Methemoglobinemia

Methemoglobinemia is a condition characterized by elevated levels of methemoglobin in the blood. Methemoglobin is the oxidized form of hemoglobin, where the heme iron has been converted from the usual ferrous (Fe2+) to the ferric (Fe3+) form. The Fe3+ form of iron cannot bind O2, and, thus, leads to tissue hypoxia. Methemoglobinemia results from congenital defects or can occur after exposure to oxidizing agents. Symptoms depend on methemoglobin levels and vary from simple cyanosis to neurologic and cardiac presentations. The condition can be fatal in the case of significant elevation of methemoglobin (> 70%). Diagnosis is established by measuring methemoglobin levels in blood using co-oximetry. Treatment of methemoglobinemia is with methylene blue or ascorbic acid, as they hasten the conversion of methemoglobin to hemoglobin.

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Overview

Definition

Methemoglobinemia occurs when RBCs contain elevated methemoglobin levels (normal range in adults is 0%–3%).

  • Leads to functional anemia
  • Cyanosis occurs at levels > 10%–15%.
  • Fatal at levels > 70%

Methemoglobin is a form of hemoglobin in which ferrous (Fe2+) heme iron is oxidized to the ferric (Fe3+) state, which is unable to bind O2.

Etiology

Congenital:

  • Due to abnormal forms of hemoglobin, i.e., hemoglobin M (more resistant to reduction)
  • Due to autosomal recessive defects in cytochrome b5 reductase (Cyb5R), the main enzyme responsible for the reduction of methemoglobin to hemoglobin:
    • Type I (majority of cases): enzyme deficiency limited to erythrocytes → cyanosis in infants
    • Type II: widespread enzyme deficiency → severe neurologic defects
    • Type III: hematopoietic system enzyme deficiency → cyanosis
    • Type IV: enzyme deficiency limited to erythrocytes → chronic cyanosis

Acquired due to exposure to oxidizing agents:

  • Nitrates/nitrites (nitrate-containing foods, NO, well water)
  • Antimalarial drugs
  • Sulfonamides
  • Dapsone
  • Topical anesthetics
  • Antifreeze and other environmental substances (i.e., naphthalene)

Epidemiology

  • Acquired methemoglobinemia is more common.
  • Congenital form is endemic in Native American tribes (Navajo and Athabaskan Alaskans)
  • Infants < 4 months of age or premature infants more susceptible to acquired forms due to immature erythrocyte protective mechanism
  • Common in children receiving dapsone for chemoprophylaxis
  • No gender predilection

Pathophysiology

Normal hemoglobin

  • 4 polypeptide globin chains 
  • 4 heme molecules containing iron
  • Each heme iron is in the Fe2+ state and can easily bind O2.
Hemoglobin structure

Hemoglobin structure: 4 globin chains (β1, β2, ɑ1, and ɑ2) and 4 heme molecules (with iron in the ferrous state) for binding with O2

Image by Lecturio.

Methemoglobin

  • 1 or more heme Fe converted to the Fe3+ state
  • Fe3+ cannot bind O2.
  • In normal circumstances, Fe3+ levels < 1%
  • Effect:
    • Remaining Fe2+ increase their affinity for O2:
      • “Left shift” on the O2-hemoglobin dissociation curve
      • ↓ O2 tissue delivery → tissue hypoxia
    • Functional anemia: functional hemoglobin < measured hemoglobin

Regulation of methemoglobin

Methemoglobin levels are limited through different mechanisms:

  • Cyb5R:
    • Physiologic pathway
    • Reduction of methemoglobin via nicotinamide adenine dinucleotide (NADH)-dependent reaction
    • Cyb5R uses NADH to reduce methemoglobin.
    • Responsible for the reduction of 95%–99% of methemoglobin
  • Utilization of nicotinamide adenine dinucleotide phosphate (NADPH) methemoglobin reductase: 
    • Alternative pathway
    • NADPH derived from the hexose-monophosphate shunt pathway via the action of glucose-6-phosphate dehydrogenase (G6PD) 
    • Under physiologic conditions, the role is insignificant because an intrinsic electron acceptor is required (and there is none in the RBC).
    • Effect on methemoglobin reduction becomes significant in the presence of certain compounds/extrinsic electron acceptors:
      • Methylene blue (MB): used as therapy
      • Riboflavin
  • Glutathione and ascorbic acid promote methemoglobin reduction through different pathways.
Pathophysiology of methemoglobin

Pathophysiology and management of methemoglobin (HbFe²⁺: hemoglobin, MetHbFe³⁺: methemoglobin, NADPH: nicotinamide adenine dinucleotide phosphate, NADH: nicotinamide adenine dinucleotide):
Oxidation of heme iron from ferrous state to ferric state produces MetHbFe³⁺. Cytochrome b5 reductase reduces MetHbFe³⁺ to HbFe²⁺. Methylene blue acts as an electron acceptor for NADPH reductase and also facilitates the reduction of methemoglobin. Other compounds that can promote MetHbFe³⁺ reduction include glutathione and ascorbic acid.

Image by Lecturio.

Clinical Presentation

Symptoms depend on the etiology, chronicity, and level of methemoglobin.

Acquired

  • Methemoglobin > 10%–15%: cyanosis or bluish/gray skin discoloration
  • Methemoglobin ≥ 20%–50%:
    • Headache
    • Dyspnea
    • Lightheadedness, even syncope
    • Weakness
    • Confusion
    • Palpitations, chest pain
  • Methemoglobin > 50%–70%:
    • Cardiovascular system: arrhythmias
    • CNS: altered mental status; seizures, delirium, coma
    • Metabolic effects: significant acidosis
  • Methemoglobin > 70%: death
Cyanosis in Methemoglobinemia

Cyanosis in methemoglobinemia:
A patient showing bluish discoloration on the right foot and left hand (cyanotic nailbeds shown)

Image: “Successful treatment of methemoglobinemia in an elderly couple with severe cyanosis” by Su YF et al. License: CC BY 2.0

Congenital

  • Infants or children with cyanosis (from chronic ↑ methemoglobin)
  • In cases of type II Cyb5R deficiency: developmental and neurologic abnormalities (i.e., seizures, microcephaly) noted

Diagnosis

Diagnostic approach

History:

  • History of exposure to oxidizing substances
  • Family history and ethnicity
  • Medications
  • Proximity to contaminated wells
  • Symptoms suggestive of the intake of toxic substances (i.e., vomiting, diarrhea)

Physical exam findings:

  • Sudden onset of cyanosis and hypoxia 
  • Altered mental status
  • Pulse oximetry O2 saturation of < 90% (usually around 85%), and does not improve with supplemental O2
  • Dark chocolate-colored blood during phlebotomy
Color code suggestive of methemoglobin Methemoglobinemia

Color code suggestive of methemoglobin:
Blood with methemoglobin concentration > 15% of total hemoglobin levels appears brownish, as seen in the image (right side).

Image: “Semiquantitative estimation of methemoglobin levels in blood” by Shihana F et al. License: CC BY 3.0

Detecting methemoglobinemia

  • Blood gases:
    • Methemoglobin level > 5% (detected using most blood-gas analyzers)
    • + Saturation gap (difference between O2 saturation on pulse oximetry and arterial blood gas) 
    • Metabolic acidosis
  • Pulse oximetry is inaccurate:
    • Routine pulse oximeter measures light absorbance at 2 wavelengths (660 nm and 940 nm) to differentiate oxyhemoglobin from deoxyhemoglobin.
    • In methemoglobinemia:
      • Methemoglobin increases the absorption of light at both wavelengths (more at 940 nm), leading to errors in measurement.
      • O2 saturation by pulse oximetry plateaus at about 85%. 
  • Co-oximetry: 
    • Provides a method of measuring methemoglobin levels
    • Utilizes multiple wavelengths of light to detect methemoglobin absorption
  • Evelin-Malloy (direct) assay:
    • Most accurate
    • Not readily available
Methemoglobin measurement Methemoglobinemia

Methemoglobin measurement:
Use of co-oximetry (multiple-wavelength oximetry). Pictured above is a Rad-57 pulse oximeter applied to the finger of a child. Instead of just 2 wavelengths, co-oximetry utilizes 8 wavelengths.

Image: “Methemoglobin measurement with the pulse oximeter” by Thomas Hänscheid et al. License: CC BY 4.0

Additional tests

  • ECG: bradyarrhythmia or ventricular dysrhythmia
  • Work-up for hemolysis:
    • CBC: generally with normal hemoglobin in conditions of acute onset
    • Reticulocyte count
    • Peripheral blood smear
    • LDH
    • Bilirubin
    • Haptoglobin
  • Genetic testing
  • Hemoglobin electrophoresis: detection of hemoglobin M
  • G6PD activity: helps determine treatment

Management

Management of methemoglobinemia depends on the severity and chronicity.

Methemoglobin levels > 30% and associated with tissue hypoxia is a medical emergency:

  • Supportive management
  • Immediate discontinuation of any suspected oxidizing agent
  • MB:
    • MB (electron acceptor for NADPH) → reduced to leukomethylene blue → reduction of methemoglobin
    • IV infusion
    • Rapid onset of action showing response within 1 hour
    • Does not work in G6PD deficiency (as MB requires NADPH generated by G6PD)
    • Cannot be administered to patients on serotonergic agents (↑ risk of serotonin syndrome)
  • High-dose ascorbic acid (vitamin C):
    • Reducing agent 
    • IV infusion
    • Symptom improvement in 1–3 days
    • Used when MB is unavailable or contraindicated
    • Useful in G6PD deficiency 
  • Consider the following in severe cases:
    • Exchange transfusion
    • Hyperbaric O2

In congenital methemoglobinemia:

  • Therapy:
    • Oral MB or ascorbic acid in Cyb5R deficiency
    • No treatment available for associated neurologic deficits
    • No treatment for hemoglobin M (course of the condition is benign) 
  • Genetic counseling for patients with congenital disease and 1st-degree relatives

Differential Diagnosis

  • CO poisoning: an odorless, tasteless, colorless, nonirritating gas that is formed by hydrocarbon combustion (fires, car exhaust, gas heaters). Carbon monoxide has a higher affinity to hemoglobin than O2, forming carboxyhemoglobin (COHb) and resulting in impaired O2 transport and utilization. Features of CO poisoning include confusion, headache, dizziness, decreased visual acuity, rose cheeks, tachycardia, syncope, coma, and death. Blood is notably cherry-red, and pulse oximetry is inaccurate. Treatment involves the use of 100% O2. In case of treatment failure, hyperbaric O2 is considered.
  • Cyanide poisoning: Hydrogen cyanide (HCN) is a colorless, extremely poisonous, and flammable liquid used in multiple industries and in the manufacture of plastics and household paints. Lethal complications of cyanide poisoning occur in closed-space fires when plastics burn. Exposure is via inhalation, dermal, or intestinal routes. Symptoms occur within minutes to seconds and involve cardiovascular, respiratory, and neurological changes. Treatment is with sodium thiosulfate, nitrites, and hydroxocobalamin.

References

  1. Denshaw-Burke M., Delgiacco, E. (2020). Methemoglobinemia. Medscape. Retrieved April 9, 2021, from https://reference.medscape.com/article/204178-overview
  2. Ludlow, J.T., Wilkerson, R.G., Nappe, T.M. (2020). Methemoglobinemia. StatPearls. Treasure Island (FL): StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK537317/
  3. Prchal, J.T. (2021). Methemoglobinemia. UpToDate. Retrieved April 9, 2021, from https://www.uptodate.com/contents/clinical-features-diagnosis-and-treatment-of-methemoglobinemia

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