Thiols as a marker of inflammatory bowel disease activity: a ... - BMC Gastroenterology
Search results
According to the search strategy (see PRISMA diagram, Figure 1), 2034 articles were found in the accessed databases. Of these, 550 articles were excluded after database screening and removal of duplicates and 1484 studies were read for titles and abstracts. Analyzing titles and abstracts resulted in the exclusion of 1473 studies for not meeting the eligibility criteria. The remaining eleven (11) records were read in full and three (3) of them were excluded for the following reasons: two (2) records had data published in poster format, which had data from two other included studies in this review, being excluded, to avoid duplication of data analysis. One (1) study published in trial format was excluded, as there were no results available; there was an attempt to contact the authors of this study to obtain information on partial data, unpublished or in preprint, however, there was no response to email.
Description of articles included in the systematic review
The included studies in this review were developed in the following countries: Turkey, Netherlands and Poland. The Table 4 shows the summary of the characteristics and main results of the studies. In total, 979 subjects were evaluated: 321 with UC, 342 with CD and 316 healthy controls participated in the studies. Only two studies [1, 7] exclusively evaluated subjects in remission (one study evaluated 20 subjects with UC in remission and the other evaluated 51 subjects with CD in remission, respectively) and only one study exclusively evaluated individuals with active CD [25]. The included studies in this review had data collected between 2006 and 2018 and were published between 2008 and 2020. There was no standardization regarding the type of thiol measured as an expression of the oxidative state nor the method used for its dosage. Of the included studies, five (1, 2, 4, 8, 25) used the method described by Elman´s et al. [20] for thiol measurement, but only four [1, 2, 4, 25] corrected for plasma albumin, as described by Hu et al. [21] and Turel et al. [22]. The method proposed by Erel & Neselioglu [23] was used for thiol dosage in one study [6]. The other two studies [5, 7] included in this review did not explain the reagent used to measure thiols. All studies described the use of spectrophotometric analysis for thiol dosage.
This systematic review included seven (7) analytical observational studies, case-control type [1, 2, 4,5,6,7,8] and only one (1) prospective clinical intervention study [25] that measured thiol levels in individuals with CD/UC with the aim of evaluating the potential association with oxidative stress and DII. Two studies [4, 7] evaluated only subjects with UC and two studies [1, 25] evaluated only subjects with CD. Only one study [1] evaluated only individuals in remission, one study [26] evaluated only individuals in active CD and two studies [5, 7] evaluated individuals with active and remitting IBD, comparing the results between individuals in different phases of the inflammatory disease. In all eight included studies [1, 2, 4,5,6,7,8, 25] there were changes in thiol levels in individuals with CD/UC and the authors inferred that there was oxidative stress associated with IBD.
Type of measured thiol
Of the eight included studies in this systematic review, four [4,5,6,7] used the levels of native and/or total serum thiols as a marker of thiol oxidation; three studies [1, 2, 25] used plasma free thiol levels adjusted for albumin levels to assess systemic oxidative stress, and only one study [8] used plasma free thiol levels, but did not report whether there was a correction by plasma albumin levels, despite the attempt to obtain this methodological detail, by contacting the research group's electronic address. The lack of standardization of the type of thiol and the thiol dosage method limited the pooled analysis of the studies and made it impossible to compare the results in combined analyzes.
Thiol expression and relationship with oxidative stress in inflammatory bowel disease
Baskol et al. [4] detected increased total thiol levels in subjects with UC compared to controls. Akinci et al. [5], when conducting the study with the largest number of individuals with IBD, included in this review, of both phenotypes, at different stages of the disease, found total thiol levels positively associated only with active CD. Yuksel et al. [6] identified a negative association between the reduction of total and native thiols in active CD and between native thiols in active UC, supported by a negative correlation between native thiol and EAI, CDAI, erythrocyte sedimentation rate (TSE) and C-reactive protein (CRP) in individuals with active CD and UC, when compared with healthy controls. Neselioglu et al. [7] found: I. negative association between: a: the levels of native and total thiols in individuals with active UC; b: native thiol and CRP; c: native thiol and TSE; d: thiol homeostasis and UC activity/severity; II. positive correlation between native thiol and albumin; III. lower total thiol levels in subjects with UC compared to healthy controls and IV. higher total and native thiol levels in subjects with UC in remission than subjects with active UC or healthy controls. From these results, these researchers related disease activity to thiol oxidation, and suggested of using thiol as a serum marker to assess activity and predict the severity of the disease course.
In 2019, the study conducted by Bourgonje et al. [1] was the precursor, among the included studies in this review, to measure the plasma concentrations of free thiols adjusting them to albumin, considering the characteristic of circulation of thiols in the human body [1, 9, 23, 24]. This group detected decreased levels of thiols in individuals with CD in remission compared to healthy controls, a negative correlation between plasma thiols and inflammation biomarkers, including CRP and IL-17A, enabling the correlation of subclinical CD activity to systemic oxidative stress. Another study, conducted by Bourgonje et al. [2] detected a strong correlation between plasma thiols and the degree of inflammatory disease activity evaluated endoscopically and a negative correlation between plasma thiol levels and fecal calprotectin (FC) levels in individuals with IBD, of both phenotypes, this time in activity, comparing them with healthy controls, allowing the discrimination, with high precision and in a significant way, of the degree of activity (mild, moderate or severe) of the disease, better than the FC. The Polish study conducted by Neubauer et al. [8] detected lower amounts of thiol in people with CD and UC, regardless of disease activity, when compared to healthy controls. Still, the thiol concentrations of individuals with CD and UC with active disease were inversely correlated with CDAI and Rachmilewitz Index (RI), respectively. However, this inverse relationship did not reach statistical significance. Based on these results, these authors suggested the use of plasma thiols as a therapeutic target to monitor IBD activity, as it is a minimally invasive strategy, presents an inverse correlation with the severity/severity of intestinal inflammation, and therapeutic modulation, through the administration of of antioxidants, considering that higher levels of plasma thiols would be associated with lower levels of inflammatory biomarkers and favorable systemic status and evolution in IBD.
It is important to consider that individuals with IBD treated with corticosteroids had lower thiol levels in the study conducted by Neubauer et al. [8]. Free thiol concentrations were decreased, mainly in the active CD, and were inversely related to inflammatory markers and oxidative stress, demonstrating depleted total antioxidant capacity, instrumentalizing these authors to conclude that the assessment of the total systemic antioxidant status can be useful in the evaluation not invasive of mucosal healing in individuals with IBD, and, additionally, that the assessment of serum thiol levels can provide relevant information about the adverse effects of corticosteroid therapy.
The most recent study included in this review was the one conducted by Von Martels et al. [25]. These researchers identified that there was no significant reduction in FC levels of the 70 patients with active CD after three weeks of riboflavin supplementation (100 mg daily). Still, thiol levels increased and clinical symptoms of CD decreased. These findings were attributed to the anti-inflammatory effects of riboflavin supplementation, which are associated with a reduction in oxidative stress, as measured by plasma levels of free thiols, which were increased.From the analysis of the included studies in this review, it was possible to identify relevant results related to systemic oxidative stress, measured by serum thiol levels, and IBD activity, and negative association with inflammatory markers. The findings of a strong correlation between the degree of endoscopic disease activity and a negative correlation between FC and serum thiols strengthen the justification for investigating the potential of thiols as a marker of oxidative stress in IBD.
Methodological Quality and Risk of Bias
The assessment of the risk of bias of the selected studies is presented in Table 2 and Table 3. Eight studies were included in the assessment of the risk of bias.
The study conducted by Von Martels et al. [25] presents a domain (related to the outcome measure) with a high risk of bias, in the assessment by ROBINS I [17], for intervention studies, as proposed by the Cochrane Handbook [18]. Carrying out the intervention without a control group, measuring oxidative stress only in individuals with active DC, is a weakness in the study design, as it prevents accurate assessments, compromising the quality of the results.The other 7 studies included in this systematic review were observational studies, of the case-control type, and, for this reason, had the risk of bias and methodological quality evaluated by the instrument The Newcastle Ottawa Scale of Case-Control Studies [27], in agreement with the recommendation of the Cochrane Handbook [26]. In According to the methodological quality assessment proposed by this scale, it was observed that most studies presented more than 77.7% of adequacy in terms of quality, with percentages that varied between 66.6% and 88.8%. The issue that most contributed to the reduction in the methodological quality assessment and the increase in the risk of bias in these studies was the criteria for selecting controls, which were not described in some studies. None of the included studies assessed the outcome non-response rate, which determined the loss of points from all included studies in this review for this domain.
Based on the evaluation criteria of The Newcastle Ottawa Scale of Case-Control Studies [27], of the seven included studies in the review, two of them [1, 2] achieved the best evaluation and scored 8/9 stars, losing points for not presenting the outcome non-response rate assessment. Three studies [4, 7, 8] scored 7/9 stars; the studies by Baskol et al. [4] and Neubauer et al. [8] lost points due to the lack of characterization of the selection of controls and for not presenting the non-response rate in the studies. As for the study by Neselioglu et al. [7], the evaluation was reduced in the comparability of cases and controls and by the absence of evaluation of the non-response rate of the outcome.
The two studies [5, 6] rated as the lowest methodological quality in this review scored 6/9 stars, with 66.6% adequacy. The domains that determined the downgrading of the evaluation of these two studies were the selection and definition of controls [5] and the comparability of cases and controls [6]; these two studies also lost points for not evaluating the outcome non-response rate.
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