Lactic acidosis refers to the process leading to the production of lactate by anaerobic metabolism. It increases hydrogen ion concentration tending to the state of acidemia or low pH. The result can be detected with high levels of lactate and low levels of bicarbonate. This is usually considered the result of illness but also results from strenuous exercise. The effect on pH is moderated by the presence of respiratory compensation. Lactic acidosis is usually the result of tissue hypoxia which is not the same as arterial hypoxia. Adequate circulation of blood and perfusion of metabolizing tissue to meet demand is necessary to prevent tissue hypoxia. Lactic acidosis can also be the result of illnesses, medications, poisonings or inborn errors of metabolism that interfere directly with oxygen utilization by cells. The symptoms are generally attributable to the underlying cause, but may include nausea, vomiting, shortness of breath, 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.
Classification The Cohen–Woods 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, or severe depletion of body fluids. Symptoms in humans include all those of typical metabolic acidosis (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, 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 Paracetamol/acetaminophen poisoning 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. The older related and now withdrawn drug phenformin carried a much higher risk of lactic acidosis. Isoniazid toxicity Propofol Epinephrine Propylene glycol (D-lactic acidosis) Nucleoside reverse-transcriptase inhibitors Abacavir/dolutegravir/lamivudine Emtricitabine/tenofovir Potassium cyanide (cyanide poisoning) 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 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 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 (the blood lactate-to-pyruvate ratio is normally 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 lactate is converted into pyruvate and then into glucose; this is known as the Cori cycle. In addition, pyruvate generated from lactate can be oxidized to acetyl-CoA, which can enter the citric acid cycle to enable ATP production by oxidative phosphorylation. 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 is highly active (e.g. severe asthma). 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 tests. 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.
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