Methemoglobinemia is a type of altered hemoglobinemia characterized by cyanosis and hypoxic symptoms, caused by excessive levels of methemoglobin (MHb) in the blood (>15 g/L). It can be classified into congenital and acquired types, with the latter being more common clinically.

Normal human red blood cells also contain a small amount (usually <1%) of methemoglobin, which contains ferric iron (Fe³⁺). Under normal circumstances, the action of hemoglobin reductase continuously reduces the generated MHb back to hemoglobin containing ferrous iron (Fe²⁺), preventing excessive accumulation of MHb. However, if oxidation is excessive, reductase is deficient, or abnormal hemoglobin chain structure makes MHb difficult to reduce, MHb may accumulate excessively, leading to the disease. MHb appears purple and cannot carry oxygen, resulting in cyanosis and hypoxic symptoms.

bubble_chart Etiology

The predisposing factors include a history of consuming large amounts of stale vegetables or fresh pickles, often leading to multiple family members falling ill simultaneously (children are particularly susceptible); or a history of ingesting or exposure to the aforementioned chemical substances.

bubble_chart Type

Congenital methemoglobinemia is divided into two types:

1. Methemoglobin reductase (NADH-flavin enzyme) deficiency: an autosomal recessive genetic disorder;
2. Hemoglobin M (HbM) disease: Methemoglobin also exhibits abnormal globin peptide chain structure, making it difficult to reduce.

Acquired methemoglobinemia mainly occurs due to excessive oxidation of normal hemoglobin and excessive generation of methemoglobin after oral intake or exposure to oxidizing substances. Oxidizing substances that can cause methemoglobinemia include:

1. Nitrites or nitrates: such as contaminated well water, spoiled vegetables, food additives, nitroglycerin, amyl nitrite, sodium nitrate, nitroprusside, bismuth subnitrate, etc.;
2. Other chemical agents or drugs: vitamin K preparations, potassium permanganate, chlorates, hydrogen peroxide, nitrobenzene compounds, phenacetin, antipyrine, sulfonamides, aniline, etc. Among these, cases caused by consuming food or beverages containing excessive nitrites, such as vegetables or well water, are referred to as enterogenous cyanosis, which is relatively more common clinically. This section focuses on this type.

bubble_chart Clinical Manifestations

The onset is sudden, with persistent grayish-blue cyanosis of the entire skin, most pronounced in the lips and extremities. There may be no or only grade I shortness of breath, which is disproportionate to the degree of cyanosis. In more severe cases, headache, dizziness, weakness, and palpitation may occur. For those with an enterogenic cause, vomiting, diarrhea, and abdominal pain may be present, and a few may have fever.

bubble_chart Auxiliary Examination

1. Blood Routine Test White blood cells may be elevated, with mostly normal differential counts.
2. Blood Gas Analysis Blood oxygen saturation and oxygen content are reduced.
3. MHb Qualitative Test Heparinized anticoagulated blood is taken in a test tube; venous blood containing MHb appears chocolate-brown in color. When shaken in air or aerated for 15 minutes, it does not turn bright red (normal blood turns bright red). After adding a few drops of 10% potassium cyanide or sodium cyanide, it immediately turns bright red.
4. MHb Absorption Spectrum Measurement After diluting a clarified, stroma-free hemolyzed sample (pH acidic), observe under a spectroscope: the MHb absorption peak appears at wavelengths 618–631 nm. After adding potassium cyanide, the 631 nm absorption peak rapidly disappears.
5. According to the Evelyn and Malloy spectrophotometric method for measuring MHb content, the MHb level in the blood should account for at least 3% of the total Hb.

bubble_chart Diagnosis

Congenital methemoglobinemia presents with cyanosis at birth or shortly after. Measuring the activity of erythrocyte NADH-methemoglobin reductase aids in diagnosing hereditary deficiency of this enzyme. Hemoglobin M can be identified by electrophoresis. Sulfhemoglobinemia presents with a blue-brown blood color that does not change upon shaking, shows an absorption peak at 620nm under a spectroscope, and does not disappear upon adding potassium cyanide. Neither methylene blue nor vitamin C is effective in treating hemoglobin M disease or sulfhemoglobinemia.

1. Congenital hereditary: Generally no treatment is required. For patients with significant cyanosis due to NADH-MHb reductase deficiency, long-term oral administration of vitamin C (200–1000 mg daily) or methylene blue (3–5 mg/kg daily) may be used. In severe cases, intravenous injection of methylene blue (1–2 mg/kg per dose) may be necessary.
2. Enterogenous cyanosis: Mild cases usually resolve spontaneously within 8–12 hours after removing the disease cause and do not require drug treatment. Severe cases require the following methods to reduce MHb.
   1. Methylene blue: 1–2.5 mg/kg per dose (1% solution 0.1–2.5 ml/kg) intravenously. The effect is usually observed within 15–30 minutes after injection and can be repeated as needed based on the condition. Glucose solution should be administered intravenously during use. Note that the dose of methylene blue should not be excessive, as doses exceeding 7–10 mg/kg per administration may convert hemoglobin into MHb.
   2. Vitamin C: Initial dose of 0.5–1 g, administered intravenously with glucose solution, followed by oral administration if necessary.

bubble_chart Differentiation

This condition must also be differentiated from cyanotic congenital heart disease.