More than 270 plant species have been identified as having hypoglycemic potential. Many of these plants are used in developing countries in the treatment of diabetes. The most well known of these plants are listed below:
Most of the plants studied have shown minimal-to-moderate effects on glucose regulation, with the exception of ackee fruit and bitter melon. Bitter melon produces hypoglycemia via steroidal saponins (charantin, insulinlike peptides, and alkaloids), but it has never been reported to result in fatality. Methylenecyclopropylglycine (MCPG) and hypoglycin A (HGA) are naturally-occurring amino acids found in some soapberry fruits. Fatalities have been reported worldwide as a result of HGA ingestion, and exposure to MCPG has been implicated recently in the Asian outbreaks of hypoglycemic encephalopathy.[1]
This article focuses on the potentially fatal effects produced by ackee fruit ingestions due to HGA contained in the fruit.[2] In addition, several references regarding other plants with hypoglycemic effects have been included.
Ackee fruit is produced biannually by the tropical evergreen tree, Blighia sapida. Although indigenous to West Africa, it is commonly found in the Caribbean islands, Central America, South America, and southern Florida. In South America, the fruit has been used to treat colds, fever, and diseases as varied as edema and epilepsy, though no clinical trials support these uses. In Jamaica, ackee fruit is a food staple, commonly prepared like scrambled eggs or boiled with fish. The fruit itself is 10 cm wide and weighs 100 g. It houses 3 glossy, black seeds contained within a straw- to red-colored husk and covered by a thick, oily appearing yellow aril. The outer aril is closed in unripe ackee fruit. Upon ripening, the aril spontaneously opens.
Unripe fruit and the water used to cook it are toxic and cause Jamaican vomiting sickness when ingested (see Ackee Fruit Toxicity).[3, 4] Fatal epidemics of this illness have been well studied in Haiti, West Africa, and Jamaica. These epidemics tend to coincide with food shortages. The disease is characterized by profound hypoglycemia and intractable vomiting. Before widespread recognition of the hypoglycemia produced by this illness, the mortality rate approached 80%.
For patient education resources, see the First Aid and Injuries Center, as well as Food Poisoning, Poisons, and Activated Charcoal.
Two water-soluble toxins are present in unripe ackee fruit, hypoglycin A and hypoglycin B. Hypoglycin A is L-alpha-amino-beta-[methylene cyclopropyl]propionic acid. Hypoglycin A is found in both the aril and the seeds of the unripe fruit. Hypoglycin B is a gamma-L-glutamyl derivative of hypoglycin A and is found only in the seeds of the fruit.
Hypoglycin A is metabolized by transamination and oxidative decarboxylation to form methylenecyclopropylacetic acid (MCPA). MCPA then forms nonmetabolizable carnitine and coenzyme A (CoA) esters, rendering them unavailable for other metabolic reactions. Hypoglycemia results because CoA and carnitine are required for long-chain fatty acid oxidation, and oxidation is required for gluconeogenesis. Thus, hypoglycemia results from an inability to perform gluconeogenesis. This inhibition of fatty acid metabolism also results in the accumulation of unusual dicarboxylic acids that are subsequently excreted in the urine such as 2-ethyl malonate, 2-methyl succinate, glutarate, and adipate.
Additionally, MCPA inhibits acyl-CoA dehydrogenases. Inhibition of butyryl CoA dehydrogenase stops the oxidation of long-chain fatty acids at the level of hexanoyl CoA and butyryl CoA, causing decreased production of nicotinamide adenine dinucleotide (NADH) and acetyl CoA. Their lowered concentration further inhibits gluconeogenesis. Hypoglycin A does not affect insulin release or serum insulin levels in animal models.
It is postulated that increased concentrations of glutaric acid may have an inhibitory effect on glutamic acid decarboxylase, causing a decrease in GABA production and an increase in concentration of glutamate. This mechanism can explain the proconvulsive effect of hypoglycin A.
Causes include ingestion of unripe ackee fruit, canned ackee fruit, ackee fruit that has been forcibly opened or water in which unripe ackee fruit has been cooked.
The true incidence of ackee poisoning is unknown. Ackee fruit sales are illegal in the United States, likely leading to underreporting. Cases have been reported after consumption of fruit illegally shipped or transported by travelers. Several isolated, nonfatal cases have been reported in Ohio, Connecticut, and New York.
In 2000, the US lifted a decades-old ban on the importation of ackee fruit. More recently, the Food and Drug Administration (FDA) is considering modifying the importation of ackee. Research by Whitaker et al has led to evaluation of sampling plans to detect hypoglycin A in ackee fruit. This research will help the FDA to develop a cost-effective monitoring program to reduce lots of misclassified product and to increase consumer safety.[5, 6]
Jamaica: Although endemic to Jamaica, the epidemiology of ackee poisoning is not well characterized. The true incidence is likely underreported. Incidence has been estimated at 2 cases per 100,000 annually for persons younger than 15 years and 0.4 case per 100,000 persons annually for those older than 15 years.[7]
West Africa: Based on recent epidemics, the incidence in children aged 2-6 years is estimated to be about 40 cases per 100,000 population.
Other: Most cases occur in developing nations in Africa and the Caribbean. Incidence rates in other areas have not been well studied.
Reported cases in Africa, Jamaica, and Haiti occurred in blacks.
In reported cases, no difference in sex distribution was noted.
Poisoning is more common in persons younger than 15 years, and severe poisoning is more common in the pediatric population.
Prognosis is good if unripe ackee fruit ingestion is promptly recognized and appropriately managed; however, deaths do occur. Ackee poisoning has killed an estimated 5,000 people since 1886. Children are more likely than adults to experience fatal complications of ackee poisoning. The most well-studied epidemics have been in Haiti, Jamaica, and West Africa.
Jamaica: Large-scale poisonings reach epidemic proportions typically during the winter months. Between January 1989 and July 1991, 28 patients reported symptoms of ackee poisoning. Six of 28 patients died. The most common symptoms were vomiting, coma, and seizures. Seven of the patients had confirmed hypoglycemia. Most of the cases occurred between January and March.[7]
West Africa: In 1998, in Burkina Faso, an epidemic of fatal encephalopathy was linked to ackee poisoning. Between January and May of 1998, 29 children aged 2-6 years died. The clinical presentation was similar to that of Jamaican vomiting sickness and toxic hypoglycemic syndrome; the most common symptoms included hypotonia, convulsions, and coma.[8]
Haiti: From November 2000 to March 2001, 60 cases with symptoms consistent of ackee poisoning (ie, continuous vomiting, abdominal pain, loss of consciousness, convulsions within 24 h) were recorded in 2 districts of Haiti's Northern Province. Retrospective analysis confirmed 31 of the 80 cases were related to consumption of ackee fruit. The mean age of the victims ranged from 6 months to 88 years, with a median of 7 and an average of 16. The case-fatality rate was 52%.[9]
Typically, ackee fruit poisoning causes epidemics, with multiple children becoming ill. The patient may provide a history of ingesting unripe ackee fruit or water in which unripe ackee had been cooked. More than one family member may be ill.
Sudden onset of vomiting begins 2-6 hours after ingestion with generalized epigastric discomfort. However, symptoms may appear within minutes.
After a period of prostration lasting up to 18 hours, a second bout of vomiting may occur. Unless treatment is given, this episode can progress to seizures, coma, and death. In severe poisoning, death usually occurs within 12 hours after ingestion.
Nausea and vomiting occur in 75% of patients; severe vomiting may be followed by a quiescent phase, followed by recurrent vomiting. Diaphoresis and pallor may be observed. Tachypnea, tachycardia, and hypotension due to dehydration may be noted. Weakness and paresthesias may be present. Seizures, generalized tonic clonic, occur in 24% of patients. Drowsiness and coma occurs in 25% of patients. Mortality in severe, untreated cases can reach 80%.
Laboratory studies include:
Nonenhanced head CT may be performed to exclude intracranial pathology as a cause for altered mental status, seizures, or focal neurologic deficits.
Gas chromatography of urine: Excess excretion of medium-chain dicarboxylic acids, such as 2-ethylmalonic, 2-methylsuccinic, and glutaric acid, is a distinctive finding in this illness.
Presence of positive serum or urine level of hypoglycin A or its metabolite methylenecyclopropyl acetic acid (MCPA) indicates exposure to ackee fruit.
Autopsy findings include massive steatosis of the liver (comparable with Reye syndrome).
Endotracheal intubation: A secure airway may be necessary for patients presenting with seizures or coma.
Intravenous access: Intravenous access may be needed to administer glucose-containing solutions, intravenous antiemetics and anticonvulsants, and volume resuscitation.
Prehospital providers are unlikely to be familiar with or recognize hypoglycemic plant poisoning, but can usually treat both seizures and hypoglycemia in the prehospital setting.
Both seizures and hypoglycemia, as well as airway compromise, should be treated according to local protocols.
Intravenous or intraosseous access should be obtained and administration of dextrose, benzodiazepines (if needed to control seizures), and dextrose-containing intravenous fluid, as necessary, should be provided.
Intranasal benzodiazepines may be useful in the actively seizing patient in whom intravenous or intraosseous access is difficult or unsuccessful.[11, 12]
ED management of ackee poisoning is mainly supportive.
Obtain a rapid fingerstick glucose and initiate early glucose replacement with D50W boluses (D25W boluses in young children and D10W in neonates) and continuous infusions of 10% dextrose, as needed.
Airway assessment and endotracheal intubation, if necessary, should be performed.
Activated charcoal may be administered once the airway is secured.
Electrolyte status should be assessed.
Antiemetics such as metoclopramide, ondansetron, or granisetron may be administered for profuse vomiting.
Seizure precautions should be followed; treat seizures with benzodiazepines and dextrose.
Theoretically, L-carnitine could be beneficial similar to its effect in valproic acid toxicity.
Methylene blue has a theoretical benefit in ackee fruit poisoning, but animal studies do not show any benefit over early glucose administration alone.[13] There are no data in humans.
There are no data on the use of glucagon or octreotide in the treatment of hypoglycemia associated with hypoglycemic plant poisoning.
Patients with the following conditions after ackee fruit poisoning should be admitted to the hospital:
The local poison center should be contacted. Consultation with a toxicologist may be helpful. Contact public health authorities for suspected outbreaks.
Patients and their families should be educated about the risks of unripe ackee fruit ingestion. Education of tribal witch doctors on the danger of ackee fruit has successfully decreased use as a medicinal substance.[14]
Supportive treatment with glucose, fluid, and electrolyte replacement is the mainstay of therapy. Antiemetics are used to control vomiting, and benzodiazepines are used to control seizures. Supplemental carnitine may be considered, although it has not been studied in this context.
Clinical Context: Emergency treatment in poisoning caused by drugs and chemicals. Network of pores present in activated charcoal adsorbs 100-1000 mg of drug per gram of charcoal. Does not dissolve in water.
For maximum effect, administer as soon as possible after ingesting poison.
These agents are used to adsorb toxin in the GI tract, limiting systemic adsorption.
Clinical Context: Monosaccharide absorbed from the intestine and then distributed, stored, and used by the tissues.
Parenterally injected dextrose is used in patients unable to sustain adequate oral intake. Direct oral absorption results in a rapid increase in blood glucose concentrations.
Dextrose is effective in small doses, and no evidence exists that it may cause toxicity. Concentrated dextrose infusions provide higher amounts of glucose and increased caloric intake in a small volume of fluid.
Clinical Context: May facilitate transport of fatty acids into mitochondria. Carnitine has been used successfully in treatment of chronic valproate toxicity associated with hyperammonemia. Chronic valproate toxicity is thought to inhibit carnitine-dependent transfer of fatty acids from cytosol into mitochondria for beta-oxidation.
Dextrose is used to reverse hypoglycemia. Carnitine, an amino acid derivative, is synthesized from methionine and lysine and is required in energy metabolism. It can promote excretion of excess fatty acids in patients with defects in fatty acid metabolism or specific organic acidopathies that bioaccumulate acyl CoA esters.
Clinical Context: Acts primarily on somatostatin receptor subtypes II and V. Inhibits GH secretion and has a multitude of other endocrine and nonendocrine effects, including inhibition of glucagon, VIP, and GI peptides. Inhibits insulin release.
These agents are used to reduce blood levels of GH glucagon and VIP peptides.
Clinical Context: Sedative hypnotic with short onset of effects and relatively long half-life.
By increasing the action of gamma-aminobutyric acid (GABA), which is a major inhibitory neurotransmitter in the brain, may depress all levels of CNS, including limbic and reticular formation.
Important to monitor patient's blood pressure after administering dose. Adjust as necessary.
Clinical Context: Selective 5-HT3-receptor antagonist that blocks serotonin both peripherally and centrally. Prevents nausea and vomiting associated with emetogenic cancer chemotherapy (eg, high-dose cisplatin) and complete body radiotherapy.
Clinical Context: Stimulates motility of the upper GI tract. Dopamine antagonist that stimulates acetylcholine release in the myenteric plexus. Acts centrally on chemoreceptor triggers in the floor of the fourth ventricle, providing important antiemetic activity.
Clinical Context: At chemoreceptor trigger zone, blocks serotonin peripherally on vagal nerve terminals and centrally.
Antiemetics may be used to control severe and persistent vomiting. Agents in this class may also prevent nausea and vomiting associated with emetogenic cancer chemotherapy