Methemoglobinemia
| Methemoglobinemia | |
| ICD-10 | D74 |
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| ICD-9 | 289.7 |
| DiseasesDB | 8100 |
| MeSH | D008708 |
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Methemoglobinemia Microchapters |
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Diagnosis |
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Treatment |
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Case Studies |
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Methemoglobinemia On the Web |
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American Roentgen Ray Society Images of Methemoglobinemia |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2]
Synonyms and keywords: Methaemoglobinaemia; methemoglobinaemia; methemoglobinuria
Overview
Methemoglobinemia is a blood disorder in which, due to increased production (congenital or acquired reasons), the red blood cells (RBCs) contain higher than normal levels of methemoglobin (MetHb) (>1%). Methemoglobin forms from the substitution of iron (Fe) in ferric/reduced (Fe2+) form, as found in normal hemoglobin, with iron in oxidized (Fe3+) form. The oxidation of Hb to MetHb ( Fe2+ to Fe3+ ) occurs naturally in healthy people, as a result of the interaction of Hb with oxygen free radicals, which are produced during normal cell metabolism. The levels of MetHb though, never exceed more than 1%, if the protective reduction enzyme systems in the RBCs are working properly.
Hemoglobin is the polypeptide protein in the RBCs, consisting of 2 alfa and 2 beta chains connected to an iron atom in ferric form, responsible for binding, carrying and distributing oxygen from the lungs to the tissues. MetHb is unable to bind oxygen, and in case of methemoglobinemia, the affinity of the remaining normal Hb (that has not been yet oxidized to MetHb) to oxygen is very high. This leads to leftward shift of the oxygen-hemoglobin dissociation curve, resulting in hypoxia and dyspnea, because no oxygen gets released to the tissues.
Historical Perspective
Classification
Classification
Congenital (Hereditary) Methemoglobinemia
There are three main congenital conditions that lead to methemoglobinemia:
1. Cytochrome b5 reductase deficiency and pyruvate kinase deficiency
2. G6PD deficiency
3. Presence of abnormal hemoglobin.
Acquired or Acute Methemoglobinemia
Most common cause include different oxidant drugs, toxins or chemicals
Pathophysiology
Hemoglobin is a protein found in all red blood cells (RBCs), that carries oxygen with the help of iron. In order for this iron to be able to combine with oxygen and turn into oxyhemoglobin, it needs to be in its reduced or ferrous state (Fe2+). Hemoglobin can only accept, transport and release oxygen to the tissues when the iron is in ferrous state.
Methemoglobin (MetHb) refers to the state of Hemoglobin (Hb) in which the iron atom is oxidized or in ferric state (Fe3+). In this state the iron is incapable of creating a bond with the oxygen, thus it neither can bind, nor deliver oxygen to the tissues. The formation of methemoglobin is the result of a normal physiologic process of losing an electron from the iron atom, after releasing the oxygen to the tissues, and we can detect methemoglobin in the blood of healthy people, but the normal levels should always be less than 1%. These levels are maintained by several enzyme systems that work to reduce the iron to its ferrous state (Fe2+). The two most important enzymes are the diaphorase I (requiring nicotinamide adenine dinucleotide -NADH as a co-factor) and diaphorase II (requiring nicotinamide adenine dinucleotide phosphate – NADPH as a co-factor).
Almost 99% of the methemoglobin normally produced is removed by the diaphorase I pathway. Here electrons from NADH are transferred to methemoglobin, with the help of cytochrome b5 reductase, to reduce it to hemoglobin.
In patients with deficiency of NADH-cytochrome b5 reductase, which is an autosomal recessive disorder, the diaphorase II pathway becomes the main enzyme system that removes methemoglobin by reducing it to hemoglobin with the help of glucose-6-phosphate dehydrogenase (G6PD).
There are two major causes that can lead to the formation of methemoglobin - acquired and congenital.
Acquired or Acute Methemoglobinemia
The acquired methemoglobinemia is significantly more common than the congenital one. It is associated with exposure to or use of oxidant drugs, toxins or chemicals, that cause acute increment in methemoglobin levels, which overwhelms the normal physiologic protective enzyme mechanisms. The most common agents are anesthetics like benzocaine, lidocaine, prilocaine, used locally or topically, antibiotics like dapsone (used for the treatment of Brown Recluse spider bites, Leprosy, PCP prophylaxis, ecc) trimethoprim, sulfonamides, nitrates (amynitrate), nitroglycerin (NG), aniline dyes, metoclopramide, chlorates and bromates.
Infants under 4 months of age are particularly susceptible to methemoglobinemia,. The most common causes in this patient population are the ingesting of nitrates in drinking water and topical anesthetic use like benzocaine and prilocaine, that are found in over-the-counter (OTC) products, used to soothe a baby’s sore gums from teething for example. For that reason The U.S. Food and Drug Administration recommends that these OTC drugs are not given to children younger than age 2.
Nitrates ingestion is especially dangerous as nitrates used in agricultural fertilizers can often leak into the ground, thus contaminating well water. Infants, particularly those younger than 4 months are most susceptible to methemoglobinemia. This is due to the fact that the NADH methemoglobin reductase activity and concentration, the main protective enzyme, against oxidative stress is not fully mature in infants. The Environmental Protection Agency (EPA) has set strict rules on the Maximum Contaminant Level (MCL) of nitrate as nitrogen in the water. The current EPA guidelines state that no more than 10 mg/L (or 10 parts per million) of nitrogen is safe in drinking water.
Congenital (Hereditary) Methemoglobinemia
There are three main congenital conditions that lead to methemoglobinemia: 1. Cytochrome b5 reductase deficiency and pyruvate kinase deficiency 2. G6PD deficiency 3. Presence of abnormal hemoglobin (Hb M)
Both cytochrome b5 reductase deficiency and pyruvate kinase deficiency can lead to NADH deficiency which in turn will lead to decreased ability to remove MetHb from the blood. Cytochrome b5 reductase deficiency is an autosomal recessive disorder with at least 2 forms that we know of. The most common form, is the Ib5R deficiency, where cyt b5 reductase is absent only in RBCs, and the levels of MetHb are around 10% to 35%. The second type, which is much less common, is the IIb5R, where MetHb varies between 10% and 15% and the cyt b5 reductase is absent in all cells. This form is associated with mental retardation, microcephaly, and other neurologic problems. The lifespan of the affected individuals is greatly affected and patients usually die very young.
Congenital deficiency in G6PD can lead to decreased levels of NADPH and thus compromising the function of the diaphorase II enzyme system.
Abnormal hemoglobins like Hb M, an autosomal dominant condition, can also lead to methemoglobinemia. Here we observe not only impaired oxygen binding due to oxidation of iron to its ferric state (Fe3+), caused by amino acid replacement in the heme molecule, but also inability of the protective enzyme systems to reduce the iron to its normal ferrous state (Fe2+).
Causes
Differentiating Methemoglobinemia from other Diseases
Epidemiology and Demographics
Epidemiology
In the United States congenital methemoglobinemia is rare. Deficiency of cytochrome b5 reductase endemic only in some Native American tribes like Navajo and Athabaskan Alaskans, and the Yakutsk people in Siberia.
The acquired methemoglobinemia is the most common form, and most cases are related to topical or local anesthetic use during medical procedures.
Demographics
Infants, particularly those younger than 4 months are most susceptible to methemoglobinemia. This is due to the fact that the NADH methemoglobin reductase activity and concentration (the main protective enzyme against oxidative stress) is not fully mature in infants. Both cytochrome b5 reductase deficiency and pyruvate kinase deficiency are autosomal recessive diseases and the Hb M has autosomal dominant pattern of inheritance. On the other hand G6PD deficiency is X-linked, therefore the risk of acquired methemoglobinemia is greater in males. The highest prevalence of G6PD deficiency is observed in the malaria-endemic regions: Sub-Saharan Afria, West Asia and Arabian Peninsula, as well as in people of Mediterranean descent. As a result these populations are at higher risk for acquired methemoglobinemia.
Risk Factors
Screening
Currently we have a screening test for G6PD deficiency. It is called methemoglobin reduction test (MRT), it is not expensive and it uses cord blood of neonates to check for the enzyme deficiency. Even though it has low sensitivity around 65%, it does have acceptable specificity around[1] 90%.
Natural History, Complications and Prognosis
Diagnosis
History and Symptoms | Physical Examination | Laboratory Findings | Chest X Ray | CT | MRI | Ultrasound | Other Imaging Findings | Other Diagnostic Studies
Treatment
Medical Therapy | Surgery | Primary Prevention | Secondary Prevention | Cost-Effectiveness of Therapy | Future or Investigational Therapies
Case Studies
- ↑ PMID: 11529386