What is the workup for a 22-year-old male with hyperbilirubinemia, elevated Aspartate Aminotransferase (AST), elevated Alanine Aminotransferase (ALT), and hypercholesterolemia?

Workup for 22-year-old Male with Elevated Bilirubin, AST, ALT, and Cholesterol

The initial workup for a 22-year-old male with elevated bilirubin, AST, ALT, and cholesterol should include ultrasound imaging, comprehensive viral hepatitis testing, autoimmune markers, and metabolic disease screening to determine the underlying cause of liver dysfunction. 1, 2

Initial Assessment

Laboratory Testing

• Complete liver panel:
  • Fractionation of bilirubin (direct vs. indirect) to determine if hyperbilirubinemia is conjugated or unconjugated 2
  • Pattern assessment using R value (ALT × ULN/ALP × ULN) to classify as hepatocellular (R>5), cholestatic (R<2), or mixed (2<R<5) 1
  • Prothrombin time/INR to assess liver synthetic function 2
  • Complete blood count to evaluate for anemia or other hematologic abnormalities 2

Imaging

• Abdominal ultrasound: First-line non-invasive imaging to differentiate between intrahepatic and extrahepatic cholestasis 1, 2

Specific Etiologic Testing

Viral Hepatitis Screening

• Hepatitis B serology (HBsAg, anti-HBc)
• Hepatitis C antibody with reflex RNA testing if positive
• Hepatitis E testing, particularly important in acute presentations
• HIV testing 2

Autoimmune Evaluation

• Antimitochondrial antibodies (AMA) - mandatory in adults with chronic intrahepatic cholestasis 1
• Antinuclear antibody (ANA) and anti-smooth muscle antibody (ASMA)
• Immunoglobulin levels (IgG, IgM, IgA) 2

Metabolic Disease Screening

• Wilson's disease evaluation:
  • Serum ceruloplasmin levels
  • 24-hour urinary copper excretion
  • Consider Leipzig scoring system if clinical suspicion is high 1
• Hereditary hemochromatosis:
  • Serum iron, total iron binding capacity, ferritin
  • Consider genetic testing for HFE mutations 3
• Alpha-1 antitrypsin deficiency:
  • Serum alpha-1 antitrypsin level
  • Consider phenotyping if levels are low 3

Medication and Toxin Evaluation

• Detailed medication history (prescription and over-the-counter)
• Toxicology screen if drug-induced liver injury is suspected
• Alcohol markers (ethyl-glucuronide, phosphatidylethanol) 2

Advanced Testing Based on Initial Results

If Initial Testing is Inconclusive

• Magnetic resonance cholangiopancreatography (MRCP): Next step for unexplained cholestasis 1
• Endoscopic ultrasound (EUS): Alternative to MRCP for evaluation of distal biliary tract obstruction 1

Genetic Testing

• Consider genetic testing for ABCB4 (encoding the canalicular phospholipid export pump) in patients with negative AMA and biopsy findings compatible with PBC or PSC 1

Liver Biopsy

• Consider in patients with unexplained intrahepatic cholestasis and negative AMA test 1
• May be necessary when serologic testing and imaging fail to elucidate a diagnosis, to stage a condition, or when multiple diagnoses are possible 3

Common Diagnostic Considerations in Young Adults

1. Gilbert's syndrome: Common cause of mild unconjugated hyperbilirubinemia in young adults (present in 5-10% of population) 4
2. Viral hepatitis: Acute or chronic viral hepatitis can present with elevated transaminases and hyperbilirubinemia 5
3. Non-alcoholic fatty liver disease (NAFLD): Increasingly common in young adults, can present with elevated transaminases and cholesterol 5
4. Autoimmune hepatitis: More common in young females but should be considered in males with elevated transaminases 1, 3
5. Drug-induced liver injury: Review all medications and supplements 2
6. Hemolytic processes: Can cause elevated unconjugated bilirubin 6
7. Malignancy: Though rare, hematologic malignancies like acute lymphoblastic leukemia can present with abnormal liver biochemistries 7

When to Refer to Hepatology

• ALT/AST >5× ULN
• ALT/AST >3× ULN with total bilirubin ≥2× ULN
• Persistent elevation >6 months despite interventions
• Development of symptoms such as jaundice, abdominal pain, or fatigue 2

Pitfalls and Caveats

• Gender differences exist in AST/ALT ratios, with females typically having higher ratios than males 6
• Mild elevation of liver enzymes may not correlate with the severity of liver damage in chronic viral hepatitis 5
• Diagnostic ERCP should be reserved for highly selected cases due to associated morbidity and mortality; MRCP or EUS are preferred if therapeutic intervention is not anticipated 1
• Non-hepatic causes of elevated AST/ALT include muscle disorders (polymyositis, acute muscle injury), cardiac conditions (myocardial infarction), and endocrine disorders (hypothyroidism) 5