From the Guidelines
Elevated indirect bilirubin is primarily caused by increased production of bilirubin or decreased liver uptake and conjugation, with common causes including hemolytic anemias, genetic conditions like Gilbert's syndrome, and certain medications. The most recent and highest quality study, 1, suggests that a predominance of unconjugated hyperbilirubinemia results from errors in enzyme metabolism in the hepatocytes, with Gilbert syndrome being a benign hereditary disorder that reduces the enzyme glucuronosyltransferase’s activity. Some key points to consider when evaluating elevated indirect bilirubin include:
- Hemolytic anemias, such as sickle cell disease, thalassemia, and autoimmune hemolytic anemia, can cause increased production of bilirubin
- Genetic conditions, such as Gilbert's syndrome, Crigler-Najjar syndrome, and neonatal jaundice, can impair the liver's ability to process bilirubin
- Certain medications, including rifampin, probenecid, and some HIV protease inhibitors, can interfere with bilirubin metabolism
- Ineffective erythropoiesis, resorption of large hematomas, and severe sepsis can also contribute to elevated indirect bilirubin
- In newborns, physiologic jaundice can occur due to immature liver enzymes, as noted in 1. Management depends on treating the underlying cause, which may involve addressing hemolysis, discontinuing offending medications, or in severe cases, considering phototherapy or exchange transfusion for dangerously high levels, as discussed in 1 and 1.
From the FDA Drug Label
Hepatotoxicity including transient abnormalities in liver function tests (e.g., elevations in serum bilirubin, alkaline phosphatase, serum transaminases, gamma-glutamyl transferase), hepatitis, a shock-like syndrome with hepatic involvement and abnormal liver function tests, and cholestasis have been reported
The FDA drug label does not specifically mention indirect bilirubin, but it does mention elevations in serum bilirubin as a possible effect of rifampicin. However, it does not specify whether this elevation is due to indirect or direct bilirubin.
- Hepatotoxicity is a possible cause of elevated bilirubin levels.
- Rifampicin may cause transient abnormalities in liver function tests, including elevations in serum bilirubin.
- The label does not provide enough information to determine the specific cause of elevated indirect bilirubin 2, 2, 2.
From the Research
Causes of Elevated Indirect Bilirubin
Elevated indirect bilirubin can be caused by several factors, including:
- Hemolysis, which is the breakdown of red blood cells [ 3, 4 ]
- Glucose-6-phosphate dehydrogenase (G6PD) deficiency, a common enzyme deficiency that can lead to hemolysis [ 3, 5,6,7 ]
- Hematoma resorption, which can also lead to elevated levels of unconjugated (indirect) bilirubin 4
- Intrahepatic disorders, such as those caused by alcohol, infectious hepatitis, drug reactions, and autoimmune disorders 4
Role of Hemolysis
Hemolysis is an important pathogenetic factor in G6PD deficiency-associated neonatal hyperbilirubinemia 3 Hemolysis can also occur in patients with acute viral hepatitis, particularly those with G6PD deficiency 5, 6 Massive intravascular hemolysis can lead to acute kidney injury and markedly raised bilirubin levels 5
G6PD Deficiency
G6PD deficiency is a common human enzymopathy caused by inherited mutations of the X-linked gene G6PD 7 G6PD deficiency makes red cells highly vulnerable to oxidative damage and susceptible to hemolysis 7 Approximately 500 million people with G6PD deficiency are mostly asymptomatic throughout their lifetime, but may develop acute hemolytic anemia when triggered by certain factors 7