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Lactic Acidosis
1. Lactic AcidosisLactic Acidosis
Wisit Cheungpasitporn, MDWisit Cheungpasitporn, MD
Division of NephrologyDivision of Nephrology
Mayo Clinic, RochesterMayo Clinic, Rochester
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. 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
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.
10. Sia P et al. Am J Kidney Dis. 2013 Sep;62(3):633-7.
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. 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. Dhup S et. al. Curr Pharm Des. 2012;18(10):1319-30.
14. Malignancy and Lactic acidosis:
Pathogenesis
Sia P et al. Am J Kidney Dis. 2013 Sep;62(3):633-7.
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.
19. Tateishi Y, et al. Transfus Apher Sci. 2009;40(1):33-40.
20. Lactic acidosis in this caseLactic acidosis in this case
• Cytokine induced lactic acidosis
• Warburg effect
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. 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. 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. 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. Potential harms of bicarbonate
• Increased arterial and tissue capillary
PCO2
• Acceleration of lactate generation
• Reduced ionized calcium
• Hypernatremia
• Extracellular fluid (ECF) volume
expansion
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. 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. 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. Tateishi Y, et al. Transfus Apher Sci. 2009;40(1):33-40.
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.