Lactic acidosis
Encyclopedia
Lactic acidosis is a physiological condition characterized by low pH in body tissues and blood (acidosis
) accompanied by the buildup of lactate
especially D-lactate, and is considered a distinct form of metabolic acidosis
. The condition typically occurs when cells receive too little oxygen (hypoxia
), for example during vigorous exercise. In this situation, impaired cellular respiration leads to lower pH levels. Simultaneously, cells are forced to metabolize glucose
anaerobically
, which leads to lactate formation. Therefore, elevated lactate is indicative of tissue hypoxia
, hypoperfusion, and possible damage. Lactic acidosis is characterized by lactate levels >5 mmol/L and serum pH <7.35.
to form water and carbon dioxide
. This is a two-step process. First, glucose is broken down to pyruvate through glycolysis
. Then, mitochondria oxidize the pyruvate into water and carbon dioxide by means of the Krebs cycle and oxidative phosphorylation
. This second step requires oxygen
. The net result is ATP
, the energy carrier used by the cell to drive useful work such as muscle contraction. When the energy in ATP is utilized during cell work (ATP hydrolysis
), protons are produced. The mitochondria normally incorporate these protons back into ATP, thus preventing buildup of protons and maintaining neutral pH.
If oxygen supply is inadequate (hypoxia
), the mitochondria are unable to continue ATP synthesis at a rate sufficient to supply the cell with the required ATP. In this situation, glycolysis is increased to provide additional ATP, and the excess pyruvate produced is converted into lactate
and released from the cell into the bloodstream, where it accumulates over time. While increased glycolysis helps compensate for less ATP from oxidative phosphorylation
, it cannot bind the protons resulting from ATP hydrolysis. Therefore, proton concentration rises and causes acidosis.
It is widely believed that the excess protons in lactic acidosis actually derive from production of lactic acid. This is incorrect as cells do not produce lactic acid; pyruvate is converted directly into lactate, the anionic form of lactic acid. When excess intracellular lactate is released into the blood, maintenance of electroneutrality requires a cation (e.g. a proton) to be released as well. This can reduce blood pH. Glycolysis coupled with lactate production is neutral in the sense that it does not produce excess protons. However, pyruvate production does produce protons. Lactate production is buffered intracellularly, e.g. the lactate-producing enzyme lactate dehydrogenase
binds one proton per pyruvate molecule converted. When such buffer systems become saturated, cells will transport lactate into the blood stream. Hypoxia certainly causes both buildup of lactate and acidification, and lactate is therefore a good "marker" of hypoxia, but lactate itself is not the cause of low pH.
Lactic acidosis sometimes occurs without hypoxia, for example in rare congenital disorders where mitochondria do not function at full capacity. In such cases, when the body needs more energy than usual, for example during exercise or disease, mitochondria cannot match the cells' demand for ATP, and lactic acidosis results. Also, muscle types that have few mitochondria and preferentially use glycolysis for ATP production (fast-twitch or type II fibers) are naturally prone to lactic acidosis.
The signs of lactic acidosis are deep and rapid breathing, vomiting, and abdominal pain—symptoms that may easily be mistaken for other problems.
Lactic acidosis may be caused by diabetic ketoacidosis
or liver
or kidney
disease, as well as some forms of medication (notably the anti-diabetic drugs phenformin
and metformin
). Some anti-HIV drugs (antiretrovirals) warn doctors in their prescribing information to regularly watch for symptoms of lactic acidosis caused by mitochondrial toxicity
. Heavy metal toxicity, including arsenic poisoning
can raise lactate levels and lead to generalized metabolic acidosis
as well.
These causes include:
. Tissue in the muscles of the deceased resort to anaerobic metabolism in the absence of oxygen and significant amounts of lactic acid are released into the muscle tissue. This along with the loss of ATP
causes the muscles to grow stiff.
Lactic acidosis may also result from vitamin B1 (thiamine) deficiency.
) for intense movements, can be particularly susceptible to lactic acidosis. In particular, during the capture of large crocodiles, the animals' use of their glycolytic muscles often alter the blood's pH to a point where they are unable to respond to stimuli or move. There are recorded cases in which particularly large crocodiles who put up extreme resistance to capture later died of the resulting pH
imbalance.
Acidosis
Acidosis is an increased acidity in the blood and other body tissue . If not further qualified, it usually refers to acidity of the blood plasma....
) accompanied by the buildup of lactate
Lactate
Lactate may refer to:*The act of lactation*The conjugate base of lactic acid...
especially D-lactate, and is considered a distinct form of metabolic acidosis
Metabolic acidosis
In medicine, metabolic acidosis is a condition that occurs when the body produces too much acid or when the kidneys are not removing enough acid from the body. If unchecked, metabolic acidosis leads to acidemia, i.e., blood pH is low due to increased production of hydrogen by the body or the...
. The condition typically occurs when cells receive too little oxygen (hypoxia
Hypoxia (medical)
Hypoxia, or hypoxiation, is a pathological condition in which the body as a whole or a region of the body is deprived of adequate oxygen supply. Variations in arterial oxygen concentrations can be part of the normal physiology, for example, during strenuous physical exercise...
), for example during vigorous exercise. In this situation, impaired cellular respiration leads to lower pH levels. Simultaneously, cells are forced to metabolize glucose
Glucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...
anaerobically
Lactic acid fermentation
Lactic acid fermentation is a biological process by which sugars such as glucose, fructose, and sucrose, are converted into cellular energy and the metabolic byproduct lactate. It is an anaerobic fermentation reaction that occurs in some bacteria and animal cells, such as muscle cells, in the...
, which leads to lactate formation. Therefore, elevated lactate is indicative of tissue hypoxia
Hypoxia (medical)
Hypoxia, or hypoxiation, is a pathological condition in which the body as a whole or a region of the body is deprived of adequate oxygen supply. Variations in arterial oxygen concentrations can be part of the normal physiology, for example, during strenuous physical exercise...
, hypoperfusion, and possible damage. Lactic acidosis is characterized by lactate levels >5 mmol/L and serum pH <7.35.
Pathophysiology
Most cells in the body normally burn glucoseGlucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...
to form water and carbon dioxide
Carbon dioxide
Carbon dioxide is a naturally occurring chemical compound composed of two oxygen atoms covalently bonded to a single carbon atom...
. This is a two-step process. First, glucose is broken down to pyruvate through glycolysis
Glycolysis
Glycolysis is the metabolic pathway that converts glucose C6H12O6, into pyruvate, CH3COCOO− + H+...
. Then, mitochondria oxidize the pyruvate into water and carbon dioxide by means of the Krebs cycle and oxidative phosphorylation
Oxidative phosphorylation
Oxidative phosphorylation is a metabolic pathway that uses energy released by the oxidation of nutrients to produce adenosine triphosphate . Although the many forms of life on earth use a range of different nutrients, almost all aerobic organisms carry out oxidative phosphorylation to produce ATP,...
. This second step requires oxygen
Oxygen
Oxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...
. The net result is ATP
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
, the energy carrier used by the cell to drive useful work such as muscle contraction. When the energy in ATP is utilized during cell work (ATP hydrolysis
ATP hydrolysis
ATP hydrolysis is the reaction by which chemical energy that has been stored and transported in the high-energy phosphoanhydridic bonds in ATP is released, for example in the muscles, to produce work. The product is ADP and an inorganic phosphate, orthophosphate...
), protons are produced. The mitochondria normally incorporate these protons back into ATP, thus preventing buildup of protons and maintaining neutral pH.
If oxygen supply is inadequate (hypoxia
Hypoxia (medical)
Hypoxia, or hypoxiation, is a pathological condition in which the body as a whole or a region of the body is deprived of adequate oxygen supply. Variations in arterial oxygen concentrations can be part of the normal physiology, for example, during strenuous physical exercise...
), the mitochondria are unable to continue ATP synthesis at a rate sufficient to supply the cell with the required ATP. In this situation, glycolysis is increased to provide additional ATP, and the excess pyruvate produced is converted into lactate
Lactate
Lactate may refer to:*The act of lactation*The conjugate base of lactic acid...
and released from the cell into the bloodstream, where it accumulates over time. While increased glycolysis helps compensate for less ATP from oxidative phosphorylation
Oxidative phosphorylation
Oxidative phosphorylation is a metabolic pathway that uses energy released by the oxidation of nutrients to produce adenosine triphosphate . Although the many forms of life on earth use a range of different nutrients, almost all aerobic organisms carry out oxidative phosphorylation to produce ATP,...
, it cannot bind the protons resulting from ATP hydrolysis. Therefore, proton concentration rises and causes acidosis.
It is widely believed that the excess protons in lactic acidosis actually derive from production of lactic acid. This is incorrect as cells do not produce lactic acid; pyruvate is converted directly into lactate, the anionic form of lactic acid. When excess intracellular lactate is released into the blood, maintenance of electroneutrality requires a cation (e.g. a proton) to be released as well. This can reduce blood pH. Glycolysis coupled with lactate production is neutral in the sense that it does not produce excess protons. However, pyruvate production does produce protons. Lactate production is buffered intracellularly, e.g. the lactate-producing enzyme lactate dehydrogenase
Lactate dehydrogenase
Lactate dehydrogenase 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 or L-lactate...
binds one proton per pyruvate molecule converted. When such buffer systems become saturated, cells will transport lactate into the blood stream. Hypoxia certainly causes both buildup of lactate and acidification, and lactate is therefore a good "marker" of hypoxia, but lactate itself is not the cause of low pH.
Lactic acidosis sometimes occurs without hypoxia, for example in rare congenital disorders where mitochondria do not function at full capacity. In such cases, when the body needs more energy than usual, for example during exercise or disease, mitochondria cannot match the cells' demand for ATP, and lactic acidosis results. Also, muscle types that have few mitochondria and preferentially use glycolysis for ATP production (fast-twitch or type II fibers) are naturally prone to lactic acidosis.
The signs of lactic acidosis are deep and rapid breathing, vomiting, and abdominal pain—symptoms that may easily be mistaken for other problems.
Lactic acidosis may be caused by diabetic ketoacidosis
Diabetic ketoacidosis
Diabetic ketoacidosis is a potentially life-threatening complication in patients with diabetes mellitus. It happens predominantly in those with type 1 diabetes, but it can occur in those with type 2 diabetes under certain circumstances...
or 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...
or kidney
Kidney
The 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...
disease, as well as some forms of medication (notably the anti-diabetic drugs phenformin
Phenformin
Phenformin is an anti-diabetic drug from the biguanide class. It was marketed as DBI by Ciba-Geigy but was withdrawn from most markets in the late 1970s due to a high risk of lactic acidosis, which was fatal in 50% of cases....
and metformin
Metformin
Metformin is an oral antidiabetic drug in the biguanide class. It is the first-line drug of choice for the treatment of type 2 diabetes, in particular, in overweight and obese people and those with normal kidney function. Its use in gestational diabetes has been limited by safety concerns...
). Some anti-HIV drugs (antiretrovirals) warn doctors in their prescribing information to regularly watch for symptoms of lactic acidosis caused by mitochondrial toxicity
Mitochondrial toxicity
Mitochondrial toxicity is a condition in which the mitochondria of a body's cells become damaged or decline significantly in number; it occurs as a side effect of certain antiretroviral drugs used to treat human immunodeficiency virus, or HIV.-Causes:...
. Heavy metal toxicity, including arsenic poisoning
Arsenic poisoning
Arsenic poisoning is a medical condition caused by increased levels of the element arsenic in the body. Arsenic interferes with cellular longevity by allosteric inhibition of an essential metabolic enzyme...
can raise lactate levels and lead to generalized metabolic acidosis
Metabolic acidosis
In medicine, metabolic acidosis is a condition that occurs when the body produces too much acid or when the kidneys are not removing enough acid from the body. If unchecked, metabolic acidosis leads to acidemia, i.e., blood pH is low due to increased production of hydrogen by the body or the...
as well.
Symptoms
The list of signs and symptoms of lactic acidosis includes the following:- NauseaNauseaNausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
- VomitingVomitingVomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...
- HyperventilationHyperventilationHyperventilation or overbreathing is the state of breathing faster or deeper than normal, causing excessive expulsion of circulating carbon dioxide. It can result from a psychological state such as a panic attack, from a physiological condition such as metabolic acidosis, can be brought about by...
(to remove CO2) - Abdominal pain
- LethargyFatigueFatigue may refer to:*Fatigue , structural damage from repeated loading*Fatigue , a state of physical and/or mental weakness*Fatigue , safety implications of tiredness...
- AnxietyAnxietyAnxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
- Severe aenemia
- HypotensionHypotensionIn physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
- Irregular heart rateCardiac dysrhythmiaCardiac dysrhythmia is any of a large and heterogeneous group of conditions in which there is abnormal electrical activity in the heart. The heart beat may be too fast or too slow, and may be regular or irregular.Some arrhythmias are life-threatening medical emergencies that can result in cardiac...
- TachycardiaTachycardiaTachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate...
Classification
The Cohen-Woods classification categorizes causes of lactic acidosis as follows:- Type A: Decreased perfusion or oxygenation
- Type B:
- B1: Underlying diseases (sometimes causing type A)
- B2: Medication or intoxication
- B3: Inborn error of metabolismInborn error of metabolismInborn errors of metabolism comprise a large class of genetic diseases involving disorders of metabolism. The majority are due to defects of single genes that code for enzymes that facilitate conversion of various substances into others...
Causes
There are several different causes of lactic acidosis.These causes include:
- Genetic conditions
- Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS)
- Diabetes mellitus and deafnessDiabetes mellitus and deafnessDiabetes mellitus and deafness or maternally inherited diabetes and deafness is a mitochondrial disease associated with the gene "Leu-UUR".-Alternative names:*diabetes and deafness, maternally inherited; MIDD*Ballinger-Wallace syndrome...
- Glucose-6-phosphatase deficiency
- Fructose 1,6-diphosphatase deficiencyFructose bisphosphatase deficiencyIn Fructose bisphosphatase deficiency, there is not enough fructose bisphosphatase for gluconeogenesis to occur correctly. Glycolysis will still work, as it does not use this enzyme.-Presentation:...
- Pyruvate dehydrogenase deficiencyPyruvate dehydrogenase deficiencyPyruvate Dehydrogenase Deficiency is a genetic disease that involves human metabolism.-Inheritance and pathophysiology:It most commonly follows an X-linked inheritance pattern, but is approximately equally prevalent in both males and females. This is because heterozygote females commonly manifest...
- Pyruvate carboxylase deficiencyPyruvate carboxylase deficiencyPyruvate carboxylase deficiency is an inherited disorder that causes lactic acid and other potentially toxic compounds to accumulate in the blood. High levels of these substances can damage the body's organs and tissues, particularly in the nervous system. Pyruvate carboxylase deficiency is a rare...
- Drugs
- phenforminPhenforminPhenformin is an anti-diabetic drug from the biguanide class. It was marketed as DBI by Ciba-Geigy but was withdrawn from most markets in the late 1970s due to a high risk of lactic acidosis, which was fatal in 50% of cases....
- metforminMetforminMetformin is an oral antidiabetic drug in the biguanide class. It is the first-line drug of choice for the treatment of type 2 diabetes, in particular, in overweight and obese people and those with normal kidney function. Its use in gestational diabetes has been limited by safety concerns...
- isoniazidIsoniazidIsoniazid , also known as isonicotinylhydrazine , is an organic compound that is the first-line antituberculosis medication in prevention and treatment. It was first discovered in 1912, and later in 1951 it was found to be effective against tuberculosis by inhibiting its mycolic acid...
toxicity - nucleosideNucleosideNucleosides are glycosylamines consisting of a nucleobase bound to a ribose or deoxyribose sugar via a beta-glycosidic linkage...
reverse transcriptase inhibitors - potassium cyanidePotassium cyanidePotassium cyanide is an inorganic compound with the formula KCN. This colorless crystalline compound, similar in appearance to sugar, is highly soluble in water. Most KCN is used in gold mining, organic synthesis, and electroplating. Smaller applications include jewelry for chemical gilding and...
(Cyanide poisoningCyanide poisoningCyanide poisoning occurs when a living organism is exposed to a compound that produces cyanide ions when dissolved in water. Common poisonous cyanide compounds include hydrogen cyanide gas and the crystalline solids potassium cyanide and sodium cyanide...
)
- phenformin
- Other
- Hypoxia and hypoperfusion
- Hemorrhage
- Ethanol toxicity
- SepsisSepsisSepsis is a potentially deadly medical condition that is characterized by a whole-body inflammatory state and the presence of a known or suspected infection. The body may develop this inflammatory response by the immune system to microbes in the blood, urine, lungs, skin, or other tissues...
- Shock
- Hepatic disease
- Diabetic ketoacidosisDiabetic ketoacidosisDiabetic ketoacidosis is a potentially life-threatening complication in patients with diabetes mellitus. It happens predominantly in those with type 1 diabetes, but it can occur in those with type 2 diabetes under certain circumstances...
- Muscular exercise
- Regional hypoperfusion (bowel ischemia, marked cellulitisCellulitisCellulitis is a diffuse inflammation of connective tissue with severe inflammation of dermal and subcutaneous layers of the skin. Cellulitis can be caused by normal skin flora or by exogenous bacteria, and often occurs where the skin has previously been broken: cracks in the skin, cuts, blisters,...
...) - Non-Hodgkin'sNon-Hodgkin lymphomaThe non-Hodgkin lymphomas are a diverse group of blood cancers that include any kind of lymphoma except Hodgkin's lymphomas. Types of NHL vary significantly in their severity, from indolent to very aggressive....
and Burkitt lymphoma
Associated conditions
Lactic acidosis is an underlying process of rigor mortisRigor mortis
Rigor mortis is one of the recognizable signs of death that is caused by a chemical change in the muscles after death, causing the limbs of the corpse to become stiff and difficult to move or manipulate...
. Tissue in the muscles of the deceased resort to anaerobic metabolism in the absence of oxygen and significant amounts of lactic acid are released into the muscle tissue. This along with the loss of ATP
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
causes the muscles to grow stiff.
Lactic acidosis may also result from vitamin B1 (thiamine) deficiency.
In animals
Reptiles, which rely primarily on anaerobic energy metabolism (glycolysisGlycolysis
Glycolysis is the metabolic pathway that converts glucose C6H12O6, into pyruvate, CH3COCOO− + H+...
) for intense movements, can be particularly susceptible to lactic acidosis. In particular, during the capture of large crocodiles, the animals' use of their glycolytic muscles often alter the blood's pH to a point where they are unable to respond to stimuli or move. There are recorded cases in which particularly large crocodiles who put up extreme resistance to capture later died of the resulting pH
PH
In chemistry, pH is a measure of the acidity or basicity of an aqueous solution. Pure water is said to be neutral, with a pH close to 7.0 at . Solutions with a pH less than 7 are said to be acidic and solutions with a pH greater than 7 are basic or alkaline...
imbalance.