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

Elevated LDH: Causes and Clinical Significance

Elevated LDH is a nonspecific marker of tissue damage or increased cellular turnover that can result from malignancies (particularly hematologic cancers and metastatic solid tumors), hemolysis, tissue infarction (myocardial, pulmonary), liver disease, muscle damage, 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
• In multiple myeloma, LDH should be measured at initial diagnostic workup as it helps assess tumor cell burden. 1
• Elevated LDH may be the only early sign of occult malignant lymphoma, appearing months before clinical manifestations. 3

Solid Tumors

• In testicular germ cell tumors, LDH is used for risk stratification: LDH <1.5× upper limit of normal (ULN) indicates good prognosis, LDH 1.5-10× ULN indicates intermediate prognosis, and LDH >10× ULN defines poor prognosis with 5-year overall survival of only 67%. 1
• In osteosarcoma, elevated serum LDH correlates with metastatic disease and worse prognosis, with 5-year disease-free survival of 39.5% for high LDH versus 60% for 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/L), present in 14% versus 3% of controls. 5

Benign Causes

Hemolysis

• Hemolysis causes LDH elevation in combination with decreased haptoglobin and elevated indirect bilirubin. 2
• Mechanical circulatory support devices cause baseline hemolysis; LDH >2.5× ULN requires evaluation for pump thrombosis. 1, 2
• Laboratory artifact from hemolyzed blood samples can falsely elevate LDH levels. 1, 2

Tissue Damage and Organ Injury

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

Infections and Inflammation

• Infections of various types (including sepsis and septic shock) can cause LDH elevation. 1, 2
• Very high isolated LDH (≥800 IU/L) is a distinguishing biomarker for infection, present in 57% versus 28% of controls. 5

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

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

Iatrogenic Causes

• Tumor lysis syndrome occurs spontaneously or after treatment with corticosteroids, monoclonal antibodies, or chemotherapeutic agents, particularly in high tumor burden malignancies. 1, 2
• Granulocyte or granulocyte-macrophage colony-stimulating factors (G-CSF/GM-CSF) can cause rising LDH during chemotherapy in lymphoma or myeloma patients, which normalizes after CSF discontinuation—this should not be mistaken for disease progression. 6
• 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

Very High Elevation (≥800 IU/L or ≥10× ULN)

• Warrants thorough investigation for severe underlying disease, mostly metastatic cancer (27% vs. 4% in controls), hematologic malignancies (5% vs. 0%), and infection (57% vs. 28%). 5
• Carries poor prognosis with hospitalization in intensive care in 73% of cases and mortality rate of 53%. 5, 7
• Is an independent predictor of mortality in admitted medical patients. 5
• The degree of elevation does not differentiate benign from malignant causes. 7

Critical Diagnostic Pitfalls

• Clinical context is essential: LDH must be interpreted alongside other clinical and laboratory findings. 1, 2
• Do not use LDH alone to guide treatment decisions in testicular cancer, particularly pure seminoma. 1
• Rising LDH during G-CSF/GM-CSF therapy may not indicate disease progression—wait until CSF discontinuation before interpreting. 6
• Tumor lysis during chemotherapy can cause transient LDH elevation; if levels rise between day 1 of cycle 1 and day 1 of cycle 2, repeat testing midway through cycle 2 is recommended. 1
• In patients with unexplained very high isolated LDH, consider abdominal CT scan and thorough investigation for occult malignancy. 3, 5