Anemia in Non-celiac Wheat Sensitivity

Anemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04377061
• Other study ID #: ACPM25
• Status: Completed
• Start date: January 1, 2020
• Est. completion date: January 1, 2022

Study information

• Verified date: February 2022
• Source: University of Palermo
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 244
• Est. completion date: January 1, 2022
• Est. primary completion date: January 1, 2021
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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.

Related Conditions & MeSH terms

• Anemia
• Hypersensitivity
• Non-celiac Gluten Sensitivity

Intervention

Diagnostic Test:
• Evaluation of anemia
Evaluation of anemia in NCWS patients, and in CD and IBS controls, with both retrospective and prospective method.

Locations

Country	Name	City	State
Italy	Department of Internal Medicine, University Hospital of Palermo	Palermo
Italy	Internal Medicine Division of the "Cervello-Villa Sofia" Hospital	Palermo	PA
Italy	Department of Internal Medicine, Giovanni Paolo II Hospital of Sciacca	Sciacca	Agrigento

Sponsors (1)

Lead Sponsor	Collaborator
University of Palermo

Country where clinical trial is conducted

Italy, 

References & Publications (14)

Caio G, Volta U, Tovoli F, De Giorgio R. Effect of gluten free diet on immune response to gliadin in patients with non-celiac gluten sensitivity. BMC Gastroenterol. 2014 Feb 13;14:26. doi: 10.1186/1471-230X-14-26. — View Citation

Carroccio A, D'Alcamo A, Cavataio F, Soresi M, Seidita A, Sciumè C, Geraci G, Iacono G, Mansueto P. High Proportions of People With Nonceliac Wheat Sensitivity Have Autoimmune Disease or Antinuclear Antibodies. Gastroenterology. 2015 Sep;149(3):596-603.e1 — View Citation

Carroccio A, Giannone G, Mansueto P, Soresi M, La Blasca F, Fayer F, Iacobucci R, Porcasi R, Catalano T, Geraci G, Arini A, D'Alcamo A, Villanacci V, Florena AM. Duodenal and Rectal Mucosa Inflammation in Patients With Non-celiac Wheat Sensitivity. Clin G — View Citation

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. A — View Citation

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. — View Citation

Carroccio A, Soresi M, D'Alcamo A, Sciumè C, Iacono G, Geraci G, Brusca I, Seidita A, Adragna F, Carta M, Mansueto P. Risk of low bone mineral density and low body mass index in patients with non-celiac wheat-sensitivity: a prospective observation study. — View Citation

De Giorgio R, Volta U, Gibson PR. Sensitivity to wheat, gluten and FODMAPs in IBS: facts or fiction? Gut. 2016 Jan;65(1):169-78. doi: 10.1136/gutjnl-2015-309757. Epub 2015 Jun 15. Review. — View Citation

Di Sabatino A, Volta U, Salvatore C, Biancheri P, Caio G, De Giorgio R, Di Stefano M, Corazza GR. Small Amounts of Gluten in Subjects With Suspected Nonceliac Gluten Sensitivity: A Randomized, Double-Blind, Placebo-Controlled, Cross-Over Trial. Clin Gastr — View Citation

Mansueto P, Seidita A, D'Alcamo A, Carroccio A. Non-celiac gluten sensitivity: literature review. J Am Coll Nutr. 2014;33(1):39-54. doi: 10.1080/07315724.2014.869996. Review. — View Citation

Mansueto P, Soresi M, La Blasca F, Fayer F, D'Alcamo A, Carroccio A. Body Mass Index and Associated Clinical Variables in Patients with Non-Celiac Wheat Sensitivity. Nutrients. 2019 May 29;11(6). pii: E1220. doi: 10.3390/nu11061220. — View Citation

Uhde M, Ajamian M, Caio G, De Giorgio R, Indart A, Green PH, Verna EC, Volta U, Alaedini A. Intestinal cell damage and systemic immune activation in individuals reporting sensitivity to wheat in the absence of coeliac disease. Gut. 2016 Dec;65(12):1930-19 — View Citation

Volta U, Caio G, De Giorgio R. Is Autoimmunity More Predominant in Nonceliac Wheat Sensitivity Than Celiac Disease? Gastroenterology. 2016 Jan;150(1):282. doi: 10.1053/j.gastro.2015.08.058. Epub 2015 Nov 23. — View Citation

Volta U, De Giorgio R, Caio G, Uhde M, Manfredini R, Alaedini A. Nonceliac Wheat Sensitivity: An Immune-Mediated Condition with Systemic Manifestations. Gastroenterol Clin North Am. 2019 Mar;48(1):165-182. doi: 10.1016/j.gtc.2018.09.012. Epub 2018 Dec 13. — View Citation

Volta U, Pinto-Sanchez MI, Boschetti E, Caio G, De Giorgio R, Verdu EF. Dietary Triggers in Irritable Bowel Syndrome: Is There a Role for Gluten? J Neurogastroenterol Motil. 2016 Oct 30;22(4):547-557. doi: 10.5056/jnm16069. Review. — View Citation

* Note: There are 14 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Presence, severity and morphologic characteristic of anemia	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	Possible pathogenic mechanisms	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