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Background: Patients suffering from non-celiac wheat sensitivity (NCWS) frequently report extra-intestinal symptoms, such as anemia., Aims: We investigated the prevalence and associated clinical features of anemia in NCWS patients., Methods: Data from 244 NCWS patients, diagnosed by double-blind placebo-controlled wheat challenge, were retrospectively reviewed and compared with 2 control groups (celiac disease (CD) and irritable bowel syndrome (IBS)). Furthermore, 31 NCWS anemic patients were prospectively re-evaluated after at least 12 months on the "strict" wheat-free diet (WFD)., Results: Anemia prevalence in NCWS patients was 34.8% (mean hemoglobin 10.4 ± 1.4 g/dl), significantly higher than in IBS (17.4%, P = 0.03), but not in CD ones. The NCWS group, on the whole, had sideropenic-like features with low serum iron and altered iron deposits. Both anemia prevalence and sideropenic-like features were more evident in CD than in NCWS patients, whereas only a few IBS subjects showed such features. Significant differences were found in anemic vs non-anemic NCWS patients as regards to female sex, diagnostic delay, poly/hypermenorrhea, iron deficiency, and higher TSH values. A long-term WFD significantly reduced anemia and improved iron metabolism., Conclusion: Microcytic/hypochromic anemia and altered iron metabolism occur frequently in NCWS and can be treated with a long-term strict WFD. NCWS should be included in differential diagnosis of anemic patients with "functional gastrointestinal troubles"., Competing Interests: Conflict of interest Guarantor of the article: Antonio Carroccio, MD. The authors declare that there are no conflicts of interest regarding the publication of this paper., (Copyright © 2022 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: Only limited studies analyzed a possible relationship between frailty and infections. Our aim was to investigate the possible association between higher multidimensional prognostic index (MPI) values, a tool for evaluating multidimensional frailty, and the prevalence of infectious diseases, including antibiotics' cost and the prevalence of MDR (multidrug resistance) pathogens., Methods: Older patients, affected by COVID-19, were enrolled in the hospital of Palermo over four months., Results: 112 participants (mean age 77.6, 55.4% males) were included. After adjusting for potential confounders, frailer participants had a higher odds of any positivity to pathogens (prevalence: 61.5%, odds ratio = 15.56, p < 0.0001) compared to a prevalence of 8.6% in more robust, including MDR, and a higher costs in antibiotics., Conclusions: Higher MPI values, indicating frailer subjects, were associated with a higher prevalence of infections, particularly of MDR pathogens, and a consequent increase in antibiotics' cost., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objective: 'Self-reported wheat sensitivity' (SRWS) is a self-reported condition caused by wheat ingestion in the absence of celiac disease or wheat allergy. The aim of the study was to investigate the frequency and characteristics of SRWS in outpatients referred for digestive endoscopy., Methods: The study, performed at the University of Palermo, enrolled 496 outpatients., Results: Seven individuals (1.4%) had an already established diagnosis of celiac disease. The questionnaire was administered to the other 489 individuals: 98 subjects (20%) were SRWS, the remaining 391 served as controls (i.e. not-SRWS). SRWS patients were younger (P < 0.001), with a higher percentage of females (P = 0.002) than not-SRWS. 'gastroesophageal reflux disease and ulcer-like dyspepsia' and 'chronic unexplained diarrhea' were more frequently the reasons for the endoscopy study in SRWS than in not-SRWS (P = 0.002, and P = 0.05, respectively). Food allergies/intolerances (P = 0.04), milk allergy/intolerance (P = 0.0001), GERD (P = 0.0001), IBS (0.0001), anxiety (P = 0.005) and depression (P = 0.04) were the previous medical diagnoses reported more frequently in SRWS patients than in not-SRWS. In the SRWS group, 38% of the patients had already undergone previous upper endoscopy and 24% colonoscopy. After these investigations, 58% of SRWS patients received no diagnosis, and the other 42% were informed that they 'were not suffering from celiac disease or wheat allergy'. Finally, 28.6% SRWS patients had followed a gluten-free diet (GFD), and 71.4% of them referred being asymptomatic on GFD., Conclusions: Our data showed a high frequency of SRWS in outpatients referred to a digestive endoscopy center and a lack of medical accuracy in identifying a possible gluten-related disease., Registration: The study was registered on Clinicaltrials.gov (registration number: NCT04154137), accessible at: https://clinicaltrials.gov/ct2/show/NCT04154137?term=non+celiac+wheat&draw=2&rank=1., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

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.

Background: Non-Celiac Wheat Sensitivity (NCWS) is characterized by both intestinal and extra-intestinal symptoms. The study aims to investigate the frequency of neuropsychiatric manifestations in NCWS patients and identify their clinical and demographic characteristics., Methods: 278 clinical records of NCWS patients, diagnosed by a double-blind placebo-controlled wheat challenge between 2006 and 2020, were retrospectively revised. Fifty-two patients with Celiac Disease (CD) and 54 patients with Irritable Bowel Syndrome (IBS) served as controls., Results: 87% of the NCWS patients had an IBS-like clinical presentation. The NCWS group showed a longer duration of symptoms, a higher frequency of positive serum anti-nuclear antibodies than CD and IBS patients, and a higher frequency of DQ2/DQ8 haplotypes and duodenal mucosa lymphocytosis than IBS controls. In addition, 50% of NCWS patients showed neuropsychiatric manifestations, while lower percentages were observed in CD (25%) and IBS (28%) controls. Neuropsychiatric symptoms in NCWS were more frequently associated with the male sex, longer duration of symptoms, and IBS-diarrhea-like clinical presentation., Conclusions: Our data suggest that in patients with IBS-like symptoms and neuropsychiatric manifestations of unknown cause, it could be useful to investigate a correlation of these symptoms with wheat ingestion to identify NCWS patients with this 'atypical' manifestation.

Introduction: Nonceliac wheat sensitivity (NCWS) is characterized by intestinal and extraintestinal manifestations consequent to wheat ingestion in subjects without celiac disease and wheat allergy. Few studies investigated the relationship between NCWS and autoimmunity. The aim of this study is to evaluate the frequency of autoimmune diseases (ADs) and autoantibodies in patients with NCWS., Methods: Ninety-one patients (13 men and 78 women; mean age of 40.9 years) with NCWS, recruited in a single center, were included. Seventy-six healthy blood donors (HBD) and 55 patients with a diagnosis of irritable bowel syndrome (IBS) unrelated to NCWS served as controls. Autoantibodies levels were measured. Human leukocyte antigen haplotypes were determined, and duodenal histology performed in all patients carrying the DQ2/DQ8 haplotypes. Participants completed a questionnaire, and their medical records were reviewed to identify those with ADs., Results: Twenty-three patients with NCWS (25.3%) presented with ADs; autoimmune thyroiditis (16 patients, 17.6%) was the most frequent. The frequency of ADs was higher in patients with NCWS than in HBD (P = 0.002) and in patients with IBS (P = 0.05). In the NCWS group, antinuclear antibodies tested positive in 71.4% vs HBD 19.7%, and vs patients with IBS 21.8% (P < 0.0001 for both). The frequency of extractable nuclear antigen antibody (ENA) positivity was significantly higher in patients with NCWS (21.9%) than in HBD (0%) and patients with IBS (3.6%) (P = 0.0001 and P = 0.004, respectively). Among the patients with NCWS, 9.9% tested positive for antithyroglobulin, 16.5% for antithyroid peroxidase, and 14.3% for antiparietal cell antibodies; frequencies were not statistically different from controls. The presence of ADs was related to older age at NCWS diagnosis, female sex, duodenal lymphocytosis, and eosinophil infiltration., Discussion: One in 4 patients with NCWS suffered from AD, and serum antinuclear antibodies were positive in a very high percentage of cases. These data led us to consider NCWS to be associated to ADs., (Copyright © 2020 by The American College of Gastroenterology.)

Background: Non-celiac wheat sensitivity (NCWS) most frequently presents clinically with irritable bowel syndrome (IBS)-like symptoms, although many extra-intestinal manifestations have also been attributed to it. No studies to date have evaluated the presence and frequency of gynecological symptoms in NCWS., Aim: To evaluate the frequency of gynecological disorders in patients with NCWS., Patients and Methods: Sixty-eight women with NCWS were included in the study. A questionnaire investigating gynecological symptoms and recurrent cystitis was administered, and patients reporting symptoms were then examined by specialists. Three control groups were selected: 52 patients with IBS not related to NCWS, 56 patients with celiac disease (CD), and 71 healthy controls., Results: 59% of the patients with NCWS showed gynecological symptoms, a higher frequency than in healthy controls (P = 0.04), IBS controls (P = 0.01) and CD controls (P = 0.02). Menstrual cycle alterations were more frequent in patients with NCWS than in healthy controls (26.5% vs 11.3%; P = 0.03); the patients with NCWS suffered from recurrent vaginitis (16%) and dyspareunia (6%) significantly more frequently than healthy controls. Twenty-nine percent of patients with NCWS reported recurrent cystitis, a finding higher than in the control groups (vs healthy P = 0.0001, vs IBS P = 0.001, vs CD controls P = 0.04). Microbiological examinations were negative in most of the patients with NCWS and recurrent vaginitis or cystitis. During the 1-year follow-up, 46% of patients with menstrual disorders and 36% with recurrent vaginitis reported resolution of symptoms on a wheat-free diet., Conclusions: Patients with NCWS showed a significantly higher frequency of gynecological symptoms and recurrent cystitis than patients with IBS.

In recent years, a new gluten- or wheat-related disease has emerged, a condition labeled "nonceliac gluten sensitivity" (NCGS) or "nonceliac wheat sensitivity" (NCWS). NCWS pathogenesis is still uncertain and attributed to very different mechanisms. We aimed to study the different T-lymphocyte subsets in the rectal mucosa of NCWS patients to demonstrate the possible contribution of adaptative immune response. Twelve patients (11 women, 1 man, age range 23-61 yr, median 32 yr) with a definitive diagnosis of NCWS were recruited at random for the present study. They underwent rectal endoscopy with multiple mucosal biopsies at the end of a double-blind placebo-controlled (DBPC) wheat challenge when they reported the reappearance of the symptoms. As controls we included 11 "healthy patients", sex- and age-matched with the patients who underwent colonoscopy evaluation for rectal bleeding due to hemorrhoids. Cells freshly obtained from rectal tissue were stained to detect anti-CD45, anti-CD3, anti-CD4, and anti-CD8. Furthermore, intracellular staining was performed with anti-tumor necrosis factor (TNF)-α, anti-interleukin (IL)-17, and anti-IL-22. Production of TNF-α by CD45 + , CD3 + , CD4 + , and CD8 + cells, as well as of IL-17 by CD4 + cells, was higher in the rectal tissue of NCWS patients than in controls. On the contrary, IL-22 production by CD8 + cells was lower in NCWS patients than in the controls. In NCWS patients diagnosed by DBPC wheat challenge, there is a complex immunological activation, with a significant role for the adaptive response. NEW & NOTEWORTHY Nonceliac wheat sensitivity (NCWS) is a syndrome characterized by symptoms triggered by gluten intake. The pathogenesis is still uncertain. Studies have shown a role for innate immunity. We demonstrated that production of TNF-α by CD45 + , CD3 + , CD4 + , and CD8 + cells and of IL-17 by CD4 + cells is higher in the rectal tissue of NCWS patients than in controls. We clearly demonstrated that in patients with NCWS there is a significant role for the adaptive response.

We have identified a clinical association between self-reported non-celiac wheat sensitivity (NCWS) and Familial Mediterranean Fever (FMF). Objectives: A) To determine whether a 2-week double-blind placebo-controlled (DBPC) cross-over wheat vs. rice challenge exacerbates the clinical manifestations of FMF; B) to evaluate innate immune responses in NCWS/FMF patients challenged with wheat vs. rice. The study was conducted at the Department of Internal Medicine of the University Hospital of Palermo and the Hospital of Sciacca, Italy. Six female volunteers with FMF/NCWS (mean age 36 ± 6 years) were enrolled, 12 age-matched non-FMF, NCWS females, and 8 sex- and age-matched healthy subjects served as controls. We evaluated: 1. clinical symptoms by the FMF-specific AIDAI (Auto-Inflammatory Diseases Activity Index) score; 2. serum soluble CD14 (sCD14), C-reactive protein (CRP), and serum amyloid A (SSA); 3. circulating CD14 + monocytes expressing interleukin (IL)-1β and tumor necrosis factor (TNF)-α. The AIDAI score significantly increased in FMF patients during DBPC with wheat, but not with rice (19 ± 6.3 vs. 7 ± 1.6; p = 0.028). sCD14 values did not differ in FMF patients before and after the challenge, but were higher in FMF patients than in healthy controls (median values 11357 vs. 8710 pg/ml; p = 0.002). The percentage of circulating CD14 + /IL-1β + and of CD14 + /TNF-α + monocytes increased significantly after DBPC with wheat vs. baseline or rice challenge. Self-reported NCWS can hide an FMF diagnosis. Wheat ingestion exacerbated clinical and immunological features of FMF. Future studies performed on consecutive FMF patients recruited in centers for auto-inflammatory diseases will determine the real frequency and relevance of this association.

Background: Non-Celiac Wheat Sensitivity (NCWS) is still a largely undefined condition, due to the lack of a diagnostic marker. Few data are available about the nutritional characteristics of NCWS patients at diagnosis., Aims: To evaluate the proportion of NCWS patients who were underweight, normal weight, overweight, or obese at diagnosis, and to search for possible correlations between their Body Mass Index (BMI) and other NCWS-related disease characteristics., Patients and Methods: The clinical charts of 145 NCWS patients (125 F, 20 M, mean age 37.1 ± 11.4 years), diagnosed between January 2012 and March 2018, were reviewed. As a comparison, 84 celiac disease (CD) patients (73 F, 11 M, mean age 39.8 ± 13.9 years) were evaluated. All NCWS diagnoses were based on a double-blind placebo-controlled wheat challenge (DBPCWC) method., Results: BMI distribution was similar in the NCWS (6.2% underweight and 15.2% obese subjects) and CD patients (6% underweight and 7.1% obese subjects). Underweight NCWS subjects were significantly younger and had a shorter clinical history than the overweight or obese ones. Unlike the other NCWS patients, none of them had a DQ2 and/or DQ8 haplotype. Overweight and obese NCWS patients were more frequently suffering from associated autoimmune diseases than the other BMI categories ( P = 0.05). Compared to the CD controls, NCWS patients showed a higher frequency of Irritable Bowel Syndrome (IBS)-like ( P = 0.01) and extraintestinal symptoms ( P = 0.03) and a longer clinical history ( P = 0.04), whereas weight loss was more frequent in CD ( P = 0.02)., Conclusions: NCWS patients showed a BMI distribution similar to CD patients. However, NCWS was found to be a heterogenous condition that regards BMI, and clinical characteristics differed between the underweight and overweight/obese patients.

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., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Goals: The goal of this study was (A) to evaluate abdominal ultrasound signs in nonceliac wheat sensitivity (NCWS) patients for features useful in diagnosis and (B) to compare these aspects with those of celiac patients to assess whether ultrasound can be useful in the differential diagnosis between NCWS and celiac disease (CD)., Background: NCWS diagnosis is difficult as no biomarkers of this condition have as yet been identified. In CD ultrasound aspects have been identified that have a good diagnostic accuracy., Study: We prospectively recruited 45 NCWS patients (11 males, 34 females; mean age 35.7 y). Three control groups were included: (A) 99 age-matched CD patients; (B) 18 patients with seronegative CD; (C) 50 patients with irritable bowel syndrome (IBS) who did not improve on a wheat-free diet. NCWS diagnosis was confirmed on the basis of an elimination diet and double-blind placebo-controlled (DBPC) challenge. Ultrasound sign investigation included: dilatation of the small bowel loops, thickening of the small bowel wall, hyperperistalsis, enlarged mesenteric lymph nodes, ascites, hyposplenism, altered diameter of the portal vein., Results: NCWS patients showed a low frequency of pathologic ultrasound findings. Dilated or thickened loops appeared more often in CD patients than in NCWS patients (88.8% vs. 20%; P<0.0001). These US signs were significantly more frequent in seronegative CD than in NCWS patients (both P<0.0001), whereas no difference was found between NCWS patients and IBS controls., Conclusions: In NCWS patients' ultrasound does not show a characteristic pattern which could be helpful for diagnosis. However, US can be useful to differentiate between NCWS and CD patients and especially those with seronegative CD. (ClinicalTrials.gov NCT03017274).

We investigated how many patients with a diagnosis of nonceliac wheat sensitivity (NCWS) still experienced wheat sensitivity after a median follow-up time of 99 months. We collected data from 200 participants from a previous study of NCWS, performed between July and December 2016 in Italy; 148 of these individuals were still on a strict wheat-free diet. In total, 175 patients (88%) improved (had fewer symptoms) after a diagnosis of NCWS; 145 of 148 patients who adhered strictly to a gluten-free diet (98%) had reduced symptoms, compared with 30 of 52 patients who did not adhere to a gluten-free diet (58%) (P < .0001). Of the 22 patients who repeated the double-blind, placebo-controlled challenge, 20 reacted to wheat. We conclude that NCWS is a persistent condition. Clinicaltrials.gov registration number: NCT02823522., (Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.)