Progressive familial intrahepatic cholestasis

Abstract

Progressive familial intrahepatic cholestasis (PFIC) is a group of rare disorders which are caused by defect in bile secretion and present with intrahepatic cholestasis, usually in infancy and childhood. These are autosomal recessive in inheritance. The estimated incidence is about 1 per 50,000 to 1 per 100,000 births, although exact prevalence is not known. These diseases affect both the genders equally and have been reported from all geographical areas. Based on clinical presentation, laboratory findings, liver histology and genetic defect, these are broadly divided into three types-PFIC type 1, PFIC type 2 and PFIC type 3. The defect is in ATP8B1 gene encoding the FIC1 protein, ABCB 11 gene encoding BSEP protein and ABCB4 gene encoding MDR3 protein in PFIC1, 2 and 3 respectively. The basic defect is impaired bile salt secretion in PFIC1/2 whereas in PFIC3, it is reduced biliary phospholipid secretion. The main clinical presentation is in the form of cholestatic jaundice and pruritus. Serum gamma glutamyl transpeptidase (GGT) is normal in patients with PFIC1/2 while it is raised in patients with PFIC3. Treatment includes nutritional support (adequate calories, supplementation of fat soluble vitamins and medium chain triglycerides) and use of medications to relieve pruritus as initial therapy followed by biliary diversion procedures in selected patients. Ultimately liver transplantation is needed in most patients as they develop progressive liver fibrosis, cirrhosis and end stage liver disease. Due to the high risk of developing liver tumors in PFIC2 patients, monitoring is recommended from infancy. Mutation targeted pharmacotherapy, gene therapy and hepatocyte transplantation are being explored as future therapeutic options.

Keywords: ABC, ATP binding cassette; ASBT, apical sodium bile salt transporter; ATP, adenosine triphosphate; ATPase, adenosine triphosphatase; BRIC, benign recurrent intrahepatic cholestasis; BSEP, bile salt exporter protein; CFTR, cystic fibrosis transmembrane conductance regulator; CYP, cytochrome P; DNA, deoxyribonucleic acid; ERAD, endoplasmic reticulum associated degradation; ESLD, end stage liver disease; FIC1, familial intrahepatic cholestasis protein 1; FXR, farnesoid X receptor; HCC, hepatocellular carcinoma; IB, ileal bypass; ICP, intrahepatic cholestasis of pregnancy; LT, liver transplant; MARS, Molecular Adsorbent Recirculating System; MDR, multidrug resistance protein; MRCP, magnetic resonance cholangiopancreaticography; PBD, partial biliary drainage; PEBD, partial external biliary drainage; PFIC, progressive familial intrahepatic cholestasis; PIBD, partial internal biliary drainage; PPAR, peroxisome proliferator activator receptor; UDCA, ursodeoxycholic acid; bile secretion; children; cholestasis; familial; mRNA, messenger ribonucleic acid; pGp, p-glycoprotein; pruritus.

Figure 1

Etiopathogenesis of PFIC (PFIC: progressive familial intrahepatic cholestasis; FIC1: familial intrahepatic cholestasis protein 1; BSEP: bile salt exporter pump; MDR3: multidrug resistance protein 3).

Figure 2

Biliary drainage procedures: a diagrammatic representation (IB: ileal bypass, NBD: nasobiliary drainage; PEBD: partial external biliary drainage; PIBD: partial internal biliary drainage).

Figure 3

Future therapies for PFIC (black arrows denote steps in transcription of transporter protein (FIC1, BSEP, MDR 3) from nucleus to endoplasmic reticulum to Golgi apparatus to canalicular membrane. Farnesoid R receptor (FXR) ligand therapy activates a number of genes like BSEP associated with bile salt homeostasis. Agents acting by read through premature stop codon help mRNA to skip a stop codon; endoplasmic reticulum associated degradation (ERAD) inhibitors act on endoplasmic reticulum to decrease degradation of misfolded/truncated protein and chaperone agents act on Golgi apparatus to correct misfolding/mistrafficking of proteins).