What are the causes of elevated total bilirubin (TBIL) levels?

From the Guidelines

Elevated total bilirubin (tbil) can result from several underlying conditions, including liver diseases, biliary obstruction, genetic disorders, hemolytic conditions, and certain medications, with the most common causes varying by geography and demographics, as noted in a study published in the Journal of the American College of Radiology 1. 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
• Biliary obstruction from gallstones, tumors, or strictures, which can block bilirubin excretion
• Genetic disorders like Gilbert's syndrome, which cause mild, harmless elevations due to reduced enzyme activity for bilirubin processing
• Hemolytic conditions where red blood cells break down excessively, increasing bilirubin production beyond the liver's processing capacity
• Certain medications that can damage the liver or interfere with bilirubin metabolism
• Severe infections, sepsis, and prolonged fasting, which may temporarily increase bilirubin levels
• Physiologic jaundice in newborns due to immature liver function Evaluation of elevated bilirubin should include assessment of other liver function tests, complete blood count, and imaging studies to determine the underlying cause, as treatment depends on addressing the specific reason for the elevation, as recommended in a consensus guideline published in Alimentary Pharmacology and Therapeutics 1. It is essential to fractionate elevated total bilirubin to determine the percentage derived from direct bilirubin, as elevated direct bilirubin often reflects liver dysfunction, which may affect drug metabolism and elimination, as noted in a study published in Alimentary Pharmacology and Therapeutics 1. In cases where Gilbert's syndrome is suspected, eligibility and on-study management should focus on elevations of direct bilirubin rather than total bilirubin, as Gilbert's syndrome can be presumed by calculating the amount of conjugated bilirubin, which is normally less than 30% of the total bilirubin, in the absence of hemolysis, as recommended in a review article published in Alimentary Pharmacology and Therapeutics 1.

From the Research

Elevated Total Bilirubin (TBil) Levels

Elevated TBil levels can be caused by various factors, including:

• Hemolysis, which is the breakdown of red blood cells 2
• Liver disease, such as alcoholic cirrhosis, which can lead to structural and metabolic abnormalities of the erythrocyte membrane 2
• Increased levels of indirect bilirubin (IBil), which has been linked to higher levels of total cholesterol (TC) and triglyceride (TG) 3

Correlations with Lipid Levels

Studies have shown that:

• Direct bilirubin (DBil) levels are negatively correlated with TC and TG levels 3
• IBil levels are positively correlated with TC and TG levels 3
• Elevated DBil levels are associated with lower TC and TG levels, while elevated IBil levels are associated with higher TC and TG levels 3

Mechanisms of Hemolysis

Hemolysis in liver disease can be caused by:

• Increase in unesterified serum cholesterol due to lecithin cholesterol acyl transferase (LCAT) deficiency 2
• Substitutions of phosphatidyl choline (PC) moieties in the erythrocyte lipid bilayer 2
• Metabolic changes involving vitamin E deficiency and pyruvate kinase instability 2