Congenital Hepatic Fibrosis

Congenital Hepatic Fibrosis is a topic covered in the 5-Minute Pediatric Consult.

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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.

Commonly 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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Citation

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TY - ELEC T1 - Congenital Hepatic Fibrosis ID - 617790 ED - Cabana,Michael D, BT - 5-Minute Pediatric Consult UR - https://peds.unboundmedicine.com/pedscentral/view/5-Minute-Pediatric-Consult/617790/all/Congenital_Hepatic_Fibrosis PB - Wolters Kluwer ET - 8 DB - Pediatrics Central DP - Unbound Medicine ER -