What are the causes of elevated direct and indirect bilirubin (Hyperbilirubinemia)?

From the Guidelines

Elevated direct and indirect bilirubin levels can be caused by a variety of conditions, including hemolysis, impaired conjugation, parenchymal liver disease, and obstruction of the biliary system, with the most common cause of isolated elevated bilirubin being Gilbert's syndrome, as stated in the guidelines on the management of abnormal liver blood tests 1.

Causes of Elevated Bilirubin

The causes of elevated bilirubin can be categorized into:

• Unconjugated hyperbilirubinemia, which is usually due to hemolysis or impaired conjugation
• Conjugated hyperbilirubinemia, which is typically due to parenchymal liver disease or obstruction of the biliary system Some of the specific causes of elevated bilirubin include:
• Hemolytic anemias, such as sickle cell disease, thalassemia, and autoimmune hemolytic anemia
• Genetic disorders, such as Gilbert's syndrome, Crigler-Najjar syndrome, Dubin-Johnson syndrome, and Rotor syndrome
• Hepatocellular damage, such as viral hepatitis, alcoholic liver disease, and drug-induced liver injury
• Biliary obstruction, such as gallstones, tumors, and strictures
• Sepsis and other infections

Diagnosis and Treatment

The pattern of bilirubin elevation helps guide diagnosis and treatment, with direct hyperbilirubinemia often indicating more serious hepatobiliary disease requiring prompt evaluation, while isolated indirect hyperbilirubinemia may represent benign genetic conditions or hemolytic processes, as discussed in the ACR Appropriateness Criteria for jaundice 1.

Key Points

• Elevated bilirubin levels can be caused by a variety of conditions, including hemolysis, impaired conjugation, parenchymal liver disease, and obstruction of the biliary system
• The most common cause of isolated elevated bilirubin is Gilbert's syndrome
• The pattern of bilirubin elevation helps guide diagnosis and treatment
• Direct hyperbilirubinemia often indicates more serious hepatobiliary disease requiring prompt evaluation, while isolated indirect hyperbilirubinemia may represent benign genetic conditions or hemolytic processes.

From the Research

Causes of Elevated Direct and Indirect Bilirubin

• Elevated direct and indirect bilirubin levels can be caused by various liver diseases, including primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) 2, 3, 4
• Cholestasis, which is the reduction or stoppage of bile flow, can also lead to elevated bilirubin levels 3, 5
• Liver inflammation and injury can cause elevated bilirubin levels, as seen in chronic hepatitis and other liver diseases 2, 6
• Bile duct destruction and cirrhosis can also lead to elevated bilirubin levels, as seen in PBC and PSC 4

Mechanisms of Action of Ursodeoxycholic Acid

• Ursodeoxycholic acid (UDCA) has been shown to improve liver function and reduce bilirubin levels in patients with chronic liver diseases 2, 3, 5
• UDCA works by protecting cholangiocytes against cytotoxicity of hydrophobic bile acids, stimulating hepatobiliary secretion, and protecting hepatocytes against bile acid-induced apoptosis 5
• UDCA has also been shown to have anti-inflammatory and immunomodulatory properties, which can help reduce liver inflammation and injury 4

Treatment of Elevated Bilirubin Levels

• UDCA has been used to treat elevated bilirubin levels in patients with PBC, PSC, and other chronic liver diseases 2, 3, 5
• The dosage of UDCA used to treat elevated bilirubin levels can vary, but typical dosages range from 13-20 mg/kg/day 2, 5
• Other treatments, such as bile-acid mimetics, may also be used to treat elevated bilirubin levels, especially in patients who do not respond to UDCA 4