Systematic Reviews
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Apr 28, 2021; 27(16): 1828-1840
Published online Apr 28, 2021. doi: 10.3748/wjg.v27.i16.1828
Surrogate markers of mucosal healing in inflammatory bowel disease: A systematic review
Monica State, Lucian Negreanu, Theodor Voiosu, Andrei Voiosu, Paul Balanescu, Radu Bogdan Mateescu
Monica State, Theodor Voiosu, Andrei Voiosu, Radu Bogdan Mateescu, Department of Gastroenterology, Colentina Clinical Hospital, Bucharest 020125, Romania
Lucian Negreanu, Department of Gastroenterology, Emergency University Hospital, Bucharest 050098, Romania
Lucian Negreanu, Theodor Voiosu, Andrei Voiosu, Paul Balanescu, Radu Bogdan Mateescu, Carol Davila University of Medicine and Pharmacy, Bucharest 020021, Romania
Paul Balanescu, Department of Internal Medicine and Research Methodology, Colentina Clinical Hospital, Bucharest 020125, Romania
Author contributions: State M, Balanescu P contributed to study design; State M, Voiosu T, Voiosu A and Balanescu P contributed to data acquisition, analysis and interpretation; State M, Voiosu T, Voiosu A, Negreanu L and Mateescu RB contributed to writing of this article; Negreanu L, State M and Mateescu RB contributed to editing, reviewing and final approval of the article.
Conflict-of-interest statement: The authors have no conflicts of interest to declare.
PRISMA 2009 Checklist statement: The authors have read the PRISMA 2009 Checklist, and the manuscript was prepared and revised according to the PRISMA 2009 Checklist.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Lucian Negreanu, MD, Assistant Professor, Department of Gastroenterology, Emergency University Hospital, Splaiul Independentei 169, Bucharest 050098, Romania.
Received: January 27, 2021
Peer-review started: January 27, 2021
First decision: February 25, 2021
Revised: March 2, 2021
Accepted: April 7, 2021
Article in press: April 7, 2021
Published online: April 28, 2021

Mucosal healing (MH) has emerged as a key therapeutic target in inflammatory bowel disease (IBD), and achievement of this goal is documented by endoscopy with biopsy. However, colonoscopy is burdensome and invasive, and substitution with an accurate noninvasive biomarker is desirable.


To summarize published data regarding the performance of noninvasive biomarkers in assessing MH in IBD patients.


We conducted a systematic review of studies that reported the performance of biomarkers in diagnosing MH in patients with IBD. The main outcome measure was to review the diagnostic accuracy of serum and fecal markers that showed promising utility in assessing MH.


We screened 1301 articles, retrieved 46 manuscripts and included 23 articles for full-text analysis. The majority of the included manuscripts referred to fecal markers (12/23), followed by circulatory markers (8/23); only 3/23 of the included manuscripts investigated combined markers (serum and/or fecal markers). Fecal calprotectin (FC) was the most investigated fecal marker for assessing MH. In ulcerative colitis, for cutoff levels ranging between 58 mcg/g and 490 mcg/g, the sensitivity was 89.7%-100% and the specificity was 62%-93.3%. For Crohn’s disease, the cutoff levels of FC ranged from 71 mcg/g to 918 mcg/g (sensitivity 50%-95.9% and specificity 52.3%-100%). The best performance for a serum marker was observed for the endoscopic healing index, which showed a comparable accuracy to the measurement of FC and a higher accuracy than the measurement of serum C-reactive protein.


Several promising biomarkers of MH are emerging but cannot yet substitute for endoscopy with biopsy due to issues with reproducibility and standardization.

Keywords: Inflammatory bowel disease, Ulcerative colitis, Crohn’s disease, Biomarkers, Serum, Fecal, Mucosal healing

Core Tip: Identification of performant biomarkers that can substitute for repeated and cumbersome invasive procedures is a priority. Although therapeutic success in both Crohn’s disease and ulcerative colitis remains to be clearly defined, mucosal healing has been one of the main therapeutic targets stipulated by recent recommendations. In inflammatory bowel disease mucosal healing, several serum- and fecal-based markers have shown promising results; however, a multimarker may improve the diagnostic accuracy of any single independent biomarker.