What causes elevated bilirubin in the system?

What Causes Elevated Bilirubin in the System

Elevated bilirubin results from three main pathophysiologic mechanisms: excessive production (prehepatic), impaired hepatic processing (intrahepatic), or obstructed excretion (posthepatic), with the pattern of elevation—unconjugated versus conjugated—being the critical first step in determining the underlying cause. 1, 2

Fundamental Pathophysiology

Bilirubin is the breakdown product of heme from hemoglobin degradation by the reticuloendothelial system. 1 It circulates as insoluble unconjugated bilirubin to the liver, where it undergoes conjugation to become water-soluble for biliary excretion. 1 The type of hyperbilirubinemia—unconjugated versus conjugated—directly points to where the problem lies in this metabolic pathway. 1, 2

Prehepatic Causes (Unconjugated Hyperbilirubinemia)

Hemolytic Disorders

• Hemolytic anemias including sickle cell disease, thalassemia, hereditary spherocytosis, and glucose-6-phosphate dehydrogenase deficiency overwhelm the liver's conjugation capacity through excessive bilirubin production. 2
• Large hematoma resorption causes transient unconjugated bilirubin elevation as red blood cells break down. 2
• Exercise-induced hemolysis can temporarily exceed hepatic conjugation capacity. 3

Impaired Conjugation

• Gilbert syndrome is the most common cause of isolated elevated bilirubin, affecting 5-10% of the population, caused by reduced glucuronosyltransferase enzyme activity. 1, 2 In the absence of hemolysis, if the majority of elevated bilirubin is unconjugated, Gilbert syndrome is virtually always the cause. 1 These patients should be fully reassured as this is benign. 1

Intrahepatic Causes (Mixed or Conjugated Hyperbilirubinemia)

Hepatocellular Injury

• Viral hepatitis (hepatitis A, B, C, D, E, Epstein-Barr virus) disrupts conjugated bilirubin transport. 2
• Alcoholic liver disease impairs hepatocyte function and bilirubin metabolism. 2, 3
• Autoimmune hepatitis causes immune-mediated hepatocyte damage affecting bilirubin processing. 2, 3
• Drug-induced liver injury from acetaminophen, penicillin, oral contraceptives, anabolic steroids, and chlorpromazine impairs hepatic function. 2, 3
• Cirrhosis affects all aspects of bilirubin metabolism due to advanced liver disease. 2

Cholestatic Disorders

• Primary biliary cholangitis and primary sclerosing cholangitis cause conjugated hyperbilirubinemia through intrahepatic cholestasis. 2, 3

Posthepatic Causes (Conjugated Hyperbilirubinemia)

Biliary Obstruction

• Gallstone disease (cholelithiasis, acute calculus cholecystitis, choledocholithiasis) causes intrinsic biliary obstruction. 2, 3
• Cholangitis produces obstruction and inflammation of bile ducts. 2, 3
• Biliary malignancy (cholangiocarcinoma, gallbladder cancer) obstructs bile flow. 2, 3

Pancreatic Disorders

• Pancreatitis and pancreatic tumors cause extrinsic biliary obstruction. 2, 3

Critical Diagnostic Algorithm

Step 1: Fractionate the bilirubin to determine if hyperbilirubinemia is predominantly unconjugated (<20-30% conjugated) or conjugated (>20-30% conjugated). 2 This single test narrows your differential dramatically. 2, 3

Step 2: If unconjugated predominates:

• Check for hemolysis markers (reticulocyte count, haptoglobin, LDH, peripheral smear). 2, 4
• If no hemolysis and bilirubin rarely exceeds 4-5 mg/dL, diagnose Gilbert syndrome—no further workup needed. 1, 2

Step 3: If conjugated predominates:

• Obtain liver enzymes (ALT, AST, alkaline phosphatase, GGT) to distinguish hepatocellular from cholestatic patterns. 1, 2
• Perform ultrasound as the initial imaging modality—it has high sensitivity for liver parenchymal disease and high specificity for biliary obstruction. 2, 3
• Consider viral hepatitis serologies, autoimmune markers, and medication review based on enzyme patterns. 2
• Advanced imaging (CT, MRI with MRCP) may be necessary if ultrasound is inconclusive or suggests obstruction. 2

Special Population: Neonates

In neonates, physiological unconjugated hyperbilirubinemia is common but may become pathological if high or prolonged. 1, 3 If conjugated bilirubin exceeds 25 μmol/L in neonates or infants, urgent referral to a pediatrician for liver disease assessment is essential. 1

Common Pitfalls

• Don't assume all elevated bilirubin indicates liver disease—Gilbert syndrome and hemolysis are common non-hepatic causes. 1, 5
• Don't overlook medication history—many drugs cause cholestasis or hepatocellular injury. 2, 3
• Don't confuse "direct" with "conjugated" bilirubin—direct bilirubin includes both conjugated bilirubin and delta bilirubin, which can persist after resolution of liver injury. 2
• Don't forget dehydration—it can concentrate blood components including bilirubin, particularly after exercise. 3