Lactic Acidosis

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Lactic Acidosis

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  • In 1924, Otto Warburg showed that tumor cells favor glycolysis even there is abundant blood supply and normal oxygen concentrations, which came to be known as aerobic glycolysis, or Warburg effect Figure 2. Changes in glucose metabolism contributing to type B lactic acidosis. (a) In neoplastic cells, glucose is preferentially shunted to anaerobic respiration instead of the tricarboxylic acid (TCA) cycle because of the Warburg effect, increasing lactate production. (b) In the presence of liver dysfunction, decreased conversion of lactate to glucose may contribute to lactic acidosis. (c) In thiamine deficiency, conversion of pyruvate to acetyl coenzyme A (acetyl CoA) is reduced and pyruvate is converted to lactate.
  • Lactic Acidosis

    1. 1. Lactic AcidosisLactic Acidosis Wisit Cheungpasitporn, MDWisit Cheungpasitporn, MD Division of NephrologyDivision of Nephrology Mayo Clinic, RochesterMayo Clinic, Rochester
    2. 2. DiagnosisDiagnosis • Normal plasma lactate: 0.5 to 1.5 meq/L. • Lactic acidosis: • plasma lactate concentration exceeds 4 to 5meq/L, even among patients without a systemic acidosis
    3. 3. Lactate metabolism in tissueLactate metabolism in tissue • The body tissues produce ~ 1500The body tissues produce ~ 1500 mmol of lactate each day (mmol of lactate each day (15 to 3015 to 30 mmol/kg per day)mmol/kg per day) • Metabolized mainly by the liver (Metabolized mainly by the liver (CoriCori cyclecycle)) • All tissues can produce lactate underAll tissues can produce lactate under anaerobic conditionsanaerobic conditions
    4. 4. Lactic acidosisLactic acidosis Madias N. Kidney Int 1986; 29:752-774.
    5. 5. Madias N. Lactic acidosis. Kidney Int 1986; 29:752-774.
    6. 6. Madias N. Lactic acidosis. Kidney Int 1986; 29:752-774.
    7. 7. Madias N. Lactic acidosis. Kidney Int 1986; 29:752-774.
    8. 8. PathophysiologyPathophysiology • Lactic acidosis occurs whenever there is an imbalance between the production and use of lactic acid. • Causes of Lactic acidosis • Type A • Type B • D Lactic acidosis: Generated from glucose and carbohydrate by bowel bacteria in short bowel syndromes Cohen R, Woods H. Clinical and Biochemical Aspects of Lactic Acidosis. Blackwell Scientific Publications; 1976.
    9. 9. Palmer BF. Comprehensive Clinical Nephrology. 4th Edition
    10. 10. Sia P et al. Am J Kidney Dis. 2013 Sep;62(3):633-7.
    11. 11. Malignancy and Lactic acidosis: Pathogenesis • Leukemia, lymphoma, and solid malignancies. • Warburg effect • Liver Metastasis. • Thiamine or riboflavin deficiency Friedenberg AS et. al. Medicine (Baltimore). 2007 Jul;86(4):225-32.
    12. 12. Warburg effect: Aerobic glycolysisWarburg effect: Aerobic glycolysis • In 1924,In 1924, Otto WarburgOtto Warburg showed thatshowed that mitochondrial respiration even in themitochondrial respiration even in the presence of oxygen. They thereforepresence of oxygen. They therefore metabolize glucose mainly to lactatemetabolize glucose mainly to lactate (aerobic glycolysis, type B lactate(aerobic glycolysis, type B lactate generation).generation). Sia P et al. Am J Kidney Dis. 2013 Sep;62(3):633-7.
    13. 13. Dhup S et. al. Curr Pharm Des. 2012;18(10):1319-30.
    14. 14. Malignancy and Lactic acidosis: Pathogenesis Sia P et al. Am J Kidney Dis. 2013 Sep;62(3):633-7.
    15. 15. de Groot R, Sprenger RA, Imholz AL, Gerding MN. Type B lactic acidosis in solid malignancies. Neth J Med. 2011 Mar;69(3):120-3.
    16. 16. Hui WF. HK J Paediatr 2012.;17:183-189
    17. 17. Larroche C, Mouthon L. Autoimmun Rev. 2004 Feb;3(2):69-75.
    18. 18. DiCarlo J et. al. Pediatr Hematol Oncol. 2006;23(7):599-610.
    19. 19. Tateishi Y, et al. Transfus Apher Sci. 2009;40(1):33-40.
    20. 20. Lactic acidosis in this caseLactic acidosis in this case • Cytokine induced lactic acidosis • Warburg effect
    21. 21. Cytokine induced lactic acidosis • 1.1. TNF-αTNF-α a increased the activity ofa increased the activity of LDH A isoform.LDH A isoform. • 2.2. TNFTNF is known to inhibit pyruvateis known to inhibit pyruvate dehydrogenase.dehydrogenase. Nehar D et. al. Endocrinology. 1997;138(5):1964-71 Kiely A et. al. J Endocrinol. 2007 Oct;195(1):113-23.
    22. 22. Cytokine induced lactic acidosis • 3.3. TNF-α, IL-1 and IFN-γ enhance the inflammatory response, leading to endothelial dysfunction and increased vascular permeability, which in turn decreases blood volume, diminishes perfusion of tissues. Kiely A et. al. J Endocrinol. 2007 Oct;195(1):113-23.
    23. 23. Cytokine induced lactic acidosis • 4.4. IL-1,IL-1, TNF-α andand IFN-γ inhibitedinhibited chronic (24 h) and acute stimulatedchronic (24 h) and acute stimulated levels of insulin release andlevels of insulin release and increased cellular glucose andincreased cellular glucose and alanine consumption, and alsoalanine consumption, and also elevated lactate and glutamateelevated lactate and glutamate release.release. Kiely A et. al. J Endocrinol. 2007 Oct;195(1):113-23.
    24. 24. Treatment of lactic acidosisTreatment of lactic acidosis 1. Treatment underlying disease1. Treatment underlying disease 2. Sodium bicarbonate:2. Sodium bicarbonate: may worsenmay worsen oxygen delivery, increase lactate productionoxygen delivery, increase lactate production (especially when hypoxia=>induce glycolysis),(especially when hypoxia=>induce glycolysis), decrease portal vein flowdecrease portal vein flow •The surviving sepsis campaign recommendedThe surviving sepsis campaign recommended holdhold sodium bicarbonate unlesssodium bicarbonate unless profound lactic acidosis and acidemia (arterial pH less than 7.1 and serum bicarbonate 6 meq/L or less). 3. Hemodialysis / CRRT3. Hemodialysis / CRRT
    25. 25. Potential harms of bicarbonate • Increased arterial and tissue capillary PCO2 • Acceleration of lactate generation • Reduced ionized calcium • Hypernatremia • Extracellular fluid (ECF) volume expansion
    26. 26. Alternatives to bicarbonate therapy • Tromethamine (tris-hydroxymethyl aminomethane; also called THAM, TRIS, and trometamol) • Carbicarb • Dichloroacetate (DCA) • None of these alternative agents have shown benefit in patients with lactic acidosis
    27. 27. Hemodialysis • Dialysis may be a useful mode of therapy when severe lactic acidosis exists in conjunction with renal failure or congestive heart failure. • Dialysis would allow bicarbonate infusion without precipitating or worsening fluid overload. Therefore, dialysis would correct acidosis by restoring the buffer pool. Guo PY, Storsley LJ, Finkle SN. Severe lactic acidosis treated with prolonged hemodialysis: recovery after massive overdoses of metformin. Semin Dial. 2006;19(1):80-3.
    28. 28. HemodialysisHemodialysis • Hemodialysis or continuous hemofiltration used in conjunction with alkali infusion may be tolerated in a patient with cardiovascular instability. • However, the overall benefit of such therapy to a patient's outcome is not known. Metformin-induced lactic acidosis has been reported to improve after prolonged hemodialysis. Guo PY, Storsley LJ, Finkle SN. Severe lactic acidosis treated with prolonged hemodialysis: recovery after massive overdoses of metformin. Semin Dial. 2006;19(1):80-3.
    29. 29. Tateishi Y, et al. Transfus Apher Sci. 2009;40(1):33-40.
    30. 30. Hui WF. HK J Paediatr 2012.;17:183-189
    31. 31. Hui WF. HK J Paediatr 2012.;17:183-189
    32. 32. Hui WF. HK J Paediatr 2012.;17:183-189

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