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[4]
• Drugs
  • Linezolid[5]
  • Paracetamol/acetaminophen poisoning[6]
  • 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where both the plasma levels of metformin are increased and lactate clearance is impaired.[7] The older related and now withdrawn drug phenformin carried a much higher risk of lactic acidosis.[8]
  • Isoniazid toxicity
  • Propofol
  • Epinephrine[9]
  • Propylene glycol (D-lactic acidosis)
  • Nucleoside reverse-transcriptase inhibitors
  • Abacavir/dolutegravir/lamivudine[10]
  • Emtricitabine/tenofovir[11]
  • Potassium cyanide (cyanide poisoning)
  • Fialuridine[12]
• 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[13]
  • D-lactic acidosis due to intestinal bacterial flora production in short gut syndrome

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 into lactate. The lactate is carried by the bloodstream to other tissues where it is converted 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.[14]

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:[15]

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]

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][16]

Lactic acidosis caused by inherited mitochondrial disorders (type B3) may be treated with a ketogenic diet and possibly with dichloroacetate (DCA),[17] although this may be complicated by peripheral neuropathy and has a weak evidence base.[18]

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%.[19]