autoantibodies in sera of patients retrospectively enrolled and divided in four groups: AIP, chronic pancreatitis, chronic asymptomatic pancreatic hyperenzymemia (CAPH), and control subjects with functional dyspepsia. The search for anti-endomysium autoantibodies was performed in those cases with borderline or positive anti-tTG values. Duodenal biopsy was offered to all cases showing positive results. One patient out of 72 (1.4%) with AIP had already been diagnosed with CD and was following a gluten-free diet, while one case out of 71 (1.4%) with chronic pancreatitis and one out of 92 (1.1%) control subjects were diagnosed with de novo CD. No cases of CD were detected in the CAPH group. By contrast, a high prevalence of cases with ulcerative colitis was found in the AIP group (13.8%). Despite a mutual association between CD and several autoimmune disorders, our data do not support the serologic screening for CD in AIP. Further studies will clarify the usefulness of CD serologic screening in other pancreatic disorders. Full article
(This article belongs to the Special Issue Extraintestinal Manifestations of Coeliac Disease)
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12 pages, 956 KiB  
Article
A Serological Diagnosis of Coeliac Disease Is Associated with Osteoporosis in Older Australian Adults
by Michael D. E. Potter, Marjorie M. Walker, Stephen Hancock, Elizabeth Holliday, Gregory Brogan, Michael Jones, Mark McEvoy, Michael Boyle, Nicholas J. Talley and John Attia
Nutrients 2018, 10(7), 849; https://doi.org/10.3390/nu10070849 - 29 Jun 2018
Cited by 7 | Viewed by 4679
Abstract
Previously thought to be mainly a disorder of childhood and early adult life, coeliac disease (CeD) is increasingly diagnosed in older adults. This may be important given the association between CeD and osteoporosis. The primary aim of this study was to determine the [...] Read more.
Previously thought to be mainly a disorder of childhood and early adult life, coeliac disease (CeD) is increasingly diagnosed in older adults. This may be important given the association between CeD and osteoporosis. The primary aim of this study was to determine the seroprevalence of undiagnosed CeD (‘at-risk serology’) in an older Australian community and relate this to a diagnosis of osteoporosis and fractures during a follow-up period of 12 years. We included participants from the Hunter Community Study (2004–2007) aged 55–85, who had anti-tissue transglutaminase (tTG) titres, human leukocyte antigen (HLA) genotypes, and bone mineral density measurements at baseline. Follow-up data included subsequent diagnosis of CeD and fractures using hospital information. ‘At-risk’ serology was defined as both tTG and HLA positivity. Complete results were obtained from 2122 patients. The prevalence of ‘at-risk’ serology was 5%. At baseline, 3.4% fulfilled criteria for a diagnosis of osteoporosis. During a mean of 9.7 years of follow-up, 7.4% of the cohort suffered at least one fracture and 0.7% were subsequently diagnosed with CeD. At-risk serology was significantly associated with osteoporosis in a multivariate model (odds ratio 2.83, 95% confidence interval 1.29–6.22); there was insufficient power to look at the outcome of fractures. The results of this study demonstrate that at-risk CeD serology was significantly associated with concurrent osteoporosis but not future fractures. Most individuals with a serological diagnosis of CeD were not diagnosed with CeD during the follow-up period according to medical records. Coeliac disease likely remains under-diagnosed. Full article
(This article belongs to the Special Issue Extraintestinal Manifestations of Coeliac Disease)
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8 pages, 229 KiB  
Article
Quality of Life in Patients with Gluten Neuropathy: A Case-Controlled Study
by Panagiotis Zis, Ptolemaios Georgios Sarrigiannis, Dasappaiah Ganesh Rao and Marios Hadjivassiliou
Nutrients 2018, 10(6), 662; https://doi.org/10.3390/nu10060662 - 23 May 2018
Cited by 23 | Viewed by 5882
Abstract
Background: Gluten neuropathy (GN) is defined as an otherwise idiopathic peripheral neuropathy in the presence of serological evidence of gluten sensitivity (positive native gliadin antibodies and/or transglutaminase or endomysium antibodies). We aimed to compare the quality of life (QoL) of GN patients with [...] Read more.
Background: Gluten neuropathy (GN) is defined as an otherwise idiopathic peripheral neuropathy in the presence of serological evidence of gluten sensitivity (positive native gliadin antibodies and/or transglutaminase or endomysium antibodies). We aimed to compare the quality of life (QoL) of GN patients with that of control subjects and to investigate the effects of a gluten-free diet (GFD) on the QoL. Methods: All consecutive patients with GN attending a specialist neuropathy clinic were invited to participate. The Overall Neuropathy Limitations Scale (ONLS) was used to assess the severity of the neuropathy. The 36-Item Short Form Survey (SF-36) questionnaire was used to measure participants’ QoL. A strict GFD was defined as effectively being able to eliminate all circulating gluten sensitivity-related antibodies. Results: Fifty-three patients with GN and 53 age- and gender-matched controls were recruited. Compared to controls, GN patients showed significantly worse scores in the physical functioning, role limitations due to physical health, energy/fatigue, and general health subdomains of the SF-36. After adjusting for age, gender, and disease severity, being on a strict GFD correlated with better SF-36 scores in the pain domain of the SF-36 (beta 0.317, p = 0.019) and in the overall health change domain of the SF-36 (beta 0.306, p = 0.017). Conclusion: In GN patients, physical dysfunctioning is the major determinant of poor QoL compared to controls. Routine checking of the elimination of gluten sensitivity-related antibodies that results from a strict GFD should be encouraged, as such elimination ameliorates the overall pain and health scores, indicating a better QoL. Full article
(This article belongs to the Special Issue Extraintestinal Manifestations of Coeliac Disease)
10 pages, 519 KiB  
Article
Prognosis of Dermatitis Herpetiformis Patients with and without Villous Atrophy at Diagnosis
by Eriika Mansikka, Kaisa Hervonen, Katri Kaukinen, Pekka Collin, Heini Huhtala, Timo Reunala and Teea Salmi
Nutrients 2018, 10(5), 641; https://doi.org/10.3390/nu10050641 - 19 May 2018
Cited by 24 | Viewed by 4780
Abstract
Dermatitis herpetiformis (DH) is a cutaneous manifestation of coeliac disease. At diagnosis, the majority of patients have villous atrophy in the small bowel mucosa. The objective of this study was to investigate whether the presence or absence of villous atrophy at diagnosis affects [...] Read more.
Dermatitis herpetiformis (DH) is a cutaneous manifestation of coeliac disease. At diagnosis, the majority of patients have villous atrophy in the small bowel mucosa. The objective of this study was to investigate whether the presence or absence of villous atrophy at diagnosis affects the long-term prognosis of DH. Data were gathered from the patient records of 352 DH and 248 coeliac disease patients, and follow-up data via questionnaires from 181 DH and 128 coeliac disease patients on a gluten-free diet (GFD). Of the DH patients, 72% had villous atrophy when DH was diagnosed, and these patients were significantly younger at diagnosis compared to those with normal small bowel mucosa (37 vs. 54 years, p < 0.001). Clinical recovery on a GFD did not differ significantly between the DH groups, nor did current adherence to a GFD, the presence of long-term illnesses, coeliac disease-related complications or gastrointestinal symptoms, or quality of life. By contrast, the coeliac disease controls had more often osteopenia/osteoporosis, thyroid diseases, malignancies and current gastrointestinal symptoms compared to the DH patients. In conclusion, villous atrophy at the time of DH diagnosis does not have an impact on the clinical recovery or long-term general health of DH patients. Full article
(This article belongs to the Special Issue Extraintestinal Manifestations of Coeliac Disease)
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15 pages, 285 KiB  
Article
Efficacy of a Gluten-Free Diet in the Gilles de la Tourette Syndrome: A Pilot Study
by Luis Rodrigo, Nuria Álvarez, Enrique Fernández-Bustillo, Javier Salas-Puig, Marcos Huerta and Carlos Hernández-Lahoz
Nutrients 2018, 10(5), 573; https://doi.org/10.3390/nu10050573 - 07 May 2018
Cited by 11 | Viewed by 18169
Abstract
The Gilles de la Tourette syndrome (GTS) and Non-Coeliac Gluten Sensitivity (NCGS) may be associated. We analyse the efficacy of a gluten-free diet (GFD) in 29 patients with GTS (23 children; six adults) in a prospective pilot study. All of them followed a [...] Read more.
The Gilles de la Tourette syndrome (GTS) and Non-Coeliac Gluten Sensitivity (NCGS) may be associated. We analyse the efficacy of a gluten-free diet (GFD) in 29 patients with GTS (23 children; six adults) in a prospective pilot study. All of them followed a GFD for one year. The Yale Global Tics Severity Scale (YGTSS), the Yale-Brown Obsessive-Compulsive Scale—Self Report (Y-BOCS) or the Children’s Yale-Brown Obsessive-Compulsive Scale—Self Report (CY-BOCS), and the Cavanna’s Quality of Life Questionnaire applied to GTS (GTS-QOL) were compared before and after the GFD; 74% of children and 50% of adults were males, not significant (NS). At the beginning of the study, 69% of children and 100% of adults had associated obsessive-compulsive disorder (OCD) (NS). At baseline, the YGTSS scores were 55.0 ± 17.5 (children) and 55.8 ± 19.8 (adults) (NS), the Y-BOCS/CY-BOCS scores were 15.3, (standard deviation (SD) = 12.3) (children) and 26.8 (9.2) (adults) (p = 0.043), and the GTS-QOL scores were 42.8 ± 18.5 (children) and 64 ± 7.9 (adults) (p = 0.000). NCGS was frequent in both groups, with headaches reported by 47.0% of children and 83.6% of adults (p = 0.001). After one year on a GFD there was a marked reduction in measures of tics (YGTSS) (p = 0.001), and the intensity and frequency of OCD (Y-BOCS/CY-BOCS) (p = 0.001), along with improved generic quality of life (p = 0.001) in children and adults. In conclusion, a GFD maintained for one year in GTS patients led to a marked reduction in tics and OCD both in children and adults. Full article
(This article belongs to the Special Issue Extraintestinal Manifestations of Coeliac Disease)
10 pages, 377 KiB  
Article
Self-Reported Fractures in Dermatitis Herpetiformis Compared to Coeliac Disease
by Camilla Pasternack, Eriika Mansikka, Katri Kaukinen, Kaisa Hervonen, Timo Reunala, Pekka Collin, Heini Huhtala, Ville M. Mattila and Teea Salmi
Nutrients 2018, 10(3), 351; https://doi.org/10.3390/nu10030351 - 14 Mar 2018
Cited by 8 | Viewed by 3681
Abstract
Dermatitis herpetiformis (DH) is a cutaneous manifestation of coeliac disease. Increased bone fracture risk is known to associate with coeliac disease, but this has been only scantly studied in DH. In this study, self-reported fractures and fracture-associated factors in DH were investigated and [...] Read more.
Dermatitis herpetiformis (DH) is a cutaneous manifestation of coeliac disease. Increased bone fracture risk is known to associate with coeliac disease, but this has been only scantly studied in DH. In this study, self-reported fractures and fracture-associated factors in DH were investigated and compared to coeliac disease. Altogether, 222 DH patients and 129 coeliac disease-suffering controls were enrolled in this study. The Disease Related Questionnaire and the Gastrointestinal Symptom Rating Scale and Psychological General Well-Being questionnaires were mailed to participants; 45 out of 222 (20%) DH patients and 35 out of 129 (27%) of the coeliac disease controls had experienced at least one fracture (p = 0.140). The cumulative lifetime fracture incidence did not differ between DH and coeliac disease patients, but the cumulative incidence of fractures after diagnosis was statistically significantly higher in females with coeliac disease compared to females with DH. The DH patients and the coeliac disease controls with fractures reported more severe reflux symptoms compared to those without, and they also more frequently used proton-pump inhibitor medication. To conclude, the self-reported lifetime bone fracture risk is equal for DH and coeliac disease. After diagnosis, females with coeliac disease have a higher fracture risk than females with DH. Full article
(This article belongs to the Special Issue Extraintestinal Manifestations of Coeliac Disease)
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Review

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14 pages, 612 KiB  
Review
Neurological Manifestations of Neuropathy and Ataxia in Celiac Disease: A Systematic Review
by Elizabeth S. Mearns, Aliki Taylor, Kelly J. Thomas Craig, Stefanie Puglielli, Allie B. Cichewicz, Daniel A. Leffler, David S. Sanders, Benjamin Lebwohl and Marios Hadjivassiliou
Nutrients 2019, 11(2), 380; https://doi.org/10.3390/nu11020380 - 12 Feb 2019
Cited by 50 | Viewed by 8466
Abstract
Celiac disease (CD) is an immune-mediated gastrointestinal disorder driven by innate and adaptive immune responses to gluten. Patients with CD are at an increased risk of several neurological manifestations, frequently peripheral neuropathy and gluten ataxia. A systematic literature review of the most commonly [...] Read more.
Celiac disease (CD) is an immune-mediated gastrointestinal disorder driven by innate and adaptive immune responses to gluten. Patients with CD are at an increased risk of several neurological manifestations, frequently peripheral neuropathy and gluten ataxia. A systematic literature review of the most commonly reported neurological manifestations (neuropathy and ataxia) associated with CD was performed. MEDLINE, Embase, the Cochrane Library, and conference proceedings were systematically searched from January 2007 through September 2018. Included studies evaluated patients with CD with at least one neurological manifestation of interest and reported prevalence, and/or incidence, and/or clinical outcomes. Sixteen studies were included describing the risk of gluten neuropathy and/or gluten ataxia in patients with CD. Gluten neuropathy was a neurological manifestation in CD (up to 39%) in 13 studies. Nine studies reported a lower risk and/or prevalence of gluten ataxia with a range of 0%–6%. Adherence to a gluten-free diet appeared to improve symptoms of both neuropathy and ataxia. The prevalence of gluten neuropathy and gluten ataxia in patients with CD varied in reported studies, but the increased risk supports the need for physicians to consider CD in patients with ataxia and neurological manifestations of unknown etiology. Full article
(This article belongs to the Special Issue Extraintestinal Manifestations of Coeliac Disease)
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12 pages, 1349 KiB  
Review
Gluten-Induced Extra-Intestinal Manifestations in Potential Celiac Disease—Celiac Trait
by Alina Popp and Markku Mäki
Nutrients 2019, 11(2), 320; https://doi.org/10.3390/nu11020320 - 01 Feb 2019
Cited by 28 | Viewed by 7678
Abstract
Celiac disease patients may suffer from a number of extra-intestinal diseases related to long-term gluten ingestion. The diagnosis of celiac disease is based on the presence of a manifest small intestinal mucosal lesion. Individuals with a normal biopsy but an increased risk of [...] Read more.
Celiac disease patients may suffer from a number of extra-intestinal diseases related to long-term gluten ingestion. The diagnosis of celiac disease is based on the presence of a manifest small intestinal mucosal lesion. Individuals with a normal biopsy but an increased risk of developing celiac disease are referred to as potential celiac disease patients. However, these patients are not treated. This review highlights that patients with normal biopsies may suffer from the same extra-intestinal gluten-induced complications before the disease manifests at the intestinal level. We discuss diagnostic markers revealing true potential celiac disease. The evidence-based medical literature shows that these potential patients, who are “excluded” for celiac disease would in fact benefit from gluten-free diets. The question is why wait for an end-stage disease to occur when it can be prevented? We utilize research on dermatitis herpetiformis, which is a model disease in which a gluten-induced entity erupts in the skin irrespective of the state of the small intestinal mucosal morphology. Furthermore, gluten ataxia can be categorized as its own entity. The other extra-intestinal manifestations occurring in celiac disease are also found at the latent disease stage. Consequently, patients with celiac traits should be identified and treated. Full article
(This article belongs to the Special Issue Extraintestinal Manifestations of Coeliac Disease)
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8 pages, 562 KiB  
Review
Fatigue as an Extra-Intestinal Manifestation of Celiac Disease: A Systematic Review
by Lars-Petter Jelsness-Jørgensen, Tomm Bernklev and Knut E. A. Lundin
Nutrients 2018, 10(11), 1652; https://doi.org/10.3390/nu10111652 - 03 Nov 2018
Cited by 9 | Viewed by 8838
Abstract
Celiac disease may present with a range of different symptoms, including abdominal problems in a broader sense, iron deficiency and “constant tiredness”. All of these symptoms should consequently lead the clinicians to consider celiac disease as a potential etiopathogenetic cause. Although the pathophysiology [...] Read more.
Celiac disease may present with a range of different symptoms, including abdominal problems in a broader sense, iron deficiency and “constant tiredness”. All of these symptoms should consequently lead the clinicians to consider celiac disease as a potential etiopathogenetic cause. Although the pathophysiology of celiac disease is well documented, the actual mechanisms for disease presentation(s) are less well understood. We here address the topic of fatigue in celiac disease. A systematic literature search identified 298 papers of which five met the criteria for full evaluation. None of the reviewed papers were of high quality and had several methodological weaknesses. We conclude that there is an unmet need to study the contributing factors and management of fatigue in celiac disease. Full article
(This article belongs to the Special Issue Extraintestinal Manifestations of Coeliac Disease)
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11 pages, 2913 KiB  
Review
Headache Associated with Coeliac Disease: A Systematic Review and Meta-Analysis
by Panagiotis Zis, Thomas Julian and Marios Hadjivassiliou
Nutrients 2018, 10(10), 1445; https://doi.org/10.3390/nu10101445 - 06 Oct 2018
Cited by 43 | Viewed by 10233
Abstract
Objective: The aim of this systematic review was to explore the relationship between coeliac disease (CD) and headache. The objectives were to establish the prevalence of each entity amongst the other, to explore the role of gluten free diet (GFD), and to describe [...] Read more.
Objective: The aim of this systematic review was to explore the relationship between coeliac disease (CD) and headache. The objectives were to establish the prevalence of each entity amongst the other, to explore the role of gluten free diet (GFD), and to describe the imaging findings in those affected by headaches associated with CD. Methodology: A systematic computer-based literature search was conducted on the PubMed database. Information regarding study type, population size, the age group included, prevalence of CD amongst those with headache and vice versa, imaging results, the nature of headache, and response to GFD. Results: In total, 40 articles published between 1987 and 2017 qualified for inclusion in this review. The mean pooled prevalence of headache amongst those with CD was 26% (95% CI 19.5–33.9%) in adult populations and 18.3% (95% CI 10.4–30.2%) in paediatric populations. The headaches are most often migraine-like. In children with idiopathic headache, the prevalence of CD is 2.4% (95% CI 1.5–3.7%), whereas data for adult populations is presently unavailable. Brain imaging can be normal, although, cerebral calcifications on CT, white matter abnormalities on MRI and deranged regional cerebral blood flow on SPECT can be present. GFD appears to be an effective management for headache in the context of CD, leading to total resolution of headaches in up to 75% of patients. Conclusions: There is an increased prevalence of CD amongst idiopathic headache and vice versa. Therefore, patients with headache of unknown origin should be screened for CD, as such patients may symptomatically benefit from a GFD. Full article
(This article belongs to the Special Issue Extraintestinal Manifestations of Coeliac Disease)
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16 pages, 284 KiB  
Review
Autoantibodies in the Extraintestinal Manifestations of Celiac Disease
by Xuechen B. Yu, Melanie Uhde, Peter H. Green and Armin Alaedini
Nutrients 2018, 10(8), 1123; https://doi.org/10.3390/nu10081123 - 20 Aug 2018
Cited by 28 | Viewed by 6939
Abstract
Increased antibody reactivity towards self-antigens is often indicative of a disruption of homeostatic immune pathways in the body. In celiac disease, an autoimmune enteropathy triggered by the ingestion of gluten from wheat and related cereals in genetically predisposed individuals, autoantibody reactivity to transglutaminase [...] Read more.
Increased antibody reactivity towards self-antigens is often indicative of a disruption of homeostatic immune pathways in the body. In celiac disease, an autoimmune enteropathy triggered by the ingestion of gluten from wheat and related cereals in genetically predisposed individuals, autoantibody reactivity to transglutaminase 2 is reflective of the pathogenic role of the enzyme in driving the associated inflammatory immune response. Autoantibody reactivity to transglutaminase 2 closely corresponds with the gluten intake and clinical presentation in affected patients, serving as a highly useful biomarker in the diagnosis of celiac disease. In addition to gastrointestinal symptoms, celiac disease is associated with a number of extraintestinal manifestations, including those affecting skin, bones, and the nervous system. Investigations of these manifestations in celiac disease have identified a number of associated immune abnormalities, including B cell reactivity towards various autoantigens, such as transglutaminase 3, transglutaminase 6, synapsin I, gangliosides, and collagen. Clinical relevance, pathogenic potential, mechanism of development, and diagnostic and prognostic value of the various identified autoantibody reactivities continue to be subjects of investigation and will be reviewed here. Full article
(This article belongs to the Special Issue Extraintestinal Manifestations of Coeliac Disease)
14 pages, 445 KiB  
Review
Movement Disorders Related to Gluten Sensitivity: A Systematic Review
by Ana Vinagre-Aragón, Panagiotis Zis, Richard Adam Grunewald and Marios Hadjivassiliou
Nutrients 2018, 10(8), 1034; https://doi.org/10.3390/nu10081034 - 08 Aug 2018
Cited by 25 | Viewed by 10910
Abstract
Gluten related disorders (GRD) represent a wide spectrum of clinical manifestations that are triggered by the ingestion of gluten. Coeliac disease (CD) or gluten sensitive enteropathy is the most widely recognised, but extra-intestinal manifestations have also been increasingly identified and reported. Such manifestations [...] Read more.
Gluten related disorders (GRD) represent a wide spectrum of clinical manifestations that are triggered by the ingestion of gluten. Coeliac disease (CD) or gluten sensitive enteropathy is the most widely recognised, but extra-intestinal manifestations have also been increasingly identified and reported. Such manifestations may exist in the absence of enteropathy. Gluten sensitivity (GS) is another term that has been used to include all GRD, including those where there is serological positivity for GS related antibodies in the absence of an enteropathy. Gluten ataxia (GA) is the commonest extraintestinal neurological manifestation and it has been the subject of many publications. Other movement disorders (MDs) have also been reported in the context of GS. The aim of this review was to assess the current available medical literature concerning MDs and GS with and without enteropathy. A systematic search was performed while using PubMed database. A total of 48 articles met the inclusion criteria and were included in the present review. This review highlights that the phenomenology of gluten related MDs is broader than GA and demonstrates that gluten-free diet (GFD) is beneficial in a great percentage of such cases. Full article
(This article belongs to the Special Issue Extraintestinal Manifestations of Coeliac Disease)
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14 pages, 413 KiB  
Review
Extraintestinal Manifestations of Celiac Disease: Early Detection for Better Long-Term Outcomes
by Pilvi Laurikka, Samuli Nurminen, Laura Kivelä and Kalle Kurppa
Nutrients 2018, 10(8), 1015; https://doi.org/10.3390/nu10081015 - 03 Aug 2018
Cited by 78 | Viewed by 7238
Abstract
Population-based screening studies have shown celiac disease to be one of the most common chronic gastrointestinal diseases. Nevertheless, because of the diverse clinical presentation, the great majority of patients remain unrecognized. Particularly difficult to identify are the multifaceted extraintestinal symptoms that may appear [...] Read more.
Population-based screening studies have shown celiac disease to be one of the most common chronic gastrointestinal diseases. Nevertheless, because of the diverse clinical presentation, the great majority of patients remain unrecognized. Particularly difficult to identify are the multifaceted extraintestinal symptoms that may appear at variable ages. Although the pathogenesis and long-term outcome of these manifestations are still poorly established, there is some evidence that unrecognized celiac disease predisposes to severe complications if not diagnosed and prevented with an early-initiated gluten-free diet. Therefore, it is of utmost importance that physicians of different disciplines learn to recognize celiac disease in individuals with non-gastrointestinal symptoms. In the future, more studies are needed to clarify the factors affecting development and prognosis of the extraintestinal manifestations. Full article
(This article belongs to the Special Issue Extraintestinal Manifestations of Coeliac Disease)
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17 pages, 600 KiB  
Review
Celiac Disease and Liver Disorders: From Putative Pathogenesis to Clinical Implications
by Iva Hoffmanová, Daniel Sánchez, Ludmila Tučková and Helena Tlaskalová-Hogenová
Nutrients 2018, 10(7), 892; https://doi.org/10.3390/nu10070892 - 12 Jul 2018
Cited by 39 | Viewed by 7229
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Extraintestinal Manifestations of Coeliac Disease)
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29 pages, 604 KiB  
Review
Psychiatric Comorbidity in Children and Adults with Gluten-Related Disorders: A Narrative Review
by Mahmoud Slim, Fernando Rico-Villademoros and Elena P. Calandre
Nutrients 2018, 10(7), 875; https://doi.org/10.3390/nu10070875 - 06 Jul 2018
Cited by 31 | Viewed by 7028
Abstract
Gluten-related disorders are characterized by both intestinal and extraintestinal manifestations. Previous studies have suggested an association between gluten-related disorder and psychiatric comorbidities. The objective of our current review is to provide a comprehensive review of this association in children and adults. A systematic [...] Read more.
Gluten-related disorders are characterized by both intestinal and extraintestinal manifestations. Previous studies have suggested an association between gluten-related disorder and psychiatric comorbidities. The objective of our current review is to provide a comprehensive review of this association in children and adults. A systematic literature search using MEDLINE, Embase and PsycINFO from inception to 2018 using terms of ‘celiac disease’ or ‘gluten-sensitivity-related disorders’ combined with terms of ‘mental disorders’ was conducted. A total of 47 articles were included in our review, of which 28 studies were conducted in adults, 11 studies in children and eight studies included both children and adults. The majority of studies were conducted in celiac disease, two studies in non-celiac gluten sensitivity and none in wheat allergy. Enough evidence is currently available supporting the association of celiac disease with depression and, to a lesser extent, with eating disorders. Further investigation is warranted to evaluate the association suggested with other psychiatric disorders. In conclusion, routine surveillance of potential psychiatric manifestations in children and adults with gluten-related disorders should be carried out by the attending physician. Full article
(This article belongs to the Special Issue Extraintestinal Manifestations of Coeliac Disease)
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9 pages, 204 KiB  
Review
Celiac Disease and Glandular Autoimmunity
by George J. Kahaly, Lara Frommer and Detlef Schuppan
Nutrients 2018, 10(7), 814; https://doi.org/10.3390/nu10070814 - 25 Jun 2018
Cited by 45 | Viewed by 7102
Abstract
Celiac disease is a small intestinal inflammatory disease with autoimmune features that is triggered and maintained by the ingestion of the storage proteins (gluten) of wheat, barley, and rye. Prevalence of celiac disease is increased in patients with mono- and/or polyglandular autoimmunity and [...] Read more.
Celiac disease is a small intestinal inflammatory disease with autoimmune features that is triggered and maintained by the ingestion of the storage proteins (gluten) of wheat, barley, and rye. Prevalence of celiac disease is increased in patients with mono- and/or polyglandular autoimmunity and their relatives. We have reviewed the current and pertinent literature that addresses the close association between celiac disease and endocrine autoimmunity. The close relationship between celiac disease and glandular autoimmunity can be largely explained by sharing of a common genetic background. Further, between 10 and 30% of patients with celiac disease are thyroid and/or type 1 diabetes antibody positive, while around 5–7% of patients with autoimmune thyroid disease, type 1 diabetes, and/or polyglandular autoimmunity are IgA anti-tissue transglutaminase antibody positive. While a gluten free diet does not reverse glandular autoimmunity, its early institution may delay or even prevent its first manifestation. In conclusion, this brief review highlighting the close association between celiac disease and both monoglandular and polyglandular autoimmunity, aims to underline the need for prospective studies to establish whether an early diagnosis of celiac disease and a prompt gluten-free diet may positively impact the evolution and manifestation of glandular autoimmunity. Full article
(This article belongs to the Special Issue Extraintestinal Manifestations of Coeliac Disease)
20 pages, 4456 KiB  
Review
Cutaneous and Mucosal Manifestations Associated with Celiac Disease
by Luis Rodrigo, Valia Beteta-Gorriti, Nuria Alvarez, Celia Gómez de Castro, Alvaro De Dios, Laura Palacios and Jorge Santos-Juanes
Nutrients 2018, 10(7), 800; https://doi.org/10.3390/nu10070800 - 21 Jun 2018
Cited by 46 | Viewed by 16819
Abstract
Celiac disease (CD) is an immune-mediated, gluten-induced enteropathy that affects predisposed individuals of all ages. Many patients with CD do not report gastrointestinal symptoms making it difficult to reach an early diagnosis. On the other hand, CD is related to a wide spectrum [...] Read more.
Celiac disease (CD) is an immune-mediated, gluten-induced enteropathy that affects predisposed individuals of all ages. Many patients with CD do not report gastrointestinal symptoms making it difficult to reach an early diagnosis. On the other hand, CD is related to a wide spectrum of extra-intestinal manifestations, with dermatitis herpetiformis (DH) being the best characterized. These associated conditions may be the clue to reaching the diagnosis of CD. Over the last few years, there have been multiple reports of the association between CD and several cutaneous manifestations that may improve with a gluten-free diet (GFD). The presence of some of these skin diseases, even in the absence of gastrointestinal symptoms, should give rise to an appropriate screening method for CD. The aim of this paper is to describe the different cutaneous manifestations that have been associated with CD and the possible mechanisms involved. Full article
(This article belongs to the Special Issue Extraintestinal Manifestations of Coeliac Disease)
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11 pages, 208 KiB  
Review
Extra-Intestinal Manifestation of Celiac Disease in Children
by Hilary Jericho and Stefano Guandalini
Nutrients 2018, 10(6), 755; https://doi.org/10.3390/nu10060755 - 12 Jun 2018
Cited by 45 | Viewed by 8201
Abstract
The aim of this literature review is to discuss the extra-intestinal manifestations of celiac disease within the pediatric celiac population. Full article
(This article belongs to the Special Issue Extraintestinal Manifestations of Coeliac Disease)
9 pages, 713 KiB  
Review
Dermatitis Herpetiformis: A Common Extraintestinal Manifestation of Coeliac Disease
by Timo Reunala, Teea T. Salmi, Kaisa Hervonen, Katri Kaukinen and Pekka Collin
Nutrients 2018, 10(5), 602; https://doi.org/10.3390/nu10050602 - 12 May 2018
Cited by 59 | Viewed by 26920
Abstract
Dermatitis herpetiformis (DH) is a common extraintestinal manifestation of coeliac disease presenting with itchy papules and vesicles on the elbows, knees, and buttocks. Overt gastrointestinal symptoms are rare. Diagnosis of DH is easily confirmed by immunofluorescence biopsy showing pathognomonic granular immunoglobulin A (IgA) [...] Read more.
Dermatitis herpetiformis (DH) is a common extraintestinal manifestation of coeliac disease presenting with itchy papules and vesicles on the elbows, knees, and buttocks. Overt gastrointestinal symptoms are rare. Diagnosis of DH is easily confirmed by immunofluorescence biopsy showing pathognomonic granular immunoglobulin A (IgA) deposits in the papillary dermis. A valid hypothesis for the immunopathogenesis of DH is that it starts from latent or manifest coeliac disease in the gut and evolves into an immune complex deposition of high avidity IgA epidermal transglutaminase (TG3) antibodies, together with the TG3 enzyme, in the papillary dermis. The mean age at DH diagnosis has increased significantly in recent decades and presently is 40–50 years. The DH to coeliac disease prevalence ratio is 1:8 in Finland and the United Kingdom (U.K.). The annual DH incidence rate, currently 2.7 per 100,000 in Finland and 0.8 per 100,000 in the U.K., is decreasing, whereas the reverse is true for coeliac disease. The long-term prognosis of DH patients on a gluten-free diet is excellent, with the mortality rate being even lower than for the general population. Full article
(This article belongs to the Special Issue Extraintestinal Manifestations of Coeliac Disease)
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