Buenos Aires 01 de Octubre del 2022
Clinical Features, Diagnosis and Treatment of Methamoglobinem
Clinical features, diagnosis, and treatment of methemoglobinem
Josef T. Prchal
UpTo Date - May 2008
There are two types of methemoglobinemia - congenital and acquired:
- Congenital methemoglobinemia is characterized by diminished enzymatic reduction of methemoglobin (ie, hemoglobin with its iron in the ferric state) back to functional hemoglobin (ie, hemoglobin with its iron in the ferrous state). Affected patients appear cyanotic but are generally asymptomatic.
- Acquired methemoglobinemia typically results from ingestion of specific drugs or agents that cause an increase in the production of methemoglobin. It can be a fatal disease.
The pathophysiology, clinical features, diagnosis, and treatment of methemoglobinemia will be reviewed here. The genetics and pathogenesis of methemoglobinemia are discussed elsewhere, but will be briefly summarized below.
Methemoglobin is an altered state of hemoglobin in which the ferrous (Fe2+) irons of heme are oxidized to the ferric (Fe3+) state. The ferric hemes of methemoglobin are UNABLE to bind oxygen. In addition, the oxygen affinity of any remaining ferrous hemes in the hemoglobin tetramer is increased . As a result, the oxygen dissociation curve is "left-shifted"
The net effect is that the patient with increased concentrations of methemoglobin has a greater functional anemia than suggested by the laboratory data. The circulating methemoglobin-containing hemoglobin molecules are unable to carry oxygen and the remaining oxyhemoglobin has increased oxygen affinity, resulting in impaired oxygen delivery to the tissues.
Formation and reduction of methemoglobin - In normal individuals, autooxidation of hemoglobin to methemoglobin occurs spontaneously at a slow rate, each day converting 0.5 to 3 percent of the available hemoglobin to methemoglobin [2,3]. This autooxidation, combined with the subsequent reduction of methemoglobin by the mechanisms described below, acts to maintain a steady-state level of methemoglobin of about 1 percent of total hemoglobin in normal individuals.
There are two pathways for reduction of methemoglobin back to hemoglobin:
- The only physiologically important pathway is the NADH-dependent reaction catalyzed by cytochrome b5 reductase (b5R).
- An alternative pathway, that is not physiologically active, utilizes NADPH generated by glucose-6-phosphate dehydrogenase (G6PD) in the hexose monophosphate shunt. However, there is normally no electron carrier present in red blood cells to interact with NADPH methemoglobin reductase. Extrinsically administered electron acceptors, such as methylene blue (MB) and riboflavin are required for this pathway to be activated . This pathway becomes clinically important for the treatment of methemoglobinemia.
Most cases of methemoglobinemia are acquired, resulting from increased methemoglobin formation by various exogenous agents [5,6].
Most cases of the less common hereditary methemoglobinemias are due to homozygous or compound heterozygous deficiency (ie, autosomal recessive) of cytochrome b5 reductase (cytochrome b5R). This disorder is typically seen in three settings: endemic methemoglobinemia; in individuals of consanguineous unions; or in compound heterozygous cytochrome b5 reductase deficiency, which is primarily seen in sporadic cases. Another congenital cause of methemoglobinemia is hemoglobin M disease, which is due to mutations in either the alpha, beta, or rarely gamma globin molecule . In most of the mutations, tyrosine is substituted for either the proximal or distal histidine in the heme pocket, and forms an Fe3+-phenolate complex that resists reduction of Fe3+ heme iron to the divalent state. The net effect is life-long methemoglobinemia. Administration of methylene blue does not correct this type of congenital methemoglobinemia.
Deficiency of cytochrome b5 is the rarest form of congenital methemoglobinemia, and has been described in only one or two families [7,8].
# Congenital methemoglobinemia - Most individuals with congenital, chronically elevated methemoglobin concentrations are asymptomatic (although some complain of headache and easy fatiguability) even with methemoglobin levels as high as 40 percent of total hemoglobin .
Cyanosis - The main complaint of subjects with congenital methemoglobinemia is "cyanosis" or a slate-blue color of the skin and mucous membranes, a finding that is due to the different absorbance spectrum of methemoglobin compared to oxyhemoglobin.
Cyanosis is clinically detected when the absolute concentration of methemoglobin exceeds 1.5 g/dL, equivalent to 8 to 12 percent methemoglobin at normal hemoglobin concentrations [6,9]. In contrast, the most common cause of cyanosis is decreased hemoglobin oxygen saturation, which is observed when the absolute level of deoxygenated hemoglobin (reduced hemoglobin) exceeds 4 to 5 g/dL, as in severe respiratory failure or cardiac abnormalities due to right-to-left shunts. This form of cyanosis cannot be clinically differentiated from that due to methemoglobinemia; thus, testing for methemoglobinemia is required.
Symptoms in type I disease - Significant polycythemia (ie, compensatory erythrocytosis) is only rarely observed in congenital methemoglobinemia. Life expectancy is not shortened and pregnancies occur normally. The general lack of symptoms (other than cyanosis) and normal life expectancy in patients with cytochrome b5 reductase deficiency applies only to the more common type I disease in which the enzymatic defect is limited to red cells.
Symptoms in type II disease - In contrast to type I congenital methemoglobinemia, all cells are affected in patients with type II methemoglobinemia, who exhibit, in addition to cyanosis, mental retardation and developmental delay with failure to thrive [10,11]. Other neurologic manifestations may be present, including microcephaly, opisthotonus, athetoid movements, strabismus, seizures, and spastic quadriparesis. Life expectancy is significantly shortened, and most die in infancy. Neurologic problems may result from abnormal lipid elongation and desaturation affecting the central nervous system [12,13].
Because the enzymatic defect is also found in fibroblasts, prenatal diagnosis is possible by analysis of cytochrome b5R activity in cultured amniotic cells [14,15].
# Acquired methemoglobinemia - Acquired methemoglobinemia typically results from ingestion of specific drugs or agents that cause an increase in the production of methemoglobin, which can be fatal.
Signs and symptoms - Symptoms in patients with acquired methemoglobinemia result from an acute impairment in oxygen delivery to tissues that does not allow sufficient time for compensatory mechanisms to take place. Early symptoms include headache, fatigue, dyspnea, and lethargy. At higher methemoglobin levels, respiratory depression, altered consciousness, shock, seizures, and death may occur . Acquired methemoglobinemia is life-threatening when methemoglobin comprises more than 50 percent of total hemoglobin.
Dapsone and local anesthetic agents (eg,benzocaine, lidocaine) appear to be the most common precipitating agents of acquired methemoglobinemia [16,17]. In a review of 138 patients with acquired methemoglobinemia, use of dapsone accounted for 42 percent of cases, with a mean methemoglobin level of 7.6 percent (range 2 to 34 percent) .
However, the most severe cases were seen after the use of 20 percent benzocaine spray for topical anesthesia (mean peak methemoglobin level 44 percent, range: 19 to 60 percent). High mean peak methemoglobin levels (mean 32 percent) following benzocaine administration was also noted in a series of 19 patients who underwent transesophageal echocardiography .
The incidence of methemoglobinemia in this setting was 0.7 percent.
The molecular mechanism underlying this association has not been elucidated, as previous or subsequent exposure to benzocaine may not be associated with methemoglobinemia.
Among the patients who underwent transesophageal echocardiography, those who developed methemoglobinemia were significantly more likely, compared to random controls, to have active infection (68 versus 7 percent) and anemia (84 versus 45 percent).
Cyanosis during endoscopic procedures - The occurrence of acute cyanosis during endoscopic procedures, such as bronchoscopy, may be due to airway obstruction, but another possibility is the induction of acute methemoglobinemia as a result of the topical anesthetic agent used prior to the procedure.
Clues that methemoglobinemia is present in such settings include the development of cyanosis in the presence of a normal arterial PO2 and/or the presence of "chocolate brown blood" in the videoscopic field .
* Clinical suspicion - Methemoglobinemia may be clinically suspected by the presence of clinical "cyanosis" in the presence of a normal arterial pO2 (PaO2) as obtained by arterial blood gases. The blood in methemoglobinemia has been variously described as dark-red, chocolate, or brownish to blue in color, and, unlike deoxyhemoglobin, the color does not change with the addition of owygen.
Routine pulse oximetry may be INACCURATE in monitoring oxygen saturation in the presence of methemoglobinemia, and may not be used to make the diagnosis of this disorder. However, the presence of methemoglobin can be suspected when the oxygen saturation as measured by pulse oximetry is significantly different from the oxygen saturation calculated from arterial blood gas analysis ("saturation gap") [16,21,22].
A pulse oximeter that uses eight wavelengths of light and can accurately measure both methemoglobin and carboxyhemoglobin (the Rainbow-SET Rad-57 Pulse CO-Oximeter, Masimo, Inc., Irvine, CA) has been developed and is available in some medical centers [23,24]. It is capable of giving continuous readings of methemoglobin level at the bedside, allowing continuous monitoring of the patient's response to treatment. .
* Laboratory diagnosis - The laboratory diagnosis of methemoglobinemia is based upon analysis of its absorption spectrum, which has peak absorbance at 631 nm. A fresh specimen should always be obtained as methemoglobin levels tend to increase with storage. The standard method of assaying methemoglobin utilizes a microprocessor-controlled, fixed wavelength co-oximeter. This instrument interprets all readings in the 630 nm range as methemoglobin; thus, false positives may occur in the presence of other pigments including sulfhemoglobin and methylene blue [25,26].
As a result, methemoglobin detected by the co-oximeter should be confirmed by the specific Evelyn-Malloy method . This assay involves the addition of cyanide which binds to the positively charged methemoglobin, eliminating the peak at 630 to 635 nm in direct proportion to the methemoglobin concentration. The subsequent addition of ferricyanide converts the entire specimen to cyanomethemoglobin for measurement of the total hemoglobin concentration. Methemoglobin is then expressed as a percentage of the total concentration of hemoglobin.
Sulfhemoglobin, in concentrations greater than 0.5 gm/dL also causes "cyanosis" with a normal PaO2 and may be erroneously measured as methemoglobin. Sulfhemoglobin can be distinguished from methemoglobin by virtue of its peak absorption at 620 nm which, unlike methemoglobin, is not abolished by the addition of cyanide.
Distinguishing among the hereditary forms of congenital methemoglobinemia is aided by interpretation of family pedigrees as well as biochemical analyses. Cyanosis in successive generations suggests the presence of the autosomal dominant Hb M disease, whereas normal parents but possibly affected siblings implies the presence of autosomal recessive deficiency of cytochrome b5R,rarely,cytochrome b5.
- Incubation of blood with methylene blue distinguishes cytochrome b5R deficiency from Hb M disease; this treatment will result in the rapid reduction of methemoglobin through the NADPH-flavin reductase pathway in cytochrome b5R deficiency but not in Hb M disease [28-30].
- Measurement of the level of cytochrome b5R activity or cytochrome b5 is required to distinguish cytochrome b5R deficiency from cytochrome b5 deficiency; however, these assays are not commercially available.
* Assays of enzyme activity - Types I and II cytochrome b5R deficiency are distinguished by clinical phenotype as described above and analysis of enzymatic activity in erythroid and nonerythroid cells. Reports of decreased cytochrome b5R activity are difficult to compare since several different assays of cytochrome b5R activity, varying in their substrate and in their normal values, have been used [6,31-37]. These assays also vary in their technical difficulty.
The first widely accepted cytochrome b5R activity assay used a difficult to produce and standardize methemoglobin-ferrocyanide complex and its reduction by an enzyme containing hemolysate or other tissue homogenate . The most rigorous cytochrome b5R enzyme activity is based on partial purification of the enzyme by ultracentrifugation and uses the physiological enzyme substrate (cytochrome b5 prepared by a recombinant DNA technology) . This assay is not readily available and is too complex for nonspecialized research laboratories.
A subsequently developed assay uses readily available ferricyanide  and easily differentiates type I and type II cytochrome b5R deficiency. As mentioned above, patients with type I deficiency have normal enzyme activity in platelets, fibroblasts, Epstein-Barr virus-transformed lymphocytes and granulocytes while, in type II deficiency, the activity in nonerythroid tissues is markedly to moderately decreased [34,39-41]. Two families with "type III" deficiency have been described in which cytochrome b5R activity was allegedly decreased not only in erythrocytes but in also in platelets and leukocytes [42,43]. Re-evaluation of one of the patients using the rigorous recombinant cytochrome b5 assay confirmed cytochrome b5R activity in platelets, leukocytes, and fibroblasts consistent with the presence of type I deficiency , and discrediting the existence of "type III" cytochrome b5R deficiency.
Treatment of methemoglobinemia depends upon the clinical setting (ie, acute onset of methemoglobinemia due to drugs or other toxic agents versus congenital life-long methemoglobinemia).
General precautions - All patients with hereditary methemoglobinemia should avoid exposure to aniline derivatives, ].
Cytochrome b5R deficiency - Treatment of cyanosis in individuals with type I and II cytochrome b5R deficiency is indicated only for cosmetic reasons, if so desired. Treatment options include methylene blue (100 to 300 mg/day orally) or ascorbic acid (300 to 1000 mg/day orally in divided doses).
Concerns about kidney stone formation with ascorbic acid therapy remain unproven, although high dose therapy may be associated with some risk. Riboflavin (20 to 30 mg/day) has also been used with some success , although clinical experience with its use is very limited.
Although effective for reducing the cyanosis, neither methylene blue nor ascorbic acid has any effect on the neurologic abnormalities in type II disease. Theoretically, a bone marrow or liver transplant would alleviate these neurologic problems if they were due to a problem with circulating fatty acids; however, these approaches have not yet been tested.
Acquired methemoglobinemia - Offending agents in acquired methemoglobinemia should be discontinued .
- In lesser degrees of methemoglobinemia (ie, an asymptomatic patient with a methemoglobin level <20 percent), no therapy other than discontinuation of the offending agent(s) may be required.
- If the patient is symptomatic, or if the methemoglobin level is >20 percent, which is often the case in deliberate or accidental overdoses or toxin ingestion, specific therapy with methylene blue is indicated.
- Blood transfusion or exchange transfusion may be helpful in patients who are in shock. Hyperbaric oxygen has been used with anecdotal success in severe cases .
Acute use of methylene blue - Acquired methemoglobinemia is life-threatening when methemoglobin comprises >40 percent of total hemoglobin. In such cases, the use of methylene blue can be life-
Methylene blue (MB), given intravenously in a dose of 1 to 2 mg/kg over five minutes provides an artificial electron acceptor for the reduction of methemoglobin via the NADPH-dependent pathway[6,17]. The response is usually rapid; the dose may be repeated in one hour, but is frequently not necessary.
However, rebound methemoglobinemia as high as 60 percent may occur up to 18 hours after methylene blue administration, due to prolonged absorption of the implicated agent from topical or enteric sites . Accordingly, it is reasonable to perform serial measurements of methemoglobin levels following treatment with MB in order to evaluate the patient for subsequent worsening.
Caution should be exercised to avoid overdosage, as large (>7 mg/kg) cumulative doses of MB can cause dyspnea and chest pain, as well as hemolysis in some susceptible subjects [48,49]. Since co-oximetry detects MB as methemoglobin, this technique cannot be used to follow the response of methemoglobin levels to treatment with MB. If needed, the specific Evelyn-Malloy method will discriminate between methemoglobin and MB.
Dapsone-induced methemoglobinemia - Marked methemoglobinemia may occur after treatment of dermatitis herpetiformis or pneumocystis infection with dapsone. Cimetidine, used as a selective inhibitor of N-hydroxylation, may be effective in increasing patient tolerance to dapsone, chronically lowering the methemoglobin level by more than 25 percent [45,50]. Since it works slowly, cimetidine is not helpful for the management of acute symptomatic methemoglobinemia arising from the use of dapsone.
Patients with G6PD deficiency - Methylene blue should not be administered to patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency, since the reduction of methemoglobin by MB is dependent upon NADPH generated by G6PD . As a result, MB may not only be ineffective but it is also potentially dangerous, since MB has an oxidant potential that may induce hemolysis in G6PD deficient subjects .
In order to avoid these problems, pretreatment screening of populations with a high incidence of G6PD deficiency (eg, African- Americans, subjects of Mediterranean descent, and southeast Asians) is reasonable, although not usually practical. If Methylene blue is contraindicated, only moderate doses of ascobic acid (300 to 1000 mg/day orally in divided doses) should be given, as this drug may also cause oxidant hemolysis in G6PD deficient patients when given in very high doses .
Hemoglobin M disease - Individuals with hemoglobin M disease are generally without symptoms and should be counseled about the benign nature of their condition . However, there is no effective treatment for the methemoglobinemia seen in this condition, should it be required.
SUMMARY AND RECOMMENDATIONS
- Patients with congenital forms of methemoglobinemia have life-long cyanosis and are usually asymptomatic.
- Patients with acute acquired methemoglobinemia may be asymptomatic at lower levels of methemoglobin (ie, <20 percent). Symptoms, when present, include headache, fatigue, dyspnea, and lethargy. At methemoglobin levels >40 percent, respiratory depression, altered consciousness, shock, seizures, and death may occur.
Suspecting the diagnosis
- The presence of methemoglobin (ie, hemoglobin with its iron in the oxidized (Fe3+) state) is suspected when there is clinical "cyanosis" in the presence of normal arterial pO2.
- The blood in methemoglobinemia has been variously described as dark-red, chocolate, or brownish to blue in color, which, if noted during a procedure associated with the use of a topical anesthetic agent, is a valuable clue for making this diagnosis in a timely manner.
Confirming the diagnosis
The laboratory diagnosis of methemoglobinemia is based upon analysis of its absorption spectrum, which has peak absorbance at 631 nm. Methemoglobin detected by the co-oximeter should be confirmed by the specific Evelyn-Malloy method.
General treatment principles
- In children and adults with acute acquired methemoglobinemia, levels of methemoglobin >20 percent are associated with clinical symptoms. Mortality rates are high when methemoglobin levels exceed 40 percent. Accordingly, acute acquired methemoglobinemia should be considered a MEDICAL EMERGENCY.
- All patients with hereditary methemoglobinemia should avoid exposure to aniline derivatives, nitrates, and other agents that may, even in normal individuals, induce methemoglobinemia Known heterozygotes for cytochrome b5R deficiency should be similarly counseled.
- Treatment of cyanosis in individuals with cytochrome b5R deficiency is indicated for cosmetic reasons only. Treatment options include methylene blue (100 to 300 mg/day orally) or ascorbic acid (300 to 1000 mg/day orally in divided doses).
Treatment of acute acquired methemoglobinemia
- A thorough search for an offending agent should be made and, if found, removed and/or discontinued. The most commonly implicated agents include dapsone, local (topical) anesthetic agents, aniline dyes, and high nitrate levels in water supplies .
- If the patient is symptomatic, we recommend the immediate use of intravenous methylene blue (Grade 1A). The usual dose in this setting is 1 to 2 mg/kg, given over five minutes The response is usually rapid; the dose may be repeated in one hour if high levels of methemoglobin persist. methemoglobinemia and glucose 6-phosphate dehydrogenase deficiency may worsen after treatment with methylene blue.
An alternative treatment for such patients, which is less effective than methylene blue, is ascorbic acid.
- Severely affected patients may benefit from adjunctive treatment with exchange transfusion and/or hyperbaric oxygen, although evidence of their efficacy is only anecdotal.
- In asymptomatic patients, usually those with methemoglobin levels <20 percent, no therapy other than discontinuation of the offending agent(s) may be required.
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