What is the differential diagnosis approach for a patient presenting with jaundice?

Differential Diagnosis of Jaundice

Primary Classification Framework

The differential diagnosis of jaundice begins by distinguishing unconjugated (nonobstructive) from conjugated (obstructive) hyperbilirubinemia using fractionated bilirubin levels, which determines the entire diagnostic pathway. 1, 2

Unconjugated (Indirect) Hyperbilirubinemia

Prehepatic Causes:

• Hemolytic disorders - including autoimmune hemolytic anemia, hereditary spherocytosis, G6PD deficiency, and sickle cell disease 3
• Hematoma resorption - particularly large hematomas releasing bilirubin into circulation 3
• Inherited bilirubin metabolism defects - Gilbert syndrome (accounts for 5.6% of jaundice cases) and Crigler-Najjar syndrome 4

Key Laboratory Pattern: Elevated indirect bilirubin with elevated reticulocyte count and low haptoglobin suggests hemolysis 5

Conjugated (Direct) Hyperbilirubinemia

Intrahepatic Causes (Hepatocellular):

• Viral hepatitis - hepatitis A, B, C, D, E 2
• Alcoholic liver disease - accounts for 16% of jaundice cases, often presenting as first manifestation of decompensated disease 1, 4
• Drug-induced liver injury - from medications, herbal supplements, or toxins (one of four most common causes in the U.S.) 1, 4
• Autoimmune hepatitis 2
• Cirrhosis decompensation - represents 20.5% of new-onset jaundice cases 4
• Sepsis - the most common cause at 22-27% of cases, creating dual mechanisms through hemolysis and hepatic dysfunction 4, 5

Posthepatic Causes (Cholestatic/Obstructive):

• Choledocholithiasis - accounts for 13-14% of cases; multiple small gallstones (<5 mm) create 4-fold increased CBD migration risk 1, 4
• Malignancy - pancreatic cancer, cholangiocarcinoma, ampullary carcinoma (6.2% of U.S. cases but most common cause of severe jaundice in Europe) 4
• Cholangitis - requires urgent recognition and decompression 6
• Primary sclerosing cholangitis 6
• Primary biliary cholangitis 6
• Pancreatitis - causing extrinsic CBD compression 1

Diagnostic Algorithm

Step 1: Initial Laboratory Evaluation

Obtain the following tests immediately:

• Fractionated bilirubin (total, direct, indirect) - determines conjugated vs. unconjugated pattern 6, 2
• Complete blood count with peripheral smear - evaluates for hemolysis, anemia, infection 5, 2
• Hepatic enzyme panel - AST, ALT (hepatocellular injury), alkaline phosphatase, GGT (cholestatic pattern) 6, 2
• Albumin and coagulation studies (PT/INR) - assess hepatic synthetic function 6, 2
• Reticulocyte count - elevated in hemolysis 5
• Lactate dehydrogenase and haptoglobin - if hemolysis suspected 5

Critical Pattern Recognition:

• Elevated transaminases (>500 U/L) with modest alkaline phosphatase elevation = hepatocellular injury (viral hepatitis, drug-induced, alcoholic hepatitis, autoimmune) 6, 7
• Elevated alkaline phosphatase (>3x normal) with modest transaminase elevation = cholestatic/obstructive pattern (stones, strictures, malignancy) 6, 7
• Unconjugated hyperbilirubinemia with elevated reticulocyte count = hemolysis; proceed to direct Coombs test 5

Step 2: Initial Imaging

Abdominal ultrasound is the mandatory first-line imaging modality for all patients with jaundice of unclear etiology. 1, 6

Ultrasound capabilities:

• Detects biliary obstruction with sensitivity 32-100% and specificity 71-97% 1
• Identifies cirrhosis with sensitivity 65-95% and positive predictive value 98%; nodular liver surface is most accurate finding 1, 6
• Normal CBD caliber has 95-96% negative predictive value for choledocholithiasis 1
• No radiation exposure - ideal for younger patients 6

Common pitfall: Ultrasound has limited sensitivity (22.5-75%) for CBD stones due to overlying bowel gas obscuring the subhepatic common duct 1

Step 3: Advanced Imaging (When Indicated)

If ultrasound shows biliary dilation but unclear etiology:

• MRCP - superior for defining level and cause of obstruction, detecting subtle bile duct abnormalities, PSC, and hepatolithiasis 6
• Contrast-enhanced CT abdomen - sensitivity 74-96% and specificity 90-94% for biliary obstruction; better than ultrasound for determining site and cause 1

If ultrasound shows no obstruction but jaundice persists:

• MRI with MRCP - 70.3% accuracy for cirrhosis detection, superior soft tissue characterization 6
• Consider liver biopsy if imaging unrevealing and no clear parenchymal process identified 6, 2

Step 4: Targeted History Elements

Obtain specific details about:

• Alcohol consumption - quantity and duration (>50 g/day for >6 months increases risk dramatically) 4
• Medication exposure - prescription drugs, over-the-counter medications, herbal supplements 4, 6
• Recent infections or systemic illness - sepsis is the leading cause at 22-27% 4
• Risk factors for viral hepatitis - IV drug use, transfusions, sexual exposure 2
• Family history - Gilbert syndrome, hemolytic disorders 4
• Constitutional symptoms - weight loss suggests malignancy; fever with RUQ pain (Charcot's triad) indicates cholangitis 6

Red Flags Requiring Urgent Intervention

Immediate hepatology consultation and ICU consideration if:

• Coagulopathy (INR >1.5) - suggests acute liver failure 6
• Encephalopathy with jaundice - indicates fulminant hepatic failure 6
• Fever with jaundice and RUQ pain - cholangitis requiring urgent biliary decompression 6
• Hemodynamic instability with hemolysis - may require urgent transfusion if hemoglobin <7 g/dL or symptomatic 5

Common Diagnostic Pitfalls

Avoid these errors:

• Do not assume hepatobiliary disease without checking reticulocyte count in patients with sudden onset pallor and tachycardia - hemolysis is more likely 5
• Do not repeat normal ultrasound - proceed to advanced imaging or biopsy instead 6
• Do not overlook drug-induced causes - obtain comprehensive medication history including supplements 4, 5
• Do not miss sepsis as the underlying cause - it accounts for the highest proportion of jaundice cases 4, 5
• Do not assume alcoholic liver disease is unlikely in younger patients - early-onset alcohol use disorder carries 40-50% 90-day mortality without treatment 6