What is the appropriate work‑up plan to determine the cause of elevated transaminases (aspartate aminotransferase 46 U/L, alanine aminotransferase 97 U/L) in a child?

Diagnostic Workup for Elevated Transaminases in a Child

A child with AST 46 U/L and ALT 97 U/L requires immediate assessment of synthetic liver function (INR, albumin, bilirubin) and systematic evaluation to exclude treatable causes, with urgent hepatology referral if bilirubin is >2× upper limit of normal or INR is elevated. 1

Immediate Risk Stratification

First, determine if this represents acute liver injury requiring urgent intervention:

• Check synthetic function immediately: Obtain fractionated bilirubin, complete blood count, comprehensive metabolic panel, prothrombin time/INR, and ammonia level 1
• Urgent hepatology referral is mandatory if: Bilirubin >2× ULN, INR elevation, or any signs of hepatic encephalopathy are present 1
• This ALT level (97 U/L) represents moderate elevation (~4× ULN for pediatric reference ranges), which does not meet criteria for severe injury (>10× ULN) but requires systematic evaluation 1

Critical History and Physical Examination Elements

Obtain targeted history focusing on red flags that dictate urgent specialist consultation: 2

• Medication review: Check all medications against the LiverTox® database for hepatotoxic potential; discontinue suspected agents immediately 1
• Viral exposure: Recent illness, fever, travel history, sick contacts 1
• Metabolic symptoms: Morning tachycardia, dizziness, or hypoglycemic episodes suggest glycogen storage disease 3
• Wilson disease features: Progressive jaundice, asterixis, hemolytic anemia, neurologic symptoms 4
• Obesity and metabolic syndrome: BMI, acanthosis nigricans, family history of type 2 diabetes 5
• Autoimmune features: Fatigue, arthralgia, rash, inflammatory bowel disease symptoms 5

Physical examination must assess:

• Hepatomegaly, splenomegaly, ascites 1
• Kayser-Fleischer rings (slit-lamp examination if Wilson disease suspected) 4
• Signs of chronic liver disease: spider angiomata, palmar erythema, jaundice 1

Initial Laboratory Workup

The first-tier testing should include: 1, 6

• Viral hepatitis panel: Hepatitis A IgM, hepatitis B surface antigen, hepatitis B core IgM antibody, hepatitis C antibody 1
• Metabolic screening: Fasting lipid profile, glucose, hemoglobin A1c 5
• Iron studies: Serum iron, ferritin, total iron-binding capacity (to screen for hemochromatosis) 6
• Celiac screening: Tissue transglutaminase antibodies with total IgA 6
• Thyroid function: TSH 6
• Muscle enzymes: Creatine kinase (to exclude muscular dystrophy as extrahepatic cause) 6, 7

Second-Tier Testing (If Initial Workup Negative)

If transaminases remain elevated after 4-6 weeks with negative initial testing: 2, 6

• Alpha-1 antitrypsin: Phenotyping by isoelectric focusing 1, 7
• Ceruloplasmin and 24-hour urinary copper: For Wilson disease screening (note: 5-15% of Wilson disease patients have normal ceruloplasmin) 4
• Autoimmune markers: Antinuclear antibody, smooth muscle antibody, liver/kidney microsomal antibody type 1, immunoglobulin G level 6, 7
• Abdominal ultrasound: To assess for hepatic steatosis (84.8% sensitivity, 93.6% specificity for moderate-severe steatosis), biliary obstruction, focal lesions, hepatomegaly 1

Genetic and Metabolic Disease Considerations

Genetic disorders account for 12% of persistent hypertransaminasemia in children and must be actively excluded: 7

• Wilson disease is the most critical diagnosis not to miss, as it is treatable but fatal if undiagnosed; liver biopsy provides definitive diagnosis 4, 7
• Glycogen storage diseases present with elevated transaminases, hepatomegaly, and hypoglycemic symptoms; require fasting metabolic panel (lactate, uric acid, cholesterol, triglycerides, beta-hydroxybutyrate) and genetic testing 3
• Alpha-1 antitrypsin deficiency should be tested in all cases of unexplained hypertransaminasemia 1, 7
• Muscular dystrophies can present with isolated transaminase elevation without muscle symptoms; CK screening is essential 7

Follow-Up Strategy

Proper monitoring is critical, as studies show 71-78% of children with unexplained hypertransaminasemia receive inadequate follow-up: 2, 8

• If initial workup is negative: Repeat liver enzymes in 4-6 weeks 2, 6
• If transaminases normalize: No further workup needed unless recurrence 2
• If transaminases remain elevated >6 months: Referral to pediatric gastroenterology/hepatology for consideration of liver biopsy 6, 7
• Higher transaminase levels warrant earlier and more aggressive follow-up 8

Common Pitfalls to Avoid

• Do not assume obesity-related fatty liver disease without excluding other causes, particularly Wilson disease and autoimmune hepatitis, which can be fatal if missed 4, 7
• Do not rely solely on ceruloplasmin to exclude Wilson disease; proceed to liver biopsy if clinical suspicion exists 4
• Do not fail to follow up normalized transaminases; 33% of children with identified causes never have normalization confirmed 8
• Do not overlook extrahepatic causes (thyroid, celiac, muscle disorders) that are easily treatable 6
• Do not delay hepatology referral if synthetic dysfunction is present; this represents acute liver failure risk requiring urgent transplant evaluation 1, 4