Low red blood cell glutathione reductase and pyridoxine phosphate oxidase activities not related to dietary riboflavin: selection by malaria?

This study was designed to confirm that low dietary riboflavin does not contribute to the flavin-deficient red blood cells commonly found in subjects in Ferrara Province, northern Italy. In this area it is primarily an inherited characteristic believed to have been selected for by malaria, which was endemic from the 12th century. In parallel with assessment of daily riboflavin intake (DRI), flavin adenine dinucleotide-dependent glutathione reductase (EGR) and flavin mononucleotide-dependent pyridoxine phosphate oxidase (PPO) were measured in beta-thalassemic heterozygotes, their normal relatives, and normal spouses (representative of the normal population). In all of these groups there is a high incidence of deficiency of these flavin enzymes. We found that the majority had an adequate riboflavin intake and there was no significant correlation of EGR and PPO activities with DRI. Thus, interpretation of low EGR activity is discussed with reference to studies of EGR done to detect nutritional riboflavin deficiency in countries where there is malnutrition and endemic malaria.

Deficiency of two red-cell flavin enzymes in a population in Sardinia: was glutathione reductase deficiency specifically selected for by malaria?

In two areas in Italy where malaria was endemic--in the Po delta and Maremma on the west coast--we have found a high prevalence of an inherited flavin-deficient red cell in the normal population, suggesting selection by malaria. This study in Sardinia enabled a direct comparison of red-cell activities of FAD-dependent glutathione reductase (EGR) and FMN-dependent pyridoxine phosphate (PNP) oxidase in an ethnically homogeneous population, between two coastal villages where malaria was endemic from 300 B.C. and two mountain villages with no history of malaria. Both enzyme activities were significantly lower on the coast, and it did not seem that this could be explained by possible small differences in dietary riboflavin. As was thought to be the case in Ferrara and Grosseto, it is probable that a genetically controlled flavin-deficient red cell was selected for by malaria. Low EGR apoenzyme activity was more common on the coast, usually explaining the accompanying low basic EGR activity, and may also have been selected for by malaria. This adds to evidence from others that the mechanism of defence of a flavin-deficient red cell against malaria may be through EGR deficiency. It could also play a part in the protection given by heterozygous beta-thalassemia. The multifactorial protection of the population against malaria is discussed.

Is the flavin-deficient red blood cell common in Maremma, Italy, an important defense against malaria in this area?

There is a high prevalence of a familial flavin-deficient red blood cell in Ferrara province in the Po delta in northern Italy, believed to have been selected for by malaria which was endemic from the 12th century. In the present study, activities of FAD-dependent red-cell glutathione reductase (EGR) in the Grosseto area of Maremma on the west coast of Italy where malaria was endemic from 300 B.C. are compared both with activities in the Ferrara area and with activities where there was no history of endemic malaria--in the Florence area and in London in people of Anglo-Saxon origin. EGR activities were similar in Grosseto and Ferrara and were significantly lower than in Florence and London. As previously found in Ferrara, low EGR activity in Grosseto was shown to be unrelated to low dietary riboflavin intake. These findings in Grosseto, suggesting selection by malaria, are particularly interesting because, unlike the situation in Ferrara and most other malarial areas, the prevalence of thalassemia and glucose-6-phosphate dehydrogenase deficiency is very low, and they do not appear to have been selected for in Maremma. It is possible that a flavin-deficient red cell, known to inhibit growth of the malaria parasite, was an important protecting factor in the population of this area over the centuries.

Pattern of iron excretion in relation to haemoglobin level and iron load in 8 haematological patients following the administration of subcutaneous deferrioxamine.

Iron excretion following subcutaneous administration of deferrioxamine (DFO) was measured between two transfusions of packed red cells in 6 patients with beta-thalassaemia major on the high level Hb transfusion regime; and in a single 3-day period in 2 other patients, 1 with transfused beta-thalassaemia major and the other with haemolytic anaemia due to PK deficiency. The pattern of iron excretion did not change significantly during the period between the two transfusions and was found to be related to serum ferritin levels. The proportion of iron excreted in the stools was inversely related to the serum ferritin level. These observations on iron excretion are of practical importance in relation to DFO administration, especially when evaluated in thalassaemics with normal haemoglobin levels and low iron stores.