Introduction

Inherited cholestasis of hepatocellular origin has long been described in the neonate or during the first year of life [1]. Many of these infants were categorized as having idiopathic neonatal hepatitis after biliary atresia, metabolic diseases, and congenital infections were excluded [2,3]. The prognosis in familial cholestasis was poor compared with sporadic cholestasis that sometimes had an identifiable etiology. As the clinical and genotypic heterogeneity of these inherited disorders has become apparent, it is now recognized that patients may present initially and progress to end-stage liver disease at ages ranging from infancy to adulthood [4]. There may be significant overlap in clinical features such as intense pruritus and a low serum concentration of gamma-glutamyltransferase (GGT). The histopathology, immunohistochemical staining, and hepatic ultrastructure may provide additional diagnostic clues as to the underlying defect. However, the identification of the genes responsible for several of these disorders now allows a specific diagnosis in many cases, may suggest therapy with varying success based on the genotype of the patient, and has advanced our understanding of molecular mechanisms of bile secretion and acquired cholestasis. It is not surprising that, so far, mutations in three genes encoding ATP-dependent transport proteins localized to the canalicular membrane that result in progressive cholestasis and liver injury have been discovered. The features of these disorders are compared in Table 13.1. Other genes encoding proteins involved in membrane transport, vesicular trafficking, and integrity of the cell junction may also be mutated in some patients. Owing to an immaturity of hepatic excretory function, cholestasis may occasionally occur in inherited diseases because of systemic illness rather than a primary defect in the liver (see Table 9.1). These disorders will not be considered in this review.