Clinical Pearls & Morning Reports
Favism is by far the most common form of glucose-6-phosphate dehydrogenase (G6PD) deficiency–related acute hemolytic anemia. Since in Europe and the United States the incidence of autoimmune acute hemolytic anemia is estimated to be on the order of 1 case per 50,000 population, favism is also one of the most common types of acute hemolytic anemia, especially among children. Read the lastest NEJM Review Article.
Q: Where is favism most prevalent?
A: Favism occurs commonly only where the frequency of G6PD deficiency is relatively high and where fava beans (also known as broad beans) are a popular food item, which reflects its bifactorial nature. This is true, for instance, in southern Europe, in the Middle East, and in Southeast Asia but not, for example, in northern Germany, where fava beans are grown but G6PD deficiency is rare, or for instance, in West Africa, where G6PD deficiency has a high prevalence but fava beans are not grown.
Q: Where is the G6PD gene located?
A: The G6PD gene maps to the subtelomeric region of the long arm of the X chromosome, and it is subject to the phenomenon of X-chromosome inactivation. In most cases, the patient presenting with an attack of favism is a boy between the ages of 2 and 10 years who is brought to the emergency department because he appears to be quite ill, with pallor, jaundice, abdominal pain, and often fever. The parents, if asked, almost always report that their son has dark urine and has eaten fava beans. Any series of patients with favism also includes females, most of whom are heterozygous. In a heterozygous female patient, X inactivation produces a dual red-cell population: some red cells have normal levels of G6PD, whereas others are G6PD-deficient. The latter, on exposure to redox agents, are just as susceptible to hemolysis as G6PD-deficient red cells in a hemizygous male.
A: Red-cell destruction in favism is a complex process, but it has gradually been clarified. The fava bean plant contains high concentrations of two β-glucosides (up to 2% in dry weight): vicine and convicine. On ingestion of fava beans, vicine and convicine undergo hydrolysis by glucosidases present both in the beans and in the gastrointestinal tract, releasing the respective aglycones: divicine and isouramil. These highly reactive redox compounds have antifungal and pesticide activity, which probably helps prevent fava beans from rotting, but the compounds are also capable of triggering a favism attack. When fava beans are cooked, the glucosidases are largely inactivated. This is probably the main reason why in most cases an attack of favism is triggered by eating raw beans rather than cooked beans.
A: Divicine and isouramil, transferred through the intestinal epithelium into the blood, produce reactive oxygen species such as superoxide anion, as well as hydrogen peroxide, which rapidly oxidize NADPH and glutathione. In red cells with normal G6PD activity, hydrogen peroxide is detoxified by catalase and by glutathione peroxidase. Both these enzymatic reactions depend on NADPH. Since NADPH is in short supply in G6PD-deficient red cells, they are unable to reverse glutathione depletion and they therefore sustain severe oxidative damage. The most severely damaged red cells undergo intravascular hemolysis, but much of the hemolysis is extravascular. Without the protective action of glutathione and NADPH, a chain of oxidative events leads to deposition on clustered band 3 of autologous IgG and factor C3c produced by the complement alternative pathway (tick-over mechanism). The red cells thus opsonized are subject to erythrophagocytosis.