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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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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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 Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview
  • 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 Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritancedefects 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 Erythrocytes Erythrocytes, or red blood cells (RBCs), are the most abundant cells in the blood. While erythrocytes in the fetus are initially produced in the yolk sac then the liver, the bone marrow eventually becomes the main site of production. 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 Erythrocytes Erythrocytes, or red blood cells (RBCs), are the most abundant cells in the blood. While erythrocytes in the fetus are initially produced in the yolk sac then the liver, the bone marrow eventually becomes the main site of production. Erythrocytes → chronic cyanosis

Acquired due to exposure to oxidizing agents:

  • Nitrates Nitrates Nitrates are a class of medications that cause systemic vasodilation (veins > arteries) by smooth muscle relaxation. Nitrates are primarily indicated for the treatment of angina, where preferential venodilation causes pooling of blood, decreased preload, and ultimately decreased myocardial O2 demand. Nitrates/nitrites (nitrate-containing foods, NO, well water)
  • Antimalarial drugs Antimalarial drugs Malaria, a vector-borne parasitic disease caused by Plasmodium spp., is transmitted via injection of sporozoites or immature forms of the parasite into a person's bloodstream. Sporozoites then infect the hepatocytes and differentiate into schizonts, which subsequently rupture, and merozoites invade red blood cells. 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 Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview: 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 Nicotinamide adenine dinucleotide phosphate Nicotinamide adenine dinucleotide phosphate. A coenzyme composed of ribosylnicotinamide 5'-phosphate (nmn) coupled by pyrophosphate linkage to the 5'-phosphate adenosine 2. Pentose Phosphate Pathway ( NADPH NADPH Nicotinamide adenine dinucleotide phosphate. A coenzyme composed of ribosylnicotinamide 5'-phosphate (nmn) coupled by pyrophosphate linkage to the 5'-phosphate adenosine 2. Pentose Phosphate Pathway) methemoglobin reductase: 
    • Alternative pathway
    • NADPH NADPH Nicotinamide adenine dinucleotide phosphate. A coenzyme composed of ribosylnicotinamide 5'-phosphate (nmn) coupled by pyrophosphate linkage to the 5'-phosphate adenosine 2. Pentose Phosphate Pathway 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 NADPH Nicotinamide adenine dinucleotide phosphate. A coenzyme composed of ribosylnicotinamide 5'-phosphate (nmn) coupled by pyrophosphate linkage to the 5'-phosphate adenosine 2. Pentose Phosphate Pathway: nicotinamide adenine dinucleotide phosphate Nicotinamide adenine dinucleotide phosphate Nicotinamide adenine dinucleotide phosphate. A coenzyme composed of ribosylnicotinamide 5'-phosphate (nmn) coupled by pyrophosphate linkage to the 5'-phosphate adenosine 2. Pentose Phosphate Pathway, 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 NADPH Nicotinamide adenine dinucleotide phosphate. A coenzyme composed of ribosylnicotinamide 5'-phosphate (nmn) coupled by pyrophosphate linkage to the 5'-phosphate adenosine 2. Pentose Phosphate Pathway 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 Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin discoloration
  • Methemoglobin ≥ 20%–50%:
    • Headache
    • Dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea
    • Lightheadedness, even syncope Syncope Syncope is a short-term loss of consciousness and loss of postural stability followed by spontaneous return of consciousness to the previous neurologic baseline without the need for resuscitation. The condition is caused by transient interruption of cerebral blood flow that may be benign or related to a underlying life-threatening condition. Syncope
    • Weakness
    • Confusion
    • Palpitations, chest pain Chest Pain Chest pain is one of the most common and challenging complaints that may present in an inpatient and outpatient setting. The differential diagnosis of chest pain is large and includes cardiac, gastrointestinal, pulmonary, musculoskeletal, and psychiatric etiologies. Chest Pain
  • Methemoglobin > 50%–70%:
    • Cardiovascular system: arrhythmias
    • CNS: altered mental status; seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures, delirium Delirium Delirium is a medical condition characterized by acute disturbances in attention and awareness. Symptoms may fluctuate during the course of a day and involve memory deficits and disorientation. Delirium, coma Coma Coma is defined as a deep state of unarousable unresponsiveness, characterized by a score of 3 points on the GCS. A comatose state can be caused by a multitude of conditions, making the precise epidemiology and prognosis of coma difficult to determine. Coma
    • Metabolic effects: significant acidosis
  • Methemoglobin > 70%: death
Cyanosis in methemoglobinemia

Cyanosis in methemoglobinemia:
A patient showing bluish discoloration on the right foot Foot The foot is the terminal portion of the lower limb, whose primary function is to bear weight and facilitate locomotion. The foot comprises 26 bones, including the tarsal bones, metatarsal bones, and phalanges. The bones of the foot form longitudinal and transverse arches and are supported by various muscles, ligaments, and tendons. Foot and left hand Hand The hand constitutes the distal part of the upper limb and provides the fine, precise movements needed in activities of daily living. It consists of 5 metacarpal bones and 14 phalanges, as well as numerous muscles innervated by the median and ulnar nerves. 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 Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. 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 Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. 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 Metabolic acidosis The renal system is responsible for eliminating the daily load of non-volatile acids, which is approximately 70 millimoles per day. Metabolic acidosis occurs when there is an increase in the levels of new non-volatile acids (e.g., lactic acid), renal loss of HCO3-, or ingestion of toxic alcohols. 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 Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and 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 Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and 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 ECG An electrocardiogram (ECG) is a graphic representation of the electrical activity of the heart plotted against time. Adhesive electrodes are affixed to the skin surface allowing measurement of cardiac impulses from many angles. The ECG provides 3-dimensional information about the conduction system of the heart, the myocardium, and other cardiac structures. Normal Electrocardiogram (ECG): bradyarrhythmia Bradyarrhythmia Bradyarrhythmia is a rhythm in which the heart rate is less than 60/min. Bradyarrhythmia can be physiologic, without symptoms or hemodynamic change. Pathologic bradyarrhythmia results in reduced cardiac output and hemodynamic instability causing syncope, dizziness, or dyspnea. Bradyarrhythmias 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 NADPH Nicotinamide adenine dinucleotide phosphate. A coenzyme composed of ribosylnicotinamide 5'-phosphate (nmn) coupled by pyrophosphate linkage to the 5'-phosphate adenosine 2. Pentose Phosphate Pathway) → reduced to leukomethylene blue → reduction of methemoglobin
    • IV infusion
    • Rapid onset of action showing response within 1 hour
    • Does not work in G6PD deficiency G6PD Deficiency Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a type of intravascular hemolytic anemia. The condition is inherited in an X-linked recessive manner. Patients have episodic hemolysis due to an oxidative stressor that causes damage to red blood cells, which lack sufficient NADPH to protect them from oxidative injury. Glucose-6-phosphate Dehydrogenase (G6PD) Deficiency (as MB requires NADPH NADPH Nicotinamide adenine dinucleotide phosphate. A coenzyme composed of ribosylnicotinamide 5'-phosphate (nmn) coupled by pyrophosphate linkage to the 5'-phosphate adenosine 2. Pentose Phosphate Pathway generated by G6PD)
    • Cannot be administered to patients on serotonergic agents (↑ risk of serotonin syndrome Serotonin syndrome Serotonin syndrome is a life-threatening condition caused by large increases in serotonergic activity. This condition can be triggered by taking excessive doses of certain serotonergic medications or taking these medications in combination with other drugs that increase their activity. 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 G6PD Deficiency Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a type of intravascular hemolytic anemia. The condition is inherited in an X-linked recessive manner. Patients have episodic hemolysis due to an oxidative stressor that causes damage to red blood cells, which lack sufficient NADPH to protect them from oxidative injury. Glucose-6-phosphate Dehydrogenase (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 CO poisoning Carbon monoxide (CO) is an odorless, colorless, tasteless, nonirritating gas formed by hydrocarbon combustion (e.g., fires, car exhaust, gas heaters). Carbon monoxide has a higher affinity to hemoglobin than oxygen, forming carboxyhemoglobin (COHb). Increased levels of COHb lead to tissue hypoxia and brain damage. Carbon Monoxide 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 CO poisoning Carbon monoxide (CO) is an odorless, colorless, tasteless, nonirritating gas formed by hydrocarbon combustion (e.g., fires, car exhaust, gas heaters). Carbon monoxide has a higher affinity to hemoglobin than oxygen, forming carboxyhemoglobin (COHb). Increased levels of COHb lead to tissue hypoxia and brain damage. Carbon Monoxide Poisoning include confusion, headache, dizziness, decreased visual acuity, rose cheeks, tachycardia, syncope Syncope Syncope is a short-term loss of consciousness and loss of postural stability followed by spontaneous return of consciousness to the previous neurologic baseline without the need for resuscitation. The condition is caused by transient interruption of cerebral blood flow that may be benign or related to a underlying life-threatening condition. Syncope, coma Coma Coma is defined as a deep state of unarousable unresponsiveness, characterized by a score of 3 points on the GCS. A comatose state can be caused by a multitude of conditions, making the precise epidemiology and prognosis of coma difficult to determine. 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 Cyanide Poisoning Hydrogen cyanide is an extremely poisonous, colorless, flammable liquid used in multiple industries and includes rubber, plastic, and household paints. Exposure to cyanide can occur via inhalation, dermal contact, or intestinal ingestion. 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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