In this retrospective study, the ALBI score was associated with an increased risk of mortality among NHL-sHLH patients with hepatic injuries. The combination of pretreatment ALBI score and serum ferritin, a benchmark prognostic marker in sHLH patients, improved prognostic prediction discrimination. Our data revealed that ALBI was a better prognostic tool in predicting short-term (30 days) or long-term (≥1 year) survival, which persisted after extensive adjustment of confounding variables, including demographic, clinical, laboratory examinations and traditional sHLH risk factors. Moreover, we demonstrated that the ALBI score has a direct positive association with mortality in the total cohort by restricted cubic spline (RCS) modeling. In addition, the combination of the ALBI score and ferritin provided incremental prognostic value for each measure separately for both 30-day and 1-year survival. These results suggest that the ALBI score is a better predictive marker for survival in patients with hepatic injuries.
Lymphoma is a common trigger identified in adult sHLH, especially non-Hodgkin lymphoma-associated sHLH (NHL-sHLH), which has a high mortality rate, with an estimated 30-day survival of approximately 56-70% and 2-year survival of 8-34.3%21–23. These patients frequently present a combination of persistent fever, elevated aminotransferase (AST, ALT), decreased serum albumin, jaundice, and hepatomegaly or splenomegaly. Several studies have evaluated whether sHLH patients with hepatic involvement have a poorer prognosis8, 14; therefore, early prediction of survival outcome contributes greatly to patient management and aids in making appropriate risk assessments as well as treatment decisions. Clinically, the ALBI score has been widely used for assessing liver function and predicting survival outcomes in various diseases with liver dysfunction. Takeshi et al prospectively evaluated the ALBI grade as a predictor of survival in a multicenter cohort of 1,190 patients with acute heart failure (AHF). After adjusting for pre-existing prognostic factors, the ALBI score was associated with 1-year mortality (HR= 2.11, 95% CI: 1.60–2.79, P<0.001)12. Zhang also showed similar findings; the ALBI grade appears to be a promising prognostic biomarker associated with overall survival (HR=1.60, 95% CI: 1.12–2.29, P=0.02) in critically ill patients with acute pancreatitis13. Moreover, several studies have described that serum albumin and total bilirubin are significantly associated with mortality in HLH patients8, 24. Our study, by multivariate regression analysis and RCS modeling, clearly demonstrated that ALBI was strongly associated with survival outcomes (both 30-day mortality and overall survival (≥ 1 year)). In addition, our investigation in this study demonstrated that the combination analysis of ALBI score and ferritin had a significant improvement over either ALBI score (AUC 30 days: 0.820 vs 0.693, P = 0.001; AUC1 year: 0.754 vs 0.681, P = 0.043) or ferritin (AUC30 days: 0.820 vs 0.724, P = 0.005; AUC1 year: 0.754 vs 0.658, P = 0.031) alone.
The increased risk of mortality associated with a higher ALBI score might be ascribed to uncontrolled proliferation of cytotoxic CD8+ T lymphocytes (CTLs) and macrophages, creating an uncontrolled loop of inflammation that is responsible for hepatic injuries. ALBI, consisting of serum albumin and total bilirubin, could reflect the systemic inflammatory response. On the one hand, serum albumin plays an important role in modulating systemic inflammatory reactions and organic oxidation resistance25; on the other hand, serum total bilirubin is always elevated with hepatobiliary dysfunction in response to various cytokines in circulating blood, such as interferon-g (IFN-γ), interleukin-1beta (IL-1β), and interleukin-6 (IL-6)8. All of the above mechanisms, alone or together, may be attributed to decreased serum albumin and elevated total bilirubin and indirectly reflect the degree of hepatic injury.
Our findings provide references that routine clinical laboratory assays such as serum albumin and total bilirubin can be used to identify patients at higher risk of death while applying an advanced evaluation for NHL-sHLH patients. This is the first study that addressed the ALBI score, a promising hepatic injury tool, and the risk of mortality (both short-term and long-term survival). The ALBI score improved risk predictions of mortality in both the short and long term and could provide clinical guidance for timely multidisciplinary discussions of when to initiate HLH-directed immune suppressants and NHL-directed intensive chemotherapy. However, several limitations of our study were noted. First, the enrolled study population was small, and the study was retrospective in nature. Second, although we had fully adjusted a broad set of covariates, we could not rule out the role of unmeasured or unrecognized confounders. Finally, the observational study could only demonstrate the association between ALBI score/grade and the prognosis of patients but could not provide conclusions for causality.