Arteriohepatic Dysplasia in Infancy and Childhood: A Longitudinal Study of Six Patients

Abstract

Arteriohepatic dysplasia (syndromatic ductular hypoplasia, Alagille syndrome) is a condition of chronic cholestasis dating from infancy accompanied by characteristic facies, pulmonic stenosis, and other somatic abnormalities. The pathologic hallmark of arteriohepatic dysplasia is a paucity or absence of intrahepatic bile ducts, wildely regarded as a congenital deficiency. We present a longitudinal study of six infants and children with arteriohepatic dysplasia, stressing evolution of the characteristic pathology on liver biopsy. All patients were biopsied twice. All five liver biopsies performed during infancy (<6 months old) showed intrahepatic cholestasis and portal inflammation, and two infants had, in addition, giant cell transformation. No infant showed congenital absence of interlobular bile ducts. Three of five infants had normal numbers of interlobular bile ducts (0.5 to 1.0 interlobular bile ducts per triad) and two infants had a paucity of interlobular bile ducts (<0.5 per triad). Three infants showed focal destructive inflammation of interlobular bile ducts. All biopsies performed later in childhood, between 3 and 20 years of age, showed a paucity or absence of interlobular bile ducts. At this time cholestasis and inflammation had largely resolved but some fibrosis persisted. The number of interlobular bile ducts decreased with age in each patient but there was no characteristic age at which interlobular bile ducts disappeared completely. The presence of interlobular bile ducts in infancy followed later in childhood by paucity or absence of interlobular bile ducts, suggests that intrahepatic bile duct deficiency in some patients with arteriohepatic dysplasia is acquired rather than congenital. The mechanism of bile duct disappearance in these patients may have been destructive inflammation of duct epithelium. Histopathologic diagnosis of arteriohepatic dysplasia may be difficult or impossible in infancy since interlobular bile ducts may be present at that time. However, arteriohepatic dysplasia should be considered in the differential diagnosis of all infants with cholestasis and such infants should have careful clinical evaluation for the syndromatic features of arteriohepatic dysplasia. Evaluation of their liver biopsies should include specific morphometric assessment of interlobular bile ducts.

Human hepatic organoids for the analysis of human genetic diseases

“…The inability to do this during the postnatal period generates the paucity of bile ducts in ALGS liver. Consistent with this, the extent of bile duct paucity varies with location in ALGS liver (7,52,53), and is most severe in the liver periphery (56). Based upon analysis of ALGS liver tissue, it has been proposed that altered Notch signaling impairs the formation of the distal branches of the biliary tree during the postnatal period in ALGS liver (57).…”

“…ALGS patients are born with an intact biliary system (51), but the ratio of bile ducts to liver tissue quickly declines with age after birth, which leads to cholestasis and presentation with ALGS liver disease (7,52,53). The proximal branches of the biliary tree are formed in embryonic liver from a single layer of bipotent precursor cells that surround the portal vein (the ductal plate), which are progressively remodeled to generate intrahepatic bile ducts (54), and this requires an interaction with surrounding mesodermal tissues (55).…”

A Chinese girl molecularly diagnosed with Alagille syndrome

“…Liver biopsies performed after 6 months of age may typically show the characteristic paucity of bile ducts; however, the biopsies performed before 6 months of age may show non-specific intrahepatic cholestasis and portal inflammation. [10] The present case presented with 3 of the 5 major features of AGS (chronic cholestasis, congenital heart disease and characteristic face) associated with a paucity of interlobular bile duct in liver biopsy specimen. Cutaneous anomalies including excoriations and lichenification were apparent because intense pruritus caused by cholestasis can be an important indication for clinical evaluation of AGS.…”

Metabolic liver disease in childhood

“…22 This pattern can simulate a simple drug induced cholestasis, or the cholestasis associated with lymphoma, and in particular Hodgkin disease. 23 Alagille syndrome can manifest histologically with lobular cholestasis associated with progressive bile duct loss and periportal deposits of copper and copperbinding protein 24 (Figure 8). In MDR3 deficiency, lobular cholestasis may be associated with portal periportal features including ductular reaction, and periportal deposits of copper/ copper-binding protein, resembling sclerosing cholangitis.…”