What does a high lactate dehydrogenase (LDH) level indicate?

What Does High LDH Mean?

High lactate dehydrogenase (LDH) is a nonspecific marker of tissue damage or increased cellular turnover that can indicate serious conditions ranging from malignancies (especially hematologic cancers, testicular tumors, and osteosarcoma) to hemolysis, organ damage (liver, heart, kidney, muscle), infections, and pleural/peritoneal fluid disorders—requiring clinical context and additional testing to determine the underlying cause. 1, 2

Understanding LDH Elevation by Degree

The magnitude of LDH elevation provides important prognostic information:

• Mild elevation (<5× upper limit of normal): Most commonly associated with benign causes including liver disease, hemolysis, myocardial infarction, kidney disease, muscle damage from exercise, and infections 1, 2
• Moderate elevation (2-10× normal): Can be either benign or malignant; does not reliably distinguish between the two 3
• Extreme elevation (>10× normal): Carries a poor prognosis with hospitalization in intensive care required in 73% of cases and mortality rate of 53%, regardless of whether the underlying cause is benign or malignant 1, 4, 3

Major Categories of Causes

Malignancies (Most Important to Rule Out)

Hematologic malignancies are among the most common causes of marked LDH elevation, particularly those with high proliferative rates like Burkitt's lymphoma, B-cell acute lymphoblastic leukemia, and other non-Hodgkin's lymphomas 1, 2. Very high isolated LDH (≥800 IU/mL) is a distinguishing biomarker for cancer presence (27% vs. 4% in controls) and hematologic malignancies specifically (5% vs. 0% in controls) 4.

Testicular germ cell tumors use LDH as a critical tumor marker for diagnosis, prognosis, and treatment monitoring 5, 1. LDH is measured post-orchiectomy and before chemotherapy for risk stratification, with LDH >2.5× upper limit of normal defining worse prognosis (3-year progression-free survival of 75-80% vs. 92-93% for good-prognosis group) 1, 2. In males with unexplained LDH >1.5× upper limit of normal, serum AFP and β-hCG testing should be included 1.

Osteosarcoma patients with elevated LDH have significantly worse outcomes, with 5-year disease-free survival of 39.5% versus 60% for those with normal values, and elevated LDH correlates with metastatic disease at presentation 5, 1.

Metastatic solid tumors frequently elevate LDH, with very high isolated LDH indicating liver metastases in 14% vs. 3% of controls 4. In stage IV melanoma, elevated LDH is an independent predictor of poor outcome and has been incorporated into AJCC staging 1.

Tissue Damage and Hemolysis

Hemolysis causes LDH elevation in combination with decreased haptoglobin and elevated indirect bilirubin 2, 6. This combination of thrombocytopenia, elevated LDH, and decreased haptoglobin is specific for hemolysis and defines thrombotic microangiopathy (TMA) when renal involvement is present 6. In-vitro hemolysis from blood sample handling can falsely elevate LDH and requires repeat testing 1, 2.

Myocardial infarction releases LDH from damaged cardiac tissue 2, 7. Liver disease of various etiologies elevates LDH nonspecifically 2. Muscle damage from strenuous exercise or rhabdomyolysis temporarily elevates LDH 5, 2. Kidney disease contributes to elevated levels 2.

Infections and Inflammation

Infections are a major cause, with very high isolated LDH indicating infection in 57% vs. 28% of controls 4. Sepsis and septic shock can elevate LDH in critically ill patients 2. In pediatric COVID-19, increased LDH levels are typical markers of systemic inflammation in multisystem inflammatory syndrome in children (MIS-C) 5.

Pleural and Peritoneal Fluid Disorders

Exudative pleural effusions show pleural fluid LDH >2/3 the upper limit of normal serum LDH (or >67% of upper limit normal) or pleural fluid LDH/serum LDH ratio >0.6 by Light's criteria 1, 2, 8. Pleural fluid LDH <250 U/L suggests cardiac origin when other criteria are met 1.

Secondary peritonitis from perforated viscus shows ascitic LDH levels higher than serum LDH levels 1, 2.

Pregnancy-Related and Device-Related Causes

Preeclampsia causes LDH elevation requiring evaluation for underlying pathological processes 2. Mechanical circulatory support devices cause baseline hemolysis; LDH >2.5× upper limit of normal requires evaluation for pump thrombosis 2.

Tumor lysis syndrome occurs spontaneously or after treatment with corticosteroids, monoclonal antibodies, or chemotherapeutic agents, particularly in high tumor burden malignancies, with tumor burden reflected by serum LDH being the main predictor 1, 2.

Diagnostic Approach Algorithm

1. Assess the degree of elevation and clinical context 1, 2
2. When LDH is mildly elevated (≈1.5× upper limit of normal), order ALT, AST, alkaline phosphatase, and total bilirubin to identify hepatitis, cirrhosis, or biliary obstruction 1
3. Repeat LDH measurement if the blood sample appears hemolyzed to exclude laboratory artifact 1, 2
4. In males with unexplained LDH >1.5× upper limit of normal, include serum AFP and β-hCG testing for testicular tumors 1
5. Check for hemolysis by measuring haptoglobin and indirect bilirubin, especially if thrombocytopenia is present 6
6. Consider imaging (chest and abdomen CT scan) for suspected neoplasm 2
7. Do not rely on LDH alone; combine with disease-specific markers to improve specificity 1

Prognostic Significance

Very high isolated LDH is an independent predictor of mortality in hospitalized medical patients (26.6% vs. 4.3% mortality in controls), associated with more admission days (9.3 vs. 4.1 days) and significantly more in-hospital major complications 4. In cancer patients, elevated LDH often indicates more aggressive disease and poorer prognosis 1.

Critical Pitfalls to Avoid

• Never use LDH elevation alone to diagnose cancer; it requires clinical context and additional testing 1, 2, 7
• Do not assume extreme elevation (>10× normal) means malignancy; benign causes occurred in 11 of 15 cases in one study, though prognosis remains poor regardless 3
• Always consider laboratory artifact from hemolyzed samples before pursuing extensive workup 1, 2
• In testicular cancer follow-up, do not use LDH concentrations alone to guide treatment decisions for pure seminoma 1