Research Article: A new mutation of congenital methemoglobinemia exacerbated after methylene blue treatment

Date Published: February 15, 2018

Publisher: John Wiley and Sons Inc.

Author(s): Fuminori Yamaji, Akio Soeda, Hiroki Shibata, Takuya Morikawa, Kodai Suzuki, Shozo Yoshida, Shinji Ogura.


Methylene blue is useful for the treatment of methemoglobinemia. However, even after the patient’s methemoglobin (metHb) rate has improved, careful observation is important because they could have undiagnosed congenital methemoglobinemia. In this case, a 67‐year‐old man underwent gastrointestinal endoscopy with the use of lidocaine for local anesthesia. During the examination, he complained of dyspnea and had low SpO2 despite normal PaO2 and SaO2. He was transferred to our department as a suspected case of acquired methemoglobinemia.

The patient’s metHb level was 26.2%. We administered methylene blue i.v. and his metHb level subsequently decreased to 1.6%. However, his metHb level gradually increased to 18.2%, and we suspected that he had congenital methemoglobinemia. We administered riboflavin and ascorbic acid orally, and his metHb level decreased to 6.4%. We also obtained genomic DNA from the patient and identified a novel variant of CYB5R3.

We report a novel variant of congenital methemoglobinemia that deteriorated after methylene blue treatment.

Partial Text

Methemoglobinemia is a rare condition and classified as either acquired or congenital. Acquired methemoglobinemia is more common and results from exposure to several oxidizing agents such as dapsone and acetaminophen as well as local anesthetics.1 Methemoglobin (metHb) levels >10% cause clinically recognizable cyanosis, >30% cause confusion, and >70% is lethal.2 Both the recessive and dominant forms of congenital methemoglobinemia have been reported and are characterized by diminished enzymatic reduction of metHb. These patients have abnormal amounts of metHb and low oxygen‐carrying capacity, and their metHb levels may be easily elevated by several oxidizing agents. Oxygenation and i.v. methylene blue are effective for the treatment of both acquired and congenital forms. Although this treatment rapidly reduces metHb levels, the levels can increase again to their daily levels in patients with congenital methemoglobinemia.

A 67‐YEAR‐OLD MAN had a loss of appetite, which prompted him to visit his primary care physician. He underwent gastrointestinal endoscopy with the use of 8% lidocaine spray for local anesthesia. During an examination, he complained of dyspnea and had low SpO2 (88% on 100% oxygen). However, his arterial blood gases showed normal PaO2 and SaO2 (PaO2, 206 mmHg; SaO2, 99.0%). Therefore, he was transferred to our department as a suspected case of acquired methemoglobinemia.

Most congenital methemoglobinemias are caused by a cytochrome b5 reductase deficiency. This deficiency can be of two types: type I (also called erythrocyte reductase deficiency) occurs when red blood cells lack the enzyme, and type II (also called generalized reductase deficiency) occurs when the function of this enzyme is altered. In type II deficiency, cyanosis is accompanied by neurological impairment and reduced life expectancy.5 However, in type I, clinical symptoms are generally insignificant even with metHb levels up to 40%.6 Thus, patients with type I deficiency are able to have a normal life without any limitations in their daily activities. However, these patients are sensitive to oxidants, and reducing their metHb levels is useful in emergency cases.

We have to keep in mind that patients who are admitted to the hospital with a suspected case of acquired methemoglobinemia may instead have congenital methemoglobinemia. In cases of congenital methemoglobinemia, metHb levels may increase after methylene blue treatment; therefore, careful observation is mandatory. Ascorbic acid and riboflavin are useful for alleviating hereditary methemoglobinemia.

Approval of the research protocol: The study design was approved by the appropriate ethics review boards. We obtained genomic DNA from participants with approval from the Ethical Medical Review Board of Gifu University and the Ethics Committee of the School of Medicine, Kyushu University.Informed consent: All study participants provided informed consent. Registry and registration no. of the study/trial: N/A. Animal studies: N/A.Conflict of interest: None declared.




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