lactic acidosis

Lactic AcidosisLactic Acidosis

Wisit Cheungpasitporn, MDWisit Cheungpasitporn, MD

Division of NephrologyDivision of Nephrology

Mayo Clinic, RochesterMayo Clinic, Rochester

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

Lactate metabolism in tissueLactate metabolism in tissue

• The body tissues produce ~ 1500 The body tissues produce ~ 1500 mmol of lactate each day (mmol of lactate each day (15 to 30 15 to 30 mmol/kg per day)mmol/kg per day)

• Metabolized mainly by the liver (Metabolized mainly by the liver (Cori Cori cyclecycle))

• All tissues can produce lactate under All tissues can produce lactate under anaerobic conditionsanaerobic conditions

Lactic acidosisLactic acidosis

Madias N. Kidney Int  1986; 29:752-774.

Madias N. Lactic acidosis. Kidney Int  1986; 29:752-774.

Madias N. Lactic acidosis. Kidney Int  1986; 29:752-774.

Madias N. Lactic acidosis. Kidney Int  1986; 29:752-774.

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.

Palmer BF. Comprehensive Clinical Nephrology. 4th Edition

Sia P et al. Am J Kidney Dis. 2013 Sep;62(3):633-7. 

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.

Warburg effect: Aerobic glycolysisWarburg effect: Aerobic glycolysis

• In 1924, In 1924, Otto Warburg Otto Warburg showed that showed that mitochondrial respiration even in the mitochondrial respiration even in the presence of oxygen. They therefore presence of oxygen. They therefore metabolize glucose mainly to lactate metabolize 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. 

Dhup S et. al. Curr Pharm Des. 2012;18(10):1319-30. 

Malignancy and Lactic acidosis:Pathogenesis

Sia P et al. Am J Kidney Dis. 2013 Sep;62(3):633-7. 

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.

Hui WF. HK J Paediatr 2012.;17:183-189

Larroche C, Mouthon L. Autoimmun Rev. 2004 Feb;3(2):69-75. 

DiCarlo J et. al. Pediatr Hematol Oncol. 2006;23(7):599-610.

Tateishi Y, et al. Transfus Apher Sci. 2009;40(1):33-40.

Lactic acidosis in this caseLactic acidosis in this case

• Cytokine induced lactic acidosis

• Warburg effect

Cytokine induced lactic acidosis

• 1. 1. TNF-αTNF-α a increased the activity of a increased the activity of LDH A isoform.LDH A isoform.

• 2. 2. TNFTNF is known to inhibit pyruvate is 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.

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.

Cytokine induced lactic acidosis

• 4. 4. IL-1, IL-1, TNF-α and and IFN-γ inhibited inhibited chronic (24 h) and acute stimulated chronic (24 h) and acute stimulated levels of insulin release and levels of insulin release and increased cellular glucose and increased cellular glucose and alanine consumption, and also alanine consumption, and also elevated lactate and glutamate elevated lactate and glutamate release.release.

Kiely A et. al. J Endocrinol. 2007 Oct;195(1):113-23.

Treatment of lactic acidosisTreatment of lactic acidosis

1. Treatment underlying disease1. Treatment underlying disease

2. Sodium bicarbonate: 2. Sodium bicarbonate: may worsen oxygen delivery, may worsen oxygen delivery, increase lactate production (especially when hypoxia=>induce increase lactate production (especially when hypoxia=>induce glycolysis), decrease portal vein flowglycolysis), decrease portal vein flow

•The surviving sepsis campaign recommended The surviving sepsis campaign recommended hold sodium hold sodium bicarbonate unless bicarbonate unless profound lactic acidosis and acidemia (arterial pH less than 7.1 and serum bicarbonate 6 meq/L or less).

3. Hemodialysis / CRRT 3. Hemodialysis / CRRT

Potential harms of bicarbonate

• Increased arterial and tissue capillary PCO2

• Acceleration of lactate generation

• Reduced ionized calcium

• Hypernatremia

• Extracellular fluid (ECF) volume expansion

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

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. 

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. 

Tateishi Y, et al. Transfus Apher Sci. 2009;40(1):33-40.

Hui WF. HK J Paediatr 2012.;17:183-189

Hui WF. HK J Paediatr 2012.;17:183-189

Hui WF. HK J Paediatr 2012.;17:183-189