Patient and Community Health Global Burden in a World With More Celiac Disease.

Celiac disease is one of the most common life-long disorders worldwide, with a prevalence mostly ranging between 0.7% and 2.9% in the general population and a higher frequency in females and well-defined at-risk groups, such as relatives of affected individuals and patients with autoimmune comorbidities. Increasing clinical detection is facilitated by improving awareness, implementation of a case-finding approach, and serology availability for screening at-risk patients, among other factors. Nevertheless, due to huge clinical variability, many celiac disease cases still escape diagnosis in most countries, unless actively searched by proactive policies. The burden of celiac disease is increasing, as is the need for better longitudinal care. Pediatric screening of the general population could represent the road ahead for an efficient intervention of secondary prevention aimed to reduce the social and health burden of celiac disease. This review analyses the epidemiology of celiac disease continent by continent, discusses current strategies to improve the detection of celiac disease, and highlights challenges related to the burden of celiac disease globally.

The use of urine peptidomics to define dietary gluten peptides from patients with celiac disease and the clinical relevance.

INTRODUCTION: Determination of urinary gluten immunogenic peptides (GIP) has emerged as one of the most attractive test to monitor the adherence to the gluten-free diet (GFD) of patients with celiac disease (CD), being a simple, noninvasive and direct method to detect gluten contamination of the GFD. AREAS COVERED: We conducted a scoping review in Medline (PubMed) of articles published up to April 2023 that analyzed any aspect of the clinical relevance of the use of urinary GIP measurement in patients with CD. A total of 17 articles reporting the clinical use of urinary peptidomics for the follow-up of CD patients were finally included. EXPERT OPINION: Available data suggest that a negative urinary GIP result is a reliable noninvasive predictor of intestinal mucosa healing in CD patients treated with the GFD, especially if testing three urine samples on different days including the weekend. Due to conflicting results about the sensitivity and the specificity of the urinary GIP determination, additional in-depth information is needed, particularly related to (1) the relationship between the amount of ingested gluten and the quantity of urinary GIP excreted in treated CD patients, (2) the GIP kinetics and best timing for sample collection.

First experience of combined enzyme replacement therapy and hematopoietic stem cell transplantation in alpha-mannosidosis.

We describe the first case of bridge therapy in alpha-mannosidosis (AM) in an infant diagnosed at only 5 months of life who underwent enzyme replacement therapy (ERT) in the pre- and peri-transplant phases. Eight ERT infusions were administered before hematopoietic stem cell transplantation (HSCT) and continued for additional 90 days until complete engraftment. The clinical and laboratory data after 3 years post-HSCT show that the early combined intervention may reduce the disease progression and the urine and plasma content of mannosyl-oligosaccharides (OS) monitored by liquid chromatography tandem mass spectrometry (LC-MS/MS). This report highlights that early diagnosis and prompt initiation of such treatments in AM are the best chance to minimize the progression of symptoms.

Nonceliac gluten sensitivity.

PURPOSE OF REVIEW: To describe recent advances on nonceliac gluten sensitivity (NCGS), a recently described disorder characterized by variable symptoms and frequent irritable bowel syndrome (IBS)-like manifestations. RECENT FINDINGS: The recent description of disease-triggering wheat components other than gluten, such as fructans and amylase-trypsin inhibitors (ATIs), definitely suggests that nonceliac wheat sensitivity (NCWS) is a better 'umbrella' terminology than NCGS. Self-reported NCWS is very common worldwide, particularly in patients seen at the gastroenterology clinic, but many of these diagnoses are not confirmed by standard clinical criteria. A biomarker of NCWS is still lacking, however, subtle histological features at the small intestinal biopsy may facilitate diagnosis. Treatment of NCWS is based on the gluten-free diet (GFD). The GFD has proven to be an effective treatment of a significant proportion of NCWS-related IBS patients. Dietary therapies for IBS, including the GFD, should be offered by dietitians who first assess dietary triggers and then tailor the intervention according to patient choice. Pioneer studies are under way to test the therapeutic efficacy of supplemental gluten-digesting enzyme preparations in patients with NCWS. SUMMARY: Recent studies highlight interesting pathophysiological and clinical features of NCWS. Many questions remain, however, unanswered, such as the epidemiology, a biomarker(s), and the natural history of this clinical entity.

Wheat consumption and prevalence of celiac disease: Correlation from a multilevel analysis.

Celiac disease (CD) is triggered by both genetic and environmental factors. More than 1% of the world's population is affected by CD. In recent years, studies have confirmed a worldwide rising trend in CD prevalence. "Westernized diet" is one of the main factors of this increasing prevalence. However, the relationship between wheat consumption, its dynamics, and CD has not been adequately investigated on a global scale. This study aimed to perform a multilevel analysis of the association between wheat consumption and CD. Wheat consumption data from countries and continents were obtained from the database. The relative increase/decrease in wheat consumption over a long period (since 1961) and a short period (since 2004) were calculated using various statistical tools. The relationship between wheat consumption and celiac frequency was determined using the R-commander R package version 2.6-2. Pearson's correlation coefficient (r = 0.88) confirmed a high positive correlation between wheat consumption and the prevalence of biopsy-proven CD by estimating continent-wide wheat consumption data, but an insignificant correlation was found when the data were compared country-wide.

Coeliac disease.

Coeliac disease is an autoimmune disorder that primarily affects the small intestine, and is caused by the ingestion of gluten in genetically susceptible individuals. Prevalence in the general population ranges from 0·5% to 2%, with an average of about 1%. The development of the coeliac enteropathy depends on a complex immune response to gluten proteins, including both adaptive and innate mechanisms. Clinical presentation of coeliac disease is highly variable and includes classical and non-classical gastrointestinal symptoms, extraintestinal manifestations, and subclinical cases. The disease is associated with a risk of complications, such as osteoporosis and intestinal lymphoma. Diagnosis of coeliac disease requires a positive serology (IgA anti-transglutaminase 2 and anti-endomysial antibodies) and villous atrophy on small-intestinal biopsy. Treatment involves a gluten-free diet; however, owing to the high psychosocial burden of such a diet, research into alternative pharmacological treatments is currently very active.

Gluten Induces Subtle Histological Changes in Duodenal Mucosa of Patients with Non-Coeliac Gluten Sensitivity: A Multicentre Study.

Background: Histological changes induced by gluten in the duodenal mucosa of patients with non-coeliac gluten sensitivity (NCGS) are poorly defined. Objectives: To evaluate the structural and inflammatory features of NCGS compared to controls and coeliac disease (CeD) with milder enteropathy (Marsh I-II). Methods: Well-oriented biopsies of 262 control cases with normal gastroscopy and histologic findings, 261 CeD, and 175 NCGS biopsies from 9 contributing countries were examined. Villus height (VH, in µm), crypt depth (CrD, in µm), villus-to-crypt ratios (VCR), IELs (intraepithelial lymphocytes/100 enterocytes), and other relevant histological, serologic, and demographic parameters were quantified. Results: The median VH in NCGS was significantly shorter (600, IQR: 400−705) than controls (900, IQR: 667−1112) (p < 0.001). NCGS patients with Marsh I-II had similar VH and VCR to CeD [465 µm (IQR: 390−620) vs. 427 µm (IQR: 348−569, p = 0·176)]. The VCR in NCGS with Marsh 0 was lower than controls (p < 0.001). The median IEL in NCGS with Marsh 0 was higher than controls (23.0 vs. 13.7, p < 0.001). To distinguish Marsh 0 NCGS from controls, an IEL cut-off of 14 showed 79% sensitivity and 55% specificity. IEL densities in Marsh I-II NCGS and CeD groups were similar. Conclusion: NCGS duodenal mucosa exhibits distinctive changes consistent with an intestinal response to luminal antigens, even at the Marsh 0 stage of villus architecture.

Circulating microRNAs as novel non-invasive biomarkers of paediatric celiac disease and adherence to gluten-free diet.

BACKGROUND: Celiac Disease (CD) is a multifactorial autoimmune enteropathy (with a prevalence of approximately 1% worldwide) that exhibits a wide spectrum of clinical, serological and histological manifestations. For the diagnosis of paediatric CD, the gold standard is the combination of serological tests (with high TGA-IgA values greater than 10 times the upper limit of normal) and duodenal biopsy (with a positive TGA-IgA but low titer). Therefore, a diagnostic test that totally excludes an invasive approach has not been discovered so far and the discovery of novel biological markers would represent an undoubted advantage for the diagnosis of CD and prognostic evaluation. MicroRNAs (miRNAs), small non-coding RNAs (18-22 nucleotides) that regulate gene expression at post-transcriptional level and play important roles in many biological processes, represent a novel class of potential disease biomarkers. Their presence in biological fluids (i.e., serum, plasma, saliva, urine) provides the opportunity to employ circulating miRNAs as novel non-invasive biomarkers. METHODS: In our prospective observational study, we examined the expression of circulating miRNAs in a cohort of CD patients (both at diagnosis and on gluten-free diet, respectively referred as CD and GFD) compared to healthy controls. By small RNA-Seq we discovered a set of circulating miRNAs that were further validated by qPCR with specific assays. FINDINGS: We found that out of the 13 miRNAs able to discriminate the three groups (i.e., CD, GFD and controls), three of them, namely miR-192-5p, miR-215-5p and miR-125b-5p (alone or in combination), were able to discriminate these three groups with high accuracy and specificity. INTERPRETATION: Our conclusions emphasize that these circulating miRNAs can be employed not only for the diagnosis of CD patients with a low TGA-IgA titer but also to monitor the adherence to a gluten-free diet by CD patients. In conclusion, we suggest the use of the circulating miRNAs identified in this work as a novel diagnostic and follow-up tool for paediatric CD. FUNDING: This work was supported by Fondazione Celiachia Onlus (FC) Grant n° 018/FC/2013 and by Italian Ministry of Health (Ricerca Corrente).

The global burden of coeliac disease: opportunities and challenges.

Coeliac disease is a systemic disorder characterized by immune-mediated enteropathy, which is caused by gluten ingestion in genetically susceptible individuals. The clinical presentation of coeliac disease is highly variable and ranges from malabsorption through solely extra-intestinal manifestations to asymptomatic. As a result, the majority of patients with coeliac disease remain undiagnosed, misdiagnosed or experience a substantial delay in diagnosis. Coeliac disease is diagnosed by a combination of serological findings of disease-related antibodies and histological evidence of villous abnormalities in duodenal biopsy samples. However, variability in histological grading and in the diagnostic performance of some commercially available serological tests remains unacceptably high and confirmatory assays are not readily available in many parts of the world. Currently, the only effective treatment for coeliac disease is a lifelong, strict, gluten-free diet. However, many barriers impede patients' adherence to this diet, including lack of widespread availability, high cost, cross-contamination and its overall restrictive nature. Routine follow-up is necessary to ensure adherence to a gluten-free diet but considerable variation is evident in follow-up protocols and the optimal disease management strategy is not clear. However, these challenges in the diagnosis and management of coeliac disease suggest opportunities for future research.

The Clinical Spectrum of Inflammatory Bowel Disease Associated With Specific Genetic Syndromes: Two Novel Pediatric Cases and a Systematic Review.

Background and Aims: Inflammatory bowel disease (IBD) is a typical polygenic disorder and less frequently shows a monogenic origin. Furthermore, IBD can originate in the context of specific genetic syndromes associated with a risk of autoimmune disorders. We aimed to systematically evaluate the prevalence of IBD in specific genetic syndromes and to review the clinical characteristics of the published cases. Methods: According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, studies describing patients with IBD and a genetic syndrome and/or studies indicating the prevalence or incidence of IBD in subjects with a genetic syndrome were included. Results: Forty-six studies describing a total of 67 cases of IBD in six genetic syndromes and two personally assessed unpublished cases were included in the review. The majority of cases were associated with Turner syndrome (TS) (38 cases), Down syndrome (DS) (18 cases) and neurofibromatosis type 1 (NF1) (8 cases). Sporadic cases were described in DiGeorge syndrome (2), Kabuki syndrome (2), and Williams syndrome (1). The prevalence of IBD ranged from 0.67 to 4% in TS and from 0.2 to 1.57% in DS. The incidence of IBD was increased in TS and DS compared to the general population. Eight cases of IBD in TS had a severe/lethal course, many of which described before the year 2000. Two IBD cases in DS were particularly severe. Conclusion: Evidence of a greater prevalence of IBD is accumulating in TS, DS, and NF1. Management of IBD in patients with these genetic conditions should consider the presence of comorbidities and possible drug toxicities. Systematic Review Registration: PROSPERO, identifier: CRD42021249820.

Determination of Urinary Gluten Immunogenic Peptides to Assess Adherence to the Gluten-Free Diet: A Randomized, Double-Blind, Controlled Study.

INTRODUCTION: The adherence to a gluten-free diet (GFD) is a trending topic in the management of celiac disease. The aim of our study was to evaluate the diagnostic performance of urinary gluten immunogenic peptides (GIP) determination to detect gluten contamination of the GFD. METHODS: In study A, 25 healthy adults on a standard GFD performed 6 gluten challenges (0, 10, 50, 100, 500, and 1,000 mg) with quantification of urinary GIP before (T0) and during the following 24 hours. In study B, 12 participants on a gluten contamination elimination diet underwent urinary GIP determination at T0 and after challenge with 5 or 10 mg gluten. Urine GIP concentration was determined by an immunochromatographic assay. RESULTS: In study A, 51 of 150 baseline urine samples were GIP+ on GFD and 7 of 17 were GIP+ after the zero-gluten challenge, whereas only 55 of 81 were GIP+ after the 10-1,000 mg gluten challenges. There was no significant change in the 24-hour urinary GIP when increasing gluten from 10 to 1,000 mg. In study B, 24 of 24 baseline urine samples were GIP-, whereas 8 of 24 were GIP+ after 5 or 10 mg of gluten. DISCUSSION: Traces of gluten in the standard GFD may cause positivity of urinary GIP determination, whereas a false negativity is common after a gluten intake of 10-1,000 mg. Owing to the impossibility of standardizing the test in normal conditions, it seems unlikely that urinary GIP determination may represent a reliable tool to assess the compliance to the GFD of patients with celiac disease or other gluten-related disorders.

Navigating celiac disease and the gluten-free diet in China.

BACKGROUND: Little is known about celiac disease (CeD) diagnosis and management in China. AIM: This pilot aimed to be the first study to describe, quantitatively and qualitatively, how individuals living in China navigate CeD and the gluten-free diet (GFD). METHODS: Participants were 13 adults and four parents of children with reported CeD, recruited from 11 mainland China cities via an online GFD support group. CeD-specific quality of life (CD-QOL and CD-PQOL) and diet adherence (CDAT) were assessed. In-depth interviews addressed experiences with CeD and the GFD. RESULTS: Six of 17 participants reported biopsy- or serology-confirmed CeD. The mean (SD) adult CDAT score was 15.2 (3.6), > 13 indicating inadequate GFD adherence. The mean adult CD-QOL score was 62.1 (24.1) out of 100, in the "medium" to "good" range. Results were similar in children. Major interview themes included: (1) a challenging journey to obtain diagnosis; (2) social and structural barriers to maintaining the GFD; and (3) reliance on self in management of CeD. CONCLUSION: Obtaining a diagnosis, maintaining a GFD, and living with CeD can be extremely challenging in mainland China. Results suggest an urgent need for CeD-specific education and Asian-adapted GFD guidance for both healthcare practitioners and patients.

Diagnostic Accuracy of IgA Anti-Transglutaminase and IgG Anti-Deamidated Gliadin for Diagnosis of Celiac Disease in Children under Two Years of Age: A Systematic Review and Meta-Analysis.

The need of adding the determination of anti-deamidated gliadin peptide (DGP) IgG to anti-transglutaminase (TTG) IgA antibodies for diagnosis of celiac disease (CD) in children <2 years of age is controversial. We performed a systematic review and meta-analysis to evaluate, by head-to-head comparison, the diagnostic accuracy of TTG IgA and DGP IgG antibodies. We searched PubMed, MEDLINE, and Embase databases up to January 2021. The diagnostic reference was intestinal biopsy. We calculated the sensitivity and specificity of these tests and the odds ratio (OR) between the tests. Fifteen articles were eligible for the systematic review and ten were eligible for the meta-analysis. Sensitivity and specificity were 0.96 (95% confidence interval (CI), 0.91-0.98) and 0.96 (95% CI, 0.85-0.99) for DGP IgG and 0.93 (95% CI, 0.88-0.97) and 0.98 (95% CI, 0.96-0.99) for TTG IgA, respectively. TTG IgA specificity was significantly higher (OR 9.3 (95% CI, 2.3-37.49); p < 0.001) while the sensitivity of DGP IgG was higher without reaching statistical significance (OR: 0.6 (95% CI, 0.24-1.51); p = 0.28). Both the meta-analysis and the systematic review showed that some children with early CD are missed without the DGP IgG test. In children <2 years of age, TTG IgA is the best CD screening test; however, the addition of DGP IgG may increase the diagnostic sensitivity.

Early biochemical effects of velmanase alfa in a 7-month-old infant with alpha-mannosidosis.

Alpha mannosidosis is an ultrarare pathology with variable phenotypic manifestations, characterized by the deficiency of lysosomal alpha mannosidase which causes accumulation of neutral oligosaccharides. Until recently, the hematopoietic stem cell transplantation was the only clinical feasible therapeutic option. Only in 2018, the European Medicines Agency's committee approved the recombinant enzyme velmanase alfa for long-term treatment of non-neurological manifestations in mild and moderate forms of alpha-mannosidosis. In this study, the very early biochemical effects of enzyme replacement therapy in in a 7-month-old patient with alpha-mannosidosis were described. Velmanase alpha was administered as supporting therapy awaiting for hematopoietic stem cell transplantation, the treatment chosen for the patient because of the early onset form. The results showed that the enzyme replacement therapy was able to reduce the content of three different mannosyl-oligosaccharides monitored by tandem mass spectrometry after 2 months of treatment. In particular, the mean relative changes from baseline values were -67% in urine and -53% in serum at the latest observation. The study also showed that the enzymatic activity detected in serum 1 week after the first infusion was four times higher than the normal values and constant in the following points of observation. These findings led us to assume that velmanase alfa might be biologically active in this young patient.

Celiac disease: a comprehensive current review.

BACKGROUND: Celiac disease remains a challenging condition because of a steady increase in knowledge tackling its pathophysiology, diagnosis, management, and possible therapeutic options. MAIN BODY: A major milestone in the history of celiac disease was the identification of tissue transglutaminase as the autoantigen, thereby confirming the autoimmune nature of this disorder. A genetic background (HLA-DQ2/DQ8 positivity and non-HLA genes) is a mandatory determinant of the development of the disease, which occurs with the contribution of environmental factors (e.g., viral infections and dysbiosis of gut microbiota). Its prevalence in the general population is of approximately 1%, with female predominance. The disease can occur at any age, with a variety of symptoms/manifestations. This multifaceted clinical presentation leads to several phenotypes, i.e., gastrointestinal, extraintestinal, subclinical, potential, seronegative, non-responsive, and refractory. Although small intestinal biopsy remains the diagnostic 'gold standard', highly sensitive and specific serological tests, such as tissue transglutaminase, endomysial and deamidated gliadin peptide antibodies, have become gradually more important in the diagnostic work-up of celiac disease. Currently, the only treatment for celiac disease is a life-long, strict gluten-free diet leading to improvement in quality of life, ameliorating symptoms, and preventing the occurrence of refractory celiac disease, ulcerative jejunoileitis, and small intestinal adenocarcinoma and lymphoma. CONCLUSIONS: The present review is timely and provides a thorough appraisal of various aspects characterizing celiac disease. Remaining challenges include obtaining a better understanding of still-unclear phenotypes such as slow-responsive, potential (minimal lesions) and seronegative celiac disease. The identification of alternative or complementary treatments to the gluten-free diet brings hope for patients unavoidably burdened by diet restrictions.

Celiac Disease Prevalence is Increased in Primary Sjögren's Syndrome and Diffuse Systemic Sclerosis: Lessons from a Large Multi-Center Study.

Association of celiac disease (CD) with systemic autoimmune diseases (ADs) remains controversial. Awareness of CD in these patients is important to prevent complications, including lymphoproliferative disorders. We evaluated previously diagnosed CD prevalence in systemic lupus erythematosus (SLE), primary Sjögren's syndrome (pSS) and systemic sclerosis (SSc) patients in comparison to 14,298 matched controls. All patients were screened for subclinical CD. Data from 1458 unselected consecutive SLE (580), pSS (354) and SSc (524) patients were collected. Previously biopsy-proven CD diagnosis and both CD- and AD-specific features were registered. All patients without previous CD were tested for IgA transglutaminase (TG). Anti-endomysium were tested in positive/borderline IgA TG. Duodenal biopsy was performed in IgA TG/endomysium+ to confirm CD. CD prevalence in AD was compared to that observed in 14,298 unselected sex- and age-matched adults who acted as controls. CD was more prevalent in pSS vs controls (6.78% vs 0.64%, p < 0.0001). A trend towards higher prevalence was observed in SLE (1.38%, p = 0.058) and SSc (1.34%, p = 0.096). Higher CD prevalence was observed in diffuse cutaneous SSc (4.5%, p ≤ 0.002 vs controls). Subclinical CD was found in two SLE patients and one pSS patient. CD diagnosis usually preceded that of AD. Primary SS and SSc-CD patients were younger at AD diagnosis in comparison to non-celiac patients. Autoimmune thyroiditis was associated with pSS and CD. CD prevalence is clearly increased in pSS and diffuse SSc in comparison to the general population. The association of CD with diffuse but not limited SSc may suggest different immunopathogenic mechanisms characterizing the two subsets. CD screening may be considered in pSS and diffuse SSc in young patients, particularly at the time of diagnosis.

Long-Term Outcome of Potential Celiac Disease in Genetically at-Risk Children: The Prospective CELIPREV Cohort Study.

BACKGROUND: The long-term outcome of potential celiac disease (CD) is still a debated issue. We aimed to evaluate the progression of potential CD versus overt CD after 10-years of follow-up in a cohort of children genetically predisposed to CD. METHODS: The CELIPREV study is prospectively following from birth 553 children with CD-predisposing HLA genes. Children with a diagnosis of potential CD continued to receive a normal diet and repeated the serological screening for CD every year. An intestinal biopsy was taken in presence of persistent positive serology. RESULTS: Overall, 26 (4.7%) children received a diagnosis of potential CD (50% females, median age 24 months). All children were symptom-free. Twenty-three children continued a gluten-containing diet; at 10 years from the first biopsy, three children developed overt CD (13%), 19 (83%) became antibodies negative at 1 year from the first biopsy and remained negative up to 10 years of follow-up and one subject (4%) had fluctuating antibody course with transiently negative values and persistently negative biopsy. CONCLUSIONS: In children genetically predisposed to CD with a diagnosis of potential CD the risk of progression to overt CD while on a gluten-containing diet is very low in the long-term.