AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Background

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: 

• Herb fenugreek (Trigonella foenum-graecum)
• Bitter melon gourd (Momordica charantia)
• Climbing ivy gourd (Coccinia indica)
• Mamijava (Enicostemma littorale)
• Asian ginseng (Panax ginseng)
• American ginseng (Panax quinquefolius)
• Siberian ginseng (Eleutherococcus senticosus)
• Ackee tree (Blighia sapida)
• Prickly pear (Opuntia robusta)
• Yellow bells (Tecoma stans [family Bignoniaceae])

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. This article focuses on the potentially fatal effects produced by ackee fruit ingestions. Ackee fruit causes profound hypoglycemia due to hypoglycin A, a toxic compound contained in the fruit. 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.

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%.

Pathophysiology

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.

Frequency

United States

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.

International

• 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.¹
• 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.

Mortality/Morbidity

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.¹
• 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.² 
• 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%.³

Race

Reported cases in Africa, Jamaica, and Haiti occurred in blacks.

Sex

In reported cases, no difference in sex distribution was noted.

Age

Poisoning is more common in persons younger than 15 years, and severe poisoning is more common in the pediatric population.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

History

• 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.

Physical

• 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.
• Death in severe, untreated cases can reach 80%.

Causes

• 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.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Other Problems to be Considered

Fatty liver of pregnancy
Chronic valproic acid use
Chronic nucleoside analog (eg, didanosine [DDL], zidovudine [AZT]) use
Ingestion of outdated tetracycline
Ingestion of oral hypoglycemics (sulfonylureas) (eg, metformin, phenformin, chlorpropamide)
Quinine ingestion
Disopyramide ingestion
Pentamidine ingestion
Streptozotocin exposure
Vacor exposure
Herbal product and tea consumption (eg, pennyroyal oil, margosa oil, comfrey, chaparral, germander, groundsel or senecio, Jin Bu Huan, and Syo-saiko-to)

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Lab Studies

• Fingerstick glucose/rapid glucose determination to evaluate for hypoglycemia (Glucose levels as low as 3 mg/dL have been reported.)
• Chemistry panel (sodium, potassium, chloride, carbon dioxide, blood urea nitrogen, and creatinine levels) to evaluate for acidosis, hypokalemia, and electrolyte disturbance as a cause for vomiting
• Serum ketone levels (if present, suggest other cause of hypoglycemia)
• Urinalysis in ackee poisoning shows acidosis and no ketosis.
• Serum ammonia level (Hyperammonemia is characteristic.)
• Liver transaminase level and prothrombin time (PT)/activated partial thromboplastin time (aPTT) to assess extent of liver toxicity
• Arterial pH to evaluate acid/base status
• Serum lactate levels (may be elevated)
• Cerebrospinal fluid (generally reveals low glucose level)

Imaging Studies

• Nonenhanced head CT may be performed to exclude intracranial pathology as a cause for altered mental status, seizures, or focal neurologic deficits.

Other Tests

• 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).

Procedures

• 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.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Prehospital Care

• Hypoglycemia and airway compromise should be identified.
• Intravenous access and administration of dextrose, benzodiazepines (if needed to control seizures), and dextrose-containing intravenous fluid, as necessary, should be provided.

Emergency Department Care

• ED management of ackee poisoning is mainly supportive.
• Obtain a rapid fingerstick glucose and initiate 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, odansetron, 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.

Consultations

• Consultation with a poison center and toxicologist may be helpful.
• Contact public health authorities for suspected outbreaks.

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

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.

Drug Category: GI decontaminant

These agents are used to adsorb toxin in the GI tract, limiting systemic adsorption.

Drug Category: Nutrients

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.

Drug Name	Levocarnitine (Carnitor)
Description	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.
Adult Dose	1-3 g/d PO divided in 3 or 4 doses; typical replacement dose is three 330-mg tabs tid; 50-100 mg/kg IV over 30 min bolus, followed by 15 mg/kg q4h over 10-30 min
Pediatric Dose	50-100 mg/kg/d PO divided in 4 doses; 50 mg/kg IV over 30 min
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Monitor blood chemistries, vital signs, and overall clinical condition of the patient; nausea, vomiting, abdominal cramps, and diarrhea may occur

Drug Category: Somatostatin analogs

These agents are used to reduce blood levels of GH glucagon and VIP peptides.

Drug Category: Antianxiety Agent

Benzodiazepines may be used to treat seizures.

Drug Category: Antiemetics

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

Drug Name	Metoclopramide (Reglan)
Description	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.
Adult Dose	10 mg IV/IM q2-3h prn
Pediatric Dose	0.5-2 mg/kg IV q2-4h prn; not to exceed adult dose
Contraindications	Documented hypersensitivity; pheochromocytoma or GI hemorrhage, obstruction, or perforation; history of seizure disorders
Interactions	Anticholinergic agents may antagonize effects of metoclopramide; opiate analgesics may increase metoclopramide toxicity in CNS
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Caution in history of mental illness and Parkinson disease

Drug Name	Granisetron (Kytril)
Description	At chemoreceptor trigger zone, blocks serotonin peripherally on vagal nerve terminals and centrally.
Adult Dose	10 mcg/kg IV over 5 min
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	CYP-450 3A substrate, inducers (eg, phenobarbital) may decrease granisetron effect, while inhibitors (eg, erythromycin, clarithromycin) may increase granisetron toxicity
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Caution in liver disease

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Further Inpatient Care

Patients with the following conditions after ackee fruit poisoning should be admitted to the hospital:

• Severe, persistent hypoglycemia
• Intractable vomiting
• Seizures
• Altered mental status
• Hypotension
• Elevated liver enzyme levels or other evidence of liver damage

Deterrence/Prevention

• Patients and their families should be educated about the risks of unripe ackee fruit ingestion.

Prognosis

• Prognosis is good if unripe ackee fruit ingestion is promptly recognized and appropriately managed; however, deaths do occur.

Patient Education

• For patient education resources, visit eMedicine's Poisoning Center and Poisoning - First Aid and Emergency Center. Also, see eMedicine's patient education articles Food Poisoning, Wilderness: Poisons, and Activated Charcoal.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Medical/Legal Pitfalls

• Failure to observe seizure precautions (eg, adequately control seizures and secure airway of seizing or obtunded patients)
• Failure to aggressively monitor and treat hypoglycemia
• Failure to consider other causes of hypoglycemia and liver failure
• Failure to adequately assess and manage fluid and electrolyte status
• Failure to consider diagnosis of ackee fruit ingestion
• Failure to consider potential exposure of family members or community of exposed patient

Special Concerns

• Pregnancy: In Jamaica, concern exists that ackee fruit ingestion may be associated with anencephaly, spina bifida, and hydrocephalus; however, teratogenic effects are not well established.
• Pediatric: Most cases occur in children. Generally, full recovery can be expected if hypoglycemia is identified and treated early and if liver failure and metabolic acidosis do not ensue.

ACKNOWLEDGMENTS

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

The authors and editors of eMedicine gratefully acknowledge the contributions of previous authors, Suzanne M Shepherd, MD, MS, DTM&H, and Edward Boyer, MD, PhD, to the development and writing of this article.

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

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5. Billington D, Osmundsen H, Sherratt HS. The biochemical basis of Jamaican akee poisoning. N Engl J Med. Dec 23 1976;295(26):1482. [Medline].
6. Bressler R. Editorial: The unripe akee - forbidden fruit. N Engl J Med. Aug 26 1976;295(9):500-1. [Medline].
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9. Escoffery CT, Shirley SE. Fatal poisoning in Jamaica: a coroner's autopsy study from the University Hospital of the West Indies. Med Sci Law. Apr 2004;44(2):116-20. [Medline].
10. Hernandez-Galicia E, Aguilar-Contreras A, Aguilar-Santamaria L, Roman-Ramos R, Chavez-Miranda AA, Garcia-Vega LM. Studies on hypoglycemic activity of Mexican medicinal plants. Proc West Pharmacol Soc. 2002;45:118-24. [Medline].
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12. Khanna P, Jain SC, Panagariya A, Dixit VP. Hypoglycemic activity of polypeptide-p from a plant source. J Nat Prod. Nov-Dec 1981;44(6):648-55. [Medline].
13. Mentreddy S, Mohamed A, Rimando A. Medicinal Plants with Hypoglycemic/ant-Hyperglycemic Properties: a Review. USDA: Agricultural Research Services. August 2005;Association for the Advancement of Industrial Crops Conference: 20:341-353.
14. Mills J, Melville GN, Bennett C, West M, Castro A. Effect of hypoglycin A on insulin release. Biochem Pharmacol. Feb 15 1987;36(4):495-7. [Medline].
15. Mukherjee PK, Maiti K, Mukherjee K, Houghton PJ. Leads from Indian medicinal plants with hypoglycemic potentials. J Ethnopharmacol. Jun 15 2006;106(1):1-28. [Medline].
16. Nicola WG, Ibrahim KM, Mikhail TH, Girgis RB, Khadr ME. Role of the hypoglycemic plant extract cleome droserifolia in improving glucose and lipid metabolism and its relation to insulin resistance in fatty liver. Boll Chim Farm. Oct 1996;135(9):507-17. [Medline].
17. Persuad TVN. Foetal abnormalities caused by the active principle of the fruit of Blighia sapida (Akee). West Indian Med J. 1967;16:193-97.
18. Quere M, Ogouassangni A, Bokossa A, Perra A, Van Damme W. Methylene blue and fatal encephalopathy from ackee fruit poisoning. Lancet. May 8 1999;353(9164):1623. [Medline].
19. Saxena A, Vikram NK. Role of selected Indian plants in management of type 2 diabetes: a review. J Altern Complement Med. Apr 2004;10(2):369-78. [Medline].
20. Sherratt HS, Turnbull DM. Methylene blue and fatal encephalopathy from ackee fruit poisoning. Lancet. May 8 1999;353(9164):1623-4. [Medline].
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Article Last Updated: Nov 5, 2007