What are the differential diagnoses for elevated liver enzymes with otherwise normal liver function tests and negative hepatitis?

Differential Diagnoses for Mildly Elevated Transaminases with Normal Synthetic Function

The most likely diagnosis is nonalcoholic fatty liver disease (NAFLD), which accounts for 20-30% of cases in the general population and presents with this exact pattern of AST:ALT ratio <1 with preserved synthetic function. 1, 2

Primary Differential Diagnoses

Most Common Causes (in order of likelihood)

• Nonalcoholic Fatty Liver Disease (NAFLD) is the leading cause in developed countries, characterized by AST:ALT ratio <1 (your ratio is 1.14, slightly elevated but close), affecting up to 70% of obese patients and 90% of diabetics 1, 2

• Alcohol-induced liver disease should be strongly considered, though typically presents with AST:ALT ratio >2 (yours is 1.14), making this less likely unless alcohol consumption is moderate 1, 2

• Medication-induced liver injury accounts for 8-11% of cases with mildly elevated liver enzymes and should prompt a thorough review of all prescribed medications, over-the-counter drugs, and herbal supplements 3, 4

• Chronic viral hepatitis B or C can present with this pattern, though typically causes higher elevations; however, negative hepatitis testing makes this unlikely 1, 4

Less Common but Important Causes

• Autoimmune hepatitis typically presents with higher ALT elevations and elevated autoantibodies, but should be considered if other causes are excluded 1, 3

• Hereditary hemochromatosis is an uncommon cause that requires screening with iron studies (ferritin, transferrin saturation) 1, 4

• Wilson disease is a rare cause but should be considered in patients under age 40, requiring ceruloplasmin and 24-hour urine copper testing 1, 4

• Alpha-1 antitrypsin deficiency is rare but should be screened for, particularly with family history 1, 4

Non-Hepatic Causes to Exclude

• Muscle disorders including recent strenuous exercise, rhabdomyolysis, or polymyositis can elevate AST more than ALT; check creatine kinase (CK) to exclude muscle origin 1, 3, 2

• Thyroid disease (both hypothyroidism and hyperthyroidism) can affect liver enzymes and should be screened with TSH 1, 3, 2

• Hemolysis can elevate AST and should be considered if other hematologic abnormalities are present 1, 2

• Cardiac injury from recent myocardial infarction can elevate AST 5

Recommended Diagnostic Approach

Immediate History and Risk Factor Assessment

• Obtain detailed alcohol consumption history using AUDIT-C questionnaire, with ≥14-21 drinks/week in men or ≥7-14 drinks/week in women suggesting alcoholic liver disease 1, 3

• Complete medication review including all prescribed drugs, over-the-counter medications, herbal supplements, and any recent medication changes 1, 3, 4

• Assess for metabolic syndrome components including central obesity (BMI), diabetes/insulin resistance, hypertension, and dyslipidemia, as these are major risk factors for NAFLD 1, 3

• Screen for recent strenuous exercise or muscle injury that could explain transaminase elevation 3, 2

Initial Laboratory Testing

• Repeat complete liver panel including AST, ALT, alkaline phosphatase, GGT, total and direct bilirubin, albumin, and PT/INR to establish trend and confirm pattern 1, 3, 4

• Viral hepatitis serologies (if not already done): HBsAg, anti-HBc, anti-HCV to definitively exclude viral causes 3, 4

• Metabolic and autoimmune screening: fasting glucose, lipid panel, iron studies (ferritin, transferrin saturation), TSH, ANA, anti-smooth muscle antibody 3, 4

• Creatine kinase (CK) to exclude muscle origin of enzyme elevation 3, 2

First-Line 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 (>30% fat content) 1, 3

• Ultrasound can identify biliary obstruction, focal liver lesions, and signs of cirrhosis that may explain the enzyme elevation 1, 3

Clinical Significance and Prognosis

• Your enzyme elevations are mild (<2× upper limit of normal), which typically indicates early or mild disease without immediate concern for severe hepatocellular injury 1, 3

• Normal albumin, bilirubin, and INR indicate preserved liver synthetic function, suggesting no significant cirrhosis or acute liver failure 3, 4

• The AST:ALT ratio of 1.14 is slightly elevated but not the classic >2 ratio seen in alcoholic liver disease, making NAFLD or early alcohol-related disease most likely 1, 2

Important Caveats and Pitfalls

• Do not simply repeat the same tests without investigating the cause, as 84% of abnormal liver tests remain abnormal at 1 month and 75% at 2 years 1

• Normal liver enzymes do not exclude significant liver disease, as up to 10% of patients with advanced fibrosis may have normal ALT using conventional thresholds 3

• The extent of enzyme elevation does not necessarily correlate with disease severity, particularly in chronic viral hepatitis and NAFLD where significant fibrosis can exist with minimal enzyme elevation 1, 5

• More than 30% of mild asymptomatic ALT/AST elevations (<3× ULN) may spontaneously normalize during follow-up, but this should not delay initial diagnostic evaluation 2, 6

• Consider choledocholithiasis if there is any abdominal pain, as biliary obstruction can occasionally present with predominantly elevated transaminases rather than alkaline phosphatase 7