Liver Injury in Children With Sepsis Signals Higher Death Risk, But Evidence Remains Weak

When a child’s body is overwhelmed by sepsis, the cascade of inflammation and failing organs can strike almost any tissue, but one organ has long been overlooked in pediatric critical care: the liver. A new systematic review and meta-analysis published in BMC Pediatrics by researchers from the Gastrohepatology Division of Cipto Mangunkusumo Hospital at the Faculty of Medicine, Universitas Indonesia, has now pulled together the scattered evidence on sepsis-associated liver injury, or SALI, in children. The team, led by Nathaniel Evan Raphaela Wiriadinata and senior author Hanifah Oswari, set out to answer a deceptively simple question: does liver injury during pediatric sepsis actually predict which children die? Their conclusion is a careful one. Children whose livers falter during sepsis do face roughly four times higher odds of dying in hospital, but the certainty of that evidence is very low, and the finding may simply reflect how sick these children already are rather than any independent contribution of the liver itself.

Sepsis remains one of the leading causes of death in children worldwide, arising when an infection triggers a dysregulated immune response that damages the body’s own organs. In adults, clinicians have long recognized that the liver is both a victim and a signal in this process. Hepatic dysfunction in adult sepsis is considered an independent predictor of mortality, meaning that even after accounting for other factors, a failing liver marks a patient at elevated risk. Whether the same holds true for children, however, had never been systematically examined. Individual pediatric studies had reported varying rates of liver injury and conflicting associations with death, but no one had pooled the data. The Indonesian team registered their review prospectively with PROSPERO under the identifier CRD420261387360 and searched five major databases, including PubMed, Scopus, MEDLINE via EBSCO, the Cochrane Library, and ClinicalTrials.gov, from their inception through 21 May 2026, without language restrictions. Notably, Embase was not searched, a limitation the authors acknowledge.

The eligibility criteria were strict. Studies had to enroll children aged one month to 18 years, define sepsis according to consensus criteria, and report outcomes stratified by the presence or absence of liver injury. Two reviewers independently screened records and extracted data, a standard safeguard against individual error. Risk of bias was evaluated using two prespecified instruments: the Newcastle-Ottawa Scale for the observational studies included in the mortality analysis and the Quality in Prognosis Studies tool, known as QUIPS, which is specifically designed for prognostic research. Statistical pooling employed a Mantel-Haenszel random effects model for mortality odds ratios, while the proportion of children developing liver injury was estimated with a logistic-normal generalized linear mixed model, an approach better suited to proportions than naive averaging. Certainty of the evidence was graded using GRADE, the framework that rates confidence in findings from high to very low.

After screening, ten studies made the final cut. The headline result came from five of these studies, encompassing 1,717 children, that reported mortality according to liver injury status. Pooling their unadjusted data, the researchers found that children with SALI had nearly four times the odds of dying compared with those without it, with an odds ratio of 3.88 and a 95 percent confidence interval of 2.21 to 6.80. Three of the studies measured death during hospital admission, one measured death in the pediatric intensive care unit, and one did not specify the timing. On the surface, this is a striking signal: a liver under assault during sepsis appears to mark a child in grave danger.

But the statistical fine print tells a more cautious story. The prediction interval, which estimates the range of true effects one might expect in future studies, stretched from 0.63 to 23.80, crossing the value of 1.0 that would indicate no association at all. In other words, some future pediatric population might show no link between liver injury and death, while another might show an enormous one. The Hartung-Knapp adjusted confidence interval, a more conservative calculation that accounts for uncertainty in the between-study variance, widened further to 1.65 to 9.12. Combined with a GRADE rating of very low certainty, these numbers mean clinicians should treat the fourfold figure as a hypothesis-generating signal rather than a settled fact. The heterogeneity across studies, likely driven by different definitions of liver injury, different patient populations, and different measurement schedules, is substantial enough to temper any confident clinical claim.

The deeper problem is confounding by severity. Children whose livers fail during sepsis are, almost by definition, sicker than children whose livers hold out. Two of the included studies attempted to address this statistically. Saini and colleagues reported that SALI remained associated with mortality after adjustment for selected clinical covariates, but their mortality model did not include pSOFA, the pediatric Sequential Organ Failure Assessment score, or any other validated global severity measure. Without such a score, it is impossible to know whether the liver adds information beyond what general illness severity already captures. Only Koca and colleagues adjusted hepatic markers for validated pediatric severity scores, namely PRISM III, the Pediatric Risk of Mortality Score, and PELOD-2, the Pediatric Logistic Organ Dysfunction Score. In that analysis, neither alanine aminotransferase, the enzyme ALT commonly used to detect liver cell damage, nor total bilirubin, the pigment that accumulates when the liver fails to clear it, remained independently associated with death. Once a child’s overall severity was accounted for, the liver’s apparent prognostic power evaporated.

Beyond mortality, the review also estimated how often liver injury occurs in pediatric sepsis at all. Across seven studies covering 1,876 children, the pooled proportion was 29 percent, with a wide 95 percent confidence interval of 17 to 46 percent. That range is itself informative: it reveals how inconsistently SALI is defined and detected across the pediatric literature. Some studies may rely on a single elevated transaminase value, others on bilirubin thresholds, and still others on composite criteria, and the timing of measurement during the septic episode varies just as widely. The authors argue that this heterogeneity makes a strong case for standardized pediatric definitions of sepsis-associated liver injury and for agreed ascertainment schedules, so that future studies measure the same thing at the same moments. The Pediatric Organ Dysfunction Information Update Mandate, or PODIUM, represents one ongoing effort to bring consistency to organ dysfunction definitions in pediatric critical care.

The review also examined candidate biomarkers that might identify liver injury or predict outcomes earlier than conventional tests. The most promising was APRI, the AST-to-platelet ratio index, a simple calculation combining aspartate aminotransferase levels with platelet counts. In two cohorts, APRI showed areas under the receiver operating characteristic curve, or AUROCs, of 0.83 to 0.89, values generally considered good discriminative ability. Yet the authors urge caution on two fronts. First, the diagnostic thresholds differed substantially between the two cohorts, meaning a child classified as having liver injury by one study’s cutoff might be classified as normal by another’s. Second, the APRI is built on AST, while the outcome definitions in these studies were based on ALT, creating an overlap problem that limits how the biomarker’s performance can be interpreted. Other markers examined in the underlying studies, including lactate dehydrogenase, apolipoprotein A-V, and the albumin-corrected anion gap, remain at even earlier stages of evaluation. The authors conclude that no candidate biomarker is ready for clinical use without prospective multicenter validation.

What does this mean for the pediatric intensivist at the bedside? The practical takeaway is nuanced. An elevated ALT or bilirubin in a septic child should certainly prompt attention, and the unadjusted association suggests these children warrant heightened vigilance. But the evidence does not yet support treating liver injury as an independent prognostic marker that adds value beyond established severity scores such as PRISM III, PELOD-2, or pSOFA. The honest answer to whether hepatic dysfunction carries prognostic information of its own is that nobody currently knows, and the review makes that uncertainty explicit rather than papering over it. This kind of transparency is increasingly valued in evidence-based medicine, where overconfident meta-analytic estimates can mislead practice as surely as absent evidence can.

The study, published open access on 7 October 2026 and available under a Creative Commons license, received no external funding and its authors declare no competing interests. Its limitations are clearly stated: only ten studies were available, Embase was not searched, adjusted analyses were rare, and the underlying literature is dominated by observational designs vulnerable to confounding. The research team, which also included Ade Gautama and Khanyfah Syagita, notes with gratitude that Dr. Abdulkerim Elmas provided unpublished subgroup data through personal correspondence, strengthening the primary mortality analysis. For now, the review stands as both a warning and a roadmap: liver injury during pediatric sepsis is common, appears dangerous, and demands rigorous, standardized study before it can be woven into the scoring systems that guide care for the world’s sickest children.

Subject of Research: Sepsis-associated liver injury and mortality outcomes in children

Article Title: Sepsis-associated liver injury and clinical outcomes in children: a systematic review and meta-analysis

Article References: Wiriadinata, N. E. R., Gautama, A., Syagita, K., & Oswari, H. (2026). Sepsis-associated liver injury and clinical outcomes in children: a systematic review and meta-analysis. BMC Pediatrics. https://doi.org/10.1186/s12887-026-07775-6

Image Credits: AI Generated

DOI: 10.1186/s12887-026-07775-6

Keywords: sepsis, liver injury, pediatrics, meta-analysis, mortality, PICU, biomarkers, APRI, PRISM III, PELOD-2, pSOFA, systematic review