Subphenotypes and the De Ritis ratio for mortality risk stratification in sepsis-associated acute liver injury: a retrospective cohort study

Abstract

Background: Sepsis-associated liver injury (SALI) is associated with poor outcomes and increased mortality. However, effectively stratifying SALI patients according to prognosis remains challenging. This study evaluates laboratory-based clustering filters for stratifying SALI patients by 30-day mortality risk, utilizing data mining techniques for novel pattern discovery.

Methods: This retrospective cohort study analyzed SALI patients from two ICU databases: Medical Information Mart for Intensive Care (MIMIC)-IV database (n = 73,181, study period: 2008 to 2019) and Amsterdam UMC (n = 16,194, study period: 2003 to 2016). Patients were identified using Sepsis-3 criteria and liver injury markers. Risk stratification employed three laboratory-based approaches: (I) De Ritis ratio (aspartate aminotransferase/alanine aminotransferase), (II) R-factor (alanine aminotransferase and alkaline phosphatase relative to their upper limits of normal), and (III) alanine aminotransferase elevation. Kaplan-Meier analysis and multivariable Cox regression assessed the association between stratification methods and 30-day mortality risk.

Findings: SALI patients had almost a 2-fold higher risk of 30-day mortality than those without SALI (hazard ratio: 1.73; 95%-CI: 1.58-1.90, p < 0.0001). Each stratification method (I-III) successfully classified patients into statistically distinct risk strata. The De Ritis ratio emerged as the strongest prognostic differentiation method: a ratio ≤1 indicated no significant increase in mortality risk (hazard ratio: 0.86; 95%-CI: 0.68-1.09, p = 0.21), whereas ratios of 1-2 and ≥2 were significantly associated with higher mortality (hazard ratio: 1.56; 95%-CI: 1.37-1.78, p < 0.0001 and hazard ratio: 2.46; 95%-CI: 2.18-2.77, p < 0.0001, respectively). All findings were confirmed in the validation cohort.

Interpretation: The De Ritis ratio serves as a valuable prognostic tool for 30-day mortality in SALI patients. Our findings indicate that patients with a ratio ≥1 face significantly worse outcomes, highlighting the need for targeted interventions. These results refine risk stratification in SALI subphenotypes, enhancing our understanding of its prognostic implications.

Funding: This study received no external funding and was solely financed through the departmental resources of the authors.

Keywords: Acute liver injury; De Ritis ratio; Phenotype; SALI; Sepsis; Subphenotype.

Fig. 1

30-day survival of sepsis patients with and without SALI. Kaplan–Meier survival curves for patients with SALI in both the MIMIC-IV derivation cohort (A) and the Amsterdam UMC validation cohort (B). In both cohorts, patients with SALI exhibited significantly lower 30-day survival probabilities compared to those without SALI, with a HR of 1.73 (95% CI: 1.58–1.90, p < 0.0001) in the MIMIC-IV cohort and an HR of 1.46 (95% CI: 1.28–1.67, p < 0.0001) in the Amsterdam UMC cohort. SALI: Sepsis-associated liver injury; MIMIC-IV: Medical Information Mart for Intensive Care-IV database, HR: Hazard ratio; CI: Confidence Interval.

Fig. 2

30-day survival of SALI patients stratified by the De Ritis ratio. (A) Kaplan–Meier survival curves stratified by the De Ritis ratio show a clear separation in 30-day survival probabilities. Patients with a De Ritis ratio ≥2 had a significantly higher risk of mortality (HR 2.46, 95% CI: 2.18–2.77, p < 0.0001) compared to those with a ratio between 1 and 2 (HR 1.56, 95% CI: 1.37–1.78, p < 0.0001) and those with a ratio ≤1, who did not exhibit an increased mortality risk (HR: 0.86; 95% CI: 0.68–1.09, p = 0.21). (B) Stratification by the R-factor identified patients at elevated risk, with those in the R ≥ 5 category showing the highest mortality risk (HR 2.19, 95% CI: 1.93–2.49, p < 0.0001), followed by the 5 > R ≥ 2 group (HR 1.43, 95% CI: 1.12–1.82, p = 0.0045) and the R < 2 group (HR 1.53, 95% CI: 1.36–1.72, p < 0.0001). (C) Stratification by ALT concentrations demonstrated increased mortality in patients with ALT levels ≥5 times the ULN (HR 2.16, 95% CI 1.91–2.44, p < 0.0001), with progressively lower risks in the 5 ULN > ALT ≥2 ULN group (HR 1.42, 95% CI: 1.16–1.73, p < 0.0001) and the ALT <2 ULN group (HR 1.41, 95% CI: 1.23–1.60, p < 0.0001). SALI: Sepsis-associated liver injury; HR: Hazard ratio; CI: Confidence Interval; ALT: Alanine aminotransferase; ULN: Upper limit of normal.