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The structure of the enzyme that converts methemoglobin to hemoglobin^[1]

Methemoglobin (English: methaemoglobin) (pronounced "met-hemoglobin") is a form of the oxygen-carrying metalloprotein hemoglobin, in which the iron in the heme group is in the Fe³⁺ (ferric) state, not the Fe²⁺ (ferrous) of normal hemoglobin. Methemoglobin cannot bind oxygen, unlike oxyhemoglobin.^[2] It is bluish chocolate-brown in color. In human blood a trace amount of methemoglobin is normally produced spontaneously, but when present in excess the blood becomes abnormally dark bluish brown. The NADH-dependent enzyme methemoglobin reductase (diaphorase I) is responsible for converting methemoglobin back to hemoglobin.

Normally one to two percent of a person's hemoglobin is methemoglobin; a higher percentage than this can be genetic or caused by exposure to various chemicals and depending on the level can cause health problems known as methemoglobinemia. A higher level of methemoglobin will tend to cause a pulse oximeter to read closer to 85% regardless of the true level of oxygen saturation.^[3]

Common causes of elevated methemoglobin

Reduced cellular defense mechanisms
- Children younger than 4 months exposed to various environmental agents
- Pregnant women are considered vulnerable to exposure of high levels of nitrates in drinking water^[4]
- Cytochrome b5 reductase deficiency
- G6PD deficiency
- Hemoglobin M disease
- Pyruvate kinase deficiency
Various pharmaceutical compounds
- Local anesthetic agents, especially prilocaine and benzocaine.^[5]
- Amyl nitrite, chloroquine, dapsone, nitrates, nitrites, nitroglycerin, nitroprusside, phenacetin, phenazopyridine, primaquine, quinones and sulfonamides
Environmental agents
- Aromatic amines (e.g. p-nitroaniline, patient case)
- Arsine
- Chlorobenzene
- Chromates
- Nitrates/nitrites
Inherited disorders
- Some family members of the Fughate family in Kentucky, due to a recessive gene, had blue skin from an excess of methemoglobin.^[6]
In cats
- Ingestion of Paracetamol (i.e. acetaminophen, tylenol)^{[citation needed]}

Therapeutic uses

Amyl nitrite is administered to treat cyanide poisoning. It works by converting hemoglobin to methemoglobin, which allows for the binding of cyanide and the formation of non-toxic cyanomethemoglobin.^[7]

Methemoglobin saturation

Methemoglobin saturation is expressed as the percentage of hemoglobin in the methemoglobin state; That is MetHb as a proportion of Hb.

1-2% Normal
Less than 10% metHb - No symptoms
10-20% metHb - Skin discoloration only (most notably on mucous membranes)
20-30% metHb - Anxiety, headache, dyspnea on exertion
30-50% metHb - Fatigue, confusion, dizziness, tachypnea, palpitations
50-70% metHb - Coma, seizures, arrhythmias, acidosis
Greater than 70% metHb - Death

Blood stains

Increased levels of methemoglobin are found in blood stains. Upon exiting the body, bloodstains transit from bright red to dark brown, which is attributed to oxidation of oxy-hemoglobin (HbO₂) to methemoglobin (met-Hb) and hemichrome (HC).^[8]

References

^ Bando, S.; Takano, T.; Yubisui, T.; Shirabe, K.; Takeshita, M.; Nakagawa, A. (2004). "Structure of human erythrocyte NADH-cytochromeb5reductase". Acta Crystallographica Section D. 60 (11): 1929–1934. doi:10.1107/S0907444904020645. PMID 15502298.
^ http://www.rtso.ca/methemoglobin-causes-effects/
^ Denshaw-Burke, Mary (2006-11-07). "Methemoglobinema". Retrieved 2008-03-31.
^ Manassaram, D. M.; Backer, L. C.; Messing, R.; Fleming, L. E.; Luke, B.; Monteilh, C. P. (2010). "Nitrates in drinking water and methemoglobin levels in pregnancy: A longitudinal study". Environmental Health. 9: 60. doi:10.1186/1476-069X-9-60. PMC 2967503. PMID 20946657.
^ http://www.fda.gov/Drugs/DrugSafety/ucm250024.htm
^ http://abcnews.go.com/Health/blue-skinned-people-kentucky-reveal-todays-genetic-lesson/story?id=15759819#.T2oS0HqV2So
^ Vale, J. A. (2001). "Cyanide Antidotes: from Amyl Nitrite to Hydroxocobalamin - Which Antidote is Best?". Toxicology. 168 (1): 37–38.
^ Bremmer et al PloS One 2011 http://www.plosone.org/article/info:doi/10.1371/journal.pone.0021845

External links

Methemoglobin at the US National Library of Medicine Medical Subject Headings (MeSH)
MetHb Formation
The Blue people of Troublesome Creek

UpToDate Contents

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1. メトヘモグロビン血症の臨床的特徴、診断、および治療 clinical features diagnosis and treatment of methemoglobinemia
2. メトヘモグロビン血症の遺伝学および病因 genetics and pathogenesis of methemoglobinemia
3. 下肢末梢動脈疾患の症状を治療するための試験的治療 investigational therapies for treating symptoms of lower extremity peripheral artery disease
4. 煙の吸入 smoke inhalation
5. 動脈血液ガス arterial blood gases

English Journal

Prolonged Intravenous Infusion of Sodium Nitrite Delivers Nitric Oxide (NO) in Humans.

Pluta RM.SourceSurgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 5512 Pembroke Terrace, Bethesda, MD, USA, rysiek@ninds.nih.gov.
Acta neurochirurgica. Supplement.Acta Neurochir Suppl.2013;115:49-51.
In preclinical studies, infusion of sodium nitrite delivers nitric oxide (NO) as treatment of vasospasm after subarachnoid hemorrhage. We evaluated safety and toxicity of intravenous nitrite administration in healthy volunteers infused with increasing doses of sodium nitrite for 48 h. Twelve volunte
PMID 22890643

Metabolic activation by human arylacetamide deacetylase, CYP2E1, and CYP1A2 causes phenacetin-induced methemoglobinemia.

Kobayashi Y, Fukami T, Higuchi R, Nakajima M, Yokoi T.SourceDrug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
Biochemical pharmacology.Biochem Pharmacol.2012 Nov 1;84(9):1196-206. doi: 10.1016/j.bcp.2012.08.015. Epub 2012 Aug 23.
Phenacetin has been used as an analgesic antipyretic but has now been withdrawn from the market due to adverse effects such as methemoglobinemia and renal failure. It has been suggested that metabolic activation causes these adverse effects; yet, the precise mechanisms remain unknown. We previously
PMID 22940574

Japanese Journal

Regulation of Cytochrome b5 Expression by miR-223 in Human Liver: Effects on Cytochrome P450 Activities

Takahashi Kei,Oda Yuki,Toyoda Yasuyuki,Fukami Tatsuki,Yokoi Tsuyoshi,Nakajima Miki
Pharmaceutical Research 31(3), 780-794, 2014-03
… Purpose: Cytochrome b 5 (b 5) is a hemoprotein that transfers electrons to several enzymes to fulfill functions in fatty acid desaturation, methemoglobin reduction, steroidogenesis, and drug metabolism. …
NAID 120005596360

The influence of anticoagulant and temperature in measurement of plasma hemoglobin concentration for hemolysis test

, , , , ,
生体医工学 52(Supplement), O-544-O-545, 2014
… The reason for the decrease in hemoglobin concentration is considered to be the formation of methemoglobin. …
NAID 130004948247

17-2 Drinking mineral waters, the actual medical benefit - data of evidence

,
日本温泉気候物理医学会雑誌 77(5), 546-546, 2014
… <BR> Sulfide waters can be damageable for erythrocyte through their deleterious action on enzymatic pathways (GAPDH, G6PDH) and methemoglobin (Albertini, 2008).<BR> Epidemiologic studies emphasized the ability of some tap waters to facilitate some disorders, mainly acid waters and type I diabetes (Skenes, 2002), poorly silicated waters and Alzheimer's disease (Gillette Guyonnet, 2005).<BR> If the studies demonstrated actual pharmacological effects of mineral waters, the clinical relevance of these properties as the medical benefit …
NAID 130004719536

Related Pictures

★リンクテーブル★

リンク元	「MRI」「コンピュータ断層撮影」「メトヘモグロビン」「methaemoglobin」「MetHb」
拡張検索	「methemoglobin reductase activity」「acquired methemoglobinemia」「idiopathic methemoglobinemia」「blood methemoglobin」「methemoglobinemia」

「MRI」

　　[★]

同: magnetic resonance imaging、核磁気共鳴画像、磁気共鳴撮像、磁気共鳴断層撮影 magnetic resonance computed tomography MR-CT、磁気共鳴映像法、磁気共鳴画像法、核磁気共鳴画像診断法

頭部MRIにて使用するシークエンス

造影剤を使わない方法

TOF法(time-of-flight法)

流入してくるプロトンの量を強調→流入する血流のみを高信号に描出

PC法(phase contrast法)

流速に応じた位相の変化を利用

造影剤を使用する方法

MRDSA(MR digital subtraction angiography)

造影剤の急速注入→適応：動静脈病変、血行動態、例えば脳動静脈奇形

T2*強調画像：出血性病変
ダイナミックMRI：下垂体、vascularity

Perfusion imaging：vascularity

3D-MRI
FLAIR法(fluid attenuated inversion recovery)

頭蓋内スクリーニング(T2より病変がわかりやすい)

拡散強調画像 diffusion imaging

適応：急性期脳梗塞

functional MRI(fMRI)：術前マッピング
MR spectroscopy（MRS）：代謝物質

MRIの撮像条件と信号強度

		水	脂肪	骨
T1強調画像	T1WI	黒	白	黒
T2強調画像	T2WI	白	白	黒
FLAIR		黒	白	黒
拡散強調画像	DWI	黒	黒	黒

基本的な物質のMRI画像

参考2 SOR.122

T2 強調画像	高信号		水					出血「メトヘモグロビン」



									脂肪


					線維組織

			皮質骨空気血流
	低信号
		低信号	.	.	.	.	.	.	高信号
		T1強調画像

YN.J-60

MRIの組織間信号強度
MRIの血液信号の強度経時的変化(脳出血)

整形外科分野でのMRI信号強度(SOR.122)

脳のCT, MRIの比較

	CT	MRI
	CT	T1	T2
灰白質	high	low	high
白質	low	high	low
CSF	low	low	high
血液	high	void	void

疾患とMRI

脳出血

超急性期：oxyhemoglobin
急性期：deoxyhemoglobin
亜急性期：methemoglobin
慢性期：hemosiderin

wiki_jaを引用改変

病期	ヘム鉄の性状		磁性	局在	T2WI	T1WI	CT
超急性期（24時間以内）	オキシヘモグロビン	oxyhemoglobin	Fe2+/反磁性	赤血球内	軽度高信号	軽度低信号	高吸収域
急性期（3日以内）	デオキシヘモグロビン	deoxyhemoglobin	Fe2+/常磁性	赤血球内	低信号	軽度低信号	高吸収域
急性期（7日以内）	メトヘモグロビン	methemoglobin	Fe3+/常磁性	赤血球内	低信号	高信号	高吸収域
亜急性期（2週間以内）	フリーメトヘモグロビン		Fe3+/常磁性	赤血球外	高信号	高信号	辺縁部から低下
慢性期（1か月以後）	ヘモジデリン	hemosiderin	Fe3+/常磁性	赤血球外	低信号	低信号	低吸収域

脳梗塞

CTでは発症早期の所見は取りづらく(early CT signは除く)、12-24時間後に低吸収が出現するため、拡散強調画像(DWI)による発症1-3時間後の高信号をとらえるのが早期診断に有用である。

肝臓

SRA.482

正常：T1　＞筋肉、脾臓、T2　脾臓、腎臓＞　＞筋肉。
病変：T1　軽度低信号、T2　軽度高信号
T1強調画像で高信号：脂肪沈着を伴う病変(脂肪肝、肝細胞癌、線種様過形成)、高蛋白貯留液を含む嚢胞性病変(粘液性嚢胞、感染後の嚢胞)、線種様過形成、常磁体物の沈着(亜急性期メトヘモグロビン)、メラニン、ガドリニウム
T2強調画像で著明な高信号：液体の貯留　→　肝嚢胞、海綿状血管腫
T2強調画像で低信号：水分減少を伴う病変(凝固壊死、線種様過形成)、メラニン、デオキシヘモグロビン、ヘモジデリン

DWI

肝臓では占拠性病変が高信号として描出される。悪性腫瘍では細胞密度が増加し水分子の拡散が制限された結果、高信号を示すと考えられている。

ADC

各肝腫瘍における見かけの拡散係数（ADC：apparent diffusion coefficient）を比較し、血管腫では高ADC、悪性腫瘍では低ADCであった。

血腫

参考5改変

血腫におけるヘモグロビンの変性とMRI所見
出血	血液成分	T1強調画像	T2強調画像
直後(～24時間)	オキシヘモグロビン	軽度低信号	軽度高信号
1～3日(急性期)	デオキシヘモグロビン	軽度低信号	低信号
3日～1カ月(亜急性期)	血球外メトヘモグロビン	高信号	高信号
1カ月以上(慢性期)	ヘモジデリン	軽度低信号	低信号

T1とT2

T1が場所、T2が性質を知るために行う？

造影

ガドリニウム：MRIで造影といえばこれ。
超磁性体酸化鉄粒子 SPIO：肝網内系をターゲットとした造影剤である。SPIOはKupffer細胞に貪食されリソソームにクラスター化される家庭でT2*緩和時間およびT2緩和時間を短縮させる。ゆえにKupffer細胞を含む正常肝組織の信号が低下し、含まない腫瘍とのコントラストを強調することができる。(参考1)