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To the Editors:

With great interest, we read the study by Bohra et al,1 in which they evaluated serum free thiols (FTs) as biomarker reflecting systemic oxidative stress in patients with inflammatory bowel disease (IBD), relating these with endoscopic/histological disease activity. They also compared the discriminative capacity of FTs with established biomarkers, including C-reactive protein and fecal calprotectin, and identified independent associations with clinical and laboratory parameters. We value their prospective evaluation of FTs in IBD, advancing our prior work.2,3 Still, we would like to emphasize a critical aspect concerning the quantification and interpretation of circulating FT levels: the contribution of albumin to the extracellular FT status.4,5

Serum FTs are indicative of the overall in vivo redox status because they are readily oxidized by reactive species, particularly during inflammation.6 Extracellular FTs may be considered as a buffer, neutralizing reactive species, and they function as mediators linking the precursors of reactive species (via the reactive species interactome)4 to various biological thiol targets.6 Most circulating FTs (estimated at 60% to 75%) are represented by the single redox-active FT group in the primary structure of albumin (Cys34). Additionally, albumin is also a carrier for other low-molecular-weight FTs, aiding in its role as antioxidant.5,7 Albumin-associated FTs predominate in the circulation and are more frequently in a reduced state (~75%) compared with other thiols.5 In line, Bohra et al and other clinical studies similarly observed a strong correlation between albumin and circulating FTs.1-3,6 Total protein levels may also reflect protein-embedded FTs not accounted for by albumin.5,8 Thus, analyzing solely FTs instead of the ratio of free to oxidized thiols, while adjusting for albumin or total protein, can be regarded as an indirect (relative) way of accounting for total thiol content.4 The authors rightfully suspect albumin as a potential confounder given the substantial variation in serum albumin levels (median 39 g/L [range 24–50 g/L]) and its consistent appearance as strongly associated parameter across all multivariate analyses. Therefore, adjusting for albumin, either as a ratio or through residual correction, is highly recommended and will further substantiate the robustness of their key findings.

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