NORD gratefully acknowledges John Shields, NORD Editorial Intern from the University of Notre Dame, and Meral Gunay-Aygun, MD, National Human Genome Research Institute, National Institutes of Health, for assistance in the preparation of this report.
Congenital hepatic fibrosis (CHF) is a rare disease that is present at birth (congenital) and affects the liver. CHF rarely occurs as an isolated problem, and is usually associated with ciliopathies that affect the kidneys, called hepatorenal fibrocystic diseases (FCD). These include polycystic kidney disease (PKD), nephronophthisis (NPHP) chronic tubulointerstitial disease, and others. Typical liver abnormalities include an enlarged liver (hepatomegaly), increased pressure in the venous system that carries blood from different organs to the liver (portal hypertension), and fiber-like connective tissue that spreads over and through the liver (hepatic fibrosis). Gastrointestinal (stomach and intestine) bleeding, splenomegaly (enlarged spleen) and hypersplenism (decreased platelet and other blood counts due to enlarged spleen) may be early signs of this condition.
The more obvious symptoms are a swollen abdomen, a firm, slightly enlarged and abnormally shaped liver and vomiting blood (hematemesis) due to bleeding from the enlarged blood vessels (varices) under the inner lining of the esophagus, stomach, and intestines. There is an increased risk for inflamed bile ducts (cholangitis) as well. The main findings in this disorder are identified through diagnostic testing. Many of the following signs are present in affected individuals with this disorder:
Portal Hypertension: increased pressure in the venous system that carries blood from multiple organs to the liver (portal system). This increased blood pressure is caused by the probable congenital abnormality of the portal vein as well as blockage of the portal blood supply to the liver due to excess connective tissue growth in the liver. Portal hypertension can cause enlargement of the spleen and swollen or dilated veins of the esophagus. Hepatic Fibrosis: a fiber-like connective tissue that spreads through the liver. Nephromegaly: enlarged kidney. Gastrointestinal Bleeding: bleeding from the esophagus, and/or stomach and intestines that may cause the affected individual to vomit red blood or have dark black stools. Polycystic Kidney Disease: an inherited disorder in which cysts invade both kidneys. This causes enlargement in the size of the kidney while at the same time, reducing the amount of functional kidney tissue by compression. (For more information on this disorder choose “Polycystic Kidney Disease” as your search term in the Rare Disease Database). Splenomegaly: an enlarged spleen. Liver function tests are usually normal in people with CHF.
CHF is caused by abnormal development of the portal veins and bile ducts that begins with a malformation in the embryonic structure called the ductal plate. CHF rarely occurs as an isolated problem, and is usually associated with ciliopathies that are associated with kidney disease, called hepatorenal fibrocystic diseases (FCD). These include polycystic kidney disease (PKD), nephronophthisis (NPHP) chronic tubulointerstitial disease, and others. FCDs are caused by defects in proteins on the primary (immotile) cilia that interfere with receiving signals from other cells or fluids nearby. FCDs can be inherited as autosomal recessive, autosomal dominant or X-linked disorders. Mutations in many different genes are associated with the various FCDs. No specific genes have been associated with isolated CHF.
Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene with a disease-causing mutation (gene change). The person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. All individuals carry 5-10 abnormal recessively inherited trait genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.
X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and manifest mostly in males. Females that have a defective gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one X chromosome carries the defective gene. Males have only one X chromosome and it is inherited from their mother. If a male inherits an X chromosome that contains a defective gene, he will develop the disease.
Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.
If a male with an X-linked disorder is able to reproduce, he will pass the defective gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.
The frequency of CHF is not known. The prevalence has been estimated to be 1/10,000 -20,000 based on the prevalence of ciliopathies that are associated with CHF.
CHF is diagnosed by ultrasound exam and magnetic resonance imaging of the liver and kidneys, and rarely, by liver biopsy. CHF and Caroli’s syndrome are often associated with cystic disease of the kidneys. Family history, physical exam, and various tests including kidney ultrasound exam, kidney function tests, X-rays, eye exam, brain MRI, and molecular genetic testing can help to determine the underlying FCD syndrome.
Treatment of CHF is symptomatic and supportive. Complications of CHF including gastrointestinal bleeding, hypersplenism and cholangitis can be routinely treated. Treatment is not available to correct the developmental abnormalities in the portal veins and bile ducts or reverse the fibrosis.
Affected individuals should avoid alcohol, medications known to impair liver function, and nonsteroidal anti-inflammatory drugs (NSAIDS).
Genetic counseling is recommended for affected individuals and their families.
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Simkes AM. Congenital Hepatic Fibrosis. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:691-92.
Gunay-Aygun M, Gahl WA, Heller T. Congenital Hepatic Fibrosis Overview. 2008 Dec 9 [Updated 2014 Apr 24]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. Available from: https://www.ncbi.nlm.nih.gov/books/NBK2701/ Accessed July 26, 2018.
Nazer H, Nazer D. Congenital Hepatic Fibrosis. Medscape. Updated Apr 26, 2017. https://emedicine.medscape.com/article/927984-overview. Accessed July 26, 2018.
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