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Favism

G6PD Deficiency

Acute development of symptoms such as fever, headache, abdominal pain and severe anemia after ingestion of fava beans is known as favism. It is almost exclusively seen in patients with glucose-6-phosphate dehydrogenase deficiency, an X-linked hemolytic anemia, which is why the vast majority of patients are males. The diagnosis is made through patient history, while treatment includes supportive measures.


Presentation

Symptoms usually appear 24-48 hours after ingestion of fava beans and are related to the development of hemolytic anemia. Most prominent symptoms include weakness, headaches, pallor, abdominal pain, dark urine due to hemoglobinuria and in some cases jaundice [13]. Syncope was also documented in some cases [14], while kidney and liver function may be significantly impaired due to extensive hemolysis. Patients may report a history of these symptoms having already occurred, indicating previous fava bean ingestion. On physical examination, splenomegaly and jaundice may be observed.

Anemia
  • Symptoms usually appear 24-48 hours after ingestion of fava beans and are related to the development of hemolytic anemia.[symptoma.com]
  • anemias, not elsewhere classified D53.2 Scorbutic anemia D53.8 Other specified nutritional anemias D53.9 Nutritional anemia, unspecified D55 Anemia due to enzyme disorders D55.0 Anemia due to glucose-6-phosphate dehydrogenase [G6PD] deficiency D55.1[icd10data.com]
  • At birth there were clinical and hematologic signs of hemolytic anemia, hemoglobinuria, and no blood group immunization.[ncbi.nlm.nih.gov]
  • Hemolytic anemia exceptionally occurred later. The same was not true of drug-induced hemolytic anemia, since a longer time elapsed between the ingestion of drugs and the appearance of clinical symptoms (usually 4-5 days).[g6pd.org]
  • Sudden onset of anemia was found within 1 to 3 days after ingestion of dried fava beans. The classic features of favism, which are pallor, hemoglobinuria, and jaundice, were detected in all cases.[ncbi.nlm.nih.gov]
Fever
  • Abstract During a routine screening for G6PD deficiency in the Province of Matera (Southern Italy), an eleven-year-old boy was brought to our attention who had fever obviously caused by a viral infection, but who also had hepatosplenomegaly and haemoglobinuria[ncbi.nlm.nih.gov]
  • […] fa·vism ( fā'vizm ), An acute condition suffered after ingestion of certain species of beans, for example, Vicia faba , or inhalation of the pollen of its flower; characterized by fever, headache, abdominal pain, severe anemia, prostration, and coma;[medical-dictionary.thefreedictionary.com]
  • Acute development of symptoms such as fever, headache, abdominal pain and severe anemia after ingestion of fava beans is known as favism.[symptoma.com]
  • Attack can cause the patient to feel headache, dizziness, fever, vomiting and diarrhea. The person can also feel abdominal pain. He may also feel tiredness all the time.[trivology.com]
  • They include headaches, dizziness, nausea, yawning -- vomiting, abdominal pain, and fever -- at this point, symptoms either spontaneously subside, or -- acute hemolytic anemia occurs.[poisonousplants.ansci.cornell.edu]
Fatigue
  • During a hemolytic crisis when a person's red cells rupture, the sufferer can have symptoms such as jaundice (yellow eyes and skin), paleness, weakness, fatigue, shortness of breath, chest pain, or fainting.[lydiakang.blogspot.com]
  • Signs and symptoms (which are primarily a result of hemolysis) include: Dark urine Enlarged spleen Fatigue Paleness Rapid heart rate Shortness of breath Yellow skin color jaundice Causes Mutations in the G6PD gene cause glucose-6-phosphate dehydrogenase[ourmed.org]
  • Sensitive individuals suffer from acute hemolytic anemia upon exposure with characteristic symptoms that include pallor, fatigue, dyspnea, nausea, abdominal and/or back pain, fever, and chills.[farrp.unl.edu]
Diarrhea
  • Página 54 - Pedigree demonstrating a sex-linked recessive condition characterized by draining ears, eczematoid dermatitis and bloody diarrhea. ‎ Página 51 - Selective IgA deficiency: presentation of 30 cases and a review of the literature. ‎[books.google.es]
  • Attack can cause the patient to feel headache, dizziness, fever, vomiting and diarrhea. The person can also feel abdominal pain. He may also feel tiredness all the time.[trivology.com]
  • Symptoms include dizziness, headache, vomiting, fever, jaundice, eosinophilia, and often diarrhea. The condition occurs primarily in persons of southern Italian extraction and is treated by blood transfusion and avoidance of fava beans and pollen.[medical-dictionary.thefreedictionary.com]
  • The characteristic symptoms of lactose intolerance are bloating, flatulence, abdominal cramping, and frothy diarrhea.[farrp.unl.edu]
Nausea
  • The patient may feel tired, feverish, or experience a headache, and the condition can also cause abdominal pain, nausea, and vomiting . If left untreated, it can result in serious health problems, like a coma.[wisegeekhealth.com]
  • They include headaches, dizziness, nausea, yawning -- vomiting, abdominal pain, and fever -- at this point, symptoms either spontaneously subside, or -- acute hemolytic anemia occurs.[poisonousplants.ansci.cornell.edu]
  • Sensitive individuals suffer from acute hemolytic anemia upon exposure with characteristic symptoms that include pallor, fatigue, dyspnea, nausea, abdominal and/or back pain, fever, and chills.[farrp.unl.edu]
Jaundice
  • Abstract Jaundice and bilirubin levels varied widely in 85 children with favism.[ncbi.nlm.nih.gov]
  • The classic features of favism, which are pallor, hemoglobinuria, and jaundice, were detected in all cases.[ncbi.nlm.nih.gov]
  • The main clinical manifestations are acute hemolytic anemia and jaundice, triggered by infection or ingestion of Fava beans or oxidative drugs. A predominant variant of G6PD named Mediterranean is often associated with favism.[ncbi.nlm.nih.gov]
  • Attention is called to the widespread use of fava beans in this area and the possibility of favism as a cause of unexplained cases of acute hemolytic anemia or jaundice. Received December 1, 1949.[pediatrics.aappublications.org]
  • The main characteristics are a fulminant onset, jaundice, anemia and hemoglobinuria.[nejm.org]
Dark Urine
  • Early warning signs include jaundice , dark urine , and a general sense of feeling run down and tired all the time. People who think that they may have favism can be tested for it.[wisegeekhealth.com]
  • Most prominent symptoms include weakness, headaches, pallor, abdominal pain, dark urine due to hemoglobinuria and in some cases jaundice.[symptoma.com]
  • Signs and symptoms (which are primarily a result of hemolysis) include: Dark urine Enlarged spleen Fatigue Paleness Rapid heart rate Shortness of breath Yellow skin color jaundice Causes Mutations in the G6PD gene cause glucose-6-phosphate dehydrogenase[ourmed.org]
Decreased Renal Function
  • Abstract Intolerance to fava beans in subjects with glucose-6-phosphate-dehydrogenase deficiency (favism) may lead to severe hemolytic crises and decreased renal function.[ncbi.nlm.nih.gov]

Workup

Patients with favism require a thorough diagnostic workup, including CBC, reticulocyte count, haptoglobin, bilirubin levels, blood urea nitrogen (BUN), creatinine, urinalysis (with a particular emphasis on hemoglobinuria and proteinuria), liver function tests (alanine and aspartate aminotransferases - AST and ALT) and lactate dehydrogenase (LDH). Laboratory tests will show low levels of hemoglobin and often high reticulocyte count, together with raised indirect bilirubin, while abdominal ultrasound may be useful in excluding splenomegaly which may be suspected during the physical examination. In all patients, a G6PD assay should be performed, to confirm the presence of G6PD deficiency. A vital component in establishing the diagnosis of favism is patient history, which may reveal key information regarding recent consumption of fava beans and provide key pieces in establishing the diagnosis early on.

Treatment

Supportive treatment is the mainstay of managing patients with favism. Because patients may deteriorate rapidly, immediate transfer to intensive care upon admission should be considered. Basic measures include maintenance of blood pressure and kidney perfusion through correction of fluids and electrolytes and preservation of adequate ventilation as well as oxygen saturation. In the case of hemoglobinuria, iron supplementation may be useful in restoring hemoglobin levels. The use of folic acid may be recommended as well. In severe cases when hemolysis is significant, blood transfusions may be indicated, but iron supplementation should be closely monitored, as it can lead to iron overload. High-dose vitamin E has been recommended according to certain studies [15], but its effects remain controversial.

Prognosis

The prognosis may be correlated with the severity of G6PD deficiency, since various forms of favism, including mild, moderate and severe anemia have been mentioned in literature [11]. With adequate supportive treatment, the prognosis is generally good, but favism may cause life-threatening symptoms and complications, such as kidney failure and result in significant morbidity [12]. A prompt diagnosis and appropriate treatment may be life-saving.

Etiology

Favism occurs as a result of either ingestion of fava beans or inhalation of pollen from the fava plant, Vicia faba. This condition is almost exclusively diagnosed in patients with G6PD deficiency, a type of hemolytic anemia in which insufficient production of GSH leads to accumulated free-radical mediated oxygen stress. Presumably, certain substances located inside fava beans, with vicine and convicine being the most prominent candidates, induce oxidative injury in the erythrocytes that cannot be surmounted in G6PD patients because of GSH deficiency. Other theories include infectious pathogens as possible causative agents, due to very rare recurrence of symptoms, as well as most frequent appearance among the pediatric population in a seasonal fashion [2]. Immune mechanisms have also been hypothesized to play a role in the development of favism, including the complement system and anti-band-3 antibodies and their respective roles in the mediation of oxygen-induced stress in erythrocytes [3]. However, the exact cause, as well as, the mechanisms of the disease remain unknown.

Epidemiology

Because favism is almost exclusively diagnosed in patients with G6PD deficiency, and also because of the cultivation of fava beans, countries of the Mediterranean region report the majority of cases [4]. Favism is most commonly diagnosed in children between 1-5 years of age with G6PD, while cases of favism in adults have been infrequently reported. Because G6PD is inherited via the X chromosome, virtually all patients with favism are males [4]. The majority of cases occur during spring and during harvesting of fava beans, while inhalation of fava pollen is also a known mode of the disease [5]. In very rare cases, neonatal favism due to consumption of fava beans by mothers prior to delivery may occur [6], while some studies established lactation as a mode of transmission of toxic substances after recent fava bean ingestion.

Sex distribution
Age distribution

Pathophysiology

It is reported that all patients in whom ingestion of fava beans produces symptoms are G6PD deficient and that the pathogenesis invariably involves this genetic condition [7]. G6PD is an essential constituent in the synthesis of glutathione peroxidase (GSH), one of the most important enzymes in battling oxidative stress in many cells, including erythrocytes. In the setting of G6PD deficiency, red blood cells are not able to sustain free radical injury. Hydrogen peroxide, one of the more potent free radicals generated in erythrocytes, targets primarily globin chains, which oxidize and damage the cell wall. Eventually,there is mild damage to erythrocytes with subsequent splenic degradation, but the end-result is diffuse hemolysis. In patients with favism, substances that have been hypothesized to induce such changes include vicine and convicine and their biologically active forms, divicine and isouramil, respectively [8]. Supposedly, these substances induce oxidative stress within erythrocytes [9], but further evidence is necessary to confirm the exact mechanism of damage. Animal models have shown evident hematotoxicity of these substances [10].

Prevention

Since the introduction of screening for G6PD deficiency in certain countries, markedly reduced rates of favism have been observed, which indicates that screening programs may significantly aid in reducing the burden of favism in medical practice and everyday life [16]. These studies have also shown that there is an increasing incidence of favism in female patients, suggesting the involvement of other factors in the pathogenesis of this syndrome. However, an increased awareness of this disease among patients at-risk has been achieved [16]. For these reasons, screening can be initially targeted at individuals with known family history for this X-linked genetic disease. On the other hand, avoidance of fava bean consumption has been recommended as a form of prevention. Certain studies have discovered that favism usually occurs in patients when ingesting fava beans accidentally or for the first time. This may be the reason why the majority of patients are young children.Interestingly recurrence of symptoms with repeated fava bean ingestion is rarely observed. This questions the role of avoiding fava beans as a preventive strategy [2].

Summary

Favism is a condition characterized by the development of hemolytic anemia after ingestion of fava beans and it is almost exclusively seen in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. G6PD deficiency impairs production of anti-oxidative enzymes such as glutathione peroxidase (GSH) and occurs as a result of mutations in the X chromosome [1]. This syndrome predisposes individuals to favism presumably because fava beans contain several substances that induce oxidative stress inside erythrocytes, with vicine and convicine being the most recognizable toxins. Uncontrolled intraerythrocytic oxidative stress leads to red blood cell hemolysis and anemia. However, the exact pathogenic mechanisms of red blood cell damage and actions of the toxins that cause this phenomenon remain unknown. Infectious pathogens, as well as immune-mediated mechanisms, are thought to be a contributing factor[2]. The mode of G6PD transmission implies an almost total predominance of male patients. Countries around the Mediterranean report a high incidence of cases as they have both: fava bean consumption and high prevalence rates of G6PD deficiency. Most commonly, favism is diagnosed in children, but patients of any age may be affected. Because of the disease mechanism, anemia is the main clinical feature, while other accompanying symptoms may include fever, headache, weakness and appear approximately 1-2 days after eating fava beans [2]. Symptoms may last up to 5 days and can range from mild to severe [2]. Since no specific tests exist for the diagnosis of favism, patient history is the most important component in the diagnostic workup and all patients should be evaluated for G6PD deficiency, if not diagnosed already with this disease. Laboratory workup should include a complete blood count (CBC), serum electrolytes, as well as kidney and liver function tests since favism has been documented as a cause of renal failure. Treatment includes management of symptoms, while prevention strategies could include avoiding fava beans in patients with known G6PD deficiency. However, symptoms rarely recur with repeated ingestion of fava beans, which further brings into question the exact etiology of the disease.

Patient Information

Favism is an illness that occurs after ingestion of fava beans. In virtually all cases, favism occurs in patients with an inherited disease called glucose-6-phosphate dehydrogenase (G6PD) deficiency, which is most commonly seen in the countries around the Mediterranean. This genetic disorder is characterized by the impaired function of enzymes that are involved in the production of substances that should regulate free-radical damage of cells, primarily in the red blood cells. G6PD is an important factor in the synthesis of glutathione peroxidase (GSH), one of the main enzymes involved in reducing the number of active free radicals. The exact sequence of events in favism is not entirely known, but it is assumed that certain substances located inside the fava beans induce significant free-radical mediated injury of red blood cells, which cannot be stopped due to deficient levels of GSH, ultimately leading to their damage and rupture, thus causing anemia. This genetic disease is transmitted via the X chromosome, meaning that males are much more frequently affected. In addition to ingestion of fava beans, inhalation of pollen from the fava bean plant (Vicia faba) has also been established to be a mode of disease. The main clinical feature of patients with favism is the appearance of symptoms such as pallor, abdominal pain, weakness and severe anemia 1-2 days after ingestion of fava beans. Symptoms may be mild, or they may be severe and life-threatening, which necessitates rapid diagnostic workup and appropriate therapeutic measures. Since the exact diagnosis cannot be established by laboratory tests, patients should be asked for recent fava bean consumption, while a detailed workup should include a complete blood count (which will reveal anemia and increased count of immature red blood cells, known as reticulocytes) and evaluation of kidney and liver function, since many patients may excrete hemoglobin through urine (hemoglobinuria). All patients should be tested for G6PD deficiency since this disorder is termed to be a necessary component in the development of favism. Treatment primarily includes supportive measures such as maintaining adequate blood pressure and breathing, correction of serum electrolytes and fluid imbalance to prevent kidney damage, while blood transfusions may be necessary in severe cases. Significant steps in prevention can be made by the screening of family members with G6PD deficiency. Avoiding fava bean consumption in these patients is strongly recommended.

References

Article

  1. Szeinberg A, Asher Y, Sheba C. Studies on glutathione stability in erythrocytes of cases with past history of favism or sulfa-drug-induced hemolysis. Blood. 1958;13:348.
  2. Ahmed SN. Do favic patients resume fava beans ingestion later in their life, a study for this, and a new hypothesis for favism etiology. Hematol Oncol Stem Cell Ther. 2013;6(1):9-13.
  3. Arese P, Mannuzzu L, Turrini F. Pathophysiology of favism. Folia Haematol Int Mag Klin Morphol Blutforsch. 1989;116(5):745-752.
  4. Kurdi-Haidar B, Mason PJ, Berrebi A, et al. Origin and spread of the glucose-6-phosphate dehydrogenase variant (G6PD-Mediterranean) in the Middle East. Am J Hum Genet. 1990;47(6):1013-1019.
  5. John P. Greer, John Foerster, John N Lukens. Wintrobe’s clinical hematology. 11th ed. Lippincott Williams & Wilkins Publishers; 2003.
  6. Corchia C, Balata A, Meloni GF, Meloni T. Favism in a female newborn infant whose mother ingested fava beans before delivery. J Pediatr. 1997;130:680–681.
  7. Beutler E. G6PD deficiency. Blood. 1994;84:3613.
  8. Mager J, Glaser G, Razin A, et al. Metabolic effects of pyrimidines derived from fava bean glycosides on human erythrocytes deficient in glucose-6-phosphate dehydrogenase. Biochem Biophys Res Commun. 1965;20:235–240.
  9. Chevion M, Navok T, Glaser G, et al. The chemistry of favism-inducing compounds. The properties of isouramil and divicine and their reaction with glutathione. Eur J Biochem. 1982;127:405–409.
  10. McMillan D C, and Jollow D J. Favism: Divicine hemotoxicity in the rat. Toxicol Sci. 1999;51:310–316.
  11. Donsoso, G, Hedayat, H, and Khayatian H. Favism, with Special Reference to Iran. Bull World Health Organ. 1969;40:513–519.
  12. Montasser DI, Benyahia M, Zajjari Y, et al. Acute renal failure in favism revealing familial glucose-6-phosphate dehydrogenase deficiency. Indian J  Nephrol. 2012;22(1):67-68.
  13. Luisada A. Favism. Medicine (Baltimore). 1941;20:229.
  14. Soyuncu S, Bektas F, Isik S, Yigit O. An unusual syncope cause in the ED: favism. Hum Exp Toxicol. 2011;30(4):335-337.
  15. Corash L, Spielberg S, Bartsocas C, et al. Reduced chronic hemolysis during high-dose vitamin E administration in Mediterranean-type glucose-6-phosphate dehydrogenase deficiency. N Engl J Med. 1980;303:416.
  16. Meloni T, Forteleoni G, Meloni GF. Marked decline of favism after neonatal glucose-6-phosphate dehydrogenase screening and health education: the northern Sardinian experience. Acta Haematol. 1992;87(1-2):29-31.

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Last updated: 2017-08-09 18:20