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 "Diagnosis and management 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.
RED CELL CHANGES IN OXIDANT STATES
When disorders of the hexose monophosphate shunt and glutathione metabolism result in anemia, this happens because of oxidant damage to circulating red cells with resultant decreased survival (ie, increased hemolysis), with the following changes.
●Biochemical – Increased hemolysis is associated with increases in indirect bilirubin and lactate dehydrogenase and reductions in haptoglobin, and is usually accompanied by an abrupt fall in hemoglobin if hemolysis is severe. If intravascular hemolysis is present, there will be hemoglobinuria, dark urine, and the presence of hemosiderin-laden cells in the urine sediment.
●Red cell changes – Red cell changes in oxidant-related hemolysis include the presence of microspherocytes, red cell fragments, and eccentrocytes or "bite cells" (picture 1). Special stains document the production of Heinz bodies, which are collections of denatured globin chains often attached to the red cell membrane. If and when the bone marrow responds to the acute anemia, there will be an increase in reticulocytes.
- Caprari P, Caforio MP, Cianciulli P, et al. 6-Phosphogluconate dehydrogenase deficiency in an Italian family. Ann Hematol 2001; 80:41.
- Vives Corrons JL, Colomer D, Pujades A, et al. Congenital 6-phosphogluconate dehydrogenase (6PGD) deficiency associated with chronic hemolytic anemia in a Spanish family. Am J Hematol 1996; 53:221.
- Parr CW, Fitch LI. Inherited quantitative variations of human phosphogluconate dehydrogenase. Ann Hum Genet 1967; 30:339.
- Dern RJ, Brewer GJ, Tashian RE, Shows TB. Hereditary variation of erythrocytic 6-phosphogluconate dehydrogenase. J Lab Clin Med 1966; 67:255.
- Krauth-Siegel RL, Blatterspiel R, Saleh M, et al. Glutathione reductase from human erythrocytes. The sequences of the NADPH domain and of the interface domain. Eur J Biochem 1982; 121:259.
- Cole HS, Lopez R, Epel R, et al. Nutritional deficiencies in institutionalized mentally retarded and physically disabled individuals. Am J Ment Defic 1985; 89:552.
- Frischer H. Erythrocytic glutathione reductase deficiency in a hospital population in the United States. Am J Hematol 1977; 2:327.
- Warsy AS, el-Hazmi MA. Glutathione reductase deficiency in Saudi Arabia. East Mediterr Health J 1999; 5:1208.
- Frischer H, Ahmad T. Consequences of erythrocytic glutathione reductase deficiency. J Lab Clin Med 1987; 109:583.
- Mojzikova R, Dolezel P, Pavlicek J, et al. Partial glutathione reductase deficiency as a cause of diverse clinical manifestations in a family with unstable hemoglobin (Hemoglobin Haná, β63(E7) His-Asn). Blood Cells Mol Dis 2010; 45:219.
- Frischer H, Ahmad T. Severe generalized glutathione reductase deficiency after antitumor chemotherapy with BCNU" [1,3-bis(chloroethyl)-1-nitrosourea]. J Lab Clin Med 1977; 89:1080.
- Sagone AL Jr, Burton GM. The effect of BCNU and adriamycin on normal and G6PD deficient erythrocytes. Am J Hematol 1979; 7:97.
- Loos H, Roos D, Weening R, Houwerzijl J. Familial deficiency of glutathione reductase in human blood cells. Blood 1976; 48:53.
- Kamerbeek NM, van Zwieten R, de Boer M, et al. Molecular basis of glutathione reductase deficiency in human blood cells. Blood 2007; 109:3560.
- Roos D, Weening RS, Voetman AA, et al. Protection of phagocytic leukocytes by endogenous glutathione: studies in a family with glutathione reductase deficiency. Blood 1979; 53:851.
- Kumar D, Lim JC, Donaldson PJ. A link between maternal malnutrition and depletion of glutathione in the developing lens: a possible explanation for idiopathic childhood cataract? Clin Exp Optom 2013; 96:523.
- Pretsch W. Glutathione reductase activity deficiency in homozygous Gr1a1Neu mice does not cause haemolytic anaemia. Genet Res 1999; 73:1.
- Steinberg M, Brauer MJ, Necheles TF. Acute hemolytic anemia associated with erythrocyte glutathione-peroxidase deficiency. Arch Intern Med 1970; 125:302.
- Boivin P, et al. Anemie hemolytique avec deficit en glutathion-peroxidase chez un adulte. Enzyme 1969; 10:68.
- Gondo H, Ideguchi H, Hayashi S, Shibuya T. Acute hemolysis in glutathione peroxidase deficiency. Int J Hematol 1992; 55:215.
- Nishimura Y, Chida N, Hayashi T, Arakawa T. Homozygous glutathione-peroxidase deficiency of erythrocytes and leukocytes. Tohoku J Exp Med 1972; 108:207.
- Glader BE, Conrad ME. Decreased glutathione peroxidase in neonatal erythrocytes: lack of relation to hydrogen peroxide metabolism. Pediatr Res 1972; 6:900.
- Miwa S, Nakashima K, Ariyoshi K, et al. Heterozygous erythrocyte glutathione peroxidase deficiency associated with neonatal hyperbilirubinemia found in a Japanese family. Nihon Ketsueki Gakkai Zasshi 1974; 37:266.
- Whaun JM, Oski FA. Relation of red blood cell glutathione peroxidase to neonatal jaundice. J Pediatr 1970; 76:555.
- Gross RT, Bracci R, Rudolph N, et al. Hydrogen peroxide toxicity and detoxification in the erythrocytes of newborn infants. Blood 1967; 29:481.
- Beutler E, Matsumoto F. Ethnic variation in red cell glutathione peroxidase activity. Blood 1975; 46:103.
- Thomson CD, Robinson MF, Campbell DR, Rea HM. Effect of prolonged supplementation with daily supplements of selenomethionine and sodium selenite on glutathione peroxidase activity in blood of New Zealand residents. Am J Clin Nutr 1982; 36:24.
- Thomson CD, Rea HM, Doesburg VM, Robinson MF. Selenium concentrations and glutathione peroxidase activities in whole blood of New Zealand residents. Br J Nutr 1977; 37:457.
- Ristoff E, Larsson A. Inborn errors in the metabolism of glutathione. Orphanet J Rare Dis 2007; 2:16.
- Hirono A, Iyori H, Sekine I, et al. Three cases of hereditary nonspherocytic hemolytic anemia associated with red blood cell glutathione deficiency. Blood 1996; 87:2071.
- Beutler E, Gelbart T, Kondo T, Matsunaga AT. The molecular basis of a case of gamma-glutamylcysteine synthetase deficiency. Blood 1999; 94:2890.
- Hamilton D, Wu JH, Alaoui-Jamali M, Batist G. A novel missense mutation in the gamma-glutamylcysteine synthetase catalytic subunit gene causes both decreased enzymatic activity and glutathione production. Blood 2003; 102:725.
- Richards F 2nd, Cooper MR, Pearce LA, et al. Familial spinocerebellar degeneration, hemolytic anemia, and glutathione deficiency. Arch Intern Med 1974; 134:534.
- Konrad PN, Richards F 2nd, Valentine WN, Paglia DE. -Glutamyl-cysteine synthetase deficiency. A cause of hereditary hemolytic anemia. N Engl J Med 1972; 286:557.
- Beutler E, Moroose R, Kramer L, et al. Gamma-glutamylcysteine synthetase deficiency and hemolytic anemia. Blood 1990; 75:271.
- Mañú Pereira M, Gelbart T, Ristoff E, et al. Chronic non-spherocytic hemolytic anemia associated with severe neurological disease due to gamma-glutamylcysteine synthetase deficiency in a patient of Moroccan origin. Haematologica 2007; 92:e102.
- Njålsson R. Glutathione synthetase deficiency. Cell Mol Life Sci 2005; 62:1938.
- Larsson A, Anderson ME. Glutathione synthetase deficiency and other disorders of the gamma-glutamyl cycle. In: The Metabolic and Molecular Bases of Inherited Disease, 8th ed, Scriver CR, Beaudet AL, Sly WS, et al. (Eds), McGraw-Hill, New York 2001. p.2205.
- Mohler DN, Majerus PW, Minnich V, et al. Glutathione synthetase deficiency as a cause of hereditary hemolytic disease. N Engl J Med 1970; 283:1253.
- Beutler E, Gelbart T, Pegelow C. Erythrocyte glutathione synthetase deficiency leads not only to glutathione but also to glutathione-S-transferase deficiency. J Clin Invest 1986; 77:38.
- Spielberg SP, Kramer LI, Goodman SI, et al. 5-oxoprolinuria: biochemical observations and case report. J Pediatr 1977; 91:237.
- Skullerud K, Marstein S, Schrader H, et al. The cerebral lesions in a patient with generalized glutathione deficiency and pyroglutamic aciduria (5-oxoprolinuria). Acta Neuropathol 1980; 52:235.
- Prchal JT, Crist WM, Roper M, Wellner VP. Hemolytic anemia, recurrent metabolic acidosis, and incomplete albinism associated with glutathione synthetase deficiency. Blood 1983; 62:754.
- Simon E, Vogel M, Fingerhut R, et al. Diagnosis of glutathione synthetase deficiency in newborn screening. J Inherit Metab Dis 2009; 32 Suppl 1:S269.
- Boxer LA, Oliver JM, Spielberg SP, et al. Protection of granulocytes by vitamin E in glutathione synthetase deficiency. N Engl J Med 1979; 301:901.
- Wiencke JK, Kelsey KT, Lamela RA, Toscano WA Jr. Human glutathione S-transferase deficiency as a marker of susceptibility to epoxide-induced cytogenetic damage. Cancer Res 1990; 50:1585.
- Beutler E, Dunning D, Dabe IB, Forman L. Erythrocyte glutathione S-transferase deficiency and hemolytic anemia. Blood 1988; 72:73.
- RED CELL CHANGES IN OXIDANT STATES
- 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
- AVAILABLE REFERENCE LABORATORIES