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Managing Late-Onset Genetic Cholestasis: Drawing on Pediatric PFIC Expertise

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Released: October 02, 2026

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Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of disorders caused by variations in multiple genes that are critical for bile formation and transport. Typically, PFIC has been identified as a severe condition presenting in young children, and it has been managed by pediatric specialists. However, advances in genetic diagnosis have revealed that PFIC also affects adolescents and adults. In addition, with improvements in PFIC management, more pediatric patients are transitioning to adult care. In this commentary, a specialist in management of pediatric PFIC shares insights relevant to the care of these diseases in adult patients.

James E. Squires
James E. Squires, MD, MS
PFIC Pearls From a Pediatric Expert

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Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of disorders caused by variations in genes responsible for the makeup and stability of proteins critical to the bile acid (BA) transport system. The rare, heritable cholestatic liver disorders are characterized by altered BA secretion/transport, elevated serum BA levels, and disrupted bile flow. PFIC is also associated with diminished quality of life and a range of hepatic and systemic effects, including progressive hepatic injury and debilitating cholestatic pruritus, which is a hallmark of PFIC. Although it has been considered a pediatric disease, healthcare professionals (HCPs) who care for adult patients need to know about PFIC, as increased understanding of the disease state and advances in diagnosis and treatment are likely to lead to more patients with PFIC in adult care practices, including adults diagnosed later in life and patients transitioning to adult care practice.

Comparing Pediatric and Adult-Onset PFIC
Affected genes are generally similar for pediatric and adult-onset PFIC (eg, ATP8B1, ABCB11, ABCB4), but the overall penetrance of disease often differs based on the degree of residual protein function. Historically, PFIC has been identified in children presenting with severe infantile cholestasis, resulting from genetic variants that produce profound loss of protein function. Comparatively, adult-onset disease is typically driven by milder missense variants, variants of unknown significance, and heterozygous states that result in varying degrees of residual protein function. Practically, PFIC is a clinical manifestation across a disease spectrum that is largely determined by affected genes. Children often have a severe progressive form, whereas adults often have a subtler, easily missed version, underscoring the importance of genetic testing in otherwise unexplained cholestasis.

Monitoring PFIC Over Time
PFIC is a heterogeneous group of disorders—resulting in not one disease but many—and longitudinal management should be both genotype and phenotype specific, focusing on both symptoms of and complications of progressive liver disease. At regular intervals, standard liver biochemistry and function measurements should be augmented by assessments of growth and nutritional status, including levels of fat-soluble vitamins; BAs; and pruritus. Evaluations monitoring for progressive liver disease should also be documented, including fibrosis, portal hypertension, and other complications of chronic liver disease, and response to therapies, like ileal BA transporter (IBAT) inhibitors, should be assessed using both biochemical and patient-reported outcomes (eg, itch assessment). Escalation to surgical treatment (ie, diversion, transplant) should be considered when symptoms are refractory or disease is inadequately controlled.

Genotype specific monitoring should include assessment for:

  • Hepatocellular malignancy, which is associated with variants in BSEP, MDR3, TJP2
  • Extrahepatic complications, like pancreatitis, diarrhea, and hearing loss, associated with FIC1 and TJP2 variants, and gallstone formation, associated with MDR3 variants
  • Other rare complications.

Transitioning From Pediatric to Adult Care
Retrospective analysis of a large dataset suggests nearly one third of children with severe BSEP disease and approximately 40% to 45% with FIC1 deficiency reach adulthood with their native liver. Of note, these data predate approval of more novel therapies, specifically IBAT inhibitors. Evidence indicates that, with improved understanding and management of PFIC, even more patients will require transition to HCPs who care for adults, and the transition from pediatric to adult care is becoming increasingly important for patients with PFIC. Like other chronic disease states, transition should be a planned, gradual process that promotes disease knowledge, medication independence, and self-management. In addition, HCPs must ensure continuity of genotype-specific liver surveillance along with nutritional and extrahepatic monitoring. Attention should also be given to reproductive and genetic counseling, psychosocial health, and transplant preparedness. A comprehensive transfer summary and direct communication between pediatric and adult hepatology teams are particularly important given the relative rarity of PFIC in practices providing care for adults.

Recent Treatment Advances 
The most exciting recent development in the treatment of PFIC has been the approval of the IBAT inhibitors odevixibat and maralixibat, which act by reducing intestinal BA reabsorption and interrupting the enterohepatic circulation. These agents have been shown to significantly decrease pruritus and serum BA levels in patients with PFIC, and data also indicate improved growth and quality of life. Although these medications have shown efficacy and safety in children, evidence in adult populations is lacking. However, these therapies are applicable for adults who have PFIC, with odevixibat indicated for people 3 months of age or older and maralixibat indicated for people 12 months of age or older. It also remains to be seen whether IBAT inhibitors are disease modifying as well as addressing symptoms. Ongoing real-world experiences in both pediatric and adult populations should provide valuable information regarding use of these agents in adults and on their disease-modifying effects.

Patient Organizations
Organizations such as PFIC Network can be particularly valuable to HCPs because with rare diseases, like PFIC, expertise is often distributed across only a few centers. PFIC Network can serve as a conduit among patients, pediatric and adult HCPs, researchers, and industry partners, providing centralized, accessible disease and treatment education; facilitating pediatric-to-adult transition; disseminating rapidly evolving treatment information; and connecting adult HCPs with PFIC experts. In addition, as a collaborative research organization, PFIC Network can aggregate experience across these rare and heterogeneous diseases, identify patient-centered knowledge gaps, and support research to improve care across the lifespan.

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