Differential Diagnoses for Pathological Jaundice
The differential diagnosis for pathological jaundice should be systematically organized by categorizing hyperbilirubinemia as unconjugated (prehepatic/hepatocellular) versus conjugated (cholestatic/obstructive), with the most common etiologies being hepatitis/sepsis, alcoholic liver disease, common bile duct obstruction, and drug-induced liver injury. 1
Primary Classification Framework
The American College of Radiology recommends distinguishing between unconjugated (nonobstructive) and conjugated (obstructive) hyperbilirubinemia based on laboratory findings, as this fundamentally guides the differential diagnosis 1, 2:
Unconjugated Hyperbilirubinemia (Prehepatic/Hepatocellular Causes)
Hemolytic disorders:
- Hemolysis accounts for 2.5% of jaundice cases in U.S. studies 1
- Coombs-negative hemolytic anemia occurs in 10-25% of chronic liver disease patients presenting with jaundice 3
- Hematoma resorption can elevate unconjugated bilirubin 4
Inherited bilirubin metabolism defects:
- Gilbert syndrome represents 5.6% of jaundice cases 1, 3
- Crigler-Najjar syndrome creates constitutional predisposition to unconjugated hyperbilirubinemia 3
Conjugated Hyperbilirubinemia (Hepatocellular and Cholestatic Causes)
Hepatocellular dysfunction (elevated transaminases):
Sepsis/shock: The most common etiology in U.S. studies (22-27% of severe jaundice cases), creating mixed unconjugated and conjugated hyperbilirubinemia through both hemolysis and hepatic dysfunction 1, 2, 3
Alcoholic liver disease: Accounts for 16% of jaundice cases, with alcoholic hepatitis commonly presenting as the first manifestation of decompensated disease 1, 3
Decompensation of pre-existing cirrhosis: The second most common cause of new-onset jaundice (20.5%), representing the primary mechanism in established chronic liver disease patients 1, 3
Viral hepatitis: Accounts for only 0.2% of severe jaundice cases but remains an important consideration 1
Drug-induced liver injury: Represents 0.5-7% of cases and constitutes one of the four most common causes of jaundice in the United States 1, 3
Autoimmune hepatitis: Accounts for 0.2% of severe jaundice cases 1
Cholestatic/obstructive causes (elevated alkaline phosphatase):
Choledocholithiasis (CBD stones): Represents 13-14% of jaundice cases, with multiple small gallstones (<5 mm) creating 4-fold increased risk for CBD migration 1, 3
Malignancy: Accounts for 6.2% of U.S. jaundice cases but represents the most common etiology of severe jaundice in European populations (varies by geography) 1, 3
Biliary strictures and pancreatitis: Mechanical obstruction causes post-hepatic jaundice with dark urine and pale stools 2, 5
Critical Diagnostic Pitfalls
Mixed patterns require imaging correlation: Severe hepatic disease can mimic post-hepatic obstruction, and patients with sepsis can have both hemolysis and hepatic dysfunction, necessitating bilirubin fractionation and ultrasound imaging to differentiate intrahepatic from extrahepatic obstruction 2, 3
Geographic and demographic variations significantly affect prevalence: The dominant etiology varies by geography, tertiary referral versus community hospital settings, inpatient versus outpatient setting, ethnicity, and socioeconomic status 1, 3
Algorithmic Approach to Laboratory Differentiation
Step 1: Alkaline phosphatase elevation suggests cholestatic (post-hepatic) causes, while transaminase elevation suggests hepatocellular (hepatic) causes 2
Step 2: Urine bilirubin testing indicates conjugated hyperbilirubinemia is present 4
Step 3: Hepatic profile with conjugated versus unconjugated bilirubin fractionation, complete blood count, and infectious hepatitis serologies guide categorization 1, 4
Step 4: Abdominal ultrasound serves as the initial imaging test, with 65-95% sensitivity for detecting cirrhosis and 32-100% sensitivity for biliary obstruction 1, 3