What are the possible causes of elevated bilirubin levels in adults?

Causes of Elevated Bilirubin

Elevated bilirubin results from three main pathophysiologic categories: prehepatic (increased production), intrahepatic (impaired hepatocyte processing), and posthepatic (biliary obstruction), with the pattern of conjugated versus unconjugated hyperbilirubinemia directing the diagnostic approach. 1, 2

Prehepatic Causes (Unconjugated Hyperbilirubinemia)

These conditions overwhelm the liver's conjugation capacity through excessive bilirubin production:

• Hemolytic anemias including sickle cell disease, thalassemia, hereditary spherocytosis, and glucose-6-phosphate dehydrogenase deficiency cause increased red blood cell destruction 2, 3
• Large hematoma resorption produces transient unconjugated bilirubin elevation 2
• Exercise-induced hemolysis can temporarily exceed hepatic conjugation capacity, particularly during intense physical activity 3

Intrahepatic Causes

Unconjugated Hyperbilirubinemia

• Gilbert syndrome is the most common benign cause, affecting 5-10% of the population, characterized by reduced UDP-glucuronosyltransferase activity with bilirubin rarely exceeding 4-5 mg/dL and conjugated bilirubin <20-30% of total 2, 4

Conjugated Hyperbilirubinemia

• Viral hepatitis (A, B, C, D, E, Epstein-Barr virus) disrupts conjugated bilirubin transport and typically presents with transaminases >400 IU/mL 1, 2
• Alcoholic liver disease impairs hepatocyte function and all aspects of bilirubin metabolism 2, 3
• Autoimmune hepatitis causes immune-mediated hepatocyte damage affecting bilirubin processing 2, 3
• Primary biliary cholangitis and primary sclerosing cholangitis are cholestatic disorders causing conjugated hyperbilirubinemia 1, 2
• Drug-induced liver injury from acetaminophen, penicillin, oral contraceptives, estrogenic/anabolic steroids, and chlorpromazine can present with isolated bilirubin elevation 2-12 weeks after drug initiation, sometimes before transaminase elevation 1, 2
• Cirrhosis represents advanced liver disease affecting all bilirubin metabolism pathways 2

Critical pitfall: Cholestatic drug-induced liver injury can present with isolated bilirubin elevation before other liver enzymes rise, and continued exposure risks progression to vanishing bile duct syndrome causing irreversible biliary fibrosis. 1

Posthepatic Causes (Obstructive/Conjugated Hyperbilirubinemia)

These conditions prevent bile from reaching the small bowel:

• Choledocholithiasis is the most common cause, occurring in 10-15% of patients with gallstones 1, 2
• Acute calculous cholecystitis causes intrinsic biliary obstruction 1, 3
• Cholangitis produces obstruction and inflammation of the biliary tract 1, 2
• Cholangiocarcinoma and gallbladder cancer cause malignant biliary obstruction 1, 2
• Pancreatic disorders including pancreatitis and pancreatic tumors cause extrinsic biliary compression 2, 3

Key imaging finding: Bile duct dilation on ultrasound distinguishes extrahepatic obstruction from intrahepatic parenchymal disease, with ultrasound having 98% positive predictive value for detecting biliary pathology and 71-97% specificity for excluding mechanical obstruction. 1

Diagnostic Algorithm

Step 1: Fractionate Bilirubin

• Determine if hyperbilirubinemia is predominantly unconjugated (indirect) or conjugated (direct) 1, 2
• Conjugated bilirubin >35% of total indicates conjugated hyperbilirubinemia and warrants urgent evaluation 1

Step 2: Initial Laboratory Testing

• Complete blood count (evaluate for hemolysis) 5
• ALT, AST (hepatocellular injury pattern) 1
• Alkaline phosphatase and GGT (cholestatic pattern; GGT confirms hepatic origin of elevated alkaline phosphatase) 1
• Prothrombin time/INR, albumin (assess hepatic synthetic function) 5

Step 3: First-Line Imaging

• Abdominal ultrasound is mandatory for conjugated hyperbilirubinemia, with 98% positive predictive value for cirrhosis and 65-95% sensitivity for biliary obstruction 1
• Normal caliber extrahepatic bile ducts effectively exclude posthepatic obstruction 1

Step 4: Etiology-Specific Testing

• Viral hepatitis serologies for hepatitis A, B, C 1, 2
• Autoimmune markers (ANA, anti-smooth muscle antibody, anti-mitochondrial antibody) 1
• Medication and toxin exposure review including all prescribed drugs, over-the-counter medications, herbal supplements, and alcohol intake 1
• Iron studies, ceruloplasmin, alpha-1 antitrypsin if metabolic disease suspected 1

Step 5: Advanced Imaging When Indicated

• CT or MRI with MRCP for further characterization of biliary obstruction or masses 1, 3
• ERCP for therapeutic intervention in biliary obstruction 1

Urgent Referral Indications

Immediate specialist referral is required for: 1

• Clinical jaundice with suspicion of hepatobiliary malignancy
• Markedly elevated transaminases (typically >10x upper limit of normal)
• Evidence of hepatic decompensation (coagulopathy, encephalopathy, ascites)
• Progressive bilirubin elevation despite drug discontinuation

Critical pitfall: Absence of symptoms does not indicate benign disease—many patients with significant liver fibrosis remain asymptomatic until advanced disease develops, making prompt evaluation of any bilirubinuria or hyperbilirubinemia essential. 1