Chapter 101. Hemolytic Anemias and Anemia Due to Acute Blood Loss (Part 9)

Pyruvate Kinase Deficiency: Treatment Management of PK deficiency is mainly supportive. In view of the marked increase in red cell turnover, oral folic acid supplements should be given constantly. Blood transfusion should be used as necessary, and iron chelation may have to be added if the blood transfusion requirement is high enough to cause iron overload. In these patients, who have more severe disease, splenectomy may be beneficial. There is a single case report of curative treatment of PK deficiency by bone marrow transplantation from an HLA-identical PK normal sib: this seems a viable option for severe cases when...
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Chapter 101. Hemolytic Anemias and Anemia Due to Acute Blood Loss (Part 9) Chapter 101. Hemolytic Anemias and Anemia Due to Acute Blood Loss (Part 9) Pyruvate Kinase Deficiency: Treatment Management of PK deficiency is mainly supportive. In view of the markedincrease in red cell turnover, oral folic acid supplements should be givenconstantly. Blood transfusion should be used as necessary, and iron chelation mayhave to be added if the blood transfusion requirement is high enough to cause ironoverload. In these patients, who have more severe disease, splenectomy may bebeneficial. There is a single case report of curative treatment of PK deficiency bybone marrow transplantation from an HLA-identical PK normal sib: this seems aviable option for severe cases when a sib donor is available. Other Glycolytic Enzyme Abnormalities All of these defects are rare to very rare (Table 101-4), and all cause HA ofvarying degrees of severity. It is not unusual for the presentation to be in the guiseof severe neonatal jaundice, which may require exchange transfusion; if theanemia is less severe, it may present later in life or may even remainasymptomatic and be detected incidentally when a blood count is done forunrelated reasons. The spleen is often enlarged. When other systemicmanifestations occur, they involve the central nervous system, sometimes entailingsevere mental retardation (particularly in the case of triose phosphate isomerasedeficiency) or the neuromuscular system, or both. The diagnosis of HA is usuallynot difficult, thanks to the triad of normo-macrocytic anemia, reticulocytosis, andhyperbilirubinemia. Enzymopathies should be considered in the differentialdiagnosis of any chronic Coombs-negative HA. In most cases of glycolyticenzymopathies, the morphologic abnormalities of red cells characteristically seenin membrane disorders are absent. A definitive diagnosis can be made only bydemonstrating the deficiency of an individual enzyme by quantitative assayscarried out in only a few specialized laboratories. If a particular molecularabnormality is already known in the family, then of course one could test directlyfor that defect at the DNA level, bypassing the need for enzyme assays. Abnormalities of Redox Metabolism G6PD Deficiency Glucose 6-phosphate dehydrogenase (G6PD) is a housekeeping enzymecritical in the redox metabolism of all aerobic cells (Fig. 101-4). In red cells, itsrole is even more critical because it is the only source of reduced nicotinamideadenine dinucleotide phosphate (NADPH), which, directly and via reducedglutathione (GSH), defends these cells against oxidative stress. G6PD deficiencyis a prime example of an HA due to interaction between an intracorpuscular and anextracorpuscular cause, because in the majority of cases hemolysis is triggered byan exogenous agent. Although in G6PD-deficient subjects there is a decrease inG6PD activity in most tissues, this is less marked than in red cells, and it does notseem to produce symptoms. Figure 101-4 Diagram of redox metabolism in the red cell. G6P, glucose 6-phosphate;6PG, 6-phosphogluconate; G6PD, glucose 6-phosphate dehydrogenase; GSH,reduced glutathione; GSSG, oxidized glutathione; Hb, hemoglobin; MetHb,methemoglobin; NADP, nicotinamide adenine dinucleotide phosphate; NADPH,reduced nicotinamide adenine dinucleotide phosphate. Genetic Considerations The G6PD gene is X-linked, and this has important implications. First, asmales have only one G6PD gene (i.e., they are hemizygous for this gene), theymust be either normal or G6PD-deficient. By contrast, females, having two G6PDgenes, can be normal, deficient (homozygous), or intermediate (heterozygous). Asa result of the phenomenon of X-chromosome inactivation, heterozygous femalesare genetic mosaics, with a highly variable ratio of G6PD-normal to G6PD-deficient cells and an equally variable degree of clinical expression; someheterozygotes can be just as affected as hemizygous males. The enzymaticallyactive form of G6PD is either a dimer or a tetramer of a single protein subunit of514 amino acids. G6PD-deficient subjects have been found invariably to havemutations in the coding region of the G6PD gene. Almost all of the 140 differentmutations known are single missense point mutations, entailing single amino acidreplacements in the G6PD protein. In most cases these mutations cause G6PDdeficiency by decreasing the in vivo stability of the protein, and thus thephysiologic decrease in G6PD activity that takes place with red cell ageing isgreatly accelerated. In some cases an amino acid replacement can also affect thecatalytic function of the enzyme. Among the mutations, those underlyin ...