Lactic acidosis is a physiological condition characterized by low pH in body tissues and
blood 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, 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 The signs of lactic acidosis are deep and
rapid breathing, vomiting, and abdominal pain. These symptoms are not specific for lactic
acidosis. The deep breathing, which occurs in other types of metabolic acidosis, arises
as an attempt to reduce blood acidity by exhaling carbon dioxide.
The list of signs and symptoms of lactic acidosis includes the following:
Nausea Vomiting
Hyperventilation Abdominal pain
Lethargy Anxiety
Severe anemia Hypotension
Irregular heart rate Tachycardia
Causes 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
Pyruvate dehydrogenase deficiency Pyruvate carboxylase deficiency
Drugs Phenformin
Metformin Isoniazid toxicity
Nucleoside reverse transcriptase inhibitors Potassium cyanide
Fialuridine Truvada
Other Hypoxia and hypoperfusion
Hemorrhage Ethanol toxicity
Sepsis Shock
Hepatic disease Diabetic ketoacidosis
Excessive exercise Regional hypoperfusion
Non-Hodgkin's and Burkitt lymphomas
Pathophysiology 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 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, 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. There is a view
that in 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 are naturally prone to lactic acidosis.
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.
Classification The Cohen-Woods classification categorizes
causes of lactic acidosis as follows: Type A: Decreased perfusion or oxygenation
Type B: B1: Underlying diseases
B2: Medication or intoxication B3: Inborn error of metabolism
Treatment Direct removal of lactate from the body 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.
In lactic acidosis secondary to medication, withdrawal of the medication may be necessary.
Lactic acidosis in the context of mitochondrial disorders may be treated with a ketogenic
diet and possibly with dichloroacetate, although this may be complicated by peripheral neuropathy
and has a weak evidence base. Other animals
Reptiles Reptiles, which rely primarily on anaerobic
energy metabolism 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.
Ruminants In ruminant livestock, the cause of clinically
serious lactic acidosis is different from the causes described above.
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, 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. 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.
References