Methemoglobinemia pathophysiology: Difference between revisions
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'''Acquired or Acute Methemoglobinemia''' | '''Acquired or Acute Methemoglobinemia''' | ||
The [[acquired methemoglobinemia]]<ref>{{Dent Clin North Am. 2010 Oct;54(4):665-75. doi: 10.1016/j.cden.2010.06.007. Epub 2010 Aug 7. | *The [[acquired methemoglobinemia]]<ref>{{Dent Clin North Am. 2010 Oct;54(4):665-75. doi: 10.1016/j.cden.2010.06.007. Epub 2010 Aug 7. | ||
Acquired methemoglobinemia revisited. | Acquired methemoglobinemia revisited. | ||
Trapp L1, Will J. pmid=20831930 }}</ref> is significantly more common than the [[congenital]] one. It is associated with exposure to or use of [[oxidant drugs]], [[toxins]] or [[chemicals]]<ref>{{Med Toxicol. 1986 Jul-Aug;1(4):253-60. Drug- and chemical-induced methaemoglobinaemia. Clinical features and management. Hall AH, Kulig KW, Rumack BH.pmid=PMID: 3537620}}</ref> <ref>{{South Med J. 2011 Nov;104(11):757-61. doi: 10.1097/SMJ.0b013e318232139f. | Trapp L1, Will J. pmid=20831930 }}</ref> is significantly more common than the [[congenital]] one. It is associated with exposure to or use of [[oxidant drugs]], [[toxins]] or [[chemicals]]<ref>{{Med Toxicol. 1986 Jul-Aug;1(4):253-60. Drug- and chemical-induced methaemoglobinaemia. Clinical features and management. Hall AH, Kulig KW, Rumack BH.pmid=PMID: 3537620}}</ref> <ref>{{South Med J. 2011 Nov;104(11):757-61. doi: 10.1097/SMJ.0b013e318232139f. | ||
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Gay HC1,2, Amaral AP3. pmid=PMID: 29627919 }}</ref>, [[prilocaine]], used locally or topically, [[antibiotics]] like [[dapsone]] (used for the treatment of [[Brown Recluse spider]] bites, [[Leprosy]], [[PCP]] prophylaxis, ecc) [[trimethoprim]], [[sulfonamides]], [[nitrates]] ([[amynitrate]]), [[nitroglycerin]] ([[NG]]), [[aniline dyes]], [[metoclopramide]], [[chlorates]] and [[bromates]]. | Gay HC1,2, Amaral AP3. pmid=PMID: 29627919 }}</ref>, [[prilocaine]], used locally or topically, [[antibiotics]] like [[dapsone]] (used for the treatment of [[Brown Recluse spider]] bites, [[Leprosy]], [[PCP]] prophylaxis, ecc) [[trimethoprim]], [[sulfonamides]], [[nitrates]] ([[amynitrate]]), [[nitroglycerin]] ([[NG]]), [[aniline dyes]], [[metoclopramide]], [[chlorates]] and [[bromates]]. | ||
Infants under 4 months of age are particularly susceptible to methemoglobinemia. The most common causes in this patient population are the ingesting of [[nitrates]] in drinking water and topical [[anesthetic]] use like [[benzocaine]] and [[prilocaine]], that are found in over-the-counter (OTC) products, used to soothe a baby’s sore gums from teething for example. For that reason The U.S. Food and Drug Administration recommends that these OTC drugs are not given to children younger than age 2. <ref> [www.fda.gov/Drugs/DrugSafety/ucm250024.htm]</ref> <ref> [www.fda.gov/forconsumers/consumerupdates/ucm306062.htm]</ref> | *Infants under 4 months of age are particularly susceptible to methemoglobinemia. The most common causes in this patient population are the ingesting of [[nitrates]] in drinking water and topical [[anesthetic]] use like [[benzocaine]] and [[prilocaine]], that are found in over-the-counter (OTC) products, used to soothe a baby’s sore gums from teething for example. For that reason The U.S. Food and Drug Administration recommends that these OTC drugs are not given to children younger than age 2. <ref> [www.fda.gov/Drugs/DrugSafety/ucm250024.htm]</ref> <ref> [www.fda.gov/forconsumers/consumerupdates/ucm306062.htm]</ref> | ||
[[Nitrates]] ingestion is especially dangerous as [[nitrates]] used in agricultural fertilizers can often leak into the ground, thus contaminating well water. Infants, particularly those younger than 4 months are most susceptible to methemoglobinemia. This is due to the fact that the [[NADH methemoglobin reductase]] activity and concentration, the main protective [[enzyme]], against [[oxidative stress]] is not fully mature in infants. The Environmental Protection Agency (EPA) has set strict rules on the Maximum Contaminant Level (MCL) of [[nitrate]] as [[nitrogen]] in the water. The current EPA guidelines state that no more than 10 mg/L (or 10 parts per million) of [[nitrogen]] is safe in drinking water. <ref> [www.epa.gov/dwstandardsregulations]</ref> | *[[Nitrates]] ingestion is especially dangerous as [[nitrates]] used in agricultural fertilizers can often leak into the ground, thus contaminating well water. Infants, particularly those younger than 4 months are most susceptible to methemoglobinemia. This is due to the fact that the [[NADH methemoglobin reductase]] activity and concentration, the main protective [[enzyme]], against [[oxidative stress]] is not fully mature in infants. The Environmental Protection Agency (EPA) has set strict rules on the Maximum Contaminant Level (MCL) of [[nitrate]] as [[nitrogen]] in the water. The current EPA guidelines state that no more than 10 mg/L (or 10 parts per million) of [[nitrogen]] is safe in drinking water. <ref> [www.epa.gov/dwstandardsregulations]</ref> | ||
'''Congenital (Hereditary) Methemoglobinemia''' | '''Congenital (Hereditary) Methemoglobinemia''' | ||
There are three main congenital conditions that lead to methemoglobinemia: | *There are three main congenital conditions that lead to methemoglobinemia<ref>{{Del Med J. 2011 Jul;83(7):203-8. Methemoglobinemia: a systematic review of the pathophysiology, detection, and treatment. Ashurst J1, Wasson M. pmid=PMID: 21954509}}</ref> : | ||
1. [[Cytochrome b5 reductase deficiency]] and [[pyruvate kinase deficiency]] | 1. [[Cytochrome b5 reductase deficiency]] and [[pyruvate kinase deficiency]]<ref>{{Haematologia (Budap). 1982 Dec;15(4):389-99. Enzymopenic hereditary methemoglobinemia. Jaffé ER. pmid=PMID: 6764628}}</ref> | ||
2. [[G6PD deficiency]] | 2. [[G6PD deficiency]] | ||
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3. Presence of abnormal hemoglobin ([[Hb M]]) | 3. Presence of abnormal hemoglobin ([[Hb M]]) | ||
*Both [[cytochrome b5 reductase]] deficiency and [[pyruvate kinase]] deficiency can lead to [[NADH]] deficiency which in turn will lead to decreased ability to remove MetHb from the blood. [[Cytochrome b5 reductase]] deficiency is an [[autosomal recessive]] disorder with at least 2 forms that we know of. | |||
Both [[cytochrome b5 reductase]] deficiency and [[pyruvate kinase]] deficiency can lead to [[NADH]] deficiency which in turn will lead to decreased ability to remove MetHb from the blood. [[Cytochrome b5 reductase]] deficiency is an [[autosomal recessive]] disorder with at least 2 forms that we know of. | |||
The most common form, is the [[Ib5R deficiency]], where [[cyt b5 reductase]] is absent only in [[RBCs]], and the levels of MetHb are around 10% to 35%. | The most common form, is the [[Ib5R deficiency]], where [[cyt b5 reductase]] is absent only in [[RBCs]], and the levels of MetHb are around 10% to 35%. | ||
The second type, which is much less common, is the [[IIb5R], where MetHb varies between 10% and 15% and the [[cyt b5 reductase]] is absent in all cells. This form is associated with [[mental retardation]], [[microcephaly]], and other neurologic problems. The lifespan of the affected individuals is greatly affected and patients usually die very young. | The second type, which is much less common, is the [[IIb5R], where MetHb varies between 10% and 15% and the [[cyt b5 reductase]] is absent in all cells. This form is associated with [[mental retardation]], [[microcephaly]], and other neurologic problems. The lifespan of the affected individuals is greatly affected and patients usually die very young. <ref>{{ Rev Bras Anestesiol. 2008 Nov-Dec;58(6):651-64. Methemoglobinemia: from diagnosis to treatment. [Article in English, Portuguese] do Nascimento TS1, Pereira RO, de Mello HL, Costa J.pmid=PMID: 19082413}}</ref> | ||
[[Congenital]] deficiency in [[G6PD]] can lead to decreased levels of [[NADPH]] and thus compromising the function of the [[diaphorase II]] enzyme system. | *[[Congenital]] deficiency in [[G6PD]] can lead to decreased levels of [[NADPH]] and thus compromising the function of the [[diaphorase II]] enzyme system. | ||
Abnormal hemoglobins like [[Hb M]], an [[autosomal dominant]] condition, can also lead to [[methemoglobinemia]]. Here we observe not only impaired [[oxygen]] binding due to [[oxidation]] of iron to its [[ferric]] state (Fe3+), caused by amino acid replacement in the [[heme]] molecule, but also inability of the protective enzyme systems to reduce the iron to its normal [[ferrous]] state (Fe2+). | *Abnormal hemoglobins like [[Hb M]], an [[autosomal dominant]] condition, can also lead to [[methemoglobinemia]]. Here we observe not only impaired [[oxygen]] binding due to [[oxidation]] of iron to its [[ferric]] state (Fe3+), caused by amino acid replacement in the [[heme]] molecule, but also inability of the protective enzyme systems to reduce the iron to its normal [[ferrous]] state (Fe2+). | ||
==Gross Pathology== | ==Gross Pathology== | ||
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Template:Aksiniya K. Stevasarova, M.D.
Overview
Methemoglobin (MetHb) refers to the state of hemoglobin (Hb) in which the [[iron atom)] is oxidized or in ferric state (Fe3+). In this state the iron is incapable of creating a bond with the oxygen, thus it neither can bind, nor deliver oxygen to the tissues.The formation of methemoglobin can be a result of a normal physiologic process of losing an electron from the iron atom, after releasing the oxygen to the tissues, and we can detect methemoglobin in the blood of healthy people, but the normal levels should always be less than 1%. These levels are maintained by several enzyme systems that work to reduce the iron to its ferrous state (Fe2+). [1]
Pathogenesis
- Hemoglobin is a protein found in all red blood cells (RBCs), that carries oxygen with the help of iron. In order for this iron to be able to combine with oxygen and turn into oxyhemoglobin, it needs to be in its reduced or ferrous state (Fe2+). Hemoglobin can only accept, transport and release oxygen to the tissues when the iron is in ferrous state.
- Methemoglobin (MetHb) is the oxidized form of hemoglobin (Hb) in which the [[iron atom)] is oxidized or in ferric state (Fe3+) and cannot bind oxygen.
- The formation of methemoglobin is a normal physiologic process of losing an electron from the iron atom, after releasing the oxygen to the tissues. Normal levels of MetHb should always be less than 1%. These levels are maintained by several enzyme systems that work to reduce the iron to its ferrous state (Fe2+). [2]
- Almost 99% of the methemoglobin normally produced, is removed by the diaphorase I pathway. Here electrons from NADH are transferred to methemoglobin, with the help of cytochrome b5 reductase, to reduce it to hemoglobin. The second most important protective enzyme is the diaphorase II (requiring nicotinamide adenine dinucleotide phosphate – NADPH as a co-factor). [3]
- In patients with deficiency of NADH-cytochrome b5 reductase, which is an autosomal recessive disorder, the diaphorase II pathway becomes the main enzyme system that removes methemoglobin by reducing it to hemoglobin with the help of glucose-6-phosphate dehydrogenase (G6PD). [4]
There are two major mechanisms that can lead to the formation of methemoglobin - acquired and congenital. [5]
Acquired or Acute Methemoglobinemia
- The acquired methemoglobinemia[6] is significantly more common than the congenital one. It is associated with exposure to or use of oxidant drugs, toxins or chemicals[7] [8], that cause acute increment in methemoglobin levels, which overwhelms the normal physiologic protective enzyme mechanisms. The most common agents are anesthetics[9] like benzocaine[10], lidocaine[11], prilocaine, used locally or topically, antibiotics like dapsone (used for the treatment of Brown Recluse spider bites, Leprosy, PCP prophylaxis, ecc) trimethoprim, sulfonamides, nitrates (amynitrate), nitroglycerin (NG), aniline dyes, metoclopramide, chlorates and bromates.
- Infants under 4 months of age are particularly susceptible to methemoglobinemia. The most common causes in this patient population are the ingesting of nitrates in drinking water and topical anesthetic use like benzocaine and prilocaine, that are found in over-the-counter (OTC) products, used to soothe a baby’s sore gums from teething for example. For that reason The U.S. Food and Drug Administration recommends that these OTC drugs are not given to children younger than age 2. [12] [13]
- Nitrates ingestion is especially dangerous as nitrates used in agricultural fertilizers can often leak into the ground, thus contaminating well water. Infants, particularly those younger than 4 months are most susceptible to methemoglobinemia. This is due to the fact that the NADH methemoglobin reductase activity and concentration, the main protective enzyme, against oxidative stress is not fully mature in infants. The Environmental Protection Agency (EPA) has set strict rules on the Maximum Contaminant Level (MCL) of nitrate as nitrogen in the water. The current EPA guidelines state that no more than 10 mg/L (or 10 parts per million) of nitrogen is safe in drinking water. [14]
Congenital (Hereditary) Methemoglobinemia
- There are three main congenital conditions that lead to methemoglobinemia[15] :
1. Cytochrome b5 reductase deficiency and pyruvate kinase deficiency[16]
3. Presence of abnormal hemoglobin (Hb M)
- Both cytochrome b5 reductase deficiency and pyruvate kinase deficiency can lead to NADH deficiency which in turn will lead to decreased ability to remove MetHb from the blood. Cytochrome b5 reductase deficiency is an autosomal recessive disorder with at least 2 forms that we know of.
The most common form, is the Ib5R deficiency, where cyt b5 reductase is absent only in RBCs, and the levels of MetHb are around 10% to 35%. The second type, which is much less common, is the [[IIb5R], where MetHb varies between 10% and 15% and the cyt b5 reductase is absent in all cells. This form is associated with mental retardation, microcephaly, and other neurologic problems. The lifespan of the affected individuals is greatly affected and patients usually die very young. [17]
- Congenital deficiency in G6PD can lead to decreased levels of NADPH and thus compromising the function of the diaphorase II enzyme system.
- Abnormal hemoglobins like Hb M, an autosomal dominant condition, can also lead to methemoglobinemia. Here we observe not only impaired oxygen binding due to oxidation of iron to its ferric state (Fe3+), caused by amino acid replacement in the heme molecule, but also inability of the protective enzyme systems to reduce the iron to its normal ferrous state (Fe2+).
Gross Pathology
Microscopic Pathology
References
- ↑ {{J Clin Invest. 1963 Apr; 42(4): 581–588. doi: 10.1172/JCI104747 IS HEMOGLOBIN AN ESSENTIAL STRUCTURAL COMPONENT OF HUMAN ERYTHROCYTE MEMBRANES?* Robert I. Weed, Claude F. Reed, and George Berg PMID: 13999462 PMCID: PMC289318 DOI: 10.1172/JCI104747}}
- ↑ {{Del Med J. 2011 Jul;83(7):203-8. Methemoglobinemia: a systematic review of the pathophysiology, detection, and treatment. Ashurst J1, Wasson M. pmid=PMID: 21954509 }}
- ↑ {{Rev Bras Anestesiol. 2008 Nov-Dec;58(6):651-64. Methemoglobinemia: from diagnosis to treatment. [Article in English, Portuguese] do Nascimento TS1, Pereira RO, de Mello HL, Costa J. pmid=PMID:19082413 }}
- ↑ Template:Del Med J. 2011 Jul;83(7):203-8. Methemoglobinemia: a systematic review of the pathophysiology, detection, and treatment. Ashurst J1, Wasson M. pmid=PMID: 21954509
- ↑ Template:Prog Clin Biol Res. 1981;51:133-51. Methemoglobin pathophysiology. Jaffé ER. pmid=PMID: 7022466
- ↑ {{Dent Clin North Am. 2010 Oct;54(4):665-75. doi: 10.1016/j.cden.2010.06.007. Epub 2010 Aug 7. Acquired methemoglobinemia revisited. Trapp L1, Will J. pmid=20831930 }}
- ↑ Template:Med Toxicol. 1986 Jul-Aug;1(4):253-60. Drug- and chemical-induced methaemoglobinaemia. Clinical features and management. Hall AH, Kulig KW, Rumack BH.pmid=PMID: 3537620
- ↑ {{South Med J. 2011 Nov;104(11):757-61. doi: 10.1097/SMJ.0b013e318232139f. Methemoglobinemia: pathogenesis, diagnosis, and management. Skold A1, Cosco DL, Klein R. pmid=22024786 }}
- ↑ {{ J Emerg Med. 2018 Mar 5. pii: S0736-4679(18)30095-7. doi: 10.1016/j.jemermed.2018.01.039. [Epub ahead of print] Local Anesthetic-Induced Methemoglobinemia During Pregnancy: A Case Report and Evaluation of Treatment Options. Faust AC1, Guy E1, Baby N2, Ortegon A3.pmid=29519718}}
- ↑ {{ Ann Pharmacother. 1994 May;28(5):643-9. Benzocaine-induced methemoglobinemia: report of a severe reaction and review of the literature. Rodriguez LF1, Smolik LM, Zbehlik AJ.pmid=8069004 }}
- ↑ {{Drug Saf Case Rep. 2018 Apr 7;5(1):15. doi: 10.1007/s40800-018-0081-4. Acquired Methemoglobinemia Associated with Topical Lidocaine Administration: A Case Report. Gay HC1,2, Amaral AP3. pmid=PMID: 29627919 }}
- ↑ [www.fda.gov/Drugs/DrugSafety/ucm250024.htm]
- ↑ [www.fda.gov/forconsumers/consumerupdates/ucm306062.htm]
- ↑ [www.epa.gov/dwstandardsregulations]
- ↑ Template:Del Med J. 2011 Jul;83(7):203-8. Methemoglobinemia: a systematic review of the pathophysiology, detection, and treatment. Ashurst J1, Wasson M. pmid=PMID: 21954509
- ↑ Template:Haematologia (Budap). 1982 Dec;15(4):389-99. Enzymopenic hereditary methemoglobinemia. Jaffé ER. pmid=PMID: 6764628
- ↑ {{ Rev Bras Anestesiol. 2008 Nov-Dec;58(6):651-64. Methemoglobinemia: from diagnosis to treatment. [Article in English, Portuguese] do Nascimento TS1, Pereira RO, de Mello HL, Costa J.pmid=PMID: 19082413}}