Definitions, Etiologies, and Outcomes of Acute on Chronic Liver Failure: A Systematic Review and Meta-analysis.

Background & Aims: Acute-on-chronic liver failure (ACLF) is a major public health concern. We aimed to assess the definitions, etiologic spectrum, organ failure (OF), and outcomes of ACLF globally.

Methods: Three databases were searched for studies on ACLF from 1990 until September 2022. Information regarding definitions, acute precipitants, underlying chronic liver disease (CLD), OF, and mortality were extracted. Meta-analyses were performed for pooled prevalence rates (95% confidence interval [CI]) using random-effects model for each definition of ACLF.

Results: Of the 11,451 studies identified, 114 articles (142 cohorts encompassing 210,239 patients) met the eligibility criteria. Most studies (53.2%) used the European Association for the Study of the Liver (EASL) definition, followed by Asia-Pacific Association for the Study of the Liver (APASL) (33.3%). Systemic infection was the major acute precipitant, and alcohol use was the major cause of CLD in EASL-defined studies, whereas alcohol was both the major acute precipitant and cause of CLD in APASL-defined studies. Liver failure was the major OF in APASL-based studies, whereas renal failure was predominant in EASL-based studies. Thirty-day mortality varied across definitions: APASL: 38.9%, 95% CI, 31.2%-46.9%; EASL: 47.9%, 95% CI, 42.2%-53.5%; and NACSELD: 52.2%, 95% CI, 51.9%-52.5%. Diagnostic overlap between definitions ranged from 7.7% to 80.2%. Meta-regression suggested that the World Health Organization region influenced 30-day mortality in studies using EASL definition.

Conclusions: Heterogeneity in the definition of ACLF proposed by different expert societies and regional preferences in its use result in differences in clinical phenotype and outcomes. A uniform definition would enhance the comparability and interpretation of global data.