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Friday, February 3, 2017

(The Lancet) 過量食用荔枝(litchi, Lychee)小心hypoglycin A, MCPG (methylenecyclopropylglycine): 低血糖抽搐


印度百童怪病亡 疑因空腹吃荔枝 20170203日【國際中心╱綜合報導】印度東北部一個小鎮每年夏天都有數百名兒童突然發高燒、抽搐,上百人因此死亡。專家研究多年,發現死因可能跟當地盛產的荔枝有關。近日刊於《刺胳針-全球衛生》期刊的研究指,印度穆札佛普爾鎮2014年時,近400名兒童突然染怪病,其中122人死亡。起初專家以為是貧窮地區營養不足或吃太多含農藥的農作物導致。但印度與美國專家聯手調查發現,染病的兒童發病前通常吃了許多荔枝,回家後可能就不想晚飯,導致血糖降低。正常狀況,血糖降低後,身體開始代謝脂肪酸,製造所需的葡萄糖,但這些病童的尿液樣本顯示,約2/3病童體內含存在於荔枝種子的毒素、次甘氨酸,使其體內無法合成葡萄糖。血糖過低時很快就出現急性腦腫而抽搐、失去知覺等症狀。印度政府前天據此研究,呼籲家長限制孩童吃荔枝的量且確保一定要吃晚餐。但研究也稱,盛產荔枝地區的兒童約每百人才1人發病,顯示可能不僅和吃荔枝有關,可能還包括遺傳基因變異等問題,須進一步研究。林口長庚臨床毒物科主任顏宗海昨表示,荔枝糖分高,吃多會致血糖升高,印度例子較特別,不能以單一因素解釋,有可能是小朋友本身營養不良,或遺傳基因變異,加上空腹大量吃荔枝,導致低血糖。台灣臨床沒有大量吃荔枝導致低血糖的病例。他提醒,若家人出現大量冒汗、意識不清,甚至抽搐或昏迷,可能是血糖過低的警訊,趕緊讓他們吃一顆糖並盡快送醫。

Lychee identified as cause for mystery deadly childhood illness in India Updated yesterday at 2:13pm For more than two decades, apparently healthy children in the Indian region of Bihar suffered sudden seizures and lost consciousness. A third of them died, leaving doctors baffled. But a team of American and Indian scientists say they have found the cause of the mystery illness, which killed more than 100 children a year: eating too many lychees on an empty stomach. The research, published in medical journal The Lancet, has found lychees — particularly unripe fruits — contain an amino acid that affects blood glucose levels. "Parents in affected villages report that during May and June, young children frequently spend their day eating lychees in the surrounding orchards; many return home in the evening uninterested in eating a meal," the researchers wrote, saying most children then arrived at hospital unconscious or having seizures in the middle of the night or early morning.  In South-East Asia, outbreaks of similar illnesses have been reported from lychee-growing areas of Bangladesh and Vietnam. 

How has this link not been made before?  The researchers said the lychee's potential toxic effects were noted in ancient literature from China, where the fruit originates, however the commercial lychee industry in India is relatively young and has expanded quickly. "This knowledge has been slow to reach certain parts of Asia where the so-called mysterious lychee disease has been attributed to various causes (fruit colouring, heat stroke) in Bihar, India, to an unidentified pesticide in north-west Bangladesh and, after an exhaustive negative virological search, to a yet-to-be-discovered neurotropic virus in northeast Vietnam," Professor Peter Spencer and Dr Valerie Palmer wrote in a Lancet paper discussing the research. The amino acid found to be the culprit is found in the fruit of many members of the Soapberry family, which also includes the lychee, along with rambutan, longan and ackee. To guard against the illness, the researchers recommended minimising lychee consumption and making sure children had an evening meal. The children's age and state of nourishment were also factors. If a child did become ill, the researchers said they should be treated quickly to correct their glucose levels to prevent lasting damage such as mental impairment, muscle weakness and movement disorders.  "Fortunately, the high cost of these imported fruits and the likelihood that would be eaten in small quantities by well-nourished consumers, suggests there is little reason for concern in the USA," Professor Spencer and Dr Palmer noted.  However, lychee production is increasing in Australia. The researchers also said there were now studies looking at how to put the lychee's glucose-lowering properties to good use in treating metabolic syndrome.

Association of acute toxic encephalopathy with litchi consumption in an outbreak in Muzaffarpur, India, 2014: a case-control study  (The Lancet) , Published: 30 January 2017

Background Outbreaks of unexplained illness frequently remain under-investigated. In India, outbreaks of an acute neurological illness with high mortality among children occur annually in Muzaffarpur, the country's largest litchi cultivation region. In 2014, we aimed to investigate the cause and risk factors for this illness.

Methods In this hospital-based surveillance and nested age-matched case-control study, we did laboratory investigations to assess potential infectious and non-infectious causes of this acute neurological illness. Cases were children aged 15 years or younger who were admitted to two hospitals in Muzaffarpur with new-onset seizures or altered sensorium. Age-matched controls were residents of Muzaffarpur who were admitted to the same two hospitals for a non-neurologic illness within seven days of the date of admission of the case. Clinical specimens (blood, cerebrospinal fluid, and urine) and environmental specimens (litchis) were tested for evidence of infectious pathogens, pesticides, toxic metals, and other non-infectious causes, including presence of hypoglycin A or methylenecyclopropylglycine (MCPG), naturally-occurring fruit-based toxins that cause hypoglycaemia and metabolic derangement. Matched and unmatched (controlling for age) bivariate analyses were done and risk factors for illness were expressed as matched odds ratios and odds ratios (unmatched analyses).

Findings Between May 26, and July 17, 2014, 390 patients meeting the case definition were admitted to the two referral hospitals in Muzaffarpur, of whom 122 (31%) died. On admission, 204 (62%) of 327 had blood glucose concentration of 70 mg/dL or less. 104 cases were compared with 104 age-matched hospital controls. Litchi consumption (matched odds ratio [mOR] 9·6 [95% CI 3·6 – 24]) and absence of an evening meal (2·2 [1·2–4·3]) in the 24 h preceding illness onset were associated with illness. The absence of an evening meal significantly modified the effect of eating litchis on illness (odds ratio [OR] 7·8 [95% CI 3·3–18·8], without evening meal; OR 3·6 [1·1–11·1] with an evening meal). Tests for infectious agents and pesticides were negative. Metabolites of hypoglycin A, MCPG, or both were detected in 48 [66%] of 73 urine specimens from case-patients and none from 15 controls72 (90%) of 80 case-patient specimens had abnormal plasma acylcarnitine profiles, consistent with severe disruption of fatty acid metabolism. In 36 litchi arils tested from Muzaffarpur, hypoglycin A concentrations ranged from 12·4 μg/g to 152·0 μg/g and MCPG ranged from 44·9 μg/g to 220·0 μg/g.

Interpretation Our investigation suggests an outbreak of acute encephalopathy in Muzaffarpur associated with both hypoglycin A and MCPG toxicity. To prevent illness and reduce mortality in the region, we recommended minimising litchi consumption, ensuring receipt of an evening meal and implementing rapid glucose correction for suspected illness. A comprehensive investigative approach in Muzaffarpur led to timely public health recommendations, underscoring the importance of using systematic methods in other unexplained illness outbreaks.

Funding US Centers for Disease Control and Prevention.

Evidence before this study We searched PubMed between Jan 30, and April 30, 2013, before our 2013 field investigation, for any studies related to the acute unexplained neurological illness in Muzaffarpur using the search terms "Muzaffarpur," AND ("encephalitis" OR "encephalopathy" OR "seizure.") This identified two articles that suggested potential causes for the outbreak illness varying from Japanese Encephalitis virus, another unknown virus, to heat stroke. Following the results of our 2013 investigation, which suggested hypoglycaemia might be an important factor in illness, and raised the possibility of a toxic origin, we repeated a PubMed search in December, 2013, using terms ("ackee hypoglycin" OR "ackee encephalopathy" OR "glycine analog AND litchi" OR "litchi encephalopathy" or "litchi methylenecyclopropylglycine" (MCPG), OR "Jamaican vomiting sickness") for studies describing an association between litchis, ackee fruit, hypoglycin, MCPG and acute neurologic illness published between Jan 1, 1954, and Dec 1, 2013. We found 61 studies; 11 described cases or outbreaks of ackee fruit poisoning which implicated hypoglycin toxicity; an additional 11 studies described the pathophysiology of hypoglycin A in animal models, and five described methods to characterise hypoglycin A in ackee fruits. An ecological study from 2012 from Vietnam indicated an association between litchi plantation surface area and acute encephalitis incidence. A study from 1962 described the isolation of MCPG in litchi seeds, and two studies from 1989 and 1991 described the hypoglycaemic effect of MCPG in animal studies. No studies implicated a direct epidemiological association between litchi consumption in affected individuals and encephalopathy. No studies showed hypoglycin or MCPG or their metabolites in affected individuals.

Added value of this study This study, to the best of our knowledge, is the largest investigation of the Muzaffarpur outbreak and the first comprehensive confirmation that this recurring outbreak illness is associated with litchi consumption and toxicity from both hypoglycin A and MCPG. We confirm the presence of MCPG and hypoglycin in litchis, and, for the first time, our data show the metabolites of these toxins in human biological specimens, the biological impact of these toxins on human metabolism, and the modifying effect of the lack of an evening meal on the impact of these toxins.

Implications of all the available evidence  Based on the results of our investigation, public health and clinical recommendations targeted at preventing illness and reducing morbidity and mortality from the Muzaffarpur outbreak illness were provided to state and national health authorities. This included recommendations to minimise litchi consumption among young children in the affected area, to ensure that children receive an evening meal throughout the outbreak period, and to rapidly assess and correct hypoglycaemia in any child suspected of having the outbreak illness. Evaluation of other potential factors, including missed evening meal, poor nutritional status, and as yet unidentified genetic differences, may provide further insights into additional risk factors for this outbreak illness. Application of a similar comprehensive and systematic approach to the evaluation of both infectious and non-infectious aetiologies of unexplained illness outbreaks in other parts of the world has the potential to contribute toward identifying interventions that can reduce morbidity and mortality.

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