What investigations should be ordered for a 31-year-old female with elevated liver enzymes (Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP), and Gamma-Glutamyl Transferase (GGT)) without jaundice?

Diagnostic Investigations for a 31-Year-Old Female with Elevated Liver Enzymes Without Jaundice

A comprehensive diagnostic workup for a 31-year-old female with elevated AST, ALT, ALP, and GGT without jaundice should include tests for viral hepatitis, autoimmune conditions, metabolic disorders, and structural liver abnormalities.

Initial Laboratory Investigations

First-Line Tests

• Complete blood count with platelets
• Serum albumin and total protein
• Prothrombin time/INR
• Total and direct bilirubin
• Calculation of R value [(ALT/ULN)/(ALP/ULN)] to determine pattern of liver injury 1
  • Hepatocellular pattern: R ≥5
  • Cholestatic pattern: R ≤2
  • Mixed pattern: R >2 and <5

Viral Hepatitis Screening

• Hepatitis B surface antigen (HBsAg)
• Hepatitis B core antibody (anti-HBc IgM)
• Hepatitis C antibody (anti-HCV)
• If clinically indicated: Hepatitis A (anti-HAV IgM), Hepatitis E (anti-HEV IgM)
• Consider EBV, CMV, HSV in cases of marked transaminase elevation 1

Metabolic and Autoimmune Workup

• Fasting lipid profile
• Fasting glucose or HbA1c
• Serum ferritin, iron, and total iron-binding capacity
• Ceruloplasmin (especially if AST:ALT ratio >2.2) 1
• Antinuclear antibody (ANA)
• Anti-smooth muscle antibody (ASMA)
• Anti-mitochondrial antibody (AMA) and AMA-M2
• Anti-liver kidney microsomal antibody (anti-LKM)
• Immunoglobulin levels (IgG, IgM, IgA)

Additional Tests Based on Clinical Suspicion

• Alcohol consumption assessment (AUDIT score) 2
• Thyroid function tests (TSH, free T4)
• Celiac disease antibodies (tissue transglutaminase antibody)
• Alpha-1 antitrypsin level
• 24-hour urinary copper (if ceruloplasmin is low) 1

Imaging Studies

First-Line Imaging

• Abdominal ultrasound (to evaluate liver parenchyma, biliary tract, and rule out obstruction) 2

Second-Line Imaging (Based on Initial Results)

• Transient elastography (FibroScan) to assess liver fibrosis
• Magnetic resonance cholangiopancreatography (MRCP) if cholestatic pattern or suspicion of biliary disease
• CT scan or MRI if ultrasound identifies focal lesions or is inconclusive

Special Considerations

For Cholestatic Pattern (R ≤2)

• Focus on biliary tract evaluation with MRCP
• Consider anti-sp100 antibodies if AMA is negative but PBC is suspected 3
• Evaluate for drug-induced cholestasis

For Hepatocellular Pattern (R ≥5)

• Focus on viral, autoimmune, and metabolic causes
• Calculate AST:ALT ratio (>2 suggests alcoholic liver disease, Wilson's disease, or advanced fibrosis) 2
• Consider drug-induced liver injury (DILI) if history of medication use

For Mixed Pattern (R >2 and <5)

• Consider overlap syndromes and infiltrative diseases
• Evaluate for both hepatocellular and cholestatic etiologies

When to Consider Liver Biopsy

• Persistent unexplained elevation despite comprehensive workup
• Suspected autoimmune hepatitis with negative serology
• Suspected Wilson's disease with normal ceruloplasmin
• Suspected NAFLD with risk factors for advanced fibrosis

Important Clinical Pitfalls

• Normal AST and ALT do not exclude significant liver disease, as both can be normal even in cirrhosis 2
• GGT elevation alone is not sufficient to diagnose liver injury and may be elevated due to alcohol use, medications, or oxidative stress 2
• In early Primary Biliary Cholangitis, GGT may be disproportionately elevated compared to ALP 3
• Isolated ALP elevation may be of bone origin; confirm hepatic source with concurrent GGT elevation 1
• Consider medication history carefully, as drug-induced liver injury can present with various patterns

By following this systematic approach, the underlying cause of elevated liver enzymes in this young female patient can be identified efficiently, allowing for appropriate management and prevention of disease progression.