Lactate Dehydrogenase

Lactate dehydrogenase (LDH) is a cytoplasmic enzyme that interconverts lactate and pyruvate with NAD, and it is present in almost every tissue. Serum activity is low in health and rises when cells are damaged, when cell turnover is high, or when clearance falls. It is measured by following NADH change spectrophotometrically at 340 nm. Isoenzyme fractions (LDH-1 to LDH-5) are separated by electrophoresis and are rarely needed.

It is a sensitive but non-specific marker of tissue injury. Its main uses are the assessment of haemolysis and ineffective erythropoiesis, the staging and prognosis of lymphoma, germ cell tumours, melanoma and myeloma, early recognition of tumour lysis and thrombotic microangiopathy, and the classification of pleural and other body fluids.

Raised LDH is found in a large share of hospital patients and is rarely diagnostic alone. It is most useful when interpreted with haemoglobin, bilirubin, liver enzymes, CK and the clinical context.

Indications. Suspected haemolysis or megaloblastic anaemia, thrombotic microangiopathy, lymphoma, leukaemia, myeloma, testicular or other germ cell tumours, melanoma, bulky malignancy before chemotherapy, suspected tumour lysis, Pneumocystis pneumonia, pleural effusion, severe pre-eclampsia, and unexplained fever or weight loss.

Specimen. Serum or heparin plasma, separated promptly from red cells. Haemolysed samples are rejected. Do not refrigerate or freeze samples for isoenzyme analysis, since LDH-4 and LDH-5 are cold labile.

Reference range. About 120 to 250 U/L, assay specific. Neonates and young children have higher values, and age specific ranges apply.

Isoenzymes.

• LDH-1 and LDH-2: heart, red cells, kidney. Raised in haemolysis, megaloblastic anaemia, myocardial injury, and germ cell tumours (LDH-1).
• LDH-3: lung, spleen, lymphoid tissue, platelets. Raised in lymphoma, leukaemia and pulmonary disease.
• LDH-4 and LDH-5: liver and skeletal muscle. Raised in hepatic injury and muscle injury.

Causes of raised LDH.

• Red cell destruction and ineffective erythropoiesis: haemolytic anaemia, paroxysmal nocturnal haemoglobinuria, thrombotic microangiopathy, megaloblastic anaemia (often over 2000 U/L), myelodysplasia, in vitro haemolysis.
• Malignancy: lymphoma (including Burkitt), acute leukaemia, myeloma, germ cell tumours, melanoma, neuroblastoma, Ewing sarcoma, liver metastases, and tumour lysis.
• Tissue injury: myocardial infarction, muscle injury and rhabdomyolysis, pulmonary embolism, renal infarction, stroke, bowel ischaemia, pancreatitis, hepatitis and ischaemic hepatitis, severe sepsis.
• Infection: Pneumocystis pneumonia (usually over 500 U/L), tuberculosis, EBV, HIV, malaria.
• Others: haemophagocytic lymphohistiocytosis, HELLP syndrome, seizures, strenuous exercise, hypothyroidism, macro-LDH.

Causes of lowered LDH. No clinical significance. Rare inherited deficiency of the M subunit (LDHA) causes exertional myopathy and a very low LDH.

Haemolysis pattern. Raised LDH with raised unconjugated bilirubin, raised reticulocytes and low haptoglobin. In intravascular haemolysis and thrombotic microangiopathy, LDH is often several times the upper limit.

Tumour staging and prognosis.

• Germ cell tumours: serum LDH is part of the S category. S1 is under 1.5 times the upper limit, S2 is 1.5 to 10 times, and S3 is over 10 times.
• Melanoma: raised LDH defines stage IV subgroup M1c with a poor outlook.
• Lymphoma: a raised value is part of the usual prognostic indices and indicates bulk and proliferation.
• Myeloma and acute leukaemia: a raised value predicts high risk disease.

Tumour lysis. LDH over 2 times the upper limit with bulky disease predicts risk, and rising LDH after chemotherapy is part of the picture with potassium, phosphate, urate and calcium changes.

Body fluids. A pleural fluid LDH over two thirds of the upper limit of the serum reference range, or a pleural to serum LDH ratio over 0.6, indicates an exudate. Pleural LDH over 1000 U/L suggests empyema, malignancy or rheumatoid effusion.

Pregnancy. LDH over 600 U/L with haemolysis, raised liver enzymes and low platelets defines HELLP syndrome.

Critical values and findings needing immediate action. Triggers vary by laboratory.

• LDH several times the upper limit with anaemia, thrombocytopenia, schistocytes and neurological or renal features, indicating thrombotic microangiopathy and needing urgent haematology contact.
• Rising LDH with potassium, phosphate and urate in a patient starting chemotherapy for bulky disease.
• LDH over 500 U/L with fever, hypoxia and a diffuse chest radiograph in HIV infection.
• LDH and ALT over 1000 U/L with hypotension, indicating ischaemic hepatitis.
• LDH with hypertension, headache or right upper quadrant pain in the third trimester.

Interferences and pitfalls.

• In vitro haemolysis is the commonest cause of a spuriously raised result, because red cells contain about 150 times the plasma concentration. Delayed separation and traumatic venepuncture have the same effect.
• Serum samples carry LDH released from platelets, so very high platelet counts raise results.
• Cold storage lowers LDH-4 and LDH-5 activity.
• Macro-LDH (LDH bound to IgG or IgA) causes a persistent isolated rise without disease.
• Strenuous exercise, muscle injury and intramuscular injections raise results.
• Methods based on lactate to pyruvate and pyruvate to lactate directions give different ranges.
• A normal LDH does not exclude haemolysis, malignancy or tissue injury.

Special groups.

• Neonates and infants: values are higher, up to about 2 times the adult limit in the first weeks.
• Children: age specific ranges apply, and high values suggest leukaemia, lymphoma, neuroblastoma or haemolysis.
• Pregnancy: values are normal or mildly raised, and a marked rise suggests HELLP syndrome.
• Older adults: mild rises are common and non-specific.
• Regions: malaria, sickle cell disease, G6PD deficiency, endemic Burkitt lymphoma and tuberculosis are frequent causes.

Follow up tests. Reticulocyte count, haptoglobin, bilirubin, direct antiglobulin test, blood film, ADAMTS13 activity, vitamin B12 and folate, full blood count, liver function tests, creatine kinase, troponin, urate, potassium, calcium and phosphate, creatinine, AFP and hCG, serum protein electrophoresis, flow cytometry, bone marrow examination, imaging for lymphoma and metastases, pleural fluid analysis, HIV test, serum beta-D-glucan, LDH isoenzymes, polyethylene glycol precipitation for macro-LDH.