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{{Methemoglobinemia }}
{{Methemoglobinemia }}


{{CMG}}; {{AE}}{{Aksiniya K. Stevasarova, M.D.}}
{{CMG}}; {{AE}}{{AKS}}


==Overview==
==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+).  <ref>{{J Clin Invest. 1963 Apr; 42(4): 581–588.
[[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+).  <ref name="pmid13999462">{{cite journal| author=WEED RI, REED CF, BERG G| title=Is hemoglobin an essential structural component of human erythrocyte membranes? | journal=J Clin Invest | year= 1963 | volume= 42 | issue=  | pages= 581-8 | pmid=13999462 | doi=10.1172/JCI104747 | pmc=289318 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13999462  }} </ref>
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}}</ref>


==Pathogenesis==
==Pathogenesis==
Line 18: Line 14:
*[[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.  
*[[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+). <ref>{{Del Med J. 2011 Jul;83(7):203-8.
*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+). <ref name="pmid21954509">{{cite journal| author=Ashurst J, Wasson M| title=Methemoglobinemia: a systematic review of the pathophysiology, detection, and treatment. | journal=Del Med J | year= 2011 | volume= 83 | issue= 7 | pages= 203-8 | pmid=21954509 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21954509 }} </ref>
Methemoglobinemia: a systematic review of the pathophysiology, detection, and treatment.
Ashurst J1, Wasson M. pmid=PMID: 21954509 }}</ref>


*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). <ref>{{Rev Bras Anestesiol. 2008 Nov-Dec;58(6):651-64.
*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). <ref name="pmid19082413">{{cite journal| author=do Nascimento TS, Pereira RO, de Mello HL, Costa J| title=Methemoglobinemia: from diagnosis to treatment. | journal=Rev Bras Anestesiol | year= 2008 | volume= 58 | issue= 6 | pages= 651-64 | pmid=19082413 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19082413 }} </ref>
Methemoglobinemia: from diagnosis to treatment.
[Article in English, Portuguese]
do Nascimento TS1, Pereira RO, de Mello HL, Costa J. pmid=PMID:19082413 }}</ref>  


*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]]). <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>
*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]]). <ref name="pmid21954509">{{cite journal| author=Ashurst J, Wasson M| title=Methemoglobinemia: a systematic review of the pathophysiology, detection, and treatment. | journal=Del Med J | year= 2011 | volume= 83 | issue= 7 | pages= 203-8 | pmid=21954509 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21954509 }} </ref>


There are two major mechanisms that can lead to the formation of [[methemoglobin]] - acquired and congenital.  <ref>{{Prog Clin Biol Res. 1981;51:133-51. Methemoglobin pathophysiology. Jaffé ER. pmid=PMID: 7022466}}</ref>
There are two major mechanisms that can lead to the formation of [[methemoglobin]] - acquired and congenital.  <ref name="pmid7022466">{{cite journal| author=Jaffé ER| title=Methemoglobin pathophysiology. | journal=Prog Clin Biol Res | year= 1981 | volume= 51 | issue=  | pages= 133-51 | pmid=7022466 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7022466 }} </ref>




'''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 name="pmid20831930">{{cite journal| author=Trapp L, Will J| title=Acquired methemoglobinemia revisited. | journal=Dent Clin North Am | year= 2010 | volume= 54 | issue= 4 | pages= 665-75 | pmid=20831930 | doi=10.1016/j.cden.2010.06.007 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=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 name="pmid3537620">{{cite journal| author=Hall AH, Kulig KW, Rumack BH| title=Drug- and chemical-induced methaemoglobinaemia. Clinical features and management. | journal=Med Toxicol | year= 1986 | volume= 1 | issue= 4 | pages= 253-60 | pmid=3537620 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3537620 }} </ref> <ref name="pmid22024786">{{cite journal| author=Skold A, Cosco DL, Klein R| title=Methemoglobinemia: pathogenesis, diagnosis, and management. | journal=South Med J | year= 2011 | volume= 104 | issue= 11 | pages= 757-61 | pmid=22024786 | doi=10.1097/SMJ.0b013e318232139f | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22024786 }} </ref>, that cause acute increment in [[methemoglobin]] levels, which overwhelms the normal physiologic [[protective enzyme mechanisms]]. The most common agents are [[anesthetics]]<ref name="pmid29519718">{{cite journal| author=Faust AC, Guy E, Baby N, Ortegon A| title=Local Anesthetic-Induced Methemoglobinemia During Pregnancy: A Case Report and Evaluation of Treatment Options. | journal=J Emerg Med | year= 2018 | volume= 54 | issue= 5 | pages= 681-684 | pmid=29519718 | doi=10.1016/j.jemermed.2018.01.039 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29519718 }} </ref> like [[benzocaine]]<ref name="pmid8069004">{{cite journal| author=Rodriguez LF, Smolik LM, Zbehlik AJ| title=Benzocaine-induced methemoglobinemia: report of a severe reaction and review of the literature. | journal=Ann Pharmacother | year= 1994 | volume= 28 | issue= 5 | pages= 643-9 | pmid=8069004 | doi=10.1177/106002809402800515 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8069004 }} </ref>, [[lidocaine]]<ref name="pmid29627919">{{cite journal| author=Gay HC, Amaral AP| title=Acquired Methemoglobinemia Associated with Topical Lidocaine Administration: A Case Report. | journal=Drug Saf Case Rep | year= 2018 | volume= 5 | issue= 1 | pages= 15 | pmid=29627919 | doi=10.1007/s40800-018-0081-4 | pmc=5889764 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=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]].
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.
Methemoglobinemia: pathogenesis, diagnosis, and management.
Skold A1, Cosco DL, Klein R. pmid=22024786 }}</ref>, that cause acute increment in [[methemoglobin]] levels, which overwhelms the normal physiologic [[protective enzyme mechanisms]]. The most common agents are [[anesthetics]]<ref>{{ 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}}</ref> like [[benzocaine]]<ref>{{ 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 }}</ref>, [[lidocaine]]<ref>{{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 }}</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''' <ref>{{Haematologia (Budap). 1982 Dec;15(4):389-99. Enzymopenic hereditary methemoglobinemia. Jaffé ER. pmid=PMID: 6764628}}</ref>    <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>    <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=3537620}}</ref>  <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 (Hereditary) Methemoglobinemia'''      


There are three main congenital conditions that lead to methemoglobinemia:
*There are three main congenital conditions that lead to methemoglobinemia<ref name="pmid21954509">{{cite journal| author=Ashurst J, Wasson M| title=Methemoglobinemia: a systematic review of the pathophysiology, detection, and treatment. | journal=Del Med J | year= 2011 | volume= 83 | issue= 7 | pages= 203-8 | pmid=21954509 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21954509  }} </ref>:


1. [[Cytochrome b5 reductase deficiency]] and [[pyruvate kinase deficiency]]
1. [[Cytochrome b5 reductase deficiency]] and [[pyruvate kinase deficiency]]<ref name="pmid6764628">{{cite journal| author=Jaffé ER| title=Enzymopenic hereditary methemoglobinemia. | journal=Haematologia (Budap) | year= 1982 | volume= 15 | issue= 4 | pages= 389-99 | pmid=6764628 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6764628  }} </ref>


2. [[G6PD deficiency]]
2. [[G6PD deficiency]]
Line 60: Line 41:
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 M[[etHb]] 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. <ref name="pmid19082413">{{cite journal| author=do Nascimento TS, Pereira RO, de Mello HL, Costa J| title=Methemoglobinemia: from diagnosis to treatment. | journal=Rev Bras Anestesiol | year= 2008 | volume= 58 | issue= 6 | pages= 651-64 | pmid=19082413 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19082413  }} </ref>


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.
*[[Congenital deficiency]] in [[G6PD]] can lead to decreased levels of [[NADPH]] and thus compromising the function of the [[diaphorase II enzyme system]].
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.


[[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==
 
 
==Microscopic Pathology==


==References==
==References==

Latest revision as of 20:38, 31 July 2018

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aksiniya 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

There are two major mechanisms that can lead to the formation of methemoglobin - acquired and congenital. [4]


Acquired or Acute Methemoglobinemia

  • 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. [11] [12]
  • 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. [13]

Congenital (Hereditary) Methemoglobinemia

  • There are three main congenital conditions that lead to methemoglobinemia[2]:

1. Cytochrome b5 reductase deficiency and pyruvate kinase deficiency[14]

2. G6PD deficiency

3. Presence of abnormal hemoglobin (Hb M)

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. [3]

References

  1. ↑ WEED RI, REED CF, BERG G (1963). "Is hemoglobin an essential structural component of human erythrocyte membranes?". J Clin Invest. 42: 581–8. doi:10.1172/JCI104747. PMC 289318. PMID 13999462.
  2. ↑ 2.0 2.1 2.2 Ashurst J, Wasson M (2011). "Methemoglobinemia: a systematic review of the pathophysiology, detection, and treatment". Del Med J. 83 (7): 203–8. PMID 21954509.
  3. ↑ 3.0 3.1 do Nascimento TS, Pereira RO, de Mello HL, Costa J (2008). "Methemoglobinemia: from diagnosis to treatment". Rev Bras Anestesiol. 58 (6): 651–64. PMID 19082413.
  4. ↑ Jaffé ER (1981). "Methemoglobin pathophysiology". Prog Clin Biol Res. 51: 133–51. PMID 7022466.
  5. ↑ Trapp L, Will J (2010). "Acquired methemoglobinemia revisited". Dent Clin North Am. 54 (4): 665–75. doi:10.1016/j.cden.2010.06.007. PMID 20831930.
  6. ↑ Hall AH, Kulig KW, Rumack BH (1986). "Drug- and chemical-induced methaemoglobinaemia. Clinical features and management". Med Toxicol. 1 (4): 253–60. PMID 3537620.
  7. ↑ Skold A, Cosco DL, Klein R (2011). "Methemoglobinemia: pathogenesis, diagnosis, and management". South Med J. 104 (11): 757–61. doi:10.1097/SMJ.0b013e318232139f. PMID 22024786.
  8. ↑ Faust AC, Guy E, Baby N, Ortegon A (2018). "Local Anesthetic-Induced Methemoglobinemia During Pregnancy: A Case Report and Evaluation of Treatment Options". J Emerg Med. 54 (5): 681–684. doi:10.1016/j.jemermed.2018.01.039. PMID 29519718.
  9. ↑ Rodriguez LF, Smolik LM, Zbehlik AJ (1994). "Benzocaine-induced methemoglobinemia: report of a severe reaction and review of the literature". Ann Pharmacother. 28 (5): 643–9. doi:10.1177/106002809402800515. PMID 8069004.
  10. ↑ Gay HC, Amaral AP (2018). "Acquired Methemoglobinemia Associated with Topical Lidocaine Administration: A Case Report". Drug Saf Case Rep. 5 (1): 15. doi:10.1007/s40800-018-0081-4. PMC 5889764. PMID 29627919.
  11. ↑ [www.fda.gov/Drugs/DrugSafety/ucm250024.htm]
  12. ↑ [www.fda.gov/forconsumers/consumerupdates/ucm306062.htm]
  13. ↑ [www.epa.gov/dwstandardsregulations]
  14. ↑ Jaffé ER (1982). "Enzymopenic hereditary methemoglobinemia". Haematologia (Budap). 15 (4): 389–99. PMID 6764628.

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