Putative biomarkers of hepatic dysfunction in critically ill sepsis patients

Sepsis is a major cause of morbidity and mortality worldwide. Among the various types of end-organ damage associated with sepsis, hepatic injury is linked to significantly higher mortality rates compared to dysfunction in other organ systems. This study aimed to investigate potential biomarkers of hepatic injury in sepsis patients through a multi-center, case-control approach. We enrolled three matched cohorts: 37 sepsis patients with hepatic dysfunction (S-HD), 37 sepsis patients without hepatic dysfunction (S-CON), and 18 healthy controls (HC). We measured five proposed biomarkers of hepatic dysfunction-ARG1, MDH1, GSTα, 5-NT, and SDH-using multiplex immunoassays. These biomarkers were compared to traditional markers of hepatic dysfunction, including albumin, bilirubin, ALT, AST, and GGT, across the cohorts using both conventional statistical methods and machine learning techniques. The median age of participants was comparable across cohorts: S-HD (65.0 years, IQR 49.5-82.5), S-CON (65.0 years, IQR 48.0-81.5), and HC (62.5 years, IQR 53.0-65.0; P = 0.794). Patients with hepatic dysfunction (S-HD) exhibited higher illness severity scores compared to those without hepatic dysfunction (S-CON): MODS scores were median 7.0 (IQR 4.0-10.0) in S-HD versus median 4.0 (IQR 2.0-7.0) in S-CON (P = 0.005), and SOFA scores were median 7.0 (IQR 4.0-11.0) in S-HD versus median 3.0 (IQR 2.0-6.0) in S-CON (P < 0.001). Hemoglobin and platelet counts were lower, while creatinine levels were higher in S-HD compared to S-CON (P < 0.05). On ICU Day 1, bilirubin, ALT, AST, GGT, and INR were significantly elevated in S-HD relative to S-CON (P ≤ 0.001), and albumin levels were lower (P < 0.05). Additionally, ARG1, GSTα, 5-NT, and SDH were significantly higher in S-HD patients on ICU Day 1 compared to S-CON (P < 0.05). ARG1, MDH1, and SDH showed positive correlations with AST, ALT, and MODS (P < 0.01). From ICU Day 1 to Day 7, ARG1, GSTα, SDH, and AST levels significantly decreased in S-HD patients (P < 0.05), whereas MDH1 and 5-NT levels did not. Among the proposed biomarkers, GSTα and 5-NT did not correlate with traditional hepatic dysfunction markers but were significant in identifying S-HD patients (feature importance 0.131 and 0.097, respectively) in a random forest classification model. This comprehensive model demonstrated excellent performance in distinguishing sepsis patients with hepatic injury, with sensitivity 0.93, specificity 0.94, NPV 0.94, PPV 0.94, and AUC 0.94. The biomarkers ARG1, MDH1, GSTα, 5-NT, and SDH show promise as novel indicators of hepatic dysfunction associated with sepsis. This study provides a foundational basis for subsequent research aimed at characterizing and clinically validating these markers. Future investigations should focus on integrating these potential biomarkers into routine laboratory assessments for sepsis and related hepatic injury.

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