L-lactate is produced in the cytosol from pyruvate by the enzyme lactate dehydrogenase (LDH) during normal glycolysis in cells. The reaction catalyzed by LDH is bidirectional, but the drive is towards lactate production, such that lactate exceeds pyruvate (by around 10:1) (Suetrong and Walley 2016). Most of the lactate released into blood from lactate-producing tissues crosses cell membranes via monocarboxylic acid transporters (MCT) and enters plasma and red blood cells. The latter take up lactate via diffusion, MCT and the band 3 anion exchanger and carry about 30% of total lactate in blood. Once the blood reaches low lactate-producing tissue (liver, in particular, and to a lesser extent, kidney), lactate is taken up (diffuses down a concentration gradient). Under conditions of increased energy demand, other tissues (e.g. muscle) can use the lactate for energy. The L-lactate is used in the liver and kidney for gluconeogenesis and by other cells for energy production, where it is oxidized through the tricarboxylic acid cycle (after being converted back to pyruvate). The movement of lactate from one cell in which it is produced (e.g. skeletal muscle during exercise) to another cell, such as the hepatocyte, where it is metabolized is called the “lactate shuttle” (Gladden 2004). Note that this shuttling can occur within an organ between different cell types (skeletal muscle and fibroblasts or astrocytes and neurones, with one cell being a producer and the other a consumer of lactate). The main sources of L-lactate in health or physiologic circumstances (e.g. exercise) are skeletal muscle, intestine, red blood cells, brain and skin, but other tissues can produce L-lactate under pathophysiologic conditions (eg. in acute liver failure, the liver can produce rather than consume lactate). Lactic acid can be increased in blood (called hyperlactatemia) without causing an acidosis (i.e. no decrease in pH or bicarbonate). Indeed, lactate levels increase after exercise, but the increases are rapidly offset by uptake and use by cells, thereby preventing an acidosis. If excessive lactate is produced, excess bicarbonate is consumed resulting in an acidosis and acidemia. Unfortunately, the levels distinguishing hyperlactatemia from L-lactic acidosis have not been defined in veterinary medicine, although the value of >5 mmol/L has been used in human medicine (Mizock and Falk 1992). In several conditions, a high L-lactic acid or persistently high L-lactic acid despite treatment is associated with a poor prognosis in dogs (Holahan et al 2010, Hall et al 2014, Mooney et al 2014) and horses (Johnston et al 2007, Radcliffe et al 2012, Viu et al 2015).
Lactate can be produced in excess under the following conditions:
- Tissue hypoxia: This is also called type A lactic acidosis and is because of decreased aerobic glycolysis from tissue hypoxia (e.g. anemia, hypovolemia from dehydration), leading to accumulation of pyruvate in the cytosol, which then gets converted to lactate. This frequently results in lactic acidosis, if lactate levels are sufficiently high. Note that localized tissue hypoxia (from regional abnormalities in blood flow) result in defective mitochondrial function and anaerobic glycolysis. If local normally functioning cells cannot take up the excess lactate produced by the hypoxic cells, the excess lactate will enter the circulation.
- No tissue hypoxia: This is also called type B lactic acidosis and occurs where there is increased aerobic glycolysis (producing more pyruvate, in excess of mitochondria to handle), defects in the ability of mitochondria to take up pyruvate (e.g. thiamine deficiency – thiamine is a cofactor required for the enzyme, pyruvate dehydrogenase, which metabolizes pyruvate so that it can participate in the tricarboxylic acid cycle in mitochondria), or decreased consumption of lactate by tissues (eg. acute liver failure). Aerobic glycolysis can be stimulated by several factors, including norepinephrine and epinephrine, which stimulate glycolysis directly and via activation of the muscle Na/K ATPase pump (which requires lots of energy). Increased metabolism or inflammatory cytokine stimulation of glycolysis can also occur. In alkalemic states, glycolysis is also stimulated, producing lactic acid, which offsets the alkalemia. Sepsis and trauma are two conditions known to be associated with both type A and B lactic acidosis (Suetrong and Wallis 2016, Kraut and Madias 2014).
L-lactate is typically measured using amperometry (oxidation/reduction reactions which generate an electric current that is detected by an electrode) on blood-gas analyzers. A false increase in lactic acid concentration has been identified in 2 dogs with ethylene glycol poisoning (Hopper and Epstein 2013). This is thought to be due to the fact that ethylene glycol intermediates (glycolic acid, glyoxalic acid) act as substrates for the L-lactate oxidase enzyme, which is added to the reaction to accelerate the oxidation of the lactic acid. Spectrophotometric measurement of lactate can be used to obtain more accurate concentrations of lactate (Meng et al 2010, Hopper and Epstein 2013).
This has been primarily reported in ruminants (cattle especially, but also lambs and calves), although it may occur in other herbivores (we just have not recognized it yet). It is one form of type B lactic acidosis, because the acidosis is not associated with tissue hypoxia (see above). D-lactate acidosis has been reviewed by Lorenz and Gentile (2014). D-lactate is a mirror image of L-lactate (also called an optical isomer or stereoisomer – think about it being the right handed version of L-lactate) and is produced by bacteria in the intestinal tract (upper and lower). There are particular acid-producing bacteria (e.g. lactobacilli) that can proliferate or dominate the microbiotica under certain conditions, e.g. stress, short bowel syndrome in humans, feeding calves spoilt milk or excess carbohydrates. When produced in excess, the D-lactate is absorbed into the circulation and can cause an encephalopathy, with clinical signs of recumbency, disorientation, anorexia, and depression, with loss of the palpebral reflex. In goats, it is called “floppy kid” syndrome (Bleul et al 2006). It appears to affect neonates more than adults, although adult ruminants can get D-lactate ruminal acidosis from excess carbohydrates in the diet. Neonates appear to suffer from D-lactate acidosis when they have a dysfunctional esophageal groove, which delivers milk into the reticulorumen, instead of the stomach. Esophageal groove dysfunction can occur with neonatal diarrhea (resulting in an acute syndrome), pain, forcefeeding or chronic stress/poor feeding practices (resulting in a chronic syndrome). The excess carbohydrates in milk are fermented by rumen microbes into D-lactate which is then absorbed. Alterations in the gut microbiotica with diarrhea can also cause D-lactate production in the colon without esophageal dysfunction. The absorption of excess lactic acid consumes bicarbonate, resulting in a high anion gap metabolic acidosis. Unfortunately, D-lactate requires high performance liquid chromatography for measurement and will not be detected by L-lactate electrodes on blood-gas analyzers, however an enzymatic assay is available (Lorenz et al 2003). However increases in D-lactate should be suspected in non-dehydrated animals with the above clinical signs and a high anion gap metabolic acidosis that cannot be explained by L-lactate results or other other acids (e.g. ketones). Note, that even in dehydrated animals with abnormalities in gut microbiotica or excess carbohydrate fermentation (e.g. neonatal diarrhea in calves), D-lactate may be a substantial contributor to the observed acidosis, even if L-lactate concentrations are concurrently increased. Reported clinically relevant concentrations are > 3 mmol/L (Lorenz 2004), although the upper limit of a reference interval in 150 Simmental calves was 3.96 mmol/L (Lorenz et al 2003). Affected animals appear to respond to bicarbonate infusion (Bleul et al 2006, Lorenz and Gentile 2014).