Conditions in which lactate dehydrogenase levels are increased
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Conditions with Elevated Lactate Dehydrogenase (LDH)
LDH is a ubiquitous intracellular enzyme found in virtually every tissue. Because it is non-specific, elevated LDH simply reflects cell/tissue injury or increased cell turnover - the pattern of elevation and isoenzyme fractionation narrows the source.
Biochemical Background
LDH catalyzes the reversible conversion of L-lactate ↔ pyruvate (with NAD+/NADH). It is a tetramer composed of M (muscle) and H (heart) subunits, forming 5 isoenzymes:
| Isoenzyme | Subunit | Primary Tissue | Normal Serum Order |
|---|---|---|---|
| LDH-1 (H4) | Heart | Heart, RBCs, Kidney | 2nd highest |
| LDH-2 (H3M) | Heart-dominant | Heart, RBCs, Kidney | Highest (LD2 > LD1 normally) |
| LDH-3 (H2M2) | Mixed | Lung, Spleen, Lymphocytes, Pancreas | 3rd |
| LDH-4 (HM3) | Muscle-dominant | Liver, Skeletal muscle | 4th |
| LDH-5 (M4) | Muscle | Liver, Skeletal muscle | Lowest |
Normal serum pattern: LD2 > LD1 > LD3 > LD4 > LD5 A "flipped LD ratio" (LD1 > LD2) = acute MI, hemolysis, or renal infarction
- Quick Compendium of Clinical Pathology, 5th ed., p. 51-65
- Tietz Textbook of Laboratory Medicine, 7th ed., p. 563-591
Conditions Causing Elevated LDH
1. Hematological Disorders
These are among the highest elevations seen:
- Megaloblastic anemia (pernicious anemia, B12/folate deficiency) - markedly elevated, due to ineffective erythropoiesis and intramedullary hemolysis
- Hemolytic anemias - autoimmune hemolytic anemia (AIHA), hereditary spherocytosis, sickle cell disease, G6PD deficiency, microangiopathic hemolysis (TTP, HUS, DIC)
- Hemoglobin disorders - thalassemias
- Note: In hemolysis, elevated LDH + decreased haptoglobin + indirect hyperbilirubinemia + reticulocytosis is the classic triad
- Washington Manual of Medical Therapeutics, p. 1532
- Goldman-Cecil Medicine, p. 3518
2. Cardiac Conditions
- Acute Myocardial Infarction (AMI): LDH rises ~10 hours post-infarct, peaks 24-48 hours, remains elevated up to 14 days (historically useful when troponin was unavailable); LD1 > LD2 ("flipped ratio")
- Myocarditis, cardiac failure with hepatic congestion
- Quick Compendium of Clinical Pathology, 5th ed.
3. Liver Diseases
- Ischemic hepatitis ("shock liver") - extreme LDH elevation
- Drug-induced hepatotoxicity (e.g., acetaminophen overdose) - massive elevation
- Malignant infiltration of the liver - LDH elevated alongside alkaline phosphatase (ALP)
- Viral hepatitis, cirrhosis, hepatic necrosis
- LDH-4 and LDH-5 are the relevant isoenzymes; LDH-5 is specific to liver
- Miller's Anesthesia, 10th ed., p. 3441
4. Malignancies
LDH is a non-specific tumor marker reflecting tumor burden and necrosis:
- Lymphomas - Hodgkin's and Non-Hodgkin's lymphoma (elevated LDH = poor prognostic indicator)
- Leukemias - acute and chronic
- Germ cell tumors - LDH is a primary marker for seminomas; also elevated in NSGCT (associated with high tumor burden and recurrence risk)
- Melanoma - elevated LDH in stage IV = adverse prognostic factor (used in TNM staging)
- Wide variety of carcinomas - lung, breast, colorectal, renal cell carcinoma
- Quick Compendium of Clinical Pathology, 5th ed., p. 55
- Bailey & Love's Surgery, 28th ed.
- Berek & Novak's Gynecology
5. Muscle Disorders
- Rhabdomyolysis - crush injury, extreme exertion, seizures, statin-induced myopathy
- Muscular dystrophies
- Inflammatory myopathies (dermatomyositis, polymyositis)
- LDH-4 and LDH-5 elevations
6. Pulmonary Conditions
- Pulmonary embolism - moderate elevation
- Pneumocystis jirovecii pneumonia (PCP) - LDH is a useful marker of severity in PCP (HIV patients); marked elevation correlates with poor prognosis
- Pulmonary infarction
- ARDS, pneumonia
- LDH-3 is the relevant isoenzyme (lung source)
7. Renal Conditions
- Renal infarction - elevated LDH-1 (LD1 > LD2 flip can occur)
- Renal cell carcinoma
- Renal insufficiency - LDH can be elevated in chronic kidney disease
- Nephrotic syndrome
8. Neurological Conditions
- Acute stroke - reflects ischemic neuronal damage
- Meningitis (bacterial/viral) - elevated in CSF and serum
- Cerebral infarction
9. Infectious Diseases
- Severe malaria (P. falciparum)
- Severe sepsis with multiorgan hypoperfusion
- Infectious mononucleosis (EBV)
- Viral hepatitis
10. Rheumatological / Inflammatory Conditions
- Systemic Lupus Erythematosus (SLE) - can reflect hemolysis or serositis
- Rheumatoid arthritis - elevated in synovial fluid
- Gout - elevated in synovial fluid
- Failed joint arthroplasty (elevated in SF)
- Henry's Clinical Diagnosis and Management, p. 514
11. Pancreatitis
- Acute severe pancreatitis - used in Ranson's criteria (LDH > 350 IU/L on admission is a poor prognostic sign)
- Bailey & Love's Surgery, 28th ed. (Summary box 72.7)
12. Other Causes
- Hypothyroidism (mild elevation due to muscle involvement)
- Hyperthyroidism
- Sarcoidosis
- Heat stroke
- Intestinal ischemia/infarction
- Trauma/burns
Marked vs. Moderate Elevations - A Clinical Guide
| Degree of Elevation | Likely Conditions |
|---|---|
| Markedly elevated (>5-10x ULN) | Megaloblastic anemia, Pernicious anemia, Lymphoma, Ischemic hepatitis, Rhabdomyolysis, PCP |
| Moderately elevated (2-5x ULN) | AMI, Hemolytic anemia, Liver disease, Pulmonary embolism, Malignancy |
| Mildly elevated | Renal disease, Pancreatitis, Inflammatory conditions |
Isoenzyme Pattern and Clinical Correlation
| Isoenzyme Elevated | Condition |
|---|---|
| LDH-1 > LDH-2 ("flipped") | AMI, Hemolysis, Renal infarction |
| LDH-4 and LDH-5 | Liver disease, Skeletal muscle injury |
| LDH-3 | Lung disease, Lymphoma, Platelet destruction |
| LDH-6 (rare) | Severely ill patients |
- Quick Compendium of Clinical Pathology, 5th ed., p. 61-65
LDH in Body Fluids
- Pleural fluid LDH: Used in Light's criteria to distinguish exudate (pleural LDH/serum LDH > 0.6) from transudate; elevated in malignancy, TB, parapneumonic effusion
- CSF LDH: Elevated in bacterial meningitis, CNS malignancy, CNS infarction
- Synovial fluid LDH: Elevated in RA, gout, septic arthritis
- Tintinalli's Emergency Medicine; Textbook of Family Medicine, 9th ed.
Key takeaway: Because LDH is so ubiquitous, an isolated elevated LDH is not diagnostic of any single condition. The clinical context, degree of elevation, isoenzyme pattern, and associated tests (haptoglobin, bilirubin, troponin, ALP, CBC) together determine the etiology.
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