Hepatobiliary involvement in Kawasaki disease: from cholestatic hepatitis to the hepatic vascular-biliary unit hypothesis-a state-of-the-art review.

BACKGROUND: This review provides a comprehensive synthesis of hepatobiliary involvement in Kawasaki disease (KD), with emphasis on cholestatic hepatitis as a clinical sentinel of hyperinflammation. We critically evaluate current evidence, propose an integrated pathogenic framework-the hepatic vascular-biliary unit injury hypothesis-and identify priority research areas. DATA SOURCES: Narrative review of high-quality literature (2015-2025) with inclusion of seminal historical studies, using Oxford Centre for Evidence-Based Medicine (OCEBM) evidence-level grading. RESULTS: Cholestatic hepatitis occurs in 5.2%-17.8% of acute KD cases, rising to 22%-35% among intravenous immunoglobulin (IVIG)-resistant patients. Large retrospective cohort studies (OCEBM Level 3b) have identified a clinical "risk triangle" comprising IVIG resistance, coronary artery lesions (CALs), and cholestasis as interdependent factors. We propose the hepatic vascular-biliary unit injury hypothesis as an integrated pathogenic framework, supported by correlative pathological and molecular evidence (OCEBM Level 3-4), though causality remains unproven and requires validation in conditional endothelial-specific animal models. Current therapeutic evidence for moderate-to-severe cholestasis derives exclusively from retrospective cohorts and case series (OCEBM Level 3-4). Emerging evidence from Phase I/IIa trials supports the use of interleukin-1 blockade (anakinra) in refractory cases, predominantly derived from studies of coronary artery aneurysms rather than cholestasis-specific populations. CONCLUSIONS: KD-associated cholestatic hepatitis is a critical marker of disease severity with prognostic significance. The hepatic vascular-biliary unit hypothesis provides a mechanistic framework linking systemic vasculitis to cholestasis, pending experimental validation. Definitive evidence for optimal therapeutic strategies is lacking; well-designed randomized controlled trials specifically targeting the cholestasis subpopulation are urgently needed. Given the highest incidence in East Asian populations, clinicians in this region should maintain a particularly high index of suspicion for KD-associated cholestasis, particularly in infants presenting with unexplained jaundice.