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Table 1 Characteristic features of the different types of progressive familial intrahepatic cholestasis [102,103,104]

From: Neonatal cholestasis: recent insights

Item PFIC 1 Byler disease PFIC 2 PFIC 3 PFIC 4 PFIC5
Both genders are equally affected, incidence 1/50000–100,000
 Genetics
  Inheritance AR AR AR AR AR
  Gene ATP8B1/F1C1 ABCB11/BSEP ABCB4/MDR3 TJP2 NR1H4
  Protein Familial intrahepatic cholestasis 1 (FICI) Bile salt export protein (BSEP) Multidrug resistance protein 3 (MDR3) TJP2 protein FXR, the key regulator of BS metabolism
  Chromosome 18q21-q22 2q24 7q21 9q12 12q23.1
  Location Wide tissue distribution including almost all epithelial cells; on apical membranes Hepatocyte canalicular membrane Hepatocyte canalicular membrane Tight junctions Bile canaliculi, FXR is highly expressed in liver and pancreatic β cells
 Pathophysiology
  Function of hereditary defect Aminophospholipid flippase Bile acid secretion Phosphatidylcholine secretion Integral tight junction protein (claudin-1) Farnesoid X receptor loss
  Clinical findings
  Age of onset Neonates Neonates 1 month–20 years Infancy, childhood Neonate
  Course Progressive Progressive Progressive Progressive Rapidly progressive
  Cholestasis Chronic Chronic Chronic Chronic Chronic
  Pruritus Severe Severe Moderate Severe Severe
  Others Other features include short stature, diarrhoea, hepatosplenomegaly, malabsorption, pancreatitis, respiratory disease, and occasionally sensorineural hearing loss Growth failure gallbladder stones Later onset cholestasis, portal hypertension, minimal pruritus, gall bladder stone, cupper accumulation in liver tissue, and increase in urinary cupper. Intrahepatic cholestasis, early childhood liver failure, portal hypertension, neurological and respiratory symptoms Coagulopathy a direct consequence of the loss of FXR function. Failure to thrive and ascites, gallstones pleural effusions, and intraventricular haemorrhage at birth
  Risk of malignancy +
HCC/cholangiocarcinoma (in 30% of patients)
+ +
HCC
 
 Laboratory findings  
  Serum GGT Normal/low Normal/low High Normal or mildly increased Low to normal
  Serum ALT Mildly elevated > 5 × normal > 5 × normal Elevated Elevated
  Serum AFP Normal Elevated Normal Elevated Elevated
  Serum primary bile acid concentration Very high + normal cholesterol Very high High   
  Biliary bile acid secretion Low Low Low   
 Liver biopsy
  Histology Minimal giant cell transformation, intracanalicular cholestasis, no ductal proliferation, minimal inflammation. Late fibrosis Giant cell transformation, intracanalicular cholestasis, no ductular proliferation, moderate inflammation, fibrosis, extramedullary hemopoiesis Giant cell transformation,intracanalicular cholestasis, ductular proliferation, moderate inflammation, marked fibrosis, lipid crystals within bile ducts, and fibroobliterative bile duct lesions Ductular reaction, diffuse giant cell transformation, and ballooning of hepatocytes and intralobular cholestasis Intralobular cholestasis, diffuse giant cell transformation, ballooning hepatocytes, and ductular reaction. Micronodular cirrhosis and fibrosis were evident at later stages
  Electron microscopy Byler type coarsely granular bile; loss of microvilli, swollen microvilli Amorphous filamentous bile; loss of microvilli Presence of cholesterol crystals; loss of microvilli, bile is dense and amorphous. Elongated tight junctions between adjacent hepatocytes and biliary canaliculi seen on biopsy  
  Immunohistochemistry BSEP positive BSEP negative BSEP positive   BSEP negative
MDR3 positive MDR3 positive MDR3 negative   MDR3 positive
GGT negative GGT negative to weakly positive GGT positive   GGT positive
 Treatment
  UDCA, rifampin fat-soluble vitamins + biliary diversion, ileal exclusion, liver transplantation; post-orthotropic liver transplantation diarrhoea, pancreatitis, steatorrhea, fatty liver with possible progression to cirrhosis Biliary diversion, liver transplantation (possible recurrent disease after transplantation) UDCA if residual PC secretion; liver transplantation Liver transplantation Liver transplantation
  1. AR autosomal recessive, GGT gamma-glutamyl transferase, AFP alpha fetoprotein, ALT alanine aminotransferase, BSEP bile salt export pump, UDCA ursodeoxycholic acid, HCC hepatocellular carcinoma