What is the likely cause of elevated Lactate Dehydrogenase (LDH)?

Elevated LDH: Differential Diagnosis and Clinical Approach

Elevated LDH is a nonspecific marker of tissue damage or increased cellular turnover that requires systematic evaluation based on the degree of elevation and clinical context, with hematologic malignancies, solid tumors, hemolysis, tissue infarction, and infections representing the most common etiologies. 1

Categorization by Degree of Elevation

Mild Elevation (<5× Upper Limit Normal)

• Benign causes predominate in mild LDH elevations, including liver disease, hemolysis, myocardial infarction, kidney disease, muscle damage from exercise or rhabdomyolysis, and various infections 1, 2
• Drug-induced liver injury represents an uncommon cause of mild aminotransferase and LDH elevation 1
• Laboratory artifact from hemolyzed blood samples can falsely elevate LDH levels 1, 2

Moderate Elevation (5-10× Upper Limit Normal)

• Both benign and malignant etiologies occur with similar frequency at this level 3
• Average LDH values do not distinguish between benign (2708 IU/L) versus malignant (2842 IU/L) causes 3

Extreme Elevation (>10× Upper Limit Normal)

• Carries a poor prognosis regardless of etiology, with 73% requiring intensive care admission and 53% mortality rate 1, 3
• Benign causes still account for the majority (11 of 15 cases) even at this extreme level 3
• Hematologic malignancies with high proliferative rates—particularly Burkitt's lymphoma and B-cell acute lymphoblastic leukemia—represent the highest risk for extreme elevations 2

Primary Diagnostic Categories

Hematologic Malignancies

• Primary plasma cell leukemia demonstrates markedly elevated LDH (>3× normal), reflecting high tumor burden and aggressive disease 4
• Patients with multiple myeloma who develop secondary plasma cell leukemia more frequently show increased LDH at diagnosis, suggesting origin from an ancestral high-risk clone 4
• Occult malignant lymphoma can present with isolated LDH elevation (595-615 IU/mL) as the only early sign, with predominance of LDH isoenzymes 2 and 3, appearing months before clinical manifestations 5
• LDH measurement is required at initial diagnostic workup for multiple myeloma to assess tumor cell burden 2

Solid Tumors

• Osteosarcoma patients with elevated serum alkaline phosphatase or LDH demonstrate adverse outcomes, with 5-year disease-free survival of 39.5% versus 60% for normal values 4, 2
• Elevated LDH correlates with proximal extremity or axial tumor site, large tumor volume, and detectable primary metastases in osteosarcoma 4
• Testicular germ cell tumors utilize LDH for risk stratification: good prognosis requires LDH <2.5× upper limit normal, while LDH >10× normal defines poor prognosis with 5-year overall survival of only 67% 2
• Bulky small cell lung cancer and metastatic germ cell carcinoma represent high-risk solid tumors for marked LDH elevation 2

Hemolysis

• The combination of elevated LDH with decreased haptoglobin is specific for hemolysis, distinguishing it from other causes of LDH elevation such as liver disease, myocardial infarction, or muscle damage 6
• Indirect bilirubin should be elevated in hemolysis; reticulocyte count, direct Coombs test, and peripheral blood smear are necessary for differentiation 6
• Mechanical circulatory support devices cause baseline hemolysis with LDH elevation; levels >2.5× upper limit normal require urgent evaluation for pump thrombosis 1, 2

Tissue Infarction and Organ Damage

• Myocardial infarction releases LDH from damaged cardiac tissue 1
• Liver disease of various etiologies elevates LDH nonspecifically 1
• Kidney disease contributes to elevated LDH in patients with renal impairment 1

Infection and Critical Illness

• Sepsis and septic shock elevate lactate levels, often accompanied by LDH elevation in critically ill patients 1
• Very high isolated LDH (≥800 IU/mL) is a distinguishing biomarker for infection (57% vs 28% in controls, P<0.0001) 7

Pleural and Peritoneal Fluid Disorders

• Exudative pleural effusions demonstrate pleural fluid LDH >2/3 the upper limit of normal serum LDH OR pleural fluid LDH/serum LDH ratio >0.6 by Light's criteria 1, 2
• Pleural fluid LDH <250 U/L suggests cardiac origin when albumin gradient >1.2 and bilateral effusion are present 2
• Secondary peritonitis from perforated viscus shows ascitic LDH levels higher than serum LDH levels 1, 2

Pregnancy-Related Causes

• Preeclampsia causes LDH elevation and requires evaluation for underlying pathological processes including HELLP syndrome 1, 2

Iatrogenic Causes

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

Diagnostic Algorithm

Step 1: Assess Clinical Context

• Review medication history for drug-induced liver injury or hemolytic agents 1, 6
• Evaluate for pregnancy and preeclampsia in women of childbearing age 1
• Assess for recent chemotherapy or high tumor burden malignancies suggesting tumor lysis syndrome 2

Step 2: Confirm True Elevation

• Exclude laboratory artifact by checking for hemolyzed sample 1, 2
• Repeat testing if hemolysis suspected 1

Step 3: Evaluate for Hemolysis

• Measure haptoglobin (decreased), indirect bilirubin (elevated), reticulocyte count, direct Coombs test, and examine peripheral blood smear 6
• In patients with anemia and thrombocytopenia, urgently determine ADAMTS13 activity and check renal function to evaluate for thrombotic microangiopathy 6
• Review for mechanical heart valves or circulatory support devices 6

Step 4: Assess for Malignancy

• Very high isolated LDH (≥800 IU/mL) warrants investigation for metastatic cancer (27% vs 4% in controls), liver metastases (14% vs 3%), and hematologic malignancies (5% vs 0%) 7
• Consider abdominal CT scan and thorough evaluation when no apparent cause exists for elevated LDH 5
• Measure LDH at initial diagnostic workup for suspected multiple myeloma 2

Step 5: Evaluate Organ-Specific Causes

• Assess liver function tests, cardiac biomarkers, renal function, and creatine kinase based on clinical presentation 1
• For pleural effusions, apply Light's criteria using pleural fluid and serum LDH measurements 1, 2
• For ascites with suspected peritonitis, compare ascitic fluid LDH to serum LDH 1

Critical Pitfalls to Avoid

• Do not use LDH elevation alone to distinguish benign from malignant disease, as average values are similar (2708 vs 2842 IU/L) and 43 different etiologies can cause elevation 3
• Do not dismiss extreme LDH elevation (>10× normal) as benign without thorough investigation, despite benign causes being more common, given the 53% mortality rate 3
• Clinical context is essential—LDH must be interpreted alongside other clinical and laboratory findings, never in isolation 1, 2
• In cancer follow-up, measure LDH at distance from treatments (blood transfusions, growth factors, radiotherapy, chemotherapy) as these can transiently affect levels 3
• Haptoglobin can be decreased in patients with mechanical heart valves without clinically relevant hemolysis 6
• Schizocytes may be absent in early thrombotic microangiopathy 6