Congenital Hepatic Fibrosis

Basics

Description

  • Congenital hepatic fibrosis (CHF) is an inherited, noncirrhotic liver disease.
  • Prominent clinical features include the following:
    • Portal hypertension
    • Increased risk of ascending cholangitis
  • Liver biopsy shows the classic lesion of ductal plate malformation.
  • Majority of patients with CHF have associated autosomal recessive polycystic kidney disease (ARPKD). However, several other genetic diseases also result in CHF.

Epidemiology

  • The incidence of ARPKD is 1/20,000–1/40,000 live births.
  • Carrier frequency of PKHD1 mutation in the general population is ∼1:70.

Risk Factors

Genetics

  • Inheritance is autosomal recessive in most families, but X-linked and autosomal dominant patterns are also seen.
  • Penetrance is 100% but marked intrafamilial variation in severity is observed.
  • PKHD1, the ARPKD/CHF disease gene, is located on chromosome 6p12.
  • The gene is large, consisting of at least 86 exons extending over 469 kb of genomic DNA.
  • It is expressed at high levels in fetal and adult kidneys and at lower levels in the liver and pancreas.
  • More than 300 mutations of the PKHD1 gene have been reported with variable rates of progression of hepatic/renal disease, even with the same PKHD1 mutation, indicating the presence of modifier genes.
  • Mutations of the PKHD1 gene include frameshift, nonsense, and out-of-frame splicing alterations that are consistent with a loss of function mechanism.
  • The presence of 2 truncating mutations leads to the most severe phenotype, associated with death in the neonatal period.
  • The PKHD1 gene product is a protein called polyductin or fibrocystin.
  • Transmembrane protein
  • Located mostly on the primary cilia and apical surface of renal tubular cells and cholangiocytes
  • It complexes with polycystin 1 and polycystin 2, the mutated proteins in autosomal dominant polycystic kidney disease (ADPKD).
  • Together, the complex is thought to function as mechanotransducer, detecting the shear force from urine and bile flow. Further studies will be needed to identify the biologic function of polyductin and to determine how mutations of the protein cause disease.

Pathophysiology

  • Ductal plate malformation is a characteristic histologic lesion of the liver, implying a disturbance of the normal development of the bile ducts.
  • Hallmarks include the following:
    • Irregularly shaped, dilated, proliferating bile ducts, often described as staghorn shaped
    • Noninflammatory periportal fibrosis
    • Normal appearance of hepatocytes and lobular architecture
  • The primary defect in ARPKD may be linked to ciliary dysfunction.
    • The ciliary structure is abnormal in ARPKD renal tubule cells and cholangiocytes.
  • Developmental abnormalities involve the liver and kidneys and, less commonly, the vasculature and the heart.
  • Portal hypertension is thought to result from the fibrosis in the portal tracts as well as, in some patients, from portal vein abnormalities.

Commonly Associated Conditions

  • Portal hypertension leading to varices and hypersplenism
  • Hepatomegaly
  • Systemic hypertension
  • Renal dysfunction
  • Cholangitis
  • Conditions associated with the finding of ductal plate malformation/CHF:
    • ARPKD; most frequent association
    • ADPKD, rare
    • Caroli syndrome (CHF and intrahepatic bile duct dilation)
    • Juvenile nephronophthisis
    • Congenital disorder of glycosylation type 1b (phosphomannose isomerase deficiency)
    • Congenital malformation syndromes
      • Meckel Gruber syndrome
      • Joubert syndrome
      • Jeune syndrome
      • Bardet-Biedl syndrome

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