Methemoglobinemia is an excessively high level of methemoglobin in the blood. This disease is also called blue baby syndrome when it affects a very young child, due to the presence of blue stain around the mouth, on the hands and feet.

Methemoglobinemia is characterized by an inherited or acquired decrease in the ability of the blood to carry vital oxygen throughout the body due to:

• decreased levels of normal hemoglobin;
• that methemoglobin is a derivative of hemoglobin incapable of efficiently transporting oxygen.

Indeed, methemoglobin is none other than hemoglobin in which oxidized iron changes from the ferrous state (Fe2 +) to the ferric state (Fe3 +), which makes it unfit for the transport of oxygen. During normal metabolism, there is a small amount of methemoglobin (0,5-1%) in the blood which is reduced as it is formed. A methemoglobin level greater than 1% of total hemoglobin defines methemoglobinemia.

The presence in the blood of methemoglobin in excess of normal amounts is due to acquired or hereditary causes.

Poisoning under the effect of a toxicant

Acquired methemoglobinemia can result from exposure to certain drugs and chemical agents, producing oxidizing agents resulting in too rapid oxidation of hemoglobin, exceeding the capacity of the enzymatic system responsible for maintaining it in the reduced state. The resulting poisonings are characterized by acute cyanosis, that is, a bluish coloration of the skin and mucous membranes. The main oxidizing agents responsible for this type of poisoning include:

• certain drugs: local anesthetics (benzocaine, lidocaine, prilocaine), antipyrine, sulfonamides and sulfones (dapsone), phenylacetamides and derivatives (acetanilide, phenacetine), quinine and its derivatives (chloroquine, pentaquine, primaquine, resorcin), metoclopramide, phenazopyridines;
• diverted vasodilators, such as “poppers”;
• ant baits;
• substances used in industry such as polyphenols, hydrazines, aminobenzenes (aniline, naphthalene), nitrobenzene and derivatives, nitrotoluene;
• oxidizing agents (chlorates, nitrites, nitrates) likely to be provided by food (well water, spinach, fertilizers, manure, preservatives).

Some of these agents are not toxic on their own, but become toxic when ingested due to the formation of an oxidizing metabolite. This is the case with nitrates reduced to nitrites by the intestinal microbial flora.

Congenital enzyme deficiency

Congenital methemoglobinemia is caused by a deficiency of the enzyme NADH-cytochrome b5 reductase, which is responsible for reducing methemoglobin to hemoglobin, and therefore for keeping the steady-state methemoglobin level below 1,0%. In this case, the methemoglobin level varies from 20 to 45% and methemoglobinemia is characterized by more or less marked cyanosis, associated with compensatory polycythemia, that is to say an increase in the total number of blood cells and therefore as a result of increased oxygen transport. 

Structural hemoglobin abnormality

Methemoglobinemia can finally result from an overproduction of methemoglobin due to a structural abnormality of hemoglobin (hemoglobin M) more prone to oxidation and unable to play its role of oxygen carrier. The level of methemoglobin in people with hemoglobin M varies from 20 to 40%.

The severity of symptoms is related to the amount of methemoglobin present in the blood. Indeed :

• from 10% methemoglobin of total hemoglobin cyanosis appears; 
• from 30% methemoglobin, the functional signs of anoxia, that is to say the decrease in the amount of oxygen that the blood distributes to the tissues, occur;
• between 30 and 50% of methemoglobin, lethargy, tachycardia, headache and respiratory disorders (dyspnea) appear;
• for a methemoglobin level greater than 50%, central nervous system damage, respiratory distress, altered mental state, convulsive seizures and neurological lesions are observed;
• death occurs with methemoglobin levels reaching 70-85%.

Some people may experience moderate to severe symptoms as early as low methemoglobin thresholds due to certain comorbidities, such as:

• anemia;
• the presence of other abnormal hemoglobin species as is the case in sickle cell anemia;
• cardiovascular disease; 
• lung disease;
• a sepsis.

Infants under 6 months of age are particularly susceptible to methemoglobinemia in cases of gastroenteritis and dehydration, particularly because of the relative ease of oxidation of fetal hemoglobin.

There is no treatment for hemoglobin M.

Treatment of acquired methemoglobinemia is based on removal of the causative agent and administration of reducing compounds.

Treatment of hereditary methemoglobinemia consists of the administration of reducing compounds.

The reducing compounds used in both cases are as follows:

• methylene blue, which makes methaemoglobin reductase II functional;
• ascorbic acid (vitamin C). 

Methylene blue is the first-line treatment in moderate to severe cases. It is administered by infusion in patients:

• showing no symptoms in the event of a methemoglobin level greater than 30%;
• having symptoms with a methemoglobin level greater than 20%. 

Patients whose methemoglobin level does not return to normal after the methylene blue infusion may require an exchange transfusion.