Sunday, June 23, 2019

Bihar children deaths: Could refeeding syndrome precipitated by litchis be the cause?

Dr KK Aggarwal

What do we know so far about these deaths: Mostly malnourished children < 10 years old, linked to lychee orchids, convulsions early in the morning, no fever, high mortality the same day, all had low sugar but mortality still high even after infusing sugar.

This only means that some other metabolic factor is also at play apart from the sugar.

What might be happening? If significantly malnourished children, who have not eaten food for more than 3 days eat oral carbohydrates (litchi in this case), it can cause electrolyte and fluid shifts that may precipitate disabling or fatal medical complications.

This is the so-called refeeding syndrome characterized by hypophosphatemia, hypokalemia, congestive heart failure, peripheral edema, rhabdomyolysis, seizures, fever and hemolysis.  The hallmark feature is hypophosphatemia.

Rapidly treating hypoglycemia with lychee will harm, if phosphate levels are not managed. The best food in such situations is sugarcane juice and not litchi. Remember, sugarcane is the juice used to break all starvation fasts.

The risk of hypophosphatemia during refeeding appears to be greater in patients who are more severely malnourished and at lower percent of ideal body weight. 

Stores of phosphate are depleted during episodes of starvation. When nutritional replenishment starts and patients are fed carbohydrates, glucose causes release of insulin, which triggers cellular uptake of phosphate (and potassium and magnesium) and a decrease in serum phosphorous levels. Insulin also causes cells to produce a variety of depleted molecules that require phosphate (adenosine triphosphate and 2,3-diphosphoglycer1ate), which further depletes the body’s stores of phosphate.

The subsequent lack of phosphorylated intermediates causes tissue hypoxia, myocardial dysfunction, respiratory failure due to an inability of the diaphragm to contract, hemolysis, rhabdomyolysis and seizures.

Risk factors for the re-feeding syndrome include low baseline levels of phosphate, potassium, or magnesium prior to re-feeding the patient; and little or no nutritional intake for the previous 5 to 10 days. Patients are at the highest risk for the re-feeding syndrome in the first 1 to 2 weeks of nutritional replenishment and weight gain.

Generally, the risk progressively dissipates over the next few weeks if there has been consistent forced intake and weight gain.

Excerpts from Dr T Jacob John, Retired Professor of Virology from CMC Vellore

·         All it would have taken was to ensure that the children had a meal the preceding night
·         The disease is not encephalitis but encephalopathy.
·         Encephalitis results from a viral infection, unless proved otherwise. The pathology is primarily in the brain. Encephalopathy is a biochemical disease, unless proved otherwise.
·         Encephalopathy is eminently treatable.
·         Hypoglycemia is usually due to an overdose of insulin in children with diabetes. It is easily corrected with oral sugar or intravenous glucose. The easily available 5% glucose solution suffices. Hypoglycaemic encephalopathy, however, is different from simple hypoglycemia.
·         The disease broke out during the months when litchi was harvested, i.e. April, May and June. The illness started suddenly; children were found vomiting, displayed abnormal movements, were semi-conscious, and were convulsing between 4 a.m. and 7 a.m. The disease progressed fast — children went into coma and died within a few days. When sick children were tested, the blood glucose level was always below normal.
·         This disease was reminiscent of the Jamaican Vomiting Disease, a form of hypoglycaemic encephalopathy. It is triggered when unripe cake fruits are eaten. These fruits contain a substance, ethylene cyclopropyl alanine, which blocks a biochemical process called fatty acid oxidation, or gluconeogenesis.
·         There are two essential steps: gluconeogenesis is turned on and is then blocked midway by methylene cyclopropyl alanine. The back-up molecules of the unfinished process are certain amino acids that are highly toxic to the brain cells. Ackee and litchi belong to one plant family. We found generous quantities of methylene cyclopropyl glycine in litchi fruit pulp.
·         The disease affected only malnourished children between the ages of two and 10.
·         A majority of them were from families camping in orchards for fruit harvesting. No child from the nearby towns fell ill. Children of well-to-do families never fell ill.
·         Litchi harvest usually begins by 4 a.m., which means that families are awake before that. They go to sleep early. If children go to sleep without dinner, parents usually do not wake them up and feed them. Litchis are collected in bunches and sent to the collection points, but single fruits fall to the ground. Children are free to collect and share the fruits with their friends.
·         After prolonged fasting, malnourished children slipped into hypoglycaemia in the morning. Since they had very little reserve glycogen in their livers, they were unable to mobilise glucose from liver glycogen, unlike well nourished children. The brain needs glucose as a source of energy. As a result of lack of liver glycogen, gluconeogenesis was turned on. Had there not been litchi methylene cyclopropyl glycine, the glucose levels would have been maintained, and the children would have come to no harm. As the children had consumed litchis the previous day, gluconeogenesis had been blocked, aminoacidemia had developed, and brain functions had been affected. Hypoglycaemic encephalopathy had set in.
·         We were unable to demonstrate aminoacidemia in children with hypoglycaemic encephalopathy, but that was done by investigators from the US Centers for Disease Control and Prevention (CDC). The only missing piece in our studies was filled in by CDC colleagues.
·         The disease can be prevented if children are well nourished, but that is not possible in the immediate term. It can also be prevented by ensuring that children eat a meal at night. All families were taught to provide a cooked meal to children before going to sleep at night. Preventing children from eating litchis is not easy, but the quantity of the fruit can be restricted with parental supervision. With all this health education, I was told that the disease number had come down drastically in 2016-18 compared to what it was in 2014-2015. I don’t know what went wrong this year.
·         In 2015, all primary health centres were supplied with glucometers to check the blood glucose levels of sick children. Doctors were instructed to take a blood sample for glucose estimation and, irrespective of the results, infuse 10% glucose intravenously. To correct mild hypoglycaemia, 5% glucose is enough, but here the problem is not hypoglycaemia alone, but aminoacidemia as a result of blocked gluconeogenesis. To prevent any further back-up amino acid from accumulating, the fatty acid oxidation process has to be turned off quickly. That requires raising blood glucose level to abnormally high levels so that insulin secretion is stimulated, and that in turn turns off the gluconeogenesis.
·         If ill children are infused with 10% glucose within four hours of onset of brain dysfunction, recovery is fast and complete. If only 5% glucose is given, or if 10% glucose is not administered within four hours, recovery is unlikely.
·         Glucometers have not been maintained well. Health education was not sustained. New doctors are not familiar with all the information. Instead of 10% glucose, 5% is given.
·         Ambulances take more than four hours to reach the city hospitals from many rural clinics.

The final answer

·         Refeeding syndrome
·         Shortened duration added with litchi toxins
·         Prevention: Evening mid-day meal
·         In hospital, treat low sugar, low phosphates, low magnesium, low potassium

Dr KK Aggarwal
Padma Shri Awardee
President Elect Confederation of Medical Associations in Asia and Oceania   (CMAAO)
Group Editor-in-Chief IJCP Publications
President Heart Care Foundation of India
Past National President IMA

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