Progressive familial intrahepatic cholestasis (PFIC)

Metabolic, Biliary Atresia & Related Diseases


Bile is essential in order to break down fats and is produced in the liver. In PFIC patients, the transport of bile from the liver to the intestine is disrupted. Therefore, bile acids and in some cases, other metabolites such as bilirubin accumulate in the liver and in the blood. This can lead to a build up and to cholestasis, driving damage to the liver cells and inflammation. As a result, scar tissue is formed in the liver (fibrosis) and bile acids can circulate throughout the body and contribute to the stressful itching.
PFIC is most often diagnosed in infants and in toddlers. In milder cases, it occurs in school-age children, adolescents and only rarely in adults. Only one in 50,000 to 100,000 children is affected by PFIC. The cause is a group of rare genetic defects. So far, we know of three main types of PFIC and their causative genetic defects, but more rare subtypes have been discovered. All those genes carry information for proteins which are somehow involved in the transport of bile ingredients from the liver cells to the bile ducts.
The severity of symptoms and the course of disease vary among individuals. Many patients experience severe itching, others experience this along with other symptoms such as jaundice and failure to thrive. Jaundice is also a sign of disruption in liver function: bilirubin, a waste product of red blood cells, which is normally excreted with the bile, accumulates in the blood. This can lead to yellow discoloration of the skin and mucous membranes.
Growth disorders and vitamin deficiencies can occur because fat and the fat-soluble vitamins A, D, E and K are less easily absorbed due to reduced levels or a lack of bile.
In severe cases, the fibrosis (still potentially reversible) progresses to cirrhosis (scarring, rarely reversible). High blood pressure may develop in the portal vein. This may lead to the spleen increasing in size and to swelling of the blood vessels in the lower oesophagus or stomach which, upon rupture, can lead to significant blood loss and vomiting of blood.
In some children, the final stage of liver failure is reached before the age of 10, which makes a liver transplant necessary.


Due to the variety of symptoms and their severity, there are several treatment options. Current drugs are primarily intended to alleviate the symptoms and slow disease progression. For some patients, the only chance of complete recovery is through liver transplantation. There is potential for gene therapy in the future.
In many cases, there are delays in diagnosing PFIC disease. The European Reference Network on Hepatological Diseases (ERN RARE-LIVER) with its > 30 centres across Europe is working to shorten this period significantly leading to earlier diagnosis and treatment initiation.
As a first diagnostic step, blood is taken from the child or adult patient to carry out liver function tests (bilirubin, enzyme GGT and others, coagulation values, albumin). These tests are also repeated as part of recurring routine checks. Imaging techniques such as ultrasound can determine the sizes of liver and spleen and monitor the blood flow to the liver. X-rays may be used to determine whether bone density has decreased due to vitamin D deficiency.
In many cases, the treating physician will also suggest a liver biopsy. This procedure is brief and carried out under anaesthesia or conscious sedation combined with pain control. The skin and underlying tissue on the right side are punctured to sample a very small cylinder of liver tissue. Specialists then examine this sample under the microscope. The risks of the procedure are low for the vast majority of patients. Families, parents and patients receive detailed information about liver biopsy in advance if this procedure is recommended.
To confirm PFIC and determine the subtype, a genetic test (analysis of the affected parts of the genetic information located on the DNA) is carried out in most cases. The blood of the parents may also be required for this. The genetic test takes two weeks or sometimes longer


Once the diagnosis has been made, therapy is determined. The choice of medication for PFIC ultimately depends on the type and severity of the symptoms. The main purpose of these drugs is to relieve the symptoms and to help slow down disease progression. PFIC patients need to be monitored for liver cancer in the native liver all their lives as the risk is increased, even in younger children.
A common treatment goal is to reduce the extremely stressful itching by alleviating cholestasis (lowering the concentration of bile acids in the blood). Ursodeoxycholic acid or rifampicin are often used in early stages to improve bile transport and metabolism. As no approved drugs for PFIC are available at this stage, doctors will frequently prescribe “off-label” drugs. New drugs are being tested in clinical trials for their potential future use in PFIC.
If the growth and development of the child is impaired by the disease, doctors prescribe a formula diet whose energy and fat content is often adapted to the special needs of children with liver disease. To improve the vitamin status, fat-soluble vitamins are given as tablets or drops. Because they have difficulty absorbing fats, children with PFIC have a greater need for energy supplies from food, but their appetite is low. This means that a feeding tube may be required in some but exceptional cases.
A surgical procedure called biliary diversion can also alleviate the symptoms in certain cases. The bile is partially drained or diverted via an external stoma on the right abdominal wall, or by an internal diversion from the gallbladder to the colon leading to a net loss of bile acids. To create this diversion, a short part of the small bowel is converted to function as a connection from the gallbladder to the abdominal wall or colon. Each option has its own advantages, but can also be associated with risks. Your or your child’s physician will provide comprehensive information before such a procedure.
If the therapies outlined are not suitable or successful, the failing liver may need to be replaced. Different technical approaches offer a good prognosis for adults, older children or young children in need of such a procedure. One of them is the splitting of donor organs and the other is living donation of (a) liver segment(s) by parents. However, in all PFIC subtypes, this operation should only be performed after carefully weighing up the benefits and risks. Many children affected by PFIC after liver transplantation will have a good prognosis and regain good quality of life. However, the majority will require lifelong immune suppression which may come with disadvantages. Depending on the disease subtype, disease specific post-operative complications have to be considered. Families will receive detailed information on liver transplantation during the initial preparation phase and during all later phases should a liver transplant be deemed necessary.