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790 Part VI: The Erythrocyte Chapter 50: Methemoglobinemia and Other Dyshemoglobinemias 791

TABLE 50–1. Some Drugs That Cause in the first year of life. 39,40 Patients with this form of disease are afflicted,
in addition to methemoglobinemia, with a progressive encephalopathy
Methemoglobinemia
and mental retardation. The finding that fatty acid elongation is defective
Phenazopyridine (Pyridium) 163–165 in the platelets and leukocytes of such patients provides a clue to the
41
Sulfamethoxazole 166 type of defect that could occur in the central nervous system, where fatty
acid elongation plays an important role in myelination. Rare patients
Dapsone 20,167,168
with deficiency of cytochrome b5 reductase in nonerythroid cells do not
Aniline 88,89 suffer any neurologic disorder, and it has been suggested that they be
42
Paraquat/monolinuron 169–171 designated as having type III disease ; however, existence of such an
entity has been challenged and type III disease likely does not exist. 43
Nitrate 22–24,81
Nitroglycerin 163,172 Heterozygosity for Cytochrome b Reductase Deficiency
5
Amyl nitrite 173 Heterozygotes for cytochrome b reductase deficiency are not usually
5
clinically methemoglobinemic or cyanotic. However, under the stress
Isobutyl nitrite 174
of administration of drugs that normally induce only slight, clinically
Sodium nitrite 23,82 unimportant, methemoglobinemia, such persons have been reported to
44
Benzocaine 175–177 become severely cyanotic because of methemoglobinemia. Although
in this report the affected patients were Ashkenazi Jews, the prevalence
Prilocaine 178–180
of cytochrome b5 reductase deficiency in 500 unselected Jewish subjects
45
Methylene blue 87 was found to be low. In addition, predisposition to acute toxic methe-
Chloramine 171,181 moglobinemia in heterozygous subjects for cytochrome b5 reductase
deficiency seems to be quite uncommon. 43
Animal models of cytochrome b5 reductase deficiency have been
described in dogs, cats, and horses. 46,47
steady-state methemoglobin level is achieved when the rate of methe-
moglobin formation equals the rate of methemoglobin reduction either Infant Susceptibility
through the cytochrome b reductase or through a relatively minor aux- A combination of both increased hemoglobin oxidation and decreased
5
iliary mechanism such as direct chemical reduction by ascorbate and methemoglobin reduction also may occur. Because the activity of cyto-
reduced glutathione. A reduced nicotinamide adenine dinucleotide chrome b5 reductase is normally low in newborn infants, they are par-
48
phosphate (NADPH)-linked enzyme, NADPH diaphorase, does not ticularly susceptible to the development of methemoglobinemia. Thus,
play a role in methemoglobin reduction except when a linking dye such serious degrees of methemoglobinemia have been observed in infants
as methylene blue is supplied (see “Therapy, Course, and Prognosis” as a result of toxic materials, such as aniline dyes used on diapers, and
49
below). A marked diminution in the activity of cytochrome b5 reduc- the ingestion of nitrate-contaminated water 24,30 and even of beets. Bac-
50
tase will result in the accumulation of the brown pigment in circulating terial action in the intestinal tract may reduce nitrates to nitrites, which,
erythrocytes. in turn, cause methemoglobinemia. In rural areas, fatal methemoglobi-
A balance to methemoglobin formation is antioxidant protein nuria in infants caused by drinking water from wells contaminated with
2 (AOP2), which is present in high concentrations in human and nitrates still occurs. 51
mouse red cells (Chap. 47). This member of the peroxiredoxin pro- Inhaled nitric oxide (NO) is approved for treatment of infants with
tein family binds to hemoglobin and prevents both spontaneous and pulmonary hypertension because of its vasodilatory effect on pulmo-
oxidant-induced methemoglobin formation. Mutations of this gene nary vessels. During the binding and release of NO from hemoglobin,
31
or its acquired deficiency are theoretical candidates responsible for methemoglobin is formed at a higher rate. In one study of 81 premature
congenital and acquired methemoglobinemia. Cyanosis resulting from and 82 term infants, methemoglobin was above 5 percent in preterm
abnormal hemoglobins (both hemoglobin M and low-oxygen affinity infants and between 2.5 and 5 percent in 16 infants. 52
hemoglobins) is inherited as an autosomal dominant disorder. In con- Methemoglobinemia occurring in acidotic infants with diarrhea is
trast, hereditary methemoglobinemia resulting from cytochrome b a syndrome that may have a fatal outcome. Such infants have normal
53
5
reductase deficiency is inherited in an autosomal recessive fashion. red cell cytochrome b5 reductase activity, and the mechanism by which
Many mutations of cytochrome b5 reductase that cause methe- methemoglobinemia occurs is unknown. However, the syndrome
8
moglobinemia have been identified at the nucleotide level, and the seems most common when soy formula is being fed and breastfeeding
54
functional effect of some of these have been deduced from the struc- appears to protect against this. 51
ture of the enzyme. 32,33 Although most of the mutants have been found
in persons of European descent, five unique mutations were found in Cytochrome b5 Deficiency
34
Chinese, at least three in Thais, two in Americans of African descent, Rarely, the defect leading to methemoglobinemia may not be in the
35
36
and one in an Asian Indian. In addition, a common polymorphism cytochrome b5 reductase that transfers hydrogen to the cytochrome b5,
37
(allele frequency = 0.023) has been identified in Americans of African but rather to a deficiency in the cytochrome b5 itself. 55
descent; it does not appear to impair the activity of the enzyme. Most
38
of the patients with cytochrome b reductase deficiency merely have Hemoglobin M
5
methemoglobinemia and the enzyme deficiency is limited to the red The molecular mechanisms by which hemoglobin binds oxygen and
cells, and these have been classified as having type I disease. In type II releases it are discussed in Chap. 49. Heme is held in a hydrophobic “heme
cytochrome b reductase deficiency, which represents 10 to 15 percent pocket” between the E and F α-helices of each of the four globin chains.
5
of cases of enzyme deficient congenital methemoglobinemia, cyto- The iron atom in the heme forms four bonds with the pyrrole nitrogen
chrome b5 reductase is decreased in all cells. In addition to cyanosis, atoms of the porphyrin ring and a fifth covalent bond with the imidazole
severe developmental abnormalities can occur; most affected infants die nitrogen of a histidine residue in the nearby F α-helix (Fig. 50–1).
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Kaushansky_chapter 50_p0789-0800.indd 790 9/17/15 2:38 PM