Congenital Hepatic Fibrosis

Congenital hepatic fibrosis (CHF) results from malformation of the ductal plate (the embryologic precursor of the biliary system), secondary biliary strictures, and periportal fibrosis. ^[7] This subsequently leads to the development of portal hypertension. It is often associated with various fibrocystic diseases of the liver and kidneys, such as autosomal recessive (AR) polycystic kidney disease (PKD) and Caroli disease. The pathophysiology of congenital hepatic fibrosis involves a complex interplay of genetic mutations, cellular changes, and altered signaling pathways, leading to the characteristic fibrotic changes in the liver.

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, termed the ductal plate malformation. ^[8]  Congenital hepatic fibrosis is a ductal plate malformation of the small interlobular bile ducts, whereas Caroli disease involves the large intrahepatic bile ducts. Disrupted bile duct morphogenesis leads to the formation of structurally abnormal and dilated bile ducts, which are prone to progressive fibrosis.

Congenital hepatic fibrosis and ARPKD have been linked to mutations in the PKHD1 gene, which encodes for fibrocystin/polyductin, a protein that is expressed by the renal and biliary epithelium and is postulated to maintain three-dimensional tubular architecture. Mutations in this gene lead to abnormal ciliary signaling, which is normally required for regulation of proliferation and differentiation of renal and biliary epithelial cells. ^[9] The relationship of ARPKD to congenital hepatic fibrosis still requires further research and investigation. These two conditions may actually be one disorder.

In all cases of CHF–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 fibrotic changes in the liver can lead to alterations in the hepatic vasculature and hemodynamics, resulting in increased resistance to blood flow within the portal system. Portal hypertension can develop, a hallmark feature of congenital hepatic fibrosis, which, in turn, can bring about splenomegaly and esophageal varices.

Congenital hepatic fibrosis is also associated with cholangitis. Structural abnormalities associated with congenital hepatic fibrosis can predispose individuals to recurrent cholangitis. The dilated and structurally abnormal bile ducts in congenital hepatic fibrosis can impede the normal flow of bile, leading to stasis and potentially providing a conducive environment for bacterial overgrowth and subsequent cholangitis.

Understanding the pathophysiology of congenital hepatic fibrosis is crucial for the development of targeted therapeutic strategies aimed at slowing or halting the progression of liver fibrosis and managing the complications associated with portal hypertension. More research is needed in these regards.

No definite cause has been identified for congenital hepatic fibrosis (CHF). However, currently, it is knowm that this condition is primarily considered to be a genetic disorder, often resulting from mutations in specific genes. One of the most commonly implicated genes associated with congenital hepatic fibrosis is the PKHD1 gene, which is also linked to autosomal recessive (AR) polycystic kidney disease (PKD). Mutations in the PKHD1 gene can lead to the development of both hepatic and renal manifestations, giving rise to the combined form of CHF-ARPKD.

The exact mechanisms by which mutations in these genes lead to the development of congenital hepatic fibrosis are not fully understood. However, it is believed that these genetic mutations disrupt the normal development and structure of the bile ducts in the liver, leading to fibrosis and dilatation of the intrahepatic bile ducts. ^[9] This abnormal development results in the characteristic features of congenital hepatic fibrosis, such as hepatic fibrosis, portal hypertension, and related complications.

It has also been hypothesized that liver fibrosis in congenital hepatic fibrosis may be mediated by hepatic stellate cells that cause upregulation of transforming growth factor-beta1 and thrombospondin-1. ^[10] In addition, abundant connective tissue growth factor retained diffusely in heparan sulfate proteoglycan in the fibrous portal tracts or septa may be responsible for nonresolving hepatic fibrosis in congenital hepatic fibrosis. ^[11]

Inheritance

Congenital hepatic fibrosis (CHF) is commonly inherited in an autosomal recessive manner: An affected individual inherits two copies of the defective gene, one from each parent who carries the mutated gene.

Frequency

Congenital hepatic fibrosis is a rare disease; the exact incidence and prevalence are not known but is estimated to be less than 1 in 20,000 live births. ^[12] The disease appears in both sporadic (≤56% of cases) and familial patterns. The prevalence of congenital hepatic fibrosis may vary among different populations, and it is more commonly reported in individuals with a family history of polycystic kidney disease or related fibrocystic liver and kidney disorders.

Sex- and age-related demographics

There does not appear to be a sex predilection in congenital hepatic fibrosis. The prevalence seems to be relatively similar between males and females.

Congenital hepatic fibrosis is typically diagnosed in childhood or adolescence, although the age of onset can vary. Symptoms may manifest during infancy, childhood, or even later in life, depending on the severity of the disease and the extent of liver involvement. Most patients with CHF-ARPKD present perinatally with oligohydramnios caused by decreased fetal urine output and related hypoplastic lungs; others present later in life when they start having complications from renal failure or hepatic dysfunction, or both. In cases of late-onset, symptoms related to the liver may become more prominent.

A 2024 report described the case of a 31-year-old female admitted for esophageal and gastric variceal bleeding. who was determined to have congenital hepatic fibrosis with portal hypertension and autosomal dominant polycystic kidney disease (ADPKD). ^[13]  In addition, she had two unique mutations in the PKD1 gene (biallelic mutations compound heterozygous mutations composed of a mutation inherited from the father (c.8296 T > C) and one from the mother (c.9653G > C)).

The prognosis of congenital hepatic fibrosis (CHF)–autosomal recessive (AR) polycystic kidney disease (PKD) in patients presenting soon after birth depends largely on the degree of pulmonary hypoplasia as a result of oligohydramnios. Although most infants presenting in the perinatal period ultimately require renal transplantation, the age of transplantation can be delayed in some cases until adulthood. Individuals who survive their neonatal respiratory complications will develop variable degrees of portal hypertension and chronic renal failure as they age. The rates of progression of hepatic and renal disease can vary, even with patients carrying the same PKHD1 mutation. Thus, current mutation analysis is not predictive of outcome. ^[9]

Most patients with congenital hepatic fibrosis do well. If bleeding from varices can be controlled and renal failure does not occur, the prognosis is expected to be favorable. Renal involvement in neonates and young infants with congenital hepatic fibrosis carries a worse prognosis, with most patients dying of renal failure within the first year of life. Respiratory insufficiency in the first month of life and renal insufficiency are primary determinant factors of mortality.

Cholangitis significantly contributes to morbidity and mortality 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.

Other major causes of death include sepsis with ascending cholangitis and hepatic failure.

Complications

Complications in congenital hepatic fibrosis are mainly related to its association with ARPKD, resulting in renal impairment.

Portal hypertension can lead to potentially life-threatening complications such as esophageal varices, splenomegaly, and ascites.

Recognition of cholangitis and prevention of its recurrence by appropriate surgical procedures are important. Transhepatic cholangiography is a safe and direct means of identifying this entity.

Cholangiocarcinoma and amyloidosis have been reported as late sequelae of congenital hepatic fibrosis.

Some patients may develop PKD.

Congenital hepatic fibrosis (CHF) is a rare genetic condition impacting the development of the liver and resulting in scarring within the liver. Other organ abnormalities, particularly in the kidneys, may be involved. Parents or guardians should be provided with the following information/recommendations:

• Inheritance: Congenital hepatic fibrosis is typically inherited in an autosomal recessive manner, indicating that both parents carry a copy of the defective gene.

• Signs and symptoms: Common manifestations include abdominal distention due to an enlarged liver and spleen. Signs of liver fibrosis and portal hypertension include ascites. Bloody vomit or stool may indicate esophageal varices.

• Diagnosis: Imaging studies (ultrasonography, magnetic resonance imaging, computed tomography scans) are utilized to visualize the liver and associated organs. Genetic testing confirms the presence of congenital hepatic fibrosis–related genetic mutations.

• Treatment: Address specific symptoms and complications to enhance the quality of life. Some cases may involve medications to manage symptoms or complications. Adopt dietary modifications and follow physical activity recommendations to support overall health.

• Regular check-ups: Monitor disease progression through regular consultations with the primary care physician, the liver specialist, and the kidney specialist. Maintain current immunizations.

• Lifestyle considerations: Adhere to dietary recommendations provided by healthcare professionals. Avoid activities that pose a risk of abdominal trauma. Stay vigilant about potential complications associated with congenital hepatic fibrosis, such as bleeding. Seek immediate medical attention for any signs of emergency.

• Emotional well-being: Consider seeking psychosocial support to cope with the emotional impact. Connect with support groups or organizations for individuals with congenital hepatic fibrosis.