What is Lactate?

Lactate is an energy source, gluconeogenic precursor, and a signaling molecule [1]. The classic understanding is that during anaerobic conditions (at the tissue, organ or organism level), metabolism of glucose would proceed to pyruvate and then shunted toward lactate to produce ATP and regenerate NAD+. This reaction occurs outside the mitochondria. Lactate builds up in the cell and is then shunted out of the cell via a concentration gradient, and facilitated by the MLT transporter. During normal aerobic conditions, the pyruvate molecule is transported into the mitochondria and then undergoes the TCA cycle for the production of ATP [2].

Summary of lactate generation:

Glucose + 2 (ADP + inorganic phosphate) -> 2 lactate + 2 H+ + 2 ATP

The Cori cycle which is the recycling lactate back to pyruvate then proceeding to gluconeogenesis. This allows RBCs without mitochondria that only go through glycolysis to have a continuous source of glucose. The transport of Lactate out of cells into the blood and to other tissues is a mechanism that is present throughout the body. A leading researcher of lactate, Brooks, proposed the lactate shuttle mechanism based on basic science studies in animals and humans that lactate is preferentially produced even in fully aerobic conditions (Brooks 2018). The lactate is then shuttled intracellularly, and extracellularly.

Interestingly, during aerobic conditions, the lactate:pyruvate ratio within the cell is 10:1 at baseline. Furthermore, lactate is not confined to the cytosol; it can be transported into the mitochondria and converted back to pyruvate for utilization into the TCA cycle. Under stressful conditions, lactate to pyruvate ratio may go up by an order of magnitude. Lactate production is matched to the severity of stress, and is utilized by vital organs, especially the heart and brain (Brooks 2018).

What causes lactate to be elevated?

Causes of elevated lactate include [1] [3]:

  • Poor O2 delivery to tissues [4]. Cardiogenic, obstructive or hypovolemic shock.
  • Thiamine deficiency.
    • Also known as vitamin B1, it is a critical co-factor of oxidative energy metabolism.
  • Sepsis - Acknowledged as a predictor for illness severity and mortality [5][6][7][8].
  • Severe trauma (many confounders).
  • Drugs or toxins causing mitochondrial dysfunction [1].
    • Metformin, cocaine, propylene glycol, salicylates, cyanide, propofol.
  • Beta-2 agonism with medications such as epinephrine [9] and albuterol [10]. Tumors such as a pheochromocytoma may also, by the same mechanism, cause an elevated lactate.
    • NOTE - Conversely, beta blockers like esmolol [11] and alpha-2 agonism like dexmedetomidine [12] can decrease lactate production.
  • In oncology, the Warburg effect refers to the observation that even in aerobic conditions, cancer cells tend to favor metabolism via glycolysis rather than the much more efficient oxidative phosphorylation pathway which is the preference of most other cells of the body.
  • D-lactate is generated by gut bacteria and can be clinically significant in patients with short gut syndrome. D-lactate and L-lactate is also generated as a product of propylene glycol metabolism
    • NOTE - D-lactate is not measured by most laboratories and thus it may be present when you have unmeasured anions causing a gap acidosis.
The simplified differential:
  • Impaired O2 delivery.
  • Macro and/or microcirculatory alteration
  • Regional hypoperfusion or ischemia. This can mean an organ (small bowel, lung, liver, kidney, etc) or limb.
  • Mitochondria are sick from drugs or sepsis.
  • The liver is not adequately clearing lactate.
  • Drugs that cause agonism of beta-2.

Is lactate bad?

Lactate is not inherently injurious to tissues nor is it "bad" but is a marker of potential disease. Brooks who is a research leader in the study of lactate stated in his recently published review: “Of the several goals in authoring this review, certainly one of them is to lift the veil of confusion around “lactate is a metabolic poison and fatigue agent. There are necessary and positive attributes to lactate formation and disposal.” [13]

Some tissues need lactate! [14][15][16]

Lactate provides 25% of energy substrate for brain metabolism during stress. During traumatic brain injury, the brain downregulates glucose uptake during which lactate becomes a major source of substrate. Additionally, early research shows that L-lactate is anti-inflammatory and small clinical trials are ongoing for the use of exogenous L-lactate to improve outcomes post TBI and SAH. As was shown by Cateron et al, hypertonic lactate improved cerebral perfusion and glucose availability after TBI [15]. Lactate is in fact the preferred fuel source for the heart [16]. Levy et al showed that decreased cardiovascular performance was associated with myocardial lactate deprivation during endotoxic shock[16]. The noted anti-inflammatory effects of L-lactate have sparked interest in its exogenous administration for various pathologies such as pancreatitis, dengue, hepatitis and sepsis [13].

What is the significance of lactic acidosis?

Elevated lactate may cause an increase in the anion gap, and result in acidosis. Lactic acidosis denotes an imbalance between production and breakdown of lactate without adequate metabolic compensation. The imbalance may be chronic, but often for acidosis to be present and clinically significant, the imbalance is likely acute or subacute. NOTE - Lactate can be elevated in the absence of an anion gap metabolic acidosis [1].

  1. 1.0 1.1 1.2 1.3 Kraut, Jeffrey A.; Madias, Nicolaos E. (2014-12-11). "Lactic Acidosis". New England Journal of Medicine. 371 (24): 2309–2319. doi:10.1056/nejmra1309483. ISSN 0028-4793.
  2. Pelley, John W. (2011). Biochemistry. Edward F. Goljan, John W. Pelley (3rd ed ed.). Philadelphia, PA: Mosby/Elsevier. ISBN 0-323-08050-2. OCLC 756822460. |edition= has extra text (help)
  3. Garcia-Alvarez, Mercedes; Marik, Paul; Bellomo, Rinaldo (2014-10). "Sepsis-associated hyperlactatemia". Critical Care. 18 (5): 503. doi:10.1186/s13054-014-0503-3. ISSN 1364-8535. PMC 4421917. PMID 25394679. Check date values in: |date= (help)CS1 maint: PMC format (link)
  4. Cilley, Robert E.; Scharenberg, Andrew M.; Bongiorno, Phillip F.; Guire, Kenneth E.; Bartlett, Robert H. (1991-11). "Low oxygen delivery produced by anemia, hypoxia, and low cardiac output". Journal of Surgical Research. 51 (5): 425–433. doi:10.1016/0022-4804(91)90145-C. Check date values in: |date= (help)
  5. Gattinoni, Luciano; Vasques, Francesco; Camporota, Luigi; Meessen, Jennifer; Romitti, Federica; Pasticci, Iacopo; Duscio, Eleonora; Vassalli, Francesco; Forni, Lui G.; Payen, Didier; Cressoni, Massimo (2019-09-01). "Understanding Lactatemia in Human Sepsis. Potential Impact for Early Management". American Journal of Respiratory and Critical Care Medicine. 200 (5): 582–589. doi:10.1164/rccm.201812-2342OC. ISSN 1073-449X.
  6. Trzeciak, Stephen; Dellinger, R. Phillip; Chansky, Michael E.; Arnold, Ryan C.; Schorr, Christa; Milcarek, Barry; Hollenberg, Steven M.; Parrillo, Joseph E. (2007-05-24). "Serum lactate as a predictor of mortality in patients with infection". Intensive Care Medicine. 33 (6): 970–977. doi:10.1007/s00134-007-0563-9. ISSN 0342-4642.
  7. Nuzzo, E; Liu, X; Berg, K; Andersen, L; Doninno, M (2015). "Pyruvate dehydrogenase levels are low in sepsis". Critical Care. 19 (Suppl 1): P33. doi:10.1186/cc14113. ISSN 1364-8535. PMC 4471046.CS1 maint: PMC format (link)
  8. Rimachi, R.; De Carvahlo, F. Bruzzi; Orellano-Jimenez, C.; Cotton, F.; Vincent, J. L.; De Backer, D. (2012-05). "Lactate/Pyruvate Ratio as a Marker of Tissue Hypoxia in Circulatory and Septic Shock". Anaesthesia and Intensive Care. 40 (3): 427–432. doi:10.1177/0310057X1204000307. ISSN 0310-057X. Check date values in: |date= (help)
  9. Wutrich, Yann; Barraud, Damien; Conrad, Marie; Cravoisy-Popovic, Aurélie; Nace, Lionel; Bollaert, Pierre-Edouard; Levy, Bruno; Gibot, Sébastien (2010-07). "EARLY INCREASE IN ARTERIAL LACTATE CONCENTRATION UNDER EPINEPHRINE INFUSION IS ASSOCIATED WITH A BETTER PROGNOSIS DURING SHOCK". Shock. 34 (1): 4–9. doi:10.1097/SHK.0b013e3181ce2d23. ISSN 1073-2322. Check date values in: |date= (help)
  10. Lewis, Lawrence M.; Ferguson, Ian; House, Stacey L.; Aubuchon, Kristen; Schneider, John; Johnson, Kirk; Matsuda, Kazuko (2014-01). "Albuterol Administration Is Commonly Associated With Increases in Serum Lactate in Patients With Asthma Treated for Acute Exacerbation of Asthma". Chest. 145 (1): 53–59. doi:10.1378/chest.13-0930. Check date values in: |date= (help)
  11. Morelli, Andrea; Ertmer, Christian; Westphal, Martin; Rehberg, Sebastian; Kampmeier, Tim; Ligges, Sandra; Orecchioni, Alessandra; D’Egidio, Annalia; D’Ippoliti, Fiorella; Raffone, Cristina; Venditti, Mario (2013-10-23). "Effect of Heart Rate Control With Esmolol on Hemodynamic and Clinical Outcomes in Patients With Septic Shock: A Randomized Clinical Trial". JAMA. 310 (16): 1683. doi:10.1001/jama.2013.278477. ISSN 0098-7484.
  12. Miyamoto, Kyohei; Nakashima, Tsuyoshi; Shima, Nozomu; Kato, Seiya; Ueda, Kentaro; Kawazoe, Yu; Ohta, Yoshinori; Morimoto, Takeshi; Yamamura, Hitoshi (2018-08). "Effect of Dexmedetomidine on Lactate Clearance in Patients With Septic Shock: A Subanalysis of a Multicenter Randomized Controlled Trial". Shock. 50 (2): 162–166. doi:10.1097/SHK.0000000000001055. ISSN 1073-2322. Check date values in: |date= (help)
  13. 13.0 13.1 Brooks, George A. (2018-04). "The Science and Translation of Lactate Shuttle Theory". Cell Metabolism. 27 (4): 757–785. doi:10.1016/j.cmet.2018.03.008. Check date values in: |date= (help)
  14. Bouzat, Pierre; Sala, Nathalie; Suys, Tamarah; Zerlauth, Jean-Baptiste; Marques-Vidal, Pedro; Feihl, François; Bloch, Jocelyne; Messerer, Mahmoud; Levivier, Marc; Meuli, Reto; Magistretti, Pierre J. (2014-03). "Cerebral metabolic effects of exogenous lactate supplementation on the injured human brain". Intensive Care Medicine. 40 (3): 412–421. doi:10.1007/s00134-013-3203-6. ISSN 0342-4642. Check date values in: |date= (help)
  15. 15.0 15.1 Carteron, Laurent; Solari, Daria; Patet, Camille; Quintard, Hervé; Miroz, John-Paul; Bloch, Jocelyne; Daniel, Roy T.; Hirt, Lorenz; Eckert, Philippe; Magistretti, Pierre J.; Oddo, Mauro (2018-10). "Hypertonic Lactate to Improve Cerebral Perfusion and Glucose Availability After Acute Brain Injury*:". Critical Care Medicine. 46 (10): 1649–1655. doi:10.1097/CCM.0000000000003274. ISSN 0090-3493. Check date values in: |date= (help)
  16. 16.0 16.1 16.2 Levy, Bruno; Mansart, Arnauld; Montemont, Chantal; Gibot, Sebastien; Mallie, Jean-Pierre; Regnault, Veronique; Lecompte, Thomas; Lacolley, Patrick (2007-01-23). "Myocardial lactate deprivation is associated with decreased cardiovascular performance, decreased myocardial energetics, and early death in endotoxic shock". Intensive Care Medicine. 33 (3): 495–502. doi:10.1007/s00134-006-0523-9. ISSN 0342-4642.