Lactic acidosis pathophysiology: Difference between revisions
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==Pathophysiology== | ==Pathophysiology== | ||
*[[Lactic Acidosis|Lactic acidosis]] occurs when cells make lactic acid faster than it can be metabolized. <ref>Sailer, Christian, Wasner, Susanne. Differential Diagnosis Pocket. Hermosa Beach, CA: Borm Bruckmeir Publishing LLC, 2002:77 ISBN 1591032016</ref> <ref>Kahan, Scott, Smith, Ellen G. In A Page: Signs and Symptoms. Malden, Massachusetts: Blackwell Publishing, 2004:68 ISBN 140510368X</ref> Both overproduction of lactate, or reduced metabolism, lead to acidosis. Normal lactate levels are less than 2 mmol/L, lactate levels between 2 mmol/L and 4 mmol/L are defined as hyperlactatemia. Severe hyperlactatemia is a level of 4 mmol/L or higher. | *[[Lactic Acidosis|Lactic acidosis]] occurs when cells make lactic acid faster than it can be metabolized. <ref>Sailer, Christian, Wasner, Susanne. Differential Diagnosis Pocket. Hermosa Beach, CA: Borm Bruckmeir Publishing LLC, 2002:77 ISBN 1591032016</ref> <ref>Kahan, Scott, Smith, Ellen G. In A Page: Signs and Symptoms. Malden, Massachusetts: Blackwell Publishing, 2004:68 ISBN 140510368X</ref> Both overproduction of [[lactate]], or reduced metabolism, lead to acidosis. Normal lactate levels are less than 2 mmol/L, lactate levels between 2 mmol/L and 4 mmol/L are defined as hyperlactatemia. Severe hyperlactatemia is a level of 4 mmol/L or higher. | ||
*Other definitions for lactic acidosis include: pH less than or equal to 7.35 and lactatemia greater than 2 mmol/L with a partial pressure of carbon dioxide (PaC02) less than or equal to 42 mmHg. | *Other definitions for lactic acidosis include: pH less than or equal to 7.35 and lactatemia greater than 2 mmol/L with a partial pressure of carbon dioxide (PaC02) less than or equal to 42 mmHg. | ||
After glycolysis, pyruvate is shunted into two main pathways. Under aerobic conditions, it is converted to acetyl-CoA by pyruvate dehydrogenase, then enters the citric acid cycle and a series of reactions occur to form ATP (Adenosine Triphosphate) and NADH (nicotinamide adenine dinucleotide), which goes into oxidative phosphorylation, producing the majority of ATP in a cell. | After [[glycolysis]], pyruvate is shunted into two main pathways. Under aerobic conditions, it is converted to acetyl-CoA by pyruvate dehydrogenase, then enters the [[citric acid cycle]] and a series of reactions occur to form ATP (Adenosine Triphosphate) and NADH (nicotinamide adenine dinucleotide), which goes into [[oxidative phosphorylation]], producing the majority of ATP in a cell. | ||
However, anaerobic conditions result in pyruvate channeling into the Cori cycle (lactic acid cycle), where pyruvate is converted to lactate, to regenerate NAD+ from NADH. The NAD+ generated can now be utilized in glycolysis again, forming two molecules of ATP per molecule of glucose. The lactate produced gets sent to the liver, for gluconeogenesis<ref name="pmid10484349">{{cite journal| author=Katz J, Tayek JA| title=Recycling of glucose and determination of the Cori Cycle and gluconeogenesis. | journal=Am J Physiol | year= 1999 | volume= 277 | issue= 3 | pages= E401-7 | pmid=10484349 | doi=10.1152/ajpendo.1999.277.3.E401 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10484349 }} </ref>. | However, anaerobic conditions result in pyruvate channeling into the [[Cori cycle]] (lactic acid cycle), where pyruvate is converted to lactate, to regenerate NAD+ from NADH. The NAD+ generated can now be utilized in glycolysis again, forming two molecules of ATP per molecule of glucose. The lactate produced gets sent to the liver, for [[gluconeogenesis]]<ref name="pmid10484349">{{cite journal| author=Katz J, Tayek JA| title=Recycling of glucose and determination of the Cori Cycle and gluconeogenesis. | journal=Am J Physiol | year= 1999 | volume= 277 | issue= 3 | pages= E401-7 | pmid=10484349 | doi=10.1152/ajpendo.1999.277.3.E401 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10484349 }} </ref>. | ||
Acid generation on the cellular level is dictated by the ratio of NAD+ and NADH. These molecules help maintain the intracellular pH by influencing the ratio of pyruvate to lactate. Therefore, an increased NADH concentration results in an increased lactate level. Causes of increased NADH include a hypoxic state, ingestion and oxidation of large amounts of ethanol. In the lactic acidosis associated with shock, a marked increase in lactate production driven by catecholamine stimulation of glycolysis is a key mechanism. A similar process is likely responsible for the lactic acidosis that occurs when high doses of inhaled beta agonists are used to treat severe asthma.<ref name="pmid21460758">{{cite journal| author=Meert KL, McCaulley L, Sarnaik AP| title=Mechanism of lactic acidosis in children with acute severe asthma. | journal=Pediatr Crit Care Med | year= 2012 | volume= 13 | issue= 1 | pages= 28-31 | pmid=21460758 | doi=10.1097/PCC.0b013e3182196aa2 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21460758 }} </ref> There are [[Lactic acidosis classification|types of lactic acidosis]] based on the process that leads to an increased lactate level. Type A is is due to hypovolemia leading to hypoxia, type B involves an offending drug (metformin has been associated<ref name="pmid16750454">{{cite journal| author=Alivanis P, Giannikouris I, Paliuras C, Arvanitis A, Volanaki M, Zervos A| title=Metformin-associated lactic acidosis treated with continuous renal replacement therapy. | journal=Clin Ther | year= 2006 | volume= 28 | issue= 3 | pages= 396-400 | pmid=16750454 | doi=10.1016/j.clinthera.2006.03.004 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16750454 }} </ref>) or toxin.<ref name="pmid16145217">{{cite journal| author=Fall PJ, Szerlip HM| title=Lactic acidosis: from sour milk to septic shock. | journal=J Intensive Care Med | year= 2005 | volume= 20 | issue= 5 | pages= 255-71 | pmid=16145217 | doi=10.1177/0885066605278644 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16145217 }} </ref> | Acid generation on the cellular level is dictated by the ratio of [[Nicotinamide adenine dinucleotide|NAD+]] and NADH. These molecules help maintain the intracellular pH by influencing the ratio of pyruvate to lactate. Therefore, an increased NADH concentration results in an increased lactate level. Causes of increased NADH include a hypoxic state, ingestion and oxidation of large amounts of ethanol. In the lactic acidosis associated with shock, a marked increase in lactate production driven by [[catecholamine]] stimulation of glycolysis is a key mechanism. A similar process is likely responsible for the lactic acidosis that occurs when high doses of inhaled beta agonists are used to treat severe asthma.<ref name="pmid21460758">{{cite journal| author=Meert KL, McCaulley L, Sarnaik AP| title=Mechanism of lactic acidosis in children with acute severe asthma. | journal=Pediatr Crit Care Med | year= 2012 | volume= 13 | issue= 1 | pages= 28-31 | pmid=21460758 | doi=10.1097/PCC.0b013e3182196aa2 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21460758 }} </ref> There are [[Lactic acidosis classification|types of lactic acidosis]] based on the process that leads to an increased lactate level. Type A is is due to hypovolemia leading to hypoxia, type B involves an offending drug (metformin has been associated<ref name="pmid16750454">{{cite journal| author=Alivanis P, Giannikouris I, Paliuras C, Arvanitis A, Volanaki M, Zervos A| title=Metformin-associated lactic acidosis treated with continuous renal replacement therapy. | journal=Clin Ther | year= 2006 | volume= 28 | issue= 3 | pages= 396-400 | pmid=16750454 | doi=10.1016/j.clinthera.2006.03.004 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16750454 }} </ref>) or toxin.<ref name="pmid16145217">{{cite journal| author=Fall PJ, Szerlip HM| title=Lactic acidosis: from sour milk to septic shock. | journal=J Intensive Care Med | year= 2005 | volume= 20 | issue= 5 | pages= 255-71 | pmid=16145217 | doi=10.1177/0885066605278644 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16145217 }} </ref> | ||
Normally, there is a very high metabolic potential for lactate utilization, as demonstrated in patients with grand mal seizures<ref name="pmid19702">{{cite journal| author=Orringer CE, Eustace JC, Wunsch CD, Gardner LB| title=Natural history of lactic acidosis after grand-mal seizures. A model for the study of an anion-gap acidosis not associated with hyperkalemia. | journal=N Engl J Med | year= 1977 | volume= 297 | issue= 15 | pages= 796-9 | pmid=19702 | doi=10.1056/NEJM197710132971502 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19702 }} </ref>. This may be due to decreased lactate clearance in hypovolemic disorders such as shock, where lactic acidosis occurs despite a mild increase in lactate formation<ref name="pmid1733331">{{cite journal| author=Lindinger MI, Heigenhauser GJ, McKelvie RS, Jones NL| title=Blood ion regulation during repeated maximal exercise and recovery in humans. | journal=Am J Physiol | year= 1992 | volume= 262 | issue= 1 Pt 2 | pages= R126-36 | pmid=1733331 | doi=10.1152/ajpregu.1992.262.1.R126 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1733331 }} </ref>. | Normally, there is a very high metabolic potential for lactate utilization, as demonstrated in patients with grand mal seizures<ref name="pmid19702">{{cite journal| author=Orringer CE, Eustace JC, Wunsch CD, Gardner LB| title=Natural history of lactic acidosis after grand-mal seizures. A model for the study of an anion-gap acidosis not associated with hyperkalemia. | journal=N Engl J Med | year= 1977 | volume= 297 | issue= 15 | pages= 796-9 | pmid=19702 | doi=10.1056/NEJM197710132971502 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19702 }} </ref>. This may be due to decreased lactate clearance in hypovolemic disorders such as shock, where lactic acidosis occurs despite a mild increase in lactate formation<ref name="pmid1733331">{{cite journal| author=Lindinger MI, Heigenhauser GJ, McKelvie RS, Jones NL| title=Blood ion regulation during repeated maximal exercise and recovery in humans. | journal=Am J Physiol | year= 1992 | volume= 262 | issue= 1 Pt 2 | pages= R126-36 | pmid=1733331 | doi=10.1152/ajpregu.1992.262.1.R126 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1733331 }} </ref>. | ||
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Pathophysiology
- Lactic acidosis occurs when cells make lactic acid faster than it can be metabolized. [1] [2] Both overproduction of lactate, or reduced metabolism, lead to acidosis. Normal lactate levels are less than 2 mmol/L, lactate levels between 2 mmol/L and 4 mmol/L are defined as hyperlactatemia. Severe hyperlactatemia is a level of 4 mmol/L or higher.
- Other definitions for lactic acidosis include: pH less than or equal to 7.35 and lactatemia greater than 2 mmol/L with a partial pressure of carbon dioxide (PaC02) less than or equal to 42 mmHg.
After glycolysis, pyruvate is shunted into two main pathways. Under aerobic conditions, it is converted to acetyl-CoA by pyruvate dehydrogenase, then enters the citric acid cycle and a series of reactions occur to form ATP (Adenosine Triphosphate) and NADH (nicotinamide adenine dinucleotide), which goes into oxidative phosphorylation, producing the majority of ATP in a cell.
However, anaerobic conditions result in pyruvate channeling into the Cori cycle (lactic acid cycle), where pyruvate is converted to lactate, to regenerate NAD+ from NADH. The NAD+ generated can now be utilized in glycolysis again, forming two molecules of ATP per molecule of glucose. The lactate produced gets sent to the liver, for gluconeogenesis[3].
Acid generation on the cellular level is dictated by the ratio of NAD+ and NADH. These molecules help maintain the intracellular pH by influencing the ratio of pyruvate to lactate. Therefore, an increased NADH concentration results in an increased lactate level. Causes of increased NADH include a hypoxic state, ingestion and oxidation of large amounts of ethanol. In the lactic acidosis associated with shock, a marked increase in lactate production driven by catecholamine stimulation of glycolysis is a key mechanism. A similar process is likely responsible for the lactic acidosis that occurs when high doses of inhaled beta agonists are used to treat severe asthma.[4] There are types of lactic acidosis based on the process that leads to an increased lactate level. Type A is is due to hypovolemia leading to hypoxia, type B involves an offending drug (metformin has been associated[5]) or toxin.[6]
Normally, there is a very high metabolic potential for lactate utilization, as demonstrated in patients with grand mal seizures[7]. This may be due to decreased lactate clearance in hypovolemic disorders such as shock, where lactic acidosis occurs despite a mild increase in lactate formation[8].
Lactic acidosis is an underlying process in the development of rigor mortis. Tissue in the muscles of the deceased resort to anaerobic metabolism and significant amounts of lactic acid are released into the muscle tissue. This along with the loss of ATP causes the muscles to grow stiff.
References
- ↑ Sailer, Christian, Wasner, Susanne. Differential Diagnosis Pocket. Hermosa Beach, CA: Borm Bruckmeir Publishing LLC, 2002:77 ISBN 1591032016
- ↑ Kahan, Scott, Smith, Ellen G. In A Page: Signs and Symptoms. Malden, Massachusetts: Blackwell Publishing, 2004:68 ISBN 140510368X
- ↑ Katz J, Tayek JA (1999). "Recycling of glucose and determination of the Cori Cycle and gluconeogenesis". Am J Physiol. 277 (3): E401–7. doi:10.1152/ajpendo.1999.277.3.E401. PMID 10484349.
- ↑ Meert KL, McCaulley L, Sarnaik AP (2012). "Mechanism of lactic acidosis in children with acute severe asthma". Pediatr Crit Care Med. 13 (1): 28–31. doi:10.1097/PCC.0b013e3182196aa2. PMID 21460758.
- ↑ Alivanis P, Giannikouris I, Paliuras C, Arvanitis A, Volanaki M, Zervos A (2006). "Metformin-associated lactic acidosis treated with continuous renal replacement therapy". Clin Ther. 28 (3): 396–400. doi:10.1016/j.clinthera.2006.03.004. PMID 16750454.
- ↑ Fall PJ, Szerlip HM (2005). "Lactic acidosis: from sour milk to septic shock". J Intensive Care Med. 20 (5): 255–71. doi:10.1177/0885066605278644. PMID 16145217.
- ↑ Orringer CE, Eustace JC, Wunsch CD, Gardner LB (1977). "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. 297 (15): 796–9. doi:10.1056/NEJM197710132971502. PMID 19702.
- ↑ Lindinger MI, Heigenhauser GJ, McKelvie RS, Jones NL (1992). "Blood ion regulation during repeated maximal exercise and recovery in humans". Am J Physiol. 262 (1 Pt 2): R126–36. doi:10.1152/ajpregu.1992.262.1.R126. PMID 1733331.