What does elevated Lactate Dehydrogenase (LDH) mean?

What Does High LDH Mean?

Elevated LDH is a nonspecific marker of tissue damage or cell turnover that requires clinical context for interpretation—it can indicate malignancy (particularly hematologic cancers, metastatic disease, or testicular cancer), hemolysis, tissue ischemia, liver disease, myocardial infarction, or simply strenuous exercise. 1

Understanding LDH Elevation by Degree

The magnitude of LDH elevation provides important diagnostic clues:

• Mild elevation (<5× upper limit of normal): Most commonly associated with benign causes and warrants basic workup 1
• Moderate elevation (5-10× normal): Raises concern for malignancy, significant hemolysis, or organ injury
• Very high elevation (≥800 IU/mL or >10× normal): Strongly associated with severe disease including metastatic cancer (27% of cases), hematologic malignancies (5%), liver metastases (14%), and serious infections (57%), with in-hospital mortality reaching 26.6% 2

Primary Diagnostic Categories to Consider

Malignancy (Most Important in High Elevations)

In cancer patients, elevated LDH indicates aggressive disease, high tumor burden, and worse prognosis across multiple cancer types. 1

• Testicular germ cell tumors: LDH >2.5× upper limit of normal defines poor prognosis with 3-year progression-free survival of 75-80% versus 92-93% for normal LDH; LDH >10× normal in non-seminomatous tumors indicates 5-year survival of only 67% 1
• Osteosarcoma: Elevated LDH correlates with metastatic disease at presentation, with 5-year disease-free survival of 39.5% versus 60% for normal values 3, 1
• Lymphoma: Can be the earliest and only sign of occult malignant lymphoma, appearing months before clinical manifestations 4
• Melanoma: Incorporated into AJCC staging for stage IV disease as a key prognostic factor 1
• Burkitt's lymphoma and B-cell ALL: Carry highest risk for extreme LDH elevation due to high proliferative rates 1

Hemolysis

The combination of elevated LDH with decreased haptoglobin is specific for hemolysis, though LDH alone is nonspecific. 5

• Confirm with indirect bilirubin elevation, reticulocyte count, direct Coombs test, and peripheral blood smear 5
• Critical caveat: In thrombotic thrombocytopenic purpura (TTP), elevated LDH is NOT primarily from red blood cell destruction—LDH5 (from skeletal muscle and liver) is consistently elevated 1-2 fold due to systemic tissue ischemia, while erythrocyte-derived isoenzymes (LDH1, LDH2) are not disproportionately elevated 6
• Haptoglobin can be decreased in patients with mechanical heart valves without clinically relevant hemolysis 5

Tissue Ischemia and Organ Damage

• Myocardial infarction: Releases cardiac-specific LDH isoenzymes 1
• Liver disease: Causes LDH elevation; review medication history for drug-induced liver injury 1
• Muscle damage: Including from strenuous exercise, which can temporarily elevate LDH 1
• Kidney disease: Contributes to elevated levels 1

Pleural Effusion Differentiation

LDH is essential for distinguishing exudative from transudative effusions using Light's criteria:

• Pleural fluid LDH/serum LDH ratio >0.6 indicates exudate 1
• Pleural fluid LDH >2/3 upper limit of normal serum LDH indicates exudate 1
• Pleural fluid LDH <250 U/L suggests cardiac origin when albumin gradient >1.2 and bilateral effusion present 1

Other Conditions

• Infections: Account for 57% of very high isolated LDH cases 2
• Preeclampsia: Can cause LDH elevation in pregnancy 1
• Tumor lysis syndrome: Tumor burden reflected by LDH is the main predictor; occurs most frequently in hematologic malignancies with high proliferative rates 1
• Secondary peritonitis: Ascitic LDH levels exceed serum LDH levels 1

Clinical Approach Algorithm

Step 1: Assess Clinical Context and LDH Magnitude

• Determine if elevation is mild (<5×), moderate (5-10×), or severe (>10× normal) 1
• Very high isolated LDH (≥800 IU/mL) warrants urgent investigation for malignancy or severe infection 2

Step 2: Rule Out Hemolysis

• Check haptoglobin (decreased), indirect bilirubin (elevated), reticulocyte count, direct Coombs test, and peripheral smear 5
• If anemia with thrombocytopenia present, urgently check ADAMTS13 activity and renal function for TMA 5

Step 3: Evaluate for Malignancy (Priority in High Elevations)

• Known cancer: Use LDH for prognostic stratification per disease-specific guidelines 1
• Suspected testicular cancer: Measure AFP, hCG, and LDH post-orchiectomy and before treatment 1
• Unexplained very high LDH: Perform thorough workup including CT imaging for occult lymphoma or metastatic disease 2, 4

Step 4: Consider Other Organ-Specific Causes

• Liver function tests for hepatic disease 1
• Cardiac markers if myocardial infarction suspected 1
• Pleural fluid analysis if effusion present 1
• Pregnancy testing and blood pressure if preeclampsia possible 1

Step 5: Assess for Preanalytical Error

• Hemolysis of blood sample can falsely elevate LDH 1

Critical Pitfalls to Avoid

• Do not dismiss very high LDH (≥800 IU/mL) as nonspecific—it independently predicts mortality and demands thorough investigation for cancer or severe infection 2
• Do not attribute all LDH elevation in TTP to hemolysis—tissue ischemia is the primary driver 6
• Do not use LDH alone to guide treatment in testicular cancer—it must be interpreted with other tumor markers and clinical factors 1
• Do not overlook occult lymphoma—elevated LDH may be the only early sign, appearing months before clinical manifestations 4
• Do not forget benign causes—strenuous exercise, medications, and minor tissue injury can transiently elevate LDH 1

Prognostic Implications

When LDH is elevated in the context of known malignancy, it consistently indicates:

• Higher tumor burden and more aggressive disease biology 7
• Worse overall survival and progression-free survival across cancer types 3, 1
• Increased risk of metastatic disease 3, 2
• Greater likelihood of major in-hospital complications and mortality in admitted patients 2