Congenital Hepatic Fibrosis
- 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.
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).
- 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.
- 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.
- Portal HTN leading to varices, hypersplenism, and some reports of hepatopulmonary syndrome (HPS)
- Systemic HTN
- Renal dysfunction
- 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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