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Lactate dehydrogenase (LDH) is an important enzyme of the anaerobic metabolic pathway. It belongs to the class of oxidoreductases, with an enzyme commission number EC 1.1.1.27. The function of the enzyme is to catalyze the reversible conversion of lactate to pyruvate with the reduction of NAD+ to NADH and vice versa.[1] The enzyme is present in a variety of organisms, that include plants and animals. It is ubiquitously present in all tissues and serves as an important checkpoint of gluconeogenesis and DNA metabolism. A species-wide analysis of LDH demonstrates its well-preserved structure with only a few changes in the amino acid sequence across species.[2] The structural similarity with slight amino acid changes provides a logical platform for designing functional molecules to modulate the catalytic potential and expression of the enzyme. This article will focus on the biochemical function, testing methods, and clinical relevance of the LDH enzyme.

The quantification of LDH is of clinical interest as a serum concentration of LDH isozymes reflect tissue-specific pathological conditions. Hence, LDH can be used as a marker for diverse tissue injuries owing to its isozyme form, and its ubiquitous presence. Upon tissue damage, the cells release LDH in the bloodstream. Depending upon the type of tissue injury, the enzyme can remain elevated for up to 7 days in the bloodstream. The elevated LDH in serum as a result of organ destruction occurs due to significant cell death that results in loss of cytoplasm. Causes of tissue damage can be diseases such as acute myocardial infarction, anemia, pulmonary embolism, hepatitis, acute renal failure, etc.[22] LDH can be used as a satisfactory marker for the staging of a disease (S-classification), monitor prognosis or response to treatment, and evaluate body fluids other than blood. The decrease in LDH levels during treatment is indicative of a better prognosis and/or good response to treatment in conditions such as acute myocardial infarction or liver injury. In acute myocardial infarction, LDH-1 isozyme remains elevated from the second day up to the 4th day. Similarly, in liver injury, LDH-5 is elevated. A significant increase in LDH-5 higher than LDH-4 is a marker of hepatocellular injuries such as hepatitis or cirrhosis. LDH increases during effusion in serous body fluids such as pericardial and peritoneal fluids. Hence, it serves to characterize effusion. In cerebrospinal fluid, LDH increases in bacterial meningitis, while it is observed to be normal in viral meningitis. The ratio of fluid LDH compared to the upper limit of normal serum LDH (> 0.6) indicates an inflammatory process, and hence exudate.[23] There is a marked increase in LDH during intracranial hemorrhage. More than 40 U/L increase above the normal levels is observed in the central nervous system lymphoma, leukemia, and metastatic carcinoma. Elevated levels of more than one isoenzyme may be indicative of more than one cause of tissue damage, e.g., in conditions where pneumonia may also be associated with a heart attack. Very levels of LDH appear to correlate with severe disease or multiple organ failure.

There is a marked increase in LDH during intracranial hemorrhage. More than 40 U/L increase above the normal levels is observed in the central nervous system lymphoma, leukemia, and metastatic carcinoma. Elevated levels of more than one isoenzyme may be indicative of more than one cause of tissue damage, e.g., in conditions where pneumonia may also be associated with a heart attack. Very levels of LDH appear to correlate with severe disease or multiple organ failure. LDH is the only serum biomarker useful for assessing metastatic melanomas.[24] In malignancy, the growth of tumor cells consumes oxygen more than the supply; thus, hypoxia is quite common. The growing tumors undergo LDH mediated energy production to fulfill the demand for fast cellular growth.[25] Hence, LDH is an established marker of metastases, especially in the liver. It is also a crucial single prognostic factor since patients with high LDH have reduced survival rates. LDH levels serve to predict incidences of metastasis in uveal melanoma.[26] LDH has a good correlation with tyrosine kinase expression in tumors.[27] This enzyme also constitutes a potential therapeutic target for diseases such as malaria and cancer. The LDH isoform expressed by Plasmodium falciparum, the malarial parasite, is a crucial enzyme for the generation of energy in the parasite. Since these malarial parasites lack a tricarboxylic acid cycle for ATP formation, anaerobic glycolysis serves as a source of energy.[28] The inhibitors of Plasmodium falciparum LDH would only be directed towards the parasite and would selectively kill the parasite. Most invasive tumors undergo a metabolic switching (Warburg effect) from oxidative phosphorylation to higher anaerobic glycolysis. This switch occurs through upregulation of the LDH-5 (also called LDH-A), the isoform normally present in muscles and the liver.[22] Hence, inhibition of LDH-5 can specifically target the site of tumor progression and invasiveness. An analog, N-hydroyxindole class LDH inhibitors are also tested effectively as anticancer agents.[29][30] Many clinical trials and translational data demonstrated that targeting LDHA genes or its protein product LDH-5 may be harnessed as a metabolic treatment of cancer.[31][28]

Most invasive tumors undergo a metabolic switching (Warburg effect) from oxidative phosphorylation to higher anaerobic glycolysis. This switch occurs through upregulation of the LDH-5 (also called LDH-A), the isoform normally present in muscles and the liver.[22] Hence, inhibition of LDH-5 can specifically target the site of tumor progression and invasiveness. An analog, N-hydroyxindole class LDH inhibitors are also tested effectively as anticancer agents.[29][30] Many clinical trials and translational data demonstrated that targeting LDHA genes or its protein product LDH-5 may be harnessed as a metabolic treatment of cancer.[31][28] Researchers have conducted clinical trials in melanoma patients with low LDH, and treatment with Ipilimumab showed higher efficacy when treatment started with low baseline LDH.[32][33] Another trial using a combination of Bcl2 antisense oligonucleotide plus dacarbazine also showed efficacy in patients with low baseline LDH.[34] Thus, the overall importance of LDH as a tumor marker becomes masked because of its low sensitivity and specificity.[35] High LDL levels are usually associated with advanced stages of cancer.[36] The deficiency of the enzyme LDH is very rare, and not much data is available for its prevalence. This deficiency can result from either the mutations in the LDHA gene or the LDHB gene leading to a deficiency in LDH-A (M- subunit protein) and LDH-B (H-subunit protein) proteins, respectively.[37] LDHA gene mutations result in the formation of an abnormal M subunit protein. This protein subunit cannot bind to other subunits to form the LDH enzyme.

The deficiency of the enzyme LDH is very rare, and not much data is available for its prevalence. This deficiency can result from either the mutations in the LDHA gene or the LDHB gene leading to a deficiency in LDH-A (M- subunit protein) and LDH-B (H-subunit protein) proteins, respectively.[37] LDHA gene mutations result in the formation of an abnormal M subunit protein. This protein subunit cannot bind to other subunits to form the LDH enzyme. LDHA gene mutation mostly affects skeletal muscles, because skeletal LDH has all M-subunits. However, a lack of a functional subunit reduces the amount of enzyme formed in all other tissues as well. This chemistry results in an ineffective breakdown of glycogen. Hence, LDHA gene deficiency is also called glycogen storage disease XI. The unavailability of sufficient energy, especially to the muscle cells, causes muscle weakness and breakdown of muscle tissue (rhabdomyolysis).[38] The effect is more pronounced during strenuous activities, and muscle tissue destruction releases protein myoglobin. This protein is processed in the kidneys and released in the urine, causing myoglobinuria. The high accumulation of myoglobin protein can damage the kidneys, which can also lead to kidney failure. In some patients, LDHA deficiency causes skin rashes of varying severity.[39] On the other hand, LDHB gene mutations affect the heart muscle primarily because the heart LDH is made of all four H-subunits. In cardiac muscle, the involuntary muscle movement is fueled by the conversion of lactate to pyruvate through the LDH enzyme. Such conditions lead to a reduced LDH activity in cardiac muscle of patients with LDHB deficiency. Interestingly, no visible phenotype, signs, or symptoms are observed in such patients. Both LDHA and LDHB gene mutations have shown relevance in tumorigenesis.[40]