Lactic acidosis

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.

Pathophysiology
Most cells in the body normally burn glucose to form water and carbon dioxide. This is 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 utilized during cell work (ATP hydrolysis), protons are produced. The mitochondria normally incorporate these protons back into ATP, thus preventing buildup of protons 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 protons resulting from ATP hydrolysis. Therefore, proton concentration rises and causes acidosis.

It is widely believed that the excess protons in lactic acidosis 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 (e.g. a proton) 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 protons. However, pyruvate production does produce protons. Lactate production is buffered intracellularly, e.g. the lactate-producing enzyme lactate dehydrogenase binds one proton per pyruvate molecule converted. When such buffer systems become saturated, cells will transport lactate into the blood stream. 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 anti-diabetic drugs phenformin and metformin). 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.

Symptoms
The list of signs and symptoms of lactic acidosis includes the following:
 * Nausea
 * Vomiting
 * Hyperventilation (to remove CO2)
 * Abdominal pain
 * Lethargy
 * Anxiety
 * Severe aenemia
 * Hypotension
 * Irregular heart rate
 * Tachycardia

Classification
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

Causes
There are several different causes of lactic acidosis.

These causes include:


 * Genetic conditions
 * Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS)
 * Diabetes mellitus and deafness
 * Glucose-6-phosphatase deficiency
 * Fructose 1,6-diphosphatase deficiency
 * Pyruvate dehydrogenase deficiency
 * Pyruvate carboxylase deficiency


 * Drugs
 * phenformin
 * metformin
 * isoniazid toxicity
 * nucleoside reverse transcriptase inhibitors
 * potassium cyanide (Cyanide poisoning)


 * Other
 * Hypoxia and hypoperfusion
 * Hemorrhage
 * Ethanol toxicity
 * Sepsis
 * Shock
 * Hepatic disease
 * Diabetic ketoacidosis
 * Muscular exercise
 * Regional hypoperfusion (bowel ischemia, marked cellulitis...)
 * Non-Hodgkin's and Burkitt lymphoma

Associated conditions
Lactic acidosis is an underlying process of rigor mortis. Tissue in the muscles of the deceased resort to anaerobic metabolism in the absence of oxygen and significant amounts of lactic acid are released into the muscle tissue. This along with the loss of ATP causes the muscles to grow stiff.

Lactic acidosis may also result from vitamin B1 (thiamine) deficiency.

In animals
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.