PFIC stands for several autosomal recessive hereditary liver diseases. The known forms are PFIC1, PFIC2 and PFIC3; variants 4-7 are rarer. In all diseases, the bile outflow from the liver does not function correctly. These diseases are inherited and can become apparent at any age, with symptoms and diagnosis typically occurring in infants and young children. The differences between the various diseases are great, which is why they are also named according to their underlying functional disorder (for the different types, see below). The disorder of bile flow and the composition of the bile differ depending on the type of PFIC.

The name PFIC is made up of the terms ‘progressive’ (advancing), ‘familial’ (inherited), ‘intrahepatic’ (in the liver) and ‘cholestasis’ (bile stasis). It is therefore a progressive, inherited bile duct disease in the liver.

Causes of PFIC

PFIC are hereditary diseases that are inherited in an autosomal recessive manner. One study showed that PFIC3 can progress to cirrhosis of the liver and cholangiocarcinoma (bile duct cancer) even in people who carry only one defective chromosome, although the course of the disease is usually milder than in carriers who have two defective chromosomes. In some families there are several cases of PFIC or similar complications. Pregnancy cholestasis in the mother or PFIC in siblings have also been observed.

Symptoms

The main symptoms are severe itching and jaundice. Typically, the first symptoms appear in infants and children, but the disease can occur at any age. Vitamin deficiencies, slower growth and impaired digestion are also common. PFIC can lead to typical symptoms and complications as liver cirrhosis progresses, such as a water belly or varicose vein haemorrhages.

The different forms of PFIC

PFIC1 (FIC-1 deficiency): FIC-1 deficiency in PFIC1 affects a specific endogenous protein called FIC-1 or ATP8B1, a transporter protein. This protein is crucial for the correct composition of bile and the proper functioning of liver cells. Jaundice and intense itching are often the first symptoms. Diarrhoea, lack of fat-soluble vitamins, growth disorders, pancreatitis, hearing problems, chronic cough and growth retardation are also typical. End-stage liver disease can occur as early as infancy. A liver transplant only leads to partial improvement.

PFIC2 (BSEP deficiency): In PFIC2, the body lacks the transport protein ABCB11 or BSEP (Bile Salt Export Pump), which is essential for the transport of bile salts, the production of bile and the flow of bile. Severe courses are typical, accompanied by intense itching and retarded growth. Jaundice, deficiency of fat-soluble vitamins and gallstones can occur. PFIC2 often progresses rapidly to cirrhosis. Complications due to portal hypertension are common, and the risk of hepatocellular carcinoma and bile duct tumours increases. After a transplant, PFIC2-like damage can also occur in the new organ.

PFIC3 (MDR3 deficiency): In PFIC3, the protein MDR3 or ABCB4, which is responsible for the transport of phospholipids, is missing. Impaired regulation of these lipids leads to an increase in bile salts, which damages the uppermost cell layer in the bile ducts. The severity of the disease and the symptoms vary greatly. Bile duct proliferation, fibrosis and even biliary cirrhosis and increased gallstone formation are possible. The itching is often less severe. The gamma-GT values in the blood are elevated. Half of those affected can be treated with ursodeoxycholic acid.

Diagnosis

PFIC diseases are difficult to diagnose quickly. The liver values and bile acids in the blood are elevated. Intense, insatiable itching in young children can lead to the initial suspicion of PFIC. Various general liver values in the blood may be elevated, including GOT, GPT and direct bilirubin. Elevated bile acids in the blood due to bile stasis are also conspicuous. Gamma-GT is usually normal but can be highly elevated in PFIC3. More specialised tests for altered bile salts in the blood or urine are time-consuming, but can provide additional information. A liver puncture is often necessary to identify specific changes in the liver tissue, and genetic tests can detect mutations. These tests can take a long time, as not all the genes responsible are known.

Treatment

‘Odevixibat’ has been approved as an active ingredient in Germany since 2021. It reduces harmful bile acids, lowers liver enzymes and alleviates itching. There are side effects such as bloody diarrhoea, abdominal pain and an enlarged liver. There are no long-term studies on this medication yet.

Various drugs such as cholestryramine, naltrexone or rifampicin are used to treat itching. Other drugs specifically for itching in PFIC are still being investigated in studies. In severe cases, bile can be drained through the nose (nasobiliary drainage).

Nutritional measures can be used as support, including an increased calorie intake, administration of fat-soluble vitamins and MCT fats. Surgical interventions can be considered in the event of complications, although the advantages and disadvantages must be assessed on an individual basis. If the liver disease is too advanced, liver transplantation is an option.

In some cases, a partial external biliary diversion (PEBD) can be performed for PFIC1 and PFIC2, in which a loop of small intestine is removed and passed through the abdominal wall as a connection from the gallbladder. The children then wear a stoma bag. A rarely used method is the partial ileum bypass, in which a short-circuit connection is made from the small intestine to the large intestine. A partial ileum bypass is used even less frequently: approx. 15% of the small intestine is bypassed so that the absorption of bile salts can be prevented. The risk of error in this surgical procedure is high.

In advanced liver disease, a liver transplant may be necessary. This can cure the liver disease in some PFIC patients, but in PFIC2 there is still a risk of recurrence of the disease in the new organ.

‘Maralixibat’, another IBAT (Ileal Bile Acid Transporter) inhibitor, is being investigated in trials for PFIC. In PFIC3, research is being conducted into whether fibrates can improve the efficacy of ursodeoxycholic acid. Gene or cell therapies could also play a role in the future.