What is the appropriate evaluation and management for a 38‑year‑old healthy woman with mildly elevated aspartate aminotransferase, normal alanine aminotransferase, and borderline total bilirubin?

Evaluation of Mildly Elevated AST with Normal ALT and Borderline Bilirubin

In a healthy 38-year-old woman with isolated AST elevation (49 U/L), normal ALT (32 U/L), and borderline bilirubin (1.6 mg/dL), the most likely explanation is a non-hepatic source of AST—particularly from muscle, cardiac tissue, or red blood cells—rather than primary liver disease. 1

Understanding the Enzyme Pattern

AST is significantly less liver-specific than ALT because it is present in cardiac muscle, skeletal muscle, kidneys, brain, and red blood cells, making it essential to determine whether the elevation originates from hepatic or non-hepatic sources. 1 In contrast, ALT is highly specific for liver injury due to its low concentrations in skeletal muscle and kidney. 1

The AST/ALT ratio of approximately 1.5 (49/32) in this case does not suggest alcoholic liver disease, which typically shows a ratio >2 in 70% of patients. 1 The pattern also differs from typical NAFLD, which characteristically presents with an AST:ALT ratio <1 (ALT higher than AST). 1

Initial Diagnostic Approach

Immediate Laboratory Testing

• Measure creatine kinase (CK) to exclude muscle injury as a source of AST elevation, particularly if the patient has engaged in intensive exercise or weight lifting recently, which can cause acute AST elevations that may be mistaken for liver injury. 1

• Obtain thyroid function tests (TSH, free T4) to rule out thyroid disorders, which can elevate transaminases. 1, 2

• Complete a comprehensive metabolic panel if not already done, including assessment of renal function, as AST can be elevated in kidney disorders. 1

• Check for hemolysis markers (LDH, haptoglobin, peripheral smear) since red blood cell disorders can elevate AST. 1

Assess for Macro-AST

Consider the polyethylene glycol precipitation method to detect macro-AST, a rare but important cause of persistent isolated AST elevation in asymptomatic individuals. 3 Macro-AST is a high-molecular mass complex that is difficult for the kidney to clear, leading to isolated elevation of serum AST activity without true liver disease. 3

Hepatic Evaluation (If Non-Hepatic Causes Excluded)

Complete Liver Panel

• Obtain alkaline phosphatase, GGT, total and direct bilirubin, albumin, and prothrombin time/INR to assess for cholestatic patterns and synthetic function. 1, 2

• The borderline bilirubin of 1.6 mg/dL warrants fractionation into direct and indirect components to determine if there is a conjugated hyperbilirubinemia suggesting hepatobiliary disease versus unconjugated elevation from hemolysis or Gilbert syndrome. 1

Viral Hepatitis Screening

• Check HBsAg, anti-HBc IgM, and anti-HCV antibody to exclude viral hepatitis, which commonly causes fluctuating transaminase elevations. 1, 2

Metabolic and Autoimmune Workup

• Assess for metabolic syndrome components including fasting glucose or HbA1c, fasting lipid panel, blood pressure, and BMI, as NAFLD is the most common cause of elevated liver enzymes in non-drinkers with metabolic risk factors. 1

• Measure iron studies (ferritin, transferrin saturation) to screen for hereditary hemochromatosis. 1

• If other causes are excluded, check autoimmune markers (ANA, anti-smooth muscle antibody, quantitative IgG) to evaluate for autoimmune hepatitis, which can present with mild enzyme elevations. 1

Imaging Strategy

Abdominal ultrasound is recommended as the first-line imaging test if liver enzymes remain elevated after repeat testing, with a sensitivity of 84.8% and specificity of 93.6% for detecting moderate to severe hepatic steatosis. 1, 2 Ultrasound can also identify biliary obstruction, focal liver lesions, and structural abnormalities. 1

Monitoring Protocol

• Repeat liver enzymes (AST, ALT, bilirubin) in 2–4 weeks to establish the trend and confirm the elevation, as a single measurement may not represent true baseline. 1, 2

• If AST normalizes or decreases and non-hepatic causes are identified, no further immediate hepatic testing is needed. 1

• If AST remains elevated (>1.5× ULN) for ≥6 months without identified cause, consider hepatology referral for further evaluation including possible liver biopsy. 1

Critical Pitfalls to Avoid

• Do not assume that mild AST elevation is benign without proper evaluation, as up to 72% of asymptomatic patients with unexplained chronic AST elevations of mild to moderate degree have chronic active hepatitis on biopsy, and many have cirrhosis. 4

• Do not overlook non-hepatic causes of elevated AST, such as intensive exercise, muscle injury, cardiac injury, hemolysis, and thyroid disorders, which can all elevate AST while sparing ALT. 1

• Do not ignore the borderline bilirubin elevation—fractionation is essential to determine if this represents early hepatobiliary dysfunction or a benign condition like Gilbert syndrome. 1

• Recognize that normal ALT does not exclude significant liver disease—up to 10% of patients with advanced fibrosis may have normal ALT using conventional thresholds. 1

Special Consideration: Macro-AST

If all other causes are excluded and AST remains persistently elevated in isolation, perform polyethylene glycol precipitation to confirm macro-AST. 3 This rare condition causes persistent isolated AST elevation without true liver damage and requires no treatment, but recognition prevents unnecessary investigation and patient anxiety. 3