The principal mechanism of nitrite toxicity is the oxidation of the ferrous iron (Fe2+) in deoxyhemoglobin to the ferric (Fe3+) valence state, producing methemoglobin.

Methemoglobin cannot reversibly bind or transport circulating oxygen. Depending on the percentage of total methemoglobin in oxidized form, the clinical picture is one of oxygen deprivation with cyanosis, cardiac dysrhythmias and circulatory failure, and progressive central nervous system (CNS) effects.

CNS effects can range from mild dizziness and lethargy to coma and convulsions

Read more at Agency for Toxic Substances & Disease Registry - CDC/DHHS

Methemoglobinemia:

Definition: Methemoglobinemia is a condition in which the iron in the hemoglobin molecule (the red blood pigment) is defective, making it unable to carry oxygen effectively to the tissues.

Causes, incidence, and risk factors: Methemoglobinemia may be inherited (congenital) or acquired. There are 2 forms of inheritable methemoglobinemia, type 1 and type 2.

Most hereditary cases are type 2, and result from a deficiency in the enzyme cytochrome b5 reductase. The other inheritable type, called hemoglobin M disease (type 1), is an autosomal dominant condition (you only need one affected parent to inherit it) characterized by an inability to convert methemoglobin back to hemoglobin. This usually causes few problems.

Acquired methemoglobinemia exposure to certain chemicals, which cause an increase in the production of methemoglobin. These chemicals include nitrites (used as additives to prevent spoilage of meat), anesthetics such as benzocaine and xylocaine, certain antibiotics (including dapsone and chloroquine), and benzene. Acquired methemoglobinemia may be severe in certain cases, and require treatment. In most mild cases, no treatment is required, other than avoiding the offending medication or chemical.

Symptoms  

• In patients with type 2 congenital cytochrome b5 reductase deficiency: mental retardation, developmental delay, failure to thrive. They may also have seizures and other neurologic problems. Most die in infancy.
• In most patients with congenital methemoglobinemia (type 1): a bluish discoloration to the skin and mucous membranes.
• In patients with acquired methemoglobinemia from chemical or drug exposure: headache, fatigue, shortness of breath, lack of energy, and potentially shock, seizures, and death.

Signs and tests  

• Cyanosis (bluish skin color) with a normal level of oxygen in the blood (Pa02 on blood gas)
• Abnormal color optical spectrum of hemoglobin
• Incubation of blood with methylene blue is used to differentiate between cytochrome b5R deficiency and Hemoglobin M disease

Methemoglobin from MedlinePlus at the National Institutes of Health/National Library of Medicine

Methemoglobin (metHb) is an abnormal form of hemoglobin in which the iron molecule is in the ferric (3+) state rather than the normal ferrous (2+) state.

When iron in hemoglobin is switched to the ferric state, it is no longer capable of carrying oxygen or carbon dioxide.

In addition, the oxy-hemoglobin dissociation curve is shifted to the left, impairing the delivery of oxygen at the tissue level. RBCs are continuously subjected to oxidative stressors that result in the formation of metHg.

The erythrocytes have 2 mechanisms that work to keep the abnormal hemoglobin percent down to generally less than 1%. One reduces the oxidizing compounds before they can change the hemoglobin; the other changes the abnormal hemoglobin back into working hemoglobin by way of 2 enzyme pathways.