Minimal Lesions of the Small Intestinal Mucosa: More than Morphology.

Minimal lesions of the small bowel are mucosal changes characterized by an increased number of intraepithelial lymphocytes (with or without crypt hyperplasia) and normal villous architecture. Such changes are associated with a wide spectrum of conditions, ranging from food intolerances to infections, and from drugs to immune diseases, with different clinical profiles and manifestations, which complicates the formulation of a differential diagnosis. Patient history, symptom evaluation, and histopathology are the diagnostic features needed to establish a correct diagnosis. Physicians should assist pathologists in formulating a precise morphological evaluation by taking well-oriented small intestinal biopsies and collecting informative clinical findings that inform histopathology. In this current clinical controversy, the authors provide the reader with an appraisal of the small intestine minimal lesions through a careful analysis of the major conditions (e.g., celiac disease and other non-celiac disorders) responsible for such changes and their differential diagnosis. Also, we acknowledge that some of the diseases detailed in this article may progress from an early minimal lesion to overt mucosal atrophy. Thus, the timing of the diagnosis is of paramount importance.

Many Patients With Irritable Bowel Syndrome Have Atypical Food Allergies Not Associated With Immunoglobulin E.

BACKGROUND & AIMS: Confocal laser endomicroscopy (CLE) is a technique that permits real-time detection and quantification of changes in intestinal tissues and cells, including increases in intraepithelial lymphocytes and fluid extravasation through epithelial leaks. Using CLE analysis of patients with irritable bowel syndrome (IBS), we found that more than half have responses to specific food components. Exclusion of the defined food led to long-term symptom relief. We used the results of CLE to detect reactions to food in a larger patient population and analyzed duodenal biopsy samples and fluid from patients to investigate mechanisms of these reactions. METHODS: In a prospective study, 155 patients with IBS received 4 challenges with each of 4 common food components via the endoscope, followed by CLE, at a tertiary medical center. Classical food allergies were excluded by negative results from immunoglobulin E serology analysis and skin tests for common food antigens. Duodenal biopsy samples and fluid were collected 2 weeks before and immediately after CLE and were analyzed by histology, immunohistochemistry, reverse transcription polymerase chain reaction, and immunoblots. Results from patients who had a response to food during CLE (CLE+) were compared with results from patients who did not have a reaction during CLE (CLE-) or healthy individuals (controls). RESULTS: Of the 108 patients who completed the study, 76 were CLE+ (70%), and 46 of these (61%) reacted to wheat. CLE+ patients had a 4-fold increase in prevalence of atopic disorders compared with controls (P = .001). Numbers of intraepithelial lymphocytes were significantly higher in duodenal biopsy samples from CLE+ vs CLE- patients or controls (P = .001). Expression of claudin-2 increased from crypt to villus tip (P < .001) and was up-regulated in CLE+ patients compared with CLE- patients or controls (P = .023). Levels of occludin were lower in duodenal biopsy samples from CLE+ patients vs controls (P = .022) and were lowest in villus tips (P < .001). Levels of messenger RNAs encoding inflammatory cytokines were unchanged in duodenal tissues after CLE challenge, but eosinophil degranulation increased, and levels of eosinophilic cationic protein were higher in duodenal fluid from CLE+ patients than controls (P = .03). CONCLUSIONS: In a CLE analysis of patients with IBS, we found that more than 50% of patients could have nonclassical food allergy, with immediate disruption of the intestinal barrier upon exposure to food antigens. Duodenal tissues from patients with responses to food components during CLE had immediate increases in expression of claudin-2 and decreases in occludin. CLE+ patients also had increased eosinophil degranulation, indicating an atypical food allergy characterized by eosinophil activation.

Duodenal and Rectal Mucosa Inflammation in Patients With Non-celiac Wheat Sensitivity.

BACKGROUND & AIMS: Studies of non-celiac gluten or wheat sensitivity (NCGWS) have increased but there are no biomarkers of this disorder. We aimed to evaluate histologic features of colon and rectal tissues from patients with NCGWS. METHODS: We performed a prospective study of 78 patients (66 female; mean age, 36.4 years) diagnosed with NCGWS by double-blind wheat challenge at 2 tertiary care centers in Italy, from January 2015 through September 2016. Data were also collected from 55 patients wither either celiac disease or self-reported NCGWS but negative results from the wheat-challenge test (non-NCGWS controls). Duodenal and rectal biopsies were collected and analyzed by immunohistochemistry to quantify intra-epithelial CD3+ T cells, lamina propria CD45+ cells, CD4+ and CD8+ T cells, mast cells, and eosinophils and to determine the presence and size of lymphoid nodules in patients with NCGWS vs patients with celiac disease or non-NCGWS controls. RESULTS: Duodenal tissues from patients with NCGWS had significantly higher numbers of intra-epithelial CD3+ T cells, lamina propria CD45+ cells, and eosinophils than duodenal tissues from non-NCGWS controls. Duodenal tissues from patients with NCGWS and dyspepsia had a higher number of lamina propria eosinophils than patients with NCGWS without upper digestive tract symptoms. Rectal mucosa from patients with NCGWS had a larger number of enlarged lymphoid follicles, intra-epithelial CD3+ T cells, lamina propria CD45+ cells, and eosinophils than rectal mucosa from non-NCGWS controls. Duodenal and rectal mucosal tissues from patients with celiac disease had more immunocytes (CD45+ cells, CD3+ cells, and eosinophils) than tissues from patients with NCGWS or non-NCGWS controls. CONCLUSIONS: We identified markers of inflammation, including increased numbers of eosinophils, in duodenal and rectal mucosa from patients with NCGWS. NCGWS might therefore involve inflammation of the entire intestinal tract. Eosinophils could serve as a biomarker for NCGWS and be involved in its pathogenesis. Clinicaltrials.gov: NCT01762579.

Discriminant value of IEL counts and distribution pattern through the spectrum of gluten sensitivity: a simple diagnostic approach.

Intraepithelial lymphocytosis (IELosis) with or without villous abnormality is a characteristic feature of gluten sensitivity (GS) including celiac disease (CD) and non-celiac-GS, although various conditions may also be associated with IELosis. In order to distinguish GS from the other causes of IELosis, a threshold for IEL counts is necessary. We aimed to determine a cut-off value for IELs and monitor its value in the spectrum of GS in a large cohort. For this purpose, the duodenal biopsies from four groups of individuals including Types 1 (n = 88) and 3 (n = 92) CD, non-CD IELosis (n = 112), and control (n = 82) cases, all strictly defined by their clinical, laboratory, and serologic features, were evaluated. The number of IELs/100 enterocytes and their distribution pattern on H&E- and CD3-immunostained sections were assessed for each group. Kruskal-Wallis test and ROC curve analysis for discriminant value were employed for statistics. The IEL counts showed an increasing trend through the spectrum of mucosal pathology including controls (12.06; 21.40), non-CD IELosis (28.62; 39.46), Type 1 CD (49.27; 60.15), and Type 3 CD (58.53; 71.74) both on H&E- and CD3-immunostained sections, respectively (p < 0.001). ROC analysis revealed 20.5 on H&E and 28.5 on CD3 as the IEL cut-off values with a sensitivity of 95.9 and 87.7% and a specificity of 98.8% and 93.9%, respectively, for controls. IELs showed a diffuse distribution pattern per biopsy piece and per villus (90.9%, 100%, respectively) in nearly all of Type 1 CD cases (p < 0.001). An IEL cut-off value of 20.5 on H&E together with a diffuse distribution pattern seem to be the most discriminant features for the diagnosis of CD, even for the milder forms of the disease.

Cutaneous Manifestations of Non-Celiac Gluten Sensitivity: Clinical Histological and Immunopathological Features.

BACKGROUND: The dermatological manifestations associated with intestinal diseases are becoming more frequent, especially now when new clinical entities, such as Non-Celiac Gluten Sensitivity (NCGS), are identified. The existence of this new entity is still debated. However, many patients with diagnosed NCGS that present intestinal manifestations have skin lesions that need appropriate characterization. METHODS: We involved 17 patients affected by NCGS with non-specific cutaneous manifestations who got much better after a gluten free diet. For a histopathological and immunopathological evaluation, two skin samples from each patient and their clinical data were collected. RESULTS: The median age of the 17 enrolled patients affected by NCGS was 36 years and 76% of them were females. On the extensor surfaces of upper and lower limbs in particular, they all presented very itchy dermatological manifestations morphologically similar to eczema, psoriasis or dermatitis herpetiformis. This similarity was also confirmed histologically, but the immunopathological analysis showed the prevalence of deposits of C3 along the dermo-epidermal junction with a microgranular/granular pattern (82%). CONCLUSIONS: The exact characterization of new clinical entities such as Cutaneous Gluten Sensitivity and NCGS is an important objective both for diagnostic and therapeutic purposes, since these are patients who actually benefit from a GFD (Gluten Free Diet) and who do not adopt it only for fashion.

Celiac disease, wheat allergy, and gluten sensitivity: when gluten free is not a fad.

As the gluten-free diet (GFD) gains in popularity with the general public, health practitioners are beginning to question its real health benefits. For those patients with celiac disease (CD), the GFD is considered medical nutrition therapy, as well as the only proven treatment that results in improvements in symptomatology and small bowel histology. Those with wheat allergy also benefit from the GFD, although these patients often do not need to restrict rye, barley, and oats from their diet. Gluten sensitivity is a controversial subject, where patients who have neither CD nor wheat allergy have varying degrees of symptomatic improvement on the GFD. Conditions in this category include dermatitis herpetiformis (DH), irritable bowel syndrome (IBS), and neurologic diseases such as gluten-sensitive ataxia and autism. It is important for patients and healthcare practitioners to understand the differences between these conditions, even though they may all respond to a GFD. Patients with CD can experience comorbid nutrition deficiencies and are at higher risk for the development of cancers and other autoimmune conditions. Those with wheat allergy and gluten sensitivity are thought not to be at higher risk for these complications. Defining the symptoms and biochemical markers for gluten-sensitive conditions is an important area for future investigations, and high-quality, large-scale randomized trials are needed to prove the true benefits of the GFD in this evolving field.