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

Causes of Elevated Lactate Dehydrogenase (LDH)

Elevated LDH results from tissue damage or increased cellular turnover across a wide spectrum of both benign and malignant conditions, with the degree of elevation and clinical context determining diagnostic significance rather than the LDH level alone. 1

Malignant Causes

Hematologic Malignancies

• Testicular germ cell tumors elevate LDH and use it as a tumor marker for diagnosis, prognosis, and treatment monitoring 1
• Osteosarcoma shows elevated serum LDH that correlates with metastatic disease, with 5-year disease-free survival of only 39.5% versus 60% for normal values 1
• Plasma cell leukemia demonstrates elevated LDH reflecting high tumor burden and aggressive clinical presentation 1
• Multiple myeloma requires LDH measurement at initial workup to assess tumor cell burden 1
• Melanoma (stage IV) incorporates elevated LDH into AJCC staging as a key prognostic factor 1
• Lymphoma can present with elevated LDH (595-615 IU/ml) as the only early sign of occult disease, appearing months before clinical manifestations 2
• Metastatic cancer, particularly liver metastases, strongly associates with very high isolated LDH (≥800 IU/ml), occurring in 14% of such cases versus 3% in controls 3

Solid Tumors

• Cancer of unknown primary (CUP) uses LDH in a two-factor prognostic score combined with ECOG performance status 1

Benign Causes

Cardiovascular Conditions

• Myocardial infarction causes LDH elevation due to cardiac muscle damage 1
• Heart failure, particularly in patients with mechanical circulatory support devices where baseline hemolysis occurs 1
• Pump thrombosis in mechanical circulatory support requires evaluation when LDH exceeds 2.5 times the upper limit of normal 1

Hematologic Conditions

• Hemolysis from any cause elevates LDH due to red blood cell destruction 1
• Thrombotic thrombocytopenic purpura (TTP) characteristically elevates LDH, though primarily from systemic tissue ischemia rather than hemolysis alone, with LDH5 (liver/skeletal muscle isoenzyme) consistently elevated 1-2 fold 4
• Blood transfusions can transiently elevate LDH levels 5

Hepatic and Renal Disease

• Liver disease of various etiologies causes LDH elevation 1
• Kidney disease contributes to elevated LDH 1
• Drug-induced liver injury is an uncommon cause of mild aminotransferase and LDH elevation 1

Infectious Causes

• Infections account for 57% of cases with very high isolated LDH (≥800 IU/ml) versus 28% in controls 3

Obstetric Conditions

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

Musculoskeletal Causes

• Strenuous exercise temporarily elevates LDH due to muscle damage 1
• Muscle disease of any etiology increases LDH from skeletal muscle breakdown 1

Other Causes

• Tumor lysis during chemotherapy causes transient LDH elevation 1
• Radiotherapy can influence LDH levels 5
• Growth factors used in treatment may affect LDH measurements 5

Clinical Interpretation by Degree of Elevation

Mild Elevation (<5× Upper Limit Normal)

• Most commonly associated with benign causes and warrants review of medication history 1
• Accounts for 45% of cases with LDH 2-3 fold normal and 47.5% with 3-10 fold elevation 5

Severe Elevation (>10× Upper Limit Normal)

• Carries high mortality rate exceeding 50% and represents a pejorative predictive criterion 1, 5
• Occurs in only 7.5% of cases but does NOT reliably differentiate benign from malignant disease (11 benign cases versus 4 malignant cases in one series) 5
• Associated with intensive care unit admission in 73% of cases 5

Very High Isolated LDH (≥800 IU/ml)

• Strongly suggests cancer (27% versus 4% in controls), liver metastases (14% versus 3%), hematologic malignancies (5% versus 0%), or infection (57% versus 28%) 3
• Predicts more admission days (9.3 versus 4.1), significantly more in-hospital major complications, and serves as an independent predictor of mortality (26.6% versus 4.3%) 3

Special Diagnostic Contexts

Pleural Effusion

• LDH is a key component of Light's criteria for distinguishing exudative from transudative effusions 1
• Pleural fluid is exudative if pleural fluid LDH/serum LDH >0.6, or if pleural fluid LDH >2/3 the upper limits of normal for serum LDH 1

Ascites

• Secondary peritonitis from perforated viscus shows ascitic LDH levels higher than serum LDH levels 1

Critical Pitfalls to Avoid

• Pre-analytical error: Hemolysis of blood samples can falsely elevate LDH levels 1
• Lack of specificity: The diagnostic value of LDH depends entirely on clinical context and must be interpreted alongside other clinical and laboratory findings 1
• Timing of measurement: During cancer follow-up, LDH determinations must be performed remote from treatments like chemotherapy, radiotherapy, blood transfusions, and growth factors to accurately reflect disease evolution 5
• Over-reliance on LDH alone: In testicular cancer, patients should NOT be treated based on elevated LDH alone 1
• Benign versus malignant: There is no difference in average LDH values between benign (2708 IU/L) and malignant (2842 IU/L) etiologies, with 43 different etiologies capable of elevating LDH 5