Lactic acidosis is a medical condition characterized by a build-up of
lactate
Lactate may refer to:
* Lactation, the secretion of milk from the mammary glands
* Lactate, the conjugate base of lactic acid
Lactic acid is an organic acid. It has a molecular formula . It is white in the solid state and it is miscible with ...
(especially -lactate) in the body, with formation of an excessively low
pH in the bloodstream. It is a form of
metabolic acidosis
Metabolic acidosis is a serious electrolyte disorder characterized by an imbalance in the body's acid-base balance. Metabolic acidosis has three main root causes: increased acid production, loss of bicarbonate, and a reduced ability of the kidneys ...
, 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
Dichloroacetic acid (DCA), sometimes called bichloroacetic acid (BCA), is the chemical compound with formula . It is an acid, an analogue of acetic acid, in which 2 of the 3 hydrogen atoms of the methyl group have been replaced by chlorine ato ...
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.
Classification
The
Cohen–
Woods
Woods or The Woods may refer to:
Common meanings
* Woodland
* Forest
* Wood, solid material from trees or shrubs
Places United States
* Woods, Kentucky
* Woods, Oregon
* Woods, a municipality in Liberty County, Florida
* The Woods, a ...
classification categorizes causes of lactic acidosis as:
* Type A: Decreased tissue oxygenation (e.g., from decreased blood flow)
* Type B
** B1: Underlying diseases (sometimes causing type A)
** B2: Medication or intoxication
** B3:
Inborn error of metabolism
Signs and symptoms
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
An injury is any physiological damage to living tissue caused by immediate physical stress. An injury can occur intentionally or unintentionally and may be caused by blunt trauma, penetrating trauma, burning, toxic exposure, asphyxiation, ...
, or severe
depletion of body fluids.
Symptoms in humans include all those of typical
metabolic acidosis
Metabolic acidosis is a serious electrolyte disorder characterized by an imbalance in the body's acid-base balance. Metabolic acidosis has three main root causes: increased acid production, loss of bicarbonate, and a reduced ability of the kidneys ...
(nausea, vomiting, generalized muscle weakness, and laboured and deep breathing).
Causes
The several different causes of lactic acidosis include:
* Genetic conditions
**
Biotinidase deficiency,
multiple carboxylase deficiency
Multiple carboxylase deficiency is a form of metabolic disorder involving failures of carboxylation enzymes.
The deficiency can be in biotinidase or holocarboxylase synthetase.
These conditions respond to biotin.
Forms include:
* Holocarboxylase ...
, or nongenetic deficiencies of
biotin
**
Diabetes mellitus and deafness
**
Fructose 1,6-bisphosphatase deficiency
**
Glucose-6-phosphatase deficiency
Glycogen storage disease type I (GSD I) is an inherited disease that results in the liver being unable to properly break down stored glycogen. This impairment disrupts the liver's ability to break down stored glycogen that is necessary to mainta ...
**
GRACILE syndrome
**
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes
**
Pyruvate dehydrogenase deficiency
**
Pyruvate carboxylase deficiency
Pyruvate carboxylase deficiency is an inherited disorder that causes lactic acid 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 defici ...
**
Leigh syndrome
Leigh syndrome (also called Leigh disease and subacute necrotizing encephalomyelopathy) is an inherited neurometabolic disorder that affects the central nervous system. It is named after Archibald Denis Leigh, a British neuropsychiatrist who fi ...
* Drugs
**
Linezolid
**
Paracetamol/acetaminophen poisoning
**
Metformin
Metformin, sold under the brand name Glucophage, among others, is the main first-line medication for the treatment of type 2 diabetes, particularly in people who are overweight. It is also used in the treatment of polycystic ovary syndrome. ...
: 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. The older related and now withdrawn drug
phenformin carried a much higher risk of lactic acidosis.
**
Isoniazid toxicity
**
Propofol
Propofol, marketed as Diprivan, among other names, is a short-acting medication that results in a decreased level of consciousness and a lack of memory for events. Its uses include the starting and maintenance of general anesthesia, sedation ...
**
Epinephrine
Adrenaline, also known as epinephrine, is a hormone and medication which is involved in regulating visceral functions (e.g., respiration). It appears as a white microcrystalline granule. Adrenaline is normally produced by the adrenal glands and ...
**
Propylene glycol
Propylene glycol ( IUPAC name: propane-1,2-diol) is a viscous, colorless liquid, which is nearly odorless but possesses a faintly sweet taste. Its chemical formula is CH3CH(OH)CH2OH.
Containing two alcohol groups, it is classed as a diol. It ...
(D-lactic acidosis)
**
Nucleoside
Nucleosides are glycosylamines that can be thought of as nucleotides without a phosphate group. A nucleoside consists simply of a nucleobase (also termed a nitrogenous base) and a five-carbon sugar ( ribose or 2'-deoxyribose) whereas a nucleoti ...
reverse-transcriptase inhibitors
Reverse-transcriptase inhibitors (RTIs) are a class of antiretroviral drugs used to treat HIV infection or AIDS, and in some cases hepatitis B. RTIs inhibit activity of reverse transcriptase, a viral DNA polymerase that is required for replicat ...
**
Abacavir/dolutegravir/lamivudine
**
Emtricitabine/tenofovir
**
Potassium cyanide
Potassium cyanide is a compound with the formula KCN. This colorless crystalline salt, similar in appearance to sugar, is highly soluble in water. Most KCN is used in gold mining, organic synthesis, and electroplating. Smaller applications i ...
(
cyanide poisoning
Cyanide poisoning is poisoning that results from exposure to any of a number of forms of cyanide. Early symptoms include headache, dizziness, fast heart rate, shortness of breath, and vomiting. This phase may then be followed by seizures, s ...
)
**
Fialuridine
* Other
** Thiamine deficiency (especially during
TPN)
** Impaired delivery of oxygen to cells in the tissues (e.g., from impaired blood flow (hypoperfusion))
**
Bleeding
**
Polymyositis
Polymyositis (PM) is a type of chronic inflammation of the muscles ( inflammatory myopathy) related to dermatomyositis and inclusion body myositis. Its name means "inflammation of many muscles" (''poly-'' + '' myos-'' + ''-itis''). The inflammat ...
**
Ethanol toxicity
Alcohol intoxication, also known as alcohol poisoning, commonly described as drunkenness or inebriation, is the negative behavior and physical effects caused by a recent consumption of alcohol. In addition to the toxicity of ethanol, the main ...
**
Sepsis
Sepsis, formerly known as septicemia (septicaemia in British English) or blood poisoning, is a life-threatening condition that arises when the body's response to infection causes injury to its own tissues and organs. This initial stage is foll ...
**
Shock
**
Advanced liver disease
**
Diabetic ketoacidosis
** Excessive exercise (
overtraining)
** Regional hypoperfusion (e.g.,
bowel ischemia or marked
cellulitis)
**
Cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal bl ...
s such as
Non-Hodgkin's and
Burkitt lymphomas
**
Pheochromocytoma
Pheochromocytoma (PHEO or PCC) is a rare tumor of the adrenal medulla composed of chromaffin cells, also known as pheochromocytes. When a tumor composed of the same cells as a pheochromocytoma develops outside the adrenal gland, it is referred ...
[
** Tumor lysis syndrome
** D-lactic acidosis due to intestinal bacterial flora production in short gut syndrome
]
Pathophysiology
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 lactic 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
Pyruvic acid (CH3COCOOH) is the simplest of the alpha-keto acids, with a carboxylic acid and a ketone functional group. Pyruvate, the conjugate base, CH3COCOO−, is an intermediate in several metabolic pathways throughout the cell.
Pyruvic aci ...
into lactate. The lactate is carried by the bloodstream to other tissues where it is converted at the expense of ATP
ATP may refer to:
Companies and organizations
* Association of Tennis Professionals, men's professional tennis governing body
* American Technical Publishers, employee-owned publishing company
* ', a Danish pension
* Armenia Tree Project, non ...
back to pyruvate by the "B" isoform of LDH (LDHB). Firstly there is gluconeogenesis
Gluconeogenesis (GNG) is a metabolic pathway that results in the generation of glucose from certain non- carbohydrate carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In verteb ...
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
The Cori cycle (also known as the lactic acid cycle), named after its discoverers, Carl Ferdinand Cori and Gerty Cori, is a metabolic pathway in which lactate, produced by anaerobic glycolysis in muscles, is transported to the liver and convert ...
. In addition, lactate moved to other tissues enters the citric acid cycle
The citric acid cycle (CAC)—also known as the Krebs cycle or the TCA cycle (tricarboxylic acid cycle)—is a series of chemical reactions to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and prote ...
and eventually oxidative phosphorylation
Oxidative phosphorylation (UK , US ) or electron transport-linked phosphorylation or terminal oxidation is the metabolic pathway in which cells use enzymes to oxidize nutrients, thereby releasing chemical energy in order to produce adenosine t ...
, a process that yields ATP.[
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.][
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
The sympathetic nervous system (SNS) is one of the three divisions of the autonomic nervous system, the others being the parasympathetic nervous system and the enteric nervous system. The enteric nervous system is sometimes considered part of ...
is highly active (e.g. severe asthma
Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, c ...
).[ 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.
]
Diagnosis
Acid-base disturbances such as lactic acidosis are typically first assessed using arterial blood gas test
An arterial blood gas (ABG) test, or arterial blood gas analysis (ABGA) measures the amounts of arterial gases, such as oxygen and carbon dioxide. An ABG test requires that a small volume of blood be drawn from the radial artery with a syringe ...
s. Testing of venous blood is also available as an alternative as they are effectively interchangeable.[ Normally resulting lactate concentrations are in the range indicated below:
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.][
]
Treatment
If elevated lactate is present in acute illness, supporting the oxygen supply and blood flow are key initial steps.[ 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
The beta-2 adrenergic receptor (β2 adrenoreceptor), also known as ADRB2, is a cell membrane-spanning beta-adrenergic receptor that binds epinephrine (adrenaline), a hormone and neurotransmitter whose signaling, via adenylate cyclase stimulation ...
can elevate the lactate further.[
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.][
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
Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar t ...
levels).[
Lactic acidosis caused by inherited mitochondrial disorders (type B3) may be treated with a ketogenic diet and possibly with ]dichloroacetate
Dichloroacetic acid (DCA), sometimes called bichloroacetic acid (BCA), is the chemical compound with formula . It is an acid, an analogue of acetic acid, in which 2 of the 3 hydrogen atoms of the methyl group have been replaced by chlorine ato ...
(DCA), although this may be complicated by peripheral neuropathy
Peripheral neuropathy, often shortened to neuropathy, is a general term describing disease affecting the peripheral nerves, meaning nerves beyond the brain and spinal cord. Damage to peripheral nerves may impair sensation, movement, gland, or or ...
and has a weak evidence base.
Prognosis
Mild and transient elevations in lactate have limited impact on mortality, whereas sustained and severe lactate elevations are associated with a high mortality.[
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%.
]
Other animals
Reptiles
Reptiles
Reptiles, as most commonly defined are the animals in the class Reptilia ( ), a paraphyletic grouping comprising all sauropsids except birds. Living reptiles comprise turtles, crocodilians, squamates (lizards and snakes) and rhynchocephali ...
, 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. Cases are recorded in which particularly large crocodiles which put up extreme resistance to capture later died of the resulting pH imbalance.
. Accessed 31 January 2009.
Certain turtle species have been found to be capable of tolerating high levels of lactic acid without experiencing the effects of lactic acidosis. Painted turtle
The painted turtle (''Chrysemys picta'') is the most widespread native turtle of North America. It lives in slow-moving fresh waters, from southern Canada to northern Mexico, and from the Atlantic to the Pacific. They have been shown to prefer l ...
s hibernate
Hibernation is a state of minimal activity and metabolic depression undergone by some animal species. Hibernation is a seasonal heterothermy characterized by low body-temperature, slow breathing and heart-rate, and low metabolic rate. It most ...
buried in mud or underwater and do not resurface for the entire winter. As a result, they rely on anaerobic respiration
Anaerobic respiration is respiration using electron acceptors other than molecular oxygen (O2). Although oxygen is not the final electron acceptor, the process still uses a respiratory electron transport chain.
In aerobic organisms undergoing ...
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
Calcium lactate is a white crystalline salt with formula , consisting of two lactate anions (CHOH) for each calcium cation . It forms several hydrates, the most common being the pentahydrate ·5.
Calcium lactate is used in medicine, mainly to t ...
. 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.
Ruminants
In ruminant
Ruminants ( suborder Ruminantia) are hoofed herbivorous grazing or browsing mammals that are able to acquire nutrients from plant-based food by fermenting it in a specialized stomach prior to digestion, principally through microbial actions. Th ...
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.[Kimberling, C. V. 1988. Jensen and Swift's diseases of sheep. 3rd Ed. Lea & Fibiger, Philadelphia. 394 pp.][Pugh, D. G. 2002. Sheep and goat medicine. Saunders. 468 pp.][Kahn, C. M. (ed.) 2005. Merck veterinary manual. 9th Ed. Merck & Co., Inc., Whitehouse Station.] Activity of various rumen organisms results in accumulation of various volatile fatty acids (normally, mostly acetic, propionic, and butyric acids), which are partially dissociated.[Van Soest, P. J. 1994. Nutritional ecology of the ruminant. 2nd Ed. Cornell Univ. Press, Ithaca. 476 pp.] 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
PKA may refer to:
* Professionally known as:
** Pen name
** Stage persona
* p''K''a, the symbol for the acid dissociation constant at logarithmic scale
* Protein kinase A, a class of cAMP-dependent enzymes
* Pi Kappa Alpha, the North-American so ...
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).[
]
References
External links
{{DEFAULTSORT:Lactic Acidosis
Acid–base disturbances