Methemoglobinemia pathophysiology

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]

• 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). ^[2]

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

Acquired or Acute Methemoglobinemia

• The acquired methemoglobinemia^[5] is significantly more common than the congenital one. It is associated with exposure to or use of oxidant drugs, toxins or chemicals^{[6] [7]}, that cause acute increment in methemoglobin levels, which overwhelms the normal physiologic protective enzyme mechanisms. The most common agents are anesthetics^[8] like benzocaine^[9], lidocaine^[10], 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. ^{[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)

• 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. ^[3]

• 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+).

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