Metabolic Dysfunction-Associated Steatotic Liver DiseaseNCT07750535
Liver Steatosis and Fibrosis in Non-Celiac Wheat Sensitivity Patients: a Prospective Study
An observational study of Metabolic Dysfunction-Associated Steatotic Liver Disease and Non Celiac Wheat Sensitivity, run by University of Palermo at 2 sites in Italy.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Metabolic Dysfunction-Associated Steatotic Liver Disease, Non Celiac Wheat Sensitivity, Irritable Bowel Syndrome
- What is being tested?
- Prevalence and severity of liver steatosis and fibrosis,
- How many people
- 250 participants
- Where
- 2 sitesItaly
- Study dates
- 1 Jan 2024to 31 Dec 2030
- Phase
- Observational
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: This is a prospective multicenter study conducted on patients with Non-Celiac Wheat Sensitivity (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 Irritable Bowel Syndrome/Functional Dyspepsia (IBS/FD) unrelated to food (including wheat) allergies/intolerances, and Celiac Disease (CeD), consecutively recruited in the same period and in the same outpatient clinics, before diagnosis (baseline) and after 1 year of follow-up.
Who may be able to join
- 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.
- Exclusion criteria for all the patients enrolled in the study
- self-exclusion of wheat from the diet and refusal to reintroduce it for diagnostic purposes, before entering the study;
- drug abuse;
Show all 19Show fewer
- treatment with steroids and/or non-steroidal anti-inflammatory drugs in the 2 weeks before duodenal biopsy;
- pregnancy or breastfeeding;
- diagnosis of chronic inflammatory bowel disease or other organic pathologies affecting the digestive system (e.g., wheat allergy, microscopic colitis, diverticulitis, segmental colitis associated with diverticulosis, etc.), neurological diseases, major psychiatric disorders, infectious diseases, immunological deficiencies, and impairments limiting physical activity;
- incomplete medical records;
- lack of clinical follow-up for at least 12 months after diagnosis with >2 outpatient visits during the follow-up period.
- Additional exclusion criteria related to liver steatosis and other liver diseases
- absence of abdominal ultrasound (US) imaging performed before diagnosis (i.e. before starting the wheat-free/gluten-free diet in NCWS and CeD patients, and before any lifestyle modifications and/or drug/prebiotic/probiotic intake in IBS/FD patients);
- incomplete clinical records, lacking the data considered for the present study;
- chronic alcohol intake (>30 g/day for men and >20 g/day for women);
- chronic hepatotropic virus infections [hepatitis B virus (HBV) and hepatitis C virus (HCV)];
- autoimmune liver diseases;
- congenital metabolic liver diseases (e.g. alpha-1 antitrypsin deficiency, hemochromatosis, Wilson's disease, porphyria, other storage diseases, etc.);
- chronic long-term treatment with drugs associated with both macrovesicular (glucocorticoids, estrogens, tamoxifen, amiodarone, methotrexate, and 5-fluorouracil) and microvesicular (glucocorticoids, valproic acid, tetracycline, and zidovudine) steatosis.
Who cannot join
None listed.
Trial locations and contacts
2 sites in 1 country. Contact the study team or a site near you to ask about taking part.
Italy2 sites, 2 recruiting
- Recruiting
Internal Medicine Unit, University Hospital of Palermo
Palermo, Palermo, 90127
Pasquale Mansueto, MD, +393477279879, pasquale.mansueto@unipa.it
- Recruiting
Internal Medicine Unit, "Villa-Sofia-Cervello" Hospital
Palermo, Palermo, 90146
Aurelio Seidita, MD, +393477279879, aurelio.seidita@unipa.it
About this study
Official title: Prevalence and Risk Factors of Liver Steatosis and Fibrosis in Non-Celiac Wheat Sensitivity Patients: a Prospective Study
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/Functional Dyspepsia (IBS/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 (US) examination, FibroScan analysis [CAP (Controlled Attenuation Parameter) and LSM (Liver Stiffness Measurement) 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.
Read the detailed description
Many people with symptoms similar to inflammatory bowel syndrome (IBS) or functional dyspepsia (FD) follow a wheat-free diet (WFD) because it is subjectively better tolerated, even if they do not suffer from celiac disease (CeD) or wheat allergy. This condition, originally named non-celiac gluten sensitivity, has been redefined as non-celiac wheat sensitivity (NCWS), because its clinical manifestations can be triggered by a spectrum of non-gluten wheat proteins, such as wheat amylase-trypsin inhibitors (ATIs), that cause a delayed type - non-IgE-mediated food allergy associated with an intestinal mucosa barrier (IB) defect.
Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the most common liver disease in countries with excess nutrient supply. In addition to the main etiopathogenetic factors, other factors must be implicated: nutrition, intestinal microbiota, intestinal permeability (IP) and the gut-liver axis might play a key role due to the translocation of nutrient-derived peptides and microbial products into the intestinal lamina propria. Here, the liver is prominently exposed to the inflammatory intestinal signals via the mesenteric-portal venous system, that significantly contributes to the onset of MASLD, metabolic disfunction-associated steatohepatitis (MASH) and liver fibrosis.
In patients with NCWS, intake of wheat and wheat ATIs (Amylase-Trypsin Inhibitors) increases IP, promotes intestinal dysbiosis, and activates the gastrointestinal and extra-intestinal immune response.
Hypothesizing an intestinal barrier impairment as a common pathophysiological substrate of both NCWS and 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 IBS/FD and freshly diagnosed 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 [CAP (Controlled Attenuation Parameter) and LSM (Liver Stiffness Measurement) 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, Non Celiac Wheat Sensitivity, Irritable Bowel Syndrome, Functional Dyspepsia, Celiac Disease
- Being tested
- Prevalence and severity of liver steatosis and fibrosis,
- Keywords
- non-celiac wheat sensitivity, metabolic dysfunction-associated steatotic liver disease
- Medical subject headings
- Irritable Bowel Syndrome, Celiac Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
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.
| Study group | Role | What they receive |
|---|---|---|
| Non-Celiac Wheat Sensitivity (NCWS) patients | Non-Celiac Wheat Sensitivity (NCWS) patients, consecutively diagnosed by double-blind placebo-controlled challenge (DBPCC) with wheat Receives: Diagnostic Test: Prevalence and severity of liver steatosis and fibrosis, | |
| Irritable Bowel Syndrome/Functional Dyspepsia (IBS/FD) patients unrelated to food allergies | Control population of Irritable Bowel Syndrome/Functional Dyspepsia (IBS/FD) patients unrelated to food (including wheat) allergies/intolerances Receives: Diagnostic Test: Prevalence and severity of liver steatosis and fibrosis, | |
| Celiac Disease (CeD) patients | Control populations of Celiac Disease (CeD) patients Receives: Diagnostic Test: Prevalence and severity of liver steatosis and fibrosis, |
What is being measured
The primary outcome is the main question the study is designed to answer.
Prevalence and severity of liver steatosis and fibrosis by Ultrasound examination
Steatosis was evaluated according to international validated Ultrasound (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.
Measured: At baseline, before diagnosis
Prevalence and severity of liver steatosis by FibroScan analysis
FibroScan analysis provides CAP (Controlled Attenuation Parameter, normal validated cut-offs of ≤275 dB/m) and LSM (Liver Stiffness Measurement, normal validated cut-offs of ≤5.5 kPa) values for liver steatosis and fibrosis, respectively. Detailed scores were, for CAP, Normal values ≤275 dB/m; Mild Steatosis (S1): 275-290 dB/m; Moderate Steatosis (S2): 290-302 dB/m; Severe Steatosis (S3): ≥302 dB/m. For LSM, F0 (No fibrosis): ≤5.5-6.0 kPa; F1 (Mild fibrosis): 5.6-7.0 kPa; F2 (Moderate/significant fibrosis): 7.1-9.4 kPa; F3 (Severe/Advanced fibrosis): 9.5-14.5 kPa; F4 (Cirrhosis): ≥14.6 kPa.
Measured: 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 and of ≥1.4 for moderate-high-risk.
Measured: 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 and of ≥1.456 for moderate-high-risk.
Measured: At baseline, before diagnosis
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 Aug 2026
- Study start1 Jan 2024
- Primary completion31 Dec 2028 (estimated)
- Study completion31 Dec 2030 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (17)Papers the sponsor has linked to this study.
- Other trials for Metabolic Dysfunction-Associated Steatotic Liver DiseaseStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case-control
- Time perspective
- Prospective
- Enrolment
- 250 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University of Palermo
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Pasquale Mansueto, University of Palermo
- Investigators
- Pasquale Mansueto, MD, Study director, University of PalermoAurelio Seidita, MD, Study chair, University of Palermo
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07750535
- Sponsor's protocol ID
- ACPM36
- Status last verified
- Aug 2026
- First submitted
- 2 Aug 2026
- Last updated
- 11 Aug 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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.
PubMed 17393509Sterling 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.
PubMed 16729309Rubio-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.
PubMed 36602836Buscemi 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.
PubMed 25830946Hernaez 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.
PubMed 21618575Seidita 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.
PubMed 38609737Schuppan 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.
PubMed 26060111Albillos 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.
PubMed 31622696Tilg 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.
PubMed 36208625European 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.
PubMed 27055256Younossi 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.
PubMed 36626630Fritscher-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.
PubMed 31100380Zevallos 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.
PubMed 27993525Carroccio 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.
PubMed 24275240Sapone 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.
PubMed 22313950
Study at a glance
From the registry record, last updated by the sponsor on 11 Aug 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Prevalence and Risk Factors of Liver Steatosis and Fibrosis in Non-Celiac Wheat Sensitivity Patients: a Prospective Study
- ClinicalTrials.gov ID
- NCT07750535
- Acronym / sponsor ID
- ACPM36
- Conditions
- Metabolic Dysfunction-Associated Steatotic Liver Disease, Non Celiac Wheat Sensitivity, Irritable Bowel Syndrome, Functional Dyspepsia, Celiac Disease
- Keywords
- non-celiac wheat sensitivity, metabolic dysfunction-associated steatotic liver disease
- Study type
- Observational
- Recruitment status
- Recruiting
- Enrolment
- 250 participants (estimated)
- Lead sponsor
- University of PalermoUniversity, hospital or other
- Study start
- 1 Jan 2024 (actual)
- Primary completion
- 31 Dec 2028 (estimated)
- Study completion
- 31 Dec 2030 (estimated)
- First posted
- 6 Aug 2026 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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/Functional Dyspepsia (IBS/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 (US) examination, FibroScan analysis [CAP (Controlled Attenuation Parameter) and LSM (Liver Stiffness Measurement) 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.
Detailed description
Many people with symptoms similar to inflammatory bowel syndrome (IBS) or functional dyspepsia (FD) follow a wheat-free diet (WFD) because it is subjectively better tolerated, even if they do not suffer from celiac disease (CeD) or wheat allergy. This condition, originally named non-celiac gluten sensitivity, has been redefined as non-celiac wheat sensitivity (NCWS), because its clinical manifestations can be triggered by a spectrum of non-gluten wheat proteins, such as wheat amylase-trypsin inhibitors (ATIs), that cause a delayed type - non-IgE-mediated food allergy associated with an intestinal mucosa barrier (IB) defect.
Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the most common liver disease in countries with excess nutrient supply. In addition to the main etiopathogenetic factors, other factors must be implicated: nutrition, intestinal microbiota, intestinal permeability (IP) and the gut-liver axis might play a key role due to the translocation of nutrient-derived peptides and microbial products into the intestinal lamina propria. Here, the liver is prominently exposed to the inflammatory intestinal signals via the mesenteric-portal venous system, that significantly contributes to the onset of MASLD, metabolic disfunction-associated steatohepatitis (MASH) and liver fibrosis.
In patients with NCWS, intake of wheat and wheat ATIs (Amylase-Trypsin Inhibitors) increases IP, promotes intestinal dysbiosis, and activates the gastrointestinal and extra-intestinal immune response.
Hypothesizing an intestinal barrier impairment as a common pathophysiological substrate of both NCWS and 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 IBS/FD and freshly diagnosed 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 [CAP (Controlled Attenuation Parameter) and LSM (Liver Stiffness Measurement) 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.
Study design
- Observational model
- Case-control
- Time perspective
- Prospective
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Non-Celiac Wheat Sensitivity (NCWS) patients | – | Diagnostic Test: Prevalence and severity of liver steatosis and fibrosis,Non-Celiac Wheat Sensitivity (NCWS) patients, consecutively diagnosed by double-blind placebo-controlled challenge (DBPCC) with wheat |
| Irritable Bowel Syndrome/Functional Dyspepsia (IBS/FD) patients unrelated to food allergies | – | Diagnostic Test: Prevalence and severity of liver steatosis and fibrosis,Control population of Irritable Bowel Syndrome/Functional Dyspepsia (IBS/FD) patients unrelated to food (including wheat) allergies/intolerances |
| Celiac Disease (CeD) patients | – | Diagnostic Test: Prevalence and severity of liver steatosis and fibrosis,Control populations of Celiac Disease (CeD) patients |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- This is a prospective multicenter study conducted on patients with Non-Celiac Wheat Sensitivity (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 Irritable Bowel Syndrome/Functional Dyspepsia (IBS/FD) unrelated to food (including wheat) allergies/intolerances, and Celiac Disease (CeD), consecutively recruited in the same period and in the same outpatient clinics, before diagnosis (baseline) and after 1 year of follow-up.
Key inclusion criteria (19 listed)
- 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.
- Exclusion criteria for all the patients enrolled in the study
- self-exclusion of wheat from the diet and refusal to reintroduce it for diagnostic purposes, before entering the study;
Key exclusion criteria (0 listed)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Prevalence and severity of liver steatosis and fibrosis,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. | Diagnostic test | Celiac Disease (CeD) patients, Irritable Bowel Syndrome/Functional Dyspepsia (IBS/FD) patients unrelated to food allergies, Non-Celiac Wheat Sensitivity (NCWS) patients |
Primary outcome
Prevalence and severity of liver steatosis and fibrosis by Ultrasound examination
Time frame: At baseline, before diagnosis
Steatosis was evaluated according to international validated Ultrasound (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.
Prevalence and severity of liver steatosis by FibroScan analysis
Time frame: At baseline, before diagnosis
FibroScan analysis provides CAP (Controlled Attenuation Parameter, normal validated cut-offs of ≤275 dB/m) and LSM (Liver Stiffness Measurement, normal validated cut-offs of ≤5.5 kPa) values for liver steatosis and fibrosis, respectively. Detailed scores were, for CAP, Normal values ≤275 dB/m; Mild Steatosis (S1): 275-290 dB/m; Moderate Steatosis (S2): 290-302 dB/m; Severe Steatosis (S3): ≥302 dB/m. For LSM, F0 (No fibrosis): ≤5.5-6.0 kPa; F1 (Mild fibrosis): 5.6-7.0 kPa; F2 (Moderate/significant fibrosis): 7.1-9.4 kPa; F3 (Severe/Advanced fibrosis): 9.5-14.5 kPa; F4 (Cirrhosis): ≥14.6 kPa.
Prevalence and severity of liver steatosis and fibrosis by FIB-4
Time frame: At baseline, before diagnosis
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 and of ≥1.4 for moderate-high-risk.
Prevalence and severity of liver steatosis and fibrosis by NFS
Time frame: At baseline, before diagnosis
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 and of ≥1.456 for moderate-high-risk.
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 Aug 2026.
- Background: PubMed 17393509Angulo 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.
- Background: PubMed 16729309Sterling 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.
- Background: PubMed 36602836Rubio-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.
- Background: PubMed 25830946Buscemi 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.
- Background: PubMed 21618575Hernaez 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.
- Background: PubMed 38609737Seidita 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.
- Background: PubMed 26060111Schuppan 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.
- Background: PubMed 31622696Albillos 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.
- Background: PubMed 36208625Tilg 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.
- Background: PubMed 27055256European 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.
- Background: PubMed 36626630Younossi 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.
- Background: PubMed 31100380Fritscher-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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Pasquale Mansueto, MD study director
University of Palermo
Aurelio Seidita, MD study chair
University of Palermo
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Metabolic Dysfunction-Associated Steatotic Liver Disease and Non Celiac Wheat Sensitivity, run by University of Palermo at 2 sites in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 19 inclusion and 0 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 11 Aug 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Antonio Carroccio, MD (+393477279879, antonio.carroccio@unipa.it), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Prevalence and severity of liver steatosis and fibrosis by Ultrasound examination (time frame: At baseline, before diagnosis). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT07750535, which also lists 17 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Aug 2026.