Congenital Hepatic Fibrosis

Basics

DESCRIPTION

  • Congenital hepatic fibrosis (CHF) is an inherited, noncirrhotic liver disease.
  • Prominent clinical features include the following:
    • Portal hypertension (portal HTN)
    • Increased risk of ascending cholangitis
    • Very likely to have associated renal disease
  • Liver biopsy is the gold standard for diagnosis and shows the classic lesion of ductal plate malformation.
  • Majority of patients with CHF have associated autosomal recessive polycystic kidney disease (ARPKD). However, CHF has a number of potential genetic associations.

EPIDEMIOLOGY

The incidence of ARPKD is 1/20,000 live births, and all individuals with ARPKD have some degree of hepatic involvement, although the spectrum of disease phenotype is broad (asymptomatic to severe fibrosis and portal HTN).

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 disease gene, is located on chromosome 6p12.
  • >300 mutations of the PKHD1 gene have been reported, yet even those with the same PKHD1 mutation may have variable rates of hepatic/renal disease progression indicating the presence of modifier genes or epigenetic factors.
  • The presence of two truncating mutations leads to the most severe phenotype, associated with death in the neonatal period.
  • The PKHD1 gene product is a transmembrane protein called fibrocystin (or polyductin).
  • Located mostly on the primary cilia and apical surface of renal tubular cells and cholangiocytes
  • It complexes with polycystin 1 (PC1) and polycystin 2 (PC2), the mutated proteins in autosomal dominant polycystic kidney disease (ADPKD).Together, the complex is thought to function as a mechanotransducer, detecting the shear force from urine and bile flow and transducing signals via a phosphorylation cascade.

PATHOPHYSIOLOGY

  • Ductal plate malformation is a characteristic histologic lesion of the liver, implying a disturbance of the normal development of the bile ducts.
  • The primary defect in ARPKD may be linked to ciliary dysfunction.
  • Defects lead to impaired calcium signaling with imbalanced proliferation and apoptosis of the ductal plate starting around the 6th to 7th week of gestation.
  • Hallmarks include the following:
    • Irregularly shaped, dilated, proliferating bile ducts, often described as staghorn shaped or saccular
    • Noninflammatory periportal fibrosis characterized by a dense extracellular matrix
    • Normal appearance of hepatocytes and lobular architecture
    • 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.
    • In concurrent cases of CHF and ARPKD, renal and liver disease progress at independent rates.
  • Portal HTN is thought to result from the fibrosis in the portal tracts as well as, in some patients, from portal vein abnormalities.

ASSOCIATED-CONDITIONS

  • Portal HTN leading to varices, hypersplenism, and some reports of hepatopulmonary syndrome (HPS)
  • Hepatomegaly
  • Systemic HTN
  • Renal dysfunction
  • Cholangitis
  • Urinary tract infections (UTIs)
  • Growth impairment
  • Neurocognitive delays
  • Conditions associated with the finding of ductal plate malformation/CHF:
    • ARPKD; most frequent association
    • ADPKD; rare
    • Caroli syndrome (CHF and intrahepatic bile duct dilation, seen especially with the neonatal phenotype)
    • Juvenile nephronophthisis
    • Congenital malformation syndromes
      • Meckel-Gruber syndrome
      • Joubert syndrome
      • Jeune syndrome
      • Bardet-Biedl syndrome
      • Oral-facial-digital syndrome

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