Though scientists have claimed that they have solved the two-decade-old mystery, enough questions remain unanswered to suspect that we haven’t seen the bottom of this issue.
Since last week, the litchi fruit has been at the receiving end of much scorn since a study was published accusing it of causing an encephalopathy outbreak in Muzaffarpur, Bihar, in 1995. However, though the scientists involved have claimed that they have ‘solved’ the two-decade-old mystery, enough questions have also remained unanswered to suspect that we haven’t yet seen the end of it.
The study, published in the journal Lancet Global Health on January 30, 2017, discussed the results of a collaboration between scientists from India’s National Centre for Disease Control (NCDC) and the US Centers for Disease Control and Prevention (CDCP). The investigation claims that the scientists zeroed in the cause behind the outbreak in Muzaffarpur, involving seizures, slipping into a coma and claiming the lives of many, mostly children.
According to them, the culprits were toxins in the litchi fruit together with them being consumed on an empty stomach. The outbreak occurs every year and coincides with the litchi harvest season. Muzaffarpur is India’s largest litchi cultivation region. Many children of labourers here consume the fruit as it falls to the ground, while skipping their evening meals. Previous studies had reached different outcomes, including heat stroke and bat viruses.
However, the study found itself embroiled in a controversy for failing to give due credit to prior research by Dr T. Jacob John and Dr. Mukul Das, who had already pointed out the link between the toxins in litchi and the incidence of encephalopathy in malnourished children. The journal has since contacted Dr Das in an attempt to rectify the omission.
But are the toxins in litchi truly behind the annual outbreak or is there more to the story? The research in Lancet points out two toxins, methylene cyclopropyl alanine (MCPA) – or hypoglycin A – and methylene cyclopropyl glycine (MCPG). It draws parallels to ackee fruit poisoning in Africa and West Indies, causing the Jamaican vomiting sickness.
Dr Vipin Vashistha, a paediatrician at the Mangla Hospital and Research Centre, Uttar Pradesh, wrote a counterpoint to Dr John’s analysis in the journal Indian Pediatrics. He told The Wire:
In unripe ackee fruit the concentration of the MCPA, a more potent toxin than MCPG, is very high (around 1,000 microgram/gram) than in unripe litchi (18.5-152 microgram/gram). In the ripe litchi, the concentration of MCPA is even much less than in unripe fruit. Furthermore, no other study from anywhere had detected hypoglycin A in litchi pulp. Similarly, the amount of MCPG is also very low in the ripe fruit than in unripe. MCPA causes hypoglycemic encephalopathy in a dose-dependent manner. The researchers have not made any comment on the amount of toxin needed to produce toxic encephalopathy in sick children. If we take into account the known lethal dose (LD50) of hypoglycin A in animals, around 90-100 mg/kg for rats, a case would need to consume a huge amount of litchi to develop the full-blown encephalopathy syndrome, hardly feasible by a malnourished young child, plus it would result in osmotic diarrhoea.
He added that the availability of unripe litchi fruits is also highly improbable in relation to when the disease peaked: in the first two weeks of June, when the whole crop would have already ripened and matured. He also pointed out the deficient control from the community in the study.
The researchers have chosen an age-matched hospitalised child from the Muzaffarpur district in the same hospital with a non-neurological illness. Ideally, they should have chosen the age-matched control either from the same household (of the affected case) or from the immediate neighbourhood for reliable information regarding the ‘exact risk factor’ for the development of the disease. Hundreds of children residing in the same community would be eating the litchis. They may be excreting the metabolites of MPCA and MCPG and other metabolites in their urine. Why is it that only one or two children out of those who had eaten the litchis developed the encephalopathy? Was it due to large binge? Or due to malnutrition? Or due to skipping the evening meals? Or was there some other risk factor hitherto unidentified?
In his article in Indian Pediatrics, he also stated that, in cases of hypoglycin A toxicity, intravenous dextrose infusions, administered during treatment in the study, have failed to prevent deaths as experiments showed that the action of hypoglycin was not like that of insulin.
The study states hypoglycemia was the key sign of the syndrome. However, Dr. Vashishtha said, “Some degree of hypoglycemia is usually encountered in many paediatric illnesses like acute encephalitis, sepsis, gastroenteritis and pneumonia. The researchers have mentioned the median level of blood glucose as being 2.66 mmol/L, i.e. around 48 mg%, which is only a mild [level of] hypoglycemia. The profound hypoglycemia encountered usually with hypoglycin-A-induced ackee fruit poisoning is missing.”
“Besides”, he added,” hypoglycin A usually leads to dysfunction of mitochondria in many tissues and organs, particularly in liver, brain and the kidneys. But no evidence of hepatic dysfunction was found. The liver enzymes were normal and histopathological examination was not done to demonstrate microscopic changes like fatty degeneration of hepatic parenchyma. Surprisingly, vomiting, the key symptom of hypoglycin A poisoning, was also not reported as a major presenting feature.”
The authors of the Lancet study had also stated, “We conclude that our findings reflect a plausible, but not necessarily sufficient, causal pathway between litchi consumption and illness.”
However, Dr John told The Wire, “Vomiting was a key symptom in the Muzaffarpur hypoglycemic encephalopathy. The illness starts in a child early in the morning with vomiting. As the initial diagnosis was encephalitis, people did not pay attention to vomiting.”
Scientists from the National Research Centre on Litchi (NRCL), in Muzaffarpur, have rejected the Lancet report. Sushil Kumar Purbey, a senior scientist at NRCL, told The Asian Age that tests carried out by the researchers seemed “inconclusive and contradictory in nature,” adding that they were “preparing a reply that we will send to the researchers associated with these findings soon.”
Brij Mohan, a professor of paediatrics at the S.K. Medical College in Muzaffarpur observed that most children who died had low blood-glucose levels but they were all malnourished and that the number of children brought to the hospital had reduced significantly to 60 admissions in 2016. He told Scroll.in, “Children are still eating litchis but not falling ill. There is more to this.”
According to Dr John, MCPA and MCPG are not usual toxins – like the cyanogens of cassava that causes massive liver cell necrosis. He explain, “MCPG does not cause liver cell necrosis. Healthy, well-nourished person can eat a lot of litchis without coming to harm. Overnight fasting and even longer fasting for religious purposes are fine as glucose is supplied from glycogen stored in the liver. But when the glycogen store is depleted, we need to keep blood glucose level normal to protect brain cells from starvation.”
One way or another, the Lancet study has cast shadows over the consumption of litchis. Perhaps there is more to this – as Mohan says – or perhaps their isn’t, but further research is definitely necessary to settle the dispute as well as better understand the syndrome that has already claimed so many lives.
Note: This article was updated on February 15, 2017, to include Dr T. Jacob John’s response.