Lactic Dehydrogenase (LDH)
PKGhatak, MD
Lactic Dehydrogenase is an enzyme present in all tissues. LDH catalyzes, in a reversible reaction, lactate to pyruvate. LDH transfers 2 electrons and one hydrogen ion to NAD and in the process generates 2 molecules of ATP per molecule of glucose. LDH is an intracellular enzyme and consists of 5 isoenzymes. The individual organ contains one predominant isoenzyme and also small but variable quantities of other isoenzymes. Tissues are capable of producing any isoenzymes given the proper substrate concentration, pH, and oxygen supply.
LDH concentration is higher in the RBC, liver, heart, brain, lungs, kidneys and bones. Any disease or infection that damages any organ will release LDH in the blood and the serum level of LDH rises - twice or many times higher than normal. LHD is an anaerobic enzyme that belongs to the oxidoreductase group. LDH is present both in the cell cytoplasm (Cytosol) and in mitochondria. The mitochondrial LDH is called mL-LDH (mitochondrial Levo LDH). The mL-LDH facilitates the oxidation of lactate to pyruvate. The RBC has no mitochondria and lacks mL-LDH as a result unable to metabolize lactate further.
Action of LDH.
The chemical reaction of LDH is as follows -
CH3 CHOH COOH+ NAD + LDH = converted to CH3 CO COOH + NADH + H+ and in reverse action -
Pyruvate + NADH + H+ in presence of LDH = Lactate + NAD +. (See footnote 2 Cori cycle)
Pyruvate then enters the Krebs cycle (see footnote 1) and generates 36 ATP molecules during its full utilization in the generating energy. Excess accumulation of NADH is the triggering point of the reverse action and produces lactate.
Blood levels of LDA.
Serum LDH level is higher than plasma level because clotting of blood releases LDH.
Normal serum level if LDH
|
Newborn |
135 to 750 units/L. In CSF < 70 units / L |
|
Children up to 12 years |
180 to 435 units/L |
|
12 to 18 years |
122 to 222 units/L |
|
Adults |
140 to 280 units/L |
|
CSF LDH in adults |
Less than 40 units/L |
Falsely elevated LDH.
Following general anesthesia, Aspirin use, alcohol, and procainamide may elevate LDH levels.
Falsely low LDH.
Vitamin C use.
LDH isoenzymes and structure;
LDH has 5 isoenzymes - 1 to 5. And each LDH molecule is a combination of two units, H and M units. H stands for heart and M for skeletal muscle.
LDH isoenzymes and composition
|
Name |
Units |
Higher levels in |
|
LDH1 |
4 H units |
Heart |
|
LDH 2 |
3 H units + 1 M unit |
RBC, Spleen, Bone marrow. |
|
LDH 3 |
2 H units + 2 M units |
Lungs |
|
LDH 4 |
1 H unit + 3 M units |
Kidneys |
|
LDH 5 |
4 M units |
Skeletal muscles, Liver. |
All tissues have the above 5 isoenzymes in variable amounts. The H Unit binds faster with the substrate but has a slow rate of metabolic activities.
Two chromosomes, 11 and 12, encode LDH. The genes of the two chromosomes are designated as LHD- A, B, C, D genes. LDH-A.B.C genes encode L- LDH (Levo LDH) isomer and LDH-D gene encode d-LDH isomer. Levo isomers are required in Lactate utilization and the Krebs cycle
Congenital absence of LDH.
The encoding genes for LHD are 4 in number, designated as A, B, C, & D. The mode of inheritance is autosomal recessive. LDH deficiency is very rare, Japan reported most cases; the incidence in Japan is 1 per million people. And known as congenital LDH – A and LDH- B deficiencies.
Deficiency in LDH-A results in absent LDH 5. Patients present with easy fatigability, muscle cramps and pain, myoglobinuria, and renal failure.
LDH -B deficiency causes LDH- 1 deficiency. The heart muscles are capable of generating energy from using other sources and patients show no effects from this deficiency.
Covid-19 and LDH.
In every study published on covid virus infected hospitalized patients, the serum LDH is universally elevated. NIH calculated that an elevated LDH increases a 6-fold increase in serious illness and a 16-fold increase in mortality. In multisystem failure all LDH isoenzymes are elevated, the higher the number the worse is the outcome. In platelet microthrombi and interstitial pneumonia, LDH3 is very high. Accumulation of lactate in tissue increases the H ion concentration and a fall in the pH, Low pH enhances macrophage metalloprotease and initiates new blood vessel growth in the inflammatory tissues.
LDH activity in specific organ/tissue.
Muscle.
Muscular activities utilize oxygen, and in a sustained activity like in a marathon run, a severe hypoxic condition is created. Since oxygen is the final electron acceptor, the ATP generation stops but the muscles continue to function by creating ATP through NAD+. The serum levels of LDH 5 are high in muscular dystrophy, HIV infection, crush injury and rhabdomyolysis. The damaged muscles release myoglobin and kidney damage is common in significant myoglobinuria.
Brain.
In normal conditions, the brain uses lactate to generate 30% of its energy needs. In anoxia, the brain can raise it to 60%. Excess lactate enters the CSF. CSF lactate levels are used for diagnosis of anoxic brain injury, and bacterial meningitis but LDH usually remains normal in viral meningitis. The CSF LDH levels are very high in subarachnoid bleeding, and high in metastatic carcinoma, CNS lymphoma, and Leukemic infiltration to the brain.
Heart.
In myocardial infarction (MI), the LDH level rises within 24 hours and stays up for 4 days then returns to a normal level. A normal heart generates LDH2. In MI the LDH1 rises over the LDH2. The elevated LDH1/LGD2 ratio is helpful in the diagnosis of MI.
Pleural effusion.
In inflammatory pleural effusion, the ratio of LDH of pleural fluid and serum LDH is >0.6.
Liver.
In cirrhosis of the liver and hepatitis, the LDH2 is proportionally higher than LDH4. In toxic hepatitis, LDH is 10 times the normal serum LDH.
Lungs.
In microvascular pulmonary embolism, LDH3 is very high, so also in pulmonary emboli and infarction, necrotizing pneumonia.
B12 deficiency and macrocytic anemia.
LDH levels are high, and the levels fall with adequate therapy.
Cancer.
All cancer cells produce excess LDH and high serum levels reflect the aggressiveness of cancer. Many cancer cells are capable of copying mitochondrial mL-LDH and use it to generate extra energy for cancer growth. This is known as the Warburg effect (see footnote 3).
Malignant melanoma metastases are associated with very high serum LDH levels, usually over 50 times the normal value. Leukemia. Lymphoma, Multiple myeloma, testicular and ovarian cancers also produce high serum LDH.
When treatment of cancer is effective the LDH level falls. The LDH level is used as a serum marker for monitoring cancer recurrence.
In colorectal, esophageal, nasopharyngeal, prostrate, germ cell cancers and malignant melanoma, the LDH levels over 1000 units/L signify a poor prognosis.
An interesting side note.
Malaria parasites lack the tricarboxylic acid cycle and depend on LDH for energy generation. Attempts are now being made to block LDH in malaria parasites and if successful it will help to control malaria.
Footnotes-
Krebs cycle is also called the tricarboxylic cycle. Two carbon compounds generated from the metabolism of glucose, fatty acids and glucogenic amino acids combine with the enzyme CoA and form Acetyl CoA. Acetyl CoA combines with Oxaloacetate to form Citric acid and enters a cycle that runs strep wise, in reversible actions, and generates ATP, CO2, and H20.
Cori Cycle.
The Cori cycle explains the steps in the conversion of lactate to Glucose. The newly formed glucose (neoglucogenesis) is added to the blood to keep blood sugar within the range.
Warburg Effect.
This is a biochemical process of speeding the rate of glucose conversion to lactate in aerobic conditions. Cancer cells use this to generate extra energy.
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