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Lactic acidosis is a physiological condition characterized by low pH in body tissues and blood (acidosis) accompanied by the buildup of lactate, especially L-lactate, and is considered a distinct form of metabolic acidosis. Lactic acidosis is characterized by lactate levels >5 mmol/L and serum pH <7.35.
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.
Signs and symptoms
Lactic acidosis is commonly found in people who are unwell for one of various reasons, such as severe heart and/or lung disease, a severe infection with sepsis, the systemic inflammatory response syndrome (SIRS) due to another cause, severe physical trauma, or severe depletion of body fluids.
The several different causes of lactic acidosis:
- Genetic conditions
- Biotinidase deficiency, Multiple carboxylase deficiency, or non-genetic deficiencies of biotin
- Diabetes mellitus and deafness
- Fructose 1,6-diphosphatase deficiency
- Glucose-6-phosphatase deficiency
- GRACILE syndrome
- Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS)
- Pyruvate dehydrogenase deficiency
- Pyruvate carboxylase deficiency
Most cells in the body normally metabolize glucose to form water and carbon dioxide in 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 for metabolic activities and perform work, such as muscle contraction. When the energy in ATP is used during cell work via ATP hydrolysis, hydrogen ions, (positively charged protons) are released. The mitochondria normally incorporate these free hydrogen nuclei back into ATP, thus preventing buildup of unbound hydrogen cations, 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 hydrogen cations that result from ATP hydrolysis. Therefore, hydrogen cation concentration rises and causes acidosis.
The excess hydrogen cations produced during lactic acidosis are widely believed to 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 of the blood requires that a cation be released into the blood, as well. This can reduce blood pH. Glycolysis coupled with lactate production is neutral in the sense that it does not produce excess hydrogen cations, however, pyruvate production does produce them. Lactate production is buffered intracellularly, e.g. the lactate-producing enzyme, lactate dehydrogenase, binds one hydrogen cation per pyruvate molecule converted. When such buffer systems become saturated, cells will transport lactate into the bloodstream. Hypoxia certainly causes both a buildup of lactate and acidification, and lactate is therefore a good "marker" of hypoxia, but lactate itself is not the cause of low pH. There is a view that during exercise and critical illness, lactate production is not generated by lack of oxygen but by catecholamine-driven glycolysis, and that the lactate serves as an energy source for other tissues.
Lactic acidosis sometimes occurs without hypoxia, for example, in rare inborn errors of metabolism 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.
Lactic acidosis is an underlying process of rigor mortis. In the absence of oxygen, tissue in the muscles of the deceased carry out anaerobic metabolism using muscle glycogen as the energy source, releasing significant amounts of lactic acid into the muscle tissue. With depletion of muscle glycogen, the loss of ATP causes the muscles to grow stiff, as the actin-myosin bonds cannot be released. (Rigor is later resolved by enzymatic breakdown of the myofibers.)
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 metabolism
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Direct removal of lactate from the body (e.g. with hemofiltration) is difficult, and there is limited evidence for benefit. In type A lactic acidosis, treatment consists of effective management of the underlying cause, and there is limited evidence to support the use of sodium bicarbonate solutions to improve the pH (which is associated with increased carbon dioxide generation and may reduce the calcium levels).
In lactic acidosis produced by medication, withdrawal of the medication may be necessary.
Lactic acidosis in the context of mitochondrial disorders (type B3) may be treated with a ketogenic diet and possibly with dichloroacetate (DCA), although this may be complicated by peripheral neuropathy and has a weak evidence base.
Reptiles, which rely primarily on anaerobic energy metabolism (glycolysis) 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.
Certain turtle species have been found to be capable of tolerating high levels of lactic acid without suffering the effects of lactic acidosis. Painted turtles hibernate buried in mud or underwater and do not resurface for the entire Winter. As a result they rely on anaerobic respiration to provide the majority of their energy needs. Adaptations in particular in the turtle's blood composition and shell allow it to tolerate high levels of lactic acid accumulation. In the anoxic conditions where anaerobic respiration is dominant, calcium levels in the blood plasma increase. This calcium serves as a buffer, reacting with the excess lactate to form the precipitate calcium lactate. It is suggested that this precipitate is reabsorbed by the shell and skeleton thereby removing it from the bloodstream; studies examining turtles who have been subjected to prolonged anoxic conditions have up to 45% of their lactate stored within their skeletal structure.
In ruminant livestock, the cause of clinically serious lactic acidosis is different from the causes described above.
In domesticated ruminants, lactic acidosis may occur as a consequence of ingesting large amounts of grain, especially when the rumen population is poorly adapted to deal with grain. Activity of various rumen organisms results in accumulation of various volatile fatty acids (normally, mostly acetic, propionic and butyric acids), which are partially dissociated. Although some lactate is normally produced in the rumen, it is normally metabolized by such organisms as Megasphaera elsdenii and, to a lesser extent, Selenomonas ruminantium and some other organisms. With high grain consumption, the concentration of dissociated organic acids can become quite high, resulting in rumen pH dropping below 6. Within this lower pH range, Lactobacillus spp. (producing lactate and hydrogen ions) are favored, and M. elsdenii and S. ruminantium are inhibited, tending to result in a considerable rise of lactate and hydrogen ion concentrations in the rumen fluid. The pKa of lactic acid is low, about 3.9, versus, for example, 4.8 for acetic acid; this contributes to the considerable drop in rumen pH which can occur.
Because of the high solute concentration of the rumen fluid under such conditions, considerable water is translocated from the blood to the rumen along the osmotic potential gradient, resulting in dehydration which cannot be relieved by drinking, and which can ultimately lead to hypovolemic shock. As more lactate accumulates and rumen pH drops, the ruminal concentration of undissociated lactic acid increases. Undissociated lactic acid can cross the rumen wall to the blood, where it dissociates, lowering blood pH. Both L and D isomers of lactic acid are produced in the rumen; these isomers are metabolized by different metabolic pathways, and activity of the principal enzyme involved in metabolism of the D isomer declines greatly with lower pH, tending to result in an increased ratio of D:L isomers as acidosis progresses.
Measures for preventing lactic acidosis in ruminants include avoidance of excessive amounts of grain in the diet, and gradual introduction of grain over a period of several days, to develop a rumen population capable of safely dealing with a relatively high grain intake. Administration of lasalocid or monensin in feed can reduce risk of lactic acidosis in ruminants, inhibiting most of the lactate-producing bacterial species without inhibiting the major lactate fermenters. Also, using a higher feeding frequency to provide the daily grain ration can allow higher grain intake without reducing the pH of the rumen fluid.
Treatment of lactic acidosis in ruminants may involve intravenous administration of dilute sodium bicarbonate, oral administration of magnesium hydroxide, and/or repeated removal of rumen fluids and replacement with water (followed by reinoculation with rumen organisms, if necessary).
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