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

Causes of Elevated Total Bilirubin

Elevated total bilirubin is primarily caused by prehepatic, intrahepatic, or posthepatic conditions that affect bilirubin production, metabolism, or excretion. Understanding these causes is essential for appropriate diagnostic evaluation and management.

Prehepatic Causes (Predominantly Unconjugated Hyperbilirubinemia)

• Hemolytic anemias (sickle cell disease, thalassemia, hereditary spherocytosis, G6PD deficiency) lead to increased bilirubin production that overwhelms the liver's conjugation capacity 1, 2
• Exercise-induced hemolysis can temporarily exceed the liver's conjugation capacity 1
• Large hematoma resorption can cause transient elevation in unconjugated bilirubin 2
• Dehydration during intense exercise can concentrate blood components, including bilirubin 1

Intrahepatic Causes

Genetic Disorders

• Gilbert syndrome - benign hereditary disorder affecting 5% of the population, characterized by reduced activity of glucuronosyltransferase 2, 3
• Crigler-Najjar syndrome - more severe deficiency of glucuronosyltransferase 4, 2

Hepatocellular Disorders

• Viral hepatitis (A, B, C, D, E, Epstein-Barr virus) disrupts transport of conjugated bilirubin 1, 2, 5
• Alcoholic liver disease impairs hepatocyte function and bilirubin metabolism 2
• Autoimmune hepatitis causes immune-mediated damage to hepatocytes 1, 2
• Drug-induced liver injury from medications like acetaminophen, penicillin, oral contraceptives, steroids, and chlorpromazine 1, 2
• Cirrhosis affects all aspects of bilirubin metabolism 2

Cholestatic Disorders

• Primary biliary cholangitis causes conjugated hyperbilirubinemia 1, 2
• Primary sclerosing cholangitis leads to episodes of cholangitis with abrupt elevations of total bilirubin 1, 2

Posthepatic Causes (Predominantly Conjugated Hyperbilirubinemia)

• Gallstone disease (cholelithiasis, acute calculus cholecystitis, choledocholithiasis) causes intrinsic biliary obstruction 1, 2, 5
• Biliary tract infection (cholangitis) causes obstruction and inflammation 1, 2
• Biliary malignancy (cholangiocarcinoma, gallbladder cancer) causes biliary obstruction 1, 2
• Pancreatic disorders (pancreatitis, pancreatic tumors) cause extrinsic biliary obstruction 1, 2

Diagnostic Approach

Initial Evaluation

• Determine whether hyperbilirubinemia is predominantly unconjugated or conjugated by fractionating total bilirubin 4, 1, 2
• Elevated alkaline phosphatase should be confirmed to be of hepatobiliary origin with gamma glutamyl transferase and/or alkaline phosphatase isoenzyme fractionation 4

Imaging

• Ultrasound is the first-line imaging modality for evaluating hyperbilirubinemia, with high sensitivity (65-95%) for liver parenchymal disease and high specificity (71-97%) for ruling out mechanical obstruction 4, 5
• MRI with MRCP may be valuable when ultrasound is negative and clinical workup is inconclusive, particularly if there is concern for primary sclerosing cholangitis or primary biliary cirrhosis 4
• When elevations in liver tests abruptly occur in PSC patients, evaluation for a dominant stricture by magnetic resonance cholangiography or endoscopic retrograde cholangiography should be considered 4, 1

Laboratory Testing

• Complete blood count to evaluate for hemolysis 6
• Liver function tests including aminotransferases, alkaline phosphatase, and gamma-glutamyl transpeptidase 2, 7
• Viral hepatitis serologies when suspected 2, 5
• Autoimmune markers when autoimmune hepatitis is suspected 5

Special Considerations

• In Gilbert syndrome, bilirubin levels typically don't exceed 3 mg/dL, but rare cases with levels above 6 mg/dL have been reported 3, 8
• Comorbid conditions like hemolytic anemia can coexist with liver diseases such as primary biliary cirrhosis, causing bilirubin levels to rise disproportionately to the severity of the liver disease 6
• In patients with PSC, total bilirubin elevations are usually less than 15 mg/dL in cholangitis but may exceed this level with complete bile duct obstruction, which can occur in PSC complicated by cholangiocarcinoma 4

Pitfalls to Avoid

• Don't attribute all hyperbilirubinemia in patients with known liver disease to the underlying condition without considering comorbid processes like hemolysis 6
• Remember that elevated bilirubin almost always indicates an underlying disease state and warrants thorough evaluation 9
• Don't overlook the possibility of drug-induced liver injury, which can present with various patterns of bilirubin elevation 1, 2