Conjugated (direct):
An abnormal increase in conjugated bilirubin is typically due to biliary obstruction, intrahepatic cholestasis, or hepatocellular injury leading to jaundice. Patients present with a variety of symptoms based on the underlying etiology, such as chronic liver failure (eg, cirrhosis) or from an acute obstruction or infection (eg, acute alcoholic hepatitis, choledocholithiasis).
Regardless of the etiology, a direct hyperbilirubinemia coincides with scleral icterus and jaundice. Somnolence, asterixis, and hepatic encephalopathy can be observed in patients with decompensated liver failure, which often coincides with a direct hyperbilirubinemia.
Unconjugated (indirect):
An abnormal increase in indirect bilirubin due to overproduction of bilirubin, reduced bilirubin uptake, or impaired bilirubin conjugation. Patients may present with scleral icterus or jaundice, depending on the serum bilirubin level. An indirect hyperbilirubinemia can be caused by primary liver disease processes as well as extrahepatic processes. Intrahepatic cholestasis, biliary obstruction, and acute hepatocellular injury can all lead to an indirect hyperbilirubinemia. Other etiologies include hereditary liver diseases (eg, Gilbert syndrome, Dubin-Johnson syndrome, Crigler-Najjar syndrome), hemolysis, or impaired bilirubin uptake as seen in cirrhosis and congestive hepatopathy.
Symptoms associated with an indirect hyperbilirubinemia vary depending on the etiology. Mixed direct / indirect hyperbilirubinemia from choledocholithiasis will often present with right upper quadrant abdominal pain, while Gilbert syndrome is often painless and asymptomatic. Jaundice can be a hallmark seen in many, although not all, causes of indirect hyperbilirubinemia.
Common causes include, but are not limited to, the following.
Conjugated:
- Biliary obstruction – Leads to both conjugated and unconjugated hyperbilirubinemia as well as elevation of alkaline phosphatase. In adults, may be secondary to cholelithiasis, intrinsic or extrinsic tumors, primary sclerosing cholangitis, parasitic infections, lymphoma, acute and chronic pancreatitis, and strictures after procedures. In children, biliary obstruction is often secondary to choledochal cysts and cholelithiasis.
- Intrahepatic cholestasis – Mimics biliary obstruction, but the bile ducts are patent. Patients also have elevated conjugated and unconjugated bilirubin as well as elevated serum alkaline phosphatase values. Conditions and factors leading to intrahepatic cholestasis are extensive and include viral hepatitis (A, B, C), alcoholic hepatitis, nonalcoholic steatohepatitis, primary biliary cirrhosis, sepsis, drugs and toxins (eg, ethinyl estradiol, chlorpromazine, and Jamaican bush tea), total parenteral nutrition, cholestasis of pregnancy, and postoperatively.
- Hepatocellular injury – Leads to cellular injury and the release of intracellular proteins; thus patients present with unconjugated and conjugated hyperbilirubinemia, elevated alkaline phosphatase, elevated aspartate aminotransferase (AST), alanine transaminase (ALT), and gamma-glutamyl transpeptidase (GGT). As this disease progresses, synthetic function of the liver is also impaired. Conditions causing direct hepatocellular injury are extensive and include various neoplastic processes, toxins and medications, infectious causes, inherited metabolic conditions, and sepsis.
- Overproduction of bilirubin – Secondary to excessive heme breakdown in the setting of extravascular or intravascular hemolysis, extravasation of blood into tissues, or dyserythropoiesis.
- Reduced bilirubin uptake – Due to impaired delivery of bilirubin to the liver from congestive heart failure or portosystemic shunts in patients with cirrhosis. Other causes include Gilbert syndrome, in which there is impaired hepatocyte uptake of bilirubin at the cell surface.
- Impaired bilirubin conjugation – Result of decreased or absent UDP-glucuronosyltransferase activity found in conditions such as Crigler-Najjar syndromes type I and II and Gilbert syndrome.
