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|Classification and external resources|
|Classification and external resources|
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.
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 to drive useful work, such as muscle contraction. When the energy in ATP is used during cell work via ATP hydrolysis, protons (positively charged hydrogen ions, or cations) are released. The mitochondria normally incorporate these free hydrogen nuclei back into ATP, thus preventing buildup of unbound hydrogen cations, 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 resulting from ATP hydrolysis. Therefore, hydrogen cation concentration rises and causes acidosis.
The excess hydrogen cations in 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 requires a cation 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 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 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 antidiabetic drugs phenformin). Metformin is, however, unlikely to cause lactic acidosis although the belief remains in clinical practice. 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.
In ruminant livestock, the cause of clinically serious lactic acidosis is different from the causes described above. See the "In animals" section, below.
The list of signs and symptoms of lactic acidosis includes the following:
The Cohen-Woods classification categorizes causes of lactic acidosis as follows:
The several different causes of lactic acidosis include:
Lactic acidosis is an underlying process of rigor mortis. Tissue in the muscles of the deceased carry out anaerobic metabolism in the absence of oxygen, using muscle glycogen as the energy source, and significant amounts of lactic acid are released 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.) In meat-producing animals, the post-mortem pH drop in muscle tissue contributes to meat quality (by influencing water retention, cutting color and texture of meat) and also contributes to food safety by inhibiting several acid-intolerant spoilage organisms that otherwise might proliferate, even at refrigerator temperature.
Lactic acidosis may also result from vitamin B1 (thiamine) deficiency.
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.
In domestic 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).