Conditions · Metabolism: heme, bilirubin and iron
Methemoglobinemia !
Excess hemoglobin with oxidised iron, which cannot carry oxygen; it causes cyanosis that does not improve with oxygen and chocolate-coloured blood.
Updated 2026-11-01
Structures involved
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In biochemistry
- Spectrophotometry and colorimetry (Beer–Lambert law)
- Nitric oxide (NO)
- Heme
- Hemoglobin variants (HbA, HbA2, HbF, HbS, HbC)
- Oxygen binding: haemoglobin versus myoglobin
In the clinical exam
In physiology
- Oxygen transport and the dissociation curve
- Oxygenation: SpO₂, PaO₂, cyanosis and oxygen therapy
- Carbon monoxide, methemoglobin and cyanide
What it is
A rise in methemoglobin (heme iron in the Fe³⁺ state) above normal (1–2 %), acquired from oxidants or congenital.
Who gets it
The acquired form is the most common: topical local anaesthetics, dapsone and nitrites. In Colombia primaquine for P. vivax malaria and nitrate-rich well water in infants are causes to keep in mind.
Causes
- Oxidant drugs: topical benzocaine and lidocaine, dapsone, primaquine, nitrates, rasburicase
- Chemicals: nitrites, anilines, nitrobenzene
- Congenital: cytochrome b5 reductase deficiency (CYB5R3) or M hemoglobins (abnormal globin)
Risk factors
- Infants under 6 months (less cytochrome b5 reductase, more oxidisable HbF)
- G6PD deficiency
- Procedures with topical mucosal anaesthesia (endoscopies)
Pathophysiology
Fe³⁺ does not bind O₂ and also raises the affinity of the other hemes in the tetramer: the curve shifts left and less oxygen is delivered. Normally cytochrome b5 reductase (with NADH) returns the iron to Fe²⁺; a backup NADPH pathway is the one methylene blue activates.
Symptoms and signs
- Grey-blue cyanosis that does not improve with oxygen
- Headache, dizziness and fatigue
- Breathlessness and tachycardia
- Chocolate-coloured blood
Diagnosis
- Clinical
- Cyanosis with normal PaO₂ and pulse-oximetry saturation around 85 % that does not change with oxygen, after an oxidant drug or chemical.
- Tests
- Co-oximetry (measures methemoglobin directly); arterial gases with normal PaO₂ (saturation gap); lactate; G6PD before methylene blue; cytochrome b5 reductase activity and hemoglobin electrophoresis in congenital cases.
- Imaging
- Does not contribute to diagnosis; chest X-ray rules out lung causes of cyanosis.
Treatment
- Acute
- Stopping the oxidising agent and giving oxygen
- Medical
- Intravenous methylene blue in symptomatic or high-level cases (contraindicated in G6PD deficiency)
- Medical
- Ascorbic acid or exchange transfusion when methylene blue cannot be used
- Procedure
- Hyperbaric oxygen in severe refractory cases
Drugs for this condition
Complications
- Myocardial ischaemia and arrhythmias
- Lactic acidosis
- Hemolysis (especially with G6PD deficiency)
Prognosis
Excellent if recognised and treated promptly; congenital type I causes only cyanosis.
Test yourself
Think of the answer, then tap the question to see it.
Why does the pulse oximeter read about 85 % in methemoglobinemia?
Methemoglobin absorbs both wavelengths the device uses equally; co-oximetry gives the true value.
How does methylene blue work?
Using NADPH (from the pentose pathway) it reduces Fe³⁺ to Fe²⁺ via NADPH-dependent methemoglobin reductase.
When is methylene blue contraindicated?
In G6PD deficiency: there is not enough NADPH, it fails and can cause hemolysis.
Which way does methemoglobin shift the oxygen dissociation curve?
To the left: the remaining hemes release less oxygen to the tissues.
Related conditions
Educational information, not medical advice. For any symptom, see a health professional.
Sources: Methemoglobinemia: MedlinePlus Medical Encyclopedia (MedlinePlus, US National Library of Medicine, 2026); CYB5R3 gene: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); Methemoglobinemia, beta-globin type: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026).
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Representative model, for educational purposes only.
