Favism - from the "avoid fava beans" of Pythagoras to the present

Haema 2004; 7(1): 17-21 Historical review John Meletis, Kostas Konstantopoulos National and Kapodistrian University of Athens, School of Medicine, First Department of Internal Medicine, Laiko General Hospital, Athens, Greece Key words: Favism + G6PD deficiency [=<] Correspondence: John Meletis, MD, National and Kapodistrian University of Athens, School of Medicine, First Department of Internal Medicine, Laiko General Hospital, Athens, Greece, Tel.:+30210.7771161, Fax: +30210.7788830, e-mail: imeletis@cc.uoa.gr “..xvauov axéyeo0e..”, “..kyamon apechesthe...” ”..be far from the fava beans consumption...” (Part of Pythagorean consultations) Favism [fabismus, kyamismos (Greece) favismo, fabism] is a reaction to ingested fava plant; beans, pods and, most likely, foliage as well, or to inhalation of fava pollen. It is a hereditary abnormality of the red Loesch MELETIS | Gdl cell enzyme glucose-6-phosphate dehydrogenase (G6PD), resulting to its sudden destruction (haemolytic anaemia and jaundice) following intake of fava beans, other legumes or various drugs. Favism is common in Mediterranean, Africa and Southern Asia. More than 400 genetic variants are recognized. Fava beans intake originated in the Near East in late Neolithic times; they were afterwards cultivated in ancient Egypt, Greece and Rome. Fava beans are mentioned several times by Homer (8'" to 9'* BC). vigorously during the cool wet months of winter, and they constitute for centuries unique and invaluable part of diet in Mediterranean people. Their history is rife with superstition, prohibition, magic and fear. It is well known that for some people, fresh fava beans can be poisonous. Although common, favism as a genetically transmitted disease was recognized only at the turn of this century. The mechanism was explained only in the last decades. Classic Greece doctors had seen through the importance of environment, natural elements and ali- Greeks apparently associated the little black spot on ments for the right balance of organism. Haemolysis due to lack of the enzyme G6PD of red cells was known for many years. It is called favism meaning “occurrence after consumption of fava beans” (Greek word the hilum with death and although the beans were “xúopor”, “kyamoi”, “xvapioudc”, “kyamismos” - favissometimes offered in sacrifices to Apollo, it was formus). The observation that the consumption of fava beans causes various disturbances was the first observation of toxic haemolytic anaemia and the rule “xudpov anéyecbat”, “kyamon apechehesthe” - ”be bidden to priests to eat or even mention their name. Unlike Egyptians and Greeks, the Romans highly respected fava beans among legumes. The beans Pythagoras is referring to are fava beans (vicia fava, Vica faba vulgaris), which botanically are a large seeded vetch. They are well-adapted to the Mediterranean area because of being very hardy to cold. They grow far from the fava beans consumption” was a Pythagorean consultation. This rule constricts a legume that is named Greek fava bean (kyamos Hellenikos, vicia fava, Vica faba) that is cultivated and used in the Medi17

J. Meletis, K. Konstantopoulos terranean already by the Prehistoric season where at Theophrastus the word kyamos (vicia fava) characterizes the plant as well the kemel. Plynio and Dioscurides distinct the Greek fava bean from fava Aegyptia reminding that the Pythagorean rule concerns only Greek fava bean. Empedocles during the 5'* century BC continues Pythagorean teaching declaring that “éerhol, névôerhor, Kvópwv and yetoas Exeodar”, “deiloi, pandeiloi kyamon apo cheiras echesthe” — “unhappy, a lot of miserables, it is not touched upon fava beans”. Kallimachos during the 3" century BC wrote “xo xuduwv and xetous ÉXELS, avióvrog edeotoú, xayú IIvôoyópas wo exéheve” “kai kyamon apo cheiras echeis, aniontos edestou, kago Pythagoras os ekeleve” - I say also, as said also the Pythagoras, you do not touch upon fava beans, that is corroded food”. Pythagoras refused to walk through fields of fava beans and discouraged his disciples from eating them. He is said to have met his death in Crotonia in Ancient Italy. Pursued by them, Pythagoras died among his enemies because he would not flee across a bean field, he came to the edge of a bean field and, rather than set foot in it, was caught and killed as motioned by Iamblichus, Diogenes Laertios, Artemidoros, Porphyry, Pausani- Aristotle and Diogenes Laertios proposed that Pythagoreans rejected fava beans because they are possibly poisonousness and provoke flatulence, which can destroy mental peace by keeping one awake with a rumbling stomach. Orphics believed that Pythagoras had forbidden eating of fava beans because they contain the souls of the dead. “Eating fava beans and gnawing on the heads of one’s parent are one and the same” was one of their saying. Herodotus reports that Egyptian priests considered beans as unclean, while Pausanias and Porphyry note that they were forbidden by Orphics and the iniates at Eleusis. They also should not be touched including them in a list along with pomegranates, recently delivered women and dead bodies, showing a possible relationship with religious dogmas. All the above testimonies emanate from authors are not doctors. The Hippocratic doctors cannot ignore the Pythagorean dietetics. However the prohibition of fava beans is not reported in their treatises. Around the turn of the 20" century, physicians began to recognize the presence of favism after eating fresh fava beans and some people began to suffer a sudden illness that, in some cases, led rapidly to death. The cause seems obvious today, but it wasn’t until 1904 as, Cicero and Grigorios Nanzyanzynos. Tamblichus tells of the time a group of Pythagoreans were being pursued by their enemies when they come across a field of favas in bloom, Rather than disobey the master’s dictates and flee through the field, they were slaughtered, and when two were captured were questioned about their beliefs, they refused to answer. The when Clemens von Pirquet came up with the medical definition for allergies. Before this, it was difficult for doctors to get a handle on the concept that what is fine for one person may be poisonous for another. The first modern report of favism (favismus, kyamismos) is husband chose death and the wife, a Spartan, bit off her tongue and spit it her captors to avoid spilling the found in a magazine of Lisbon where in 1843 Manuel Pereira de Mira Franco reported the case of an indibeans. Avoidance of fava beans is also advised by philosophers of India, probably landed by the Greeks. Whether the basis of Pythagoras’ pronouncement vidual who presented with jaundice each time where was poisoning or not, remains uncertain. This debate jaundice from different exhalations (possible by ethereal oil) of the fava beans flowers, inheritance of this illness, distinguished this icterus from the jaundice of malaria and confirmed the main role of fava beans. Mule Bertolo observed the appearance of haemoglobinuria and proposed the term “favismus”, while the Sicilian patient Salvare Greco (his surname point to a Greek origin but also his stigma) suffered from favismus as his grandfather from the part of his mother is well summed by Aristotle and Aulus Gelius, who say that Pythagoras proscribed fava beans either because they are like genitals (testicules), or because they resemble the gate of Hades, for they alone have no joints, since these two correlate well with traits connecting beans with human life and generation referred by other ancient writers, or again because they spoil, or because they resemble the batutre of the universe, or believed that beans really meaning eggs and the eating of an egg is similar to eating the animal that comes from it, or because of oligarchy, for they are used for drawing lots. 18 he ingested fava beans. From 1856 the Sicilian Antonio Mina La Grua but also other doctors as Di Pietra - Leone, Rizzo - Matera, Pietro Messina pointed out that from his experience and from the experience that he had inherited arranged itself in the consultation of Pythagoras for the not consumption of fava beans. In the threshold of the 20" century doctors showed that

pathophysiology of favismus was haemolysis (destruction of red corpuscles). In a congress in Rome (1894) G. Montano reported haemoglobinuria (not haematuria as previously believed) as the main symptom of the disease and distinguished the “decisive” reason, fava beans’) and the “predisposed” reason, idiosyncrasy. Cases in Italy were also reported by Girotti 1899, Camillis 1901, and in Sardinia by Went 1899, and Steani 1904 as well. In Greece from 1895-1905 Doukas, Skavetzos, Kavvadias, Vellopoulos, Kontogeorgis, Tselios and other realised the illness in various regions of Greece. Epidemiologic studies of Gasparrini in 1905 clarified the clinical picture, the familial character, and the defective attack of young persons particularly male. A possible explanation of favism began to appear illness in regions with malaria, with other thalassaemic syndromes, and the selection advantage offered by lack of the enzyme in malaria infection in heterozygous women (but not in the hemizygotes men). The “Mediterranean phenotype” of the illness was realized and also sub-variants of the enzyme named after Greek regions or cities (Athens, Corinthus, Orhomenos, Lavadeia, Karditsa, Attica, Thessaly etc) became known. The condition is most common in males, (women being susceptible only carry the gene from both sides of the family) and the condition is most severe among ciency is actually a defence against malaria a major infants and children. From all these it appears that even today it rather becomes acceptable that the compurgation of Pythagorean prohibition for the consumption of fava beans seems valid and useful. Fava beans contain several chemical compounds that resemble those found in quinine. Fava beans are in the 1920’s, when scientists found that G6PD defihealth problem in Greece and Southern Italy. It wasn’t rich in two glycosidic compounds, vicine and conviuntil late 1940 that W. Boyd from Boston noted that the British, in contrast to Mediterranean people, never developed favism after ingestion of fava beans suggesting genetic difference as a possible explanation. This information became more interesting during World War II, when treating malaria with quininebased drugs resulted to reaction to the medicine similar to fava beans by the same people. cine constituting some 2% of the dry weight. Upon ingestion, the glycosides are hydrolysed enzymatically to form pyrimidine aglycones, divicine and isouramil respectively. The proposed mechanism for the cause of favism is that the new compounds consequently undergo redox cycling and the process depletes reduced glutathione, leading to the formation of free radicals Later, the complex explanation of illness became After decades of research it was proven that fava beans themselves also fight malaria with the same way as G6PD deficiency (reducing the amount of oxygen in the blood). In a theoretical basis when fava beans are consumed by people with G6PD deficiency who evident as American doctors after using antimalarial drugs (“favismus of Blacks”) related it with Mediterranean favismus. Later, lack of the enzyme G6PD was clarified as the cause of haemolysis. For years various substances of the fava beans were incriminate but also rarely other legumes for the challenge of haemolysis, were also described. It was observed that the syndrome was released mainly after consumption of fresh fava and hydrogen peroxide. don’t suffer from favism (the vast majority of the population), the resistance to malaria is raised. In a theoretical basis even if fava beans are dangerous to some people, their benefits for the rest of the population far beans (likely smaller content dry or boiled fava beans, outweigh their shortcoming, Additionally, in last years release after a simple contact with fruits or flowers even in a distance) and the substance may be transported even via breast feeding. The Greek work of lipid-lowering effects and may also be a good source Choremis, Doxiadis, Kattamis, Stamatoyannopoulos, Fessas, Zannos-Mariolea and other on the subject and his extent in Greece discovered hot spots in various regions, while others gave elements for the nature and there exist some data that faba beans (Vicia faba) have of antioxidant and chemopreventive factors. Is this the secret behind Pythagoras’ puzzle? It’s hard to say, 26 centuries later. Most probably, nobody definitively knows. the inheritance of illness. Later polymorphisms of the enzyme G6PD were realized together with the exist-_ ence of irregular molecules of the enzyme. The Greek paediatricians realised the relation of enzyme insufficiency with neonatal jaundice, the correlation with bone damages as thalassaemia, the co-incidence of SELECTED REFERENCES Plutarco. De educatione puerorum, 17. 2. Plutarch. Symposium JI, 3, 635E. 3. Arie THD. Pythagoras and beans. Oxford Med School Goz 1959; 11: 75-81.

J. Meletis, K. Konstantopoulos . Ballas CN. The Pythagorean prohibition. Acta Congr Intern Hist Artis Med 1976; 24: 1343-1346. A . Bourquelot E. Remarques è propos des fOves de Pythagore. CR Soc Biol Paris, 1904, 46, 861-862, Brumbaugh RS, Schwartz J. Pythagoras and beans: a medical explanation. Class Word 1980; 63: 421-422. Brumbaugh RS. The philosophers of Greece. Albany, New York, 1981. Delatte A. Etude sur la littirature pythagoricienne. Par- 31. Theophrastus. Enquiry into Plants IV. Hort AF (transl), Harvard University Press, 1916. 32, Dioscourides. About Medical matter II, 33. Plinio, Natural History, 18, 118. 34. Eichholz DE. Pliny Natural History, Loed Classics, No 419, 35. Empedocles. Aulos-Gelios Noctes Atticae, IV. 36. Herodotus. II, 37, 81, 123. 37. Guthrie WKC. A history of Greek Philosophy II. Camis, Champion, 1915. De Vogel CJ. Pythagoras and early pythagoreanism. Assen Van Gorcum, 1966, 10. Larquier de Bancels J. Sur les origines de la notion de Fame © propos d’une interdiction de Pythagore. Arch Psychol 1918; 17: 58-66. 11. Livy I. Recherches sur les sources de la ligende de Pythagore. Leroux, Paris, 1926. 12. Navia LE. Pythagoras: An annotated bibliography. New York, 1990. 13. Sansone G, Piga AM, Segni G. Il favismo era conosciuto dai greci antichi (di S. Veras). In “Il favismo”, 5-7, Torino, 1958. 14, Stamatis ES. Pythagoras of Samos (Greek). Athens, 1981. 15. Van der Waerden BL. Science Awakening. New York, 1954. 16. Gasbarrini A. Il favismo. Policlinico Sez Prat 1915; 22, 1505. 17, Grmek MD. Diseases in the ancient Greek world. Mireille Muellner and Leonard Muellner (transl). The Johns Hopkins University Press, London, 1989, pp. 279- 283. 18, Hippocrates, Epidemics I and III. Jones WHS (transl), 139-287, in vol.1 Jones WHS, Withington ET, Potter P, Smith WD (transl), Hippocrates. Loeb Classical Library, William Heinemann. Harvard University Press, London, 1957-1995. 19, Diogene Laerzio. Vitae Philosophorum, VIII, 23, 29, 33, 39, 45, 20. Diogenes Laertius. Lives of eminent philosophers. New York, 1925. 21. Marcovic M. (ed). Dogenis Laertii vitae philosophorum: excepta Byzantina et indices. BG Taubner Publ, 1999. 22, Porfirio. Vita Pythagorae, 44. 23, Giamblico. Vita Pythagorica, 109, 189-194, 206. 24, Taylor T, Iamblichus. Life of Pythagoras. London, 1818. 25. Diels H and Kranz W. Die Fragmenten der Vorsokratiker, 6" edition, Berlin, 1971, 26, De Vogel CJ. Pythagoras and early pythareanism. Assen Van Gorcum 1966. 27, Delatte A. Faba Pythagorae cognata. Serta Leodiensia, Liege, 1930, pp. 31-57. 28. De Condolle A. Origine des plantes cultivees. Gerber Baillere, Paris, 1883. 29, Detienne M. La quisine de pythagore. Arch Sociol Rel 1970; 15: 141-162. 30. Detienne M. Les Jardins d’Adonis: La mythologie des aromates en Grôce, Paris, 1972, 20 bridge, 1965. 38. Raven JE. The presocratic Philosophers. Cambridge, 1957. 39. Kalimachos. Aulos-Gelios Noctes Atticae, IV, 40. Tertulliano. De Anima, 31, 41, Cicerone, De Divinatione, I, 62. 42, Marcus Tullius Cicero. Scripta Quae Manserunt Omnia: De Divinatione, De Fato Timaeus. Plasberg O. Biblio- 43. 44. 45. 46. 47. 48. 49. 50. 51. theca Teuneriana. Iamblichus. Vitae Pythagorae, 109, Aulus Gellius. Noctes Atticae, Lib IV, 11.10. Heraclides Ponticus. Lydus, Mens. IV, 42 Da Origene. Contra Celsum, V, 41. Artemidoro. Onirocriticon, I, 68. Porfirio. De Abstinentia, IV, 16. Pausania. Descriptio Graeciae, I, 37, 4. Gregorius Nazyanzynos. Orations XXIII. Manuel Pereira de Mira Franco. Favas verdes produsindo ictericia, Revista Universal Lisbonese, 1843 52, Mina La Grua A. Sopra l’itterizia endemica e su malattie ordinarie del condadini di Castelbuono,1856. 53. Montano G. Del favismoo intossicazione fabacea, 20" Congr Med Internationale, Roma 1894, 3, 301. 54. Fermi C, Martinetti P. Studio sul favismo. Ann Igiene Sper 1905; 15: 76. 55. Gasbarrini A, Su diuna forma ancora insufficientemente conosciuta acuta febbrile con itterizia ed emoglobinuria (il favismo). Folia Clin Chim Microscopp Salsomaggiore 1912-1914; 4: 347. 56. Gasparrini A. Il favismo, Policlinico Sez Prat 1915; 22: 1505. 57. Luisada L. Favism: singular disease affecting chiefly red blood cells, Medicine 1941; 20: 229, 58. Turchetti A. Forme poco frequenti di emoglobinuria dafarmaci in consodi infezione malarica. Roforma medoica 1948; 62: 325. 59, Sansone G, Segni G. Sensitivity to broad beans. Lancet 1957; 2: 295, 60. Sansone G, Piga AM, Segni G. Il favismo. Minerva Medica, Torino, 1958. 61, Beutler E, Kuhl W, Vives-Corrons JL, Prchal JT. Molecular heterogeneity of glucose-6-phosphate dehydrogenase A-. Blood 1959; 74: 2550-2555. 62. Chorenis C, Joannides T, Kyriakides B. Severe opthalmic complications following favism. Br J Opthalmol 1960; 44: 353-356. 63. Doxiadis SA, Fessas P, Valaes T. Erythrocyte enzyme deficiency in unexplained kernicterus. Lancet 1960; 2:

64. Zannos-Mariolea L, Kattamis C. Glucose-6-phosphate dehydrogenase deficiency in Greece. Blood 1961; 18: 34-47. 65. Formaini G, Leoncini G, Luzzatto L, Segni G. Glucose metabolism in human erythrocytes from normal and fava beans-sensitive subjects. J Clin Invest 1962; 41: 14461453. 66. Boyer SH, Porter IH, Weilbacher RG. Electrophoretic heterogeneity of glucose-6-phosphate dehydrogenase and its relationship to enzyme deficiency in man. Proc Natl Acad Sci USA 1962; 48: 1868-1876. 67. Valaes T, Doxiadis SA, Fessas P. Acute hemolysis due to naphthalene inhalation. J Pediatr 1963; 63: 904-915. 68. Stamatoyannopoulos G, Fessas P. Thalassemia, glucose6-phosphate dehydrogenase deficiency, sickling and malarial endemicity in Greece. Brit Med J 1964; 1, 875879,. 69. Stamatoyannopoulos G, Fraser GR, Motulsky AC, Fessas P, Akrivakis A, Papayannopoulou Th. On the familial predisposition to favism. Am J Hum Genet 1966; 18: 253-263. 70. Luzzatto L. Regulation of the activity of glucose-6-phosphate dehydrogenase by NADP* and NADPH. Biochimica Biophys Acta 1967; 146: 18-25. 71. Luzzatto L, Usanga EA, Reddy S. Glucose-6-phosphate dehydrogenase deficient red cells, Resistance to infection by malarial parasites, Science 1969; 164: 839-842, 72. Kattamis CA, Chaidas A, Chaidas S. G6PD deficiency and favism in the island of Rhodos (Greece). J Med Genet 1969; 6: 286-291 73. Kattamis CA. Some clinical and biochemical aspects of favism in childhood. Ann Soc Belg Med Trop 1969; 49: 298-302. 74. Lieber E. Favism in antiquity. Karot 1970; 5: 331-335. 75. Stamatoyannopoulos G, Voigtlander V, Kotsakis P, Akrivakis A. Genetic diversity of the “Mediterranean” glucose-6-phosphate dehydrogenase deficiency phenotype. J Clin Invest 1971; 50: 1253-1261. 76. Kattamis C. Favism in breast-fed infants. Arch Dic Child 1971; 46: 741. 77. Bienzle U, Ayeni O, Lucas AO, Luzzatto L. Glycose-6phosphate dehydrogenase and malaria. Lancet 1972; 1: 107-110. 78. Kattamis V, Karambula K, Ioannidou V, Hatzikou V. Jaudice and bilirubin levels in Greek children with favism. Arch Dis Child 1976; 233-235, 79. Luzzatto L, Battistuzzi G. Glucose-6-phosphate dehydrogenase. Adv Hum Genet 1985; 14: 217-329, 80. Clark IA, Cowden, WB. Antimalarials. In Oxidative stress, Sies H (ed): London, Academic Press Inc, Lon- 81. Luzzato L. Glucose-6-phosphate dehydrogenase and other genetic factors interacting with drugs. Prog Clin 82. Biol Res 1986: 214: 385-399. Beutler E, Yoshida A. Genetic variations of G6PD: a catalogue and future prospects. Medicine 1988; 67: 311- 334. 83. Lippi D. The broad bean’s syndrome in ancient Egypt. Med Secoli 1989; 1: 301-306. 84, Senozan NM, Thielman CA. Glucose-6-phosphate dehydrogenase deficiency - an inherited ailment that affects 100 million people. J Chem Educ 1991; 68: 7-10. 85. Corcoran CM, Calabro V, Tamagnini G et al. Molecular heterogeneity underlying the G6PD Mediterranean phenotype. Hum Genet 1992; 88: 688-690. 86. Beutler E. G6PD deficiency. Blood 1994; 84: 3613-3636. 87. Burbano C, Cuadrado C, Muzquiz M, Cubero JI. Variation of favism-inducing factors (vicine, convicine and LDOPA) during pod development in Vicia faba. Plant Foogs Hum Nutr 1995; 47: 265-275. 88. Luzzatto L, Mehta A. Glucose 6-phosphate dehydrogenase deficiency. In CR. Scriver et al (eds): The Metabolic and Molecular Bases of Inherited Disease. McGraw-Hill Inc., New York, 1995. 89, Luzzatto L, Mehta A, Meloni T. Haemoglobinuria and haptoglobin in G6PD deficiency. Br J Haematol 1995, 91: 511-512. 90. Mehta A, Mason PJ, Vulliamy TJ. Glucose-6-phosphate deficiency. Bailliers Best Pract Res Clin Haematol 2000; 13: 21-38, 91. Luzzatto L, Mehta A. 2001. Glucose-6-phosphate dehydrogenase deficiency. In Scriver CR, Beaudet AL, Sly WS, Valle D (eds): The metabolic and molecular bases of inherited disease, 8 edition. McGraw-Hill, Inc., New York, 2001, pp. 4517-4553. 92. Hart G. Description of blood and blood disorders before the advent of laboratory studies. Br J Haematol. 2001; 115: 719-728. 93. Madar B, Stark AH. New legume sources as therapeutic agents. Br J Nutr 2002: 88 (suppl. 3): S287-S292. 94. Beutler E. Erythrocyte disorders: Anemias due to increased destruction of erythrocytes with enzyme deficiencies. Glucose-6-phosphate dehydrogenase deficiency [from Williams’ Hematology, 6" edition], http:// www.rialto.com/favism/english/index.mv?pgid=beutler_01 95. Dye J. Explaining Pythegorean abstinence from beans. http://www.soci.edu/’phildept/Dye/Beans.html, users.ucom.net/‘vegan/beans. htm. 96. Parsons Russ. The long history of the mysterious fava bean. Los Angeles Times, http://www.s-t.com/daily/0-596/05-29-96/c011i096.htm. don, 1985, pp. 136-137.