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Causes of lactic acidosis

Michael Emmett, MD
Section Editor
Richard H Sterns, MD
Deputy Editor
John P Forman, MD, MSc


Lactic acidosis is the most common cause of metabolic acidosis in hospitalized patients. It is associated with an elevated anion gap and a plasma lactate concentration above 4 meq/L. Impaired tissue oxygenation, leading to increased anaerobic metabolism, is usually responsible for the rise in lactate production. (See "Approach to the adult with metabolic acidosis".)

The pathophysiology and causes of lactic acidosis will be reviewed here. The possible role of bicarbonate therapy in such patients is discussed separately. (See "Bicarbonate therapy in lactic acidosis".)


A review of the biochemistry of lactate generation and metabolism is important in understanding the pathogenesis of lactic acidosis [1]. Both overproduction and reduced metabolism of lactate appear to be operative in most patients.

Cellular lactate generation is influenced by the "redox state" of the cell. The redox state in the cellular cytoplasm is mainly reflected by the ratio of oxidized and reduced nicotine adenine dinucleotide (ie, NAD+ [oxidized form] and NADH [reduced form]).

NAD+ and NADH are involved in many cellular redox reactions, serving, respectively, as an electron acceptor or an electron donor. One of these cellular redox reactions is the equilibrium between pyruvic acid and lactic acid, a reaction catalyzed by the enzyme lactate dehydrogenase (figure 1). Thus, the ratio of pyruvate and lactate is influenced by the ratio of NAD+ and NADH, such that a reduced redox state (ie, low NAD+/NADH ratio) is associated with a shift in the ratio from pyruvate to lactate. Many of the factors that produce a reduced redox state also accelerate pyruvate generation and simultaneously impair mitochondrial oxidation, thereby increasing pyruvate and lactate generation (see 'Mitochondrial dysfunction' below). These factors include inadequate oxygen delivery or utilization, and rapid oxidation of certain substrates, such as ethanol.


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Literature review current through: Apr 2015. | This topic last updated: Sep 9, 2014.
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  1. Adeva-Andany M, López-Ojén M, Funcasta-Calderón R, et al. Comprehensive review on lactate metabolism in human health. Mitochondrion 2014; 17:76.
  2. Kreisberg RA. Lactate homeostasis and lactic acidosis. Ann Intern Med 1980; 92:227.
  3. Madias NE. Lactic acidosis. Kidney Int 1986; 29:752.
  4. Arieff AI, Park R, Leach WJ, Lazarowitz VC. Pathophysiology of experimental lactic acidosis in dogs. Am J Physiol 1980; 239:F135.
  5. Arieff AI, Graf H. Pathophysiology of type A hypoxic lactic acidosis in dogs. Am J Physiol 1987; 253:E271.
  6. Orringer CE, Eustace JC, Wunsch CD, Gardner LB. Natural history of lactic acidosis after grand-mal seizures. A model for the study of an anion-gap acidosis not associated with hyperkalemia. N Engl J Med 1977; 297:796.
  7. Osnes JB, Hermansen L. Acid-base balance after maximal exercise of short duration. J Appl Physiol 1972; 32:59.
  8. Lindinger MI, Heigenhauser GJ, McKelvie RS, Jones NL. Blood ion regulation during repeated maximal exercise and recovery in humans. Am J Physiol 1992; 262:R126.
  9. Luchette FA, Jenkins WA, Friend LA, et al. Hypoxia is not the sole cause of lactate production during shock. J Trauma 2002; 52:415.
  10. Levy B. Lactate and shock state: the metabolic view. Curr Opin Crit Care 2006; 12:315.
  11. Bersin RM, Arieff AI. Improved hemodynamic function during hypoxia with Carbicarb, a new agent for the management of acidosis. Circulation 1988; 77:227.
  12. Fulop M, Horowitz M, Aberman A, Jaffe ER. Lactic acidosis in pulmonary edema due to left ventricular failure. Ann Intern Med 1973; 79:180.
  13. Weil MH, Afifi AA. Experimental and clinical studies on lactate and pyruvate as indicators of the severity of acute circulatory failure (shock). Circulation 1970; 41:989.
  14. Mikkelsen ME, Miltiades AN, Gaieski DF, et al. Serum lactate is associated with mortality in severe sepsis independent of organ failure and shock. Crit Care Med 2009; 37:1670.
  15. Shapiro NI, Howell MD, Talmor D, et al. Serum lactate as a predictor of mortality in emergency department patients with infection. Ann Emerg Med 2005; 45:524.
  16. Marliss EB, Ohman JL Jr, Aoki TT, Kozak GP. Altered redox state obscuring ketoacidosis in diabetic patients with lactic acidosis. N Engl J Med 1970; 283:978.
  17. Lu J, Zello GA, Randell E, et al. Closing the anion gap: contribution of D-lactate to diabetic ketoacidosis. Clin Chim Acta 2011; 412:286.
  18. Sillos EM, Shenep JL, Burghen GA, et al. Lactic acidosis: a metabolic complication of hematologic malignancies: case report and review of the literature. Cancer 2001; 92:2237.
  19. Fraley DS, Adler S, Bruns FJ, Zett B. Stimulation of lactate production by administration of bicarbonate in a patient with a solid neoplasm and lactic acidosis. N Engl J Med 1980; 303:1100.
  20. Nadiminti Y, Wang JC, Chou SY, et al. Lactic acidosis associated with Hodgkin's disease: response to chemotherapy. N Engl J Med 1980; 303:15.
  21. Rice K, Schwartz SH. Lactic acidosis with small cell carcinoma. Rapid response to chemotherapy. Am J Med 1985; 79:501.
  22. Friedenberg AS, Brandoff DE, Schiffman FJ. Type B lactic acidosis as a severe metabolic complication in lymphoma and leukemia: a case series from a single institution and literature review. Medicine (Baltimore) 2007; 86:225.
  23. Sia P, Plumb TJ, Fillaus JA. Type B lactic acidosis associated with multiple myeloma. Am J Kidney Dis 2013; 62:633.
  24. Dhup S, Dadhich RK, Porporato PE, Sonveaux P. Multiple biological activities of lactic acid in cancer: influences on tumor growth, angiogenesis and metastasis. Curr Pharm Des 2012; 18:1319.
  25. Stacpoole PW. Lactic acidosis and other mitochondrial disorders. Metabolism 1997; 46:306.
  26. Santa KM. Treatment options for mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome. Pharmacotherapy 2010; 30:1179.
  27. Velez JC, Janech MG. A case of lactic acidosis induced by linezolid. Nat Rev Nephrol 2010; 6:236.
  28. Cope TE, McFarland R, Schaefer A. Rapid-onset, linezolid-induced lactic acidosis in MELAS. Mitochondrion 2011; 11:992.
  29. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001; 345:1368.