Write a short note on methaemoglobinaemia.

Definition

Methaemoglobinaemia is the presence of an abnormally high proportion of methaemoglobin (MetHb) — haemoglobin in which the iron of the haem group has been oxidised from the ferrous (Fe2+) to the ferric (Fe3+) state. Ferric haem cannot bind oxygen, and its presence also shifts the oxygen dissociation curve of the remaining normal haem groups to the left, impairing oxygen release to tissues. Normal MetHb is under 1–2% of total haemoglobin.

Normal Protective Mechanisms

The principal defence is the enzyme cytochrome b5 reductase (NADH-methaemoglobin reductase), which accounts for the majority of MetHb reduction. A minor NADPH-methaemoglobin reductase pathway is inactive under normal conditions but becomes important therapeutically — it is the pathway used by methylene blue, and requires NADPH generated by glucose-6-phosphate dehydrogenase.

Causes

Acquired (much commoner):

• Drugs: dapsone (a leading cause, especially in leprosy treatment), local anaesthetics — prilocaine, benzocaine, lignocaine, nitrates and nitrites, nitroglycerine, sulphonamides, primaquine and chloroquine, phenazopyridine, metoclopramide.
• Chemicals: aniline dyes, naphthalene (mothballs), nitrobenzene, chlorates, industrial solvents; contaminated well water high in nitrates, a recognised cause of "blue baby syndrome" in infants in parts of rural India.
• Infants are particularly susceptible because fetal haemoglobin is more readily oxidised and cytochrome b5 reductase activity is physiologically low in the first months of life.

Congenital:

• Cytochrome b5 reductase deficiency — autosomal recessive; chronic cyanosis, usually well tolerated.
• Haemoglobin M variants — autosomal dominant; do not respond to methylene blue.

Clinical Features

Severity broadly parallels the MetHb percentage:

• Slate-grey or bluish "chocolate" cyanosis of skin and mucous membranes.
• Cyanosis that does not improve with high-flow oxygen — the cardinal clue.
• Headache, fatigue, dizziness, dyspnoea and tachycardia as levels rise.
• Confusion, arrhythmia, seizures, metabolic acidosis, coma and death at high levels.
• Patients with anaemia, cardiac or respiratory disease become symptomatic at lower levels.

Investigations

• Co-oximetry — the definitive test, measuring MetHb directly.
• Arterial blood gas — normal PaO2 with a marked saturation gap between calculated and measured saturation.
• Bedside test: a drop of blood on white filter paper appears chocolate-brown and fails to turn bright red when waved in air, unlike normal deoxygenated blood.
• CBC — assess for accompanying haemolysis, which occurs with oxidant stress; look for Heinz bodies and bite cells on the film.
• G6PD assay — essential before or alongside methylene blue therapy.
• A careful drug, occupational and water-source history is central to identifying the cause.

Management

• Stop and remove the offending agent — the single most important step; mild cases resolve spontaneously once exposure ceases.
• High-flow oxygen — improves dissolved oxygen delivery even though it does not correct the MetHb.
• Methylene blue — the specific antidote, indicated for symptomatic patients or significantly raised MetHb levels. It is reduced to leucomethylene blue by NADPH-methaemoglobin reductase, which then reduces ferric to ferrous iron. Response is usually rapid, with cyanosis improving within 30–60 minutes; a repeat dose may be needed, particularly with dapsone, which has a long half-life and causes rebound.
• Ascorbic acid (vitamin C) — an alternative where methylene blue is contraindicated or unavailable; slower and less effective.
• Exchange transfusion or hyperbaric oxygen for severe or refractory cases, or where methylene blue cannot be used.
• Dapsone-induced cases may additionally benefit from cimetidine, which reduces formation of the toxic hydroxylamine metabolite.
• Supportive care: fluids, treatment of acidosis, and management of accompanying haemolysis.