BackgroundCeliac disease (CeD) is a systemic immune-mediated disorder triggered by gluten ingestion in genetically predisposed individuals. Further to the gastrointestinal involvement, growing evidence highlights a wide spectrum of neurological and psychiatric manifestations, with still partly understood pathophysiology and clinical relevance.AimsThis narrative review provides an updated appraisal of neuropsychiatric conditions associated with CeD, discussing their underlying mechanisms, clinical implications, and therapeutic perspectives, with particular attention to differences between paediatric and adult populations.MethodsA comprehensive literature review was conducted focusing on neurological and psychiatric complications of CD, proposed pathogenetic pathways, and outcomes following a gluten-free diet (GFD).ResultsNeurological features include cerebellar ataxia, peripheral neuropathy, epilepsy, headache, cognitive dysfunction, and sleep disorders; psychiatric manifestations encompass depression, anxiety, attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders, and schizophrenia. Possible underlying mechanisms involve autoimmune responses (anti-transglutaminase 6 antibodies), blood-brain barrier dysfunction, gut dysbiosis, neuroinflammation, micronutrient deficiencies, serotonergic dysregulation, and cerebral perfusion abnormalities. Clinical outcomes vary as some patients improve on a GFD, while others experience persistent symptoms despite strict dietary adherence. Paediatric patients usually exhibit lower prevalence and milder neurological involvement, likely due to early diagnosis and better compliance.ConclusionsNeuropsychiatric manifestations are clinically significant yet frequently underrecognized components of CeD. In some patients, they are directly evoked by gluten exposure; in others, gluten acts as a trigger of self-perpetuating neuroimmune or neuroinflammatory cascades. Early identification, multidisciplinary management, and strict dietary monitoring are essential to prevent irreversible neurological damage and optimize long-term outcomes.

BACKGROUND:Primary intestinal B-cell (IBCL) and T-cell (ITCL) lymphomas are rare and poorly characterized entities. AIM:To compare clinical features and survival outcomes of IBCL and ITCL. METHODS:We conducted a multicentre, retrospective study including patients diagnosed with primary intestinal lymphoma between 2001 and 2024. Clinical and laboratory variables were analysed using univariate and multivariate logistic regression. Discriminatory accuracy was assessed through ROC analysis. Overall survival was estimated with Kaplan-Meier curves. RESULTS:Ninety-four patients (41 IBCL and 53 ITCL) were included. IBCL were more frequently diagnosed at Lugano stage I (90% vs 5.7%; p<0.01) and showed markedly lower lactate dehydrogenase and β2-microglobulin levels compared with ITCL (p<0.01). Coeliac disease (CD) was strongly associated with ITCL (p<0.01). In multivariable analysis, CD and biomarker levels independently differentiated IBCL from ITCL, with excellent model discrimination (AUROC 0.95). Median follow-up was 56 months for IBCL and 12 months for ITCL. IBCL demonstrated significantly greater survival (HR 0.21; log-rank p=0.01). CONCLUSIONS:IBCL and ITCL exhibit distinct clinical and prognostic profiles, with IBCL showing more favourable clinical profile and better survival. Tailored diagnostic and therapeutic approaches that reflect the divergent behaviour of these lymphomas are urgently needed.

INTRODUCTION:Small bowel adenocarcinoma (SBA) and T-cell lymphoma (TCL) are rare but aggressive malignancies associated with celiac disease (CD). METHODS:We retrospectively compared 43 CD-associated SBA and 43 CD-associated TCL across international referral centers. RESULTS:CD-associated SBA showed a significantly ( P < 0.01) better survival than CD-associated TCL. TCL more frequently presented with multifocal involvement and advanced stage, whereas SBA predominantly involved the jejunum. Refractoriness to a gluten-free diet was identified in 70% of TCL but only in one SBA. DISCUSSION:Our findings demonstrated a worse prognosis of CD-associated TCL in comparison with CD-associated SBA.

Background: Non-celiac gluten/wheat sensitivity (NCGWS) is a syndrome for which pathogenesis and management remain debated. It is described as a condition characterized by gastrointestinal and extra-intestinal symptoms rapidly occurring after gluten ingestion in subjects who have had celiac disease or wheat allergy excluded. To date, the diagnosis of NCGWS is challenging as no universally recognized biomarkers have been yet identified, nor has a predisposing genetic profile been described. However, the research is moving fast, and new data regarding pathogenic pathways, patients’ classification, potential candidate biomarkers, and dietary interventions are emerging. Methods: This literature review aims to address the state of the art and summarize the latest updates in this field from 2019 to date. Results and Conclusions: Clinical studies regarding NCGWS in the last five years are reported to shed light on this complex condition and to guide specialists towards a more in-depth, prompt, and objective diagnosis.

INTRODUCTION:Long-term prognosis of nonceliac enteropathies (NCEs) is poorly understood. We aimed to evaluate long-term outcomes and develop a prognostic score for NCEs. METHODS:NCEs patients from an international multicenter cohort (4 Italian centers, 1 United Kingdom, 1 French, 1 Norwegian, 1 United States, 1 Indian) followed-up over 30 years were enrolled. Complications and mortality were analyzed with Kaplan-Meier curves, standardized mortality ratios (SMR), and multivariate Cox regression. A clinical score to identify patients at risk of poor outcomes was developed. RESULTS:Two hundred sixty-one patients were enrolled (144 female, mean age at diagnosis 49 ± 18 years, median follow-up 70 months, interquartile range 24-109). The most common etiologies were idiopathic villous atrophy (39%), drug related (17%), common variable immune deficiency (15%), infectious (10%), and autoimmune enteropathy (9%). Five-year and 10-year complication-free survival were 89% and 77%, respectively, whereas 5-year and 10-year overall survival were 88% and 74%, respectively. Causes of death included sepsis/major infections (22%), lymphoproliferative disorders (22%), solid-organ malignancies (12%), cardiovascular/metabolic disease (10%), and was unknown in 33%. Mortality was increased in NCEs compared with the general population (SMR 3.17, 95% confidence interval [CI] 2.24-4.34). Older age at diagnosis ( P < 0.001), anemia (hazard ratio [HR] 2.53, 95% CI 1.33-4.80, P < 0.01), and lack of clinical (HR 3.21, 95% CI 1.68-6.18, P < 0.01) and histological response (HR 2.14, 95% CI 1.08-4.23, P = 0.04) were independent predictors of mortality at Cox regression. A 5-point score was developed to identify high-risk patients: very low risk (0 pts), low risk (1-2 pts), intermediate risk (3 pts), and high risk (4-5 pts), with 10-year survival rates of 100%, 87%, 62%, and 16%, respectively. DISCUSSION:Mortality in NCEs is increased because of complications and lack of response to current therapies. We developed a clinical score to personalize follow-up. Targeted treatments are needed to improve outcomes.

This chapter deals with the usefulness of serology in the diagnosis and follow-up of celiac disease. It starts by exploring the literature data on the sensitivity and specificity of antitissue transglutaminase, antiendomysial, and antideamidated gliadin peptide antibodies in untreated celiac disease. It then displays the antibody protocols used in the various clinical settings (general population, malabsorption, IgA deficiency). Furthermore, the different diagnostic strategy adopted in children and adults are discussed. The best approach for identifying the “celiac iceberg” is considered by comparing the results obtained by mass screening and case finding. The main at-risk groups for celiac disease are reported. By the end of the chapter the strengths and weaknesses of serological tests in assessing the adherence and response to gluten free diet in celiac patients are analyzed.

Background Ultra-short coeliac disease (USCD) is defined as villous atrophy only present in the duodenal bulb (D1) with concurrent positive coeliac serology. We present the first, multicentre, international study of patients with USCD. Methods Patients with USCD were identified from 10 tertiary hospitals (6 from Europe, 2 from Asia, 1 from North America and 1 from Australasia) and compared with age-matched and sex-matched patients with conventional coeliac disease. Findings Patients with USCD (n=137, median age 27 years, IQR 21–43 years; 73% female) were younger than those with conventional coeliac disease (27 vs 38 years, respectively, p<0.001). Immunoglobulin A-tissue transglutaminase (IgA-tTG) titres at index gastroscopy were lower in patients with USCD versus conventional coeliac disease (1.8×upper limit of normal (ULN) (IQR 1.1–5.9) vs 12.6×ULN (IQR 3.3–18.3), p<0.001). Patients with USCD had the same number of symptoms overall (median 3 (IQR 2–4) vs 3 (IQR 1–4), p=0.875). Patients with USCD experienced less iron deficiency (41.8% vs 22.4%, p=0.006). Both USCD and conventional coeliac disease had the same intraepithelial lymphocytes immunophenotype staining pattern; positive for CD3 and CD8, but not CD4. At follow-up having commenced a gluten-free diet (GFD) (median of 1181 days IQR: 440–2160 days) both USCD and the age-matched and sex-matched controls experienced a similar reduction in IgA-tTG titres (0.5 ULN (IQR 0.2–1.4) vs 0.7 ULN (IQR 0.2–2.6), p=0.312). 95.7% of patients with USCD reported a clinical improvement in their symptoms. Interpretation Patients with USCD are younger, have a similar symptomatic burden and benefit from a GFD. This study endorses the recommendation of D1 sampling as part of the endoscopic coeliac disease diagnostic workup.

Since the rise of awareness of gluten/wheat-related disorders in the academic and clinical field in the last few decades, misinformation regarding the gluten-free diet (GFD) and its impact on health has been spreading among the general population. Despite the established link between gluten and celiac disease (CD), where a GFD is mandatory to reach clinical and histological remission, things are more complicated when it comes to non-celiac gluten/wheat sensitivity (NCGWS) and other autoimmune/dysimmune disorders. In the last conditions, a beneficial effect of gluten withdrawal has not been properly assessed, but still is often suggested without strong supporting evidence. In this context, women have always been exposed, more than men, to higher social pressure related to nutritional behaviors and greater engagement in controlling body weight. With this narrative review, we aim to summarize current evidence on the adherence to a GFD, with particular attention to the impact on women’s health.

In its conventional form, celiac disease (CeD) is characterized by both positive serology and flat villi in the duodenum, and is well known by gastroenterologists and general practitioners. The aim of this review was to shed light on 2 neglected and not yet well-defined celiac phenotypes, that is, seronegative and ultrashort CeD. Seronegative CeD can be suspected in the presence of flat villi, positive HLA-DQ2 and/or HLA-DQ8, and the absence of CeD antibodies. After ruling out other seronegative enteropathies, the diagnosis can be confirmed by both clinical and histologic improvements after 1 year of a gluten-free diet. Ultrashort CeD is characterized by the finding of flat villi in the duodenal bulb in the absence of mucosal damage in the distal duodenum and with serologic positivity. Data on the prevalence, clinical manifestations, histologic lesions, genetic features, and outcome of seronegative and ultrashort CeD are inconclusive due to the few studies available and the small number of patients diagnosed. Some additional diagnostic tools have been developed recently, such as assessing intestinal transglutaminase 2 deposits, flow cytometry technique, microRNA detection, or proteomic analysis, and they seem to be useful in the identification of complex cases. Further cooperative studies are highly desirable to improve the knowledge of these 2 still-obscure variants of CeD.

Background: Celiac disease (CD) is an autoimmune disorder triggered by gluten ingestion. Herein, we assessed clinical, serological and histopathological findings of a single-center, large cohort of CD patients diagnosed and followed-up over forty years. Methods: From January 1980 to December 2020, 1547 CD patients (1170 females; age range: 8–81 years; F:M ratio = 3.1:1) were diagnosed in an Italian tertiary referral center. Comorbidities and complications were recorded at diagnosis and during follow-up. Results: CD diagnoses quadrupled after 2000. The most frequent phenotype was the non-classical CD (63.3%), and the most prevalent histotype was Marsh 3C (44.7%). Gastrointestinal manifestations, detectable in 51% of patients, were diarrhea (24.3%), bloating (28%) and aphthous stomatitis (19.7%). The most common CD-associated disorder was osteopenia (59.9%), predominant in females (64.3%); extraintestinal manifestations included anemia (35.8% iron-deficiency; 87% folic acid malabsorption), cryptogenic hypertransaminasemia (27.9%), and recurrent miscarriages (11.5%). Thyroiditis (26.9%), type 1 diabetes mellitus (2.9%), and dermatitis herpetiformis (1.4%) were the most common CD-related autoimmune disorders. Six patients had inflammatory bowel disease. Complications and mortality rate occurred in 1.8% and 1.9%, respectively. Conclusions: This single-center, large cohort analysis confirmed that CD presentation changed over the years, with an increase of non-classical and subclinical clinical phenotypes.

Introduction We present the first international study of patients with ultrashort coeliac disease (USCD); villous atrophy limited to the duodenal bulb (D1) with concurrent positive coeliac serology. Methods Patients with USCD (Group 1, n=138, median age 27years, IQR:21–44 years, 71% female) identified from 9 tertiary hospitals (Sheffield, UK; Caceres, Spain; Columbia, USA; Palmerston North, New Zealand; Ankara, Turkey; Milano, Bologna and Pavia Italy; Tehran, Iran) were followed up and compared to age and sex matched patients with conventional CD from Sheffield, UK (Group 2) and 2072 patients with CD in Sheffield over 20 years (Group 3). Results Patients with USCD were younger than those with CD (27 vs 44 years respectively, p<0.001). Tissue transglutaminase(tTG) at index gastroscopy was lower in patients with USCD vs CD (3.0x vs 10.0x upper limit of normal respectively, p<0.001). There was no difference in HLA type (p=0.717). Presenting symptoms differed between patients with USCD and Group 2 patients: abdominal pain (41 vs 20% respectively, p<0.001), and bloating (31 vs 19% respectively, p=0.025). of those followed up 99% of patients with USCD improved clinically on a GFD. Conclusion Patients with USCD are younger than those with CD with lower tTG levels. They remain symptomatic and benefit from a GFD, therefore the diagnosis should not be missed. Finally, this study endorses taking D1 biopsies as a mandatory component of CD diagnostic work-up.