Lactic acidosis

The Cohen-Woods classification categorizes causes of lactic acidosis as:[1]

• 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

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]

The several different causes of lactic acidosis include:

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both the plasma levels of metformin are increased and lactate clearance is impaired.[6] The older related and now withdrawn drug phenformin carried a much higher risk of lactic acidosis.[7]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

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 for metabolic activities and to perform work, such as muscle contraction. When the energy in ATP is used during cell work via ATP hydrolysis, hydrogen ions, (positively charged protons) are released. The mitochondria normally incorporate these free hydrogen nuclei back into ATP, thus preventing buildup of unbound hydrogen cations, and maintaining neutral pH.

If oxygen supply is inadequate (hypoxia), the mitochondria are unable to continue creating ATP at a rate sufficient to meet the cell's energy needs. 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 that result from ATP hydrolysis. Therefore, hydrogen cation concentration rises and causes acidosis.[12]

The excess hydrogen cations produced during 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 of the blood requires that a cation be released into the blood, 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 a buildup of lactate and acidification, and lactate is therefore a good "marker" of hypoxia, but lactate itself is not the cause of low pH.[13] During exercise and some illnesses, lactate production is not generated by lack of oxygen, per se, but by the catecholamine-driven metabolism of glucose (glycolysis) that cells use when they cannot get enough energy from oxygen-based reactions.

Lactate serves as an energy source for other tissues.[14]

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 (fast-twitch or type II fibers) are naturally prone to lactic acidosis.

Lactic acidosis is also a consequence of the processes causing rigor mortis. In the absence of oxygen, tissue in the muscles of the deceased carry out anaerobic metabolism using muscle glycogen as the energy source, causing acidification. 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.)

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. Normally resulting lactate concentrations are in the range indicated below:[15]

Direct removal of lactate from the body (e.g. with hemofiltration) is difficult, with limited evidence for benefit.[16] In type A lactic acidosis, treatment consists of effective management of the underlying cause, and 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).[17]

In type B lactic acidosis produced by medication, withdrawal of the medication may be necessary to resolve the lactic acidosis.

Lactic acidosis in the context of mitochondrial disorders (type B3) may be treated with a ketogenic diet and possibly with dichloroacetate (DCA),[18] although this may be complicated by peripheral neuropathy and has a weak evidence base.[19]

The underlying cause determines the prognosis of lactic acidosis. In sepsis, elevated lactate levels correlate with 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%.[20]