Late-Onset Genetic Cholestasis: Underdiagnosis in Adults Examined

Genetic cholestatic diseases, such as progressive familial intrahepatic cholestasis (PFIC) and benign recurrent intrahepatic cholestasis (BRIC), are classically associated with pediatric onset. However, a growing body of evidence indicates that these conditions, and others like ABCB4 deficiency (formerly known as MDR3 deficiency), can manifest with a late-onset phenotype in adulthood.¹ This late presentation often leads to diagnostic delays, as symptoms like pruritus, fatigue, and jaundice are non-specific and can be attributed to more prevalent conditions such as primary biliary cholangitis (PBC) or primary sclerosing cholangitis (PSC).² The clinical dilemma lies in differentiating these genetic disorders from acquired cholestatic liver diseases, which have distinct management strategies.

The underdiagnosis of late-onset genetic cholestatic diseases in adults has significant implications for patient care. Without a precise genetic diagnosis, patients may undergo unnecessary invasive procedures, receive ineffective treatments, and miss opportunities for specific therapies that target the underlying genetic defect. For instance, some genetic cholestatic conditions may respond to ursodeoxycholic acid (UDCA) or require specific surgical interventions, while others might benefit from emerging gene-specific therapies.³ The lack of awareness among general practitioners and even some specialists contributes to this diagnostic gap, highlighting the need for increased education and a lower threshold for genetic testing in appropriate clinical scenarios.

The Diagnostic Challenge in Adults

Discussions at EASL 2026 underscored the complexity of diagnosing late-onset genetic cholestatic diseases. Expert consensus highlighted that the prevalence of these conditions in adults is likely underestimated. While precise epidemiological data for adult-onset genetic cholestasis are scarce, estimates suggest that genetic factors may account for 10-15% of unexplained chronic cholestasis in adults, particularly in cases where autoimmune or obstructive causes have been rigorously excluded.⁴ This figure represents a substantial patient population that could benefit from a definitive diagnosis.

The diagnostic pathway typically involves a comprehensive workup to rule out common causes of cholestasis. This includes liver function tests, imaging studies (ultrasound, MRI, MRCP), serological markers for autoimmune liver disease, and sometimes liver biopsy.⁵ When these investigations are inconclusive, or when there are atypical features, genetic testing becomes a critical next step. Specific gene panels, targeting genes such as ATP8B1 (PFIC1), ABCB11 (PFIC2), ABCB4 (PFIC3/MDR3 deficiency), and TJP2, are increasingly available.⁶ The interpretation of genetic variants, particularly variants of uncertain significance (VUS), remains a challenge, requiring careful correlation with clinical phenotype and family history.⁷

A key limitation in current practice is the infrequent consideration of genetic etiologies in adults with cholestasis. Many clinicians do not routinely include genetic testing in their diagnostic algorithms for adult patients, often due to a perceived rarity of these conditions or a lack of familiarity with their adult presentations.⁸ Furthermore, the cost and accessibility of comprehensive genetic panels can be barriers in some healthcare systems. Future efforts must focus on developing clear clinical guidelines for when to suspect and test for late-onset genetic cholestatic diseases in adults, potentially incorporating risk stratification tools to identify high-probability cases. This would facilitate earlier diagnosis, improve patient outcomes, and reduce the burden of undiagnosed liver disease.