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Beriberi

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Beriberi

  1. 1. Short Report Outbreak of beriberi in the state of Maranha‹ o, Brazil: revisiting the mycotoxin aetiologic hypothesis Helena Cristina Alves Vieira Lima DDS MSc* Eucilene Alves Santana Porto BS* Jose´ Ricardo Pio Marins MD§ Rejane Maria Alves RN† Rosaˆngela Rosa Machado MDV‡ Karla Neves Laranjeira Braga BS MS‡ Francisca Bernardes de Paiva SW** Greice Madeleine Ikeda Carmo MDV MS† Ana Carolina Faria Silva e Santelli MD MSc* Jeremy Sobel MD MPH*†† *Brazilian Field Epidemiology Training Program, Secretariat of Health Surveillance, Ministry of Health, Brasilia; † Foodborne and Waterborne Diseases Branch; ‡ Laboratory Coordination Branch; § Secretariat of Health Surveillance, Ministry of Health, Brasilia, DF; **Secretariat of Health Minas Gerais State, Brazil; †† Centers for Disease Control and Prevention, Atlanta, GA, USA Correspondence to: Helena Cristina Alves Vieira Lima, Centro de Pesquisa Gonc¸alo Moniz – CPqGM, Rua Waldemar Falca˜o 121, Candeal – Salvador, Bahia, Brazil, CEP: 40296-710 Email: helencris2006@gmail.com TROPICAL DOCTOR 2010; 40: 95–97 DOI: 10.1258/td.2009.090439 SUMMARY Beriberi is caused by thiamine deficiency. Early 20th century epidemics inJapan were attributed to rice contaminated by citreoviridin mycotoxin. Our investi- gation of an outbreak of beriberi in Brazil showed an association of beriberi with the consumption of poor quality subsistence farming rice, although, unlike other investigators of this outbreak, we did not identify citreo- viridin producing fungi in the implicated rice. Introduction Beriberi is a syndrome caused by thiamine deficiency. Thiamine requirements may be increased by physical exertion, hot climate, pregnancy, thyroid abnormalities, infection, alcohol consumption or a diet of simple carbohydrates.1 Beriberi manifests with peripheral neurologic symptoms of paresthesias, pain, weakness or paralysis, and, centrally, the Wernicke-Korsakoff syndrome of horizontal nystagmus, ophthalmoplegia, ataxia and memory loss. Cardiovascular involvement entails a high output cardiac failure due to pro- found vasodilatation; the Japanese literature describes fulmi- nant cardiac failure as ‘shoshin’.2 Japan experienced a massive epidemic of beriberi at the turn of the 20th century. The epidemic coincided with rapid urbaniz- ation and a shift to a diet predominantly consisting of polished rice, often visibly contaminated with molds.3 Implementation of rigorous rice quality control measures was followed by a precipitous decline in the illness.3 Subsequently, Japanese investigators suggested that this epidemic was caused by myco- toxin citreoviridin, produced by Penicillum citreonigrum, Aspergillus terreus and Eupenicillium ochrosalmoneum. Citreoviridin produces a striking cardiac beriberi-like syndrome in rodents.4–7 An outbreak of beriberi occurred in a poor, rural area of Maranha˜o state, Brazil, in 2006. A substantial proportion of rice consumed by the population is locally grown bysubsistence farmers. This rice is dried on the ground and then polished in small local unregulated rice establishments, where it is stored in precarious conditions (Figure 1). In 2007 rice samples were collected from local rice-polishing facilities; these yielded citreoviridin-producing P. citreonigrun; citreoviridin was present in the rice samples.8 Cases of beriberi continued into 2007. We conducted an investigation to test the hypothesis that this persistent out- break of beriberi was due to the contamination of rice with citreoviridin mycotoxin. Patients and methods We conducted a 1:1 matched case control study. A case was a person reported as having beriberi by Maranha˜o State between January and June 2007. A control was a neighbour residing to the right of the case-patient’s residence, who did not have beriberi and did not consume thiamine sup- plements. Data were collected by standard questionnaire. We used McNemar Chi-square, Kruskal-Wallis and Student t-tests. Analysis was conducted in EpiInfo 3.5.2. Serum was collected for determination of thiamine levels (by high performance liquid chromatography9 ), transaminase, cre- atine, kinase and creatine kinase-BB. One kilogram of rice was collected from each case and each control household. Rice was defined as commercial (subject to sanitary inspection) or subsistence farming rice (locally grown and polished in unregulated facilities). At the Instituto de Tecnologia de Alimentos, Brazil, samples were cultured and tested for the presence of mycotoxins, including aflotoxins, ocratoxin, citrinine and citreoviridin.10 Tropical Doctor April 2010, 40 95
  2. 2. Results In 2006 and 2007, 471 cases of beriberi were reported; 142 (30.0%) had onset symptoms in 2007. Of these, 52 (37.0%) were excluded because of incomplete addresses or a different final diagnosis. We enrolled 90 cases and 90 controls. Of the 90 cases, 73 (80.0%) were men, the median age was 31 years (range 14–55) and median schooling was four years (range 0–11). Among the controls, 45 (50.0%) were men, the median age was 25 years (1–86) and median schooling was three years (range 0–11). The median monthly income of the cases was US $131 (range US $0–539) and for the con- trols it was US $185 (US $0–777). For 45 (50.0%) cases the principal employment was field labour and for 43 (45.0%) controls it was homemaking. Cases and controls had a low calculated thiamine intake on a 24-hour food history – 0.7 mg/day (range 0.0–6.0 mg/day) and 0.6 mg/day Figure 1 Drying, polishing and storage of rice from the region of beriberi outbreak, Maranha˜o State, Brazil, 2007. (a) Drying the rice; (b) polishing and storing the rice Table 1 Results of univariate and multivariate analysis of exposures and beriberi, Maranha˜o, Brazil, 2007 Exposures Cases n (%) Controls n (%) mOR 95% CI P value Univariate analysis Male 73 (81) 44 (49) 3.8 1.9–8.6 ,0.01 Alcohol consumption 50 (53) 10 (11) 8.8 3.5–28.4 ,0.01 Smoking 33 (36) 12 (13) 6.0 2.1–23.8 ,0.01 Intense physical activity 79 (88) 66 (73) 2.6 1.1–6.9 ,0.05 Mainly consumes subsistence farming rice 40 (44) 22 (24) 3.1 1.4–8.0 ,0.05 Consumes fermented mandioca flour 55 (61) 50 (55) 1.5 0.6–3.5 0.37 Consumes dry mandioca flour 9 (10) 16 (17) 0.5 0.2–1.3 0.12 Exposures mOR 95% CI P value Multivariate analysis by conditional logistic regression Alcohol consumption 7.8 3.2–19.0 ,0.01 Intense physical activity 4.2 1.5–11.9 ,0.01 Mainly consumes subsistence farming rice 3.2 1.5–7.1 ,0.01 Concurrent hypertension or diabetes 2.7 1.1–6.5 0.03 Male sex 2.4 1.0–5.6 0.04 Years of schooling 1.1 0.9–1.2 0.24 Thiamine intake 1.0 0.50–1.9 1.00 OR, odds ratio; CI, confidence interval Short Report 96 Tropical Doctor April 2010, 40
  3. 3. (range 0.0–5.2 mg/day), respectively (recommended daily intake is 1.2 mg/day). Cases reported symptoms of paresthesia (77.0%); oedema (75.0%) and calf pain (63.0%); 22 (24.0%) were hospital- ized. At the time of interview, 64 (70.0%) were being treated with thiamine and 51 (56.0%) were still symptomatic. On univariate analysis, beriberi was associated with male sex, the consumption of alcohol, smoking, physical activity and consumption of subsistence farming rice. On multi- variate analysis, independently associated factors were: the consumption of alcohol; intense physical activity; consump- tion of subsistence farming rice; co-morbidity; and male sex (Table 1). Serum was collected from case-patients a median of 63 days after thiamine replacement therapy. For case-patients and controls, serum thiamine, transaminase and creatine kinase levels were within normal limits. Eighty-one rice samples were collected: 44 (55%) from case households and 37 (45%) from control households. Fifty-eight (72%) were of polished rice and 23 (28%) samples were paddy. Culture yielded xerophilic growth in 28 (64%) case and 21 (57%) control samples, including Aspergillus penicilioides and A. versicolor. Additionally, fungi producing aflotoxin (A. flavus, A. parasiticus), citrinine (P. citrinum) and ocra- toxin A (A. niger) were isolated. No citreviridin-producing fungi were cultured. Conclusions Cases of beriberi, initially detected in 2006, continue to be reported in Maranha˜o State. In addition to the established risk factors for the disease, we showed that there is an inde- pendent association of illness with the consumption of unin- spected subsistence agricultural rice, as opposed to commercially processed and government inspected rice. The main purpose of our study was to determine whether citreoviridin mycotoxin was present in rice from case-patient homes, given the extensive body of historical and toxicologi- cal research from Japan supporting a role for this mycotoxin in the pathogenesis of beriberi. However, no citreoviridin- producing fungi were identified in rice samples from case- patient or control homes. Accordingly, we cannot conclude that this mycotoxin played a role in this protracted outbreak. The limitations of this study include the obtainment of rice samples weeks to months after the onset of the illness. Samples may not have been from the same stock as that con- sumed before onset of the illness, or may have been of the same stock but, perhaps, had been subjected to conditions that may have modified the fungal flora over time. Additionally, most rice samples were of polished rice. Rice polishing heats rice grains, which could have altered the fungal flora while leaving mycotoxin intact. As no citreoviridin-producing fungi were encountered, we did not test directly for the presence of the toxin. We recommend that the active surveillance and timely treatment of case-patients, thiamine supplementation for the population and quality and safety standards for transpor- tation, storage and processing of subsistence farming rice should be continued. Acknowledgments We thank the officials of the state and the municipal sec- retaries of health in the state of Maranha˜o, Brazil, and col- leagues of the Secretariat of Health Surveillance of the Ministry of Health and the colleagues of Field Epidemiology Training Program of Brazil. References 1 Lonsdale D. A review of the biochemistry, metabolism and clini- cal benefits of thiamin(e) and its derivatives. Evid Based Complement Alternat Med 2006;3:49–59 2 Hoyumpa AM. Mechanism of vitamin deficiencies in alcoholism. Alcohol Clin Exp Res 1986;10:572–81 3 Uraguchi K. Micotoxic origin of cardiac beriberi. J Stored Prod Res 1969;5:27–36 4 Ueno Y, Ueno I. Isolation and acute toxicity of citreoviridin, a neurotoxic micotoxin of Penicillium Citreo-Viride Biourge. Jap J Exp Med 1972;42:91–105 5 Ohtsubo K. Mycotoxins in foodstuffs and their biological action on mammals. Beitr Pathol Bd 1973;148:213–20 6 Murphy PA, Hendrich S, Landgren C, Bryant C. Food mycotox- ins: an update. J Food Sci Chicago 2006;71:51–65 7 Smith JE, Henderson RS. Mycotoxins and Animal Foods. London: CRC Press, 1991 8 Rosa CA, Keller KM, Oliveira AA, et al. Production of citreovir- idin by Penicillium citreonigrum strains associated with rice con- sumption and beriberi cases in the Maranhao State, Brazil. Food Addit Contam Part A Chem Anal Control Expo Risk Assess 2009;29:1–8 9 Chatzimichalakis PF, Samanidou VF, Verpoorte R. Development of a validated HPLC method for the determination of B-complex vitamins in pharmaceuticals and biological fluids after solid phase extraction. J Sep Sci 2004;27:181–8 10 Pitt JI, Hocking AD. Fungi and Food Spoilage. 2nd edn. London: Blackie Academic & Professional, 1997: 593 Short Report Tropical Doctor April 2010, 40 97

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