What is the significance and management of elevated aldolase (enzyme) levels?

Elevated Aldolase: Clinical Significance and Management

Primary Clinical Significance

Elevated aldolase primarily indicates muscle damage or injury and serves as a valuable diagnostic marker particularly when creatine kinase (CK) levels are normal, helping identify early muscle regeneration issues or specific myopathies. 1

Aldolase elevation occurs in three main clinical contexts:

1. Muscle Disease (Most Common)

• Myositis and inflammatory myopathies represent the most important clinical scenario, where aldolase can be elevated even when CK is normal 1, 2
• Isolated aldolase elevation (with normal CK) reflects preferential immune-mediated damage of early regenerating muscle cells and serves as a biomarker of damaged early regenerative muscle cells 2
• Dermatomyositis is the most common myopathy associated with selective aldolase elevation, occurring in approximately 24% of cases in recent cohorts 3
• Progressive muscular dystrophy, polymyositis, and myotonic muscular disease all cause aldolase A elevation 4
• Eosinophilic fasciitis shows elevated aldolase in 92% of cases (11/12 patients), making it more reliable than peripheral eosinophilia, ESR, or CRP for diagnosis and monitoring 5

2. Immune Checkpoint Inhibitor Therapy

• In patients receiving immune checkpoint inhibitors, elevated aldolase along with CK helps diagnose immune-related myositis 6, 1
• Blood testing for aldolase is part of the standard workup for suspected immune-related myositis 6
• For grade 1 myositis with mild weakness, elevated CK and/or aldolase may warrant oral corticosteroid treatment starting at prednisone 0.5 mg/kg/day 6

3. Distinguishing Muscle vs. Liver Injury

• Aldolase testing helps differentiate between muscle injury and liver injury when liver enzymes (ALT/AST) are elevated 1
• In patients with elevated transaminases, normal aldolase suggests liver injury while elevated aldolase suggests muscle origin of enzyme elevations 1
• Intensive exercise or statin therapy can cause elevations in ALT and AST due to muscle injury rather than liver damage, which aldolase testing can confirm 1

Management Algorithm

When to Order Aldolase Testing

Order aldolase in the following specific scenarios:

• Suspected myositis with muscle weakness, particularly if CK is normal or only mildly elevated 6, 1
• Patients on immune checkpoint inhibitors with new muscle symptoms 6
• Elevated liver enzymes (ALT/AST) in patients who exercise intensively or take statins to determine if elevation is from muscle rather than liver 1
• Suspected eosinophilic fasciitis with skin thickening 5
• Monitoring disease activity in confirmed myositis or eosinophilic fasciitis 5

Interpretation of Results

Elevated aldolase with normal CK:

• Strongly suggests early regenerating muscle damage, particularly in dermatomyositis or immune-mediated myopathy 2, 3
• Consider EMG, MRI imaging of affected muscles, and autoimmune myositis blood panel 6
• Refer to rheumatology or neurology for further evaluation 6

Elevated aldolase with elevated CK:

• Indicates active muscle injury across the spectrum of muscle cell maturation 2
• In immune checkpoint inhibitor patients, initiate prednisone 0.5-1 mg/kg/day for grade 2 or higher myositis 6
• Check troponin to evaluate myocardial involvement 6

Elevated aldolase with elevated liver enzymes:

• If aldolase is elevated, the transaminase elevation likely originates from muscle injury 1
• If aldolase is normal, the transaminase elevation likely originates from liver injury 1
• Consider checking CK to further confirm muscle involvement 1

Treatment Approach Based on Underlying Cause

For Immune-Related Myositis (Checkpoint Inhibitors)

• Grade 1 (mild weakness): Continue checkpoint inhibitor; offer oral corticosteroids at prednisone 0.5 mg/kg/day if CK and/or aldolase are elevated 6
• Grade 2 (moderate weakness): Hold checkpoint inhibitor temporarily; initiate prednisone 0.5-1 mg/kg/day if CK is elevated ≥3× ULN; refer to rheumatology or neurology 6
• Grade 3-4 (severe weakness): Hold checkpoint inhibitor; initiate prednisone 0.5-1 mg/kg/day; consider synthetic or biologic DMARDs if no improvement after 2 weeks 6

For Statin-Related Muscle Injury

• Discontinue or reduce statin dose 1
• Monitor aldolase and liver enzymes after medication adjustment 1
• Consider alternative lipid-lowering therapy if muscle injury confirmed 1

For Eosinophilic Fasciitis

• Aldolase serves as a useful marker for following disease activity 5
• Aldolase remains elevated longer than peripheral eosinophilia during treatment 5

Critical Pitfalls to Avoid

• Failing to consider muscle injury as a cause of elevated liver enzymes in patients who exercise intensively or take statins is a common error 1
• Assuming normal CK excludes significant myopathy: Aldolase can be elevated in dermatomyositis and other myopathies even when CK is normal, reflecting damage to early regenerating muscle cells 2, 3
• Not checking aldolase in suspected eosinophilic fasciitis: Aldolase is more consistently elevated (92%) than peripheral eosinophilia and remains abnormal during treatment 5
• Overlooking cardiac involvement: Always check troponin when aldolase and CK are elevated to evaluate for myocardial involvement 6
• Delaying rheumatology referral: Early recognition and treatment of immune-mediated myositis is critical to prevent irreversible muscle damage 6

Additional Diagnostic Considerations

• Aldolase B isoenzyme rises to very high levels in acute hepatitis, but only slightly in cirrhosis and chronic hepatitis 4
• Aldolase A predominates in malignant tumors, particularly liver cell carcinoma where it may be more sensitive than alpha-fetoprotein 4, 7
• Hemolytic anemia causes aldolase elevation due to high erythrocyte aldolase content 4
• In myocardial infarction, aldolase rises within 24-48 hours and returns to normal within five days 4