LIVER STEATOSIS AND FIBROSIS IN NON-CELIAC WHEAT SENSITIVITY PATIENTS: A PROSPECTIVE STUDY

NCT07750535 | Recruiting

• 1 other identifier: ACPM36
• Study Type: observational
• Target: 250
• Locations: 1 country
• Sites: 2

Brief Summary

Hypothesizing an intestinal barrier impairment as a common pathophysiological substrate of both Non Celiac Wheat Sensitivity (NCWS) and Metabolic Dysfunction-Associated Steatotic Liver Disease (MAFLD), in a retrospective cohort study (data not yet published), demographic, clinical, laboratory and histology data of NCWS patients at the time of diagnosis, were analyzed and compared to control subjects with Irritable Bowel Syndrome (IBS)/Functional Dyspepsia (FD) and freshly diagnosed Celiac Disease (CeD). NCWS diagnosis was performed by a double-blind placebo-controlled wheat challenge. Steatosis was confirmed by ultrasound examination. Our retrospective data showed that the frequency of liver of steatosis was lower in NCWS than in IBS patients. In addition, it seems that pre-diagnosis avoidance of wheat in NCWS correlates with protection from steatosis. A subset of NCWS patients, recently exposed to wheat, with clinical features suggesting increased IP, seems to be predisposed to liver steatosis and fibrosis. To validate the results of the retrospective study, the researchers planned the present prospective study, to analyze the prevalence of liver steatosis and fibrosis, evaluated by ultrasound examination, FibroScan analysis \[LSM (Liver Stiffness Measurement) and CAP (Controlled Attenuation Parameter) values\], FIB-4 (Fibrosis-4) index, and NFS \[Non-alcoholic fatty liver disease (NAFLD) Fibrosis Score\], in patients with NCWS at the time of diagnosis, comparing them with two control populations of newly diagnosed IBS/FD and CeD patients.

Conditions

Metabolic Dysfunction-Associated Steatotic Liver Disease; Irritable Bowel Syndrome; Functional Dyspepsia; Celiac Disease; Non Celiac Wheat Sensitivity

Keywords

non-celiac wheat sensitivity; metabolic dysfunction-associated steatotic liver disease

Outcome Measures

Primary Outcomes (4)

• Prevalence and severity of liver steatosis and fibrosis by Ultrasound examination

  Steatosis was evaluated according to international validated US criteria and classified as follows: absent (score 0), when the echostructure of the liver was normal; mild (score 1), when there was a mild, diffuse increase in hepatic echogenicity, with normal visualization of the portal vein wall and diaphragm; moderate (score 2), in the case of a moderate increase in hepatic echogenicity, with a less clear/slightly altered demarcation of the portal vein wall and diaphragm; severe (score 3), in the case of markedly increased hepatic echogenicity, with little or no visualization of the portal vein wall, diaphragm and posterior part of the right hepatic lobe.

  At baseline, before diagnosis

• Prevalence and severity of liver steatosis by FibroScan analysis

  FibroScan analysis provides CAP (normal validated cut-offs of ≤275 dB/m) and LSM (normal/mild, F0-F1, validated cut-offs of ≤7 kPa) values for liver steatosis and fibrosis, respectively.

  At baseline, before diagnosis

• Prevalence and severity of liver steatosis and fibrosis by FIB-4

  A validated score was used to assess the risk for significant liver fibrosis in MASLD: the FIB-4 index. Based on this test, our cohort was stratified as being at low- or moderate-high-risk for advanced fibrosis, based on validated cut-off of ≤1.3 for a low risk.

  At baseline, before diagnosis

• Prevalence and severity of liver steatosis and fibrosis by NFS

  Another validated score was used to assess the risk for significant liver fibrosis in MASLD: the NFS. Based on this test, our cohort was stratified as being at low- or moderate-high-risk for advanced fibrosis, based on validated cut-off ≤1.455 for NFS for a low risk.

  At baseline, before diagnosis

Study Arms (3)

NCWS patients

NCWS patients, consecutively diagnosed by double-blind placebo-controlled challenge (DBPCC) with wheat

Diagnostic Test: Prevalence and severity of liver steatosis and fibrosis,

IBS/FD patients unrelated to food allergies

Control population of IBS/FD patients unrelated to food (including wheat) allergies/intolerances

Diagnostic Test: Prevalence and severity of liver steatosis and fibrosis,

CeD patients

Control populations of CeD patients

Diagnostic Test: Prevalence and severity of liver steatosis and fibrosis,

Interventions

Prevalence and severity of liver steatosis and fibrosis, DIAGNOSTIC_TEST

To establish the prevalence and severity of liver steatosis and fibrosis, the researchers will analyze data from the UltraSound (US) and FibroScan examinations, and from two validate scores performed before diagnosis.

CeD patients; IBS/FD patients unrelated to food allergies; NCWS patients

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

This is a prospective multicenter study conducted on patients with NCWS, consecutively diagnosed by double-blind placebo-controlled challenge (DBPCC) with wheat, from January 2024, in the outpatient clinics of two Internal Medicine Units: University Hospital of Palermo, Italy, and "Villa-Sofia-Cervello" Hospital, Palermo, Italy. The records of the patients were prospectively collected and analyzed, together with those of two control populations of IBS/FD unrelated to food (including wheat) allergies/intolerances, and CeD, consecutively recruited in the same period and in the same outpatient clinics, before diagnosis (baseline) and after 1 year of follow-up.

You may not qualify if:

• age \>18 and \<65 years;
• subjects with wheat-dependent symptoms, both gastrointestinal and extra-intestinal;
• negativity of IgA and IgG anti-deamidated gliadin peptide (DPG) antibodies, immunoglobulin (Ig)A and IgG anti-tissue transglutaminase (tTG) antibodies, and anti-endomysial antibodies (EMA);
• absence of duodenal villous atrophy, documented in all patients carrying the human leukocyte antigen (HLA) DQ2 and/or DQ8 haplotypes (therefore regardless of the negativity of celiac disease (CeD)-specific serum antibodies), evaluated when the patients had consumed a minimum of 100g of pasta and/or bread a day, for at least 45 days;
• absence of IgE-mediated wheat allergy (WA): negative skin prick-test and/or specific serum IgE assay for wheat, gluten and gliadin);
• resolution of symptoms on a strict standard elimination diet (i.e. extended oligoantigenic, excluding wheat, cow's milk, egg, tomato and chocolate and other foods self-reported by the patient as causing symptoms), followed for at least 4 weeks, and the recurrence of the same symptoms after double-blind placebo-controlled challenge (DBPCC) with wheat (for further details see below);
• complete medical records;
• duration of follow-up longer than 12 months after initial diagnosis, with at least 2 outpatient visits during the follow-up period.
• age \>18 and \<65 years;
• subjects diagnosed with IBS/FD and other functional gastrointestinal disorders, according to the Rome IV classification, 1 who did not specifically report symptoms/signs, whether gastrointestinal or extra-intestinal, following ingestion of wheat or other foods and who did not respond to gluten-free diet (GFD).
• age \>18 and \<65 years;
• subjects with gastrointestinal and extra-intestinal wheat-dependent symptoms that meet the diagnostic criteria of CeD 2: positivity of anti-tTG IgA and/or IgG antibodies and evidence of villous atrophy, according to the Marsh-Oberhuber classification, demonstrated by histology on duodenal biopsy;
• clinical response to the GFD: resolution of gastrointestinal and/or extra-intestinal symptoms.
• drug abuse;
• treatment with steroids and/or non-steroidal anti-inflammatory drugs in the 2 weeks before duodenal biopsy;

Sponsors & Collaborators

• University of Palermo: lead

Study Sites (2)

Internal Medicine Unit, University Hospital of Palermo

Palermo, Palermo, 90127, Italy

RECRUITING

Internal Medicine Unit, "Villa-Sofia-Cervello" Hospital

Palermo, Palermo, 90146, Italy

RECRUITING

Related Publications (17)

• Angulo P, Hui JM, Marchesini G, Bugianesi E, George J, Farrell GC, Enders F, Saksena S, Burt AD, Bida JP, Lindor K, Sanderson SO, Lenzi M, Adams LA, Kench J, Therneau TM, Day CP. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology. 2007 Apr;45(4):846-54. doi: 10.1002/hep.21496.

  PMID: 17393509 BACKGROUND

• Sterling RK, Lissen E, Clumeck N, Sola R, Correa MC, Montaner J, S Sulkowski M, Torriani FJ, Dieterich DT, Thomas DL, Messinger D, Nelson M; APRICOT Clinical Investigators. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology. 2006 Jun;43(6):1317-25. doi: 10.1002/hep.21178.

  PMID: 16729309 BACKGROUND

• Rubio-Tapia A, Hill ID, Semrad C, Kelly CP, Greer KB, Limketkai BN, Lebwohl B. American College of Gastroenterology Guidelines Update: Diagnosis and Management of Celiac Disease. Am J Gastroenterol. 2023 Jan 1;118(1):59-76. doi: 10.14309/ajg.0000000000002075. Epub 2022 Sep 21.

  PMID: 36602836 BACKGROUND

• Buscemi S, Rosafio G, Vasto S, Massenti FM, Grosso G, Galvano F, Rini N, Barile AM, Maniaci V, Cosentino L, Verga S. Validation of a food frequency questionnaire for use in Italian adults living in Sicily. Int J Food Sci Nutr. 2015;66(4):426-38. doi: 10.3109/09637486.2015.1025718. Epub 2015 Apr 1.

  PMID: 25830946 BACKGROUND

• Hernaez R, Lazo M, Bonekamp S, Kamel I, Brancati FL, Guallar E, Clark JM. Diagnostic accuracy and reliability of ultrasonography for the detection of fatty liver: a meta-analysis. Hepatology. 2011 Sep 2;54(3):1082-1090. doi: 10.1002/hep.24452.

  PMID: 21618575 BACKGROUND

• Seidita A, Giuliano A, Soresi M, Chiavetta M, Nardi E, Mogavero G, Giannone G, Carroccio A, Mansueto P. Fecal calprotectin levels in patients with non-celiac wheat sensitivity: a proof of concept. Intern Emerg Med. 2024 Aug;19(5):1255-1266. doi: 10.1007/s11739-024-03595-7. Epub 2024 Apr 12.

  PMID: 38609737 BACKGROUND

• Schuppan D, Pickert G, Ashfaq-Khan M, Zevallos V. Non-celiac wheat sensitivity: differential diagnosis, triggers and implications. Best Pract Res Clin Gastroenterol. 2015 Jun;29(3):469-76. doi: 10.1016/j.bpg.2015.04.002. Epub 2015 May 8.

  PMID: 26060111 BACKGROUND

• Albillos A, de Gottardi A, Rescigno M. The gut-liver axis in liver disease: Pathophysiological basis for therapy. J Hepatol. 2020 Mar;72(3):558-577. doi: 10.1016/j.jhep.2019.10.003. Epub 2019 Oct 14.

  PMID: 31622696 BACKGROUND

• Tilg H, Adolph TE, Trauner M. Gut-liver axis: Pathophysiological concepts and clinical implications. Cell Metab. 2022 Nov 1;34(11):1700-1718. doi: 10.1016/j.cmet.2022.09.017. Epub 2022 Oct 7.

  PMID: 36208625 BACKGROUND

• European Association for the Study of the Liver (EASL); European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines for the Management of Non-Alcoholic Fatty Liver Disease. Obes Facts. 2016;9(2):65-90. doi: 10.1159/000443344. Epub 2016 Apr 8. No abstract available.

  PMID: 27055256 BACKGROUND

• Younossi ZM, Golabi P, Paik JM, Henry A, Van Dongen C, Henry L. The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review. Hepatology. 2023 Apr 1;77(4):1335-1347. doi: 10.1097/HEP.0000000000000004. Epub 2023 Jan 3.

  PMID: 36626630 BACKGROUND

• Fritscher-Ravens A, Pflaum T, Mosinger M, Ruchay Z, Rocken C, Milla PJ, Das M, Bottner M, Wedel T, Schuppan D. Many Patients With Irritable Bowel Syndrome Have Atypical Food Allergies Not Associated With Immunoglobulin E. Gastroenterology. 2019 Jul;157(1):109-118.e5. doi: 10.1053/j.gastro.2019.03.046. Epub 2019 May 15.

  PMID: 31100380 BACKGROUND

• Zevallos VF, Raker V, Tenzer S, Jimenez-Calvente C, Ashfaq-Khan M, Russel N, Pickert G, Schild H, Steinbrink K, Schuppan D. Nutritional Wheat Amylase-Trypsin Inhibitors Promote Intestinal Inflammation via Activation of Myeloid Cells. Gastroenterology. 2017 Apr;152(5):1100-1113.e12. doi: 10.1053/j.gastro.2016.12.006. Epub 2016 Dec 16.

  PMID: 27993525 BACKGROUND

• Carroccio A, Rini G, Mansueto P. Non-celiac wheat sensitivity is a more appropriate label than non-celiac gluten sensitivity. Gastroenterology. 2014 Jan;146(1):320-1. doi: 10.1053/j.gastro.2013.08.061. Epub 2013 Nov 22. No abstract available.

  PMID: 24275240 BACKGROUND

• Sapone A, Bai JC, Ciacci C, Dolinsek J, Green PH, Hadjivassiliou M, Kaukinen K, Rostami K, Sanders DS, Schumann M, Ullrich R, Villalta D, Volta U, Catassi C, Fasano A. Spectrum of gluten-related disorders: consensus on new nomenclature and classification. BMC Med. 2012 Feb 7;10:13. doi: 10.1186/1741-7015-10-13.

  PMID: 22313950 BACKGROUND

• Carroccio A, Mansueto P, Iacono G, Soresi M, D'Alcamo A, Cavataio F, Brusca I, Florena AM, Ambrosiano G, Seidita A, Pirrone G, Rini GB. Non-celiac wheat sensitivity diagnosed by double-blind placebo-controlled challenge: exploring a new clinical entity. Am J Gastroenterol. 2012 Dec;107(12):1898-906; quiz 1907. doi: 10.1038/ajg.2012.236. Epub 2012 Jul 24.

  PMID: 22825366 BACKGROUND

• Catassi C, Alaedini A, Bojarski C, Bonaz B, Bouma G, Carroccio A, Castillejo G, De Magistris L, Dieterich W, Di Liberto D, Elli L, Fasano A, Hadjivassiliou M, Kurien M, Lionetti E, Mulder CJ, Rostami K, Sapone A, Scherf K, Schuppan D, Trott N, Volta U, Zevallos V, Zopf Y, Sanders DS. The Overlapping Area of Non-Celiac Gluten Sensitivity (NCGS) and Wheat-Sensitive Irritable Bowel Syndrome (IBS): An Update. Nutrients. 2017 Nov 21;9(11):1268. doi: 10.3390/nu9111268.

  PMID: 29160841 BACKGROUND

MeSH Terms

Conditions

Irritable Bowel Syndrome; Celiac Disease

Condition Hierarchy (Ancestors)

Colonic Diseases, Functional; Colonic Diseases; Intestinal Diseases; Gastrointestinal Diseases; Digestive System Diseases; Malabsorption Syndromes; Metabolic Diseases; Nutritional and Metabolic Diseases

Study Officials

• Pasquale Mansueto, MD

  University of Palermo

  STUDY DIRECTOR

• Aurelio Seidita, MD

  University of Palermo

  STUDY CHAIR

Central Study Contacts

Antonio Carroccio, MD

CONTACT

+393477279879; antonio.carroccio@unipa.it

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: August 2, 2026
• First Posted: August 6, 2026
• Study Start: January 1, 2024
• Primary Completion (Estimated): December 31, 2028
• Study Completion (Estimated): December 31, 2030
• Last Updated: August 6, 2026

Record last verified: 2026-08

Data Sharing

• IPD Sharing: Will not share

Locations

IT (2)