Methemoglobinemia

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

Methemoglobinemia is a blood disorder in which, due to increased production (congenital or acquired reasons), the red blood cells (RBCs) contain higher than normal levels of methemoglobin (MetHb) (>1%). Methemoglobin forms from the substitution of iron (Fe) in [[ferric/reduced (Fe²⁺) form]], as found in normal hemoglobin, with iron in [[oxidized (Fe³⁺) form]]. The oxidation of Hb to MetHb ( Fe²⁺ to Fe³⁺ ) occurs naturally in healthy people, as a result of the interaction of Hb with oxygen free radicals, which are produced during normal cell metabolism. The levels of MetHb though, never exceed more than 1%, if the protective reduction enzyme systems in the RBCs are working properly. Hemoglobin is the polypeptide protein in the RBCs, consisting of 2 alfa and 2 beta chains connected to an iron atom in ferric form, responsible for binding, carrying and distributing oxygen from the lungs to the tissues. MetHb is unable to bind oxygen, and in case of methemoglobinemia, the affinity of the remaining normal Hb (that has not been yet oxidized to MetHb) to oxygen is very high. This leads to leftward shift of the oxygen-hemoglobin dissociation curve, resulting in hypoxia and dyspnea, because no oxygen gets released to the tissues.

Methemoglobinemia may be classified into two groups, based on the mechanism of its formation- acquired and congenital methemoglobinemia.

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+).

Methemoglobinemia may be caused by either congenital or acquired conditions.

Methemoglobinemia must be differentiated from other diseases that cause hypoxia and cyanosis, such as heart failure, pulmonary embolism, polycythemia, anemia, etc.

The incidence of congenital methemoglobinemia in the United States is very low. There is no racial predilection to methemoglobinemia. The highest prevalence of G6PD deficiency is observed in the malaria-endemic regions: Sub-Saharan Afria, West Asia and Arabian Peninsula, as well as in people of Mediterranean descent.

Methemoglobinemia screening is not routinely done in the United States.

Depending on the causes that have led to methemoglobin formation, different complications and prognosis are expected respectively.

Death is the most serious complications of methemoglobinemia especially when MetHb levels approach 70%. In severely sick patients death may occur even with lower levels of MetHb. Other complications include myocardial infarction, seizure and coma. <ref name=”pmid14579544″>{{cite journal| author=Bradberry SM| title=Occupational methaemoglobinaemia. Mechanisms of production, features, diagnosis and management including the use of methylene blue.

Depending on the anoxic end-organ damage caused by MetHb, the prognosiss varies between mild and fatal.

Methemoglobinemia will present with different signs and symptoms depending on the methemoglobin levels in the blood.

Methemoglobinemia can be diagnosed with several laboratory findings such as ABG analysis, co-oximetry and pulse oximetry.

Methemoglobinemia should be promptly treated once diagnosed.

Surgery does not play a role in the treatment of Methemoglobinemia.

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

• It has been reported (Heard & Ashworth 1968 apud Basrani et al. 2007) that, when placed in an aqueous solution, Chlorhexidine Gluconate (antiseptic) slowly hydrolyzes and forms para-chloroaniline (4-Chloroaniline, p-Chloroaniline or PCA). Para-chloroaniline (PCA) has been shown to be toxic. As an aromatic amine, the primary toxic effect is methemogloblin formation. Toxicological studies in rats and mice have shown that the hemopoietic system is the major target for PCA.

• There haven’t been reported any major outbreaks of methemoglobemia.

• In 1990, Chhabra et al conducted a 90-day study (with p-chloroaniline) and found that methemoglobin formation and accompanying hemolytic anemia, extra-medullary hematopoiesis, and splenomegaly were indicative of erythrocyte toxicity and regenerative anemia.

• Methemoglobinemia will stay in history thanks to the famous painting of The Blue People of Kentucky, by Walt Spitzmiller in 1982.

• The following are a few famous cases of methemoglobinemia:

• The ‘blue men of Lurgan’ were a pair of Lurgan men suffering from what was described as ‘familial idiopathic methemoglobinemia‘ who were treated by Dr. James Deeny in 1942. Deeny, who would later become the Chief Medical Officer of the Republic of Ireland, prescribed a course of ascorbic acid and sodium bicarbonate. In case one, by the eighth day of treatment there was a marked change in appearance and by the twelfth day of treatment the patient’s complexion was normal. In case two, the patient’s complexion reached normality over a month-long duration of treatment.

• The Fugates, a family that lived in the hills of Kentucky, are the most famous example of this hereditary chromosomal error. Known as the Blue Fugates, Martin Fugate, settled near Hazard, Kentucky, circa 1800. His wife was a carrier of the recessive methemoglobinemia gene, as was a nearby clan with whom the Fugates intermarried. As a result, many descendants of the Fugates were born with methemoglobinemia.

Reference to these cases is found in the British Medical Journal, June 12, Vol. 1 ,pg. 721, written by J. Deeny, E.T. Murdock and J.J. Rogan and appears also in the book of essays, The End of an Epidemic, by James Deeny ISBN I 899047 06 9. Template:WH Template:WS

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

Methemoglobinemia may be classified into two groups, based on the mechanism of its formation- acquired and congenital methemoglobinemia.

Methemoglobinemia may be classified into two groups, based on the mechanism of its formation- acquired and congenital methemoglobinemia.

Congenital (Hereditary) Methemoglobinemia

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

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

2.G6PD deficiency

3.Presence of abnormal hemoglobin (Hb M)

Acquired or Acute Methemoglobinemia

• The most common causes are different oxidant drugs, toxins and chemicals.^[2]

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

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

Methemoglobinemia may be caused by either congenital or acquired conditions.

Congenital (Hereditary) Methemoglobinemia

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

1. Cytochrome b5 reductase deficiency and pyruvate kinase deficiency

2. G6PD deficiency

3. Presence of abnormal hemoglobin (Hb M)

Acquired or Acute Methemoglobinemia

• Some of the most common causes leading to methemoglobinemia include different oxidant drugs, toxins and chemicals.^{[1] [2]}

1. Drug Induced

• Anesthetics^[3] like benzocaine^[4], lidocaine^[5], prilocaine^[6]

• Methylene blue

• Nitric oxide

• Amyl Nitrate

• Nitroglycerin

• Antimalarial drugs like Primaquine phosphate (in nicotinamide adenine dinucleotide (NADH) methemoglobin reductase deficient individuals)

• Rasburicase ^[7]

• Sulfasalazine

• Dapsone

• Trimethoprim

• Sulfonamides

• Aniline dyes^[8]

• Metoclopramide

• Chlorates and Bromates

2. Contaminated well water (in premature infants and infants younger than 4 months) ^{[9] [10]}

3. Solid foods (not well cooked vegetables high in nitrates in premature infants and infants younger than 4 months) ^{[11] [12]}

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

Methemoglobinemia must be differentiated from other diseases that cause hypoxia and cyanosis, such as heart failure, pulmonary embolism, polycythemia, anemia, etc.

• There are several conditions that can present similar to methemoglobinemia. Note that the hypoxia in methemogobinemia will be unresponsive to oxygen treatment, in comparison to cardiac and pulmonary cause. Worth mentioning is that high doses of antidotal treatment for methemogobinemia (Methylene blue) can also cause cyanotic discoloration of the skin, but this does not mean the the treatment is not working.

• Methemoglobinemia can present with similar signs and symptoms of other conditions causing hypoxia (as listed below). Note that the hypoxia in methemogobinemia will be unresponsive to oxygen treatment, in comparison to cardiac and pulmonary causes of hypoxia.

• Heart failure

• Pulmonary embolism

• Polycythemia^[1] • Anemia

• Rasbirucase (Rx Tumor Lysis Syndrome) ^[2]

• Metabolic Acidosis

• Methylene Blue treatment

• Sulfhemoglobin

• Asthma

• High doses of antidote treatment for methemogobinemia – (Methylene blue) can also cause cyanotic discoloration of the skin as a side effect, but this should not lead you into thinking that the treatment is inefficient. ^[3]

• Depending on the levels of MetHb in the blood we can observe different clinical presentation as follows^{[3] [4]}

• MetHb levels of 15% lead to skin and blood color (chocolate-brown) changes .
• MetHb levels above 15% lead to hypoxia.
• MetHb levels above 70% lead to death.

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

The incidence of congenital methemoglobinemia in the United States is very low. There is no racial predilection to methemoglobinemia. The highest prevalence of G6PD deficiency is observed in the malaria-endemic regions: Sub-Saharan Afria, West Asia and Arabian Peninsula, as well as in people of Mediterranean descent.

The incidence of congenital methemoglobinemia in the United States is very low.

• Patients of all age groups may develop methemoglobinemia.
• The acquired methemoglobinemia is a rare disease that tends to affect infants and people exposed to local anesthetics during medical procedures.
• 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 incidence of the congenital methemoglobinemia is the same for both genders as both cytochrome b5 reductase deficiency and pyruvate kinase deficiency are autosomal recessive diseases and the Hb M has autosomal dominant pattern of inheritance.
• The incidence of ([G6PD]] deficiency is is greater in males as this condition has X-linked pattern of inheritance. There is no racial predilection to Methemoglobinemia.

• There is no racial predilection to methemoglobinemia.
• In developed countries, the incidence of acquired methemoglobinemia is higher in developing countries when people are exposed to local anesthetics during various medical procedures.
• The majority of cytochrome b5 reductase deficiency cases are found among some Native American tribes like Navajo ^[1] and Athabaskan Alaskans, and the Yakutsk people in Siberia. ^[2]

• The highest prevalence of G6PD deficiency is observed in the malaria-endemic regions: Sub-Saharan Afria, West Asia and Arabian Peninsula, as well as in people of Mediterranean descent. ^{[3] [4] [5]}

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

Some of the risk factors for the formation of [[methemoglobinemia] include topical use of various anesthetics, drinking contaminated with nitrates water or eating solid food contaminated with nitrates.

1. Anesthetics

Topical benzocaine and lidocaine are commonly used in general anesthesia to facilitate the intubation in awake patients and can cause methemoglobinemia.^{[1] [2] [3]}

2. Contaminated well water

In premature infants and infants younger than 4 months, contaminated with nitrates water can induce methemoglobinemia. Most cases occur due to contaminated well water by nitrates sprayed on different vegetables etc. ^[4]ref> [www.epa.gov/dwstandardsregulations]</ref>

3. Solid foods

Solid foods that are not well cooked, like vegetables high in nitrates, can induce methemoglobinemia in premature infants and infants younger than 4 months.

[5]  [6]

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

Methemoglobinemia screening is not routinely done in the United States.

• Methemoglobinemia screening in the United States is not routinely done.
• Newborn screening for G6PD is also not routinely done in the United States. It is performed only in neonates presenting with jaundice. ^[1]
• Currently we have a screening test for G6PD deficiency that has been tested in Thai population, since G6PD is very common in this patient population. It is called methemoglobin reduction test (MRT), it is not expensive and it uses cord blood of neonates to check for the enzyme deficiency. Even though it has low sensitivity around 65%, it does have acceptable specificity close to 90%. ^[2]

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

Depending on the causes that have led to methemoglobin formation, different complications and prognosis are expected respectively. Death is the most serious complications of methemoglobinemia especially when MetHb levels approach 70%. In severely sick patients death may occur even with lower levels of MetHb.

• Patients with hereditary forms of methemoglobinemia are generally asymptomatic, with the exception of having chronic cyanosis. Unfortunately, despite the benign nature of the congenital methemoglobinemia, people with type IIb5 cytochrome-reductase deficiency have poor prognosis and shorter lifespan, mainly due to neurologic complications.

• In acquired methemoglobinemia, depending on the amount and duration of toxin exposure, the levels of MetHb in the blood will be different. As a result we expect different outcomes, which are as follows: MetHb of 15% presents with skin and blood color changes at levels; levels above 15% will result in hypoxia and levels above 70% can lead to death. ^{[1] [2]}

• Death is the most serious complications of methemoglobinemia especially when MetHb levels approach 70%. In severely sick patients death may occur even with lower levels of MetHb.
• Other complications include myocardial infarction, seizure and coma. ^[2]

• Depending on the anoxic end-organ damage caused by MetHb, the prognosiss varies between mild and fatal. ^[1]

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