What is lactate? A good medical student will tell you something along the lines of
“Lactate is a byproduct of anaerobic respiration that is produced in response to cellular hypoxia secondary to inadequate oxygen delivery. It is a marker of tissue hypoperfusion and shock”
They might go on to say high lactates are correlated with high mortality. They might colloquially refer to lactate being ‘badness’. You’d probably look at them moderately stunned, and say they were correct.
Oh’s Intensive Care Manual states:
In critically ill patients, lactic acidosis is often due to shock. In cardiogenic and hypovoloaemic shock hypoperfusion and tissue hypoxia increase lactic acid production while decreased hepatic perfusion decreases lactic acid metabolism. In septic shock lactic acidosis is multifactorial. Contributors include global hypoperfusion, microvascular disruption causing regional hypoperfusion and impaired cellular oxygen utiliisation by mitochondria.
The actual truth is far more complex, and though Oh’s not wrong, it’s waaaaay off right. You’ll hear critical care peeps talking about optimizing lactate clearance4. Hopefully after reading these two article you’ll understand that the very concept of lactate clearance makes no sense.
Now it’s important to know what lactate is, and how it affects acid-base balance because it’s seen as a marker of disease severity in every specialty. The more you read, and the more you learn, the likelihood is that like me, you’ll realize that you’ve been taught convenient white lies about lactate to make quick intuitive leaps about people’s clinical condition. Now short cuts are all very well, but if we don’t know the full picture we make errors based on incomplete data (more on that later).
People assume lactate is the cause of the acidosis, they are wrong. People assume that lactate is a poison, they are wrong.
So here it is. Everything we should know about lactate but were never taught. It’s fully referenced, and I encourage you to delve into those references for even more detail.
Lactate was first discovered in the late 18th century in milk. It was discovered by a Swedish chemist called Carl Wilhelm Scheele in 1780. He found samples in sour milk. This led to it being called lactic acid. It should be called 2-hydroxypropanoic acid. It’s existence was verified 30 years later in 18101. Lactic acid can exist in L and D isomeric forms, and it is the L isomer that we use and produce. Now because lactic acid was originally found in fermenting products, most of the early research into it was done from that perspective.
Lactic acid is used as a preservative, it is used in the beer industry, to make cheese, and even to ferment sauerkraut. In 1922 Otto Meyerhoff unpicked most of the glycolytic pathway and demonstrated that lactic acid was produced as a side reaction to glycolysis in the absence of oxygen. Archibald Hill quantified the energy release from glucose conversion to lactic acid and proposed that glucose oxidation in times of limited oxygen availability or demand/supply imbalances can supply a rapid amount of fuel for muscle contraction. At the time in-vitro studies had shown muscle contracting in the absence of oxygen, and Hills experimental evidence suggested there had to be another fuel capable of providing up to 8 times the amount of energy that oxidative glycolysis could provide. Hill and Meyeroff didn’t know about mitochondria, or the phosphagen system and they also weren’t aware that weak acids pyruvate and lactate are produced as conjugate bases. They were also held in very high regard, so when they plotted lactate and pyruvate concentrations against pH and showed a linear relationship, they incorrectly assumed that one caused the other, they weren’t questioned in the same way as others might have been.
Correlational evidence is all very well, but what if lactate is an innocent bystander? Present in higher quantities during times of absolute clinical badness. What if lactate was there, hands’ bloodied, but trying to help?
We have to talk about the biochemistry now:
First of some basics. The molecule produced by the lactate dehydrogenase reaction is a base. Chemistry at it’s simplest tells you that if you add a base to a solution it become more alkaline, not more acidic. Lactate is a conjugate base, it accepts hydrogen ions and can become a weak acid, it’s pKA is 3.86 (that’s the pH at which 50% of lactic acid exists in its ionized form) therefore in humans nearly all of it will exist as a base. The only way we would “produce” lactic acid, is if our cellular pH was less than 3.86. I think we can all agree that if our cellular pH is less than 3.86 we probably aren’t respiring at all.
So how can adding a lot of base to a solution make you more acidotic?
Hold that thought.
If you vaguely remember your A-levels or your physiology bits at first year of med school, you’ll know that cells utilize ATP to make stuff happen. ATP is constantly recycled, and that recycling of ADP to ATP is what cellular respiration is for. We have 4 ways of making ATP from ADP.
- The mitochondria (aka oxidative phosphorylation)
- Lactate Dehydrogenase reaction
- Phophagen system (muscle)
The phosphagen system uses creatinine phosphate as a source of phosphate and creatinine kinase as it’s enzyme. It eats a proton, makes creatinine and ATP. It’s super fast, but it’s fuel (the creatinine phosphate) gets used up quickly. This system only really exists in muscle cells, as they must recycle high volumes of ADP quickly.
Glycolysis is the main respiratory pathway, here we convert either glucose from the blood, or glycogen from our cellular energy stores into 2 pyruvate molecules, 2 or 3 ATPs and produce 1 or two protons, and some water. We use an enzyme called NAD (nicotinamide adenine dinucleotide), which becomes NADH. NADH needs to be recycled, and here I think is the clever bit; the lactate dehydrogenase reaction uses the NADH to produce NAD, and converts the glucose or glycogen to pyruvate and onto lactate, and releases 2 or 3 ATPs. These reactions are linked. You need to make lactate to help refresh the NADH (though it is recycled in other ways too), the faster you refresh your NADH the more glucose you can convert to pyruvate. NADH is also needed in the mitochondria for oxidative phosphorylation, so lactate production gives us a bit of energy, and recycles a key enzyme that’s needed in mitochondria, and for basic glycolysis.
Now when you look at the above reactions you can quantify their speed. The slowest reactions become the rate-limiting step. Look at the maximal rate of mitochondrial respiration compared to the glycolytic pathway1. If glycolysis goes into overdrive lots of substrate will be provided for the lactate dehydrogenase reaction. This is rather elegant I think, as it it mitigates the potential acidifying effect of the pyruvate reaction.
So we know that lacate is a base, that it’s production most likely retards cellular acidosis.
The other common belief about lactate is that is is produced in anaerobic conditions. Now I’m not sure this really matters. The concept of aerobic and aneorobic conditions is an artificial distinction that was made in the early 1900’s to allow us to more easily understand the complex sea of interconnecting biochemical reactions that allow a cell to function. Mammallian cells don’t really function that well in the total absence of oxygen, and though I suppose it could be argued that they can survive for very short periods the distinction between one pathway and another, and the idea of a cell switching from one to another is not the case. I think this is interesting because it probably reflects our understanding at the time. The pathways were thought of as railway tracks, and we would switch between them based on what was required. The truth is more complex and harder to pin down. Mitochondria will continue to work if the oxygen tension is as low at 1 tor (though some studies have shown this critical threshold to be 0.55). For those of you who don’t know 1 tor = 0.13kpa.
Again I put it to you that if the cytoplasm has an oxygen tension that is as low as 1 tor things stopped going in the right direction some time ago. As such true anaerobic respiration is unlikely to have a clinical impact, or even really exist, what is a more accurate assessment of events is that as energy demand in the cell exceeds the supply provided by the mitochondria, glycolysis and therefore lactate production becomes upregulated. Now I think the best analogy here is that the glycolytic pathway is a bit like running your car in first gear. It will move, but it’s not very efficient and you will quickly run out of fuel (and absolutely knacker your car).
So we now know that lactate is a base, it’s production retards cellular acidosis, and that it isn’t really produced because the cell has switched to an ‘anaerobic pathway’.
Lactate is produced all the time, (we make 1400mmol/day). Now considering our normal range for lactate at any point is <2mmol we probably need to know where it is going. Also if lactate is a poison why we do make so much of it? Most textbooks say that Lactate is metabolized back into glucose by the liver (this is the Cori cycle). Why does the Cori cycle switch off when we are acidotic?
Couple of useful things to know.
The lactate dehydrogenase reaction can go forwards and backwards.
There is experimental evidence to show that some cells will use lactate to make pyruvate at times of stress, or just because. Here is a list of those cells
- Alveolar Epithelial cells6
- Cardiac myocytes3
- Renal Cortex (only uses lactate)8
- Renal Medulla8
The Cori cycle tends to down regulate or switch off during periods of acidosis. Adrenaline upregulates the rate of the lactate dehydrogenase reaction.
If lactate is bad – why would these responses evolve in mammalian physiology?
So now we know:
- Lactate is a base
- Lactate production retards cellular acidosis
- Lactate is not produced in anaerobic conditions, and that anaerobic conditions don’t really exist. Therefore, poor oxygen delivery cannot explain increased lactate production.
- Lactate is utilized by cells for energy production, therefore it is a FUEL.
So where does the acid come from?
See Part Two.
- Biochemistry of exercise-induced metabolic acidosis Robert A. Robergs, Farzenah Ghiasvand, Daryl Parker American Journal of Physiology – Regulatory, Integrative and Comparative Physiology Sep 2004, 287 (3) R502-R516; DOI:10.1152/ajpregu.00114.2004
- Lactate efflux from exercising human skeletal muscle: role of intracellular Russell S. Richardson, Elizabeth A. Noyszewski, John S. Leigh, Peter D.Wagner Journal of Applied Physiology Aug 1998, 85 (2) 627-634;
- Gladden LB. Lactate metabolism: a new paradigm for the third millennium. The Journal of Physiology. 2004;558(Pt 1):5-30. doi:10.1113/jphysiol.2003.058701.
- Jones AE. Lactate Clearance for Assessing Response to Resuscitation in Severe Sepsis. Academic emergency medicine : official journal of the Society for Academic Emergency Medicine. 2013;20(8):844-847. doi:10.1111/acem.12179.
- Lanza IR, Tevald MA, Befroy DE, Kent-Braun JA. Intracellular energetics and critical Po2 in resting ischemic human skeletal muscle in vivo. American Journal of Physiology – Regulatory, Integrative and Comparative Physiology. 2010;299(5):R1415-R1422. doi:10.1152/ajpregu.00225.2010.
- Lottes RG, Newton DA, Spyropoulos DD, Baatz JE. Lactate as substrate for mitochondrial respiration in alveolar epithelial type II cells. American Journal of Physiology – Lung Cellular and Molecular Physiology. 2015;308(9):L953-L961. doi:10.1152/ajplung.00335.2014.
- Schurr, Avital. “Lactate: the ultimate cerebral oxidative energy substrate?.” Journal of Cerebral Blood Flow & Metabolism1 (2006): 142-152.
- Bellomo, Rinaldo. “Bench-to-bedside review: lactate and the kidney.” Critical Care4 (2002): 322.