In an adult with mildly to moderately elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT) of unknown cause, should I start prednisone to lower the enzymes?

Should You Start Prednisone for Mildly to Moderately Elevated AST and ALT of Unknown Cause?

No, you should not empirically start prednisone to lower mildly to moderately elevated AST and ALT of unknown etiology—prednisone is only indicated for confirmed autoimmune hepatitis (AIH) after establishing the diagnosis through appropriate serologic testing, exclusion of other causes, and ideally liver biopsy confirmation. 1

Why Prednisone Is Not Appropriate Without a Diagnosis

The fundamental issue is that prednisone treats a specific disease (autoimmune hepatitis), not a laboratory abnormality. Starting corticosteroids empirically for elevated transaminases without establishing the underlying cause can:

• Mask the true diagnosis and delay appropriate treatment for conditions like viral hepatitis, drug-induced liver injury, or metabolic liver disease 2, 3
• Cause significant harm through immunosuppression, infection risk, metabolic complications, and bone disease if the patient doesn't actually have AIH 1
• Worsen certain conditions such as viral hepatitis or drug-induced liver injury where immunosuppression is contraindicated 1

The Correct Diagnostic Approach First

Before considering any immunosuppressive therapy, you must systematically evaluate the elevated transaminases:

Step 1: Exclude Non-Hepatic Causes

• Check creatine kinase (CK) to rule out rhabdomyolysis or muscle injury, which can significantly elevate AST 2, 3
• Obtain detailed exercise history, as intensive weight lifting can cause acute AST/ALT elevations mistaken for liver injury 2, 3
• Assess for cardiac injury with troponins if clinically indicated 2
• Check for hemolysis with complete blood count, haptoglobin, and LDH 2

Step 2: Determine the Pattern and Common Causes

• Calculate AST:ALT ratio: ratio >2:1 suggests alcoholic liver disease, while ratio <1 suggests NAFLD 2, 3
• Screen for viral hepatitis (hepatitis B surface antigen, hepatitis C antibody) 3, 4
• Obtain detailed alcohol consumption history 2, 3
• Review all medications and supplements for potential hepatotoxicity 2, 3
• Check metabolic parameters including fasting glucose, lipid panel, and consider ultrasound to assess for NAFLD (the most common cause, affecting 20-30% of the general population) 2, 3

Step 3: Evaluate for Autoimmune Hepatitis Only If Appropriate

AIH should be suspected and tested for only when:

• Other common causes have been excluded 1
• The patient has compatible clinical features (may include fatigue, jaundice, or be asymptomatic) 1
• Specific testing includes: antinuclear antibody (ANA), anti-smooth muscle antibody (SMA), anti-liver kidney microsomal antibody (anti-LKM), and serum IgG levels 1

When Prednisone IS Indicated: Confirmed Autoimmune Hepatitis

Prednisone becomes appropriate only after AIH is diagnosed. The American Association for the Study of Liver Diseases provides clear guidance:

For Non-Cirrhotic AIH Without Acute Severe Presentation

• First-line treatment: Budesonide 3 mg three times daily plus azathioprine 1-2 mg/kg/day is preferred over prednisone, as it achieves remission more effectively (47% vs 18.4%) with fewer steroid-specific side effects (72% vs 46.6% without side effects) 1, 5
• Alternative regimen: Prednisone 30-40 mg/day tapered to 10 mg/day plus azathioprine 1-2 mg/kg/day 1
• Prednisone alone: 60 mg/day tapered to 20 mg/day maintenance, reserved for patients with contraindications to azathioprine 1

For Acute Severe AIH (But Not Acute Liver Failure)

• Prednisone 0.5-1 mg/kg/day (up to 2 mg/kg in children) has been effective in 20-100% of patients 1
• Critical caveat: Treatment must be abandoned within 1-2 weeks if no improvement occurs, and the patient should be evaluated for liver transplantation 1
• Failure to improve any laboratory test or clinical deterioration justifies immediate transplant evaluation 1

For AIH With Acute Liver Failure

• Prednisone is NOT recommended as it has not improved overall survival and may be deleterious in severe decompensation 1
• Patients should be evaluated directly for liver transplantation 1
• Survival is worse in treated patients with MELD scores >40 1

Monitoring Requirements If AIH Treatment Is Started

Once AIH is confirmed and treatment initiated, rigorous monitoring is essential:

• Weekly monitoring of liver tests, blood sugar, and blood counts for the first 4 weeks 1
• Monthly monitoring thereafter (1-3 months depending on response) 1
• Serum AST/ALT should improve within 2 weeks of starting treatment; lack of improvement suggests treatment failure or wrong diagnosis 1
• Calcium and vitamin D supplementation should be started immediately 1
• DEXA bone density scans at treatment commencement and repeated at 1-2 year intervals 1

Special Consideration: Gene Therapy-Related Transaminitis

The only context where prednisone might be used for isolated transaminase elevation is in patients who have recently received gene therapy (specifically valoctocogene roxaparvovec for hemophilia A), where ALT elevation ≥1.5× baseline or above upper limit of normal triggers prednisone 60 mg/day for ≥2 weeks 1. This is an extremely specific scenario that does not apply to general practice.

Critical Pitfalls to Avoid

• Never start prednisone based solely on elevated AST/ALT values without establishing the diagnosis 1
• Wilson disease must be excluded in any patient <40 years with unexplained hepatocellular injury, as it presents with modest transaminase rises and requires specific copper-chelating therapy, not steroids 3
• Normal ALT does not exclude liver disease—up to 10% of patients with advanced fibrosis may have normal ALT 3
• Budesonide should NOT be used in patients with cirrhosis or acute severe AIH, as it undergoes first-pass hepatic metabolism and may be ineffective 1