Sections View Full Chapter Figures Tables Videos Annotate Full Chapter Figures Tables Videos Supplementary Content + DEFINITION Download Section PDF Listen +++ ++ Cyanosis is most frequently caused by low arterial oxygen saturation because of cardiac or pulmonary disease, but rarely, it may be caused by increased concentrations of methemoglobin or sulfhemoglobin, or by abnormal hemoglobins with low oxygen affinity. + METHEMOGLOBINEMIA Download Section PDF Listen +++ +++ Toxic Methemoglobinemia ++ Drugs or chemicals may cause methemoglobinemia either by oxidizing hemoglobin directly or by enhancing its oxidization by molecular oxygen. Table 19–1 lists common agents that cause methemoglobinemia. Infants are more susceptible because of low levels of NADH diaphorase (cytochrome b5 reductase) in the newborn period. A syndrome of diarrhea, acidosis, and methemoglobinuria of yet unexplained etiology occurs in infancy. Severe acute methemoglobinemia impairs oxygen delivery, and levels exceeding 50 percent can be fatal. Chronic methemoglobinemia is usually asymptomatic, but at levels greater than 20 percent, mild erythrocytosis is often present. Treatment with intravenous methylene blue (given at 1 to 2 mg/kg over 5 minutes) is rapidly effective. Excessive amounts of methylene blue, or its use in G-6-PD–deficient patients, can cause acute hemolysis. ++Table Graphic Jump LocationTABLE 19–1SOME DRUGS THAT CAUSE METHEMOGLOBINEMIAView Table||Download (.pdf) TABLE 19–1 SOME DRUGS THAT CAUSE METHEMOGLOBINEMIA Phenazopyridine (Pyridium) Sulfamethoxazole Dapsone Aniline Paraquat/monolinuron Nitrate Nitroglycerin Amyl nitrite Isobutyl nitrite Sodium nitrite Benzocaine Prilocaine Methylene blue Chloramine Source: Williams Hematology, 8th ed, Chap. 49, Table 49–1, p. 744. +++ Cytochrome b5 Reductase Deficiency ++ Cytochrome b5 reductase deficiency (also known as NADH diaphorase) catalyzes the reduction of cytochrome b5, which, in turn, reduces methemoglobin to hemoglobin. Hereditary cytochrome b5 reductase deficiency results in an accumulation of methemoglobin and is inherited as a recessive disorder. If restricted to erythrocytes, cyanosis is the only phenotype (type I cytochrome b5 reductase deficiency). This is seen sporadically in all racial groups but is reported to be endemic in certain native Siberian ethnic groups, Navajo Indians, and Athabascan natives of Alaska. In some patients, cells other than erythrocytes may be involved, and a less common hereditary syndrome of cyanosis with mental retardation and other neurologic defects may occur (type II cytochrome b5 reductase deficiency). Methemoglobin levels vary between 8 and 40 percent, and the cytochrome b5 reductase level is less than 20 percent of normal. Treatment with ascorbic acid (200 to 600 mg/d orally, divided into four doses) lowers the methemoglobin level. Infants have transiently low levels of cytochrome b5 reductase and are more likely to develop acute toxic methemoglobinemia. +++ Cytochrome b5 Deficiency ++ Rarely, cytochrome b5 itself is deficient, causing the same clinical picture as type II cytochrome b5 reductase deficiency. +++ Hemoglobins M ++ Some amino acid substitutions in hemoglobin lead to enhanced formation and inability to reduce methemoglobin. These abnormal proteins are termed hemoglobins M and the resultant cyanosis from methemoglobinemia is inherited as a recessive disorder. Cyanosis may be evident at birth in hemoglobin M disease with the α-chain mutant; in the β-chain variant, this will evolve over 6 to 9 weeks as γ-globin chains are replaced by β-chains. No effective treatment for methemoglobinemia due to hemoglobin M is known. The characteristics of M hemoglobins are shown in Table 19–2. ++Table Graphic Jump LocationTABLE 19–2PROPERTIES OF M HEMOGLOBINSView Table||Download (.pdf) TABLE 19–2 PROPERTIES OF M HEMOGLOBINS Hemoglobin Amino Acid Substitution Oxygen Dissociation and Other Properties Clinical Effect Hgb MBoston α58 (E7)His —→ Tyr Very low oxygen affinity, almost nonexistent heme–heme interaction, no Bohr effect Cyanosis resulting from formation of methemoglobin Hgb MSaskatoon β63 (E7)His —→ Tyr Increased oxygen affinity, reduced heme–heme interaction, normal Bohr effect, slightly unstable Cyanosis resulting from methemoglobin formation, mild hemolytic anemia exacerbated by ingestion of sulfonamides Hgb MIwate α87 (F8)His —→ Tyr Low oxygen affinity, negligible heme–heme interaction, no Bohr effect Cyanosis resulting from formation of methemoglobin Hgb MKankakee Hgb MOldenburg Hgb MSendai Hgb MHydePark β92 (F8)His —→ Tyr Increased oxygen affinity, reduced heme interaction, normal Bohr effect, slightly unstable Cyanosis resulting from formation of methemoglobin, mild hemolytic anemia Hgb Milwaukee 2 Hgb MAkita Hgb MMilwaukee β67 (E11)Val —→ Glu Low oxygen affinity, reduced heme–heme interaction, normal Bohr effect, slightly unstable Cyanosis resulting from methemoglobin formation Hgb FMOsaka Gγ63His —→ Tyr Low oxygen affinity, increased Bohr effect. Methemoglobinemia Cyanosis at birth Hgb FMFortRipley Gγ92His —→ Tyr Slightly increased oxygen affinity Cyanosis at birth Source: Williams Hematology, 8th ed, Chap. 49, Table 49–2, p. 745. + LOW OXYGEN AFFINITY HEMOGLOBINS Download Section PDF Listen +++ ++ Some hemoglobin variants have a decreased oxygen affinity, and therefore, an abnormal proportion of the hemoglobin is not oxygenated. The result may be cyanosis and mild anemia, the latter resulting from the fact that the body perceives adequate oxygen delivery and erythropoietin levels are therefore decreased. Table 19–3 gives features and effects of low oxygen affinity hemoglobins. ++Table Graphic Jump LocationTABLE 19–3LOW-AFFINITY HEMOGLOBINSView Table||Download (.pdf) TABLE 19–3 LOW-AFFINITY HEMOGLOBINS Hemoglobin Amino Acid Substitution Oxygen Dissociation and Other Properties Clinical Effect HgbSeattle β70 (E14)Ala —→ Asp Decreased oxygen affinity normal heme-heme interaction Mild chronic anemia associated with reduced urinary erythropoietin; physiologic adaptation to more efficient oxygen release to tissues HgbKansas β102 (G4)Asn —→ Thr Very low oxygen affinity, low heme-heme interaction, dissociates into dimers in ligand form Cyanosis resulting from deoxyhemoglobin, mild anemia Source: Williams Hematology, 8th ed, Chap. 49, Table 49–3, p. 748. + SULFHEMOGLOBIN Download Section PDF Listen +++ ++ In vitro sulfhemoglobin can be produced by addition of hydrogen sulfide to hemoglobin. In vivo sulfhemoglobin can be induced in some individuals by ingestion of drugs or may occur without apparent cause. Cyanosis is present and occasionally mild hemolysis occurs. Sulfhemoglobinemia is usually well tolerated and does not affect overall health. Sulfhemoglobin cannot be changed back to normal hemoglobin. + CARBOXYHEMOGLOBIN Download Section PDF Listen +++ ++ Carbon monoxide (CO) is an odorless, colorless, and tasteless gas. It can be unknowingly inhaled to dangerous levels when present in high concentration in the atmosphere. Acute CO intoxication is one of the most common causes of morbidity as a result of poisoning in the United States. Sign and symptoms of CO poisoning are nonspecific. A high index of suspicion should attend the simultaneous presentation of multiple patients from the same housing complex. Common symptoms of mild to moderate CO poisoning are irritability, headache, nausea, lethargy, and sometimes a flu-like condition. Acute and severe poisoning can result in cerebral edema, pulmonary edema, cardiac arrhythmias that may be deadly and significant residual neurologic deficits may remain in survivors. The most important step in the treatment for CO poisoning is prompt removal of patients from the source of CO (for mild to moderate cases of CO poisoning) followed by administering 100 percent supplemental oxygen via a tight-fitting mask (in severe cases of CO poisoning). + NITRIC OXIDE-HEMOGLOBIN Download Section PDF Listen +++ ++ Nitric oxide (NO), a soluble gas, is continuously synthesized in endothelial cells by isoforms of the NO synthase (NOS) enzyme. Vasodilation is caused by diffusion of NO into the smooth muscle cells. According to the S-nitroso hemoglobin (SNO-Hb) hypothesis, this vasodilator function is carried by a population of hemoglobin that have undergone the addition of NO to a critical cysteine (cysβ93) via S-nitrosylation, forming SNO-Hb. The allosterically controlled equilibrium of NO groups between hemes and cysteine thiols enables erythrocytes to convey a graded signal for vasodilatation, thereby enhancing perfusion. Another mechanism by which Hb may be converted to SNO-Hb is by Hb function as nitrite reductase. Deoxygenated Hb reacts with nitrite to form NO and methemoglobin. Products of the nitrite-hemoglobin reaction generate NO, promote vasodilation, and form SNO-Hb. ++ For a more detailed discussion, see Neeraj Agarwal and Josef T. Prchal: Methemoglobinemia and Other Dyshemoglobinemias. Chap. 49, p. 743 in Williams Hematology, 8th ed.