The enigma of litchi toxicity: an emerging health concern in southern Asia.

How is it possible that lychee, a deliciously sweet tropical fruit, could induce a fatal hypoglycemic encephalopathy in children? The answer is straightforward: the edible fruit (aril) of lychee or litchi (Litchi sinensis or Litchi chinensis), and other members of the Soapberry family (Sapindaceae), contains unusual amino acids that disrupt gluconeogenesis and β-oxidation of fatty acids. This is well established in relation to both litchi fruit and, more particularly, fruit of its cousin, the ackee plant (Blighia sapida), a member of the Sapindaceae originating in west Africa and transplanted in the 18th century to the Caribbean. Ingestion of immature ackee fruit has been known for decades in Jamaica to cause a toxic hypoglycaemic encephalopathy (Jamaican vomiting sickness) in children. This knowledge has been slow to reach certain parts of Asia where the so-called mysterious litchi disease has been attributed to various causes (fruit colouring, heat stroke) in Bihar, India, to an unidentifi ed pesticide in northwest Bangladesh and, after an exhaustive negative virological search, to a yet-to-be-discovered neurotropic virus in northeast Vietnam. However, the illness evolves far too quickly to be a viral disorder, with a median time of 20 h from health to death in Bangladeshi children. In The Lancet Global Health, Aakash Shrivastava and colleagues’ study of Indian children with litchi-associated encephalopathy unequivocally pins the blame on the litchi fruit itself, as predicted by previous Indian investigators and by us. Like most, if not all, neurotoxic factors, the separation between chemicalinduced health and illness depends on dosage and individual susceptibility, which in this case translates to the number of litchi fruit consumed and the concentration of hypoglycaemic amino acids, as well as the children’s age and state of nourishment. Shrivastava and colleagues report that, akin to ackee, the unripe fruit of litchi has a higher concentration of hypoglycin A and its lower homologue, α-(methylenecyclopropyl) glycine; the reported absence of a signifi cant diff erence between the two probably arises from the small number of fruit samples tested (n=6 per batch of ripe and unripe fruit). Unfortunately, the study did not compare litchi-associated cases with controls drawn from the community and, strangely, cases were compared with sick controls lacking neurological disease and no history in the previous 3 months of altered mental status or seizures, and admitted to a case-surveillance hospital less than 7 days from admission of the case. That well-established data for Sapindaceae toxicity have long existed from clinical experience in Africa and the Caribbean is an important lesson for global health and neurotoxicology. A worldwide understanding of the adverse eff ects on the nervous system of both naturally occurring as well as synthetic chemicals will speed diagnosis and treatment of other mysterious epidemics of environmental brain disease. The Indian subcontinent is no stranger to the neurological eff ects of toxins in plants—eg, food dependency on the grass pea or cassava resulting in the spastic parapareses of lathyrism and cassavism, respectively. Unlike these untreatable self-limiting neurological diseases, litchi and ackee encephalopathy can be arrested by restoring serum glucose concentrations. However, some children reportedly are left with cognitive defi cits, muscle weakness, or movement disorder; the causes of which require investigation. Why is seasonal litchi encephalopathy a relatively recent event in India, Bangladesh, and Vietnam? The most plausible explanation is the rapid expansion of commercial litchi production across Asia and beyond. Indian production is second only to China’s, from where Litchi sinensis originates and its potential toxic eff ects are noted in ancient literature. Today, several Asian countries export litchi and other Sapindaceae, including rambutan (Nephelium lappaceum) and longan (Dimocarpus longan) for consumption abroad. In the USA for instance, unlike the regulated importation of canned ackee fruit, which must be screened for hypoglycin content, there are no restrictions on other members of the Soapberry family, including litchi. 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. There is, however, cause for major concern that litchi-induced seasonal toxic hypoglycaemic Lancet Glob Health 2017