methemoglobinemia, fetal hemoglobin, rare mutations, metoclopramide, sulfhemoglobinemia - brief notes

 Another reason why infants are prone to methemoglobinemia is that fetal hemoglobin is more easily oxidized. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1071541/

"Methemoglobinemia has been reported in young infants (<6 months) in whom severe metabolic acidosis develops from diarrhea and dehydration.⁷ Young infants may be particularly susceptible to this complication because of their low stomach acid production, large number of nitrite-reducing bacteria, and the relatively easy oxidation of fetal hemoglobin. Small infants have lower erythrocyte levels of cytochrome b reductase.⁸ Higher intestinal pH of infants may promote the growth of gram-negative organisms that convert dietary nitrates to nitrites."

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I was reminded of  fetal hemoglobin when I watched a video recently where persistence of fetal hemoglobin as a rescue mutation for thalassemia was discussed; here's my comment on it:

https://youtu.be/ml1svbRo7Lg?t=990

 Great interview. I'm sure this will get a lot of views from people in the research community and be well appreciated by students. 16:30 I have wondered about some other very rare mutations. One is in aquaporin 1; it is very rare for people to be AQP1 null even though they show very few effects. However, at birth the lung changes from being a secretory organ to being absorptive - so AQP1 null people may not typically survive birth. But if that is the case, then how do the few that do survive manage it? I'll try to link to a video where this is discussed: https://youtu.be/L1TyWo86w4Q?t=1170 Another one is mutations in the uric acid transporter. I got into a bit of a heated debate on the U-shaped (or some describe it as a J) mortality curve for serum urate recently. My opponent felt that the higher mortality at the low end was due to reverse causation. I used the rarity of loss of URAT1 function mutations to support my argument that UA is needed as a peroxynitrite scavenger; people with very low serum urate due to loss of URAT1 suffer from endothelial dysfunction [PMID: 25787674]. But the rarity of the mutation may have something to do with a critical physiological point during early development and I guess I should have mentioned that. 

Can fetal hemoglobin become induced in adults in various disease states / chronic hypoxia - for example ME/CFS - perhaps explaining some of the elevation in MetHb?

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Interesting case report on sulfhemoglobinemia and discussion of differential diagnosis w/ methhemoglobinemia:

https://jamanetwork.com/journals/jamapediatrics/fullarticle/189784

"The patient received a "loading dose" of oral N-acetylcysteine, 140 mg/kg, but the dose was promptly vomited. During the next 24 hours, she had repeated episodes of emesis associated with administration of N-acetylcysteine (70 mg/kg every 4 hours). In an attempt to alleviate her gastrointestinal tract symptoms, the patient was administered metoclopramide (100 mg intravenously [IV]). Because of continued nausea and vomiting, she received ondansetron (16 mg IV) and metoclopramide (100 mg IV per dose; total dose, 500 mg) over 48 hours. By hospital day 2, the patient's gastrointestinal tract symptoms resolved and the N-acetylcysteine was administered without any problems. She completed a total of 18 doses of N-acetylcysteine by the next day.

On hospital day 3, the patient experienced several dystonic reactions, developed discoloration of her lips, face, and nailbeds, and complained of severe headaches. 

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Specifically, our case is perplexing because of the drugs that were associated with the sulfhemoglobinemia. Metoclopramide is a drug with mild oxidant activity that has been associated with rare reports of sulfhemoglobinemia after long-term use.⁵ It is structurally related to the aniline dyes and to prilocaine which are known to produce methemoglobinemia.⁶N-acetylcysteine is a biochemical precursor of glutathione⁷ and a source of hydrogen sulfide. These two drugs may have acted together in this patient to produce the sulfhemoglobinemia. Curiously, N-acetylcysteine is a commonly prescribed therapy for acetaminophen overdose and is frequently used along with metoclopramide, yet few documented cases of sulfhemoglobinemia exist.⁷ Perhaps, the very large dose of metoclopramide in this case was essential for the production of sulfhemoglobinemia."

Note that the patient was also  given ondansetron, which can have effects on dopamine:

https://pmj.bmj.com/content/postgradmedj/73/856/127.full.pdf

"Ondansetron and ICS205-930,both highly selective antagonists of 5-HT3 receptors, do not reduce the output of dopamine or its metabolites, but antagonize the facilitation of dopamine."

Could ondansetron cause the accumulation of dopamine in erythrocytes?