• Toshinori Kamisako
  • Masaki Iwai
  • Wilson M. S. TsuiEmail author


Hyperbilirubinemia is a disorder in the metabolism of bilirubin and is classified into unconjugated and conjugated hyperbilirubinemia.

Increases in serum UCB concentration can be due to an increase in the rate of the production of bilirubin, a decrease in uptake of bilirubin to hepatocytes, or a decrease in conjugation by UGT1A1. Non-hemolytic unconjugated hyperbilirubinemia caused by the mutations in UGT1A1 is classified into Crigler-Najjar syndrome type 1, Crigler-Najjar syndrome type 2, or Gilbert’s syndrome. Histological findings of liver biopsy are almost normal in these syndromes.

Most conjugated hyperbilirubinemia syndromes are caused by hepatobiliary disease, and the rest are caused by rare constitutional jaundice (Dubin-Johnson syndrome or Rotor syndrome). Reduced hepatic bilirubin clearance can be due to defective bilirubin excretion into bile in Dubin-Johnson syndrome and conjugated bilirubin reuptake in Rotor syndrome. Greenish black liver is observed in Dubin-Johnson syndrome. This is due to the presence of pigment within hepatocyte lysosome. The laparoscopic findings and histology of Rotor syndrome are normal.

The hereditary defects of three ABC transporters have been linked to several hepatobiliary disorders, ranging from the severe form of progressive familial intrahepatic cholestasis (PFIC) to the mild form of benign recurrent intrahepatic cholestasis (BRIC) and intrahepatic cholestasis of pregnancy (ICP). These are the result of mutations in the ATP8B1 (PFIC type 1), ABCB11 (PFIC type 2), and ABCB4 (PFIC type 3) genes. Liver biopsy from patients with PFIC types 1, 2, and 3 shows canalicular cholestasis with abnormal bile duct epithelium in the early stages of the diseases, and biliary cirrhosis in later phase.


Hyperbilirubinemia Crigler-Najjar syndrome type 1 Crigler-Najjar syndrome type 2 Gilbert’s syndrome Dubin-Johnson syndrome Rotor syndrome Progressive familial intrahepatic cholestasis (PFIC). 



ATP-binding cassette


Bilirubin diglucuronide


Bilirubin monoglucuronides


Benign recurrent intrahepatic cholestasis




Intrahepatic cholestasis of pregnancy


Multidrug resistance-related protein 2


Organic anion transporting polypeptides


Progressive familial intrahepatic cholestasis


Tight junction protein


Unconjugated bilirubin


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Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Toshinori Kamisako
    • 1
  • Masaki Iwai
    • 2
  • Wilson M. S. Tsui
    • 3
    Email author
  1. 1.OsakaJapan
  2. 2.KyotoJapan
  3. 3.Hong KongChina

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