From the Guidelines
Indirect bilirubin increases primarily due to conditions that cause excessive red blood cell breakdown (hemolysis) or impaired bilirubin processing in the liver, as seen in hemolytic anemias, genetic disorders, and liver diseases 1.
Causes of Indirect Bilirubin Increase
The causes of indirect bilirubin increase can be categorized into several groups, including:
- Hemolytic anemias, such as sickle cell disease, thalassemia, and autoimmune hemolytic anemia, which lead to increased red cell destruction and subsequent bilirubin production 1
- Genetic disorders affecting bilirubin metabolism, particularly Gilbert's syndrome, Crigler-Najjar syndrome, and neonatal jaundice, which impair the liver's ability to conjugate bilirubin 1
- Liver diseases, such as early cirrhosis, hepatitis, and alcoholic liver disease, which can cause indirect hyperbilirubinemia by damaging hepatocytes 1
- Physiologic conditions, including fasting, stress, and pregnancy, which can temporarily elevate indirect bilirubin levels 1
Mechanism of Indirect Bilirubin Increase
The underlying mechanism involves unconjugated bilirubin, which is fat-soluble and cannot be excreted without liver processing 1. When red blood cells break down, hemoglobin releases bilirubin that binds to albumin in the bloodstream. If this bilirubin cannot be properly taken up and conjugated by the liver, it accumulates in the blood, resulting in elevated indirect bilirubin levels and potential jaundice when levels exceed 2-3 mg/dL 1.
Clinical Implications
It is essential to identify the underlying cause of indirect bilirubin increase to provide appropriate management and prevent potential complications, such as kernicterus in neonates with Crigler-Najjar syndrome 1. The most recent and highest quality study recommends that patients with elevated indirect bilirubin levels should be evaluated for underlying hemolytic anemias, genetic disorders, and liver diseases, and managed accordingly 1.
From the Research
Causes of Indirect Bilirubin Increase
- Excess bilirubin production, such as pathologic hemolysis, can lead to an increase in indirect bilirubin levels 2
- Impaired liver uptake can also cause an elevation of indirect bilirubin 2
- Prehepatic causes of jaundice, including hemolysis and hematoma resorption, can lead to elevated levels of unconjugated (indirect) bilirubin 3
- Glucose-6-phosphate dehydrogenase (G6PD) deficiency can cause hemolysis, leading to an increase in indirect bilirubin levels 4, 5
Relationship to G6PD Deficiency
- G6PD deficiency is a common cause of pathologic hyperbilirubinemia, which can lead to an increase in indirect bilirubin levels 5
- Deficient enzyme levels in G6PD deficiency can lead to oxidative damage, hemolysis, and resultant severe hyperbilirubinemia 5
- G6PD deficiency can cause acute hemolytic anemia, which can lead to an increase in indirect bilirubin levels 4, 6
Clinical Implications
- Elevated indirect bilirubin levels can be a sign of underlying liver disease or hemolysis 2
- Accurate diagnosis of the cause of indirect bilirubin increase is important for proper treatment and management 2, 3
- Early screening for G6PD deficiency can help identify at-risk individuals and prevent complications associated with hyperbilirubinemia 5