Clinical Guidance
ATP8B1 deficiency encompasses a phenotypic spectrum ranging from severe through moderate to mild. Severe ATP8B1 deficiency is characterized by infantile-onset cholestasis that progresses to cirrhosis, hepatic failure, and death. Mild-to-moderate ATP8B1 deficiency was initially thought to involve intermittent symptomatic cholestasis with a lack of hepatic fibrosis; however, some persons with clinically diagnosed mild disease have hepatic fibrosis on biopsy. Furthermore, in some persons with ATP8B1 deficiency the clinical findings can span the phenotypic spectrum, shifting over time from the mild end (episodic cholestasis) to the severe end of the spectrum (persistent cholestasis) . Family members with the same ATP8B1 pathogenic variants do not always have disease of the same clinical severity. In addition, clinical severity can change over time: mild disease diagnosed in childhood may progress in adulthood to severe disease . Severe ATP8B1 deficiency. The age and onset of manifestations of severe ATP8B1 deficiency vary among affected individuals. Affected children typically present in the first year of life, often with severe pruritus and jaundice . The onset of pruritus is often difficult to pinpoint because detection depends on an infant's ability to scratch in a coordinated manner; thus, in some infants irritability may be an initial manifestation of pruritus. Some individuals have been treated for long periods for chronic dermatologic conditions because of longstanding pruritus without typical findings of liver disease. Secondary manifestations such as coagulopathy (due to vitamin K deficiency), malabsorption, and poor weight gain may present earlier than age three months. While onset in the first year of life with progression to cirrhosis by the end of the first decade of life is typical in severe ATP8B1 deficiency, both interfamilial and intrafamilial variability have been noted among affected individuals with the same pathogenic variants [, , , , , ]. Mild-to-moderate ATP8B1 deficiency is characterized by intermittent episodes of cholestasis, severe pruritus, and jaundice in the absence of extrahepatic bile duct obstruction. Episodes may last from weeks to months. Symptom-free intervals may last from months to years. Individuals may have variable or unknown triggers for some or all bouts of cholestasis. In truly mild disease, chronic liver damage does not develop; however, in some individuals in whom ATP8B1 deficiency initially appears mild, clinical monitoring over time or detection of fibrosis on liver biopsy may indicate disease of moderate severity . More recently, ATP8B1 pathogenic variants have been reported in some adults with cryptogenic cirrhosis, suggesting further broadening of the phenotypic spectrum of ATP8B1 deficiency to include development of liver disease beyond the first decades of life . See for an overview of the distinguishing features of the severe and mild-to-moderate phenotypes. Table 3. ATP8B1 Deficiency: Comparison of Phenotypes by Select Features
