Lactic acidosis

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Lactic acidosis

L-(+)-lactic acid

Specialty Endocrinology 

Lactic acidosis is a medical condition characterized by the buildup

of lactate (especially L-lactate) in the body, with formation of an excessively
low pH in the bloodstream. It is a form of metabolic acidosis, in which excessive
acid accumulates due to a problem with the body's oxidative metabolism.
Lactic acidosis is typically the result of an underlying acute or chronic medical
condition, medication, or poisoning. The symptoms are generally attributable to
these underlying causes, but may include nausea, vomiting, Kussmaul
breathing (laboured and deep), and generalised weakness.
The diagnosis is made on biochemical analysis of blood (often initially on arterial
blood gas samples), and once confirmed, generally prompts an investigation to
establish the underlying cause to treat the acidosis. In some
situations, hemofiltration (purification of the blood) is temporarily required. In rare
chronic forms of lactic acidosis caused by mitochondrial disease, a specific diet
or dichloroacetate may be used. The prognosis of lactic acidosis depends largely
on the underlying cause; in some situations (such as severe infections), it
indicates an increased risk of death.
 Contents

 1Classification
 2Signs and symptoms
 3Causes
 4Pathophysiology
 5Diagnosis
 6Treatment
 7Prognosis
 8Other animals
o 8.1Reptiles
o 8.2Ruminants
 9References
 10External links

Classification[edit]
The Cohen–Woods classification categorizes causes of lactic acidosis as: [1]

 Type A: Decreased tissue oxygenation (e.g., from decreased blood flow)

 Type B
o B1: Underlying diseases (sometimes causing type A)
o B2: Medication or intoxication
o B3: Inborn error of metabolism

Signs and symptoms[edit]

Lactic acidosis is commonly found in people who are unwell, such as those with
severe heart and/or lung disease, a severe infection with sepsis, the systemic
inflammatory response syndrome due to another cause, severe physical trauma,
or severe depletion of body fluids.[2] Symptoms in humans include all those of
typical metabolic acidosis (nausea, vomiting, generalized muscle weakness, and
laboured and deep breathing).[3]

Causes[edit]
The several different causes of lactic acidosis include: [citation needed]

 Genetic conditions
o
Biotinidase deficiency, multiple carboxylase deficiency, or
nongenetic deficiencies of biotin
o
Diabetes mellitus and deafness
o
Fructose 1,6-bisphosphatase deficiency
o
Glucose-6-phosphatase deficiency
o
GRACILE syndrome
o
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like
episodes
o
Pyruvate dehydrogenase deficiency
 o
Pyruvate carboxylase deficiency
o
Leigh syndrome
 Drugs
o
Linezolid[4]
o
Paracetamol/acetaminophen poisoning[5]
o
Metformin: this risk is low (less than 10 cases for 100,000 patient
years), but the risk of metformin-induced lactic acidosis (MALA) increases
in certain situations where both the plasma levels of metformin are
increased and lactate clearance is impaired.[6] The older related and now
withdrawn drug phenformin carried a much higher risk of lactic acidosis.[7]
o
Isoniazid toxicity
o
Propofol
o
Epinephrine[citation needed]
o
Propylene glycol (D-lactic acidosis)
o
Nucleoside reverse-transcriptase inhibitors
o
Abacavir/dolutegravir/lamivudine[8]
o
Emtricitabine/tenofovir[9]
o
Potassium cyanide (cyanide poisoning)
o
Fialuridine[10]
 Other
o
Thiamine deficiency (especially during TPN)
o
Impaired delivery of oxygen to cells in the tissues (e.g., from
impaired blood flow (hypoperfusion))
o
Bleeding
o
Polymyositis
o
Ethanol toxicity
o
Sepsis
o
Shock
o
Advanced liver disease
o
Diabetic ketoacidosis
o
Excessive exercise (overtraining)
o
Regional hypoperfusion (e.g., bowel ischemia or marked cellulitis)
o
Cancers such as Non-Hodgkin's and Burkitt lymphomas
o
Pheochromocytoma[2]
o
Tumor lysis syndrome[11]
o
D-lactic acidosis due to intestinal bacterial flora production in short
gut syndrome

Pathophysiology[edit]
Glucose metabolism begins with glycolysis, in which the molecule is broken
down into pyruvate in ten enzymatic steps. A significant proportion of pyruvate is
converted into lactate (usually 10:1). The human metabolism produces about 20
mmol/kg of lactate acid every 24 hours. This happens predominantly in tissues
(especially muscle) that have high levels of the "A" isoform of the enzyme lactate
dehydrogenase (LDHA), which predominantly converts pyruvate into lactate. The
lactate is carried by the bloodstream to other tissues where it is converted at the
expense of ATP back to pyruvate by the "B" isoform of LDH (LDHB). Firstly there
is gluconeogenesis in the liver (as well as the kidney and some other tissues),
where pyruvate is converted into glucose; this is known as the Cori cycle. In
addition, lactate moved to other tissues enters the citric acid cycle and
eventually oxidative phosphorylation, a process that yields ATP.[2]
Elevations in lactate are either a consequence of increased production or of
decreased metabolism. With regards to metabolism, this predominantly takes
place in the liver (70%), which explains that lactate levels may be elevated in the
setting of liver disease.[2]
In "type A" lactic acidosis, the production of lactate is attributable to insufficient
oxygen for aerobic metabolism. If there is no oxygen available for the parts of the
glucose metabolism that require oxygen (citric acid cycle and oxidative
phosphorylation), excess pyruvate will be converted in excess lactate. In "type B"
lactic acidosis the lactate accumulates because there is a mismatch between
glycolysis activity and the remainder of glucose metabolism. Examples are
situations where the sympathetic nervous system is highly active (e.g.
severe asthma).[2] There is controversy as to whether elevated lactate in acute
illness can be attributed to tissue hypoxia; there is limited empirical support for
this theoretical notion.[12]

Diagnosis[edit]
Acid-base disturbances such as lactic acidosis are typically first assessed
using arterial blood gas tests. Testing of venous blood is also available as an
alternative as they are effectively interchangeable. [2] Normally resulting lactate
concentrations are in the range indicated below: [13]

mg/dL mM

Venous blood 4.5–19.8 0.5–2.2

Arterial blood 4.5–14.4 0.5–1.6

Lactic acidosis is classically defined as an elevated lactate together with pH <

7.35 and bicarbonate below 20 mmol/l, but this is not required as lactic acidosis
may exist together with other acid-base abnormalities that may affect these two
parameters.[2]

Treatment[edit]
If elevated lactate is present in acute illness, supporting the oxygen supply and
blood flow are key initial steps.[2] Some vasopressors (drugs that augment the
blood pressure) are less effective when lactate levels are high, and some
agents that stimulate the beta-2 adrenergic receptor can elevate the lactate
further.[2]
Direct removal of lactate from the body (e.g. with hemofiltration or dialysis) is
difficult, with limited evidence for benefit; it may not be possible to keep up with
the lactate production.[2]
Limited evidence supports the use of sodium bicarbonate solutions to improve
the pH (which is associated with increased carbon dioxide generation and may
reduce the calcium levels).[2][14]
Lactic acidosis caused by inherited mitochondrial disorders (type B3) may be
treated with a ketogenic diet and possibly with dichloroacetate (DCA),[15] although
this may be complicated by peripheral neuropathy and has a weak evidence
base.[16]

Prognosis[edit]
Mild and transient elevations in lactate have limited impact on mortality, whereas
sustained and severe lactate elevations are associated with a high mortality. [2]
The mortality of lactic acidosis in people taking metformin was previously
reported to be 50%, but in more recent reports this was closer to 25%. [17]

Other animals[edit]
Reptiles[edit]
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.[18] Cases are recorded in which particularly large
crocodiles which put up extreme resistance to capture later died of the resulting
pH imbalance.[19]
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.[20] 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.[20] This calcium serves as a buffer, reacting with the
excess lactate to form the precipitate calcium lactate. This precipitate is
suggested to be reabsorbed by the shell and skeleton, thereby removing it from
the bloodstream; studies examining turtles that have been subjected to
prolonged anoxic conditions have up to 45% of their lactate stored within their
skeletal structure.[20]
Ruminants[edit]
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.[21][22][23] Activity of various rumen organisms results in
accumulation of various volatile fatty acids (normally, mostly acetic, propionic,
and butyric acids), which are partially dissociated. [24] 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.[25] 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.[24]
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.[21] 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,[26] where it dissociates, lowering blood pH. Both L and D
isomers of lactic acid are produced in the rumen; [21] 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. [25]
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.[21][22][23] Administration of lasalocid or monensin in
feed can reduce risk of lactic acidosis in ruminants, [27] inhibiting most of the
lactate-producing bacterial species without inhibiting the major lactate
fermenters.[28] 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. [29]
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). [21][22][23]

References[edit]
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