New guidance for the diagnosis and management of inherited hyperbilirubinemia

Inherited hyperbilirubinemia, encompassing Gilbert syndrome, Crigler-Najjar syndrome, Dubin-Johnson syndrome, and Rotor syndrome, represents a spectrum of disorders rooted in genetic defects affecting bilirubin metabolism and transport. The recent 2025 Expert Consensus provides a crucial framework for standardizing the diagnosis and management of these conditions. A key strength of the consensus is its clear stratification of diseases based on the underlying molecular pathology and the resultant biochemical phenotype-either predominantly unconjugated or conjugated hyperbilirubinemia. This distinction forms the cornerstone of the proposed diagnostic algorithm.

The consensus strongly advocates for the central role of genetic testing in modern diagnosis. While Gilbert syndrome can often be diagnosed clinically through exclusion, genetic confirmation of UGT1A1 variants is valuable. For Crigler-Najjar, Dubin-Johnson, and Rotor syndromes, genetic analysis is positioned as a first-line or definitive diagnostic tool. This molecular approach not only confirms the diagnosis but also aids in prognostication and family counseling. The management philosophy is notably pragmatic and risk-stratified. For the generally benign conditions like Gilbert, Dubin-Johnson, and Rotor syndromes, the emphasis is on patient reassurance, education, and avoidance of exacerbating factors, rather than active intervention.

In stark contrast, the management of Crigler-Najjar syndrome, particularly type I, requires aggressive and timely intervention. The consensus clearly outlines that for type I, liver transplantation remains the only curative option and should be considered proactively before the onset of irreversible neurological damage, guided by specific criteria such as inadequate response to phototherapy. For type II, the approach is more conservative, utilizing phenobarbital or intermittent phototherapy based on bilirubin levels and clinical context. A particularly valuable and practical section of the document addresses pharmacogenetics. It details critical drug-gene interactions, emphasizing how polymorphisms in UGT1A1, ABCC2, and SLCO genes can significantly alter the pharmacokinetics and toxicity profiles of commonly used medications like irinotecan, atazanavir, and statins. This has direct implications for personalized medicine and drug safety.

The consensus also thoughtfully addresses special populations, providing guidance on managing pregnancy in women with Crigler-Najjar syndrome type II and recognizing the atypical presentations that can occur in neonates. Looking forward, the document honestly identifies gaps in knowledge, calling for more epidemiological data in Chinese populations, better genotype-phenotype correlations, and further research into promising areas like gene therapy. It also implicitly highlights implementation challenges, including the need for wider access to genetic testing and greater clinician awareness.

In conclusion, this expert consensus successfully synthesizes current evidence into a clear, actionable, and patient-centered guide. It elevates genetic testing to a primary diagnostic role, promotes a tailored management strategy from observation to transplantation, and integrates essential pharmacogenetic principles into clinical practice. By doing so, it provides a robust foundation for improving the care of patients with these inherited disorders.