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CHAPTER 50 numerous such cases were reported. In 1948, Hörlein and Weber
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described a family in which eight members over four generations had
METHEMOGLOBINEMIA cyanosis. The absorption spectrum of methemoglobin was abnormal
and they demonstrated that the defect must reside in the globin por-
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AND OTHER tion of the molecule. Subsequently, Singer proposed that such abnor-
mal hemoglobins be given the designation hemoglobin M. The cause
of another form of methemoglobinemia that occurs independently of
DYSHEMOGLOBINEMIAS drug administration and without the existence of any abnormality of
the globin portion of hemoglobin was first explained by Gibson, who
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clearly pointed to the site of the enzyme defect, nicotinamide adenine
dinucleotide (reduced form) (NADH) diaphorase, also designated as
Archana M. Agarwal and Josef T. Prchal methemoglobin reductase, and now known as cytochrome b reductase.
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More than 50 years after Gibson’s insightful studies, the genetic disorder
that he had predicted was verified at the DNA level. 8
The existence of abnormal hemoglobins that cause cyanosis
through quite another mechanism was first recognized in 1968 with the
SUMMARY description of hemoglobin Kansas. Here the cyanosis resulted not from
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methemoglobin, as occurs in hemoglobin M, but rather from an abnor-
Normal hemoglobin can be oxidized to methemoglobin. Methemoglobinemia mally low oxygen affinity of the mutant hemoglobin. Thus, at normal
occurs because of either increased production of oxidized hemoglobin from oxygen tensions, a large amount of deoxygenated hemoglobin is present
exposure to environmental agents or diminished reduction of oxidized hemo- in the blood of affected patients.
globin because of underlying germline mutations. Cyanosis is virtually invari-
ant in patients with methemoglobinemia. Hemoglobin can also bind carbon EPIDEMIOLOGY
monoxide and nitric oxide, resulting in the formation of carboxyhemoglobin
and nitrosohemoglobin. Sulfhemoglobinemia occurs because of increased Methemoglobinemia occurring as a result of cytochrome b reductase
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production secondary to occupational exposure to sulphur compounds or deficiency is more common among Native Americans, both in Alaska
exposure to oxidant medications. These modified hemoglobins are known as and in the continental United States, and among the Evenk people of
Methemo-
Yakutia of Russian Siberia than in other ethnic groups.
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dyshemoglobins. Depending upon the severity and individual predisposition, globinemia resulting from hemoglobin M is inherited and sporadic. The
presence of dyshemoglobins can result in varying degree of clinical manifesta- occurrence of methemoglobinemia due to toxic chemicals is acquired,
tions. Prompt diagnosis is the key to effective and timely treatment. transient, and is also sporadic.

ETIOLOGY AND PATHOGENESIS
METHEMOGLOBINEMIA Methemoglobinemia decreases the oxygen-carrying capacity of blood
because the oxidized iron cannot reversibly bind oxygen. Moreover,
DEFINITION AND HISTORY when one or more iron atoms have been oxidized, the conformation
A bluish discoloration of the skin and mucous membrane, designated of hemoglobin is changed so as to increase the oxygen affinity of the
cyanosis, has been recognized since antiquity as a manifestation of lung remaining ferrous heme groups. In this way methemoglobinemia exerts
or heart disease; however, in methemoglobinemia and sulfhemoglob- a dual effect in impairing the supply of oxygen to tissues. 13
inemia, it has a different molecular basis than in hemoglobin oxygen
desaturation. Cyanosis resulting from drug administration has also Toxic Methemoglobinemia
been recognized since before 1890. Toxic methemoglobinemia occurs Hemoglobin is continuously oxidized in vivo from the ferrous to the
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when various drugs or toxic substances either oxidize hemoglobin (Hb) ferric state. The rate of such oxidation is accelerated by many drugs and
directly in the circulation or facilitate its oxidation by molecular oxygen. toxic chemicals, including sulfonamides, lidocaine and other aniline
In 1912, Sloss and Wybauw reported a case of a patient with derivatives, and nitrites. A vast number of chemical substances may
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idiopathic methemoglobinemia. Later Hitzenberger suggested that a cause methemoglobinemia. 14–16 Table 50–1 lists some of the agents that
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hereditary form of methemoglobinemia might exist and, subsequently,
are responsible for clinically significant methemoglobinemia in clinical
practice.
The most common offenders include benzocaine and lidocaine. 17–19
In some cases, the patients have been unaware that they have been
Acronyms and Abbreviations: AOP2, antioxidant protein 2; 2,3-BPG, 2,3- ingesting one of the drugs known to produce methemoglobinemia;
bisphosphoglycerate; cGMP, cyclic guanosine monophosphate; CO, carbon monox- dapsone is apparently used in some “street drugs.” 20,21 Nitrates and the
ide; COHb, carboxyhemoglobin; GSH, reduced glutathione; N O , dinitrogen trioxide; nitrites contaminating water supplies or used as preservatives in foods
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NADH, nicotinamide adenine dinucleotide (reduced form); NADPH, reduced nicotin- are also common offending agents. 22–30
amide adenine dinucleotide phosphate; NO, nitric oxide; NOS, nitric oxide synthase;
P , the partial pressure of oxygen at which 50 percent of the blood hemoglobin is Cytochrome b Reductase Deficiency
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saturated with oxygen; RBC, red blood cells; SNO-Hb, S-nitrosohemoglobin; SpCO, Cytochrome b reductase, also known as NADH diaphorase, catalyzes a
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arterial carboxyhemoglobin concentration; SpMet, arterial methemoglobin concen- step in the major pathway for methemoglobin reduction. This enzyme
tration; SpO , arterial oxygen saturation. reduces cytochrome b , using NADH as a hydrogen donor. The reduced
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cytochrome b reduces, in turn, methemoglobin to hemoglobin. A
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