Disorders of the hexose monophosphate shunt and glutathione metabolism other than glucose-6-phosphate dehydrogenase deficiency
- Bertil Glader, MD, PhD
Bertil Glader, MD, PhD
- Professor of Pediatrics
- Stanford University School of Medicine
The red blood cell is protected from oxidant injury via enzymes of the hexose monophosphate (HMP) shunt pathway and those of the glutathione synthetic and metabolic pathways (figure 1 and figure 2). The most common abnormality in this system is glucose-6-phosphate dehydrogenase deficiency, which can lead to varying degrees of hemolysis. This disorder is discussed in depth separately. (See "Genetics and pathophysiology of glucose-6-phosphate dehydrogenase deficiency" and "Clinical manifestations of glucose-6-phosphate dehydrogenase deficiency" and "Diagnosis and treatment of glucose-6-phosphate dehydrogenase deficiency".)
Abnormalities have been reported in several of the other enzymes in these two pathways, some of which are associated with increased red cell destruction (hemolysis). These disorders will be reviewed here.
6-PHOSPHOGLUCONATE DEHYDROGENASE DEFICIENCY
The enzyme 6-phosphogluconate dehydrogenase (6PGD) catalyzes the conversion of 6-phosphogluconate to ribulose-5-phosphate and carbon dioxide; in the process, NADPH is generated from NADP. Initial observations suggested that 6PGD deficiency does not alter red cell survival, presumably because NADPH is also generated by the proximal enzyme, glucose-6-phosphate dehydrogenase (G6PD). (See "Genetics and pathophysiology of glucose-6-phosphate dehydrogenase deficiency".)
While compensated hemolysis with episodic jaundice and possible oxidant sensitivity has been described in combination with partial 6PGD deficiency in two families [1,2], congenital 6PGD deficiency is generally not associated with any hematologic abnormalities. As an example, a mutant "Whitechapel" 6PGD has been described, transmitted as an autosomal recessive trait. Heterozygotes and homozygotes had 50 and 2 to 5 percent of normal enzyme activity, respectively . Neither heterozygotes nor homozygotes demonstrated clinical or hematologic abnormalities .
GLUTATHIONE REDUCTASE DEFICIENCY
Oxidized glutathione (GSSG) is reduced to glutathione (GSH) in the presence of NADPH by the enzyme glutathione reductase (GSSG-R) (figure 1) . This enzyme requires flavin adenine dinucleotide (FAD) as a cofactor and, as a result, normal enzyme activity is dependent upon the dietary availability of the water soluble vitamin riboflavin (vitamin B2) . (See "Overview of water-soluble vitamins", section on 'Vitamin B2 (riboflavin)'.)
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- 6-PHOSPHOGLUCONATE DEHYDROGENASE DEFICIENCY
- GLUTATHIONE REDUCTASE DEFICIENCY
- Acquired deficiency
- - Nutritional
- - Drug-induced
- Genetically determined deficiency
- GLUTATHIONE PEROXIDASE DEFICIENCY
- DEFECTS IN GLUTATHIONE SYNTHESIS
- Gamma-glutamyl-cysteine synthetase deficiency
- Glutathione synthetase deficiency
- - Management
- GLUTATHIONE S-TRANSFERASE DEFICIENCY
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