Causes of Elevated Lactate Dehydrogenase (LDH)
Elevated LDH is a nonspecific marker of tissue damage or increased cellular turnover that can arise from both benign and malignant conditions, with the degree of elevation and clinical context determining its significance.
Malignant Causes
Hematologic Malignancies
- Plasma cell leukemia shows elevated LDH reflecting high tumor burden and aggressive clinical presentation 1
- Testicular germ cell tumors cause LDH elevation used for diagnosis, prognosis, and treatment monitoring, with levels >2.5× upper limit of normal (ULN) defining worse prognosis 1
- Osteosarcoma with elevated LDH correlates with metastatic disease and significantly worse outcomes (5-year disease-free survival 39.5% vs 60% for normal values) 1
- Stage IV melanoma incorporates elevated LDH into AJCC staging as a key prognostic factor 1
- Multiple myeloma shows elevated LDH indicating tumor cell burden 1
Solid Tumors
- Breast and gynecological malignancies demonstrate significantly elevated serum LDH, particularly in endometrial adenocarcinoma (349 ± 100 IU/L) and ovarian cystadenocarcinomas (383 ± 116 IU/L) compared to healthy controls (256 ± 68 IU/L) 2
- Cancer of unknown primary uses LDH in prognostic scoring, with elevated LDH defining poor prognosis 1
Benign Causes
Cardiovascular Conditions
- Heart failure, particularly in patients with mechanical circulatory support devices where baseline hemolysis occurs 1
- Myocardial infarction causes LDH elevation due to cardiac tissue damage 1
- Idiopathic pulmonary arterial hypertension with right heart failure shows elevated LDH correlating with severity and mortality (69.8% mortality in patients with LDH ≥250 IU/L vs 16.7% with LDH <250 IU/L) 3
Hepatic and Gastrointestinal Disorders
- Liver disease of various etiologies causes LDH elevation 1
- Secondary peritonitis from perforated viscus shows ascitic LDH levels higher than serum LDH 1
Hematologic Conditions
- Hemolysis from any cause elevates LDH, though in thrombotic thrombocytopenic purpura (TTP), the elevation primarily reflects systemic tissue ischemia rather than red blood cell destruction alone 4
Renal and Muscular Disorders
- Kidney disease contributes to LDH elevation 1
- Skeletal muscle damage, including from strenuous exercise, temporarily elevates LDH 1
- In TTP patients, LDH5 (the isoenzyme from skeletal muscle and liver) is consistently 1-2 fold greater than normal, suggesting systemic ischemic tissue damage 4
Obstetric Complications
- Preeclampsia causes elevated LDH requiring evaluation for underlying pathology 1
Infectious Causes
- Various infections can elevate LDH levels 1
Diagnostic Approach by Degree of Elevation
Mild Elevation (<5× ULN)
- Most commonly associated with benign causes 1
- Requires correlation with clinical context and other laboratory findings 1
Moderate Elevation (5-10× ULN)
- Can occur in both benign (60%) and malignant (36%) conditions with no significant difference in average LDH values between etiologies (2708 vs 2842 IU/L) 5
Severe Elevation (>10× ULN)
- Carries high mortality rate of 53% with 73% requiring intensive care 5
- Occurs in both benign (11 cases) and malignant (4 cases) diseases, making it a poor discriminator of etiology but an important prognostic marker 5
Clinical Pitfalls and Caveats
Pre-analytical Factors
- Hemolysis of blood samples can falsely elevate LDH levels 1
- Tumor lysis during chemotherapy causes transient LDH elevation; if levels rise between day 1 of cycle 1 and day 1 of cycle 2, repeat testing midway through cycle 2 1
Interpretation Limitations
- LDH elevation alone cannot differentiate benign from malignant disease regardless of the degree of elevation 5
- The diagnostic value depends entirely on clinical context and must be interpreted alongside other findings 1
- Benign conditions including fibroadenomas and ovarian cystadenomas can show LDH levels close to those seen in carcinomas 2