Severe Methemoglobinemia Treated Successfully with Oral Ascorbic Acid: A Case Report

Nithiyananadan Ravi

Associate Consultant – Pulmonology, Kauvery Hospital, Chennai, India

Abstract

Methemoglobinemia is one of the rare causes of hypoxemia and central cyanosis. Unless there is high clinical suspicion, the diagnosis of such a condition can be delayed in patients with normal cardiac and respiratory function especially if the only presenting symptom and signs are breathlessness and cyanosis. Methylene blue and ascorbic acid are the two main treatment options for the condition depending on the severity of the illness, with the former being preferred in severe cases and the latter being an alternative treatment option. Here, we report a case of severe methemoglobinemia successfully managed with oral ascorbic acid.

Background

Methemoglobin is an altered form of hemoglobin in which the heme iron is in an oxidized [ferric form (Fe3+)] state rather than the normal ferrous (Fe2+) state thereby impairing its ability to transport and deliver oxygen to tissues, leading to hypoxia. The reducing mechanisms of the RBCs normally reduce the ferric state back to the ferrous state. However, there can be a congenital or acquired defect in such reducing mechanisms leading to methemoglobinemia [1]. Methylene blue is the preferred treatment option in acute severe settings. However, its usage is limited by the need for hospitalization, G6PD (glucose-6-phosphate dehydrogenase) level testing, and intravenous access [2]. Ascorbic acid is an effective alternative. However, it is generally being used in the intravenous form in severe cases and dosages are not standardized [3-5].

Case Presentation

A 21-year-old female presented to the outpatient department with gradually progressive dyspnea for two years, with severe activity limitation at the time of presentation. She denied a history of orthopnea, paroxysmal nocturnal dyspnea, chest pain, palpitations, pedal edema, syncope, facial puffiness, decreased urine output, cough, expectoration, wheezing, fever, or weight loss. For these complaints she visited many health care facilities and was managed as bronchial asthma with bronchodilators, but without any symptomatic relief.

She was a bachelorette, and her past history was unremarkable. She was born by third degree consanguineous marriage and had normal developmental milestones. Her parents denied history of cyanotic spells or recurrent lung infections in her childhood. She also denied any history of similar illness in her parents or her younger brother.

On examination she had a respiratory rate of 25 per minute and central cyanosis with a room air saturation of 85% with no improvement on oxygen supplementation. Rest of the physical examination was normal. Her blood investigations revealed polycythemia with a hemoglobin of 16.3 g/dl, normal platelet, and leucocyte counts. Her liver function tests, renal function tests, 2D echocardiography, chest x ray and spirometry were all normal. Her ABG at room air showed PaO2 of 100 mmHg and SaO2 of 98%. Her blood was chocolate brown colored and hence co-oximetry blood gas analysis was performed which revealed methemoglobin levels of 48.1%. Her medical history failed to reveal any drug intake predisposing her to methemoglobinemia. Hence, a diagnosis of congenital methemoglobinemia was made.

Patient was advised hospitalization; however, she denied and hence was instituted on oral ascorbic acid treatment 3 g/day since her G6PD levels were also not available. After 1 week of therapy, her repeat co-oximetry revealed MetHb levels of 15.9%, her dyspnea improved and her room air SpO2 improved to 92% with resolution of central cyanosis.

Subsequently, 6 weeks later, MetHb levels were 11.1% with room air SpO2 of 94%. She is now back to her work and is under follow up. She is now being planned to undergo whole exome sequencing to confirm the diagnosis of congenital methemoglobinemia.

Severe-Methemoglobinemia-12022-05-1102:42:49pmPatient blood sample

Severe-Methemoglobinemia-22022-05-1102:43:34pmControl  blood sample


Day



Day 0



Day 5



Day 13

MetHb levels (%)



48.1



15.9



11.1

SpO2 (%)



85



92



94

SaO2 (%)



98



98



98

Hb (g/dl)



16.3



15.6



13.7

Table showing the blood parameters from Day 0 (before ascorbic acid therapy), Day 5 and Day 13 after starting oral ascorbic acid treatment

Discussion

Adult hemoglobin has 4 subunits. Each subunit comprises a polypeptide chain and a hemo group. The polypeptide chains are 2 alpha and 2 beta globins. However, heme group is the same in each subunit with each one comprising a porphyrin ring with iron in ferrous state (Fe2+). Oxygen binding to the ferrous iron in each hemo group is reversible.

Normally, everyday about 1 % of the hemoglobin is converted to methemoglobin where iron is oxidized to ferric state (Fe3+) and the oxygen binding becomes irreversible. Under normal circumstances, the protective mechanisms convert them back to ferrous state. When the normal protective mechanisms get compromised either because of congenital or acquired causes, it results in methemoglobinemia [6].

The manifestations of methemoglobinemia depends on the concentration of methemoglobin in the blood. Levels upto 10% are usually asymptomatic and tolerated well. Levels of 10-30% manifest with cyanosis and chocolate brown blood. Levels of 30-50% manifest with dyspnea, giddiness, syncope, chest pain, palpitations, headache and confusion. Levels between 50% and 70% manifest as seizures, tachypnea, dysrhythmia, delirium and coma. Levels above 70% are fatal [1].

Manifestations are also determined by the type of methemoglobinemia. Acquired methemoglobinemia is the more common type and is due to toxins or drugs. Congenital methemoglobinemias are due to defects in cytochrome B5 reductase enzyme or Hemoglobin variants and present early in life. Type I congenital methemoglobinemia has cytochrome B5 reductase enzyme deficiency only in RBCs and while Type II congenital methemoglobinemia has the same enzyme deficiency in all tissues including RBCs and has severe neurological manifestations. Both are inherited in an autosomal recessive manner [7]. Type IV is an extremely rare autosomal recessive congenital disorder due to defect in electron acceptor cytochrome b5 and manifests with methemoglobinemia associated with ambiguous genitalia [8-10]. HbM is a hemoglobin variant with autosomal dominant inheritance which manifests with methemoglobinemia and in some cases hemolytic anemia [1].

Treatment for methemoglobinemia is determined by the severity of presentation. Adequate hydration and oxygen supplementation are instituted in all patients. Methylene blue is the preferred first line therapy in severe cases and reduces methemoglobin levels in 30-60 min. Usual dosage recommended is 1-2 mg/kg with a maximum dose upto 7 mg/kg.

However, requirement of a normal G6PD status is the main disadvantage in using methylene blue [1]. Ascorbic acid has been used an effective alternative in such a scenario. However, it has been used mostly in intravenous formulations and oral formulations were rarely used to treat severe methemoglobinemia. Also, ascorbic acid takes upto 24 h to lower methemoglobin levels [3,11].

Our index case had a methemoglobin level of 48.1%, however her symptoms progressed very slowly and G6PD levels were unavailable. Hence, she was started on oral ascorbic acid in an outpatient under close follow up in spite of very high methemoglobin levels and she recovered well with improvement in her symptoms, blood parameters and room air saturation within 5 days of treatment as shown in the table.

Conclusion

Methemoglobinemia should always be considered in the differential diagnosis of central cyanosis and hypoxemia even in the absence of a precipitating drug. Co-oximetry blood gas analysis clinches the diagnosis. Methylene blue continues to be the initial treatment option in acute severe methemoglobinemia which requires hospitalisation. However, oral ascorbic acid can be used in treating severe methemoglobinemia if the symptom progression is slow and G6PD status is unavailable.

Conflict of interest

None

References

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  9. Kok RC, Timmerman MA, Wolffenbuttel KP, et al. Isolated 17,20-lyase deficiency due to the cytochrome b5 mutation W27X. J. Clin. Endocrinol. Metab. 2010;95(3):994-9.
  10. Idkowiak J, Randell T, Dhir V, et al. A missense mutation in the human cytochrome b5 gene causes 46, XY disorder of sex development due to true isolated 17,20 lyase deficiency. J. Clin. Endocrinol. Metab. 2012;97(3):E465-75.
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Dr.-R.-Nithiyanandan

Dr. R. Nithiyanandan

Associate Consultant – Pulmonology

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