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Methemoglobin – MetHb
Physiological role and pathophysiology, reference intervals and the most likely causes of abnormalities
Methemoglobin – MetHb
Reference interval MetHb – example
What is MetHb ?
When should MetHb be measured ?
Causes of increased MetHb
Symptoms of methemoglobinemia
Cyanosis in methemoglobinemia
FMetHb is the fraction of total hemoglobin (ctHb) that is present as methemoglobin (MetHb). By convention the fraction is expressed as a percentage (%). Thus [24]:
In most medical text boxes MetHb(a) is referred to as simply methemoglobin (MetHb), which will be used in the text below.
Reference interval MetHb – example
What is MetHb?
The oxygen-binding property of hemoglobin depends on the four iron atoms contained within the structure of hemoglobin (see Hb). If the iron ions are in the reduced ferrous (Fe2+) state, a reversible bond with oxygen can be formed. The distinguishing feature of MetHb is that one or more of the four iron ions are in the oxidized ferric state (Fe3+) rather than the ferrous state (Fe2+) and MetHb is therefore incapable of binding oxygen [58], categorizing MetHb as a dyshemoglobin. Normal erythrocyte metabolism is associated with continuous production of MetHb from hemoglobin; however, erythrocytes also have mechanisms for the reversible process, conversion of MetHb back to hemoglobin. This ensures that in healthy persons no more than 1 – 2 % of total hemoglobin is present as MetHb. The reduction of ferric iron (Fe3+) to ferrous iron (Fe2+), necessary for the conversion of MetHb to hemoglobin, occurs due to the action of the enzyme cytochrome b5 reductase [9].
The oxygen-carrying capacity of blood is reduced by the presence of MetHb, and increased MetHb is associated with risk of inadequate oxygen delivery and tissue hypoxia. The severe hypoxia associated with marked increase in MetHb can have a fatal outcome.
Increased MetHb will have an impact on FO2Hb values (see O2Hb); however, the parameters pO2, sO2 and SpO2 (pulse oximetry) are unaffected by increased MetHb.
When should MetHb be measured?
The most common reason for measuring MetHb is to diagnose patients with unexplained cyanosis, and patients suspected of suffering from the toxicological effects of a range of chemicals/prescribed drugs.
Causes of increased MetHb
Methemoglobinemia is an increase in the concentration of MetHb. It may be inherited or acquired. Acquired methemoglobinemia is far more common than inherited.
Acquired methemoglobinemia (acute) occurs as a result of exposure to oxidative and toxic chemicals/drugs (see list on next page) [59, 60, 61]. The oxidative potential of these substances results in an abnormally increased production of MetHb that exceeds the maximum rate at which MetHb can be converted back to hemoglobin.
Inherited methemoglobinemia (chronic) results from a deficiency of the enzyme cytochrome b5 reductase and therefore a reduced ability to convert MetHb to hemoglobin [62, 63]. Methemoglobinemia is also a feature of hemoglobin M disease, which is characterized by an inherited defect in the hemoglobin structure that inhibits conversion of MetHb to hemoglobin [64].
A non-exhaustive list of drugs/chemicals that have the capacity to induce methemoglobinemia [58, 65, 66]:
- Dapsone
- Amyl nitrate
- Aniline
- Benzocaine
- Chloroquinone
- Lidocaine
- Mafenide acetate
- Naphthalene
- Nitric oxide
- Nitrobenzene
- Nitroglycerine
- Paraquat
- Primaquine
- Sodium valproate
- Sulphonamides
Symptoms of methemoglobinemia
Symptoms depend on the severity of the increase and whether the condition is chronic or acute. In general, with inherited methemoglobinemia MetHb rarely exceeds 30 %; higher levels (up to 50 – 70 %) are seen among those with acquired methemoglobinemia [65, 66].
- Mild increase (MetHb in the range of 2 – 10 %) is usually asymptomatic
- Moderate increase (10 – 30 %) is almost always associated with some degree of cyanosis. Breathlessness on mild exertion may be experienced
- More severe increase (30 – 50 %) may cause cyanosis, headache, breathlessness, dizziness, lethargy and fatigue
- Severe increase (50 – 70 %) may cause cyanosis, cardiac dysrythmias, confusion, seizures, drowsiness, coma and lactic acidosis
- MetHb >70 % is associated with severe tissue hypoxia with resulting organ failure and is frequently fatal
Cyanosis in methemoglobinemia
Cyanosis is almost always present in patients with methemoglobinemia; it results from the dark blue/brown color of MetHb. Unlike the cyanosis that can occur in respiratory and cardiac disease, which results from increased concentrations of deoxyhemoglobin (HHb), the cyanosis of methemoglobinemia is not alleviated by administration of supplemental oxygen and is not associated with reduced pO2. Sampled venous blood containing increased concentrations of MetHb has a characteristic dark color, often described as ”chocolate brown” [67].
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