How should I evaluate a patient with an elevated lactate dehydrogenase (LDH) level?

Evaluation of Elevated Lactate Dehydrogenase (LDH)

Begin by determining the degree of LDH elevation and immediately assess for malignancy, hemolysis, and tissue ischemia—the three most clinically significant causes that drive morbidity and mortality.

Initial Triage by LDH Level

• Mild elevation (<5× upper limit normal) most commonly reflects benign causes including liver disease, hemolysis, myocardial infarction, kidney disease, muscle damage, and infections 1.
• Extreme elevation (>10× upper limit normal) carries a mortality rate of 26.6% versus 4.3% in controls and demands immediate investigation for malignancy, sepsis, or massive tissue injury 2.
• Very high isolated LDH (≥800 IU/L without elevated ALT/AST) is a distinguishing biomarker for metastatic cancer (27% vs. 4% in controls), hematologic malignancies (5% vs. 0%), and severe infection (57% vs. 28%) 2.

Critical First Steps

Rule Out Laboratory Artifact

• Repeat the LDH measurement if the blood sample appears hemolyzed, because in-vitro hemolysis falsely elevates LDH values 1.
• Consider macro-LDH (LDH-immunoglobulin complexes) in asymptomatic patients with persistently elevated LDH and no identifiable pathology 3.

Assess Hepatic Function

• Order ALT, AST, alkaline phosphatase, and total bilirubin when LDH is mildly elevated (≈1.5× ULN) to identify hepatitis, cirrhosis, or biliary obstruction 1.

Evaluate for Hemolysis

• Measure reticulocyte count, haptoglobin, and indirect bilirubin if hemolytic anemia is suspected 1, 4.
• Note that in thrombotic thrombocytopenic purpura (TTP), elevated LDH primarily reflects systemic tissue ischemia rather than intravascular hemolysis; LDH5 (liver/skeletal muscle isoenzyme) is consistently elevated 1-2 fold above normal 5.

Malignancy-Directed Investigation

High-Yield Cancer Screening

• In males with unexplained LDH >1.5× ULN (≈450 U/L), measure serum AFP and β-hCG because LDH at this level carries prognostic significance for testicular germ cell tumors 1.
• Document B symptoms (fever, night sweats, ≥10% weight loss in 6 months), lymphadenopathy in all nodal basins, hepatosplenomegaly, and bone tenderness to identify lymphoma or other hematologic malignancies 4.
• Order complete blood count with differential to assess for cytopenias, leukocytosis, or abnormal cells suggesting hematologic malignancy 4.

Advanced Laboratory Testing When Malignancy Is Suspected

• Measure beta-2 microglobulin if lymphoma or multiple myeloma is suspected 4.
• Perform serum protein electrophoresis (SPEP), urine protein electrophoresis (UPEP), immunofixation, and quantitative immunoglobulins for suspected multiple myeloma 4.
• Obtain peripheral blood smear examination to look for abnormal cells or red cell morphology 4.

Imaging Studies

• Order CT scan of neck, chest, abdomen, and pelvis to evaluate for lymphadenopathy, organomegaly, or masses if malignancy is suspected 4.
• Consider PET-CT in selected cases, particularly for lymphoma staging 4.
• Obtain skeletal survey or MRI of spine and pelvis if multiple myeloma or bone metastases are suspected 4.

Tissue Sampling

• Perform bone marrow aspirate and biopsy with immunohistochemistry, flow cytometry, cytogenetics, and FISH if hematologic malignancy is suspected 4.
• Obtain excisional lymph node biopsy (preferred over core biopsy) if lymphoma is suspected 4.
• If elevated LDH accompanies markedly FDG-avid PET findings, immediately biopsy the most FDG-avid lesion before starting anthracycline-based therapy, as this combination strongly indicates histologic transformation of indolent lymphoma or aggressive malignancy 4.

Disease-Specific Prognostic Applications

Testicular Cancer

• Measure serum AFP, hCG, and LDH shortly after orchiectomy and before any subsequent treatment for risk stratification 1.
• LDH >2.5× ULN defines worse prognosis with 3-year progression-free survival of 75-80% versus 92-93% for good-prognosis group 1.
• Do not use LDH alone to guide treatment decisions in testicular cancer 1.

Osteosarcoma

• Elevated LDH correlates with metastatic disease and 5-year disease-free survival of 39.5% versus 60% with normal values 6, 1.
• Consider elevated LDH in overall prognostic assessment along with surgical remission and histologic response to chemotherapy 6.

Multiple Myeloma

• Measure LDH at initial diagnostic workup to assess tumor cell burden alongside beta-2 microglobulin 6, 1.
• Elevated LDH is incorporated into the Revised International Staging System (R-ISS) for multiple myeloma 6.

Melanoma Stage IV

• Elevated LDH is an independent predictor of poor outcome and is incorporated into AJCC staging for stage IV melanoma 1, 4.

Lymphoma

• Elevated LDH may be an early marker of occult lymphoma even before clinical manifestations 4.
• Rising LDH with disproportionate growth of a single site, new B symptoms, or new extranodal disease should prompt biopsy to rule out transformation 4.
• LDH is included in the Mantle Cell Lymphoma International Prognostic Index (MIPI) as a key prognostic factor 4.

Tumor Lysis Syndrome Risk Assessment

• Tumor burden reflected by serum LDH level is the main predictor for developing tumor lysis syndrome 1.
• In patients with high tumor burden (Burkitt's lymphoma, B-cell ALL, mantle-cell lymphoma), measure serum uric acid to identify risk of spontaneous tumor lysis syndrome 1.
• Tumor lysis syndrome occurs most frequently in hematologic malignancies with high proliferative rates, particularly during cytotoxic therapy 1.

Pleural Effusion Evaluation

• Pleural fluid is exudative if pleural fluid LDH >2/3 the upper limit of normal serum LDH (Light's criteria) 1, 7.
• Pleural fluid LDH/serum LDH ratio >0.6 also defines exudative effusion 1.
• Pleural fluid LDH <250 U/L suggests cardiac origin when other criteria are met (albumin gradient >1.2, bilateral effusion) 1.

Other Important Causes to Consider

Infection and Sepsis

• Sepsis and septic shock can elevate LDH levels; initiate appropriate antimicrobial therapy based on identified pathogen with supportive care 7.

Pregnancy-Related

• Preeclampsia causes LDH elevation and requires evaluation for underlying pathological processes 1, 7.

Device-Related

• In patients with mechanical circulatory support devices, LDH elevation >2.5× upper limit of normal requires evaluation for pump thrombosis 1, 7.

Common Pitfalls to Avoid

• Do not rely on LDH alone to diagnose cancer; combine LDH with disease-specific markers (AFP/β-hCG for testicular cancer, beta-2 microglobulin for multiple myeloma) to improve specificity 1.
• Elevated serum LDH (even >3 standard deviations) is an extremely nonspecific finding that does not contribute to clinical management in the majority of patients 8.
• Clinical context is essential: LDH must be interpreted alongside other clinical and laboratory findings 1, 7.
• If tumor lysis occurs during chemotherapy and LDH rises between day 1 of cycle 1 and day 1 of cycle 2, repeat testing midway through cycle 2 1.