Alagille Syndrome | Alpha-1 Antitrypsin Deficiency | Bile Acid Synthesis Defects | Mitochondrial Hepatopathies | > PFIC (Progressive Familial Intrahepatic Cholestasis)

PFIC (Progressive Familial Intrahepatic Cholestasis)

What is Progressive Familial Intrahepatic Cholestasis (PFIC)?

The name PFIC was coined in the early 1980's to describe the clinical findings in a form of liver disease that affects children. Taken word for word, it means: Progressive: tending to get worse over time; Familial: passed down to a child from the parents by way of the genes; Intrahepatic: involves disease inside the liver and not the bile ducts outside the liver; Cholestasis: means poor bile flow and build-up of substances in the liver that should be put into bile. A number of medical terms have been used to describe PFIC patients. Byler's disease was a term used to describe Amish children with PFIC, in whom “PFIC” was first identified. Three types of PFIC have been labeled as PFIC-1, PFIC-2 and PFIC-3. Milder forms of PFIC are also known by the name, benign recurrent intrahepatic cholestasis (BRIC).

In recent years, three genes (named ATP8B1, ABCB11, and ABCB4) have been discovered. These genes encode three proteins: ATP8B1 encodes FIC1, ABCB11 encodes BSEP, and ABCB4 encodes MDR3. Mutations in these genes, by leading to failure to make normal versions of these proteins, cause PFIC in most patients. As a result, we think of PFIC as a family of diseases that look much alike clinically but have different genetic causes. Thus PFIC-1 is referred to as FIC1 (familial intrahepatic cholestasis 1) deficiency or ATP8B1 disease, PFIC-2 is referred to as BSEP (bile salt export pump) deficiency or ABCB11 disease, and PFIC-3 as MDR3 (multidrug resistance-associated protein 3) deficiency or ABCB4 disease.

Three types of PFIC have been labeled as PFIC-1, PFIC-2 and PFIC-3. Milder forms of PFIC are also known by the name, benign recurrent intrahepatic cholestasis. In recent years, three genes (named FIC1, BSEP and MDR3) causing PFIC in most patients have been discovered. As a result, we think of PFIC as a family of diseases that look much alike clinically but have different genetic causes. Thus PFIC-1 is referred to as FIC1 (familial intrahepatic cholestasis 1) disease, PFIC-2 is referred to as BSEP (bile salt excretory pump) disease and PFIC-3 as MDR3 (multidrug resistance 3) disease.

What are the symptoms of PFIC?

FIC1 and BSEP disease cause similar symptoms; together they are called low-GGT PFIC because of a blood test result (GGT) that is low rather than high as in most other forms of cholestasis. These diseases cause cholestasis that begins in early childhood, with the average age at onset being 3 months.  However, some patients do not get symptoms of cholestasis until they are teenagers or young adults. These diseases can progress quickly to bad scarring of the liver (cirrhosis) in the first year of life or more slowly with minimal scarring well into the teenage years. Few patients have survived beyond 20 years without treatment.

Itching (pruritus) is the main symptom of cholestasis in many patients. Pruritus is often out of proportion to the level of jaundice (yellow eyes or skin), which is often low-grade and can wax and wane. Pruritus may be hard to identify in young babies because they lack the ability to scratch. Instead, they may be irritable and fretful and sleep poorly. Scratching starts as digging at the ears and eyes, which are the first areas to show bleeding and scarring. The itching may be very disabling and does not usually respond to medications. The scratching interferes with normal activities and sleep and may interfere with learning and schoolwork.

Problems with growth are another major feature of PFIC. Almost all patients are short for their age, but they may not be thin. Delayed puberty and sexual development is common. Patients who are treated can have normal sexual development and several have given birth to normal children. Learning and school performance is normal in most patients receiving effective treatment, but is often delayed before treatment, probably as a result of constant pruritus.

Other common problems include frequent nosebleeds and wheezing. Fat-soluble vitamin (A, E, D and K) deficiencies are common in untreated patients. Vitamin A deficiency can lead to problems with vision. Vitamin E deficiency can lead to problems with balance, strength and coordination. Vitamin D deficiency can lead to poor bone formation. Vitamin K deficiency can lead to bleeding problems. For these reasons, most patients need extra vitamins. In some patients taking a special kind of Vitamin E (TPGS Vitamin E) can help with the absorption of all of the fat-soluble vitamins. Up to a third of patients have gallstones. Most patients have an enlarged liver or enlarged spleen.

Although patients with BSEP disease and patients with FIC1 disease are similar, there are differences between them. FIC1 disease, unlike BSEP disease, can affect many organs in the body including, the pancreas, intestines, lungs and ears. As a result, patients with FIC1 disease are more likely to have watery diarrhea, which can be severe, especially after liver transplantation. Patients with FIC1 disease can also have hearing problems, a chronic cough, and inflammation of the pancreas causing abdominal pain. Patients with BSEP disease may be at an increased risk of development cancers of the liver. However, there is much that we do not yet know about these differences and this will only become clear as more patients are studied.

There is a milder form of FIC1 and BSEP disease referred to as BRIC. It is characterized by intermittent episodes of itching and jaundice. Between episodes the liver disease appears to go away and there is no progressive injury to the liver itself.

Disease in patients with PFIC but with high serum GGT has been called PFIC-3, and is now called MDR3 disease.  Some of these patients have very bad cholestasis in the first year of life, which may progress in the first few years of life toward failure of the liver to perform its normal functions. However, there are probably less severe forms of MDR3 deficiency that cause milder disease. The child and family may first become aware that there is something wrong during school age or adolescence. Sometimes, problems may not appear until adulthood. The full spectrum of liver problems caused by MDR3 disease is just now becoming known.

How do you get PFIC?

PFIC is passed from parents to children (inherited) through genes. Genes are our genetic material, and lie on our chromosomes in the cells of our bodies. Genes are codes for each trait in our bodies. Each person receives two copies of each gene in their body: one copy from their mother and one from their father. For a child to get PFIC they must receive two changed copies of a gene, one each from the mother and the father. These changes in genes are called mutations. Carrying one changed copy of a gene and one normal copy of a gene does not usually cause disease, and is relatively common. Thus parents of children with PFIC usually have no liver or other medical problems. One exception to this may be that women with one changed PFIC gene may develop liver disease during pregnancy.

What happens to the liver in PFIC?

The liver is one of the largest organs in your body. It is found in the upper right part of your abdomen. It is very important to your health because it cleans your blood and helps fight infections. The liver stores vitamins, sugars, fats and other nutrients from the foods you eat. The liver makes many substances for your body. It also breaks down alcohol, drugs and other toxic substances that can hurt your body. The liver also removes a yellow substance from the body, called bilirubin, which builds up in the blood in many liver diseases. The term "liver disease" means a number of conditions that stop the liver from working as well as it should.

The liver cell (or hepatocyte) is responsible for making bile. Bile is a yellow fluid that the liver puts into the intestine by way of a system of tubes from liver to intestines, the bile ducts. Bile is a complex fluid that contains salts and waste products from the body. It also contains two main substances that are made from the body's fats (lipids). These two substances, bile salts and phospholipids, act like detergents in bile and in the intestine. They act to help dissolve fat and vitamins to be absorbed from the diet. If the bile does not contain the enough of these substances, this can cause stones to form in the bile ducts or injury to the cells lining the bile ducts. The changed genes in PFIC interrupt the way the liver cell normally puts bile salts (in FIC1 and BSEP disease) or phospholipids (MDR3 disease) into bile. This causes poor bile flow and the build-up of bile substances in the liver, or cholestasis.

The build-up of bile in PFIC causes the liver to be damaged. This eventually leads to scarring in the liver, which causes the liver to not work. This scarring eventually leads to cirrhosis. Patients may also develop liver cancer.

How is PFIC diagnosed?

The patient is first examined by a physician familiar with childhood liver diseases.  A thorough medical and family history is taken and a complete physical examination is performed. Ultrasound or MRI testing of the liver may be done by a radiologist. Laboratory testing of blood, urine and tissues are the usual tests that are needed to find out the causes of these diseases.

The first tests are used to confirm that cholestasis is present. These include measuring bilirubin (the yellow pigment in bile), bile salts and liver enzymes, including GGT, in blood. Certain other pediatric liver diseases that can look like PFIC are tested for also. A liver biopsy is usually needed to help make the diagnosis and to find out if scarring is present. FIC1 and BSEP disease are suspected when there is chronic cholestasis and low GGT. MDR3 disease is suspected when there is chronic cholestasis and high GGT. Special tests of liver biopsies may help with the diagnosis. Genetic tests for these forms of liver disease are just now becoming available. They are expensive and may not be covered by insurance. 

What are the current therapies for PFIC and how well do they work?

Without any treatment, PFIC will lead to cirrhosis by age 10-20 years, and frequently earlier. Some mild forms may get better with ursodeoxycholic acid (a helpful bile salt) treatment. Severe disease does not usually get better with medical therapy. All young children with PFIC should receive special infant formulas that contain MCT (medium chain triglycerides), a form of fat that is better absorbed in cholestasis. Other supplements that contain MCT may also be used in older children.  Fat-soluble vitamin (A, E, D and K) monitoring and supplementation is also important. A surgery that removes bile salts from the body has been shown to help with relief of pruritus in the majority of patients. The most commonly used surgery is called a partial cutaneous biliary diversion. This means that gallbladder bile is diverted to a bag that is kept on the surface of the skin of the abdomen. The bile is thrown away. Another surgery that has been tried is the limited ileal diversion, in which there is a surgical bypass of the last 15% of the small intestine. This results in a diversion of bile salts to the colon where they are not absorbed. In many circumstances these two types of surgery can lead to a marked improvement in the pruritus and may slow the progression of the liver disease. A variation on these procedures, called nasobiliary drainage, has been tried in some adults with BRIC. In this procedure a tube is placed in the nose and goes down to the bile ducts to drain bile. The pruritus diminishes dramatically after this procedure in adults with BRIC. Use of this procedure in children is complex and not yet reported in the medical literature.

If liver failure develops, if a patient does not get better with the surgical diversions, or if there is evidence of liver cancer, then liver transplantation may be needed. Liver transplantation is removing a diseased liver and replacing it with a healthy one from another person. Survival after transplantation is excellent (>80-90%), although some medical problems may occur in children with FIC1 disease. These problems can include soreness of the pancreas, build-up of fat in the liver and diarrhea. Liver transplantation is not a complete cure: That is, the child who has had a liver transplant is not entirely healthy or entirely normal. But liver transplantation permits survival and, as a rule, problems for the child and family after liver transplantation are easier to live with than problems for the child and family before liver transplantation.

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Advocacy Groups for PFIC:

American Liver Foundation

Children's Liver Association for Support Services (CLASS)

Children's Liver Disease Foundation

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

National Organization for Rare Disorders (NORD)

Office of Rare Diseases (ORD)

Updated: 30 May 2007

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