What are the causes of elevated lactate dehydrogenase (LDH) levels?

Causes of Elevated Lactate Dehydrogenase (LDH)

Elevated LDH is a nonspecific finding that reflects tissue damage or increased cellular turnover from numerous benign and malignant conditions, requiring clinical context for interpretation. 1

Major Categories of LDH Elevation

Malignant Causes

• Hematologic malignancies are among the most common causes of marked LDH elevation, particularly Burkitt's lymphoma, B-cell acute lymphoblastic leukemia (ALL), other B-cell non-Hodgkin's lymphomas, and T-ALL due to their high proliferative rates 1
• Solid tumors including testicular germ cell tumors, osteosarcoma, melanoma, small cell lung cancer, and metastatic germ cell carcinoma frequently elevate LDH 1
• Multiple myeloma shows elevated LDH in approximately 11% of patients, particularly those with plasma cell leukemia or lymphoma-like features, reflecting high tumor burden and aggressive disease 2
• Occult lymphoma can present with isolated LDH elevation (595-615 U/L with normal <225 U/L) as the only early sign, sometimes appearing 2 months before clinical manifestations 3

Tissue Damage and Hemolysis

• Hemolysis causes LDH elevation in combination with decreased haptoglobin (a specific combination for hemolysis) and elevated indirect bilirubin 4
• Myocardial infarction releases LDH from damaged cardiac tissue 1
• Liver disease of various etiologies elevates LDH, though this is nonspecific 1
• Muscle damage from strenuous exercise or rhabdomyolysis temporarily elevates LDH 1
• Kidney disease contributes to elevated LDH levels 1

Infection and Inflammation

• Sepsis and septic shock can elevate lactate levels (though lactate is not a direct measure of tissue perfusion), which may be accompanied by LDH elevation 5
• Infections of various types can cause LDH elevation 1

Pleural and Peritoneal Fluid Disorders

• Exudative pleural effusions show pleural fluid LDH >2/3 the upper limit of normal serum LDH (>67% of upper limit normal) or pleural fluid LDH/serum LDH ratio >0.6 by Light's criteria 1
• Secondary peritonitis from perforated viscus shows ascitic LDH levels higher than serum LDH levels 1

Pregnancy-Related Causes

• Preeclampsia causes LDH elevation and requires evaluation for underlying pathological processes 1

Iatrogenic and Device-Related Causes

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

Laboratory Artifact

• Hemolysis of blood samples can falsely elevate LDH levels 1

Interpretation by Degree of Elevation

Mild Elevation (<5× Upper Limit Normal)

• Most commonly associated with benign causes 1
• Includes liver disease, hemolysis, myocardial infarction, kidney disease, muscle damage, and infections 1

Moderate to Severe Elevation (>5× Upper Limit Normal)

• Can be caused by both benign and malignant conditions; no significant difference exists between average LDH values in benign (2708 U/L) versus malignant (2842 U/L) etiologies 6
• Benign causes included 11 of 15 cases with LDH >10× normal in one series 6

Extreme Elevation (>10× Upper Limit Normal)

• Carries a poor prognosis with hospitalization in intensive care in 73% of cases and mortality rate of 53%, regardless of benign or malignant etiology 6
• Most commonly seen in Burkitt's lymphoma, B-cell ALL, bulky small cell lung cancer, and metastatic germ cell carcinoma 1

Critical Diagnostic Pitfalls

• LDH elevation alone cannot differentiate benign from malignant disease, as 43 different etiologies can elevate LDH, and the degree of elevation does not predict malignancy 6
• Clinical context is essential: LDH must be interpreted alongside other clinical and laboratory findings 1
• Tissue-specific patterns: LDH is widely distributed in heart, liver, skeletal muscle, kidney, and erythrocytes, making total LDH a nonspecific finding 7
• Isoenzyme analysis provides more clinical significance than total LDH alone, as different tissues produce different LDH isoenzyme patterns 7