What is the differential diagnosis for a patient presenting with jaundice, body malaise, and chills, without other signs, symptoms, or co-morbidities, and with unknown age, sex, and travel history?

Differential Diagnosis for Jaundice with Malaise and Chills

The triad of jaundice, malaise, and chills strongly suggests an infectious or inflammatory hepatobiliary process, with acute cholangitis, viral hepatitis, and sepsis-related cholestasis being the most critical diagnoses to exclude immediately due to their high mortality risk.

Critical Life-Threatening Diagnoses to Exclude First

Acute Cholangitis

• Chills with jaundice (part of Charcot's triad) indicates acute cholangitis requiring urgent biliary decompression 1
• Fever with jaundice mandates blood and urine cultures to exclude cholangitis or sepsis 1
• This represents a surgical emergency with significant mortality if untreated 2

Sepsis-Related Jaundice

• Sepsis accounts for 22% of new-onset jaundice cases 1
• Patients with sepsis can have both hemolysis and hepatic dysfunction, creating mixed unconjugated and conjugated hyperbilirubinemia 3
• The systemic inflammatory response can cause both hepatocellular injury and cholestasis 3

Algorithmic Approach to Diagnosis

Step 1: Immediate Laboratory Evaluation

• Obtain fractionated bilirubin (total, direct, and indirect) to differentiate conjugated from unconjugated hyperbilirubinemia, which determines the entire diagnostic pathway 1, 4
• Complete blood count to assess for hemolysis or infection 1, 4
• Hepatic enzyme panel including AST, ALT, alkaline phosphatase, and GGT to distinguish hepatocellular injury from cholestatic patterns 1, 4
• Coagulation studies (INR/PT) - INR >1.5 suggests acute liver failure requiring immediate hepatology consultation 1
• Albumin and total protein to assess hepatic synthetic function 1, 4

Step 2: Pattern Recognition Based on Laboratory Results

If Alkaline Phosphatase and GGT are Elevated (Cholestatic Pattern):

• This suggests post-hepatic or obstructive causes 3, 2
• Differential includes:
  • Choledocholithiasis (most common benign cause) 5, 6
  • Acute cholangitis 2
  • Biliary strictures 5
  • Pancreatic head mass or periampullary malignancy 5
  • Primary sclerosing cholangitis 5

If Transaminases (AST/ALT) are Markedly Elevated (Hepatocellular Pattern):

• This suggests hepatic parenchymal disease 3
• Differential includes:
  • Viral hepatitis (acute hepatitis A, B, C, or E) 6, 4
  • Drug-induced liver injury from medications, supplements, or herbal products 1, 6
  • Alcoholic hepatitis (accounts for 16% of jaundice cases) 1
  • Autoimmune hepatitis 6, 4

If Unconjugated Hyperbilirubinemia Predominates:

• Hemolytic disorders causing increased red blood cell destruction 6, 4
• Gilbert syndrome (prevalence of 5.6% of jaundice cases, often presents during physiological stress) 1, 4
• Hematoma resorption 6

Step 3: Initial Imaging Strategy

• Abdominal ultrasound is the appropriate initial imaging modality, with sensitivities of 32-100% and specificities of 71-97% for detecting biliary obstruction 5, 1
• Ultrasound has no radiation exposure and is the least invasive and least expensive method 1, 4
• Ultrasound can confirm biliary dilation, identify gallstones, detect cirrhosis (sensitivity 65-95%, positive predictive value 98%), and localize the site of obstruction 5, 1

Step 4: Advanced Evaluation if Initial Workup is Unrevealing

• If ultrasound shows no biliary obstruction and laboratory testing does not reveal the etiology, proceed to MRI with MRCP 1
• MRI with MRCP has 70.3% accuracy for detecting cirrhosis and superior soft tissue characterization 1
• MRI is particularly useful for suspected primary sclerosing cholangitis or primary biliary cirrhosis, as liver biopsy may be falsely negative in early disease 5, 1
• Liver biopsy is indicated when imaging shows no biliary obstruction and no clear parenchymal process to explain jaundice 1

Complete Differential Diagnosis List

Obstructive/Post-Hepatic Causes (Conjugated Hyperbilirubinemia):

• Choledocholithiasis 5, 6
• Acute cholangitis 2
• Acute cholecystitis 2
• Pancreatic head malignancy 5
• Cholangiocarcinoma (Klatskin tumor) 5
• Biliary strictures (post-procedural or inflammatory) 5
• Primary sclerosing cholangitis 5
• Parasitic infections 5
• Acute or chronic pancreatitis 5

Hepatocellular/Intrahepatic Causes (Mixed or Conjugated Hyperbilirubinemia):

• Viral hepatitis (A, B, C, E) 6, 4
• Alcoholic hepatitis 1, 6
• Drug-induced liver injury 1, 6
• Autoimmune hepatitis 6, 4
• Cirrhosis (any etiology) 5, 6
• Sepsis-related cholestasis 1, 3
• Primary biliary cirrhosis 5

Pre-Hepatic Causes (Unconjugated Hyperbilirubinemia):

• Hemolytic anemia 5, 6
• Gilbert syndrome 5, 1
• Crigler-Najjar syndrome 5
• Hematoma resorption 6

Critical Pitfalls to Avoid

• Do not assume alcoholic liver disease is unlikely based on young age alone, as early-onset alcohol use disorder can present with severe hepatitis and carries 40-50% 90-day mortality without treatment 1
• Do not overlook medication and supplement exposure, including over-the-counter drugs and herbal products, as drug-induced liver injury is a common and reversible etiology 1
• Encephalopathy in combination with jaundice indicates fulminant hepatic failure requiring immediate transplant evaluation 1
• Do not repeat abdominal ultrasound if already performed and normal; instead proceed to MRI with MRCP or liver biopsy 1
• In mixed laboratory patterns where severe hepatic disease mimics post-hepatic obstruction, correlation with imaging is necessary to differentiate intrahepatic from extrahepatic obstruction 3