What are the causes of elevated bilirubin (hyperbilirubinemia)?

From the Guidelines

Elevated bilirubin levels require prompt medical evaluation to determine the underlying cause, and treatment should be guided by the most recent and highest quality study, which emphasizes the importance of differentiating between unconjugated and conjugated hyperbilirubinemia 1. If you notice elevated bilirubin, seek medical attention for proper diagnosis through blood tests, imaging studies, and possibly liver function tests. The causes of elevated bilirubin can be categorized into pre-hepatic, hepatic, and post-hepatic, and treatment depends on the underlying cause - for Gilbert's syndrome, no treatment is typically needed; for hepatitis, antiviral medications may be prescribed; for gallstones, cholecystectomy might be necessary; and for hemolytic anemia, addressing the underlying condition is essential 1. While waiting for medical care, stay hydrated, avoid alcohol and hepatotoxic medications, and follow a balanced diet. Bilirubin elevation occurs when there's excessive breakdown of red blood cells (pre-hepatic), liver dysfunction preventing proper processing (hepatic), or bile duct obstruction preventing excretion (post-hepatic). Symptoms may include jaundice (yellowing of skin and eyes), dark urine, light-colored stools, fatigue, and abdominal pain. Regular follow-up with healthcare providers is important to monitor bilirubin levels and ensure effective treatment of the underlying condition. Some key laboratory tests to differentiate between the causes of jaundice include a hepatic profile, conjugated versus unconjugated bilirubinemia, complete blood count, and possibly imaging studies such as abdominal ultrasound or CT scans 1. It is essential to note that the most common cause of an isolated elevated bilirubin concentration is Gilbert’s syndrome, which is an inherited disorder of metabolism and leads to impaired conjugation via reduced activity of the enzyme glucuronyltransferase 1. In the absence of haemolysis, if the majority of the elevated bilirubin comprises the unconjugated fraction, the cause is virtually always Gilbert’s syndrome, and such individuals should be fully reassured 1. However, if the conjugated bilirubin is elevated, it may indicate parenchymal liver disease or obstruction of the biliary system, and further evaluation is necessary 1. In summary, elevated bilirubin levels require a comprehensive medical evaluation, and treatment should be guided by the underlying cause, with a focus on differentiating between unconjugated and conjugated hyperbilirubinemia.

Key Considerations

• Elevated bilirubin levels require prompt medical evaluation to determine the underlying cause
• Treatment depends on the cause, and may include antiviral medications, cholecystectomy, or addressing the underlying condition
• Differentiating between unconjugated and conjugated hyperbilirubinemia is essential for guiding treatment
• Regular follow-up with healthcare providers is important to monitor bilirubin levels and ensure effective treatment of the underlying condition
• Key laboratory tests include a hepatic profile, conjugated versus unconjugated bilirubinemia, complete blood count, and possibly imaging studies such as abdominal ultrasound or CT scans

Potential Causes

• Pre-hepatic: excessive breakdown of red blood cells
• Hepatic: liver dysfunction preventing proper processing
• Post-hepatic: bile duct obstruction preventing excretion
• Gilbert’s syndrome: an inherited disorder of metabolism leading to impaired conjugation
• Hepatitis: inflammation of the liver, which may be caused by viral or autoimmune factors
• Gallstones: obstruction of the biliary system, which may cause conjugated hyperbilirubinemia
• Hemolytic anemia: a condition characterized by the excessive breakdown of red blood cells

Important Laboratory Tests

• Hepatic profile: to evaluate liver function and differentiate between the causes of jaundice
• Conjugated versus unconjugated bilirubinemia: to differentiate between pre-hepatic, hepatic, and post-hepatic causes
• Complete blood count: to evaluate for hemolytic anemia or other hematological abnormalities
• Imaging studies: such as abdominal ultrasound or CT scans, to evaluate for bile duct obstruction or other structural abnormalities.

From the Research

Causes of Elevated Bilirubin

• Elevated bilirubin levels can be caused by various underlying disease states, including liver or biliary tract diseases 2, 3, 4
• Hyperbilirubinemia can be classified into two types: unconjugated and conjugated, each with different underlying causes 3, 4
• Unconjugated hyperbilirubinemia can occur due to increased bilirubin production, such as in hemolytic disorders, or impaired bilirubin conjugation, such as in Gilbert syndrome 4
• Conjugated hyperbilirubinemia can occur in disorders of hepatocellular damage, such as viral and alcoholic hepatitis, and cholestatic disorders, such as choledocholithiasis and neoplastic obstruction of the biliary tree 4

Evaluation of Elevated Bilirubin

• Evaluation of elevated bilirubin levels should start with a careful history and physical examination, followed by laboratory tests and imaging studies 2, 3, 4
• Laboratory tests should include fractionated bilirubin, complete blood count, liver function tests, and other relevant tests to determine the underlying cause of hyperbilirubinemia 3, 4
• Imaging studies, such as ultrasonography or computed tomography, can help differentiate between extrahepatic obstructive and intrahepatic parenchymal disorders 3, 4

Relationship between Hemolytic Anemia and Elevated Bilirubin

• Hemolytic anemia can cause elevated bilirubin levels due to increased bilirubin production from red blood cell destruction 5, 6
• Laboratory tests, such as reticulocytosis, increased lactate dehydrogenase, and decreased haptoglobin levels, can confirm hemolysis and help diagnose hemolytic anemia 6
• A peripheral blood smear can help identify abnormal red blood cell morphologies and aid in the diagnosis of hemolytic anemia 6