A Comprehensive Review of Exosomes with Therapeutic Potential in Cancer and Coeliac Disease

The aim of this review was to evaluate the therapeutic potential of exosomes, extracellular vesicles secreted by cells. They have emerged as potential therapeutic transporters for several diseases. This review provides an overview of exosomes’ therapeutic potential in cancer therapy and autoimmune conditions such as Coeliac Disease. The therapeutic effect is that the phospholipid-binding protein ANXA1 improves its anti-inflammatory properties. The review also analyzes the intricate processes of exosome production and composition ability to transport biomolecules such as proteins, microRNAs, and lipids, which promote intercellular communication and alter recipient cell behavior. Exosomes, linked to neurological disorders, cardiovascular disease, and cancer, present the means of targeted drug administration due to their innate specificity. Through genetic engineering and chemical modifications, exosomes can be tailored for specific purposes, demonstrating their versatility in targeted therapy. With ongoing research uncovering their therapeutic potential, exosomes present a promising frontier in novel medical treatments across various health conditions.

Abdominal computed tomography in refractory coeliac disease and enteropathy associated T-cell lymphoma

AIM： To evaluate computed tomography （CT） findings, useful to suggest the presence of refractory celiac disease （RCD） and enteropathy associated T cell lymphoma （EATL）. METHODS： Coeliac disease （CD） patients were divided into two groups. Group Ⅰ ： uncomplicated CD （n = 14） and RCD type Ⅰ （n = 10）. Group Ⅱ ： RCD type Ⅱ （n = 15） and EATL （n = 7）. RESULTS： Both groups showed classic signs of CD on CT. Intussusception was seen in 1 patient in group Ⅰ vs 5 in group Ⅱ （P = 0.06）. Lymphadenopathy was seen in 5 patients in group Ⅱ vs no patients in group Ⅰ （P = 0.01）. Increased number of small mesenteric vessels was noted in 20 patients in group Ⅰ vs Ⅱ in group 11 （P = 0.02）. Eleven patients （50%） in group 11 had a splenic volume 〈 122 cm^3 vs 4 in group Ⅰ （14%）, 10 patients in group Ⅰ had a splenic volume 〉 196 cm^3 （66.7%） vs 5 in group Ⅱ （33.3%） P = 0.028. CONCLUSION： CT scan is a useful tool in discriminating between CD and （Pre） EATL. RCD Ⅱ and EATL showed more bowel wall thickening, lymphadenopathy and intussusception, less increase in number of small mesenteric vessels and a smaller splenic volume compared with CD and RCD Ⅰ.

Coeliac disease in Dutch patients with Hashimoto’s thyroiditis and vice versa

AIM: To define the association between Hashimoto’s thyroiditis and coeliac disease in Dutch patients. METHODS: A total of 104 consecutive patients with Hashimoto’s thyroiditis underwent coeliac serological tests (antigliadins, transglutaminase and endomysium antibodies) and HLA-DQ typing. Small intestinal biopsy was performed when any of coeliac serological tests was positive. On the other hand, 184 patients with coeliac disease were subjected to thyroid biochemical (thyroid stimulating hormone and free thyroxine) and thyroid serological tests (thyroglobulin and thyroid peroxidase antibodies). RESULTS: Of 104 patients with Hashimoto’s thyroiditis, sixteen (15%) were positive for coeliac serology and five patients with documented villous atrophy were diagnosed with coeliac disease (4.8%; 95% CI 0.7-8.9). HLA-DQ2 (and/or -DQ8) was present in all the five and 53 patients with Hashimoto’s thyroiditis (50%; 95% CI 43-62). Of 184 patients with coeliac disease, 39 (21%) were positive for thyroid serology. Based on thyroid biochemistry, the 39 patients were subclassified into euthyroidism in ten (5%; 95% CI 2-9), subclinicalhypothyroidism in seven (3.8%; 95% CI 1.8-7.6), and overt hypothyroidism (Hashimoto’s thyroiditis) in 22 (12%; 95% CI 8-16). Moreover, four patients with coeliac disease had Graves’ disease (2%; 95% CI 0.8-5) and one patient had post-partum thyroiditis. CONCLUSION: The data from a Dutch population confirm the association between Hashimoto’s thyroiditis and coeliac disease. Screening patients with Hashimoto’s thyroiditis for coeliac disease and vice versa is recom- mended.

Fecal calprotectin in coeliac disease

We would like to share with the readers the results of our experience in 50 celiac disease (CD) patients, enrolled between September 2012 and April 2013, who were referred to our third-level CD Unit. The fecal calprotectin (FC) concentration of 50 adults with newly diagnosed CD was compared to that of a control group of 50 healthy subjects. FC level was determined by enzyme linked immunosorbent assay with diagnostic cut-off of 75 μg/g. In addition, we tried to correlate the FC level with symptoms, histological severity of CD (Marsh grade) and level of tissue transglutaminase antibodies (aTg) in CD patients. Finally, FC level was increased in five CD patients and in four controls (10% vs 8%, P = NS); mean FC concentration of patients and controls were 57.7 (SD ± 29.1) and 45.1 (SD ± 38.4) respectively. Furthermore, no significant correlation was seen between FC levels and symptoms/Marsh grade/aTg. The five CD patients did not show inflammatory lesions (e.g., ulcers, erosions) at upper endoscopy. The four healthy controls with positive FC were followed-up for further six months; in this observational period they did not show clinical signs of any underlying disease. On these bases, we think that FC is not able to investigate the subclinical inflammatory changes of active CD and FC should be considered a useless tool in the diagnostic work-up of uncomplicated CD but it should be accompanied by aTg when ruling out organic disease in patients with irritable bowel syndrome.

Malignancy and mortality in a population-based cohort of patients with coeliac disease or ‘gluten sensitivity’

AIM: To determine the risk of malignancy and mortality in patients with a positive endomysial or anti-gliadin an- tibody test in Northern Ireland. METHODS: A population-based retrospective cohort study design was used. Laboratory test results used in the diagnosis of coeliac disease were obtained from the Regional Immunology Laboratory, cancer statistics from the Northern Ireland Cancer Registry and mortal- ity statistics from the General Registrar Office, Northern Ireland. Age standardized incidence ratios of malignant neoplasms and standardized mortality ratios of all-cause and cause-specific mortality were calculated. RESULTS: A total of 13 338 people had an endomysial antibody and/or an anti-gliadin antibody test in Northern Ireland between 1993 and 1996. There were 490 pa- tients who tested positive for endomysial antibodies and they were assumed to have coeliac disease. There were 1133 patients who tested positive for anti-gliadin anti- bodies and they were defined as gluten sensitive. Ma- lignant neoplasms were not significantly associated with coeliac disease; however, all-cause mortality was signifi- cantly increased following diagnosis. The standardized incidence and mortality ratios for non-Hodgkin’s lym- phoma were increased in coeliac disease patients but did not reach statistical significance. Lung and breast cancer incidence were significantly lower and all-cause mortal-ity, mortality from malignant neoplasms, non-Hodgkin’s lymphoma and digestive system disorders were signifi- cantly higher in gluten sensitive patients compared to the Northern Ireland population. CONCLUSION: Patients with coeliac disease or gluten sensitivity had higher mortality rates than the Northern Ireland population. This association persists more than one year after diagnosis in patients testing positive for anti-gliadin antibodies. Breast cancer is significantly re- duced in the cohort of patients with gluten sensitivity.

Prevalence of coeliac disease in patients with autoimmune thyroiditis in a Turkish population

AIM:To investigate the prevalence of coeliac disease in a series of Turkish patients with autoimmune thyroiditis.METHODS:Sera from 136 consecutive patients with newly diagnosed autoimmune thyroiditis and 119 healthy blood donors were tested for IgA tissue transglutaminase antibody with enzyme-linked immunosorbent assay.Endoscopic mucosal biopsy from the second part of duodenum was performed in patients with positive antibody test.RESULTS:Eight patients(5.9%)and one control subject(0.8%)were positive for IgA tissue transglutaminase antibody(OR:7.38,95% CI:0.91-59.85,P = 0.04).Six patients and one control agreed to take biopsies.Histopathological examination revealed changes classified as Marsh Ⅲa in one,Marsh Ⅱ in one,Marsh Ⅰ in two,and Marsh 0 in two patients with autoimmune throiditis,and MarshⅠin one blood donor.CONCLUSION:Turkish patients with autoimmune thyroiditis have an increased risk of coeliac disease and serological screening may be useful for early detection of coeliac disease in these patients.Our findings need to be confirmed in a larger series of patients.

An algorithm for family screening for coeliac disease

AIM: To assess the level of undiagnosed coeliac disease (CD) in relatives of patients affected by the condition. METHODS: We collected blood from 914 relatives of probands. We screened these individuals by ELISA for IgA and IgG tTG antibodies, confirming any positive IgA tTG results with an IgA EMA and looked for evidence of IgA deficiency in those who were IgG tTG positive alone, and performed IgG1 EMA in these individuals. We undertook HLA typing where positive screening was found, and this confirmed a strong prevalence of HLA- DQ2 in the coeliac population. Follow-up small intestinal biopsy was undertaken in cases with positive serological screening, wherever possible. RESULTS:Use of this serological screening algorithm revealed a prevalence of undiagnosed CD in 5%-6% of first degree relatives of probands. CONCLUSION:Our data suggests that first degree relatives of individuals with CD should be screened for this condition.

Diagnosing coeliac disease:Out with the old and in with the new?

Coeliac disease(CD)is a complex condition resulting from an interplay between genetic and environmental factors.When diagnosing the condition,serological testing and genotyping are useful in excluding CD,although the gold standard of testing is currently histopathological examination of the small intestine.There are drawbacks associated with this form of testing however and because of this,novel forms of testing are currently under investigation.Before we develop completely novel tests though,it is important to ask whether or not we can simply use the data we gather from coeliac patients more effectively and build a more accurate snapshot of CD through statistical analysis of combined metrics.It is clear that not one single test can accurately diagnose CD and it is also clear that CD patients can no longer be defined by discrete classifications,the continuum of patient presentation needs to be recognised and correctly captured to improve diagnostic accuracy.This review will discuss the current diagnostics for CD and then outline novel diagnostics under investigation for the condition.Finally,improvements to current protocols will be discussed with the need for a holistic“snapshot”of CD using a number of metrics simultaneously.

Feasibility of a finger prick-based self-testing kit in first- and second-degree relatives of children with coeliac disease

AIM:To assess feasibility of a finger prick-based kit as method for self-testing of first and second-degree relatives of coeliac disease (CD) patients. METHODS:A total number of 379 subjects were invited to participate in this study,consisting of 197 first- degree and 182 second-degree relatives of CD patients. The self-testing kit (BiocardTM) was sent out with included instructions for use. Completed tests were sent back to the study coordinator for assessment. RESULTS:One hundred and ninety-six invited relatives carried out the BiocardTM test at home. Amongst these,70% were children. In 97% of the cases the test was performed correctly. Three tests revealed a positive result,all of which were later confirmed by serology and histology as coeliac disease.CONCLUSION:Our study indicates that BiocardTM test is a reliable,easy to use and well-accepted tool for home testing of first- and second-degree relatives of CD patients.

Clinical utility of quantitative multi-antibody Polycheck immunoassays in the diagnosis of coeliac disease

AIM:To evaluate the clinical utility of multi-antibody strategies in the diagnosis of coeliac disease(CD),the new quantitative Polycheck immunoassays were analysed.METHODS:Polycheck Celiac Panels(PCPs)are immunoenzyme screening assays for the quantitative measurement of coeliac-specific immunoglobulin class G(Ig G)or class A(Ig A)in serum.Lines of relevant antigens are coated together with five Ig G or Ig A standard lines used for the standard curve as positive control.PCP IgA consists of human recombinant human tissue transglutaminase(t TG)and deamidated gliadin peptides(DGP)as targets to detect Ig A antibodies.PCP IgG consists of t TG,DGP and IF(intrinsic factor)antigens to detect antibodies in Ig G class.PCPs were performed on 50 CD patients,including 6 cases with selective Ig A deficiency,and 50 non-coeliac controls.CD diagnosis was performed according to the ESPGHAN recommendations:The presence of specific anti-t TG-Ig A or anti-DGP-Ig G(in the case of Ig A deficiency)antibodies,typical histopathological changes in duodenal mucosa described in Marsh-Oberhüber classification as at least grade 2.The diagnosis of the majority of the control subjects was functional gastrointestinal disorders.The PCP results were compared with reference EliA Celikey.RESULTS:The usage of PCPs led to the correct identification of all CD patients.In our study,PCPs showed 100%agreement with the histopathological results.PCP IgA test showed a 98%concordance and correlated positively(R=0.651,P=0.0014)with Eli A Celikey test.The highest specificity and positive predictive value(both 100%)were observed for the detection of Polycheck anti-t TG-Ig A antibodies.The highest sensitivity and negative predictive value(both 100%)were achieved by Polycheck anti-DGPIg G antibody detection.The best performance(98%sensitivity and negative predictive value,100%specificity and positive predictive value,diagnostic accuracy-AU ROC 99%)was observed for the strategy of using both PCP IgA and IgG and determining positive outcomes of the test with two or more coeliac-specific antibodies detected.The majority of coeliac patients had multiple antibodies.All four antibodies were detected in 7(14%)cases,19 children(38%)were positive for three antibodies and 23(46%)were positive for two antibodies.CONCLUSION:The present study showed that detection of coeliac-specific antibodies with multi-antibody PCPs is effective and efficacious in the diagnosis of CD.

High prevalence of post-partum depression in women with coeliac disease

AIM： To explore the prevalence of post-partumdepression （PPD） in coeliac disease （CD）. METHODS： we performed a case-control study evaluating the prevalence of PPD in CD patients on gluten-free diet （GFD） compared to that of healthy subjects experiencing a recent delivery. All participants were interviewed about menstrual features, modality and outcome of delivery and were evaluated for PPD by Edinburgh Postnatal Depression Scale （EPDS）. RESULTS： The study included 70 CD patients on GFD （group A） and 70 controls （group B）. PPD was present in 47.1% of CD women and in 14.3% of controls （P 〈 0.01; OR = 3.3）. Mean EPDS score was higher in CD compared to the controls （mean score： group A 9.9 ± 5.9; group B 6.7 ± 3.7; P 〈 0.01）. A signifcant association was observed between PPD and menstrual disorders in CD （69.7% vs 18.9%; P 〈 0.001; OR = 3.6）.CONCLUSION： PPD is frequent in CD women on GFD, particularly in those with previous menstrual disorders. we suggest screening for PPD in CD for early detection and treatment of this condition.

Coeliac disease in the modern era： Severity of small bowel mucosal injury at diagnosis with analysis of clinical correlates and rate of improvement on a gluten free diet

AIM To analyze the relationships between pre-diagnosis coeliac serology, duodenal histopathology, primary presenting symptoms, coeliac-related comorbidity and response to treatment in a modern cohort with new diagnosis of coeliac disease(CD).METHODS A retrospective cohort study including 99 participants diagnosed with CD between 1999 and 2013. All patients had the following data recorded: baseline characteristics, coeliac serology, small bowel histopathology. A subset of this cohort underwent a repeat small bowel biopsy. Independent associations were assessed with logistic regression.RESULTS The mean age at diagnosis was 43 years(Interquartile range 30-53 years) and 68% of the cohort was female. At diagnosis 49(49%) patients had total villous blunting(MS 3c), 12(12%) had subtotal villous blunting(MS 3b), and 29(29%) had partial villous blunting(MS 3a). The prevalence of symptoms pre diagnosis was not related to the severity of villous blunting(P = 0.490). 87(88%) of the cohort underwent repeat small bowel biopsy after a median of 7 mo(IQR 6-11 mo). 34(39%) patients had biopsy results ≥ MS 3 a which compared to 90(90%) at the initial biopsy. 24(71%) of this group reported adherence to a gluten free diet(GFD). Persistent MS ≥ 3 a at repeat biopsy was not associated with symptoms(P=0.358) or persistent positive coeliac serology(P = 0.485).CONCLUSION Neither symptoms nor serology predict the severity of the small bowel mucosal lesion at CD diagnosis. Whilst a GFD was associated with histological improvement many patients with newly diagnosed CD had persistent mucosal damage despite many months of gluten restriction. Negative CD serology did not exclude ongoing mucosal injury.

Fecal calprotectin in pediatric gastrointestinal diseases:Pros and cons

BACKGROUND Fecal calprotectin is a valuable biomarker for assessing intestinal inflammation in pediatric gastrointestinal diseases.However,its role,pros,and cons in various conditions must be comprehensively elucidated.AIM To explore the role of fecal calprotectin in pediatric gastrointestinal diseases,including its advantages and limitations.METHODS A comprehensive search was conducted on PubMed,PubMed Central,Google Scholar,and other scientific research engines until February 24,2024.The review included 88 research articles,56 review articles,six metaanalyses,two systematic reviews,two consensus papers,and two letters to the editors.RESULTS Fecal calprotectin is a non-invasive marker for detecting intestinal inflammation and monitoring disease activity in pediatric conditions such as functional gastrointestinal disorders,inflammatory bowel disease,coeliac disease,coronavirus disease 2019-induced gastrointestinal disorders,gastroenteritis,and cystic fibrosis-associated intestinal pathology.However,its lack of specificity and susceptibility to various confounding factors pose challenges in interpretation.Despite these limitations,fecal calprotectin offers significant advantages in diagnosing,monitoring,and managing pediatric gastrointestinal diseases.CONCLUSION Fecal calprotectin holds promise as a valuable tool in pediatric gastroenterology,offering insights into disease activity,treatment response,and prognosis.Standardized protocols and guidelines are needed to optimize its clinical utility and mitigate interpretation challenges.Further research is warranted to address the identified limitations and enhance our understanding of fecal calprotectin in pediatric gastrointestinal diseases.

Coeliac disease as a potential cause of idiopathic portal hypertension:a case report

Idiopathic portal hypertension is a disorder that has various clinical features.It is mostly characterized by bleeding oesophageal varices,obvious splenomegaly,anaemia and,occasionally,jaundice and ascites.Here we described an interesting case of idiopathic portal hypertension caused by coeliac disease in a 38-year-old woman.By putting this patient on a gluten-free diet,liver function tests became normal and portal vein diameter returned to normal range.This report indicates that,in coeliac disease,repetitive stimulation by antigens along the portal vein—and immune responses to them—can result in the development of idiopathic portal hypertension.

Budd-Chiari syndrome associated with coeliac disease:case report and literature review

We report a case of Budd-Chiari syndrome occurring in a patient with coeliac disease,who presented with symptoms of increased abdominal girth,right upper quadrant pain and shortness of breath for three weeks prior to admission.Initial assessment revealed the presence of moderate ascites,hepatosplenomegaly and right-sided pleural effusion.Further diagnostic work-up established a diagnosis of chronic Budd-Chiari syndrome.Interestingly,complete screening for pro-thrombotic factors was negative.A review of the literature on this association disclosed only 28 similar cases,with the majority of them describing individuals of North African origin.Interestingly,in the majority of cases no specific thrombotic factor could be identified,suggesting that coeliac disease may play a role in this thrombotic disorder.

Update on Anti-Saccharomyces cerevisiae antibodies, anti-nuclear associated anti-neutrophil antibodies and antibodies to exocrine pancreas detected by indirect immunofluorescence as biomarkers in chronic inflammatory bowel diseases: Results of a multicent

AIM： Anti-Saccharomyces anti-nuclear associated cerevisiae antibodies （ASCA）, anti-neutrophil antibodies （NANA） and antibodies to exocrine pancreas （PAB）, are serological tools for discriminating Crohn＇s disease （CrD） and ulcerative colitis （UC）. Like CrD, coeliac disease （COD） is an inflammatory bowel disease （IBD） associated with （auto） antibodies. Performing a multicenter study we primarily aimed to determine the performance of ASCA, NANA and PAB tests for IBD diagnosis in children and adults, and secondarily to evaluate the prevalence of these markers in CoD. METHODS： Sera of 109 patients with CrD, 78 with UC, 45 with CoD and 50 healthy blood donors were retrospectively included. ASCA, NANA and PAB were detected by indirect immunofluorescence （IIF）. RESULTS： ASCA＋/NANA- profile displayed a positive predictive value of 94.2% for CrD. Detection of ASCA was correlated with a more severe clinical profile of CrD and treatment of the disease did not influence their serum levels. ASCA positivity was found in 37.9% of active CoD.PAB were found in 36.7% CrD and 13.3% CoD patients and were not correlated with clinical features of CrD, except with an early onset of the disease. Fifteen CrD patients were ASCA negative and PAB positive. CONCLUSION： ASCA and PAB detected by IIF are specific markers for CrD although their presence does not rule out a possible active CoD. The combination of ASCA, NANA and PAB tests improves the sensitivity of immunological markers for CrD. Repeating ASCA, NANA, and PAB testing during the course of CrD has no clinical value.

Variability of anti-human transglutaminase testing in celiac disease across Mediterranean countries

To verify the precision and accuracy of transglutaminase antibodies (TGA) assays across Mediterranean countries. METHODSThis study involved 8 referral centres for celiac disease (CD) in 7 Mediterranean countries. A central laboratory prepared 8 kits of 7 blinded and randomized serum samples, with a titrated amount of Human TGA IgA. Each sample was analysed three times on three different days, with each centre running a total of 21 tests. The results were included in a blindly coded report form, which was sent to the coordinator centre. The coordinator estimated the mean coefficient of Variation (CoVar = σ/μ), the mean accuracy (Accur = Vobserved - Vreal) and the mean percent variation (Var% = [(Vobserved - Vreal)/Vreal] × 100). RESULTSThe analysis showed that 79.17% of the mean variation fell between -25% and +25% of the expected value, with the accuracy and precision progressively increasing with higher titres of TGA. From values 1.25 times greater than the normal cut-off, the measurements were highly reliable. CONCLUSIONTGA estimation is a crucial step for the diagnosis of CD; given its accuracy and precision, clinicians could be confident in establishing a diagnosis.

Histological abnormalities of the small bowel mucosa in cirrhosis and portal hypertension

AIM: To study the small bowel (SB) mucosa on biopsy in cirrhotic patients with portal hypertension and in non-cirrhotic controls and grade fi ndings according to the Marsh criteria. METHODS: We prospectively enrolled 51 consecutive patients undergoing an upper endoscopy for their routine medical care. Twenty f ive patients with cirrhosis and portal hypertension were compared to 26 controls. We obtained coeliac serology and multiple upper small bowel biopsies on all 51 patients. A GI pathologist interpreted biopsies and graded fi ndings according to the Marsh criteria. We assessed equivalence in Marsh grade between cirrhotic and non-cirrhotic controls using the Mann-Whitney test for equivalence. RESULTS: Gender, ethnicity and age were similar between both groups. Marsh grades were equivalent between the groups. Grade of 0 was present in 96% and grade of 1 was present in 4% of both groups and there was no villus atrophy or decrease in villus/crypt ratio in patients with portal hypertension. CONCLUSION: This study provides evidence for the lack of villus atrophy in patients with cirrhosis and portal hypertension, and supports the continuous reliance on the Marsh criteria when the diagnosis of coeliac disease is to be made in the presence of cirrhosis.

Involvement of heat shock proteins in gluten-sensitive enteropathy

Gluten-sensitive enteropathy,also known as coeliac disease(CD),is an autoimmune disorder occurring in genetically susceptible individuals that damages the small intestine and interferes with the absorption of other nutrients.As it is triggered by dietary gluten and related prolamins present in wheat,rye and barley,the accepted treatment for CD is a strict gluten-free diet.However,a complete exclusion of gluten-containing cereals from the diet is often difficult,and new therapeutic strategies are urgently needed.A class of proteins that have already emerged as drug targets for other autoimmune diseases are the heat shock proteins(HSPs),which are highly conserved stress-induced chaperones that protect cells against harmful extracellular factors.HSPs are expressed in several tissues,including the gastrointestinal tract,and their levels are significantly increased under stress circumstances.HSPs exert immunomodulatory effects,and also play a crucial role in the maintenance of epithelial cell structure and function,as they are responsible for adequate protein folding,influence the degradation of proteins and cell repair processes after damage,and modulate cell signalling,cell proliferation and apoptosis.The present review discusses the involvement of HSPs in the pathophysiology of CD.Furthermore,HSPs may represent a useful therapeutic target for the treatment of CD due to the cytoprotective,immunomodulatory,and anti-apoptotic effects in the intestinal mucosal barrier.