Lactate dehydrogenase
Encyclopedia
Lactate dehydrogenase (LDH or LD) is an enzyme
present in a wide variety of organisms, including plants and animals.
Lactate dehydrogenases exist in four distinct enzyme classes. Two of them are cytochrome c
-dependent enzymes, each acting on either D-lactate (EC 1.1.2.4)
or L-lactate (EC 1.1.2.3
). The other two are NAD(P)-dependent enzymes, each acting on either D-lactate (EC 1.1.1.28) or L-lactate (EC 1.1.1.27). This article is about the NAD(P)-dependent L-lactate dehydrogenase.
with concomitant interconversion of NADH and NAD+
. It converts pyruvate, the final product of glycolysis
, to lactate when oxygen is absent or in short supply, and it performs the reverse reaction during the Cori cycle
in the liver
. At high concentrations of lactate, the enzyme exhibits feedback inhibition, and the rate of conversion of pyruvate to lactate is decreased.
It also catalyzes the dehydrogenation of 2-Hydroxybutyrate, but it is a much poorer substrate than lactate. There is little to no activity with beta-hydroxybutyrate
.
The five isoenzymes that are usually described in the literature each contain four subunits. The major isoenzymes of skeletal muscle and liver, M4, has four muscle (M) subunits, while H4 is the main isoenzymes for heart muscle in most species, containing four heart (H) subunits. The other variants contain both types of subunits.
Usually LDH-2 is the predominant form in the serum
. A LDH-1 level higher than the LDH-2 level (a "flipped pattern") suggests myocardial infarction
(damage to heart tissues releases heart LDH, which is rich in LDH-1, into the bloodstream). The use of this phenomenon to diagnose infarction has been largely superseded by the use of Troponin
I or T measurement.
s:
Mutations of the M subunit have been linked to the rare disease exertional myoglobinuria
(see OMIM article), and mutations of the H subunit have been described but do not appear to lead to disease.
. Other disorders indicated by elevated LDH include cancer, meningitis, encephalitis, acute pancreatitis, and HIV.
, LDH is often used as a marker of tissue breakdown as LDH is abundant in red blood cell
s and can function as a marker for hemolysis
. A blood sample that has been handled incorrectly can show false-positively high levels of LDH due to erythrocyte damage.
It can also be used as a marker of myocardial infarction
. Following a myocardial infarction, levels of LDH peak at 3–4 days and remain elevated for up to 10 days. In this way, elevated levels of LDH (where the level of LDH1 is higher than that of LDH2) can be useful for determining whether a patient has had a myocardial infarction if they come to doctors several days after an episode of chest pain.
in general; this is possible when there are no other indicators of hemolysis
. It is used to follow-up cancer
(especially lymphoma
) patients, as cancer cell
s have a high rate of turnover with destroyed cells leading to an elevated LDH activity.
(or pericardial effusion
) can help in the distinction between exudate
s (actively secreted fluid, e.g. due to inflammation
) or transudate
s (passively secreted fluid, due to a high hydrostatic pressure or a low oncotic pressure
). The usual criterion is that a ratio of fluid LDH versus upper limit of normal serum LDH of more than 0.6 or indicates an exudate, while a ratio of less indicates a transudate. Different laboratories have different values for the upper limit of serum LDH, but examples include 200 and 300 IU
/L. In empyema
, the LDH levels, in general, will exceed 1000 IU/L.
. In the case of viral
meningitis, high LDH, in general, indicates the presence of encephalitis
and poor prognosis
.
(PCP). Elevated LDH in the setting of upper respiratory symptoms in an HIV patient suggests, but is not diagnostic for, PCP. However, in HIV-positive patients with respiratory symptoms, a very high LDH level (>600 IU/L) indicated histoplasmosis
(9.33 more likely) in a study of 120 PCP and 30 histoplasmosis patients.
. Not all dysgerminomas produce LDH, and this is often a non-specific finding.
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
present in a wide variety of organisms, including plants and animals.
Lactate dehydrogenases exist in four distinct enzyme classes. Two of them are cytochrome c
Cytochrome c
The Cytochrome complex, or cyt c is a small heme protein found loosely associated with the inner membrane of the mitochondrion. It belongs to the cytochrome c family of proteins. Cytochrome c is a highly soluble protein, unlike other cytochromes, with a solubility of about 100 g/L and is an...
-dependent enzymes, each acting on either D-lactate (EC 1.1.2.4)
D-lactate dehydrogenase (cytochrome)
In enzymology, a D-lactate dehydrogenase is an enzyme that catalyzes the chemical reaction-lactate + 2 ferricytochrome c \rightleftharpoons pyruvate + 2 ferrocytochrome c...
or L-lactate (EC 1.1.2.3
L-lactate dehydrogenase (cytochrome)
In enzymology, a L-lactate dehydrogenase is an enzyme that catalyzes the chemical reaction-lactate + 2 ferricytochrome c \rightleftharpoons pyruvate + 2 ferrocytochrome c...
). The other two are NAD(P)-dependent enzymes, each acting on either D-lactate (EC 1.1.1.28) or L-lactate (EC 1.1.1.27). This article is about the NAD(P)-dependent L-lactate dehydrogenase.
Reactions
Lactate dehydrogenase catalyzes the interconversion of pyruvate and lactateLactic acid
Lactic acid, also known as milk acid, is a chemical compound that plays a role in various biochemical processes and was first isolated in 1780 by the Swedish chemist Carl Wilhelm Scheele. Lactic acid is a carboxylic acid with the chemical formula C3H6O3...
with concomitant interconversion of NADH and NAD+
Nicotinamide adenine dinucleotide
Nicotinamide adenine dinucleotide, abbreviated NAD, is a coenzyme found in all living cells. The compound is a dinucleotide, since it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine base and the other nicotinamide.In metabolism, NAD is involved...
. It converts pyruvate, the final product of glycolysis
Glycolysis
Glycolysis is the metabolic pathway that converts glucose C6H12O6, into pyruvate, CH3COCOO− + H+...
, to lactate when oxygen is absent or in short supply, and it performs the reverse reaction during the Cori cycle
Cori cycle
The Cori cycle , named after its discoverers, Carl Cori and Gerty Cori, refers to the metabolic pathway in which lactate produced by anaerobic glycolysis in the muscles moves to the liver and is converted to glucose, which then returns to the muscles and is converted back to lactate.-Cycle:Muscular...
in the liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
. At high concentrations of lactate, the enzyme exhibits feedback inhibition, and the rate of conversion of pyruvate to lactate is decreased.
It also catalyzes the dehydrogenation of 2-Hydroxybutyrate, but it is a much poorer substrate than lactate. There is little to no activity with beta-hydroxybutyrate
Beta-hydroxybutyrate
beta-Hydroxybutyric acid is a ketone body. It is a chiral compound having two enantiomers, D-3-hydroxybutyric acid and L-3-hydroxybutyric acid. Like the other ketone bodies , levels of beta-hydroxybutyrate are raised in ketosis...
.
Ethanol-Induced Hypoglycemia
Ethanol is broken down into acetaldehyde by alcohol dehydrogenase, and further into acetic acid by acetaldehyde dehydrogenase. During this reaction 2 NADH are produced. If large amounts of ethanol is present, then large amounts of NADH is produced, leading to a depletion of NAD+. Thus, the conversion of pyruvate to lactate is increased due to the associated regeneration of NAD+. Therefore, hypoglycemia and anion-gap metabolic acidosis (lactic acidosis) may ensue in ethanol poisoning.Enzyme isoforms
Functional lactate dehydrogenase are homo or hetero tetramers composed of M and H protein subunits encoded by the LDHA and LDHB genes, respectively:- LDH-1 (4H) - in the heartHeartThe heart is a myogenic muscular organ found in all animals with a circulatory system , that is responsible for pumping blood throughout the blood vessels by repeated, rhythmic contractions...
and RBCs - LDH-2 (3H1M) - in the reticuloendothelial systemReticuloendothelial system"Reticuloendothelial system" is an older term for the mononuclear phagocyte system. The mononuclear phagocyte system consists primarily of monocytes and macrophages. The spleen is the largest unit of the mononuclear phagocyte system. The monocyte is formed in the bone marrow and transported by the...
- LDH-3 (2H2M) - in the lungLungThe lung is the essential respiration organ in many air-breathing animals, including most tetrapods, a few fish and a few snails. In mammals and the more complex life forms, the two lungs are located near the backbone on either side of the heart...
s - LDH-4 (1H3M) - in the kidneyKidneyThe kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
s, placentaPlacentaThe placenta is an organ that connects the developing fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother's blood supply. "True" placentas are a defining characteristic of eutherian or "placental" mammals, but are also found in some snakes and...
, and pancreasPancreasThe pancreas is a gland organ in the digestive and endocrine system of vertebrates. It is both an endocrine gland producing several important hormones, including insulin, glucagon, and somatostatin, as well as a digestive organ, secreting pancreatic juice containing digestive enzymes that assist... - LDH-5 (4M) - in the liverLiverThe liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
and striated muscleStriated muscleStriated muscle tissue is a form of fibers that are combined into parallel fibers. More specifically, it can refer to:* Cardiac muscle .* Skeletal muscle* Branchiomeric muscles...
The five isoenzymes that are usually described in the literature each contain four subunits. The major isoenzymes of skeletal muscle and liver, M4, has four muscle (M) subunits, while H4 is the main isoenzymes for heart muscle in most species, containing four heart (H) subunits. The other variants contain both types of subunits.
Usually LDH-2 is the predominant form in the serum
Blood serum
In blood, the serum is the component that is neither a blood cell nor a clotting factor; it is the blood plasma with the fibrinogens removed...
. A LDH-1 level higher than the LDH-2 level (a "flipped pattern") suggests myocardial infarction
Myocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...
(damage to heart tissues releases heart LDH, which is rich in LDH-1, into the bloodstream). The use of this phenomenon to diagnose infarction has been largely superseded by the use of Troponin
Troponin
400px|thumb|right|alt = Colored dice with checkered background|Ribbon representation of the human cardiac troponin core complex in the calcium-saturated form...
I or T measurement.
Genetics in Humans
The M and H subunits are encoded by two different geneGene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s:
- The M subunit is encoded by LDHA, located on chromosomeChromosomeA chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
11p15.4 - The H subunit is encoded by LDHB, located on chromosome 12p12.2-p12.1
- A third isoform, LDHC or LDHX, is expressed only in the testis ; its gene is likely a duplicate of LDHA and is also located on the eleventh chromosome (11p15.5-p15.3)
Mutations of the M subunit have been linked to the rare disease exertional myoglobinuria
Myoglobinuria
Myoglobinuria is the presence of myoglobin in the urine, usually associated with rhabdomyolysis or muscle destruction. Myoglobin is present in muscle cells as a reserve of oxygen.-Causes:...
(see OMIM article), and mutations of the H subunit have been described but do not appear to lead to disease.
Medical use
Tissue breakdown releases LDH, and therefore LDH can be measured as a surrogate for tissue breakdown, e.g. hemolysisHemolysis
Hemolysis —from the Greek meaning "blood" and meaning a "loosing", "setting free" or "releasing"—is the rupturing of erythrocytes and the release of their contents into surrounding fluid...
. Other disorders indicated by elevated LDH include cancer, meningitis, encephalitis, acute pancreatitis, and HIV.
Hemolysis
In medicineMedicine
Medicine is the science and art of healing. It encompasses a variety of health care practices evolved to maintain and restore health by the prevention and treatment of illness....
, LDH is often used as a marker of tissue breakdown as LDH is abundant in red blood cell
Red blood cell
Red blood cells are the most common type of blood cell and the vertebrate organism's principal means of delivering oxygen to the body tissues via the blood flow through the circulatory system...
s and can function as a marker for hemolysis
Hemolysis
Hemolysis —from the Greek meaning "blood" and meaning a "loosing", "setting free" or "releasing"—is the rupturing of erythrocytes and the release of their contents into surrounding fluid...
. A blood sample that has been handled incorrectly can show false-positively high levels of LDH due to erythrocyte damage.
It can also be used as a marker of myocardial infarction
Myocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...
. Following a myocardial infarction, levels of LDH peak at 3–4 days and remain elevated for up to 10 days. In this way, elevated levels of LDH (where the level of LDH1 is higher than that of LDH2) can be useful for determining whether a patient has had a myocardial infarction if they come to doctors several days after an episode of chest pain.
Tissue turnover
Other uses are assessment of tissue breakdownNecrosis
Necrosis is the premature death of cells in living tissue. Necrosis is caused by factors external to the cell or tissue, such as infection, toxins, or trauma. This is in contrast to apoptosis, which is a naturally occurring cause of cellular death...
in general; this is possible when there are no other indicators of hemolysis
Hemolysis
Hemolysis —from the Greek meaning "blood" and meaning a "loosing", "setting free" or "releasing"—is the rupturing of erythrocytes and the release of their contents into surrounding fluid...
. It is used to follow-up cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
(especially lymphoma
Lymphoma
Lymphoma is a cancer in the lymphatic cells of the immune system. Typically, lymphomas present as a solid tumor of lymphoid cells. Treatment might involve chemotherapy and in some cases radiotherapy and/or bone marrow transplantation, and can be curable depending on the histology, type, and stage...
) patients, as cancer cell
Cancer cell
Cancer cells are cells that grow and divide at an unregulated, quickened pace. Although cancer cells can be quite common in a person they are only malignant when the other cells fail to recognize and/or destroy them. In the past a common belief was that cancer cells failed to be recognized and...
s have a high rate of turnover with destroyed cells leading to an elevated LDH activity.
Exudates and transudates
Measuring LDH in fluid aspirated from a pleural effusionPleural effusion
Pleural effusion is excess fluid that accumulates between the two pleural layers, the fluid-filled space that surrounds the lungs. Excessive amounts of such fluid can impair breathing by limiting the expansion of the lungs during ventilation.-Pathophysiology:...
(or pericardial effusion
Pericardial effusion
Pericardial effusion is an abnormal accumulation of fluid in the pericardial cavity. Because of the limited amount of space in the pericardial cavity, fluid accumulation will lead to an increased intrapericardial pressure and this can negatively affect heart function...
) can help in the distinction between exudate
Exudate
An exudate is any fluid that filters from the circulatory system into lesions or areas of inflammation. It can apply to plants as well as animals. Its composition varies but generally includes water and the dissolved solutes of the main circulatory fluid such as sap or blood...
s (actively secreted fluid, e.g. due to inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
) or transudate
Transudate
Transudate is extravascular fluid with low protein content and a low specific gravity .This is in contrast to transudate where the extracellular fluid is an ultrafiltrate of blood plasma and thus larger molecules such as proteins and cell debris are absent....
s (passively secreted fluid, due to a high hydrostatic pressure or a low oncotic pressure
Oncotic pressure
Oncotic pressure, or colloid osmotic pressure, is a form of osmotic pressure exerted by proteins in blood plasma that usually tends to pull water into the circulatory system.Throughout the body, dissolved compounds have an osmotic pressure...
). The usual criterion is that a ratio of fluid LDH versus upper limit of normal serum LDH of more than 0.6 or indicates an exudate, while a ratio of less indicates a transudate. Different laboratories have different values for the upper limit of serum LDH, but examples include 200 and 300 IU
International unit
In pharmacology, the International Unit is a unit of measurement for the amount of a substance, based on biological activity or effect. It is abbreviated as IU, as UI , or as IE...
/L. In empyema
Empyema
Pleural empyema is an accumulation of pus in the pleural cavity. Most pleural empyemas arise from an infection within the lung , often associated with parapneumonic effusions. There are three stages: exudative, fibrinopurulent and organizing. In the exudative stage, the pus accumulates...
, the LDH levels, in general, will exceed 1000 IU/L.
Meningitis and encephalitis
High levels of lactate dehydrogenase in cerebrospinal fluid are often associated with bacterial meningitisMeningitis
Meningitis is inflammation of the protective membranes covering the brain and spinal cord, known collectively as the meninges. The inflammation may be caused by infection with viruses, bacteria, or other microorganisms, and less commonly by certain drugs...
. In the case of viral
Virus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...
meningitis, high LDH, in general, indicates the presence of encephalitis
Encephalitis
Encephalitis is an acute inflammation of the brain. Encephalitis with meningitis is known as meningoencephalitis. Symptoms include headache, fever, confusion, drowsiness, and fatigue...
and poor prognosis
Prognosis
Prognosis is a medical term to describe the likely outcome of an illness.When applied to large statistical populations, prognostic estimates can be very accurate: for example the statement "45% of patients with severe septic shock will die within 28 days" can be made with some confidence, because...
.
HIV
LDH is often measured in HIV patients as a non-specific marker for pneumonia due to Pneumocystis jiroveciPneumocystis pneumonia
Pneumocystis pneumonia or pneumocystosis is a form of pneumonia, caused by the yeast-like fungus Pneumocystis jirovecii...
(PCP). Elevated LDH in the setting of upper respiratory symptoms in an HIV patient suggests, but is not diagnostic for, PCP. However, in HIV-positive patients with respiratory symptoms, a very high LDH level (>600 IU/L) indicated histoplasmosis
Histoplasmosis
Histoplasmosis is a disease caused by the fungus Histoplasma capsulatum. Symptoms of this infection vary greatly, but the disease primarily affects the lungs...
(9.33 more likely) in a study of 120 PCP and 30 histoplasmosis patients.
Dysgerminoma
Elevated LDH is often the first clinical sign of a dysgerminomaGerminoma
A germinoma is a type of germ cell tumor which is not differentiated upon examination. It may be benign or malignant.-Classification:The term germinoma most often has referred to a tumor in the brain that has a histology identical to two other tumors: dysgerminoma in the ovary and seminoma in the...
. Not all dysgerminomas produce LDH, and this is often a non-specific finding.