Page 737 - Hematology_ Basic Principles and Practice ( PDFDrive )

624 Part V Red Blood Cells

then reduces methemoglobin. Since these electron acceptors are not patients can experience progressive respiratory compromise, myocar-
physiologic, this pathway is only of importance as it is the mechanism dial ischemia, seizures, and coma. Death typically ensues at methe-
by which methylene blue treats acute toxic methemoglobinemia. moglobin levels above 70% but can occur at lower levels.
Individuals with type I b5R deficiency, which is limited to
erythrocytes, have methemoglobin concentrations of 10% to 35%
Epidemiology and appear cyanotic but are usually asymptomatic, even with levels
up to 40%. Some patients have reported headache and easy fatigabil-
Most cases of methemoglobinemia are acquired, resulting from ity. Life expectancy is not shortened and pregnancies occur normally.
increased methemoglobin formation by various exogenous agents. Compensatory polycythemia is at times observed.
Acute or toxic methemoglobinemia may occur in the setting of In addition to methemoglobinemia and cyanosis, patients with
overdose or poisoning, but also at standard doses of drugs. Acute Type II b5R deficiency exhibit mental retardation and developmental
methemoglobinemia occurs equally between males and females and delay. Other neurologic symptoms may be present, including micro-
over a wide range of ages; however, infants are more susceptible cephaly, opisthotonus, athetoid movements, strabismus, seizures, and
because their erythrocyte b5R activity is normally 50% to 60% of spastic quadriparesis. Life expectancy is significantly shortened, and
adult activity. death in infancy is typical.
Hereditary methemoglobinemia is most commonly caused by
deficiency of b5R. b5R deficiency is an autosomal recessive condition
and occurs in all racial and ethnic groups, but is endemic in certain Laboratory Manifestations
populations, including Navajo and Athabasca Native Americans and
natives of Yakutsk, Siberia. Other causes of hereditary methemoglo- The laboratory diagnosis of methemoglobinemia is based on analysis
binemia are the autosomal dominant inheritance of an abnormal of its absorption spectra. A fresh specimen should always be obtained
hemoglobin in hemoglobin M disease (see Chapter 43) and, very because methemoglobin levels tend to increase with storage. Tradi-
rarely, deficiency of cytochrome b 5 . tional pulse oximetry is unreliable in the presence of methemoglo-
binemia because of its light absorbance properties; however,
Pathobiology co-oximetry can determine the methemoglobin fraction along with
all other substances with the optical density at 630 nm.
Methemoglobin detected by co-oximeter should be confirmed by
Acute Methemoglobinemia the specific Evelyn-Malloy method if available. This method involves
direct spectrophotometric analysis and should be used when methe-
Many drugs and toxins have been implicated in acute methemoglo- moglobinemia is suspected. In the Evelyn-Malloy method, blood is
binemia. More common culprits include dapsone, local anesthetics lysed in a slightly acid buffer and the optical density is measured at
(benzocaine, lidocaine, prilocaine), and derivatives of the anesthetic 630 nm before and after adding a small amount of neutralized
phenacetin. Exposure to nitrates and nitrites, widely used as food cyanide Absorption of methemoglobin at this wavelength disappears
preservatives and found in well water can also cause methemoglobin- when it is converted to cyanmethemoglobin. This method remains
emia. Nitrates do not oxidize hemoglobin directly but are converted the most accurate technique for the estimation of methemoglobin
to nitrites by intestinal bacteria. Infants less than 6 months of age concentration.
may have increased susceptibility to methemoglobinemia at least in An eight-wavelength pulse oximeter, Masimo Rad-57 (the
part because of their lower b5R activity. Homemade baby food purees Rainbow-SET Rad-57 Pulse CO-Oximeter, Masimo Inc, Irvine, CA,
of high-nitrate-containing vegetables, well water contaminated by USA), has been approved by the US Food and Drug Administration
nitrites and diarrheal illness may all cause acute toxic methemoglo- and appears to be accurate for the measurement of both carboxyhe-
binemia in infants. moglobin and methemoglobin.
Distinguishing the hereditary forms of congenital methemoglo-
binemia requires interpretation of family pedigrees as well as bio-
B5R Deficiency chemical analyses. Cyanosis in successive generations suggests
autosomal dominant hemoglobin (Hb) M disease, whereas normal
In erythrocytes, b5R transfers electrons to methemoglobin to reduce parents but possibly affected siblings implies autosomal recessive b5R
it to hemoglobin. In other cells, b5R transfers electrons from cyto- deficiency. Incubation of blood with methylene blue distinguishes
chrome b 5 to stearyl-CoA in the endoplasmic reticulum, a reaction b5R deficiency from Hb M disease, because this treatment results in
that has an important role in cholesterol biosynthesis, fatty acid the rapid reduction of methemoglobin through the NADPH-flavin
elongation and desaturation, and drug metabolism. There are two reductase pathway in cases of b5R deficiency but not in cases of Hb
types of b5R deficiency. The more common type I b5R deficiency is M disease. Types I and II b5R deficiency are distinguished by their
usually caused by missense mutations leading to decreased stability clinical phenotype and by analysis of enzymatic activity in erythroid
of the enzyme. Thus, although b5R is abnormal in all cells, only and nonerythroid cells. Because the enzyme defect is found in fibro-
mature RBCs, which cannot synthesize proteins and replace the blasts, analysis of b5R activity in cultured amniotic cells for prenatal
enzyme, are significantly affected in patients with type I b5R defi- diagnosis is possible.
ciency. Type II b5R mutations affect the catalytic site or lead to
marked structural changes and all cells have decreased b5R activity.
Differential Diagnosis
Clinical Manifestations Sulfhemoglobin in concentrations greater than 0.5 gm% also causes
“cyanosis” with a normal PaO 2 and may be erroneously measured as
Methemoglobinemia causes clinically discernible cyanosis when the methemoglobin. Other pigments, including methylene blue, may
absolute level of methemoglobin exceeds 1.5 gm%; this correlates also produce false positive results when methemoglobin is measured
with approximately 10% to 15% methemoglobin. Methemoglobin- by co-oximetry.
emia should be clinically suspected when “cyanosis” occurs in the
presence of a normal PaO 2. Symptoms develop secondary to impaired
tissue oxygenation and the onset may be abrupt. Early symptoms Prognosis
include headache, fatigue, dyspnea, and lethargy. At higher levels,
respiratory depression, altered consciousness, shock, seizures, and Acute methemoglobinemia generally resolves promptly with treat-
death may occur. As methemoglobin levels rise above 20% to 30%, ment providing the offending cause is discontinued. Patients with