What are the differential diagnoses for hyperbilirubinemia?

Differential Diagnoses for Hyperbilirubinemia

Hyperbilirubinemia results from three main pathophysiologic mechanisms: prehepatic (increased production), intrahepatic (impaired hepatocyte function), or posthepatic (biliary obstruction), and the first critical step is determining whether the elevation is predominantly unconjugated or conjugated bilirubin. 1, 2

Classification by Bilirubin Type

Unconjugated (Indirect) Hyperbilirubinemia

Prehepatic causes:

• Hemolytic disorders including sickle cell disease, thalassemia, hereditary spherocytosis, and glucose-6-phosphate dehydrogenase (G6PD) deficiency overwhelm the liver's conjugation capacity 2, 3
• Large hematoma resorption causes transient unconjugated bilirubin elevation 2

Impaired conjugation:

• Gilbert syndrome is the most common benign cause, affecting 5-10% of the population, characterized by reduced glucuronosyltransferase activity with bilirubin rarely exceeding 4-5 mg/dL and conjugated fraction <20-30% of total 2, 3
• Crigler-Najjar syndrome represents more severe inherited defects in bilirubin conjugation 4

Conjugated (Direct) Hyperbilirubinemia

Intrahepatic causes:

Hepatocellular injury:

• Viral hepatitis (A, B, C, D, E, Epstein-Barr virus) disrupts conjugated bilirubin transport 1, 2
• Alcoholic liver disease impairs hepatocyte function and bilirubin metabolism 2, 3
• 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 1, 2
• Autoimmune hepatitis causes immune-mediated hepatocyte damage 2
• Cirrhosis affects all aspects of bilirubin metabolism in advanced disease 2

Cholestatic disorders:

• Primary biliary cholangitis and primary sclerosing cholangitis cause intrahepatic cholestasis 1, 2

Inherited conjugated hyperbilirubinemia:

• Dubin-Johnson syndrome (ABCC2 gene mutations) causes defective bilirubin excretion into bile 4, 5
• Rotor syndrome (SLCO1B1 and SLCO1B3 mutations) affects conjugated bilirubin re-uptake 4, 5

Posthepatic (obstructive) causes:

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

Geographic Variations in Etiology

In the United States, the four most common causes are hepatitis, alcoholic liver disease, common bile duct obstruction, and drug toxicity 3

In European studies, malignancy is the most common cause of severe jaundice, followed by sepsis/shock, cirrhosis, and common bile duct stones 3

Diagnostic Algorithm

Step 1: Fractionate bilirubin to determine unconjugated versus conjugated (calculated as total bilirubin minus direct bilirubin) 2, 3, 6

Step 2: If predominantly unconjugated (>65% of total):

• Obtain complete blood count to evaluate for hemolysis 7, 6
• Consider Gilbert syndrome if conjugated bilirubin <20-30% of total, bilirubin <4-5 mg/dL, and no hemolysis 2, 3
• Evaluate for hemolytic disorders if evidence of red blood cell destruction 2, 3

Step 3: If predominantly conjugated (>35% of total):

• Obtain hepatocellular enzymes (ALT, AST) to assess for parenchymal injury 1
• Obtain cholestatic enzymes (alkaline phosphatase, GGT) to evaluate biliary pathology 1
• Perform abdominal ultrasound within 24-48 hours as mandatory first-line imaging with 98% positive predictive value for cirrhosis and 71-97% specificity for excluding biliary obstruction 1, 3

Step 4: Targeted history:

• Viral hepatitis risk factors: country of birth/ethnicity, injection drug use, sexual history, transfusion history 1
• Medication and toxin exposure: all prescribed medications, over-the-counter drugs, herbal supplements, alcohol intake 1
• Symptoms: jaundice, pruritus, right upper quadrant pain, weight loss, fatigue 1

Step 5: Additional serologic testing based on ultrasound findings:

• If dilated bile ducts on ultrasound: suggests extrahepatic obstruction; proceed to MRCP or ERCP for stone removal/stenting 1
• If normal bile ducts: obtain viral hepatitis serologies (A, B, C, and consider E, EBV), autoimmune markers (ANA, ASMA, anti-LKM), and review all medications for drug-induced liver injury 1, 2

Critical Pitfalls to Avoid

Do not simply repeat testing or wait for resolution as most abnormalities represent true pathology requiring diagnosis 1

Absence of symptoms does not indicate benign disease since many patients with significant liver fibrosis remain asymptomatic until advanced disease develops 1

Recognize that "direct" bilirubin includes delta bilirubin with a 21-day half-life, causing prolonged hyperbilirubinemia even after resolution of the underlying cause 1, 3

In neonates, conjugated bilirubin >25 μmol/L requires urgent pediatric assessment for possible liver disease 1, 3

Urgent Referral Indications

Immediate referral is indicated for:

• Clinical jaundice with markedly elevated transaminases 1
• Suspicion of hepatobiliary malignancy 1
• Evidence of hepatic decompensation (ascites, encephalopathy, variceal bleeding) 1
• Progressive bilirubin elevation despite drug discontinuation 1