Medical Biology & Hematology & Oncology & Family Medicine
LDH — lactate dehydrogenase
Lactate dehydrogenase (LDH — EC 1.1.1.27) is a ubiquitous intracellular enzyme that catalyzes the reversible reaction between pyruvate and lactate in anaerobic glycolysis: Pyruvate + NADH + H⁺ ⇌ Lactate + NAD⁺. Present in the cytoplasm of virtually all cells in the body — at intracellular concentrations 500 to 1,000 times higher than those in serum — its blood level directly reflects cellular lysis or necrosis: any significant cell destruction releases LDH into the bloodstream, causing a serum elevation. Due to this cellular ubiquity, LDH is a highly sensitive but poorly specific marker of cellular distress — a large number of different pathologies can cause its elevation. Its clinical value lies in its interpretation combined with the clinical context and other biological markers. LDH exists in five isoenzymes (LDH-1 to LDH-5) composed of combinations of two subunits — H (heart) and M (muscle) — whose specific tissue distribution theoretically allows for localization to the affected organ: LDH-1 (H₄) predominant in the heart and erythrocytes + LDH-5 (M₄) predominant in the liver and skeletal muscles. In clinical practice, however, isoenzyme measurement is rarely necessary — the clinical context + other biological markers (troponin + AST + haptoglobin + bilirubin) are more informative. The reference range for total LDH varies depending on the laboratory and the enzymatic method used — typically 120–240 U/L (adult) — and should always be interpreted according to the reference ranges of the performing laboratory.
Biochemistry, Isoenzymes, and Reference Values
- Biochemistry of LDH, Isoenzymes, and Tissue Distribution: Structure and biochemistry: LDH is a tetramer composed of 4 subunits, H (heart) and/or M (muscle) → 5 isoenzymes depending on the combination: LDH-1 (H₄): predominant in the heart + erythrocytes + kidney cortex → LDH-2 (H₃M₁): predominant in the heart + erythrocytes + lungs → LDH-3 (H₂M₂): predominant in the lungs + spleen → LDH-4 (H₁M₃): predominant in the liver + skeletal muscles → LDH-5 (M₄): predominant in the liver + skeletal muscles → in normal serum: LDH-2 > LDH-1 > LDH-3 > LDH-4 > LDH-5 → reversal of the LDH-1/LDH-2 ratio (LDH-1 > LDH-2): historically suggestive of myocardial infarction — but replaced by troponin → reference values for total LDH: adult: 120–240 U/L (values vary by method — IFCC 37°C vs. Wroblewski) → higher values in children, adolescents, and pregnant women → IMPORTANT: in vitro hemolysis (hemolyzed tube) → massive release of LDH from erythrocytes → false, very high results → ALWAYS check for absence of hemolysis in the sample + intense physical exercise → release of muscle LDH → transient elevation → DO NOT collect blood immediately after exertion + half-life: approximately 24 hours (LDH-1) to 10 hours (LDH-5) → useful for assessing the timing of tissue damage + analytical interferences: hemolysis ++ (erythrocytes contain large amounts of LDH) + thrombocytosis → platelet lysis → artifactual elevations
- Clinical indications for LDH testing and interpretation strategy: LDH dosage indications: tumor burden and prognostic marker in hematologic malignancies: LDH is a component of the IPI (International Prognostic Index) for DLBCL + the FLIPI for follicular lymphoma + monitoring marker in Burkitt lymphoma + leukemias → hemolysis marker: hemolytic anemia → very high LDH (release from lysed erythrocytes) → in association with elevated indirect bilirubin + decreased haptoglobin + Coombs test → tissue necrosis marker: myocardial infarction (replaced by troponin + BNP in current practice) + rhabdomyolysis + pulmonary embolism (modest increase in severe PE) + cerebral infarction + mesenteric ischemia + liver damage marker: viral hepatitis + drug-induced hepatitis + ischemic hepatitis (shock) → very high LDH in ischemic hepatitis (sometimes > 5,000 U/L) → associated with very high transaminases → cell lysis marker in severe infections: Pneumocystis pneumonia (PCP) caused by Pneumocystis jirovecii in immunocompromised individuals — very high LDH (>300–400 U/L) → suggestive but not specific → severe COVID-19 → sepsis → marker in solid tumors: melanoma + renal cell carcinoma + testicular cancer (NSGCT — non-seminomatous germ cell tumors) + germ cell tumors + monitoring marker + interpretation strategy for elevated LDH: elevated LDH is never interpreted alone → clinical context is essential → elevated LDH suggests cell lysis but does not always specify the source tissue → isoenzymes are rarely needed in practice → associated markers guide diagnosis: decreased haptoglobin + elevated LDH + indirect bilirubin = hemolysis → elevated troponin + elevated LDH-1 = MI (rarely done today) → very high AST/ALT + very high LDH = acute ischemic or viral hepatitis → CBC + blood smear + β2-microglobulin + very high LDH = hematologic malignancy
Main causes of elevation and clinical interpretation
| Cause/Situation | Mechanism, elevation level, and supplementary balance | References and recommendations |
|---|---|---|
| Elevated LDH — Malignant blood disorders and solid tumors DLBCL lymphoma IPI — Burkitt lymphoma tumor lysis syndrome — LDH tumor mass — melanoma — renal cell carcinoma — germ cell tumors — β2-microglobulin — treatment monitoring — very high LDH tumor lysis syndrome |
LDH and Hematologic Malignancies - Prognostic and Diagnostic Value: Hematologic Malignancies: LDH reflects tumor burden and tumor cell proliferation → its value is integrated into prognostic scores: IPI (International Prognostic Index) for DLBCL (Diffuse Large B-cell Lymphoma): elevated LDH (> laboratory normal value) = 1 point → IPI 0–5 → prognosis → Shipp 1993 — NEJM: IPI + DLBCL → reference + FLIPI (Follicular Lymphoma International Prognostic Index): elevated LDH = 1 point + Burkitt lymphoma: massively elevated LDH (often >10x normal) → marker of tumor activity + risk of tumor lysis syndrome (TLS) → acute leukemias (AML + ALL): very high LDH → correlation with blast count → tumor lysis syndrome (TLS): urgent oncological complication during treatment of hematologic malignancies with high tumor burden → massive release of LDH + uric acid + potassium + phosphate during rapid destruction of tumor cells → LDH can reach >5x normal → metabolic emergency → prophylaxis with allopurinol or rasburicase + hyperhydration → solid tumors: metastatic melanoma: elevated LDH → poor prognosis → integrated into melanoma TNM classification → American Joint Committee on Cancer (AJCC) 2017: stage IV + elevated LDH = stage M1d (worst) → renal carcinoma: elevated LDH in metastatic forms + integrated into MSKCC and IMDC scores for targeted therapies + immunotherapy → non-seminomatous germ cell tumors (NSGCT): elevated LDH = tumor marker → integrated into IGCCCG classification + hepatocellular carcinoma + lung tumors + pancreatic tumors → workup if very high LDH without obvious cause: CBC + smear + β2-microglobulin + ferritin + serum uric acid + CT-TAP + PET-CT → hemato-oncology consultation | Shipp 1993 - NEJM: IPI + DLBCL → LDH prognostic value → reference + Solal-Celigny 2004 - Blood: FLIPI + follicular LH + LDH → reference FLIPI + Cairo 2004 - British Journal of Haematology: tumor lysis syndrome + definition + treatment + AJCC 2017: melanoma + TNM + LDH stage M1d + Motzer 1999 - Journal of Clinical Oncology: renal cell carcinoma + MSKCC + LDH → reference + IGCCCG 1997 - Journal of Clinical Oncology: germ cell tumors + LDH + classification + Cheson 2014 - JCO (Lugano): lymphomas + LDH + PET-CT + AHOQ: LDH + hemopathies + RAMQ: LDH + β2-microglobulin + uremia → reimbursed |
| Elevated LDH - hemolysis, ischemia, and infections Hemolytic anemia — low haptoglobin — indirect bilirubin — Coombs — TTP-HUS — ischemic hepatitis — rhabdomyolysis — CK — pulmonary embolism — Pneumocystis pneumonia PCP — COVID-19 — sepsis — myocardial infarction troponin |
LDH and hemolysis — a marker of red blood cell destruction: mechanism: Red blood cells contain large amounts of LDH (primarily LDH-1 and LDH-2) → upon red blood cell lysis → massive release → very high LDH levels → in association with: collapsed haptoglobin (<0.10 g/L — haptoglobin binds to free hemoglobin → saturation → collapse of serum levels) + elevated indirect bilirubin (metabolism of released hemoglobin) + Coombs test (direct + indirect) to distinguish autoimmune origin → causes: autoimmune hemolytic anemia (AHAI) + thrombotic microangiopathies (TTP + HUS + DIC + HELLP) → in TTP and HUS: Very high LDH + thrombocytopenia + schistocytes + negative Coombs test → marker of microangiopathy severity + malaria (Plasmodium falciparum): massive hemolysis → very high LDH + sickle cell disease in vaso-occlusive crisis + G6PD deficiency; LDH in necrosis and tissue ischemia: ischemic hepatitis (shock liver): liver damage due to low cardiac output → very high AST + ALT (sometimes >1,000 × ULN) + very high LDH (>5× ULN) → diagnosis: shock + parallel elevation of transaminases and LDH + myocardial infarction: LDH-1 and LDH-2 → now replaced by ultra-sensitive troponin + BNP → LDH is no longer routinely measured in the evaluation of AMI → rhabdomyolysis: muscle destruction → elevated LDH-5 + very high CK (CK >> LDH) + myoglobinuria → massive pulmonary embolism: moderately elevated LDH + D-dimers ++ + cerebral infarction + mesenteric ischemia; LDH in severe infections: Pneumocystis jirovecii pneumonia (PCP): LDH is consistently elevated (>300–400 U/L) in severe PCP cases in patients with HIV (CD4 <200/µL) or who are immunocompromised → Huang 1990 — JAMA: Elevated LDH + PCP → correlation with severity + prognosis → decreases with treatment (TMP-SMX) = good sign + severe COVID-19: Elevated LDH → marker of severity + prognosis → correlates with mortality → severe sepsis: Elevated LDH → multi-organ failure + tissue ischemia | Huang 1990 — JAMA: LDH + PCP + HIV → correlation severity + prognosis + treatment → foundational reference + Scully 2019 — NEJM (HERCULES): PTT + caplacizumab + LDH + schistocytes → Rock 1991 — NEJM: PTT + plasma exchange + LDH → Palevsky 1989 — Radiology: pulmonary embolism + LDH → moderate elevation + Binder 1999 — Journal of Clinical Chemistry: hemolysis + LDH + haptoglobin → combined interpretation + ASPC + INSPQ Quebec: PCP + HIV + LDH → monitoring + INESSS Quebec + RAMQ: LDH + haptoglobin + bilirubin → reimbursed + CBC smear → reimbursed if indicated |
| LDH in pleural fluid and other biological fluids Criteria Light exudate transudate — Serum pleural LDH — Pleural fluid/serum LDH ratio — Meningitis CSF LDH — Ascitic fluid LDH — Synovial fluid LDH — False positives hemolysis sampling — Very high LDH emergencies |
LDH in pleural fluid — Light’s criteria: fundamental clinical application: Light’s criteria (Light 1972 — Annals of Internal Medicine) allow for distinguishing pleural exudate from transudate → a single positive criterion is sufficient to classify it as exudate: 1/ pleural fluid protein / serum protein >0.5 → 2/ pleural fluid LDH / serum LDH >0.6 → 3/ pleural fluid LDH >2/3 of the upper normal limit of serum → sens. 98 % + spec. 77 % → exudate → infectious causes (pneumonia + empyema) + cancer + EP + tuberculosis → transudate → causes: heart failure + cirrhosis + nephrotic syndrome + very high pleural fluid LDH in neoplastic effusions + hemothorax + empyema → ; LDH in CSF: normally CSF LDH <40 U/L → elevated CSF LDH in: bacterial meningitis (released by neutrophils + cell lysis) + tuberculous meningitis + subarachnoid hemorrhages+ lymphomas + meningeal leukemias + extensive ischemic stroke + seizures → elevated CSF LDH + neutrophils → suggestive of bacterial meningitis → but multiplex CSF PCR (FilmArray) is much more sensitive and specific → LDH is rarely measured alone in CSF in current practice + LDH in other body fluids: peritoneal fluid (ascites): Elevated LDH → peritoneal carcinomatosis + secondary bacterial peritonitis → criterion: ascites LDH / serum LDH >0.4 + synovial fluid LDH: Elevated LDH → septic arthritis + microcrystalline arthritis + active inflammatory joint diseases → no diagnostic value in isolation → interpret within context → interferences and causes of false positives: hemolysis of the sample → massive release of erythrocyte LDH → ALWAYS check the appearance of the tube (red or pink liquid = hemolysis = uninterpretable result) → thrombocytosis (platelets contain LDH) → intense physical exercise (muscle LDH) → advanced pregnancy (placental LDH) | Light 1972 — Annals of Internal Medicine: Light's criteria → exudate vs. transudate → pleural LDH → absolute foundational reference → Romero-Candeira 2002 — CHEST: Light's criteria + sensitivity + specificity → meta-analysis + Porcel 2014 — Respiratory Medicine: pleural LDH + Light's criteria + differential diagnosis + Huang 1990 — JAMA: LDH + CSF + infections + Binder 1999 — JCC: LDH + hemolysis + interferences + INESSS Quebec + RAMQ: serum LDH + biological fluid LDH → reimbursed according to indication + hospital laboratories Quebec: Light's criteria + pleural LDH + routine analysis of pleural effusions |
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LDH is a very sensitive marker of cellular suffering but not very specific—its elevation does not always pinpoint the damaged tissue and must be interpreted in conjunction with the clinical context and other biological markers. A hemolyzed sample will give a falsely very high LDH – always check the appearance of the sample before interpreting. Light's criteria (Light 1972) use the pleural fluid LDH / serum LDH ratio to distinguish between exudate and transudate – one of the most widely used biological reasonings in medicine. A very high LDH (>3x N) without an obvious cause should suggest a hematologic malignancy, a thrombotic microangiopathy, or acute hepatitis.
Situations requiring urgent investigation if LDH is very high
Very high LDH (>3-5x N) + severe thrombocytopenia + anemia + schistocytes on blood smear + negative Coombs + elevated creatinine → Thrombotic microangiopathy (TTP or HUS) → hematologic emergency → ADAMTS13 + blood cultures + urgent plasma exchange if TTP (do not wait for confirmation) → immediate hospitalization.
Severely elevated LDH (>5–10x normal) + abnormal CBC (leukocytosis + blasts + thrombocytopenia) + fever + altered general condition → probable malignant hemopathy (acute leukemia + Burkitt lymphoma) → urgent CBC + expert smear + β2-microglobulin + blood urea + creatinine + phosphate + potassium → tumor lysis syndrome to prevent → urgent hemato-oncology consultation → allopurinol or rasburicase + hyperhydration.
Immunocompromised patient (HIV CD4 300–400 U/L) + hypoxemia + bilateral chest x-ray infiltrates probable pneumocystosis (PCP) → thoracic CT + BAL + P. jirovecii PCR → high-dose TMP-SMX (15–20 mg/kg/day TMP × 21 days) → corticosteroids if PaO₂ <70 mmHg → secondary prophylaxis after treatment.
Consult at Clinique Omicron
Clinique Omicron physicians prescribe and interpret LDH within its complete clinical context, use Light's criteria for the analysis of pleural effusions, recognize urgent situations (microangiopathy + hematologic malignancy + PCP), guide appropriate further investigations (haptoglobin + blood smear + β2-microglobulin + serum uric acid + CT scan depending on the context), and ensure coordination with the hematologist, oncologist, or infectologist based on the etiology. Consultations are available at several service points in Quebec and via telemedicine. To make an appointment, visit cliniqueomicron.ca.
The content of this page is for informational purposes only and does not substitute for medical advice. LDH is a nonspecific marker that should always be interpreted within its full clinical context. A hemolyzed sample renders the result uninterpretable – always check the appearance of the tube before interpreting an elevated LDH.
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