power point presentation of Clinical evaluation of strabismus
Beriberi
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. 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. (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.
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