What could be the cause of elevated liver function tests (LFTs) in a 17-year-old patient with hyperbilirubinemia (bilirubin 4.1), elevated alanine transaminase (ALT) (59), elevated aspartate transaminase (AST) (25), normal thyroid function tests (T4 1.6, TSH 1.06), and abnormal protein levels (protein 8.3, globulin 3.5)?

Differential Diagnosis: Elevated Liver Enzymes with Hyperbilirubinemia in a 17-Year-Old

The most likely cause in this 17-year-old is Gilbert's syndrome combined with mild hepatocellular injury from nonalcoholic fatty liver disease (NAFLD), viral hepatitis, or medication-induced liver injury, given the isolated hyperbilirubinemia (bilirubin 4.1) with mildly elevated ALT (59) and normal AST (25). 1, 2

Understanding the Laboratory Pattern

This patient demonstrates a hepatocellular injury pattern with:

• Elevated ALT (59 IU/L) - indicating hepatocyte damage, as ALT is highly liver-specific with minimal presence in other tissues 2, 3
• Normal AST (25 IU/L) - ruling out significant muscle injury or cardiac involvement 3, 4
• AST:ALT ratio <1 (0.42) - characteristic of NAFLD, viral hepatitis, or medication-induced injury rather than alcoholic liver disease 2, 3
• Markedly elevated total bilirubin (4.1 mg/dL) - disproportionate to the mild transaminase elevation 1
• Normal thyroid function (T4 1.6, TSH 1.06) - excluding thyroid disorders as a cause 2
• Mildly elevated globulin (3.5) with normal total protein (8.3) - suggesting possible immune activation 1

Primary Diagnostic Considerations

Gilbert's Syndrome (Most Likely for Hyperbilirubinemia)

Gilbert's syndrome is the most common cause of isolated elevated bilirubin and should be the first consideration when bilirubin is disproportionately elevated compared to transaminases 1. This inherited disorder causes impaired conjugation via reduced glucuronyltransferase activity 1.

Critical diagnostic step: Obtain fractionated bilirubin to determine unconjugated vs. conjugated fractions 1:

• If >80% unconjugated and no hemolysis → Gilbert's syndrome is virtually certain 1
• If conjugated bilirubin >25 μmol/L (>1.5 mg/dL) → suggests hepatocellular disease or biliary obstruction requiring urgent evaluation 1

Hepatocellular Injury Causes (For ALT Elevation)

For the mild ALT elevation (59 IU/L, approximately 2× upper limit of normal for males), the most common causes are 2, 3:

1. Nonalcoholic Fatty Liver Disease (NAFLD) - affects 20-30% of general population, presents with AST:ALT ratio <1 3, 4

   • Assess for metabolic syndrome: obesity, diabetes, hypertension 2
   • Most likely if patient has elevated BMI or metabolic risk factors 3

2. Viral Hepatitis - can present with fluctuating transaminase elevations 2

   • Hepatitis B, C, or acute viral infections (EBV, CMV) 2, 5
   • In pediatric patients with acute infections, respiratory viruses (especially rhinovirus) commonly cause transaminase elevation 5

3. Medication-Induced Liver Injury - accounts for 8-11% of cases with elevated liver enzymes 2, 4

   • Review ALL medications, supplements, and herbal products 2
   • Check against LiverTox® database 2

Immediate Diagnostic Workup

Essential Laboratory Tests (Order Immediately)

Complete the following panel to identify the underlying cause 2, 3, 4:

1. Fractionated bilirubin (direct and indirect) - most critical test to differentiate Gilbert's from hepatocellular disease 1
2. Complete liver panel - alkaline phosphatase, GGT, albumin, PT/INR 2, 3
3. Viral hepatitis serologies - HBsAg, anti-HBc IgM, anti-HCV, EBV panel, CMV IgM 2, 5
4. Metabolic parameters - fasting glucose, lipid panel, hemoglobin A1c 2
5. Creatine kinase - to exclude muscle injury as source of transaminase elevation 2, 4
6. Complete blood count with platelets - to assess for hemolysis and evaluate for thrombocytopenia suggesting advanced fibrosis 1
7. Reticulocyte count and haptoglobin - if hemolysis suspected 1

Imaging

Abdominal ultrasound is the recommended first-line imaging test with 84.8% sensitivity and 93.6% specificity for detecting moderate to severe hepatic steatosis 2, 3, 4. This will identify:

• Hepatic steatosis (NAFLD) 2
• Biliary obstruction or dilation 2
• Focal liver lesions 2
• Structural abnormalities 2

Age-Specific Considerations for a 17-Year-Old

Wilson disease must be excluded in any patient <40 years with unexplained hepatocellular injury 3. Key features include:

• Modest aminotransferase elevations with markedly low or normal alkaline phosphatase 3
• Order ceruloplasmin and 24-hour urine copper if other causes excluded 3
• Requires urgent evaluation as it is treatable but can progress to fulminant hepatic failure 3

Autoimmune hepatitis should also be considered in adolescents 2:

• Check ANA, anti-smooth muscle antibody, anti-LKM antibody 2
• More common in young females 2
• Can present with gradual ALT increases and elevated globulins 2

Severity Classification and Monitoring Strategy

This represents mild elevation (<5× upper limit of normal) 2, 3, 4:

• Repeat liver enzymes in 2-4 weeks to establish trend 2, 4
• If ALT increases to ≥3× ULN (>90 IU/L), intensify evaluation and repeat within 2-5 days 2
• If ALT increases to >5× ULN (>150 IU/L) or bilirubin >2× ULN (>2.6 mg/dL), refer urgently to hepatology 2, 3, 4

Management Algorithm

If Gilbert's Syndrome Confirmed (Unconjugated Hyperbilirubinemia)

• Reassure patient completely - this is benign and requires no treatment 1
• Bilirubin may fluctuate with illness, fasting, or stress 1
• No follow-up needed for bilirubin alone 1
• Continue evaluation of ALT elevation separately 2

If Hepatocellular Disease Suspected (Conjugated Hyperbilirubinemia)

• More urgent evaluation required as conjugated hyperbilirubinemia suggests parenchymal liver disease or biliary obstruction 1
• Proceed with complete diagnostic workup as outlined above 2, 3
• Consider hepatology referral if diagnosis unclear 2, 4

For Mild ALT Elevation Management

Based on identified cause 2:

• NAFLD: Lifestyle modifications (7-10% weight loss, 150-300 minutes moderate exercise weekly, low-carbohydrate diet) 2
• Viral hepatitis: Refer for specific antiviral management 2
• Medication-induced: Discontinue offending agent and monitor ALT every 3-7 days until declining 2
• Alcohol-related: Complete abstinence recommended 2

Critical Pitfalls to Avoid

1. Do not assume elevated bilirubin is "just Gilbert's" without fractionation - conjugated hyperbilirubinemia requires urgent evaluation 1

2. Do not overlook Wilson disease in this age group - it is treatable but can be fatal if missed 3

3. Do not attribute significant bilirubin elevation to mild transaminase elevation alone - the degree of hyperbilirubinemia (4.1 mg/dL) is disproportionate and suggests a separate process 1

4. Do not ignore recent exercise or supplements - these can cause transaminase elevations mistaken for liver disease 2, 4

5. Normal ALT does not exclude liver disease - up to 10% of patients with advanced fibrosis may have normal ALT 2

When to Refer to Hepatology

Immediate referral indicated if 2, 3, 4:

• ALT increases to >5× ULN (>150 IU/L for males) 2, 4
• Bilirubin increases to >2× ULN (>2.6 mg/dL) 2, 4
• Evidence of synthetic dysfunction (low albumin, prolonged PT/INR, thrombocytopenia) 2, 4
• ALT remains elevated for ≥6 months without identified cause 2, 4
• Suspicion for Wilson disease, autoimmune hepatitis, or advanced fibrosis 2, 3