What is the appropriate workup for a patient with transaminitis (elevated alanine aminotransferase and/or aspartate aminotransferase)?

Workup for Transaminitis (Elevated Liver Enzymes)

Initial Clinical Assessment

Begin with a detailed alcohol consumption history using quantitative measures: calculate grams per day using [volume in mL × alcohol % × 0.785], with risk thresholds >40 g/day for men and >20 g/day for women. 1, 2, 3 Document type, quantity, frequency, and duration of drinking, as alcoholic liver disease is one of the most common causes of elevated transaminases. 3, 4, 5

Obtain a comprehensive medication review checking all prescription drugs, over-the-counter products, herbal supplements, and dietary supplements against the LiverTox® database, as medication-induced liver injury causes 8-11% of cases with mildly elevated liver enzymes. 1, 3

Assess for metabolic syndrome components: measure waist circumference, blood pressure, and evaluate for obesity, diabetes, hypertension, and dyslipidemia, as nonalcoholic fatty liver disease (NAFLD) affects up to 30% of the population and is the most common cause of transaminitis. 1, 4, 5

Essential Laboratory Testing

First-Tier Tests (Order Immediately)

Complete liver panel: AST, ALT, alkaline phosphatase, GGT, total and direct bilirubin, albumin, and prothrombin time/INR to assess both hepatocellular injury and synthetic function. 1, 3

Viral hepatitis serologies: HBsAg, anti-HBc IgM, and anti-HCV antibody with reflex PCR to rule out viral hepatitis, which commonly causes fluctuating transaminase elevations. 1, 3, 4, 5

Metabolic parameters: fasting glucose or HbA1c and fasting lipid panel to evaluate for metabolic syndrome and NAFLD risk factors. 1, 4, 5

Iron studies: serum ferritin and transferrin saturation to screen for hereditary hemochromatosis, with transferrin saturation >45% considered clinically significant. 1, 4, 5

Complete blood count with platelets: to assess for thrombocytopenia (suggesting portal hypertension or splenic sequestration) and to provide baseline hematologic data. 1

Enzyme Pattern Interpretation

**AST/ALT ratio <1** (ALT > AST): characteristic of NAFLD, viral hepatitis, or medication-induced liver injury. 1, 3

AST/ALT ratio ≥2: highly suggestive of alcoholic liver disease, particularly alcoholic hepatitis; ratios >3 are particularly specific for alcohol-related injury. 1, 2, 3

Both AST and ALT rarely exceed 300-400 IU/L in alcoholic liver disease; levels above this threshold suggest alternative or additional causes such as acute viral hepatitis or drug-induced liver injury. 2

Elevated GGT: present in about 75% of habitual drinkers but can also occur in NAFLD, obesity, diabetes, smoking, or drug use; useful for monitoring abstinence as it recovers slowly over months. 2, 3

Risk Stratification for Fibrosis

Calculate the FIB-4 score using age, ALT, AST, and platelet count as the primary screening tool for advanced fibrosis. 1

• FIB-4 <1.3 (<2.0 if age >65): low risk for advanced fibrosis with ≥90% negative predictive value 1
• FIB-4 >2.67: high risk for advanced fibrosis requiring hepatology referral 1

First-Line Imaging

Abdominal ultrasound is the recommended initial imaging test with 84.8% sensitivity and 93.6% specificity for detecting moderate to severe hepatic steatosis. 1, 3 It also identifies biliary obstruction, focal liver lesions, portal hypertension features, and structural abnormalities. 1

Second-Tier Testing (If Initial Workup Unrevealing)

Autoimmune markers: ANA, anti-smooth muscle antibody (ASMA), anti-mitochondrial antibody, and quantitative immunoglobulins to evaluate for autoimmune hepatitis and primary biliary cholangitis. 1, 4, 5

Alpha-1 antitrypsin level: to screen for alpha-1 antitrypsin deficiency, a rare but treatable cause. 1, 4, 5

Ceruloplasmin level: to screen for Wilson disease, particularly in patients <40 years old. 1, 4, 5

Thyroid function tests: to rule out thyroid disorders as a cause of transaminase elevations. 1, 4, 5

Creatine kinase: to exclude muscle disorders as a source of AST elevation, particularly if the patient has engaged in intensive exercise. 1

Celiac disease screening: if clinically indicated based on symptoms or risk factors. 1, 4, 5

Monitoring Strategy

For mild elevations (<2× ULN): repeat liver enzymes in 2-4 weeks to establish trend. 1, 3 If values remain stable or improve, continue monitoring every 4-8 weeks until normalized. 1

For elevations 2-3× ULN: repeat testing within 2-5 days and intensify diagnostic evaluation. 1

For elevations ≥3× ULN or doubling from baseline: urgent evaluation required, including broadened infectious, metabolic, and medication reviews. 1

For elevations ≥5× ULN: urgent hepatology referral indicated. 1

Criteria for Hepatology Referral

Refer to hepatology if any of the following are present:

• Transaminases remain elevated for ≥6 months without identified cause 1, 3, 4
• ALT >5× ULN (>235 IU/L for males, >125 IU/L for females) 1
• ALT ≥3× ULN plus bilirubin ≥2× ULN (Hy's Law pattern suggesting potential acute liver failure) 1
• Evidence of synthetic dysfunction (elevated INR, low albumin, thrombocytopenia) 1
• FIB-4 score >2.67 indicating high risk for advanced fibrosis 1
• Clinical suspicion for autoimmune hepatitis or other complex liver disease 1

Management Based on Likely Etiology

For Suspected NAFLD

Lifestyle modifications are the cornerstone: target 7-10% body weight loss through caloric restriction, adopt a low-carbohydrate/low-fructose diet, and prescribe 150-300 minutes/week of moderate-intensity aerobic exercise plus resistance training ≥2 days/week. 1, 3

For Suspected Alcoholic Liver Disease

Complete alcohol cessation is essential, with repeat liver enzymes after at least one week of abstinence. 2, 3 Consider prescribing naltrexone, acamprosate, or disulfiram for alcohol use disorder. 2 If FibroScan reveals significant fibrosis (F3-F4), initiate cirrhosis surveillance protocols including upper endoscopy for variceal screening and hepatocellular carcinoma surveillance with ultrasound ± AFP every 6 months. 2

For Medication-Induced Liver Injury

Discontinue suspected hepatotoxic medications when possible, with monitoring of liver enzymes every 3-7 days until declining; expect normalization within 2-8 weeks after drug discontinuation. 1, 3

For Viral Hepatitis

Refer for specific management based on viral etiology; chronic hepatitis B may require antiviral prophylaxis with nucleoside analogues if immunosuppressive therapy is planned. 1, 3

Common Pitfalls to Avoid

Do not assume mild ALT elevations (>1× to <3× ULN) without elevated bilirubin are benign—they may be related to NAFLD, dietary changes, or vigorous exercise, but require systematic evaluation. 6, 1

Do not overlook that normal ALT does not exclude significant liver disease—up to 50% of patients with NAFLD and 10% with advanced fibrosis may have normal ALT using conventional thresholds. 1

Do not forget that AST is less liver-specific than ALT—it can be elevated from cardiac muscle, skeletal muscle, kidney, or red blood cell disorders. 1

Do not postpone calculating the FIB-4 score—it is a simple, evidence-based tool that identifies patients needing urgent specialist assessment. 1

Always consider that more than 50% of patients with advanced fibrosis from alcohol have normal or minimally elevated transaminases, making enzyme levels potentially misleading in alcoholic liver disease. 2

6, 1, 2, 3, 4, 5, 7, 8, 9