(Byler disease, Primary Familial Intrahepatic Cholestasis or PFIC)

Prevalence: 1/50.000 to 1/100.000. Autosomal recessive transmission. Aomaly in the production, transport or secretion of the biliary acids that leads to a severe cholestasis of hepatocellular origin, with normal intra- and extra-hepatic  biliary ducts. It represents 10-15 % of the causes of chronic cholestasis and approximately 10% of the indications for liver transplantation in children.

 

6 types have been identified:

-         PFIC 1: [MIM 211 600] formerly called Byler disease (FIC1 or ATP8B1 gene (18q21-22)) or a more benign phenotype, benign recurrent intrahepatic cholestasis or Summerskill syndrome (BRIC1) [MIM243 300]: disorders of the secretion of the bile salts by the hepatocytes  and of their enterohepatic cycle: onset during the first months of life; severe pruritis with normal levels of γGT and cholesterol, short stature.  The heterozygotic form causes intrahepatic cholestasis during pregnancy [MIM 147 480]. It is associated with a subexpression of the CFTR gene as in cystic fibrosis: this sometimes causes chronic diarrhea and/or pancreatic insufficiency. After liver transplantation, 46 % of patients suffer from chronic diarrhea and 26 % from graft steatohepatitis, which may require secondary biliary diversion.

-         PFIC 2: [MIM 601 847]: mutation of the ABCB11 gene (2q24), which codes for the BSEP protein, the carrier of chenodeoxycholic acid by the hepatocyte. This deficit of excretion of chenodesoxycholic acid causes sevrere  itching with normal levels of γGT and cholesterol. Risk of progression to cirrhosis. Sometimes, the phenotype is less severe: benign intrahepatic cholestasis (BRIC2 ) [MIM 605 479]

-         PFIC 3:[MIM 602 347] (ABCB4 gene (7q21)) coding for the phospholipids transporter protein, MDR3 ( Multi Drug Resistance protein 3): lack of biliary excretion of phospholipids, that induces a direct toxicity on intrahepatic biliary canaliculi; onset in infancy, elevated levels of γGT and ductal proliferation at biopsy. Biliary cirrhosis. Another mutation of the same gene leads to LPAC syndrome (see this term).

-        PFIC 4 [MIM 615 878]: mutation in the TJP2 gene (tight junction protein 2 (9q12)): with normal or slightly increased serum level of γGT

-        PFIC 5 [MIM 617 049]:  recently identified severe neonatal form of PFIC: it is due to a mutation of the NR1H4 gene (12q23.1) coding for the FXR (farsenoid X receptor), a nuclear receptor activated by bile acids and playing a key role in the regulation of the synthesis of bile acids. The other forms of PFIC also interfere  with the synthesis of the FXR. Clinical presentation: neonatal cholestasis that rapidly evolves towards hepatocellular failure with coagulopathy by deficiency in vitamin K-dependent factors, low or normal serum levels of γGT and increase of α-fetoprotein

-        PFIC 6 [MIM 619 484]: mutation of the SLC51A gene (3q29). Cholestasis and congenital diarrhea (1 case)

-        PFIC 7 [MIM 619 658]: mutation of the USPJ5 gene (4q26). Cholestasis with normal serum level of γGT. Often early deafness.

-        PFIC 8 [MIM 619 662]: mutation of the KIF12 gene (9q32). Cholestasis with elevated serum levels of γGT and cholesterol.

-        PFIC 9 [MIM 619 849]: mutation of the ZFYVE19 gene (15q15.1). Cholestasis with elevated serum γGT. Hepatosplenomegaly and portal hypertension. Could be a ciliopathy limited to the cholangiocytes.

-        PFIC 10 [MIM 619 868]: mutation of the MYO5B gene mutation (18q21.1). Intrahepatic cholestasis with normal serum levels of γGT similar to PFIC1 without digestive involvement.  Other mutations in this gene also produce the intestinal microvilli disease (see this term) with or without cholestasis.

-        PFIC 11 [MIM 619 874]: mutation of the SEAMA7A gene (15q24.1)

-        PFIC12 [MIM 620 010]: mutation of the VPS33B gene (15q26). Intrahepatic cholestasis with normal serum level of γGT.

Symptomatic treatment:

-        ursodeoxycholic acid: 10 mg/kg 3 to 4 x/day

-        surgical biliary bypass: the aim is to bypass the ileum to reduce the enterohepatic cycle of the bile salts.

1)        partial external biliary bypass: creation of an intestinal duct between the gallbladder and the skin

2)        partial internal biliary bypass: creation of an intestinal duct between the gallbladder and the ascending colon

3)        ileal exclusion

-        intestinal bile acid transport inhibitors (IBATs): maralixibat, odevixibat. More effective in cases of residual BSEP protein activity. Significant gastrointestinal side-effects.

Curative treatment in case of failure: liver transplantation.

Anesthetic implications: 

check liver function and hemostasis. Skin lesions due to pruritus. Treatment with ursodeoxycholic acid. Severe cholestasis followed by biliary cirrhosis. Frequent epistaxis. One case of association of Byler's disease with Becker's muscular dystrophy has been puublished (check CPK).

References : 

-        Müller G, Veyckemans F, Carlier M, Van Obbergh LJ, De Kock M, Sokal EM, Otte JB.
Anaesthetic considerations in progressive familial intrahepatic cholestasis. 
Can J Anaesth, 1995; 42: 1126-33.

-        Gomez-Ospina N, Potter CJ, Xiao R et al.
Mutations in the nuclear bile acid receptor FXR cause progressive familial intrahepatic cholestasis.
Nature Communications DOI 10.103/ncomms10713.

-        Almeida da Silva  HC, Hiraya M, Vainzofb M, Schmidtc B, Souza Bulle Oliveirac A, Gomes do Amaral JL.
Atypical reaction to anesthesia in Duchenne/Becker muscular dystrophy.
Rev Bras Anestesiol 2018;68 :404-7

-        Hüpper MN, Pichler J, Huber W-D, Heilos A, Schaup R, Metzelder  M,  Langer S.
Surgical versus medical management of Progressive Familial Intrahepatic Cholestasis : case compilation and review of the literature.
Children 2023 ; 10 : 949. doi.org/10.3390/children10060949

Updated: February 2024