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Review
. 2025 Jul 8;14(14):4848.
doi: 10.3390/jcm14144848.

Micronutrient Deficiencies Associated with a Gluten-Free Diet in Patients with Celiac Disease and Non-Celiac Gluten or Wheat Sensitivity: A Systematic Review and Meta-Analysis

Lindsey A Russell  1   2   3 , Paige Alliston  4 , David Armstrong  1   2 , Elena F Verdu  1   2 , Paul Moayyedi  1   2 , Maria Ines Pinto-Sanchez  1   2
Affiliations
Review

Micronutrient Deficiencies Associated with a Gluten-Free Diet in Patients with Celiac Disease and Non-Celiac Gluten or Wheat Sensitivity: A Systematic Review and Meta-Analysis

Lindsey A Russell et al. J Clin Med. .

Abstract

Background: A gluten-free diet (GFD) has been shown to be nutritionally inadequate for those with wheat-related disorders. However, the differences in findings and the absence of quantitative analysis limits the interpretation of previous reviews. Objectives: We conducted a systematic review and meta-analysis to identify the risk of micronutrient deficiencies in patients with celiac disease (CeD) and non-celiac gluten or wheat sensitivity (NCWS). Methods: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, and Web of Science (Ovid) databases. The risk of bias was determined using the ROBINS-1, and the quality of evidence was assessed using the GRADE approach. Results We identified 7940 studies; 46 observational studies (11 cohort, 9 cross-sectional, and 26 case-control) were eligible for analysis. CeD patients had an increased risk of vitamin D and E deficiencies compared with the non-CeD controls. CeD on a GFD had a decreased risk of vitamin D, B12, E, calcium, and iron deficiencies compared with untreated CeD. NCWS had an increased risk of vitamin B12, folate, and iron deficiency compared to the controls. The overall quality of evidence was rated very low. Conclusions: The risk of various micronutrient deficiencies is increased in CeD but is decreased for some after a GFD. Adequately powered studies with a rigorous methodology are needed to inform the risk of nutrient deficiencies in patients with CeD and NCWS. Protocol registration: Prospero-CRD42022313508.

Keywords: celiac disease; gluten-free diet; micronutrient deficiency; wheat-related diseases.

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Conflict of interest statement

MI Pinto-Sanchez received honoraria from Takeda for consulting and research funding from ProventBio; none of these are relevant to this manuscript. LR received an honorarium from Takeda and Baxter for presentations and holds a Napo Pharmaceuticals Inc research grant not related to this manuscript. D Armstrong has received honoraria from Takeda and Fresenius for consulting, presentations, and research funding from Nestlé© Canada; none are relevant to this manuscript. EFV received a grant from Biocodex and Gilead unrelated to this project.

Figures

Figure 1
Figure 1
Flow chart of literature search process. *—attempted retrieval was not successful.
Figure 2
Figure 2
Forest plot of micronutrient deficiencies in CeD on a GFD compared to CeD not on a GFD. (A) Vitamin 25 (OH) deficiency subgrouped by the duration of the GFD. (B) Vitamin E deficiency subgrouped by the study design. (C) Vitamin K deficiency as controlled by triglycerides. (D) Low ferritin. (E) Iron deficiency. (F) Zinc deficiency. The figure with the corresponding risk of bias is within Supplemental Figure S19. [19,20,23,24,25,26,35,38,42,50,51,54,55,57,58,62].
Figure 3
Figure 3
Forest plots’ comparison of micronutrient deficiencies in CeD on a GFD compared to non- CeD controls. (A) Vitamin D deficiency, (B) vitamin D deficiency stratified by study design, (C) vitamin D deficiency stratified by the duration of the GFD length, (D) vitamin E deficiency in a case–control study. The figure with the corresponding risk of bias is within Supplemental Figure S20. [30,31,50,54,55,57,62].
See this image and copyright information in PMC

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