Chapter 099. Disorders of Hemoglobin (Part 13)

Hemoglobin E HbE (i.e., α2β226Glu - Lys) is extremely common in Cambodia, Thailand, and Vietnam. The gene has become far more prevalent in the United States as a result of immigration of Asian persons, especially in California, where HbE is the most common variant detected. HbE is mildly unstable but not enough to affect RBC life span significantly. The high frequency of the HbE gene may be a result of the thalassemia phenotype associated with its inheritance. Heterozygotes resemble individuals with mild β-thalassemia trait. Homozygotes have somewhat more marked abnormalities but are asymptomatic. Compound heterozygotes for HbEand a β-thalassemia...
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Chapter 099. Disorders of Hemoglobin (Part 13) Chapter 099. Disorders of Hemoglobin (Part 13) Hemoglobin E HbE (i.e., α2β226Glu -> Lys) is extremely common in Cambodia, Thailand, andVietnam. The gene has become far more prevalent in the United States as a resultof immigration of Asian persons, especially in California, where HbE is the mostcommon variant detected. HbE is mildly unstable but not enough to affect RBClife span significantly. The high frequency of the HbE gene may be a result of thethalassemia phenotype associated with its inheritance. Heterozygotes resembleindividuals with mild β-thalassemia trait. Homozygotes have somewhat moremarked abnormalities but are asymptomatic. Compound heterozygotes for HbEand a β-thalassemia gene can have β-thalassemia intermedia or β-thalassemiamajor, depending on the severity of the coinherited thalassemic gene. The βE allele contains a single base change in codon 26 that causes theamino acid substitution. However, this mutation activates a cryptic RNA splicesite generating a structurally abnormal globin mRNA that cannot be translatedfrom about 50% of the initial pre-mRNA molecules. The remaining 40–50% arenormally spliced and generate functional mRNA that is translated into βE-globinbecause the mature mRNA carries the base change that alters codon 26. Genetic counseling of the persons at risk for HbE should focus on theinteraction of HbE with β-thalassemia rather than HbE homozygosity, a conditionassociated with asymptomatic microcytosis, hypochromia, and hemoglobin levelsrarely The two most important acquired hemoglobinopathies are carbon monoxidepoisoning and methemoglobinemia (see above). Carbon monoxide has a higheraffinity for hemoglobin than does oxygen; it can replace oxygen and diminish O 2delivery. Chronic elevation of carboxyhemoglobin levels to 10 or 15%, as occursin smokers, can lead to secondary polycythemia. Carboxyhemoglobin is cherry redin color and masks the development of cyanosis usually associated with poor O 2delivery to tissues. Abnormalities of hemoglobin biosynthesis have also been described inblood dyscrasias. In some patients with myelodysplasia, erythroleukemia, ormyeloproliferative disorders, a mild form of HbH disease may also be seen. Theabnormalities are not severe enough to alter the course of the underlying disease. Transfusional Hemosiderosis: Treatment Chronic blood transfusion can lead to blood-borne infection,alloimmunization, febrile reactions, and lethal iron overload (Chap. 107). A unit ofpacked RBCs contains 250–300 mg iron (1 mg/mL). The iron assimilated by asingle transfusion of two units of packed RBCs is thus equal to a 1- to 2-yearintake of iron. Iron accumulates in chronically transfused patients because nomechanisms exist for increasing iron excretion: an expanded erythron causesespecially rapid development of iron overload because accelerated erythropoiesispromotes excessive absorption of dietary iron. Vitamin C should not besupplemented because it generates free radicals in iron excess states. Patients who receive >100 units of packed RBCs usually develophemosiderosis. The ferritin level rises, followed by early endocrine dysfunction(glucose intolerance and delayed puberty), cirrhosis, and cardiomyopathy. Liverbiopsy shows both parenchymal and reticuloendothelial iron. The superconductingquantum-interference device (SQUID) is accurate at measuring hepatic iron butnot widely available. Cardiac toxicity is often insidious. Early development ofpericarditis is followed by dysrhythmia and pump failure. The onset of heartfailure is ominous, often presaging death within a year (Chap. 351). The decision to start long-term transfusion support should also prompt oneto institute therapy with iron-chelating agents. Desferoxamine (Desferal) is forparenteral use. Its iron-binding kinetics require chronic slow infusion via ametering pump. The constant presence of the drug improves the efficiency ofchelation and protects tissues from occasional releases of the most toxic fraction ofiron—low-molecular-weight iron—which may not be sequestered by protectiveproteins. Desferoxamine is relatively nontoxic. Occasional cataracts, deafness, andlocal skin reactions, including urticaria, occur. Skin reactions can usually bemanaged with antihistamines. Negative iron balance can be achieved, even in theface of a high transfusion requirement, but this alone does not prevent long-termmorbidity and mortality in chronically transfused patients. Irreversible end-organdeterioration develops at relatively modest levels of iron overload, even ifsymptoms do not appear for many years thereafter. To enjoy a significant survivaladvantage, chelation must begin before 5–8 years of age in β-thalassemia major.