From the Guidelines
Elevated total bilirubin (TBIL) is most commonly caused by liver diseases, hemolytic disorders, genetic conditions like Gilbert's syndrome, medications, and sepsis or severe infections, and evaluation should include assessment of direct and indirect bilirubin fractions, liver enzymes, and complete blood count to determine the underlying cause and guide treatment. The causes of elevated TBIL can be broadly categorized into:
- Liver diseases such as hepatitis, cirrhosis, and alcoholic liver disease, which impair the liver's ability to process bilirubin 1
- Hemolytic disorders like sickle cell anemia and autoimmune hemolytic anemia, which increase bilirubin production by accelerating red blood cell breakdown 1
- Genetic conditions, particularly Gilbert's syndrome, which cause mild hyperbilirubinemia due to reduced activity of the enzyme that conjugates bilirubin 1
- Medications including certain antibiotics, oral contraceptives, and statins, which can induce hyperbilirubinemia through various mechanisms 1
- Sepsis and severe infections, which may cause hyperbilirubinemia through multiple pathways including hemolysis and liver dysfunction 1 Some key points to consider in the evaluation of elevated TBIL include:
- Measurement of total and direct bilirubin to help identify patients with indirect hyperbilirubinemia due to Gilbert's syndrome or hemolysis versus liver injury 1
- Investigation of alternative causes of liver test abnormalities, including cholestatic DILI, and management accordingly 1
- Initial monitoring should be 2–3 times a week, with frequency of monitoring adjusted based on clinical scenario and magnitude of liver biochemical test elevations 1
- Clinical monitoring should also include observation for clinical features of hepatic decompensation such as ascites and encephalopathy 1 According to the most recent and highest quality study 1, a reasonable threshold is to use direct bilirubin >2 x baseline to trigger action in the same way as for an elevation of TBIL >2x ULN from a normal baseline (or >3x ULN from an elevated baseline).
From the Research
Causes of Elevated Total Bilirubin (TBIL)
- Hemolytic anemia: Certain types of hemolytic anemia, such as sickle cell anemia, paroxysmal nocturnal hemoglobinuria, glucose-6-phosphate dehydrogenase deficiency, hereditary spherocytosis, and HELLP syndrome, can cause liver injury and lead to elevated TBIL levels 2.
- Liver disease: Liver disease, particularly alcoholic cirrhosis, can cause hemolysis due to structural and metabolic abnormalities of the erythrocyte membrane, leading to elevated TBIL levels 3.
- Autoimmune hemolytic anemia: This condition can occur in patients with liver and bowel disorders, such as autoimmune or acute viral hepatitis, primary biliary cholangitis, and inflammatory bowel disease, and can cause elevated TBIL levels 4.
- High levels of indirect bilirubin (IBil): Elevated IBil levels have been associated with increased total cholesterol (TC) and triglyceride (TG) levels, which can contribute to elevated TBIL levels 5.
- Thrombosis of the hepatic or portal vein: This condition can cause severe liver injury and lead to elevated TBIL levels 2, 6.