The new england journal of medicine Review Article Disorders of Fluids and Electrolytes Julie R. Ingelfinger, M.D., Editor Lactic Acidosis Jeffrey A. Kraut, M.D., and Nicolaos E. Madias, M.D. actic acidosis results from the accumulation of lactate and From Medical and Research Services, protons in the body fluids and is often associated with poor clinical out- Membrane Biology Laboratory, and the Division of Nephrology, David Geffen comes. The effect of lactic acidosis is governed by its severity and the clinical School of Medicine, University of Califor- L nia, Los Angeles, and the Veterans Af- context. Mortality is increased by a factor of nearly three when lactic acidosis ac- companies low-flow states or sepsis,1 and the higher the lactate level, the worse fairs Greater Los Angeles Healthcare Sys- 2 tem — both in Los Angeles (J.A.K.); and the outcome. Although hyperlactatemia is often attributed to tissue hypoxia, it can the Department of Medicine, Division of result from other mechanisms. Control of the triggering conditions is the only Nephrology, St. Elizabeth’s Medical Cen- effective means of treatment. However, advances in understanding its pathophysio- ter, and the Department of Medicine, Tufts University School of Medicine — logical features and the factors causing cellular dysfunction in the condition could both in Boston (N.E.M.). Address reprint lead to new therapies. This overview of lactic acidosis emphasizes its pathophysi- requests to Dr. Kraut at the Division of ological aspects, as well as diagnosis and management. We confine our discussion Nephrology, VHAGLA Healthcare Sys- tem, 11301 Wilshire Blvd., Los Angeles, to disorders associated with accumulation of the L optical isomer of lactate, which CA 90073; or at jkraut@ ​­ucla . edu; or to represent the vast majority of cases of lactic acidosis encountered clinically. Dr. Madias at the Department of Medi- cine, St. Elizabeth’s Medical Center, 736 Cambridge St., Boston, MA 02135, or at Pathophysiological Features nicolaos . madias@ steward . org. N Engl J Med 2014;371:2309-19. Normal Lactate Metabolism DOI: 10.1056/NEJMra1309483 The reaction integral to the generation or consumption of lactate is shown below: Copyright © 2014 Massachusetts Medical Society. pyruvate + NADH + H+ ←→ lactate + NAD+. Pyruvate is generated largely by anaerobic glycolysis (Embden–Meyerhof path- way). The redox-coupled interconversion of pyruvate and lactate occurs in the cytosol and is catalyzed by lactate dehydrogenase (LDH), a tetramer with five isoforms, each made up of different combinations of two subunits, LDHA and LDHB.3 The LDHA subunit has a higher affinity for pyruvate and its reduction than does LDHB; thus, the nature of the LDH isoforms in tissues affects lactate metabolism. The blood lactate:pyruvate ratio is normally 10:1, but it rises with an increased ratio of NADH concentration ([NADH]) to NAD+ concentration ([NAD+]) (redox state).4 Approximately 20 mmol of lactate per kilogram of body weight is produced in the human body daily, primarily by highly glycolytic tissues containing LDHA-rich LDH, such as skeletal muscle.3,5 Lactate is reconverted to pyruvate and consumed in the mitochondria of the liver, kidney, and other tissues, which have LDHB-rich LDH. The pathways include the Cori cycle, which generates glucose but consumes ATP in the liver and kidney (gluconeogenesis), as well as the tricarboxylic acid cycle and oxidative phosphorylation in the liver, kidney, muscle, heart, brain, and other tissues, which generate ATP when pyruvate is oxidized to carbon dioxide and water. Lactate consumption is subserved by intraorgan and interorgan lactate shuttles fa- cilitated by monocarboxylic acid transporters (MCTs), which mediate the influx and efflux of lactate and accompanying protons. Normally, the generation and consump- n engl j med 371;24 nejm.org December 11, 2014 2309 The New England Journal of Medicine Downloaded from nejm.org on December 11, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved. The new england journal of medicine tion of lactate are equivalent, which results in a Supplementary Appendix). Other disorders as- stable concentration of lactate in the blood.4,6 Lac- sociated with elevated epinephrine levels, such tate production can rise markedly, as exempli- as severe asthma (especially with overuse of fied by its increase by a factor of several hundred β2-adrenergic agonists), extensive trauma, cardio- during maximal exercise,5 but it can also be rap- genic or hemorrhagic shock, and pheochromocy- idly consumed, as seen after cessation of exercise, toma, can cause hyperlactatemia through this seizures, or exogenous lactate loads.5,7 mechanism.9 In inflammatory states, aerobic gly- The bioenergetics of lactate generation can be colysis can also be driven by cytokine-dependent summarized as follows: stimulation of cellular glucose uptake10; in alka- lemic disorders, it can be driven by stimulation of glucose + 2(ADP + inorganic phosphate) 6-phosphofructokinase.4 Aerobic glycolysis and tis- → 2 lactate + 2 H+ + 2 ATP. sue hypoxia are not mutually exclusive; under cer- tain circumstances, both can contribute to hyper- Production of lactate ions by means of glycoly- lactatemia.4,9 sis is accompanied by the release of an equivalent Drugs that impair oxidative phosphorylation, number of protons from the hydrolysis of the such as antiretroviral agents and propofol, can generated ATP. Conversely, lactate consumption augment lactic acid production and on rare occa- removes an equivalent number of protons, there- sions cause severe lactic acidosis. Patients receiv- by maintaining the internal acid–base balance.4 ing these drugs should be monitored carefully. The liver accounts for up to 70% of whole- Hyperlactatemia body lactate clearance.11 In patients with sepsis, Hyperlactatemia occurs when lactate production even when they are hemodynamically stable and exceeds lactate consumption. It also signifies the have normal liver function, lactate clearance can addition of a number of protons equivalent to be reduced, possibly through inhibition of pyru- the number of excess lactate ions, regardless of vate dehydrogenase.12 Chronic liver disease exac- the prevailing acid–base status. Establishing the erbates hyperlactatemia due to sepsis or other pathogenesis of hyperlactatemia can be a valu- disorders,7,11 but in the absence of such disorders, able guide to therapy. even severe cirrhosis rarely generates blood lac- In tissue hypoxia, whether global or localized, tate levels that are more than minimally elevated. lactate is overproduced and underutilized as a However, hyperlactatemia is common in acute result of impaired mitochondrial oxidation (see fulminant liver disease, reflecting both reduced Fig. S1A and S1B in the Supplementary Appendix, clearance and increased production of lactate by available with the full text of this article at NEJM the liver,13 and is an important prognostic factor. .org).4 Even if systemic oxygen delivery is not low enough to cause generalized hypoxia, microcir- Effects on Cellular Function culatory dysfunction can cause regional tissue hy- The cellular dysfunction in hyperlactatemia is com- poxia and hyperlactatemia.8 Coexisting acidemia plex. Tissue hypoxia, if present, is a major factor. contributes to decreased lactate removal by the If the cellular milieu is also severely acidic, cel- liver; severe hypoxia and acidemia can convert the lular dysfunction is likely to be exacerbated. The liver into a net lactate-producing organ.4 latter factor alone can decrease cardiac contrac- Hyperlactatemia can also result from aerobic tility, cardiac output, blood pressure, and tissue glycolysis, a term denoting stimulated glycolysis perfusion; can sensitize the myocardium to car- that depends on factors other than tissue hypoxia. diac arrhythmias; and can attenuate the cardio- Activated in response to stress, aerobic glycolysis vascular responsiveness to catecholamines.14 is an effective, albeit inefficient, mechanism for In some studies, the severity of the acidemia rapid generation of ATP. In the hyperdynamic was a better predictor of cellular dysfunction and stage of sepsis, epinephrine-dependent stimula- clinical outcomes than the hyperlactatemia.15 tion of the β2-adrenoceptor augments the glyco- However, acidemia is often absent as a result of lytic flux both directly and through enhancement coexisting acid–base disorders.7,14 The interaction of the sarcolemmal Na+,K+-ATPase (which con- of systemic acidity and blood lactate and their sumes large quantities of ATP)9 (Fig. S1C in the effect on clinical outcomes require further study. 2310 n engl j med 371;24 nejm.org December 11, 2014 The New England Journal of Medicine Downloaded from nejm.org on December 11, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved. Lactic Acidosis Whether hyperlactatemia itself has an effect ing acid–base disturbances.19 In lactic acidosis, − on cellular function remains unclear. In vitro stud- the ΔAG:ΔHCO3 ratio is often greater than 1, in ies suggest that lactate can depress cardiac con- part because the apparent space of distribution tractility,4,16 yet sodium lactate infusions that raised of protons exceeds that of lactate19,20; therefore, blood lactate to levels as high as 15 mmol per liter an increased ratio might not always suggest a did not depress hemodynamic measures in pa- coexisting acid–base disorder. tients after cardiac surgery.16 An elevated blood lactate level is essential for confirmation of the diagnosis. The lower limit Causes of the normal range for the blood lactate level, 0.5 mmol per liter, is consistent among clinical The major causes of lactic acidosis and their laboratories, but the upper limit can vary sub- presumed mechanisms are listed in Table 1. stantially, from as low as 1.0 mmol per liter to as Typically, they have been divided into disorders high as 2.2 mmol per liter.6,21,22 Therefore, the associated with tissue hypoxia (type A) and cutoff for abnormal values often differs among disorders in which tissue hypoxia is absent laboratories.