Anemia in Non-celiac Wheat Sensitivity

February 4, 2022 updated by: Pasquale Mansueto, University of Palermo

Clinical Characteristics and Pathogenic Mechanisms of Anemia in Non-celiac Wheat Sensitivity Compared to Celiac Disease and Irritable Bowel Syndrome

In recent years, a new gluten- or wheat-related disease has emerged, a condition labelled "non-celiac gluten sensitivity" (NCGS) or "non-celiac wheat sensitivity" (NCWS). This is very often a self-reported condition, since patients refer to intestinal [mainly irritable bowel syndrome (IBS)-like] and/or extra-intestinal symptoms (i.e. fatigue, headache, anemia) caused by gluten or wheat ingestion, even though they do not suffer from celiac disease (CD) or wheat allergy (WA).

Among the extra-intestinal symptoms, several studies have shown, in patients with NCWS, the presence of anemia, generally mild, often with iron or folate deficiency characteristics, but no research has ever been planned with the specific intention of analyze this particular aspect of the disease.

Therefore, the aim of the present multicentric research was to analyze, both retrospectively and prospectively, the laboratory data of NCWS patients, compared to CD and IBS controls, to identify: a) the presence, severity and morphologic characteristic of anemia; 2) possible pathogenic mechanisms.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

In recent years, a new gluten- or wheat-related disease has emerged, a condition labelled "non-celiac gluten sensitivity" (NCGS) or "non-celiac wheat sensitivity" (NCWS). This is very often a self-reported condition, since patients refer to intestinal [mainly irritable bowel syndrome (IBS)-like] and/or extra-intestinal symptoms (i.e. fatigue, headache, anemia) caused by gluten or wheat ingestion, even though they do not suffer from celiac disease (CD) or wheat allergy (WA).

There are conflicting data about the real mechanisms which induce symptoms in NCGS/NCWS patients after wheat ingestion. Some authors suggested a prevalent role for Fermentable Oligosaccharides-Disaccharides-Monosaccharides and Polyols (FODMAPs), rather than gluten in determining the symptoms. Other studies underlined the activation of mechanisms of both innate and acquired immunity in NCWS patients after wheat ingestion.

Given the lack of a diagnostic biomarker, NCGS/NCWS mostly remains a diagnosis of exclusion, especially respect to CD and WA, so a confirmatory test is required. The "Salerno criteria" suggested the double-blind, placebo-controlled (DBPC), cross-over, gluten/wheat challenge as the gold standard test to discriminate true NCGS/NCWS patients.

By definition, NCGS/NCWS symptoms generally occur after the ingestion of gluten/wheat, disappear within a few days of a gluten-free diet (GFD) and quickly reappear when gluten/wheat is, voluntarily or accidentally, reintroduced. However, GDF is very difficult and onerous from a social (presence of gluten in many industrial food products and "contamination", both domestic and extra-domestic), psychological (e.g. for adolescents, exclusion from the "peer group", with difficulty in accepting the diagnosis) and economic point of view.

Among the extra-intestinal symptoms, several studies have shown, in patients with NCWS, the presence of anemia, generally mild, often with iron or folate deficiency characteristics, but no research has ever been planned with the specific intention of analyze this particular aspect of the disease.

Therefore, the aim of the present multicentric research was to analyze, both retrospectively and prospectively, the laboratory data of NCWS patients, compared to CD and IBS controls, to identify: a) the presence, severity and morphologic characteristic of anemia; 2) possible pathogenic mechanisms, with particular attention to iron, vitamin B12 and folate metabolism, thyroid hormones, and autoimmune gastric involvement.

Study Type

Observational

Enrollment (Actual)

244

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Italy
      • Palermo, Italy, 90129
        • Department of Internal Medicine, University Hospital of Palermo
    • Agrigento
      • Sciacca, Agrigento, Italy, 92019
        • Department of Internal Medicine, Giovanni Paolo II Hospital of Sciacca
    • PA
      • Palermo, PA, Italy, 90129
        • Internal Medicine Division of the "Cervello-Villa Sofia" Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

N/A

Genders Eligible for Study

All

Sampling Method

Probability Sample

Study Population

We will enroll NCWS patients, both with retrospective and prospective methods. As controls groups, we will enroll CD and IBS patients, both with retrospective and prospective methods.

Description

Inclusion Criteria:

  1. To diagnose NCWS the recently proposed criteria will be adopted. All the patients will meet the following criteria:

    - negative serum anti-transglutaminase (anti-tTG) and anti-endomysium (EmA) immunoglobulin (Ig)A and IgG antibodies, absence of intestinal villous atrophy, negative IgE-mediated immune-allergy tests to wheat (skin prick tests and/or serum specific IgE detection), resolution of the IBS symptoms on standard elimination diet, excluding wheat, cow's milk, egg, tomato, chocolate, and other self-reported food(s) causing symptoms, symptom reappearance on double-blind placebo-controlled (DBPC) wheat challenge. As the investigators previously described in other studies, DBPC cow's milk protein challenge and other "open" food challenges will be performed too.

  2. To diagnose CD the standard criteria will be adopted. All the patients will meet the following criteria:

    - positive serum anti-transglutaminase (anti-tTG) and anti-endomysium (EmA) immunoglobulin (Ig)A and IgG antibodies presence of intestinal villous atrophy.

  3. To diagnose IBS the standard Rome II (for retrospective patients) and Rome III (for prospective patients) Criteria will be adopted. None of these subjects improved on an elimination diet without wheat, cow's milk, egg, tomato, or chocolate.

Exclusion Criteria:

For NCWS diagnosis it will be evaluated the following exclusion criteria:

- positive EmA in the culture medium of the duodenal biopsies, also in the case of normal villi/crypts ratio in the duodenal mucosa, self-exclusion of wheat from the diet and refusal to reintroduce it before entering the study, other previously diagnosed gastrointestinal disorders, other previously diagnosed gynaecological disorders, nervous system disease and/or major psychiatric disorder, physical impairment limiting physical activity.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Case-Control
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
NCWS retrospective and prospective patients
The clinical charts of NCWS patients, diagnosed by DBPC gluten/wheat challenge, between January 2001 and December 2019, attending the Department of Internal Medicine at the University Hospital of Palermo, the Department of Internal Medicine of the Hospital of Sciacca, and the Department of Medical and Surgical Sciences of the University of Bologna, will be reviewed retrospectively. The investigators prospectively will also survey patients with functional gastroenterological symptoms according to the Rome III criteria, and a definitive diagnosis of NCWS by DBPC gluten/wheat challenge. The patients will be recruited between January 2019 and January 2022 at the same centers, and at the Internal Medicine Division of the "Cervello-Villa Sofia" Hospital of Palermo, Palermo.
Diagnostic test: Evaluation of anemia
Evaluation of anemia in NCWS patients, and in CD and IBS controls, with both retrospective and prospective method.
CD retrospective and prospective control patients
To compare the presence and characteristics of anemia in NCWS patients, the clinical charts of a control group of CD patients had been randomly chosen by a computer-generated method from patients diagnosed in the same centers, during the same period (2001-2019), and age- and sex-matched with the NCWS patients. The investigators prospectively will also survey a control group of CD patients randomly chosen by a computer-generated method from subjects diagnosed in the same centers, during the same period (2019-2022), and age- and sex-matched with the NCWS patients.
Diagnostic test: Evaluation of anemia
Evaluation of anemia in NCWS patients, and in CD and IBS controls, with both retrospective and prospective method.
IBS retrospective and prospective control patients
To compare the presence and characteristics of anemia in NCWS patients, the clinical charts of another control group of IBS patients had been randomly chosen by a computer-generated method from patients diagnosed in the same centers, during the same period (2001-2019), and age- and sex-matched with the NCWS patients. The investigators prospectively will also survey a control group of IBS patients randomly chosen by a computer-generated method from subjects diagnosed in the same centers, during the same period (2019-2022), and age- and sex-matched with the NCWS patients.
Diagnostic test: Evaluation of anemia
Evaluation of anemia in NCWS patients, and in CD and IBS controls, with both retrospective and prospective method.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Presence, severity and morphologic characteristic of anemia
Time Frame: At baseline and at 24 months
red blood cells (adults references ranges, RR, 4.5-5.9 million cells/mcL, men, 4.1-5.1 million cells/mcL, women), hemoglobin (RR 13-17 g/dL, men, 12-15 g/dL, women), hematocrit (RR 40%-52%, men, 36%-47%, women), mean corpuscular volume (RR 80-100 fL), mean corpuscular hemoglobin (RR 0.4-0.5 fmol/cell), mean corpuscular hemoglobin concentration (RR 30-35 g/dL), red cell distribution width (RR 11.5%-14.5%)
At baseline and at 24 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Possible pathogenic mechanisms
Time Frame: At baseline and at 24 months
reticulocytes count (RR 0.5%-1.5%), total serum iron (RR 65-180 µg/dL, men, 30-170 µg/dL, women), ferritin (RR 12-300 ng/mL, men, 12-150 ng/mL, women), transferrin (200-350 mg/dL), total iron-binding capacity (RR 45-85 µmol/L), vitamin B12 (RR 130-700 ng/L), folic acid (RR 7-36 nmol/L), thyroid-stimulating hormone (TSH, RR 2-10 μU/mL), anti-nuclear antibodies (ANA), anti-intrinsic factor (IFA) and/or parietal cell (APCA) antibodies
At baseline and at 24 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Palermo

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 1, 2020

Primary Completion (Actual)

January 1, 2021

Study Completion (Actual)

January 1, 2022

Study Registration Dates

First Submitted

May 1, 2020

First Submitted That Met QC Criteria

May 1, 2020

First Posted (Actual)

May 6, 2020

Study Record Updates

Last Update Posted (Actual)

February 7, 2022

Last Update Submitted That Met QC Criteria

February 4, 2022

Last Verified

February 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ACPM25

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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