Expanding etiology of progressive familial intrahepatic cholestasis

Short Background:

A gene is a part of a chromosome that provides the code to build a specific protein. Proteins are involved in pretty much all processes in the human body, including liver function. Mutations are changes in the code of a gene. Changes in the code can lead to proteins that do not function correctly, or even that the protein is not produced at all. The severity of the resulting symptoms often depends on the severity of the mutation. 


This article is a review of research concerning the genetics and characteristics of the different PFIC subtypes. It includes more recent findings that go beyond the more classic PFIC1, PFIC2, and PFIC3 subtypes. The authors of this paper looked at over 900 scientific papers that involved genes associated with PFIC in order to select relevant research and provide an overview of the current status quo.  

            Bile is produced by the liver, transported out of the liver into the small intestine, and then reabsorbed and transported back to the liver. This circuit depends on several different proteins along the way that are coded by different genes. Mutations in any of these genes can cause a disruption of the normal bile flow, which can then result in liver damage. How and where the bile flow is disrupted depends on which protein is defective, and this is mainly why the different subtypes of PFIC have somewhat different characteristics.

            The first reported PFIC is PFIC1 (aka Byler’s disease). It is caused by mutations of the ATP8B1 [SJ1] gene, which encodes the FIC1 protein. The precise function(s) of this protein is not yet known. It is possible that it is involved in the transport of phospholipids, which are needed inside the liver cells to prevent bile acids from causing damage to the liver cells. Defects in the FIC1 protein can lead to low GGT cholestasis (bile built up in the liver). Since FIC1 is also found outside the liver, the spectrum of symptoms of PFIC1 is often broader than in other subtypes of PFIC.  In addition to jaundice, pruritis (itch), and in severe cases progressive liver disease, symptoms of PFIC1 children can also include severe diarrhea, poor growth, and problems with pancreas function. Medical treatment is challenging. Often surgical intervention is needed, which can result in improvement. Partial external biliary diversion (PEBD), ileal bypass, and partial internal biliary bypass (PIBD) are three options that all aim at reducing bile build up in the liver. As of right now neither procedure is clearly superior to the others. Patients who develop end stage liver disease need liver transplant, and it is important to consider that diarrhea can persist or even get worse post-transplant.

            PFIC2 results from mutations in the ABCB11 gene which encodes the Bile Salt Export Pump (BSEP) protein. The function of this protein is to transport bile salts out of the liver cells. Early symptoms of PFIC2 include jaundice, itch, and progressive liver damage which can result in an increase of pressure in the vein that carries blood from the intestines to the liver (“portal hypertension”). In addition, poor growth due to lack of fat absorption and fat-soluble vitamin deficiency can occur, but in general symptoms not directly related to the liver are less severe compared to PFIC1. Initial treatment is similar to PFIC1 and focuses on nutritional supplements and dealing with the itch. Success of biliary diversion seems to depend on the severity of the mutation of the ABCB11 gene. In addition to liver disease there a high chance of cancer (up to 15%) even in very young children.

            PFIC3 is caused by mutations in the ABCB4 gene, which encodes the MDR3 protein. MDR3 helps to incorporate a chemical (phosphatidylcholine) into the bile that neutralizes the detergent qualities of bile acids, which  if left unmitigated would otherwise cause harm. Similar to the other PFIC diseases, the severity of the symptoms seems to depend on the severity of the mutation. This subtype of PFIC often presents later in adolescence or early adulthood. Depending on the severity of the disease liver transplant is often the only therapy.

            More recently, several other proteins have been identified that can cause disease symptoms similar to PFIC if they are defective. The first protein listed in this paper is TJP2, which is a so-called tight junction protein. These types of proteins keep cells together and regulate the flow of specific molecules in between cells. More research is needed to figure out the exact function of TJP2, and why mutations can cause PFIC like disease. The second one is FXR[SJ2] , which regulates the BSEP protein. Without proper regulation of the BSEP protein patients have shown to rapidly develop end stage liver disease. The third protein is MYO5B. The BSEP protein depends on MYO5B to find its way to the cell membrane where it then transports bile salts out of the cell. The symptoms of defective MYO5B are similar to PFIC2, but the disease can include symptoms outside the liver because MYO5B also has other functions. Treatment is similar to PFIC 2 and starts with nutritional supplements and anti-itch medication. In case the itch remains PEBD has been somewhat successful. Finally, liver transplant has been carried out if PEBD is not solving the problems, but this does not resolve the symptoms that are not related directly to the liver. In addition to TJP2, FXR and MYO5B, two other proteins, USP53 and LSR have been found to be related to liver disease. Defects of USP53 were found in 3 children belonging to one family. This protein is thought to work together with TJP2. A mutation in the LSR coding gene was found in one boy, but more research is needed to uncover how this mutation can lead to liver disease. Importantly, these new PFIC-related disorders have only been described in a very small number of children, thus much more information is needed to truly understand how these diseases progress and what treatments may be best.

            This review paper also includes a short overview how the PFIC genes described above can contribute to disease in adults. In adults, disease is mostly limited to Benign Recurrent Intrahepatic Cholestasis (BRIC), and Intrahepatic Cholestasis of Pregnancy (ICP). BRIC in adults is characterized by episodes of more or less severe liver disease. ICP occurs in about 1% of pregnancies. While there are usually no harmful effects for the mother, there can be adverse effects for the child such as premature birth, and also in rare cases stillbirth. Medication has shown to decrease these risks.


PFIC subtypes, genetics


Henkel et al. Expanding Etiology of Progressive Familial Intrahepatic Cholestasis. World Journal of Hepatology, 11(5), 450-463. 2019

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