What is Progressive Familial Intrahepatic Cholestasis (PFIC)?

 

Progressive Familial Intrahepatic Cholestasis (PFIC) is a rare form of cholestasis that commonly manifests in early infancy and childhood, progressing to cirrhosis within the first decade of life. It is inherited in an autosomal recessive pattern and develops due to mutations in genes coding for hepatobiliary transporter proteins. The main clinical symptoms include jaundice, itching, growth retardation, hepatosplenomegaly, and cholestasis. The incidence of PFIC ranges from 1 in 50,000 to 1 in 100,000. 

 

What are the Subtypes of Progressive Familial Intrahepatic Cholestasis (PFIC)?

 

Molecular genetic investigations can establish the definitive diagnosis and subtype classification of Progressive Familial Intrahepatic Cholestasis (PFIC). PFIC now has nine subtypes, including recently identified ones, each showing distinct genotypic characteristics. The first three types are the most commonly observed: 

PFIC Type 1, or Byler disease, results from mutations in the ATP8B1 gene, leading to defects in the Familial Intrahepatic Cholestasis 1 (FIC1) protein. PFIC Type 2 is characterised by variations in the ABCB11 gene, resulting in down-regulation or absence of the bile salt export pump (BSEP). PFIC Type 3 is caused by mutations in the ABCB4 gene, leading to MDR3 deficiency. Unlike FIC1 and BSEP deficiencies, MDR3 deficiency can present with a clinical phenotype even with a single ABCB4 mutation, which may manifest in childhood (e.g., cholelithiasis) or adulthood. 

PFIC Type 4, related to TJP2 gene deficiencies, is rarer than the classic PFIC types 1-3. PFIC Type 5 involves mutations in the MYO5B gene, causing progressive cholestasis early in life. However, limited information exists regarding the pathophysiology and natural history of this subtype. 

A study by Maddirevula et al. 2019 discovered three additional gene loci: USP53, LSR, and WDR83OS. The USP53 gene is thought to interact with TJP2, leading to a defective tight junction complex and a phenotype similar to TJP2 deficiency, resulting in cholestasis, itching, hypocalcemia, and hearing loss in affected individuals. 

 

How is PFIC Diagnosed? 

 

Diagnosis can be established through characteristic clinical and laboratory parameters and genetic testing after excluding other liver diseases that cause intrahepatic cholestasis. Therefore, it is essential to exclude anatomical abnormalities first. For this purpose, imaging techniques such as ultrasound, magnetic resonance cholangiopancreatography (MR-CP), percutaneous transhepatic cholangiography (PTC), and endoscopic retrograde cholangiopancreatography (ERCP) can be used. 

The definitive diagnosis of the disease can be made through genetic investigations. 

 

What are the Treatment Options for PFIC?

 

Treatment of PFIC cases involves both medical and surgical methods. 

Medical Treatment: 

• IBAT Inhibitors 
• Ursodeoxycholic Acid (UDCA) 
• Cholestyramine 
• Phenobarbital 
• Rifampicin 

Surgical Methods: 

•  Nasojejunal Drainage 
• Biliary Diversion 
• Liver Transplantation 

 

Source: 

1. Cavestro GM, Frulloni L, Cerati E, Ribeiro LA, Corrente V, Sianesi M, Franze A, Di Mario F. Progressive familial intrahepatic cholestasis. Acta Biomed. 2002; 73: 53-56.
2. Davit-Spraul, A., Gonzales, E., Baussan, C., & Jacquemin, E. (2009). Progressive familial intrahepatic cholestasis. Orphanet journal of rare diseases, 4(1), 1-12.
3. Jacquemin E. Progressive familial intrahepatic cholestasis. Genetic basis and treatment. Clin LiverDis 2000; 4: 753-63.
4. Felzen, A., & Verkade, H. J. (2021). The spectrum of Progressive Familial Intrahepatic Cholestasis diseases: Update on pathophysiology and emerging treatments. European journal of medical genetics, 64(11), 104317.
5. Mehl, A., Bohorquez, H., Serrano, M.S., Galliano, G., Reichman, T.W., 2016. Liver transplantation and the management of progressive familial intrahepatic cholestasis in children. World J. Transplant. 6 (2), 278–290.
6. Gomez-Ospina, N., Potter, C.J., Xiao, R., Manickam, K., Kim, M.S., Kim, K.H., et al., 2016. Mutations in the nuclear bile acid receptor FXR cause progressive familial intrahepatic cholestasis. Nat. Commun. 7, 10713.
7. Gonzales, E., Taylor, S.A., Davit-Spraul, A., Thebaut, A., Thomassin, N., Guettier, C., et al., 2017. MYO5B mutations cause cholestasis with normal serum gamma-glutamyl transferase activity in children without microvillous inclusion disease. Hepatology 65 (1), 164–173.
8. Maddirevula, S., Alhebbi, H., Alqahtani, A., Algoufi, T., Alsaif, H.S., Ibrahim, N., et al., 2019. Identification of novel loci for pediatric cholestatic liver disease defined by KIF12, PPM1F, USP53, LSR, and WDR83OS pathogenic variants. Genet. Med. 21 (5), 1164–1172.
9. Rebhandl W, Felberbauer FX, Huber WD, et al. Progressive familial intrahepatic cholestasis (Byler disease): current genetics and therapy. Klin Padiatr 2000; 212: 64-70.