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

Elevated Aldolase: Clinical Significance and Management

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

Primary Clinical Applications

Muscle Disease Diagnosis

• Aldolase should be measured alongside CK, AST, ALT, and LDH in all patients with suspected myositis, including dermatomyositis, polymyositis, and immune-related myopathies. 2, 1
• Aldolase can be elevated even when CK is normal in several treatable myopathies, most commonly dermatomyositis (the most frequent cause), overlap myositis, and nonspecific myopathy. 3
• In dermatomyositis with isolated aldolase elevation (normal CK), patients have less frequent cutaneous involvement (50% vs 100%) and fibrillation potentials (50% vs 90.5%) but higher ESR and more perimysial mitochondrial pathology compared to those with elevated CK. 3
• Aldolase elevation with normal CK occurs in approximately 50% of cases with perimysial pathology, including inflammation, fragmentation, vasculitis, or calcified perimysial vessels. 3

Differentiating Muscle vs Liver Injury

• When liver enzymes (ALT/AST) are elevated, aldolase testing distinguishes between muscle injury and hepatic injury. 1, 4
• In patients with NASH or those on clinical trials for liver disease, elevated transaminases with normal aldolase suggest liver injury, while elevated aldolase indicates muscle origin of enzyme elevations. 2, 1
• Intensive exercise or statin therapy can cause ALT/AST elevations due to muscle injury rather than liver damage, which aldolase testing confirms. 1, 4

Immune Checkpoint Inhibitor Therapy

• In patients receiving immune checkpoint inhibitors, elevated aldolase along with CK helps diagnose immune-related myositis. 2, 1
• For grade 1 myositis (mild weakness), if both CK and aldolase are elevated, initiate oral corticosteroids (prednisone 10-20 mg/day). 2, 1
• For grade 2 myositis (CK ≥3× ULN with moderate weakness), hold the immune checkpoint inhibitor temporarily and initiate prednisone 0.5-1 mg/kg/day with rheumatology or neurology referral. 2, 1
• For grade 3-4 myositis (severe weakness), permanently discontinue the immune checkpoint inhibitor if any myocardial involvement exists, initiate prednisone 1 mg/kg or IV methylprednisolone, and consider plasmapheresis or IVIG. 2

Other Causes of Elevated Aldolase

Hepatic Conditions

• Aldolase B isozyme rises to very high levels in acute hepatitis but is only slightly elevated in cirrhosis, chronic hepatitis, and obstructive jaundice. 5
• Aldolase A predominates in liver cell carcinoma tissue and serum, with 94% (32/34) of primary liver cell carcinoma patients showing elevated serum aldolase A levels—more sensitive than alpha-fetoprotein. 6
• In fulminant hepatitis, aldolase A levels increase remarkably, while in most other nonmalignant liver diseases, levels remain below 210 ng/ml. 6

Hematologic Conditions

• Aldolase rises in hemolytic anemia due to erythrocyte destruction, as red blood cells are rich in aldolase. 5
• In acute leukemia, 85.2% of patients have serum aldolase A levels >210 ng/ml (range 125-1,550 ng/ml, mean 480 ng/ml), and all chronic myelocytic leukemia patients show elevated levels. 7
• Multiple blood transfusions can lead to increased aldolase levels. 4

Cardiac Conditions

• Aldolase A rises in myocardial infarction, reaches maximum within 24-48 hours, and returns to normal within five days. 5

Other Conditions

• Aldolase is elevated in eosinophilic fasciitis and may be more reliable than peripheral eosinophilia, hypergammaglobulinemia, or ESR for diagnosis and monitoring disease activity. 8
• Aldolase may be elevated in Pompe disease and other glycogen storage disorders, reflecting enzymes released from muscle tissue. 1

Management Algorithm Based on Aldolase Elevation

When Muscle Disease is Suspected

1. Measure aldolase alongside CK, AST, ALT, LDH, troponin, ESR, and CRP. 2, 1
2. Perform comprehensive muscle strength testing, as muscle weakness is more typical of myositis than pain alone. 2
3. Check troponin and ECG to evaluate myocardial involvement, which dramatically changes management. 2

Treatment Based on Severity

• Mild symptoms (pain without significant weakness): Continue normal activities, initiate acetaminophen or NSAIDs. 2
• Moderate symptoms (moderate weakness with elevated CK/aldolase): Hold causative agents, refer to rheumatology/neurology, initiate prednisone 0.5-1 mg/kg/day. 2, 1
• Severe symptoms (severe weakness limiting self-care): Hospitalize, initiate prednisone 1 mg/kg or IV methylprednisolone 1-2 mg/kg, consider plasmapheresis or IVIG. 2

When Liver Enzyme Elevation is Present

• If aldolase is normal with elevated ALT/AST, suspect primary liver injury. 1, 4
• If aldolase is elevated with elevated ALT/AST, suspect muscle injury (from exercise, statins, or myopathy). 1, 4
• Review medication history for statins, conduct exercise history, and consider muscle biopsy if diagnosis remains uncertain. 1

Critical Pitfalls to Avoid

• Do not assume all CK elevations require corticosteroids, as exercise-induced muscle damage can produce CK levels exceeding 10,000 U/L without renal impairment or need for treatment. 9
• Always evaluate for cardiac involvement by checking troponin and ECG, as myocardial involvement requires permanent discontinuation of causative agents and more aggressive immunosuppression. 2, 9
• Failing to consider muscle injury as a cause of elevated liver enzymes in patients who exercise intensively or are on statins is a common error. 1, 4
• In patients with cirrhosis, aldolase testing may yield false negative results for alcohol consumption monitoring. 2
• Do not overlook aldolase testing in suspected eosinophilic fasciitis, as it may be more consistently abnormal than peripheral eosinophilia, particularly after starting treatment. 8