In Reference to <i>The Role of Hypoalbuminemia in the Development of Reinke's Edema: A Prospective Cohort Study</i>

We read the paper of Li et al. who prospectively investigated the association between hypoalbuminemia and Reinke's edema (RE) development [1]. Authors compared 41 patients with hypoalbuminemia related to nephrotic syndrome and 43 controls, reporting a significantly higher prevalence of RE in the hypoalbuminemia group compared to the control. Based on a logistic regression, they suggested that hypoalbuminemia is an independent etiological factor for RE [1]. We thank the authors for this interesting study. In this letter, we wish to draw attention to many points. First, the exclusive focus on nephrotic syndrome patients as the hypoalbuminemic cohort introduces a systematic bias, as this specific etiology represents merely one subset of hypoalbuminemic conditions with distinct pathophysiological mechanisms. Precisely, nephrotic syndrome involves a chronic systematic inflammation characterized by elevated pro-inflammatory cytokines, including IL-6 and TNF-α, which may independently promote laryngeal tissue edema through increased vascular permeability [2, 3]. Second, the common distal tissue edema associated with nephrotic syndrome [2] may affect laryngeal tissues independently of serum albumin levels, which should be an indirect indicator of edema severity rather than an independent etiological factor of RE. Third, the deficit of proteins in nephropathy is frequently associated with micronutrient deficiencies (zinc, vitamin D) that may compromise epithelial integrity and wound healing through an increase of inflammation and oxidative stress [4, 5]. In that way, the potential benefit of D Vitamin and Zinc in the vocal fold mucosa healing led some authors to prescribe such micronutrients in recalcitrant granuloma [5]. Finally, patients with nephrotic syndrome are found to have significant higher proportions of worse fatigue, pain interference, sleep impairment, depression, and anxiety [6]; all being associated with autonomic nerve dysfunction and potential related laryngopharyngeal reflux disease (LPRD). Before establishing a causality between RE and nephrotic syndrome related hypoalbuminemia, authors should exclude confounding such as reflux [7]. For the above-mentioned reasons, rather than direct etiology, hypoalbuminemia may represent a biomarker of underlying systemic pathophysiology associated with a permissive environment for RE development. To conclude, the association between hypoalbuminemia and RE needs to be investigated through a more heterogeneous group of individuals with hypoalbuminemia and should consider the overall tissue edema related to the reduction of the blood osmolality rather than a mechanistic association between albuminemia and RE. The authors have nothing to report. The authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request.