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

Causes of Elevated Lactate Dehydrogenase (LDH)

Elevated LDH reflects tissue damage, increased cellular turnover, or high tumor burden across a wide spectrum of benign and malignant conditions, with the degree of elevation and clinical context determining diagnostic and prognostic significance. 1

Malignant Causes

Hematologic Malignancies

• Burkitt's lymphoma and B-cell acute lymphoblastic leukemia (ALL) 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
• Multiple myeloma with high LDH levels (>500 U/L) defines a "high-grade lymphoma-like myeloma" with extraosseous disease features and aggressive clinical course 2
• Plasma cell leukemia shows elevated LDH reflecting high tumor burden and aggressive presentation 1
• Occult malignant lymphoma may present with isolated LDH elevation (595-615 U/L) as the only early sign, appearing months before clinical manifestations 3

Solid Tumors

• Osteosarcoma with elevated LDH correlates with metastatic disease at presentation, with 5-year disease-free survival of 39.5% versus 60% for normal values 4, 1
• Testicular germ cell tumors use LDH for risk stratification: LDH >2.5× upper limit of normal (ULN) defines worse prognosis (3-year progression-free survival 75-80% versus 92-93%), and LDH >10× ULN indicates poor prognosis with 5-year overall survival of only 67% 1
• Bulky small cell lung cancer and metastatic germ cell carcinoma are high-risk solid tumors for marked LDH elevation 1
• Stage IV melanoma incorporates elevated LDH into AJCC staging as a key prognostic factor 1
• Liver metastases from any cancer strongly associate with elevated LDH (14% of very high LDH cases versus 3% in controls) 5

Benign Causes

Tissue Damage and Hemolysis

• Hemolysis is a common benign cause, including mechanical hemolysis in patients with circulatory support devices where baseline elevation occurs 1
• Hemolysis of blood samples can falsely elevate LDH levels 1
• Myocardial infarction causes LDH elevation due to cardiac tissue damage 1
• Strenuous exercise temporarily elevates LDH due to muscle damage 1

Organ-Specific Diseases

• Liver disease of various etiologies elevates LDH 1
• Kidney disease contributes to elevated levels 1
• Heart failure, particularly in mechanical circulatory support patients, causes elevation; levels >2.5× ULN require evaluation for pump thrombosis 1
• Preeclampsia in pregnancy causes LDH elevation and requires evaluation for underlying pathology 1

Infections

• Infections account for 57% of very high isolated LDH cases (≥800 IU/mL) versus 28% in controls 5
• Various infectious processes cause tissue damage leading to LDH release 1

Pleural and Peritoneal Fluid Disorders

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

Clinical Interpretation by Degree of Elevation

Mild Elevation (<5× ULN)

• Most commonly associated with benign causes 1
• Review medication history for drug-induced liver injury 1
• Benign etiologies account for 60% of cases with LDH >2-fold normal 6

Moderate to Severe Elevation (5-10× ULN)

• No reliable differentiation between benign and malignant causes based on absolute value alone 6
• Requires clinical context for interpretation 1

Very High Elevation (>10× ULN)

• Carries a pejorative prognosis with 73% ICU admission rate and 53% mortality, regardless of benign or malignant etiology 6
• Found in both benign (11 cases) and malignant (4 cases) diseases in one series 6
• Very high isolated LDH (≥800 IU/mL) is an independent predictor of mortality in hospitalized medical patients 5

Diagnostic Approach Algorithm

Step 1: Assess clinical context and degree of elevation

• Mild elevation: Consider benign causes first (hemolysis, liver disease, muscle damage, infection) 1
• Very high elevation (>800 IU/mL): Investigate for cancer (27% prevalence), liver metastases (14%), hematologic malignancies (5%), and infection (57%) 5

Step 2: Rule out artifactual elevation

• Exclude hemolyzed blood sample 1
• Consider recent strenuous exercise 1

Step 3: Evaluate for malignancy in appropriate contexts

• Measure tumor-specific markers (AFP, hCG in testicular cancer; beta-2 microglobulin in myeloma) 1
• Consider imaging (CT scan) for occult lymphoma if no apparent cause identified 3
• In known cancer patients, use LDH for prognostic stratification per disease-specific guidelines 1

Step 4: Monitor for tumor lysis syndrome in high-risk patients

• Tumor burden reflected by serum LDH is the main predictor for developing tumor lysis syndrome 1
• If LDH rises between day 1 of cycle 1 and day 1 of cycle 2 of chemotherapy, repeat testing midway through cycle 2 1

Critical Prognostic Considerations

• Very high isolated LDH (≥800 IU/mL) warrants thorough investigation as it associates with 26.6% mortality versus 4.3% in controls, more admission days (9.3 versus 4.1), and significantly more in-hospital major complications 5
• In cancer follow-up, LDH normalization indicates effective treatment, while elevation suggests therapeutic failure, provided measurements are obtained remote from treatments that independently affect LDH (transfusions, growth factors, radiotherapy, chemotherapy) 6
• Do NOT use LDH concentrations alone to guide treatment decisions, particularly in pure seminoma 1