Chapter 099. Disorders of Hemoglobin (Part 4)

Epidemiology Hemoglobinopathies are especially common in areas in which malaria is endemic. This clustering of hemoglobinopathies is assumed to reflect a selective survival advantage for the abnormal RBC, which presumably provide a less hospitable environment during the obligate RBC stages of the parasitic life cycle. Very young children with αthalassemia are more susceptible to infection with the nonlethal Plasmodium vivax. Thalassemia might then favor a natural protection against infection with the more lethal P. falciparum.Thalassemias are the most common genetic disorders in the world, affecting nearly 200 million people worldwide. About 15% of American blacksare silent carriers for α...
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Chapter 099. Disorders of Hemoglobin (Part 4) Chapter 099. Disorders of Hemoglobin (Part 4) Epidemiology Hemoglobinopathies are especially common in areas in which malaria isendemic. This clustering of hemoglobinopathies is assumed to reflect a selectivesurvival advantage for the abnormal RBC, which presumably provide a lesshospitable environment during the obligate RBC stages of the parasitic life cycle.Very young children with αthalassemia are more susceptible to infection with thenonlethal Plasmodium vivax. Thalassemia might then favor a natural protectionagainst infection with the more lethal P. falciparum. Thalassemias are the most common genetic disorders in the world,affecting nearly 200 million people worldwide. About 15% of American blacksare silent carriers for α thalassemia; α-thalassemia trait (minor) occurs in 3% ofAmerican blacks and in 1–15% of persons of Mediterranean origin. Β-Thalassemia has a 10–15% incidence in individuals from the Mediterranean andSoutheast Asia and 0.8% in American blacks. The number of severe cases ofthalassemia in the United States is about 1000. Sickle cell disease is the mostcommon structural hemoglobinopathy occurring in heterozygous form in ~8% ofAmerican blacks and in homozygous form in 1 in 400. Between 2 and 3% ofAmerican blacks carry a hemoglobin C allele. Inheritance and Ontogeny Hemoglobinopathies are autosomal co-dominant traits—compoundheterozygotes who inherit a different abnormal mutant allele from each parentexhibit composite features of each. For example, patients inheriting sickle β-thalassemia exhibit features of β-thalassemia and sickle cell anemia. The α-chainis present in HbA, HbA2, and HbF; α-chain mutations thus cause abnormalities inall three. The α-globin hemoglobinopathies are symptomatic in utero and afterbirth because normal function of the α-globin gene is required throughoutgestation and adult life. In contrast, infants with β-globin hemoglobinopathies tendto be asymptomatic until 3–9 months of age, when HbA has largely replaced HbF. Detection and Characterization of Hemoglobinopathies—GeneralMethods Of the many methods available for hemoglobin analysis, electrophoretictechniques are used for routine clinical purposes. Electrophoresis at pH 8.6 oncellulose acetate membranes is especially simple, inexpensive, and reliable forinitial screening. Agar gel electrophoresis at pH 6.1 in citrate buffer is often usedas a complementary method because each method detects different variants.Comparison of results obtained in each system usually allows unambiguousdiagnosis, but some important variants are electrophoretically silent. These mutanthemoglobins can usually be characterized by more specialized techniques such asisoelectric focusing and/or high-pressure liquid chromatography (HPLC). Quantitation of the hemoglobin profile is often desirable. HbA2 isfrequently elevated in β-thalassemia trait and depressed in iron deficiency. HbF iselevated in HPFH, some β-thalassemia syndromes, and occasional periods oferythroid stress or marrow dysplasia. For characterization of sickle cell trait, sicklethalassemia syndromes, or HbSC disease, and for monitoring the progress ofexchange transfusion therapy to lower the percentage of circulating HbS,quantitation of individual hemoglobins is also required. In most laboratories,quantitation is performed only if the test is specifically ordered. Because some variants can comigrate with HbA or HbS (sicklehemoglobin), electrophoretic assessment should always be regarded as incompleteunless functional assays for hemoglobin sickling, solubility, or oxygen affinity arealso performed, as dictated by the clinical presentation. The best sickling assaysinvolve measurement of the degree to which the hemoglobin sample becomesinsoluble, or gelated, as it is deoxygenated (i.e., sickle solubility test). Unstablehemoglobins are detected by their precipitation in isopropanol or after heating to50°C. High-O2 affinity and low-O2 affinity variants are detected by quantitatingthe P50, the partial pressure of oxygen at which the hemoglobin sample becomes50% saturated with oxygen. Direct tests for the percent carboxyhemoglobin andmethemoglobin, employing spectrophotometric techniques, can readily beobtained from most clinical laboratories on an urgent basis. Complete characterization, including amino acid sequencing or genecloning and sequencing, is available from several investigational laboratoriesaround the world. Polymerase chain reaction (PCR), allele-specificoligonucleotide hybridization, and automated DNA sequencing allowidentification of globin gene mutations in a few days. Laboratory evaluation remains an adjunct, rather than the primarydiagnostic aid. Diagnosis is best established by recognition of a characteristichistory, physical findings, peripheral blood smear morphology, and abnormalitiesof the complete blood cell count (e.g., profound microcytosis with minimal anemiain thalassemia trait).