What are the possible causes of significantly elevated Lactate Dehydrogenase (LDH) levels?

Causes of Elevated Lactate Dehydrogenase (LDH)

Elevated LDH is a nonspecific marker of tissue damage or increased cellular turnover that can arise from numerous benign and malignant conditions, requiring clinical context and degree of elevation to guide diagnostic evaluation. 1, 2

Malignant Causes

Hematologic Malignancies

• Lymphomas (particularly Burkitt's lymphoma and B-cell acute lymphoblastic leukemia) carry the highest risk for extreme LDH elevation due to high proliferative rates. 1
• Multiple myeloma shows elevated LDH in 11% of patients, with levels >300 U/L associated with high tumor burden, extraosseous disease, and significantly worse prognosis (median survival 9 months versus longer survival in those with normal LDH). 3
• Plasma cell leukemia demonstrates elevated LDH reflecting high tumor burden and aggressive clinical presentation. 1
• Occult malignant lymphoma can present with isolated LDH elevation (595-615 U/L with predominance of LDH isoenzymes 2 and 3) as the only early sign, appearing months before clinical manifestations. 4

Solid Tumors

• Osteosarcoma shows elevated LDH in patients with metastatic disease; 5-year disease-free survival is 39.5% for high LDH versus 60% for normal values. 5, 1
• Testicular germ cell tumors use LDH for risk stratification, with LDH >2.5× upper limit of normal (ULN) defining worse prognosis (3-year progression-free survival 75-80% versus 92-93% for good-prognosis group). 1
• Metastatic cancer (particularly liver metastases) is strongly associated with very high isolated LDH (≥800 IU/mL), present in 14% of such patients versus 3% of controls. 6
• Small cell lung cancer (bulky disease) and metastatic germ cell carcinoma are high-risk solid tumors for marked LDH elevation. 1

Benign Causes

Hemolysis and Hematologic Disorders

• Hemolytic anemia causes LDH elevation combined with decreased haptoglobin and elevated indirect bilirubin. 2
• Thrombotic thrombocytopenic purpura (TTP) shows elevated total LDH primarily from LDH5 (skeletal muscle and liver origin) due to systemic ischemic tissue damage, not predominantly from erythrocyte hemolysis as commonly assumed. 7
• Laboratory artifact from hemolyzed blood samples can falsely elevate LDH. 1, 2

Tissue Damage

• Myocardial infarction releases LDH from damaged cardiac tissue. 1, 2
• Liver disease of various etiologies elevates LDH nonspecifically. 1, 2
• Muscle damage from strenuous exercise or rhabdomyolysis temporarily elevates LDH. 1, 2
• Kidney disease contributes to elevated LDH in patients with renal impairment. 1, 2

Infections and Inflammation

• Infections of various types (57% of patients with very high isolated LDH versus 28% of controls) are a major cause of marked elevation. 6
• Sepsis and septic shock can elevate LDH in critically ill patients. 2

Pregnancy-Related

• Preeclampsia causes LDH elevation requiring evaluation for underlying pathological processes. 1, 2

Fluid Disorders

• Exudative pleural effusions show pleural fluid LDH >2/3 the upper limit of normal serum LDH or pleural fluid LDH/serum LDH ratio >0.6 by Light's criteria. 1, 2
• Secondary peritonitis from perforated viscus shows ascitic LDH levels higher than serum LDH levels. 1, 2

Iatrogenic Causes

• Mechanical circulatory support devices cause baseline hemolysis; LDH >2.5× ULN requires evaluation for pump thrombosis. 1, 2
• Tumor lysis syndrome occurs spontaneously or after treatment with corticosteroids, monoclonal antibodies, or chemotherapeutic agents in high tumor burden malignancies. 1, 2
• Drug-induced liver injury is an uncommon cause of mild aminotransferase and LDH elevation. 1, 2

Interpretation by Degree of Elevation

Mild Elevation (<5× ULN)

• Most commonly associated with benign causes including liver disease, hemolysis, myocardial infarction, kidney disease, muscle damage, and infections. 1, 2
• In one retrospective study, 60% of LDH elevations >2-fold normal were benign, 36% malignant, and 5% undetermined, with no difference in average values between benign (2708 U/L) and malignant (2842 U/L) etiologies. 8

Moderate to Severe Elevation (5-10× ULN)

• Warrants thorough investigation including abdominal CT scan for occult malignancy, particularly lymphoma. 4

Extreme Elevation (>10× ULN)

• Carries poor prognosis regardless of benign or malignant etiology, with 73% requiring intensive care hospitalization and 53% mortality rate. 8
• Very high isolated LDH (≥800 IU/mL) is an independent predictor of mortality (26.6% versus 4.3% in controls), more admission days (9.3 versus 4.1), and significantly more in-hospital major complications. 6

Critical Diagnostic Pitfalls

• LDH elevation alone cannot differentiate benign from malignant disease, as 43 different etiologies can cause elevation, and average values overlap significantly. 8
• Clinical context is essential; LDH must be interpreted alongside other clinical and laboratory findings. 1, 2
• In cancer follow-up, LDH normalization indicates effective treatment, while rising levels suggest therapeutic failure, but measurements must be obtained remote from treatments like blood transfusions, growth factors, radiotherapy, and chemotherapy to avoid confounding. 8