Background
Congenital hepatic fibrosis (CHF) is an autosomal recessive disease that primarily affects the hepatobiliary and renal systems. It is characterized by hepatic fibrosis, portal hypertension, and renal cystic disease. Pathologically, it is defined by its variable degree of periportal fibrosis and irregularly shaped proliferating bile ducts. Congenital hepatic fibrosis is one of the fibropolycystic diseases, which also include Caroli disease, autosomal dominant polycystic kidney disease (ADPKD), and autosomal recessive polycystic kidney disease (ARPKD). [1, 2] ARPKD is reported to be caused by mutations in the PKHD1 gene. More than 300 different mutations in the PKHD1 gene have been described but with no genotype-phenotype correlation. [2]
Congenital hepatic fibrosis is associated with an impairment of renal functions, usually caused by an ARPKD, which is a severe form of polycystic kidney disease. [1] The hepatic manifestations of CHF with rather similar kidney manifestations were first described by Bristowe in 1856. [3] In 1961, the term congenital hepatic fibrosis, with its varied clinical manifestations, was recognized by Kerr. [4]
Because of the variable clinical presentations, congenital hepatic fibrosis is believed to represent a broad spectrum of hepatic and renal lesions rather than a single clinical entity. Symptoms, which may be early or late, are mostly related to an associated portal hypertension. [2, 5]
Pathophysiology
Congenital hepatic fibrosis results from a malformation of the ductal plate (the embryological precursor of the biliary system), secondary biliary strictures, and periportal fibrosis. [6] This subsequently results in the development of portal hypertension.
The ductal plate is the cylindrical layer of cells that surrounds a branch of the portal vein. It is a precursor of the intrahepatic bile ducts. Ductal plates arise around the smaller portal vein branches at a distance from the hilum. Progressive remodeling starts at 12 weeks' gestation. Both interlobular and intralobular bile ductules develop from the ductal plate. The lack of remodeling of the ductal plate results in persistence of an excess of embryonic duct structures. This abnormality has been termed the ductal plate malformation [7] and consists of persistence of the ductal plate with an increase in duct elements and an increase in portal fibrous tissue.
The family of fibropolycystic diseases are characterized by varying degrees of persistent bile duct structures, fibrosis, and duct dilatation. They are all developmental anomalies of the duct plate and occurred at various stages of remodeling. Congenital hepatic fibrosis is a ductal plate malformation of the small interlobular bile ducts, whereas Caroli disease involves the large intrahepatic bile ducts.
The classic renal lesion associated with congenital hepatic fibrosis is ARPKD, which results in an impairment of renal functions. Its association with ADPKD is also recognized, especially among adults. The relationship of ARPKD to congenital hepatic fibrosis remains a controversial issue. The 2 conditions may actually be one disorder with different clinico-pathological presentations.
ARPKD is caused by mutations in the polycystic kidney and hepatic disease 1 (PKHD1) gene, [8] which consists of 86 exons that are variably assembled into numerous alternatively spliced transcripts. [9] Most cases of ARPKD and congenital hepatic fibrosis are genetically homogeneous. However, the exact pathogenesis of association between congenital hepatic fibrosis and ADPKD still requires further research and study.
In all cases of congenital hepatic fibrosis–ARPKD, a hepatic lesion of ductal plate malformation of the interlobular bile ducts is found; the difference in its presentation is primarily age dependent. Gradual disappearance of bile duct profiles associated with increased periportal fibrosis results from a progressive destructive cholangiopathy that involves the immature bile duct structures.
The hepatic disease progresses to develop portal hypertension associated with splenomegaly and esophageal varices. Congenital hepatic fibrosis is characterized by the intrahepatic form of portal hypertension, which is caused by the intrahepatic obstruction that affects the blood supply to the liver and subsequently leads to the development of cavernous transformations of the portal vein with a rise in portal venous pressure.
Congenital hepatic fibrosis is also associated with cholangitis. The presence of cholangitis or its repeated occurrence may influence the status of the hepatic lesion and the prognosis of the disease. Commonly, the hepatic lesion is associated with renal involvement characterized by cystic tubular dilatations, which affect both the cortical and medullary portions of the kidney. The longer the patient survives, the less characteristic the renal pathology becomes.
Epidemiology
Frequency
International
Congenital hepatic fibrosis is a rare autosomal recessive disease; the exact incidence and prevalence are not known. Only a few hundred patients with congenital hepatic fibrosis have been reported in the literature. The disease appears in both sporadic (in as many as 56% of cases) and familial patterns. Congenital hepatic fibrosis–ARPKD is estimated to occur in 1 in 20,000 live births. [10]
Mortality/Morbidity
Most neonates and young infants with predominant renal involvement die of renal failure in early infancy. As many as 25% of patients may succumb to renal failure, according to estimates. Cholangitis significantly contributes to morbidity and mortality rates in congenital hepatic fibrosis. When hepatic lesions dominate the clinical expression of the disease, children who are affected may remain asymptomatic until late childhood or even adulthood. Most patients do well. Coexisting renal lesions may also remain asymptomatic until early adulthood.
Sex
No sex predilection is observed.
Age
Congenital hepatic fibrosis may present in the neonatal period, but delayed presentation in late childhood or even adulthood is reported.
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Histopathology of liver biopsy in congenital hepatic fibrosis, which shows a widened portal tract with bands of fibrous tissue that separate areas of normal hepatic parenchyma. Note the multiple irregularly shaped narrow and elongated bile ducts and the absent lobular and portal inflammation.
