What causes elevated lactate dehydrogenase (LDH) levels?

What Causes Elevated LDH?

Elevated LDH is a nonspecific marker of tissue damage or increased cellular turnover that occurs in numerous conditions, including malignancies (particularly hematologic cancers, testicular germ cell tumors, and metastatic disease), hemolysis, myocardial infarction, liver disease, muscle damage, kidney disease, infections, and pleural/peritoneal fluid disorders. 1, 2

Malignant Causes

Hematologic Malignancies

• Burkitt's lymphoma and B-cell acute lymphoblastic leukemia carry the highest risk for extreme LDH elevation due to high proliferative rates and tumor sensitivity to chemotherapy 1
• Other B-cell non-Hodgkin's lymphomas and T-cell ALL also produce marked elevations 1
• Plasma cell leukemia presents with elevated LDH reflecting high tumor burden and aggressive clinical presentation 1
• Elevated LDH (595-615 IU/mL with normal <225 IU/mL) can be the earliest and only sign of occult malignant lymphoma, appearing months before clinical manifestations 3

Solid Tumors

• In testicular germ cell tumors, LDH is a critical tumor marker used for diagnosis, prognosis, and treatment monitoring, though it is less specific than AFP and β-HCG 4, 1
• In osteosarcoma, elevated LDH correlates with metastatic disease and significantly worse outcomes, with 5-year disease-free survival of 39.5% versus 60% for those with normal values 4, 1
• Bulky small cell lung cancer and metastatic germ cell carcinoma are high-risk solid tumors for marked LDH elevation 1
• Liver metastases are strongly associated with very high isolated LDH (≥800 IU/mL), occurring in 14% versus 3% in controls 5

Tissue Damage and Hemolysis

Hemolytic Conditions

• Hemolysis causes LDH elevation in combination with decreased haptoglobin and elevated indirect bilirubin 2
• Chronic anemia, particularly hemolytic anemias, can elevate LDH to approximately 500 units due to ongoing red blood cell destruction and LDH release 6
• Mechanical circulatory support devices cause baseline hemolysis; LDH elevation >2.5 times upper limit of normal requires evaluation for pump thrombosis 1, 2

Organ-Specific Damage

• Myocardial infarction releases LDH from damaged cardiac tissue 2
• Liver disease of various etiologies elevates LDH, though this finding is nonspecific 1, 2
• Kidney disease contributes to elevated LDH levels 1, 2
• Muscle damage from strenuous exercise or rhabdomyolysis temporarily elevates LDH 1, 2

Infectious and Inflammatory Causes

• Infections are strongly associated with very high isolated LDH (≥800 IU/mL), occurring in 57% versus 28% in controls 5
• Sepsis and septic shock can elevate lactate levels accompanied by LDH elevation 2

Pleural and Peritoneal 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

Pregnancy-Related and Iatrogenic Causes

• Preeclampsia causes LDH elevation requiring evaluation for underlying pathological processes 1, 2
• Tumor lysis syndrome occurs spontaneously or after treatment with corticosteroids, monoclonal antibodies, or chemotherapeutic agents, particularly in high tumor burden malignancies 1, 2
• 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—this must be excluded before clinical interpretation 1, 2

Clinical Significance by Degree of Elevation

Mild Elevation (<5× Upper Limit Normal)

• Most commonly associated with benign causes including liver disease, hemolysis, myocardial infarction, kidney disease, muscle damage, and infections 1, 2

Moderate to Marked Elevation (5-10× Upper Limit Normal)

• Can occur in both benign and malignant conditions 7
• In one series, 60% of cases with LDH >1236 IU/L were benign, 36% malignant, and 5% undetermined 7

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 7
• Does not reliably differentiate benign from malignant disease (11 benign cases versus 4 malignant cases in one series) 7

Critical Diagnostic Pitfalls

• LDH elevation alone cannot differentiate benign from malignant disease—there is no significant difference in average LDH values between benign (2708 IU/L) and malignant (2842 IU/L) etiologies 7
• Clinical context is essential: LDH must be interpreted alongside other clinical and laboratory findings, as 43 different etiologies can elevate LDH 2, 7
• Very high isolated LDH (≥800 IU/mL without concomitant ALT/AST elevation) warrants thorough investigation for metastatic cancer, hematologic malignancies, and infection, as it is an independent predictor of mortality 5