Time-dependent pattern of liver injury biomarkers in neonates with hypoxic-ischemic encephalopathy undergoing therapeutic hypothermia

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Hypoxic-ischemic encephalopathy (HIE) often results in multi-organ damage. Liver injury following HIE is typically characterized by time-dependent altered patterns of alanine aminotransferase (ALT), aspartate aminotransferase (AST) or total bilirubin (TB) concentrations. This study aims to describe age-dependent patterns of liver injury biomarkers during and after therapeutic hypothermia (TH). Liver injury biomarkers (ALT, AST, TB) over the first 10 days of postnatal age (PNA) from six cohorts, including 428 neonates with moderate-to-severe HIE treated with TH were pooled. Statistical modelling with linear mixed models and quantile regression was applied to assess trends and correlations with HIE severity, gestational age, and birth weight. ALT and AST concentrations were highest on PNA day 1 (median [IQR]: 37.5 [18.75-85.50] U/L), and 154 [79-345 U/L], respectively) and declined thereafter. ALT and AST values were both associated with HIE severity (p < 0.001). The AST/ALT (De Ritis) ratio remained > 3.0 throughout PNA days 1-10. CONCLUSION: We characterize age-dependent reference values of liver-injury biomarkers in HIE neonates treated with TH. Along with PNA, HIE severity has a strong association with liver biomarkers, while the De Ritis ratio reflects ischemic hepatic injury throughout PNA (day 1-10). These age-dependent reference values can be used to assess intra- and interpatient variability, or to explore other causes of hepatic toxicity like drug-induced liver injury, preferably following external validation. WHAT IS KNOWN: • Moderate to severe hypoxic-ischemic encephalopathy in neonates undergoing therapeutic hypothermia is often associated with multi-organ damage, including liver injury. • Except for acid/base parameters, laboratory values are inconsistently collected and reported in this specific population, so that reference values are warranted. WHAT IS NEW: • We report time-dependent reference values of liver injury biomarkers during and after therapeutic hypothermia. • These reference values can be used to assess intra- or interpatient variability and patterns in this specific population.

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