Celiac Disease Revisited.

Celiac disease (CD) is a systemic disease triggered by gluten ingestion in genetically predisposed individuals. It manifests primarily as an autoimmune enteropathy associated with specific circulating autoantibodies and a human leukocyte antigen haplotype (HLA-DQ2 or HLA-DQ8). It afflicts roughly 1% of the population, though the majority of patients remain undiagnosed. Diarrhea and malabsorption are classic manifestations of CD; however, both children and adults can be paucisymptomatic and present extraintestinal manifestations such as anemia, osteoporosis, and abnormal liver tests. CD screening is not recommended for the general population, and it should be focused on high-risk groups. CD diagnosis is challenging and relies on serological tests, duodenal histology, and genetic testing. Particularly difficult presentations to manage are seronegative patients, seropositive patients without villus atrophy, and patients who have started a gluten-free diet before the diagnostic workup. The only proven treatment is a lifelong gluten-free diet. We present an in-depth review on the physiopathology and management of CD, with a particular emphasis on diagnostic challenges.

A doença celíaca (DC) é uma doença sistémica desencadeada pela exposição ao glúten em doentes geneticamente susceptíveis. Manifesta-se maioritariamente por uma enteropatia auto-imune associada a auto-anticorpos e aos haplotipos HLA-DQ2 ou HLA-DQ8. A DC afecta aproximadamente 1% da população mundial admitindose, no entanto, que a maioria dos doentes não esteja diagnosticada. As manifestações clássicas de DC são a diarreia e sintomas de malabsorção, no entanto tanto crianças como adultos podem ser pauci-sintomáticos ou apresentar manifestações extra-intestinais incluindo anemia, osteoporose ou alteração das provas hepáticas. O rastreio de base populacional não está recomendado, devendo o foco ser nos grupos de risco para DC. O diagnóstico de DC é um desafio e assenta em três pilares: testes serológicos, histologia duodenal e testes genéticos. Apresentações particularmente difíceis de manejar são os doentes sero-negativos, doentes sero-positivos sem atrofia vilositária e doentes que iniciam dieta sem glúten antes da marcha diagnóstica. O único tratamento com eficácia comprovada é a dieta sem glúten. Apresentamos uma revisão aprofundada da fisiopatologia e manejo da DC, com particular ênfase nos desafios diagnósticos.

Whole Cow's Milk but Not Lactose Can Induce Symptoms in Patients with Self-Reported Milk Intolerance: Evidence of Cow's Milk Sensitivity in Adults.

BACKGROUND: Lactose intolerance is the most frequent food intolerance, but many subjects with self-reported milk intolerance (SRMI) are asymptomatic at lactose hydrogen breath test (LHBT). The aim of this study was to evaluate the frequency of lactose intolerance in SRMI patients and their clinical characteristics. METHODS: In a retrospective study, the clinical records of 314 SRMI patients (259 females, mean age: 39.1 ± 13.5 years) were reviewed; 102 patients with irritable bowel syndrome (IBS) served as controls. In a prospective study, 42 SRMI patients, negatives at the LHBT, underwent a double-blind, placebo-controlled (DBPC) whole cow's milk challenge. RESULTS: In the retrospective study, only 178 patients (56%) were lactose maldigesters and intolerant at LHBT; 68% of the subjects with SRMI were suffering from IBS; 74% reported dyspepsia (p = 0.0001 vs. IBS controls); and weight loss was recorded in 62 SRMI patients (20%) (p = 0.01 vs. IBS controls). Duodenal histology showed intra-epithelial lymphocytosis in about 60% of cases. In the prospective study, 36 patients (86%) experienced symptoms during the DBPC cow's milk challenge, and only 4 patients (9%) reacted to placebo (p = 0.0001). CONCLUSIONS: A percentage of SRMI patients were not suffering from lactose intolerance. DBPC revealed that SRMI patients had clinical reactions when exposed to whole cow's milk.

Relationship between Persistent Gastrointestinal Symptoms and Duodenal Histological Findings after Adequate Gluten-Free Diet: A Gray Area of Celiac Disease Management in Adult Patients.

A gluten-free diet (GFD) leads to a rapid improvement in gastrointestinal (GI) symptoms, biochemical alterations and duodenal histological damage in the majority of celiac disease (CD) patients. This study aimed to assess the frequency and factors associated with the persistence of GI symptoms/malabsorption signs and their relationship with duodenal histological findings among CD patients on an adequate GFD (mean duration 16 months, range 12-28 months). This longitudinal cohort study included 102 adult CD patients (median age 38.5 years, range 18-76 years, F = 71.6%) diagnosed between 2012 and 2018. A total of 36.3% of the included patients had persistent GI symptoms and/or malabsorption signs (Group 1), while the remaining patients had complete GI well-being without malabsorption signs (Group 2) at the time of histological re-evaluation. The persistence of GI symptoms/signs was associated with a long duration of symptoms/signs before CD diagnosis (≥5 years) (OR 5.3; 95% CI 1.3-21.8) and the presence of constipation at the time of CD diagnosis (OR 7.5; 95% CI 1.3-42) while for other variables, including age at CD diagnosis, sex, duration of GFD, comorbidities, CD serology positivity and severity of duodenal damage at histological re-evaluation, no association was found. According to our results, the persistence of symptoms/signs is not associated with histological findings, and their relationship could be a gray area in CD management.

Prospective study using villous length morphometry as an adjunctive tool to assess modified Marsh grade in patients with coeliac disease.

Coeliac disease, an autoimmune disease, is caused by ingestion of gluten in genetically susceptible individuals. The currently used modified-Marsh grading, used to assess mucosal injury, is fraught with interobserver and intraobserver variability. The aim is to reduce this variability by villous length morphometry. Our prospective study was conducted on newly diagnosed cases of coeliac disease that were assessed by serohaematological profile, and duodenal biopsies were evaluated by modified Marsh grading. Villous length was measured in Grades 2, 3a and 3b using an eyepiece graticule lens calibrated with a stage micrometer. Severity of mucosal injury in different Marsh grades was significantly correlated to mean villous length, elevation of mean IgA tTG and drop in haemoglobin.

Towards the Probabilistic Analysis of Small Bowel Capsule Endoscopy Features to Predict Severity of Duodenal Histology in Patients with Villous Atrophy.

Small bowel capsule endoscopy (SBCE) can be complementary to histological assessment of celiac disease (CD) and serology negative villous atrophy (SNVA). Determining the severity of disease on SBCE using statistical machine learning methods can be useful in the follow up of patients. SBCE can play an additional role in differentiating between CD and SNVA. De-identified SBCEs of patients with CD and SNVA were included. Probabilistic analysis of features on SBCE were used to predict severity of duodenal histology and to distinguish between CD and SNVA. Patients with higher Marsh scores were more likely to have a positive SBCE and a continuous distribution of macroscopic features of disease than those with lower Marsh scores. The same pattern was also true for patients with CD when compared to patients with SNVA. The validation accuracy when predicting the severity of Marsh scores and when distinguishing between CD and SNVA was 69.1% in both cases. When the proportions of each SBCE class group within the dataset were included in the classification model, to distinguish between the two pathologies, the validation accuracy increased to 75.3%. The findings of this work suggest that by using features of CD and SNVA on SBCE, predictions can be made of the type of pathology and the severity of disease.

Clinical expression of lymphocytic duodenosis in "mild enteropathy" celiac disease and in functional gastrointestinal syndromes.

OBJECTIVE: Abnormally high number of duodenal intraepithelial lymphocytes is frequently found in many conditions including mild enteropathy celiac disease (CD) and functional gastrointestinal syndromes, but is unclear whether lymphocytosis affects the clinical phenotype particularly in functional syndromes. MATERIALS AND METHODS: We compared clinical characteristics of celiac patients with lymphocytic duodenosis and normal villous structure with those of patients with functional gastrointestinal syndromes with and without lymphocytic duodenosis. We retrospectively identified 3 cohorts among patients referred for suspected CD: (1) "CoelD", 135 patients (age 36 ± 14 years) with mild enteropathy CD; (2) "LymD", 245 patients (38 ± 12 years) with functional gastrointestinal syndromes and lymphocytic duodenosis; and (3) "NorD", 147 patients (37 ± 15 years) with functional syndromes and normal duodenal histology. RESULTS: Prevalence of gastrointestinal symptoms was similar in the three cohorts, but prevalence of extra-intestinal manifestations (42% vs. 27% vs. 18%, p < 0.003) and of associated diseases (35% vs. 15% vs. 14%, p < 0.0001) was higher in "CoelD" than in "LymD" and "NorD", respectively. Prevalence of Helicobacter pylori infection was similar in the three cohorts. The proportion of patients with final diagnosis of irritable bowel syndrome-diarrhea (38% vs. 37%), dyspepsia (31% vs. 27%), functional pain (14% vs. 19%), and functional diarrhoea (14% vs. 11%) was virtually the same in the cohorts with (LymD) and without (NorD) lymphocytic duodenosis. CONCLUSIONS: Lymphocytic duodenosis has different clinical presentation in patients with mild enteropathy CD than those with functional gastrointestinal syndromes, and is not specific for any particular functional syndrome.

Quantitative Study of Brunner's Glands in the Human Duodenal Submucosa / Estudio cuantitativo de las Glándulas de Brunner en la Submucosa Duodenal Humana

The existence of Brunner's glands (BGs) in the duodenal submucosa is uncontestable, but their exact distribution along the full extent of the duodenal wall is unknown. Objective: To verify the BGs distribution along the human duodenum. Material and method: Twenty normal duodenums were examined. Two samples were removed from each of the four anatomical portions of the duodenum using a scalpel, in such a way that the whole circumference of each portion was excised. Sections were prepared and stained with hematoxylin-eosin. Twelve microscope fields were examined on each duodenal section. The mean numbers of glandular points per field were computed and compared, for the 12 microscope fields of each duodenal section examined. Results: The first duodenal portion presented large quantities of BGs in all of the fields examined. The second duodenal portion also showed the presence of BGs in all the fields examined, albeit in smaller quantities than in the first portion. In the third duodenal portion, BGs were present in six of the duodenums examined. In the fourth duodenal portion, there was a minimal quantity of glands, all located in only ten of the duodenums studied. Conclusions: BGs are present in the submucosa of all duodenal portions, with the greatest concentration in the first portion. Their concentration decreases significantly in the second portion of the duodenum. Furthermore, they become even fewer in number in the third portion and are minimally present in the fourth portion.

La presencia de las glándulas de Brunner en la submucosa duodenal es innegable, pero se desconoce su exacta distribución a lo largo de toda la extensión de la pared duodenal. El objetivo del presente estudio fue analizar la distribución de las glándulas duodenales de Brunner (GDB) en la submucosa de duodenos humanos. Para ello, se examinaron 20 duodenos normales en los que fueron seccionados 22cm de cada porción duodenal, retirados con bisturí, de forma tal, que toda la circunferencia de cada segmento fuese extraída. Cada porción seleccionada fue preparada, teñida con hematoxilina-eosina y observada en 12 campos microscópicos diferentes. Las medias de los puntos glandulares por campo fueron computadas y comparadas para 12 campos microscópicos de cada porción del duodeno examinado. El primer segmento duodenal presenta un gran número de GDB en todos los campos microscópicos examinados. El segundo segmento también mostró la presencia de GDB, aunque el número encontrado fue menor. En el tercer segmento GDB fueron encontradas en 6 de los duodenos estudiados. En el cuarto segmento, el número de GDB fue aún menor y se encontraron solamente en 10 de los duodenos analizados. Así, la presencia de GDB ocurre en la submucosa de todos los segmentos duodenales y la mayor incidencia se encuentra en la primera porción, disminuyendo significativamente en la segunda, mucho más en la tercera, siendo mínima en la cuarta.