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794 Part VI: The Erythrocyte Chapter 50: Methemoglobinemia and Other Dyshemoglobinemias 795

CLINICAL FEATURES or reference laboratories. A mathematical formula has been developed
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Sulfhemoglobinemia is characterized by cyanosis. Drugs that cause that can be used to calculate P reliably from a venous blood sample.
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sulfhemoglobinemia often have the capacity to produce accelerated red Calculating P using this formula requires the following venous gas
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cell destruction as well. Thus, mild hemolysis is sometimes observed in parameters: partial pressure of oxygen (venous), venous pH, and venous
patients with sulfhemoglobinemia. oxygen saturation, and uses an antilog mathematical function that many
clinicians find difficult to use for calculation. An electronic version (in
Microsoft Excel) of this mathematical formula is available for rapid cal-
LABORATORY FEATURES culation of P from venous blood gases. The P of a healthy person
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50
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Sulfhemoglobin is detected in the lysate of blood treated with ferricya- with normal hemoglobin is 26 ± 1.3 torr. An abnormally low P reflects
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nide, cyanide, and ammonia by comparing the optical density at 620 nm an increased affinity of hemoglobin for oxygen and vice versa, and is
with that at 540 nm. 63,64 especially useful for detecting those high affinity hemoglobin mutants
associated with polycythemia (Chaps. 49 and 57).
TREATMENT AND COURSE
Sulfhemoglobinemia is almost always a benign disorder. Unlike methe- DIFFERENTIAL DIAGNOSIS
moglobin, sulfhemoglobin does not produce a left shift in the oxygen Cyanosis resulting from methemoglobinemia or sulfhemoglobinemia
dissociation curve; instead, it decreases the affinity of hemoglobin for should be differentiated from cyanosis resulting from cardiac or pul-
oxygen. The disorder tends to recur in the same persons after exposure monary disease, particularly when right-to-left shunting is present. In
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to drugs but does not generally appear to affect their overall health. Unlike the latter instances, the arterial oxygen tension will be low, whereas in
methemoglobin, sulfhemoglobin cannot be converted to hemoglobin. methemoglobinemia and sulfhemoglobinemia it should be normal.
Thus, once sulfhemoglobinemia occurs, it will persist until the erythro- One should be certain, however, that the oxygen tension was measured
cytes carrying the abnormal pigment reach the end of their life span. directly and not deduced from the percent saturation of hemoglobin.
Blood from a patient with cyanosis because of arterial oxygen desatura-
tion promptly becomes bright red upon being shaken with air. In addi-
LOW-OXYGEN-AFFINITY tion, these causes of cyanosis are readily differentiated by carrying out
HEMOGLOBINS: A CAUSE OF CYANOSIS quantitative blood methemoglobin and sulfhemoglobin levels. Because
of the potential lethal nature of high levels of methemoglobin and
ETIOLOGY AND PATHOGENESIS because prompt treatment may be life-saving, a high index of suspicion
In some hemoglobin variants, the deoxy conformation of the hemo- is important. A patient with cyanosis whose arterial blood is brown with
an SpO that is found to be normal on blood gas examination is likely
globin molecule is favored because the angle of the heme is altered to have methemoglobinemia. One should not rely on the readings of a
2
from that found normally in deoxyhemoglobin. Such changes occur in standard pulse oximeter, as false readings may be obtained in the pres-
Hb Hammersmith , Hb Bucuresti , Hb Torino , and Hb Peterborough . In other instances, the ence of methemoglobin. Rapid examination of a blood sample using an
quaternary conformation is changed by mutations involving the α β automatic analyzer, such as a cooximeter, is the first step in confirming
1 2
contact (Hb Kansas , Hb Titusville , and Hb Yoshizuka ). Table 50–3 summarizes the the diagnosis. Treatment should not be delayed, but, as pointed out in
properties of abnormal hemoglobins associated with low oxygen affinity.
“Laboratory Features” above, direct spectrophotometric analysis should
be carried out on the pretreatment sample as soon as possible to distin-
CLINICAL FEATURES guish between methemoglobinemia and sulfhemoglobinemia.
In response to the improved tissue oxygen supply brought about by a A family history, as well as any information as to whether it is
right-shifted oxygen dissociation curve, the “oxygen sensor” of the body acquired or congenital, is helpful in differentiating hereditary methe-
decreases the output of erythropoietin. As a result, the steady-state moglobinemia as a result of cytochrome b5 reductase deficiency from
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level of hemoglobin is diminished; mild anemia and cyanosis are char- hemoglobin M disease. The former has a recessive mode of inheritance,
acteristics of patients with hemoglobins with a decreased oxygen affinity. the latter a dominant mode. Thus, cyanosis in successive generations
suggests the presence of hemoglobin M; normal parents but possibly
affected siblings implies the presence of cytochrome b5 reductase. Con-
LABORATORY FEATURES sanguinity is more common in cytochrome b5 reductase deficiency.
The affinity of hemoglobin with oxygen is expressed as P , which is the In cytochrome b5 reductase deficiency, incubation of the blood with
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partial pressure of oxygen at which 50 percent of the blood hemoglo- small amounts of methylene blue will result in rapid reduction of the
bin is saturated with oxygen. The venous P can be measured directly methemoglobin; in hemoglobin M disease, such reduction does not
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using a cooximeter, which is no longer easily available in either routine take place. The absorption spectra of methemoglobin and its derivatives

TABLE 50–3. Some Abnormal Hemoglobins Associated with Low Oxygen Affinity
Amino Acid Oxygen Dissociation and
Hemoglobin Substitution Other Properties Clinical Effect Reference
Hb β70 (E14) Decreased O affinity normal Mild chronic anemia associated with reduced uri- 104
Seattle 2
Ala→Asp heme–heme interaction nary erythropoietin; physiologic adaptation to more
efficient oxygen release to tissues
Hb β102 (G4) Very low O affinity, low heme– Cyanosis resulting from deoxyhemoglobin, mild 187
Kansas 2
Asn→Thr heme interaction, dissociates anemia
into dimers in ligand form

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