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Litchis – other than simply delicious?

You may be aware of a recent media story describing childhood deaths in India following litchi (Litchi chinensis) consumption. It arises from a study entitled Association of acute toxic encephalopathy with litchi consumption in an outbreak in Muzaffarpur, India, 2014: a case-control study by a large authoritative team of Indian and US researchers that was published in one of The Lancet specialty journals (Lancet Global Health, January 30, 2017). Here is a summary of their work covering the essence of the problem, how they tackled it and what they found:

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. In this hospital-based surveillance and 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 each 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 (HPGA) 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 odds ratios. 

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 concentrations of 3.9mmol/L or less. 104 cases were compared with 104 age-matched hospital controls. The matched odds ratio for illness with litchi consumption was 9.6, visiting a fruit orchard it was 6.0 and for the absence of an evening meal in the 24hr preceding illness onset 2.2. Among those who consumed litchis, cases were more likely to have eaten unripe or rotten litchis (7.9 and 7.4 respectively). The absence of an evening meal significantly modified the effect of eating litchis – with and without the evening meal odds ratios were 3.6 and 7.8 respectively. Tests for infectious agents and pesticides were negative. Metabolites of HPGA , MCPG, or both were detected in 48 [66%] of 73 urine specimens from case-patients and none from 15 controls; 72 (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, HPGA 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. 

Our investigation suggests an outbreak of acute encephalopathy in Muzaffarpur associated with both HPGA 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.

Does this mean litchis could be a health risk for we who live in the West, even if you haven’t had an acute problem serious enough to require hospitalisation? The reassuring answer is most likely no, given (i) we have more than an ample supply of a wide range of alternative and affordable foods, leading to better overall nutrition in the population and (ii) litchis are mainly grown in tropical developing countries and their price and availability elsewhere can substantially limit possible over-consumption. Relevant features of this question follow.

HPGA and MCPG are two non-standard homolog amino acids produced as secondary phytochemicals, not only by litchi plants but also by many others in the Sapindaceae family, such as rambutan, longan and ackee. All species in the plant kingdom have evolved over eons to synthesise many thousands of these non-nutrient chemicals for all sorts of reasons, including as protective agents from pests, diseases and fauna (herbivory), and even for competing with other plants (allelopathy). When consumed, compounds like antioxidants have very beneficial spin-off effects for our health and well-being and others are downright poisonous that we never knowingly eat, eg strychnine produced by Strychnos nux-vomica.

Many plants have anti-nutrient factors (eg pulses) or bitter agents like oleuropein in table olives that lie somewhere in the middle ground between the all good/all bad extremes that we can learn to manipulate within certain acceptable levels without total rejection. The all-or-none acceptance approach would leave us very short in the food security and nutrition stakes. Reduction or alteration of key harmful or unpleasant substances can happen in a number of ways including learning when the plant itself solves the problem for us (eg astringent tannins with persimmon ripening), or breeding better varieties (eg lowering erucic acid in canola oil), or processing the food in some way such as soaking, drying or cooking.

With the ackee the pharmacological effects of HPGA and MCPG were documented way back in the 1930s and later it was suggested they may have some connection with Jamaican vomiting sickness that was sometimes fatal. This was particularly important in that country because it’s their national dish and is heavily consumed. Since that time deaths from ackee have been reported in many other countries (the Ivory Coast, Burkina Faso, Togo, Haiti and the US) and as a consequence the US government banned all fruit importation in the 1970s. Later however a more flexible approach was instituted where similarly to contaminant and pesticide residues, importation was then allowed provided acceptable levels were not exceeded.

In the 1990s, toxicity reports associated with litchi and other Sapindaceous fruits containing HPGA and MCPG appeared, but as the present study indicates it had not been possible to definitively establish they were the reason for hospital admissions and fatalities. All sorts of nebulous causes had subsequently been suggested (it was called the ‘mystery disease’ for years), although in India the association with the litchi season each year had been noted. Nevertheless, association does not represent proof of cause and effect and the evidence for this had to wait till the cited study finally brought together the epidemiology, the known pharmacology and toxicology of HPGA and MCGP, detection of the known metabolites in the urine of affected children, and exclusion of other suggested causes including drinking water, heat stroke, unusual medications, viral infections and exposure to pesticides, herbicides or heavy metals.

How is it that litchis are so much enjoyed round the world and this possible negative effect is not more widely recognised? In litchi-growing areas of Bangladesh and Vietnam there had been similar reports to those in India, but again without any clear identification of the cause/s. Most Indian cases have been recorded with fatalities early in the morning, and in young children from poor socio-economic backgrounds rather than the adults. Many of these children suffer from various degrees of on-going malnutrition and have limited body stores of glycogen that can be metabolised in times of need to maintain blood glucose levels, the essential energy source for the brain.

In the main litchi growing areas of India, the harvest is undertaken mainly by itinerant worker families who camp on site during the harvest season. Litchis are sold commercially by the bunch and free fruit is basically un-marketable. So given food is in short supply for these people, the children may feast on the readily-available fallen fruit throughout much of the day while their parents work in the orchards. As a consequence they can consume large quantities and then be un-interested in having a properly cooked evening meal. Plus as children they likely pay less attention to only eat ripe fruit as it’s now known that HPGA and MCPG levels in unripe fruit are much higher. HPGA and MCGP block the breakdown of glycogen to glucose, so these children rapidly become severely hypoglycemic (31% of cases in the above study had blood glucose levels of 1.7mmol/L or less) to the extent of life-threatening delirium, coma, acute febrile seizures etc without aggressive intervention.

Compounding the problem, these two substances interfere with fatty acid metabolism (found in 89% of cases in the study) that could otherwise supply an alternative source of energy. With these pharmacological effects they recommended that the first corrective treatment step for admitted patients is to immediately supply glucose. As quoted above, for children who had gorged on litchi all day the illness odds ratio for those who didn’t eat an evening meal compared to those who did and therefore had the chance to replenish glucose and glycogen levels overnight was more than halved (7.8 vs 3.6). The possibility that the hypoglycemic activity of HPGA and MCPG could be therapeutically useful in the management of diabetes is currently being studied.

The take home message is to only ever eat the flesh (aril) of fully ripe fruit; some HPGA and MCPG is still there but 3-5 fold less than that in unripe fruit. For comparison in ackee, the HPGA concentration ratio of unripe to ripe fruit is 10-100 fold, and consequently there are very strong recommendations that it should only ever be eaten when fully ripe (capsule open). Litchi seeds should not be eaten at all as they have approximately 20 times the level of HPGA as ripe fruit, plus they also have an additional hypoglycin (hypoglycin B) which can increase as the fruit ripens. As concluded in the Lancet Editorial commenting on the above study, we in the West can be reasonably confident of enjoying litchis without great concern provided a properly balanced diet is maintained where litchi or other Sapindaceous fruit like rambutan and longan are only eaten as a snack and don’t become the main course. With this attitude, you can go ahead and relish the exquisite flavour and aroma of these beauties the next time you think you deserve that special treat!