[Studies on favism; production of favism phyto-agglutinin in rabbit; preliminary note].
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Agglutinins↗
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[Primaquine sensitivity in patients with favism; possibility of producing hemolytic episodes in patients with favism by the administration of primaquine].
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Antimalarials↗
[Experimental studies of favism in animals with G-6-P dehydrogenase deficiency in connection with 8 cases of favism].
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Adult↗
Marked decline of favism after neonatal glucose-6-phosphate dehydrogenase screening and health education: the northern Sardinian experience.
Favism is a potentially fatal manifestation of glucose-6-phosphate dehydrogenase (G6PD) deficiency, and it is therefore a public health problem in areas where this genetic abnormality is common. In the district of Sassari (northern Sardinia), the frequency of G6PD male hemizygotes is approximately 7.5%, and therefore all newborns since 1971 have been screened for G6PD deficiency. We have analyzed the incidence of favism in this community in two 10-year periods: (1) 1961-1970; and (2) 1981-1990. In period 1, there were 508 cases of favism, of which 76% occurred in boys. In period (2) there were 144 cases of favism, of which only 52% in boys. Thus, between the two periods there was an overall decrease in the incidence of favism of 75%, whereas the proportion of girls affected has approximately doubled. These data suggest that neonatal screening and health education programs can produce a substantial decrease in the number of cases of favism, and that the relative increase in favism in girls is possibly due to failure of the screening method used to detect all the heterozygotes for G6PD deficiency.
Child↗
Pathophysiology of favism.
Haemolytic crises occurring in G6PD-deficient individuals after ingestion of fava beans (favism) are much less frequent than in the past. However, favism is a unique natural model of oxidant damage in vivo, useful for the study of senescent or damaged red blood cells (RBC) clearance from circulation. The following aspects have been considered: 1. Pathophysiology of favism, including incidence, salient features, and sequence of events. 2. RBC alterations during the haemolytic crisis: biochemical, rheological and morphological alterations occurring in RBC isolated at different stages of the crisis. 3. Toxic substances of Vicia faba and their mechanism of action: treatment of G6PD-deficient RBC with divicine or isouramil (redox substances present in fava beans) provokes the same changes as observed during favism. 4. Intravascular vs. extravascular haemolysis: extravascular (i.e. phagocytic) removal of damages RBC seems predominant in favism. 5. The signal for RBC removal: in analogy with a recent model for recognition and removal of oxidant-stressed or senescent RBC, we propose removal of fava bean damaged RBC be mediated by apposition of antiband 3 antibodies and complement C3 fragments, recognized as non-self recognition signal by monocytes and macrophages.
Animals↗
Mechanisms of perturbation of erythrocyte calcium homeostasis in favism.
Favism is an acute hemolytic anemia triggered by ingestion of fava beans in genetically susceptible subjects with severe deficiency of glucose-6-phosphate dehydrogenase (G6PD) activity. Erythrocytes from 10 favic patients had constantly and markedly increased calcium levels, as compared with values detected in 4 asymptomatic G6PD-deficient controls. Correspondingly, the calcium permeability of erythrocytes, estimated as the fraction of intracellular calcium exchangeable with externally added 45Ca2+, was invariably enhanced in favism and returned to normal patterns after several months from the acute hemolytic crisis. In favic patients, the levels of erythrocyte calcium ATPase activities showed wide variability, ranging from 2.0-12.9 mumol Pi/ml RBC/h, while control values in asymptomatic G6PD-deficient subjects were 10.62 +/- 2.03 mumol Pi/ml RBC/h. Analysis of the calcium ATPase in situ in erythrocyte membranes from favic patients showed the same molecular mass of 134 kD as observed in the control subjects. Exposure of G6PD-deficient erythrocytes in vitro to autoxidizing divicine, a pyrimidine aglycone strongly implicated in the pathogenesis of favism which leads to late accumulation of intracellular calcium, caused: (i) a marked inactivation of calcium ATPase, without changes in the molecular mass of 134 kD; and (ii) the concomitant loss of spectrin, band 3 and band 4.1, all known substrates of the calcium activated procalpain-calpain proteolytic system. Thus, the increased intraerythrocytic calcium apparently results in the degradation of calcium ATPase observed in some favic patients. It is proposed that both enhanced calcium permeability and a calcium-stimulated degradation of the calcium pump are the mechanisms responsible for the perturbation of erythrocyte calcium homeostasis in favism.
Calcimycin↗
Favism: divicine hemotoxicity in the rat.
Favism is an acute hemolytic anemia known to occur in susceptible individuals who ingest fava beans. Susceptibility to favism is conferred by a genetic deficiency in erythrocytic glucose-6-phosphate dehydrogenase (G6PD) activity. Although the fava bean pyrimidine aglycones, divicine and isouramil, have been implicated in the onset of favism in humans, the lack of a well-defined experimental animal model for favism has hampered progress in elucidating the mechanism underlying hemotoxicity. We have examined whether a favic-like response could be provoked in G6PD-normal rats treated with synthetic divicine. Intraperitoneal administration of divicine to rats preloaded with 51Cr-tagged erythrocytes resulted in a severe, dose-dependent decrease in blood radioactivity (TD50 approximately 0.5 mmol/kg) within 24 h. The increased rate of removal of blood radioactivity was accompanied by a rapid decline in reduced glutathione levels in the blood, decreased hematocrits, marked hemoglobinuria, splenic enlargement, and reticulocytosis. In vitro exposure of 51Cr-tagged red cells to divicine before their re-administration to isologous rats also resulted in a sharp, concentration-dependent decrease in erythrocyte survival in vivo (TC50 approximately 1.5 mM), and these divicine-damaged red cells were removed from the circulation by the spleen. These data demonstrate that a favic response can be induced in G6PD-normal rats treated with divicine, and that hemolytic activity can be reproduced in isolated red cells under conditions that will allow a direct examination of the mechanism underlying this hemotoxicity.
Animals↗
Favism: looking for an autosomal gene associated with glucose-6-phosphate dehydrogenase deficiency.
Favism is a severe, acute haemolytic anaemia which occurs in about 20% of G6PD deficient subjects after ingestion of fava beans. Since not all G6PD deficient subjects are sensitive to fava beans, the possibility has been suggested that extra erythrocytic factors may play an important role in the susceptibility to haemolytic favism. To test the hypothesis that an autosomal enzyme is involved in the pathogenesis of favism, we carried out a beta-glucosidase assay in small intestine biopsies from normal subjects and G6PD deficient subjects with or without favism. Beta-glucosidase might be involved in the absorption and metabolism of fava beans and a quantitative polymorphism could explain the different susceptibility to fava beans of G6PD deficient subjects. Our observation showed no consistent quantitative polymorphism of beta-glucosidase in the subjects examined.
Favism↗
Favism, with special reference to Iran.
Fava beans (Vicia fava) are cultivated rather widely in most countries of the Eastern Mediterranean area and provide a cheap but protein-rich food that can be eaten alone, in various culinary preparations, including bread, or as a dietary supplement. However, the ingestion of fava beans may induce a haemolytic disease-favism-in some susceptible individuals and this might appear to limit the use of this pulse crop in those regions where favism occurs frequently. The uses of fava beans in Iran, the characteristics of favism and the present state of knowledge of the pathology of the disease are reviewed in this paper. Although some progress has been made in identifying the toxic substances and in explaining their mode of action, our understanding of favism is still limited. It appears that the disease is seen particularly in young children and is associated with a deficiency of glucose-6-phosphate dehydrogenase (G6PD) in the blood.
Child↗
Biological activities of broad bean (Vicia faba L.) extracts cultivated in South Anatolia in favism sensitive subjects.
Aqueous extracts of a different variety of fresh broad bean seeds obtained from a favism endemic area in Turkey, were incubated with blood from sensitive and non-sensitive (control) subjects. Red blood cells were characterized by a whole blood glutathione (GSH) and a deficiency of Glucose-6-phosphate dehydrogenase (G-6-PD) activity. As the decrease in GSH percent is taken as an index of haemolytic activity, the test results were as following: Sakiz , Milas -Region, French broad bean extracts reduced the blood GSH levels 48%, 70%, 46% and 53%, respectively, in favism sensitive subjects. Active principles which are responsible for the haemolysis ( Vicine and Convicine ) were isolated from broad beans and their effects on GSH levels of blood were 99% and 81%, respectively, in favism sensitive subjects and 33.3% and 19% in normal subjects.
Fabaceae↗
Favism: a hemolytic disease associated with increased superoxide dismutase and decreased glutathione peroxidase activities in red blood cells.
Red blood cells of favism patients with acute hemolytic crisis have markedly more superoxide dismutase (superoxide:superoxide oxidoreductase, EC 1.15.1.1) and less glutathione peroxidase (glutathione:hydrogenperoxide oxidoreductase, EC 1.11.1.9) than either normal controls, glucose-6-phosphate dehydrogenase-deficient subjects or favism patients outside hemolytic crisis. This altered value of the two enzyme activities is not due to increased reticulocyte content of blood. The electrophoretic triplet pattern of superoxide dismutase is also changed, with significant increase of the most positively charged band. Similar modifications of the two enzyme activities are observed after treatment of normal red blood cells with high concentrations of divicine and ascorbate, which are redox compounds that are contained in fava seeds. This treatment produces no hemolysis, but leads to hemolysis if the treated cells are resuspended in the homologous plasma. These results suggest a possible role of active oxygen species in the development of favism.
Ascorbic Acid↗
Lactose absorption in patients with glucose 6-phosphate dehydrogenase deficiency with and without favism.
BACKGROUND: It has recently been suggested that primary lactase deficiency might have been selected for by malaria, as has been previously shown to occur for thalasaemia and glucose 6-phosphate dehydrogenase (G6PD) deficiency. AIMS: To test this hypothesis, the prevalence of primary lactase deficiency in G6PD deficient subjects and in controls from the area of Sassari (Northern Sardinia) was determined, which in the past was characterised by an intermediate malarial endemicity. SUBJECTS: 70 adult subjects with G6PD deficiency, 34 of whom had a past history of favism, and 50 age matched control subjects. METHODS: The capacity to absorb lactose was assessed by measuring breath hydrogen production after oral administration of lactose (50 g) by a gas chromatographic method. RESULTS: Twenty per cent of G6PD deficient subjects with a positive history of favism and 22% of G6PD deficient subjects without a positive history of favism were lactose absorbers compared with 14% lactose absorbers in the control group. The differences were not statistically significant. CONCLUSIONS: These data show that the prevalence of primary lactase deficiency in the area of Sassari is relatively high, but comparable to that seen in the adult population from another area of southern Italy (Naples) where malaria was less endemic.
Adult↗
Ahaptoglobinemia in Favism patients from Iran.
Haptoglobin patterns were studied in Favism patients (n = 361). G6PD deficients (n = 42) and healthy controls (n = 168). A high frequency of ahaptoglobinemia (79.50%) was found in Favism patients. No such type was detected in the G6PD deficients and the control group. In the Favism patients, the Hp2-1 and Hp2-2 patterns exhibited the normal and weak (Hypo) type, whereas the G6PD deficient and normal samples did not show such a differentiation. The Hp2 allele frequency was noted to be slightly higher in the G6PD deficient persons.
Favism↗
The epidemiology of favism.
Favism is a potential obstacle to the use of the fava bean in the development of a locally produced, inexpensive weaning food for the Middle East and North Africa. The purposes of this study were to define the epidemiology of favism, to evaluate the advisability of using the fava bean in a weaning food, and to suggest ways of avoiding or eliminating the toxic factor in the bean. Field observations, locally acquired data, and a literature review suggested that the use of the fava bean in a weaning food would be hazardous, but that the hazard might be overcome by using certain strains of the bean or, more particularly, by using old dried beans. The disease is usually directly related in time to the harvesting and availability of fresh beans, but it is also associated with fresh dried beans. On the basis of the age distribution of the disease, patterns of bean consumption, and local food taboos it appears that the toxic factor is concentrated in the skin of the bean, that it is heat-stable, that in dried beans it decreases with age, and that it crosses into the breast milk of lactating mothers. It also appears that disease expression may be a result of the interaction of several host factors, such as nutritional status and the consumption of other foods. These observations are consistent with the results of laboratory studies, which incriminate vicine, divicine, and DOPA in the etiology of favism.
Adolescent↗
Heterogeneity of "Mediterranean type" glucose-6-phosphate dehydrogenase (G6PD) deficiency in Spain and description of two new variants associated with favism.
Glucose-6-phosphate dehydrogenase (G6PD); EC 1.1.1.49 from thirty-six unrelated Spanish males was partially purified from blood, and the variants were characterized biochemically and electrophoretically according to the methods recommended by the world Health Organization. Subjects were from multiple geographic regions within Spain, and all suffered from hemolytic anemia, either acute (34 cases) or chronic nonspherocytic (2 cases). Almost all the variants studied presented residual erythrocyte G6PD activity ranging from 0 to 10% of normal, and five different mutants were responsible for the deficient phenotype. Three variants were similar to others previously described: G6PD Mediterranean (11 cases), G6PD Athens-like (3 cases), and G6PD Union (2 cases). The remaining variants were different from the numerous variants already reported and have been considered as new mutants. Provisionally they are called G6PD Betica (19 cases) and G6PD Menorca (1 case). The present study constitutes the first attempt to characterize the deficient G6PD variants found in Spain and supplies new data on the relationship between molecular characteristics of deficient variants and their clinical manifestations. The most important findings can be summarized as follows: (1) The Spanish population is characterized by an important heterogeneity in G6PD deficiency. (2) Although G6PD Mediterranean is very frequent, it presents a relatively high degree of polymorphism. (3) Favism has been observed associated with all kinds of variants described here. (4) G6PD Betica, which is the most frequent variant found in subjects of Southern Spanish origin, has been observed associated with favism in all cases except one.
Adolescent↗
Malaria, favism and glucose-6-phosphate dehydrogenase deficiency.
Although glucose-6-phosphate dehydrogenase deficient individuals may suffer (sometimes fatally) from favism, a high incidence of this trait occurs in many Mediterranean populations. This apparent paradox is explained on the basis of a synergistic interaction between favism and G-6-PD deficiency that provides increased protection against malaria compared to that of the G-6-PD deficiency alone. This relationship is analogous to that between various hemoglobins and malaria in that there is selection for a more severe trait if it provides more protection against malaria.
Favism↗
Effect of factors of favism on the protein and lipid components of rat erythrocyte membrane.
Erythrocytes prepared from riboflavin- and tocopherol-deficient (RT-) and from control rats were used to investigate the mechanism of oxidative hemolysis by the factors of favism. RT- erythrocytes have a defense system against the oxidative stress which is blocked either where regeneration of GSH occurs or the scavenging of the radicals from the membrane is prevented. The oxidative factors used were isouramil, divicine and diamide. When RT- erythrocytes were treated with isouramil, GSH decreased to undetectable levels and was not regenerated. Complete hemolysis occurred, but no oxidation of SH groups of membrane proteins or formation of spectrin polymers was detected. A similar effect was observed with diamide. However, SH groups of membrane proteins were completely oxidized and spectrin polymers were formed. Extensive lipid peroxidation was also detected together with a 30% fall in the arachidonic acid level. Control erythrocytes treated with either isouramil or diamide were not hemolyzed. When treated with isouramil, after a fall in the first few minutes, the GSH level was completely regenerated after 20 min. Incubation with diamide caused extensive oxidation of SH groups of membrane proteins and formation of spectrin polymers. No lipid peroxidation was detected after treatment with isouramil, but the same decrease of arachidonic acid occurred as in RT- erythrocytes. These results support the hypothesis that oxidative hemolysis by the factors of favism is caused by uncontrolled peroxidation of membrane lipids.
Animals↗
Transition metals mediate enzymatic inactivation caused by favism-inducing agents.
Enzymatic activity of purified or membrane-bound acetylcholine esterase was lost when incubated aerobically in the presence of both favism-inducing agent (isouramil or divicine) and copper ions. The requirement for oxygen could be substituted by hydrogen peroxide. Chelating agents provided total protection to the proteins. The suggested mechanism of enzymatic inactivation is analogous to that suggested earlier for the effects of superoxide and ascorbate, and involves the site-specific formation of hydroxyl radicals in the metal-mediated Haber-Weiss reaction. These findings may be relevant to the understanding of the pathogenesis of favism.
Ascorbic Acid↗