Progressive familial intrahepatic cholestasis

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Synonyms

Byler disease, Byler syndrome, ABCB11-related intrahepatic cholestasis, PFIC, ABCB4-related intrahepatic cholestasis, ATP8B1-related intrahepatic cholestasis, BSEP deficiency, FIC1 deficiency, Low γ-GT familial intrahepatic cholestasis, MDR3 deficiency,

Overview

Progressive familial intrahepatic cholestasis (PFIC) is a disorder that causes progressive liver disease, which typically leads to liver failure. In people with PFIC, liver cells are less able to secrete a digestive fluid called bile. The buildup of bile in liver cells causes liver disease in affected individuals.

Signs and symptoms of PFIC typically begin in infancy and are related to bile buildup and liver disease. Specifically, affected individuals experience severe itching, yellowing of the skin and whites of the eyes (jaundice), failure to gain weight and grow at the expected rate (failure to thrive), high blood pressure in the vein that supplies blood to the liver (portal hypertension), and an enlarged liver and spleen (hepatosplenomegaly).

There are three known types of PFIC: PFIC1, PFIC2, and PFIC3. The types are also sometimes described as shortages of particular proteins needed for normal liver function. Each type has a different genetic cause.

In addition to signs and symptoms related to liver disease, people with PFIC1 may have short stature, deafness, diarrhea, inflammation of the pancreas (pancreatitis), and low levels of fat-soluble vitamins (vitamins A, D, E, and K) in the blood. Affected individuals typically develop liver failure before adulthood.

The signs and symptoms of PFIC2 are typically related to liver disease only; however, these signs and symptoms tend to be more severe than those experienced by people with PFIC1. People with PFIC2 often develop liver failure within the first few years of life. Additionally, affected individuals are at increased risk of developing a type of liver cancer called hepatocellular carcinoma.

Most people with PFIC3 have signs and symptoms related to liver disease only. Signs and symptoms of PFIC3 usually do not appear until later in infancy or early childhood; rarely, people are diagnosed in early adulthood. Liver failure can occur in childhood or adulthood in people with PFIC3

Symptoms

Progressive familial intrahepatic cholestasis (PFIC) is a group of genetic liver diseases characterized by impaired bile flow within the liver, leading to various symptoms. The main symptoms include jaundice (yellowing of the skin and eyes), severe itching (pruritus), failure to thrive (poor weight gain and growth), and an enlarged liver and spleen (hepatosplenomegaly). Other potential symptoms include bleeding, poor bone growth due to vitamin deficiencies, and in some types, diarrhea. 

Causes

ATP8B1 gene mutations cause PFIC1. The ATP8B1 gene provides instructions for making a protein that helps to maintain an appropriate balance of bile acids, a component of bile. This process, known as bile acid homeostasis, is critical for the normal secretion of bile and the proper functioning of liver cells. In its role in maintaining bile acid homeostasis, some researchers believe that the ATP8B1 protein is involved in moving certain fats across cell membranes. Mutations in the ATP8B1 gene result in the buildup of bile acids in liver cells, damaging these cells and causing liver disease. The ATP8B1 protein is found throughout the body, but it is unclear how a lack of this protein causes short stature, deafness, and other signs and symptoms of PFIC1.

Mutations in the ABCB11 gene are responsible for PFIC2. The ABCB11 gene provides instructions for making a protein called the bile salt export pump (BSEP). This protein is found in the liver, and its main role is to move bile salts (a component of bile) out of liver cells. Mutations in the ABCB11 gene result in the buildup of bile salts in liver cells, damaging these cells and causing liver disease.

ABCB4 gene mutations cause PFIC3. The ABCB4 gene provides instructions for making a protein that moves certain fats called phospholipids across cell membranes. Outside liver cells, phospholipids attach (bind) to bile acids. Large amounts of bile acids can be toxic when they are not bound to phospholipids. Mutations in the ABCB4 gene lead to a lack of phospholipids available to bind to bile acids. A buildup of free bile acids damages liver cells and leads to liver disease.

Some people with PFIC do not have a mutation in the ATP8B1, ABCB11, or ABCB4 gene. In these cases, the cause of the condition is unknown.

Diagnosis

Given that so many other conditions are associated with cholestasis in infants and the pediatric population, the differential is alarmingly broad. The following is a list of etiologies of cholestasis that are more commonly seen and is not an exhaustive list:

  • Biliary atresia
  • Infections (e.g., cytomegalovirus, human immunodeficiency virus, syphilis)
  • Alpha 1-antitrypsin deficiency
  • Alagille syndrome
  • Cystic fibrosis
  • Neonatal/infantile asphyxia
  • Neonatal sclerosing cholangitis
  • Common bile duct lithiasis
  • Panhypopituitarism
  • Choledochal cysts
  • Galactosemia
  • Tyrosinemia

Prognosis

Most patients with PFIC will develop end-stage liver disease with significant fibrosis by adulthood. Given the progressive nature of this condition, if patients do not undergo a liver transplant, there is high morbidity and mortality associated with it.

Treatment

A variety of treatments exist which include both medical and surgical interventions. The front-line treatment available for all three variants of PFICs is medical management with ursodeoxycholic acid (UDCA). This secondary bile acid has numerous benefits, including reversal of hepatotoxicity from bile acid accumulation, increasing mitochondrial integrity, and decreasing the degree of cholestasis present. Additional agents such as cholestyramine, a bile acid-binding resin, can be used to treat pruritis associated with PFIC. Rifampicin is thought to work via FXR related mechanisms to upregulate specific detoxification enzymes. Phenobarbital has long been used in the treatment of newborn hyperbilirubinemia through its ability to induce CYP enzymes. Lastly, there are other medications such as antihistamines, steroids, anti-emetics, all of which have been utilized for symptomatic relief.