Table 1 Characteristic features of the different types of progressive familial intrahepatic cholestasis [102,103,104]
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 | Â | MDR3 positive | |
GGT negative | GGT negative to weakly positive | GGT positive | Â | GGT positive | |
 Treatment | |||||
| Â | 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 |