Handbook of Benign Hematology by unknow

Author:unknow
Language: eng
Format: epub
ISBN: 9780826149879
Publisher: Springer Publishing Company, Inc.
Published: 2019-12-09T21:00:00+00:00

NON-SICKLE HEMOGLOBINOPATHIES

Altered Oxygen Affinity

Hgb mutations that stabilize the R state of the Hgb tetramer or destabilize the T state result in a high-oxygen-affinity globin. These 249

can be mutations in the alpha or beta chain, and patients typically have erythrocytosis with autosomal dominant inheritance. EPO levels may be normal, but may also increase dramatically after phlebotomy. Diagnosis is made by measuring the P50, but this requires the ability to perform an oxygenation equilibrium curve, a specialized test performed in limited labs. Variants include Hgb Yakima, Ypsilanti, and Ranier (6).

Unstable Hgbs have mutations that interfere with the secondary, tertiary, or quaternary structure of the globin tetramer. Tetramer instability results in intracellular precipitates, which can be detected by a Heinz body stain similar to the precipitates seen with glucose 6-phosphate dehydrogenase (G6PD) deficiency and oxidant exposure. The isopropanol test is also used to screen for unstable Hgb. Hemolysis occurs and patients have anemia, reticulocytosis, pigmenturia, and splenomegaly (6).

Methemoglobin (Met-Hgb) is an altered state of Hgb in which heme’s ferrous (Fe++) iron is oxidized to the ferric (Fe+++) state. Methemoglobinemia can be congenital or acquired. Most cases of hereditary methemoglobinemia are autosomal recessive and are due to homozygous or compound heterozygous deficiency of cytochrome b5 reductase (nicotinamide adenine dinucleotide [NADH] is a cofactor). It is included here because of its association with cyanosis. Treatment, ironically, is with methylene blue, which uses an alternative enzyme NADPH-methemoglobin reductase to redox balance. Another congenital cause of methemoglobinemia is autosomal dominant HgbM (Milwaukee) disease due to mutations in either the alpha or beta or, rarely, gamma globin gene. In most of the mutations, tyrosine is substituted for either proximal or distal histidine in the heme pocket and forms a Fe3+–phenolate complex that resists reduction of Fe3+ heme iron to the divalent state. The result is lifelong methemoglobinemia. Administration of methylene blue does not correct this type of congenital methemoglobinemia. There is no effective treatment for the methemoglobinemia seen in this condition, but, in fact, no treatment is required as patients are not symptomatic—they are “more blue than sick” (6,28).

Acquired methemoglobinemia results from increased Met-Hgb formation by various exogenous agents including sulfa-containing medications, nitrates- and nitrites-containing medications, local anesthesia medications, and other chemicals (Table 8.5). A risk factor for acute acquired methemoglobinemia is the asymptomatic heterozygous state for cytochrome b5 reductase deficiency. Presence of abnormal Met-Hgb can be directly analyzed if there is clinical suspicion following the sudden onset of cyanosis with symptoms of hypoxia after administration or ingestion of an agent with oxidative potential. If the patient is symptomatic or if the Met-Hgb level is >20%, specific therapy is urgently indicated. The two treatments most often employed are methylene blue and ascorbic acid. Methylene blue is relatively contraindicated when the patient has G6PD deficiency (28).

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