Of rare acid-base disturbances, some are inexplicably favoured by CICM examiners, and other are inexplicably neglected. For some reason pyroglutamic acidosis has been the subject of several SAQs, whereas D-lactic acidosis has never appeared in the exam. It is not even mentioned as one of the worthy differentials. However, this oversight is only a matter of time. The savvy trainee will ensure their own minimal workmanlike understanding of this disorder, so they may make the right kind of sounds at some hypothetical future viva.
Lactic acid comes in two enantiomers: L-lactate and D-lactate.
As is often the case with isomers, they have very different chemical properties. One isomer might be a completely normal member of the metabolic milieu of the organism, and the other might be a toxic disrupting influence. And they might have completely different pharmacokinetic properties because (for example) they might have very different affinities for the enzyme which is supposed to metabolise them.
Old familiar L-lactate is the standard form of lactate produced by multicellular organisms. The reason for this isomeric preference is a mystery, which fits into the much greater mystery of biological homochirality, i.e. the situation we all currently find ourselves in, where everything is levorotary. How this situation came about, nobody knows; presumably the early ocean biome was racemic, and the L-isomers won some sort of chemical popularity contest, becoming dominant. Still, some remnants from the other side of the mirror are found in nature (eg. D-glucose, or dextrose); but more often than not, and organism will have physiological processes which favour the use of one isomer only, and eschew the other to the point of it becoming toxic.
So it is with D-lactate. Most eukaryotes are unable to produce D-lactate, as our L-lactate dehydrogenase is incapable of it. However, some bacteria produce D-lactate preferentially, and some others have the capability of producing both D and L isoforms (eg. Leuconostoc mesenteroides, an organism also known for its total inborn resistance to vancomycin). The D-lactate producers are usually described as "fermenters", and their names would not be instantly recognisable to the person who mainly deals with microbiology through reported blood culture results. They are bacteria like Pediococcus and fungi like Sapromyces. Additionally, some old favourites such as Pseudomonas and E.coli are also able to express the appropriate enzymes. In humans affected by pathological D-lactic acidosis, the D-lactate is usually being synthesised by the Lactobacillus, Bifidobacterium, Eubacterium and Streptococcus bovis, which are endemic to the colon.
So, how does D-lactate become so noxious, givin normal L-lactate is so benign? Apparently, but its effect on mitochondrial transport of pyruvate. Pyruvate and L-lactate generated during mormal metabolism are transported into the mitochondria via monocarboxylate transporters. These transporter proteins are just as likely to use D-lactate as a substrate, i.e. the D-lactate in in competition with pyruvate and its other isoform. Unfortunately, unlike the other two, D-lactate cannot become a substrate for mitochondrial energy production. Ling et al (2012) determined that this is the case by exposing mitochiondria to D-lactate and demonstrating that their oxygen consumption greatly decreases. As the result, ATP synthesis suffers, and cell function deteriorates. This is seen in rat brain and hear mitochondria, but not liver mitochondria; which is consistent with the usual clinicial features of this syndrome (mainly neurological and cardiac manifestations).
D-lactate has a direct neurotoxic effect. In 2007, Abeyasekara et al put central lines into eight calves, and infused them with D-lactate. The neurological effect was likened to ethanol intoxication, which relies on the reader's familiarity with what a drunken cow behaves like. Not a problem for the investigators, clearly ("We were impressed with the “drunken” appearance of our calves", they guffawed). In short, clinical features of D-lactic acidosis in humans consist of:
Tthat confusion and encephalopathy progresses into a profoundly decreased level of consciousness, decribed by Chan et al (1994) as "coma characterized by unresponsiveness to toe pinching" in a series of rats, apparently functionally equivalent to a blood alcohol level of 75 mmol/L (approximately 0.30%). It is difficult to tell from these rat experiments what sort of serum D-lactate level you would expect from a human blood sample in order to get this level of depressed consciousness, but most case reports do not report coma (confusion and delirium are more common). For some frame of reference, Scully et al (1989) reported on the case of a "16-year old white boy" in whom the D-lactate level was 6.7, whose main clinical features were described as "stupour" with slurred speach and abusive language.
D-lactate is not routinely measured, and with ane a very high D-lactate the L-lactate levels look normal. The ABG machine lactate-selective electrode does not detect D-lactate, and the ABG result will look like an unexplained high anion gap metabolic acidosis with a normal lactate. The tools for measuring D-lactate often run to the expensive; it is a test which will, from a small regional hospital, take potentially days to return results from large univesity-affiliated lab. Pohanka (2020) describes options such as specialised amperometric sensors, mass pectrometry and high-performance liquid chromatography.
Most of the risk factors for this condition fall into the category of "things which can deliver a huge sugar hit to the microbes of the colon". This category includes any scenario where carohydrates fail to be absorbed or metabolised in the upper GI tract. This can be because the upper GI tract has been disabled enzymatically, or has suffered the loss of villi, or has been remover alltogether. Classical scenarios include:
Symptoms are usually exacerbated by increased food intake, and are relieved by fasting