What are the causes of elevated lactate dehydrogenase (LDH) levels?

Causes of Elevated Lactate Dehydrogenase (LDH)

Elevated LDH is a non-specific marker of cell damage or increased cellular turnover that can indicate multiple pathological processes including malignancy, hemolysis, tissue injury, or inflammation, and requires further investigation to identify the underlying cause. 1, 2

Common Causes of Elevated LDH

Malignancies

• Hematologic malignancies such as non-Hodgkin's lymphoma, where LDH is included in prognostic indices 2
• Testicular germ cell tumors, where LDH is used as a tumor marker for diagnosis, prognosis, and treatment monitoring 3, 1
• Osteosarcoma, where elevated LDH correlates with metastatic disease and worse prognosis 1
• Melanoma, where LDH is incorporated into AJCC staging for stage IV disease 1
• Plasma cell leukemia, where elevated LDH reflects high tumor burden and aggressive clinical presentation 1

Cardiovascular Conditions

• Myocardial infarction due to cardiac tissue damage 1, 4
• Renal infarction, which can cause strikingly elevated LDH levels with minimal increases in other liver enzymes 5
• Heart failure, particularly in patients with mechanical circulatory support devices where baseline hemolysis occurs 3
• Pump thrombosis in patients with ventricular assist devices, where LDH elevation can occur up to 3 months before clinically significant thrombosis 3

Hematologic Disorders

• Hemolytic anemias of various etiologies 1, 6
• Thrombotic thrombocytopenic purpura (TTP), though the elevation may be due to systemic tissue ischemia rather than hemolysis alone 6

Hepatobiliary Conditions

• Liver disease including hepatitis, cirrhosis, and biliary tract obstruction 3, 4
• Alcohol abuse 3

Other Tissue Damage

• Muscle disease or injury, including strenuous exercise 1, 4, 7
• Tissue hypoxia and ischemia in various organs 6, 4
• Mechanical circulatory support devices causing hemolysis 3

Miscellaneous Causes

• Infections and inflammatory conditions 2, 4
• Marijuana use 3
• Hypogonadism 3
• Preeclampsia 3

Diagnostic Approach

Initial Evaluation

• Complete blood count to assess for cytopenias, leukocytosis, or abnormal cells 2
• Comprehensive metabolic panel including liver and kidney function tests 2
• Peripheral blood smear to look for abnormal cells or red cell morphology 2

Additional Laboratory Tests

• Other markers of hemolysis if suspected: reticulocyte count, haptoglobin, indirect bilirubin 2
• Specific tumor markers based on clinical suspicion (e.g., AFP, hCG for suspected testicular cancer) 3
• LDH isoenzyme analysis can help identify the tissue source of LDH elevation 6, 4

Imaging Studies

• CT scan of neck, chest, abdomen, and pelvis if malignancy is suspected 2
• PET-CT may be useful in selected cases, particularly for lymphoma staging 2

Clinical Significance

Diagnostic Value

• LDH elevation alone has limited diagnostic specificity, with studies identifying up to 43 different etiologies 8
• The degree of elevation does not reliably differentiate between benign and malignant causes 8

Prognostic Value

• LDH elevations greater than 10-fold normal are associated with poor prognosis regardless of etiology, with mortality rates exceeding 50% 8
• In cancer patients, elevated LDH often indicates more aggressive disease and poorer outcomes 1, 2
• In mechanical circulatory support patients, LDH elevation above 2.5 times the upper limit of normal requires evaluation for pump thrombosis 3

Management Approach

• Treatment should be directed at the underlying cause rather than at the LDH elevation itself 2
• Serial LDH measurements can be useful for monitoring disease activity and response to therapy 2, 8

Important Caveats

• LDH elevation in pregnancy: CA-125 can be elevated in normal pregnancy, while LDH typically remains within normal limits unless there is a pathological process 3
• Hemolysis of blood samples can falsely elevate LDH levels 3
• LDH isoenzyme patterns vary between species, which is important to consider in veterinary medicine 4