What is the management of elevated transaminases (liver enzymes)?

Management of Elevated Transaminases

For patients with elevated transaminases, begin with risk factor assessment and repeat testing in 2-4 weeks to establish persistence, followed by a systematic laboratory evaluation targeting the most common causes: nonalcoholic fatty liver disease (NAFLD), alcohol-related liver disease, viral hepatitis, and medication-induced injury. 1

Initial Assessment and Risk Stratification

History and Physical Examination

• Obtain detailed alcohol consumption history using standardized tools (AUDIT or AUDIT-C), with thresholds of ≥14-21 drinks/week in men or ≥7-14 drinks/week in women suggesting alcoholic liver disease 1, 2
• Conduct comprehensive medication review including prescription drugs, over-the-counter medications, and herbal supplements, checking against the LiverTox® database for hepatotoxic potential, as medication-induced injury causes 8-11% of cases 1
• Assess for metabolic syndrome components: measure waist circumference, blood pressure, and evaluate for obesity, diabetes, and hypertension as NAFLD risk factors 3, 1
• Evaluate for symptoms of chronic liver disease including fatigue, jaundice, and pruritus 1
• Assess recent exercise history, as intensive physical activity can cause transient AST and ALT elevations that may be mistaken for liver injury 1

Severity Classification

• Classify ALT elevations as mild (<5× upper limit of normal [ULN]), moderate (5-10× ULN), or severe (>10× ULN), using sex-specific reference ranges: 29-33 IU/L for males and 19-25 IU/L for females 1
• Recognize that ALT is more liver-specific than AST, which can be elevated from cardiac muscle, skeletal muscle, kidney, or red blood cell disorders 1
• Note that AST:ALT ratio <1 is characteristic of NAFLD, viral hepatitis, or medication-induced injury, while ratio >2 suggests alcoholic liver disease 1

Laboratory Evaluation

First-Tier Testing

• Obtain complete liver panel including AST, ALT, alkaline phosphatase, GGT, total and direct bilirubin, albumin, and prothrombin time/INR 1
• Perform complete blood count with platelets to assess for thrombocytopenia suggesting advanced fibrosis 1
• Check viral hepatitis serologies: hepatitis B surface antigen (HBsAg), hepatitis B core antibody (anti-HBc), and hepatitis C antibody (anti-HCV) 1, 4, 5
• Obtain fasting glucose or HbA1c and fasting lipid panel to assess for metabolic syndrome 1, 4
• Measure serum iron, total iron-binding capacity, and ferritin to screen for hereditary hemochromatosis 4, 5
• Check thyroid-stimulating hormone (TSH) to exclude thyroid disorders as a cause of transaminase elevation 1
• Measure creatine kinase (CK) if AST is disproportionately elevated to exclude muscle injury 1

Second-Tier Testing (if initial workup unrevealing)

• Check antinuclear antibody (ANA), anti-smooth muscle antibody (ASMA), and immunoglobulin G levels if autoimmune hepatitis is suspected, particularly with ALT >3× ULN 1
• Measure alpha-1-antitrypsin level and phenotype for patients with emphysema or family history 4, 5
• Check ceruloplasmin level in patients under age 40 to screen for Wilson disease 4, 5
• Perform tissue transglutaminase antibody testing to exclude celiac disease 5

Risk Stratification for Advanced Fibrosis

FIB-4 Score Calculation

• Calculate FIB-4 score using age, ALT, AST, and platelet count as the primary screening tool for advanced fibrosis 3, 2
• Interpret FIB-4 score <1.3 (<2.0 in those older than 65 years) as low risk for advanced fibrosis with negative predictive value ≥90% 3
• Recognize FIB-4 score >2.67 as indicating high risk for advanced fibrosis requiring hepatology referral 3, 2
• Consider vibration-controlled transient elastography (FibroScan) for intermediate FIB-4 scores (1.3-2.67) 2

Imaging Evaluation

Abdominal Ultrasound

• Order abdominal ultrasound as first-line imaging with sensitivity of 84.8% and specificity of 93.6% for detecting moderate to severe hepatic steatosis 3, 1
• Use ultrasound to identify biliary obstruction, focal liver lesions, and features of portal hypertension 1
• Recognize that ultrasound has suboptimal sensitivity for mild steatosis but high accuracy for moderate and severe steatosis 3

Management Based on Etiology

Nonalcoholic Fatty Liver Disease

• Implement lifestyle modifications targeting 7-10% body weight loss through caloric restriction as the cornerstone of NAFLD management 3, 1, 2
• Prescribe 150-300 minutes of moderate-intensity aerobic exercise weekly (50-70% of maximal heart rate), as exercise reduces liver fat even without significant weight loss 1
• Recommend low-carbohydrate, low-fructose diet 1, 2
• Consider vitamin E 800 IU daily for biopsy-proven NASH without diabetes or cirrhosis, as this improves liver histology in 43% versus 19% with placebo 1
• Treat metabolic comorbidities aggressively: use statins for dyslipidemia, GLP-1 receptor agonists or SGLT2 inhibitors for diabetes, and optimize blood pressure control 1, 2
• Consider bariatric surgery for morbidly obese NAFLD patients who fail conservative management 2

Alcoholic Liver Disease

• Recommend complete alcohol abstinence, as even moderate consumption can exacerbate liver injury and impede recovery 1
• Monitor transaminases every 4 weeks after alcohol cessation, expecting improvement within 4-6 weeks 1

Medication-Induced Liver Injury

• Discontinue suspected hepatotoxic medications when possible 1
• Monitor ALT every 3-7 days until declining, with expectation of normalization within 2-8 weeks after drug discontinuation 1

Viral Hepatitis

• Refer patients with confirmed hepatitis B or C for antiviral therapy consideration 1
• Consider antiviral prophylaxis with nucleoside analogues for chronic HBV if immunosuppressive therapy is planned 1

Monitoring and Follow-up

Repeat Testing Schedule

• Repeat liver enzymes in 2-4 weeks to establish trend and persistence for mild elevations without identified cause 3, 1
• If ALT remains <2× ULN, continue monitoring every 4-8 weeks until stabilized or normalized 1
• If ALT increases to 2-3× ULN, repeat testing within 2-5 days and intensify evaluation 1
• If ALT increases to >3× ULN or bilirubin >2× ULN, obtain more urgent follow-up within 2-3 days 1

Hepatology Referral Criteria

• Refer if ALT increases to >5× ULN (>235 IU/L for males, >125 IU/L for females) or bilirubin >2× ULN 1
• Refer if transaminases remain elevated for ≥6 months without identified cause 3, 1, 5
• Refer if FIB-4 score >2.67 indicating high risk for advanced fibrosis 3, 2
• Refer if evidence of synthetic dysfunction (low albumin, prolonged prothrombin time) develops 3, 1
• Refer if autoimmune markers (ANA, ASMA) are positive with titers >1:80 1

Role of Liver Biopsy

• Recognize that liver biopsy is not mandatory to initiate therapy but provides information on prognosis 3
• Consider liver biopsy when results will influence treatment decisions, particularly in patients with HCV genotype-1 infection 3
• Obtain liver biopsy if diagnosis remains unclear after non-invasive evaluation, if ALT remains elevated >6 months without identified cause, or if suspicion for autoimmune hepatitis or advanced fibrosis exists 1
• Note that 14-24% of persons with persistently normal aminotransferase values have more-than-portal fibrosis on liver biopsy 3

Common Pitfalls to Avoid

• Do not assume ALT elevation is benign without proper evaluation, as ALT elevation ≥5× ULN is rare in NAFLD/NASH and usually indicates viral hepatitis, autoimmune hepatitis, or drug-induced injury 1
• Do not overlook non-hepatic causes of elevated transaminases including intensive exercise, muscle injury, cardiac injury, hemolysis, and thyroid disorders 1
• Do not use conventional ALT thresholds rigidly, as normal ALT does not exclude significant liver disease—up to 10% of patients with advanced fibrosis may have normal ALT 1
• Do not delay evaluation in women with ALT >125 IU/L (>5× ULN for females), as this represents moderate-to-severe elevation requiring prompt assessment 1
• Do not attribute persistent cholestatic pattern (elevated alkaline phosphatase and GGT) to NAFLD without checking antimitochondrial antibody for primary biliary cholangitis 6