Progressive familial intrahepatic cholestasis

Group of rare, congenital, genotypically different, autosomal recessive, cholestatic liver diseases that occur with varying degrees of severity (Henkel SA et al. 2019).

Progressive familial intrahepatic cholestasis is divided into the clinical subgroups PFIC-1 (Byler syndrome) to PFIC-4.

PFIC-1 to PFIC-4 are cholestatic liver diseases of varying severity, which have an autosomal recessive inheritance and often lead to progressive liver cirrhosis in infancy.

PFIC-1 to -3 are the fourth most common cause of neonatal cholestasis in German hospitals (about 10% of cases).

Disturbances of bile acid homeostasis due to misregulation in the channelicular membranes of the hepatobiliary system caused by different mutations in different genes: (ATP8B1 gene for FIC1; bile salt export pump (BSEP; ABCB11) for FIC2; multidrug resistance protein 3 (MDR3; ABCB4); TJP2 gene coding for tight junction protein 2 (FIC4). Further gene mutations have been described for FXR (NR1H4), MYO5B (MYO5B) (Keitel V et al. 2019).

PFIC-1 (synonym: Byler's disease): Caused by mutations in the familial intrahepatic cholestasis associated protein type 1 (FIC1; ATP8B1), which as an aminophospholipid flippase is important for the membrane asymmetry of the canalicular membrane. FIC1 transports phosphatidylserine from the outer to the inner layer of the membrane and thus acts complementary to MDR3.

PFIC-2: Mutations of the bile salt export pump (BSEP; ABCB11), which transports bile salts into the bile, are responsible. More than 80 mutations leading to PFIC-2 are known. The vast majority of PFIC-2-causing BSEP mutations are associated with a lack of BSEP at the channelicuvian membrane, so that immune staining with BSEP-specific antibodies for primary differentiation of PFIC-1 and PFIC-2 can be used diagnostically before a more complex sequencing is connected (Saha H et al. 2019).

PFIC-3: This is caused by mutations of multidrug resistance protein 3 (MDR3; ABCB4), which acts as a floppase and transports phospholipids from the inner to the outer layer of the lipid bilayer membrane, where they are released from the membrane by bile salts and enter the bile. There are some mutations that, despite the development of PFIC-3, show a normal localization of MDR3 in liver biopsies. Mutations in the MDR3 gene can also become conspicuous only in adolescence or adulthood in the form of liver cirrhosis (late-onset PFIC-3).

PFIC-4 This form of autosomal recessive inherited low-γGT cholestasis or low-γGT PFIC can be triggered by mutations in the cell-cell adhesion molecule tight junction protein 2 (TJP2). TJP2 is expressed almost ubiquitously in the body. In the liver, the protein is localized at the cell contacts in the area of the canalicular membrane and between the cholangiocytes. While in other organs the cell-cell contacts are little affected by mutations in TJP2, the toxic effects of bile salts in the area of the channel membrane and between the cholangiocytes lead to the dissolution of these cell-cell contacts and the development of severe liver damage.

PFIC5: is triggered by mutations in the NR1H4 gene, which codes for the farnesoid X receptor (Vitale G et al. 2019) The ligand-activated transcription factor farnesoid X receptor (FXR) is a nuclear hormone receptor with high expression in the liver, intestine and kidney, which is activated by the primary bile acid chenodeoxycholic acid (CDCA) and by synthetic agonists.

Wu SH et al. (2019) reported a congenital severe cholestasis in which a mutation in the plectin gene was detected. Other organ alterations were missing.

Mutations in the PFIC genes seem to increase the risk of liver carcinoma (Vitale G et al. 2019).

1. Henkel SA et al (2019) Expanding etiology of progressive familial intrahepatic cholestasis. World J Hepatol 11:450-463.
2. Keitel V et al (2019) Targeting FXR in cholestasis. Handb Exp Pharmacol doi: 10.1007/164_2019_231.
3. Saha H et al (2019) Two Cases of Progressive Familial Intrahepatic Cholestasis Type 2: Role of Surgery with Brief Review of Literature. J Indian Assoc Pediatrics Surgery 24:75-77
4. Vitale G et al (2019) Familial intrahepatic cholestasis: New and wide perspectives. Dig Liver Dis 51:922-933.
5. Wu SH et al (2019) Plectin Mutations in Progressive Familial Intrahepatic Cholestasis. Hepatology doi: 10.1002/hep.30841.