Normal hemoglobin can be oxidized to methemoglobin.
Methemoglobinemia occurs because of either increased production
of oxidized hemoglobin because of exposure to environmental agents
or diminished reduction of oxidized hemoglobin because of underlying
germ line mutations. Hemoglobin can also bind gases such as carbon
monoxide (CO) and nitric oxide (NO), resulting in the formation
of carboxyhemoglobin (COHb) and nitrosohemoglobin. Sulfhemoglobinemia
only occurs because of increased production secondary to occupational
exposure to sulphur compounds or exposure to oxidant medications.
These modified hemoglobins, also known as dyshemoglobins, depending
upon the severity and individual predisposition, can result in varying
degree of clinical manifestations. Prompt diagnosis is the key to
effective and timely treatment.
and abbreviations that appear in this chapter include: AOP2, antioxidant
protein 2; 2,3-BPG, 2,3-bisphosphoglycerate; cGMP, cyclic guanosine monophosphate;
cNOS, constitutive nitric oxide synthase; CO, carbon monoxide; COHb,
carboxyhemoglobin; eNOS, endothelial NO synthase; GSH, reduced glutathione;
Hgb, hemoglobin; iNOS, inducible nitric oxide synthase; NADH, nicotinamide
adenine dinucleotide (reduced form); NADPH, nicotinamide adenine
dinucleotide phosphate (reduced form); NO, nitric oxide; NOS, nitric
oxide synthase; SNO-Hgb, S-nitroso hemoglobin; SpCO, arterial carboxyhemoglobin
concentration; SpMet, arterial methemoglobin concentration; SpO2,
arterial oxygen saturation.
A bluish discoloration of the skin and mucous membrane, designated cyanosis,
has been recognized since antiquity as a manifestation of lung or
heart disease. Cyanosis resulting from drug administration has also
been recognized since before 1890.1 Toxic methemoglobinemia
occurs when various drugs or toxic substances either oxidize hemoglobin directly
in the circulation or facilitate its oxidation by molecular oxygen.
In 1912, Sloss and Wybauw2 reported a case of
a patient with idiopathic methemoglobinemia. Later Hitzenberger3 suggested
that a hereditary form of methemoglobinemia might exist, and subsequently, numerous
such cases were reported.4 In 1948, Hörlein
and Weber5 described a family in which eight members
over four generations manifested cyanosis. The absorption spectrum
of methemoglobin was abnormal. They demonstrated that the defect
must reside in the globin portion of the molecule. Subsequently,
Singer6 proposed that such abnormal hemoglobins
be given the designation hemoglobin M. The cause of another form
of methemoglobinemia that occurs independently of drug administration
and without the existence of any abnormality of the globin portion
of hemoglobin was first explained by Gibson,7 who
clearly pointed to the site of the enzyme defect, nicotinamide adenine
dinucleotide (reduced form; NADH) diaphorase, also designated as
methemoglobin reductase, and currently cytochrome b5 reductase.
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 description
of hemoglobin Kansas.9 Here the cyanosis resulted
not from methemoglobin, as occurs in hemoglobin M, but rather from
an abnormally low oxygen affinity of the mutant hemoglobin. Thus,
at normal ...