Introduction

Celiac disease (CD) is a gluten-related autoimmune enteropathy affecting human leukocyte antigen (HLA) DQ2 or DQ8 positive subjects.¹ CD onset can occur at any age and with several clinical phenotypes. Modern serological markers have significantly improved the diagnosis of the disease, which affects about 1% of the population worldwide.^1-3 Hence, CD serology helps to detect CD in patients with non-classical symptoms or even in those who are asymptomatic.

Aims & Methods

This study aims to analyze the clinical presentation, serology, histology, associated diseases, complications, and death rate of a large cohort of CD patients diagnosed and followed up over forty years. This is a retrospective study on 1547 CD patients (1170 females and 377 males; mean age at diagnosis: 33.1±24.4 years; F:M ratio = 3.1:1), consecutively diagnosed from January 1980 to December 2020 at our referral center (Department of Medical and Surgical Sciences, St. Orsola-Malpighi Hospital, Bologna, Italy). CD diagnosis was established following positive serological tests and confirmed by duodenal histology. The evaluated serological markers included: total immunoglobulin A (IgA), anti-transglutaminase(TG)-2 and anti-endomysium (EmA), both of IgA type; in cases with IgA deficiency, the immunoglobulin G (IgG) antibody anti-TG2 or against deamidated gluten peptides were considered.⁴ Comorbidities and complications were recorded at diagnosis and during follow-up.

Results

The rate of CD diagnoses quadrupled after the year 2000. The most prevalent phenotype was the non-classical CD (63.3%), and the most frequent histotype was Marsh 3C (44.7%). Gastrointestinal manifestations, affecting about half of patients (51%), included diarrhea (24.3%), bloating (28%), and aphthous stomatitis (19.7%). Among the CD-associated disorder, osteopenia was the most common (59.9%) and predominantly affecting females (64.3%). Extraintestinal manifestations were anemia (35.8%, with low levels of ferritin and folic acid malabsorption detectable in 87% of patients), cryptogenic hypertransaminasemia (27.9%), and recurrent miscarriages (11.5%). The prevailing CD-related autoimmune disorders were thyroiditis (26.9%), type 1 diabetes mellitus (2.9%), and dermatitis herpetiformis (1.4%). Six patients had inflammatory bowel disease (2 Crohn’s disease and 4 ulcerative colitis). Complications occurred in 1.8% of cases, and the mortality rate was 1.9%.

Conclusion

This forty-year, single-center, large cohort analysis showed that the clinical presentation of CD changed over the years, with an increase of non-classical and subclinical phenotypes. Our study highlighted three main aspects: i) the non-classical and subclinical phenotypes prevailed over the classical forms, according to the recently established criteria; ii) modern serological tests allowed an earlier, faster, and more precise CD diagnosis, even at the subclinical stage, thus contributing to explain the increased diagnostic yield; iii) some CD-associated disorders correlated with gender (e.g., osteopenia which prevailed in women). In conclusion, our data confirmed and broadened current knowledge on CD, and help physicians to recognize new CD presentations, thus avoiding diagnostic delay and inappropriate management.

References

1. Caio, G., Volta, U., Sapone, A., Leffler, D. A., De Giorgio, R., Catassi, C., & Fasano, A. (2019). Celiac disease: a comprehensive current review. BMC medicine, 17(1), 142. https://doi.org/10.1186/s12916-019-1380-z
2. Volta, U., Caio, G., Stanghellini, V., & De Giorgio, R. (2014). The changing clinical profile of celiac disease: a 15-year experience (1998-2012) in an Italian referral center. BMC gastroenterology, 14, 194. https://doi.org/10.1186/s12876-014-0194-x
3. Dieterich, W., Laag, E., Schöpper, H., Volta, U., Ferguson, A., Gillett, H., Riecken, E. O., & Schuppan, D. (1998). Autoantibodies to tissue transglutaminase as predictors of celiac disease. Gastroenterology, 115(6), 1317–1321. https://doi.org/10.1016/s0016-5085(98)70007-1
4. Villalta, D., Tonutti, E., Prause, C., Koletzko, S., Uhlig, H. H., Vermeersch, P., Bossuyt, X., Stern, M., Laass, M. W., Ellis, J. H., Ciclitira, P. J., Richter, T., Daehnrich, C., Schlumberger, W., & Mothes, T. (2010). IgG antibodies against deamidated gliadin peptides for diagnosis of celiac disease in patients with IgA deficiency. Clinical chemistry, 56(3), 464–468. https://doi.org/10.1373/clinchem.2009.128132

Introduction

Celiac disease (CD) is an autoimmune enteropathy induced by the ingestion of gluten in genetically predisposed individuals. Although its clinical expression is most often digestive, extra-digestive manifestations can occur, among which thromboembolic complications, although rare, deserve particular attention.
The aim of this study is to describe the profiles of coeliac patients with thromboembolic complications, analyze their clinical, paraclinical and etiological characteristics, and discuss the underlying pathophysiological mechanisms.

Aims & Methods

This is a retrospective, descriptive, monocentric study conducted in the hepato-gastroenterology department of Ibn Sina Hospital in Rabat over a 30-year period, from 1995 to 2025. The records of 344 patients followed for celiac disease were reviewed. Patients with one or more documented thromboembolic complications during follow-up were included in the study. Clinical, biological, endoscopic and histological data were collected and analyzed.

Results

Of a total of 344 patients followed for celiac disease in the department, 5.5% (n=19) developed a thromboembolic complication during follow-up. The population concerned was predominantly female, with 89.5% women (n=17) versus only 10.5% men (n=2). The mean age at the time of complication was 39.6 years, with a median of 35.5 years, and extremes ranging from 18 to 62 years.
Endoscopic exploration (oesogastro duodenal fibroscopy) in these patients showed lesions suggestive of celiac disease in 68.4% (n=12), while it was non-specific in 31.6% (n=6), and normal in 5.3% (n=1). Histologically, villous atrophy was found in all patients, with 78.9% (n=15) showing total atrophy (Marsh IIIc) and 21.1% (n=4) subtotal atrophy (Marsh IIIb).
As regards thromboembolic manifestations, portal vein thrombosis was the most frequent complication, observed in 57.9% of cases (n=11). It was followed by deep vein thrombosis of the lower limbs, reported in 15.8% of cases (n=3), and ischemic stroke in 10.5% (n=2). Isolated cases of thrombosis of the inferior vena cava, axillary vein and femoral vein were recorded, each accounting for 5.3% of cases (n=1).
The etiological study revealed hyperhomocysteinemia in 36.8% of patients (n=7) and protein C and/or S deficiency in 21.1% (n=4). In the remaining 42.1% of patients (n=8), the thrombophilia work-up was normal, suggesting that celiac disease itself was the cause of the thrombotic event.
Therapeutically, all patients were treated with oral anticoagulation. One patient required a vena cava filter because of the risk of bleeding on anticoagulation, and another underwent surgical treatment for axillary thrombosis. The outcome was favorable in all cases, with no recurrence or major complication during follow-up.

Conclusion

Thromboembolic complications in celiac disease are rare but potentially serious. This study highlights the predominance of women, the diversity of thrombotic localizations, and the possible involvement of hyperhomocysteinemia and C/S protein deficiencies. In almost half the cases, no thrombophilic cause has been identified, suggesting a role for celiac disease in the genesis of these events. Clinical vigilance is essential, particularly in cases of late diagnosis or poor compliance with the gluten-free diet.

Clinical Case Summary

Non celiac gluten wheat sensitivity (NCGWS) is a syndrome whose symptoms are strictly related to gluten ingestion and presents with both intestinal and extraintestinal manifestations. However a liver involvement has never been shown. We report one case of NCGWS presenting with altered bowel habits, a persistent raise of alanine aminotransferase (ALT), aspartate aminotransferase (AST) since childhood and migraines. Gamma GT, alcaline phosphatase, bilirubin, were all within the range of normality over multiple testing. Viral serology (HAV, HBV, HCV), markers for autoimmune hepatitis (ANA, anti-smooth muscle and liver kidney microsome), protein electrophoresis, iron metabolism markers, urinary and blood copper were normal. Abdominal ultrasound reported liver size within the range of normality, regular structure and without focal lesions. No gallstones nor biliary tract dilation. Hepatic elastography was normal. Patient denied alcohol consumption at the time. Coeliac screening was negative (total IgA, IgA tTg-2 and IgA anti-endomysium). She performed a gastroscopy which showed regular macroscopic features of both stomach and duodenum. The histology showed non-specific signs of inflammation (Marsh 0). We found a rise of native IgG anti gliadin (AGA) >100 U/ml and serum zonulin (47,4 ng/ml, ULN <38). Therefore, we proposed a possible diagnosis of NCGWS following Salerno criteria and a gluten free diet (GFD) was recommended to the patient. The adherence to a GFD normalised bowel habits, migraines and the levels of liver enzymes. The pathogenesis of the liver damage in NCGWS is unclear. We hypothesized that the gut barrier dysfunction led to a translocation of toxins and antigens to the liver, therefore creating damage and a mild raise of hepatic transaminase. To date, this case is the first reporting a relation between altered liver enzymes and NCGWS. Further evidence is needed to better establish the link between these two conditions.

References

Hollon J, Puppa EL, Greenwald B, Goldberg E, Guerrerio A, Fasano A. Effect of Gliadin on Permeability of Intestinal Biopsy Explants from Celiac Disease Patients and Patients with Non-Celiac Gluten Sensitivity. Nutrients. 2015 Mar;7(3):1565–76.
Tripathi A, Debelius J, Brenner DA, Karin M, Loomba R, Schnabl B, et al. The gut-liver axis and the intersection with the microbiome. Nat Rev Gastroenterol Hepatol. 2018 Jul;15(7):397–411.
​Garcia-Mazcorro JF, Rivera-Gutierrez X, Cobos-Quevedo ODJ, Grube-Pagola P, Meixueiro-Daza A, Hernandez-Flores K, et al. First Insights into the Gut Microbiota of Mexican Patients with Celiac Disease and Non-Celiac Gluten Sensitivity. Nutrients. 2018 Nov;10(11):1641.

Introduction

Celiac disease (CD) is a chronic autoimmune enteropathy triggered by gluten ingestion in genetically predisposed individuals. While isolated hypertransaminasemia is the most frequent hepatic manifestation of CD, its association with portal hypertension (PHT) remains rare and poorly understood.

Aims & Methods

This study aims to describe this association and evaluate the impact of a gluten-free diet (GFD) on the progression of PHT-related complications.
We conducted a 30-year retrospective study including 20 patients with both histologically and serologically confirmed CD and PHT, among a total cohort of 344 CD patients. Clinical, biological, endoscopic, imaging, and histological data were analyzed.

Results

Among the 20 patients (75% female, F/M ratio 3; mean age 34.2 years), the most frequent symptoms were abdominal pain and weight loss (45% each), followed by ascites (35%), malabsorptive diarrhea (30%), atypical diarrhea (20%), and vomiting (15%). One patient presented with upper gastrointestinal bleeding. Splenomegaly was observed in 70%, and collateral venous circulation in 30%. Liver was clinically normal in 80%, cirrhotic in 20%. Imaging showed a regular liver in 65%, nodular in 35%, with 25% having portal cavernoma and one patient with focal IVC thrombosis.
Liver biopsy findings included porto-sinusoidal vascular disease (40%), celiac cirrhosis (20%), granulomatous hepatitis (15%), and normal histology (25%). Upper endoscopy revealed esophageal varices in 55%. PHT led to the diagnosis of CD in 4 patients. In non-adherent patients, progression of varices and cirrhosis occurred in 20% over 5 years.

Conclusion

The CD–PHT association is rare (5.8% in our series) but clinically significant. Various mechanisms may underlie this link, highlighting the importance of screening for CD in unexplained PHT. GFD adherence appears to slow hepatic deterioration and variceal progression, reinforcing its therapeutic value.

Introduction

Celiac disease (CD) is a chronic autoimmune enteropathy triggered by gluten ingestion in genetically predisposed individuals. Diagnosis is based on clinical, biological, serological, and especially histological criteria, including villous atrophy and intraepithelial lymphocytic infiltration (>30%).

Aims & Methods

The aim of this study is to highlight the importance of clinical presentation, biological markers, and histology in the diagnosis of seronegative CD, particularly since serological testing often guides biopsy decisions.
We conducted a retrospective descriptive study over a 30-year period, from January 1995 to March 2025, including all patients with histologically confirmed CD based on jejunal biopsy and clinical response to a gluten-free diet (GFD), but with negative anti-transglutaminase IgA and/or anti-endomysial antibodies. All seropositive patients were excluded.

Results

Out of 344 patients diagnosed with CD in our department, 74 (21.3%) were seronegative. The mean age was 65 years (range: 20–65), with a female-to-male ratio of 3.1.
From a clinical standpoint, nutritional deficiency syndromes were present in 95.9% (n=71), malabsorptive chronic diarrhea in 77% (n=57), diffuse abdominal pain in 71.6% (n=53), weight loss in 54% (n=40), and chronic evacuation constipation in 6.7% (n=5). Clinical examination showed anemia in 70.3% (n=52) and neurological signs in 25.6% (n=19).
Endoscopic findings were suggestive of CD in 43.2% of cases, including duodenal fold reduction in 37.8% (n=28), and a 'scalloping' appearance in 5.4% (n=4). Duodenal mucosa and folds appeared normal in 44.6% (n=33).
Histological analysis of jejunal biopsies in all patients revealed intraepithelial lymphocytosis >30%. Severe villous atrophy (Marsh stage IIIc) was found in 71.5% (n=53), and partial atrophy (Marsh IIIa) in 10.8% (n=8).

Conclusion

In our study, seronegative CD represented 21.3% of all celiac patients. These patients had more severe clinical presentations and more advanced villous atrophy (Marsh stage III), despite negative serology. This underlines the importance of histology and clinical judgment in diagnosing CD in seronegative individuals.

Introduction

Non-celiac gluten/wheat sensitivity (NCG/WS) is a clinical condition in which gluten/wheat ingestion evokes, while withdrawal ameliorates or reverts gastrointestinal (GI) and extra-GI symptoms. The pathogenetic mechanisms of NCG/WS are poorly understood and no diagnostic biomarker is so far available. NCG/WS diagnosis is established by excluding celiac disease (CD) and wheat allergy (WA), evaluating response to a gluten-free diet (GFD) and the effects of gluten reintroduction. Initial evidence suggests a central role played by the gut microbiota in NCG/WS.

Aims & Methods

This study aimed to identify: i) microbiota species valid as biomarkers for rapid and non-invasive NCG/WS diagnosis; ii) the effects of GFD on microbiota in NCG/WS. Subjects with a clinical suspect of either NCG/WS or CD and healthy volunteers (Ctrl) were enrolled while on a free diet. A thorough work-up (including clinical, endoscopic, allergologic and serological evaluations) was applied to diagnose NCG/WS or CD while excluding WA. Instructions for GFD were provided to all participants. Stool samples for gut microbiome were obtained from NCG/WS and CD before (t0) and after 3, 7, 30 and 200 days of GFD (t1, t2, t3, t4). Stool samples from Ctrl were obtained at t0, t1, t2, and t3. The presence and severity of GI (GI Symptom Rating scale) and extra-GI symptoms of NCG/WS were recorded at each time point (t0-t4). NCG/WS diagnosis was confirmed in participants with a 30% improvement in symptom scores in t3 vs. t0. Metagenome from stools was shotgun-sequenced. Data were processed and microbiome profiled with MetaPhlAn v.4.1 (Jun.23). Alpha-diversity (Shannon index, SI), beta-diversity and relative abundances were computed. Principal coordinates analysis was performed (Bray-Curtis dissimilarity test) and groups were compared (PERMANOVA test). Differences in SI at t0 among cohorts were assessed (Mann-Whitney U-test). Species present at any time point in at least 10 subjects were assessed. Candidate biomarkers were validated in newly diagnosed NCG/WS and CD cohorts. Species varying relative abundance during the GFD were identified (linear mixed model and Friedman's ANOVA). P-values were combined with the harmonic mean and corrected for multiple testing (Benjamini-Hochberg method, q-value).

Results

Twenty-eight NCG/WS (F, 37±16 yrs), 11 CD (9 F, 32±15 yrs) and 37 Ctrl (25 F, 33±14 yrs) were enrolled. Alpha-diversity at t0 was comparable (p>0.19) in NCG/WS (SI=4.0), CD (SI=3.7) and Ctrl (SI=4.1), whereas beta-diversity was different among groups (p=0.026). A total of 507 species were identified. The candidate biomarker Clostridiaceae bacterium (SGB47672) showed lower abundance in NCG/WS vs. Ctrl (q<0.2), data confirmed in validation cohorts (172 NCG/WS, 243 CD). Alpha-diversity was preserved (p>0.05) in NCG/WS and CD up to t4 and in Ctrl (t3) in GFD, whereas concerning changes in relative abundance (q<0.2; p<0.05) we identified a reduction of Bifidobacterium longum (SGB17248).

Conclusion

We showed that NCG/WS exhibits a peculiar metagenomic signature with C. bacterium (SGB47672) being a potential biomarker for NCG/WS diagnosis. Our study suggests that the use of probiotic supplements can help to restore B. longum (SGB17248) deficiency during GFD. Beyond integrating GFD treatment, probiotics containing Bifidobacteria can positively contribute by exerting anti-inflammatory and protective effects on the intestinal epithelial barrier in NCG/WS.

References

Volta U, De Giorgio R, Caio G, Uhde M, Manfredini R, Alaedini A. Nonceliac Wheat Sensitivity: An Immune-Mediated Condition with Systemic Manifestations. Gastroenterol Clin North Am. 2019 Mar;48(1):165-182
Beghini F, McIver LJ, Blanco-Míguez A, Dubois L, Asnicar F, Maharjan S, Mailyan A, Manghi P, Scholz M, Thomas AM, Valles-Colomer M, Weingart G, Zhang Y, Zolfo M, Huttenhower C, Franzosa EA, Segata N. Integrating taxonomic, functional, and strain-level profiling of diverse microbial communities with bioBakery 3. Elife. 2021 May 4;10:e65088.
Yao S, Zhao Z, Wang W, Liu X. Bifidobacterium Longum: Protection against Inflammatory Bowel Disease. J Immunol Res. 2021 Jul 23;2021:8030297.