What is the cause of elevated unconjugated bilirubin (hyperbilirubinemia)?

From the Guidelines

Elevated unconjugated bilirubin is usually due to haemolysis or impaired conjugation, with the most common cause being Gilbert’s syndrome, an inherited disorder of metabolism characterized by reduced activity of the enzyme glucuronyltransferase 1. The causes of elevated unconjugated bilirubin can be broken down into several key categories:

• Haemolysis: This is a condition where red blood cells break down prematurely, releasing more bilirubin than the liver can process.
• Impaired conjugation: This can occur due to various liver disorders or genetic conditions, such as Gilbert’s syndrome.
• Gilbert’s syndrome: This is a common benign genetic condition affecting about 5-10% of the population, characterized by mild elevations in unconjugated bilirubin without liver disease. Some key points to consider when evaluating elevated unconjugated bilirubin include:
• The majority of measurable bilirubin should be conjugated, even in individuals with significant liver disease, so if the majority of the elevated bilirubin comprises the unconjugated fraction, the cause is virtually always Gilbert’s syndrome, in the absence of haemolysis 1.
• In the neonatal period, there may be a physiological increase in total bilirubin, which is unconjugated, but this may be pathological if high or prolonged 1.
• Patients with elevated unconjugated bilirubin may appear jaundiced (yellowing of skin and eyes) when levels exceed 2-3 mg/dL. Management of elevated unconjugated bilirubin depends on the underlying cause, with no treatment typically needed for Gilbert’s syndrome, while hemolytic disorders require treatment of the underlying condition 1.

From the Research

Causes of Elevated Unconjugated Bilirubin

• Elevated unconjugated bilirubin (hyperbilirubinemia) can be caused by several factors, including:
  • Increased bilirubin production due to red blood cell destruction, such as hemolytic disorders 2
  • Impaired bilirubin conjugation, such as Gilbert syndrome, which is characterized by a deficiency in hepatic UDP-glucuronosyltransferase 1A1 (UGT1A1) enzyme activity 3, 4
  • Acquired depression of hepatic bilirubin UDP-glucuronyltransferase activity, which can occur in chronic persistent hepatitis 5
  • Chemotherapy-induced hyperbilirubinemia, which can be aggravated by infection and fasting 3
• Unconjugated hyperbilirubinemia can also be associated with certain conditions, such as:
  • Non-alcoholic steatohepatitis (NASH), where unconjugated hyperbilirubinemia is inversely associated with the histopathological severity of liver damage 6
  • Crigler-Najjar syndrome, a rare but devastating hereditary disorder of bilirubin metabolism 4

Mechanisms of Unconjugated Hyperbilirubinemia

• The plasma concentration of unconjugated bilirubin is determined by the rate at which newly synthesized bilirubin enters the plasma (bilirubin turnover) and the rate of irreversible bilirubin removal by the liver (hepatic bilirubin clearance) 4
• Measurement of bilirubin turnover and hepatic bilirubin clearance can help classify cases of unconjugated hyperbilirubinemia into those due to increased bilirubin turnover, decreased bilirubin clearance, or both 4

Evaluation of Unconjugated Hyperbilirubinemia

• The evaluation of jaundice in adults, which can be caused by elevated serum bilirubin levels, relies on history, physical examination, and laboratory tests, including fractionated bilirubin and liver function tests 2
• Imaging studies, such as ultrasonography or computed tomography, can help differentiate between extrahepatic obstructive and intrahepatic parenchymal disorders 2