What are the causes of elevated bilirubin levels?

Causes of Elevated Bilirubin

Elevated bilirubin results from disruption at any stage of bilirubin metabolism—from overproduction (hemolysis), to impaired hepatic uptake/conjugation, to obstructed excretion—and should be systematically categorized as prehepatic, intrahepatic, or posthepatic based on whether the hyperbilirubinemia is predominantly unconjugated or conjugated. 1

Initial Diagnostic Framework

The critical first step is fractionating total bilirubin to determine the proportion of unconjugated (indirect) versus conjugated (direct) bilirubin, which immediately narrows your differential diagnosis. 1, 2

• Unconjugated (indirect) bilirubin = Total bilirubin - Direct bilirubin 1
• Conjugated bilirubin <20-30% of total suggests unconjugated hyperbilirubinemia 1
• Conjugated bilirubin ≥20-30% of total indicates conjugated hyperbilirubinemia 1

Prehepatic Causes (Predominantly Unconjugated Hyperbilirubinemia)

These conditions produce excess bilirubin that overwhelms the liver's conjugation capacity:

Hemolytic Disorders

• Hemolytic anemias including sickle cell disease, thalassemia, hereditary spherocytosis, and glucose-6-phosphate dehydrogenase (G6PD) deficiency 1, 3
• Exercise-induced hemolysis can temporarily exceed hepatic conjugation capacity 2, 3
• Large hematoma resorption causes transient unconjugated bilirubin elevation 1, 3

Physiologic Factors

• Dehydration during intense exercise concentrates blood components including bilirubin 2

Intrahepatic Causes

Unconjugated Hyperbilirubinemia (Impaired Conjugation)

Gilbert syndrome is the most common benign cause, affecting 5-10% of the population, characterized by reduced glucuronosyltransferase enzyme activity 1, 3

• Total bilirubin rarely exceeds 4-5 mg/dL 1
• Exacerbations occur during fasting, illness, or stress 3
• Conjugated bilirubin remains <20-30% of total 1

Conjugated Hyperbilirubinemia (Impaired Hepatocyte Function or Bile Transport)

Viral hepatitis (hepatitis A, B, C, D, E, Epstein-Barr virus) disrupts conjugated bilirubin transport and typically presents with aminotransferases >400 IU/mL 1, 2

Alcoholic liver disease impairs hepatocyte function and bilirubin metabolism 1, 2

Autoimmune hepatitis causes immune-mediated hepatocyte damage affecting bilirubin processing 1, 2

Cholestatic disorders:

• Primary biliary cholangitis causes conjugated hyperbilirubinemia 1, 2
• Primary sclerosing cholangitis causes conjugated hyperbilirubinemia with episodes of abrupt total bilirubin elevation due to transient stricture obstruction 2

Drug-induced liver injury from acetaminophen, penicillin, oral contraceptives, estrogenic/anabolic steroids, and chlorpromazine 1, 2

Cirrhosis affects all aspects of bilirubin metabolism in advanced disease 1

Posthepatic Causes (Conjugated Hyperbilirubinemia from Biliary Obstruction)

Intrinsic Biliary Obstruction

Gallstone disease:

• Cholelithiasis, acute calculus cholecystitis, and choledocholithiasis cause intrinsic biliary obstruction 1, 2

Biliary tract infection such as cholangitis causes obstruction and inflammation 1, 2

Biliary malignancy including cholangiocarcinoma and gallbladder cancer 1, 2

Extrinsic Biliary Obstruction

Pancreatic disorders including pancreatitis and pancreatic tumors compress the bile duct externally 1, 2

Special Populations

Neonatal hyperbilirubinemia represents physiological unconjugated hyperbilirubinemia, but conjugated bilirubin >25 μmol/L requires urgent assessment for liver disease 1

Diagnostic Algorithm

Step 1: Fractionate Bilirubin

Order total and direct bilirubin to calculate unconjugated fraction 1, 3

Step 2: If Predominantly Unconjugated (>70-80% indirect)

• Check complete blood count, reticulocyte count, peripheral smear for hemolysis 3
• Review medication list and recent exercise history 2, 3
• Consider Gilbert syndrome if bilirubin <5 mg/dL with normal liver enzymes and no hemolysis 1

Step 3: If Predominantly Conjugated (>20-30% direct)

• Order liver function tests: ALT, AST, alkaline phosphatase, GGT 1, 3
• Obtain abdominal ultrasound as the initial imaging modality with high sensitivity for liver parenchymal disease and high specificity for biliary obstruction 1, 2
• Check viral hepatitis serologies based on clinical suspicion 1
• Consider advanced imaging (CT, MRI with MRCP) if ultrasound is inconclusive or suggests obstruction 1, 2

Step 4: Pattern Recognition

• Hepatocellular pattern: ALT/AST elevation predominates over alkaline phosphatase—consider viral hepatitis, alcoholic liver disease, autoimmune hepatitis, drug-induced injury 1, 2
• Cholestatic pattern: Alkaline phosphatase/GGT elevation predominates—consider biliary obstruction, cholestatic liver disease 1, 2

Critical Pitfalls to Avoid

Do not confuse "direct" with "conjugated" bilirubin—direct bilirubin includes both conjugated bilirubin and delta bilirubin, which can persist in serum after resolution of acute liver injury 1

Persistent hyperbilirubinemia of any etiology warrants expeditious evaluation—do not dismiss elevated bilirubin as benign without proper workup 1

In suspected Gilbert syndrome, verify that conjugated bilirubin is <20-30% of total in the absence of hemolysis to avoid unnecessary testing and misdiagnosis 1

When drug-induced liver injury presents with indirect hyperbilirubinemia, suspect hemolysis rather than hepatocellular damage 3

If exercise is suspected, repeat testing after 24-48 hours of rest to confirm transient nature 2

In primary sclerosing cholangitis patients with abrupt bilirubin elevation, evaluate for dominant stricture with MRCP or ERCP 2