Ciguatera

Uses

None.

Dosing

The dose of ciguatoxin required to poison a human has not been established.

Contraindications

Contraindications have not yet been identified.

Pregnancy/Lactation

Documented adverse reactions. Avoid use.

Interactions

None well documented.

Adverse Reactions

Ciguatera is a toxin that sometimes contaminates reef fish. Symptoms may be delayed up to 30 hours. Sensitization can render subsequent ingestion far more dangerous.

Toxicology

Ciguatoxin is one of the most potent known marine toxins.

Ciguatera poisoning

Vertebrate fish may contain toxins capable of causing human illness. These can be divided into 3 major groups based on the location of the toxin: ichthyosacotoxic fish (hagfish, lamprey, puffer, snapper, barracuda) contain toxin in their musculature, viscera, skin, or mucus and are responsible for most fish poisonings; ichthyo-ootoxic fish contain toxins in their gonads; and ichthyohemotoxic species contain toxins in their blood. The most frequently implicated ichthyosarcotoxism is ciguatera. 1 Ciguatera poisoning is on the increase because of a reappearance in normally edible fish, the sporadic and unpredictable nature of the toxicity, and the increased demand for seafood worldwide. 2

History

Ciguatera (from cigua , a poisonous tuban snail of the Spanish Antilles) is primarily a tropical disease but is also seen in the southern coastal United States. It is caused by the ingestion of a wide variety of normally safe, bottom-feeding coral-reef fish that contain toxins accumulated through the marine food chain. Ciguatera outbreaks are usually localized and often follow major disturbances of reefs, as in construction of wharves. 3

The environmental factors responsible for blooms of the dinoflagellate organism Gambierdiscus toxicus , which actually produce the toxins, are not well understood, despite the critical role that an understanding of the biogenesis of ciguatera could play in the toxin's mitigation. Several studies have linked anthropogenic effects to upsurges of ciguatera. However, the specific factors involved have not been identified, and many human and natural disturbances do not trigger an increase in ciguatera risk. 4 Over 400 species of fish and several invertebrates are known to contain ciguatera toxin (ciguatoxin), but only a relatively small number of species are regularly contaminated. 5 Ciguatoxic fish are restricted to species feeding on organisms around tropical reefs and include sturgeon, reef sharks, moray eels, parrotfish, jacks, snappers, sea bass, and barracuda. 6 Red snapper and barracuda are the most frequently implicated, although in Miami, grouper has been implicated in 60% of cases. The sale of barracuda is now prohibited there. 2

Chemistry

Although ciguatera poisoning is caused by ciguatoxin believed to be acquired by fish through the food chain, other compounds may also be involved including maitotoxin, lysophosphatidylcholine, scaritoxin, and ciguatoxin-associated adenosine triphosphatase inhibitor. 5 , 7 The marine reef dinoflagellate G. toxicus (formerly misidentified as Diplopsalis spp.) is the most likely source of the toxin. 8 Reef disruptions release unusually large numbers of the organisms into surrounding waters. These organisms are first eaten by reef herbivores and then by larger carnivores, which concentrate the toxin in their muscle, liver, brain, intestines, and gonads. For this reason, large fish are more likely to be toxic. In a study of Pacific red snapper, 69% of fish weighing more than 2.8 kg were toxic compared with 18% of smaller fish. 9

The concentration of ciguatoxin in a fish depends on fishing area and depth, fish size and tissues, and climatic disturbances. 8 Large piscivorous fish can accumulate ciguatoxin over time and produce toxicity well after a bloom of G. toxicus , the producer of the ciguatoxin, has faded. 10

Ciguatoxin is difficult to characterize because it is present only in minute quantities. About 1,000 kg of toxic eel liver yielded approximately 1 mg of purified toxin. Ciguatoxin is a crystalline, colorless, heat-stable solid; because it is heat-stable, it cannot be deactivated by freezing or cooking. 2 Certain features of ciguatera are thought to be caused by several polycyclic ethers. 7 Chemistry and toxicology have been reviewed. 11

Uses and Pharmacology

The main pharmacologic action of ciguatoxin is an increase in cell permeability to sodium, causing sustained depolarization. This change can be antagonized by large doses of calcium. The toxin has been shown to inhibit red cell cholinesterase in vitro. 12 Its mechanism of action in humans is dependent not only on anticholinesterase activity, but also in part to a transmitter-like cholinomimetic action. 13

Ciguatoxin CTX3C has now been chemically synthesized, allowing further studies of its action. Ciguatoxins are known to be receptor site-5 neurotoxins that open voltage-sensitive sodium channels (VSSC). However, the toxin's physiological effects are poorly understood because of extremely limited availability. CTX3C shifted the activation potential in neurons for the NZ current in the negative direction, resulting in a 30-mV hyperpolarizing shift of the threshold potential. In addition, it also shortened the time to peak current and shifted the inactivation potential in the negative direction. Most importantly, the recovery from slow inactivation induced by a prolonged depolarizing prepulse was dramatically delayed by CTX3C. Thus, it would appear that CTX3C exerts multimodal effects on VSSC, with simultaneous stimulatory and inhibitory aspects. 14

Pacific ciguatoxin -1 causes tetrodotoxin-sensitive sodium channels to open near their resting membrane potential and tetrodotoxin-resistant sodium channels to recover quickly from inactivation, with these effects resistant to lengthy washout. Neurophysiological study of experimental animals has found slowing of mixed and motor conduction velocities. In patients poisoned with Pacific ciguatoxin -1, neurophysiology may be normal. Although severe poisoning can slow sensory conduction, this action is associated with an increase of the refractory period, indicative of impaired recovery of sodium channels from their inactivated state. 15

Dosage

The dose of ciguatoxin required to poison a human has not been established.

Pregnancy/Lactation

Documented adverse reactions. Avoid use. 16

Interactions

None well documented.

Adverse Reactions

Immune sensitization is a major feature of ciguatera and can lead to substantial hypotension; sensitization can make responses to subsequent ingestions more serious. Hypotension can be a particular problem for patients who have been treated with opiates, which are cyclic ether histamine releasers. A “ciguatera diet” has been proposed that is high in protein, carbohydrates, and vitamins and prohibits fish or fish products, shellfish or shellfish products, seeds, nuts, mayonnaise, or alcohol. The diet also specifies avoidance of marijuana, opiates, barbiturates, solvents, herbicides, cosmetics, and other substances, as a means of reducing the potential effects of sensitization. 6

Toxicology

Ciguatoxin is one of the most potent marine toxins known, with a median lethal dose (LD 50 ) of 0.45 mcg/kg to mice IP. In an outbreak involving 14 people who ate portions of a 25-pound barracuda caught near Freeport, Bahamas, the Centers for Disease Control (CDC) determined from remaining fish parts that the fish had an LD 50 (mouse IP) equivalent to 2 to 5 g of original fish flesh. 17

All people known to have eaten at least 1 bite of fish associated with a documented outbreak developed symptoms of ciguatera poisoning. 18

The symptoms of ciguatera poisoning are various and complex, with over 175 manifestations. 8 Diagnosis is based largely on clinical symptoms and history of fish consumption. Poisoning is usually characterized by GI symptoms (abdominal cramps, nausea, vomiting, diarrhea) appearing within 1 to 6 hours after ingestion. However the onset of symptoms is highly variable, and studies have shown a range from less than 1 hour to 48 hours. GI effects occur first and resolve over 24 hours. Neurological features develop over 24 hours, with initial paraesthesia and numbness of the lips and extremities. 16 Numbness of the tongue and throat, blurred vision, hypotension, bradycardia, and itching have also been reported; reversal of hot and cold sensations (the feeling of heat when in contact with cold, or vice versa) is often diagnostic.

Coma is unusual, but has been reported, suggesting possible confounding factors such as coingestion of alcohol or nonseafood related toxins or a genetic susceptibility to a more severe response to ciguatera toxin. 19 The GI symptoms usually subside within 24 hours, but muscular weakness and numbness may persist for weeks to months. 3 Cases of persistent bradycardia have been reported following the consumption of barracuda eggs found to contain ciguatoxin in Taiwan. 6 In severe cases shock, muscular paralysis, and death may occur. Recovery is often prolonged.

The severity, number, and duration of ciguatera symptoms reflect a combined influence of dose, toxin profile, and individual susceptibility. In the Pacific Ocean region, neurological symptoms predominate; whereas in the Caribbean area, GI symptoms are more common. These symptoms provided a clue that differing ciguatoxins may be present in the ciguatera of Pacific and Caribbean waters, which has now been confirmed. Following the isolation of different ciguatoxins in each region, the structures of the major ciguatoxins were determined. 5

Persistent effects of ciguatera poisoning have been reported, including subacute and chronic effects and sensitization to the toxins. Reported chronic effects include fatigue, loss of energy, arthralgia (especially knees, ankles, shoulders and elbows), myalgia, headache, and pruritus. A further syndrome characterized by hallucinations, incoordination, loss of equilibrium, depression, and nightmares has been related to consumption of Indian Ocean fish. Depression and anxiety have been associated with chronic ciguatera poisoning. Sensitization has been reported with repeated exposure to the toxins. People with previous exposure seem to have a more rapid onset of effects, although this has never been documented in rigorous studies. There have been rare reports that eating fish not typically associated with ciguatera, eating chicken, or drinking alcohol can sometimes provoke a recurrence. 16 Repeated episodes may be more severe. 3 During the recovery phase, it is recommended that patients avoid fish and alcohol for 3 to 6 months. 5

Ciguatera poisoning has a low mortality rate (< 0.5%), although it is a substantial cause of morbidity in areas where ciguatera is endemic. Ciguatera-endemic US states and territories include Hawaii, Florida, Puerto Rico, Guam, the Virgin Islands, American Samoa, and the commonwealth of Northern Marianas Islands; 5 (Florida) to 70 (Virgin Islands) cases per 10,000 population are estimated to occur each year. Because of confirmation difficulties and the absence of a reliable assay for human exposure, the number of cases reported to health departments is estimated at 2% to 10% of the actual number of cases in the United States and its territories. 20

Ciguatera poisoning is endemic in islands of the Pacific, with a 43% annual incidence in 1 household study. 21 Florida and Hawaii are the states with the highest incidence. In an analysis of 129 cases reported to the Dade County (Miami) Department of Public Health from 1974 to 1976, 18 the estimated incidence was 5 cases per 10,000 residents. Ciguatera poisoning accounts for more than half of all foodborne outbreaks related to fish in the in the United States. 22 More than 600 people in the Hawaiian Islands reported contracting ciguatera from 1900 to 1980. 23 Mortality rates as high as 20% have been reported 24 ; some deaths occurred in the 184 cases reported to the CDC between 1970 and 1974 25 and among 129 cases reported in Dade County, Florida, between 1974 and 1976. Isolated outbreaks in nonendemic areas such as Maryland, North Carolina, and Vermont have been reported. Usually, these are attributed to importation of fish, recent travel to endemic areas, or migration of fish from endemic areas. 19

In a study in the Pacific island nation of Vanuatu, more than 40% of patients admitted to the hospital with ciguatera poisoning were in their thirties or forties, an observation that is consistent with previous studies. A possible explanation was that eating fish with low levels of toxin over many years may lead to accumulation of, or sensitization to, the toxin in older patients, a hypothesis supported by the worsening of symptoms with repeated episodes of ciguatera poisoning. Studies have shown evidence of seasonality of fish poisoning that has been ascribed to fluctuation in the abundance of dinoflagellate organisms. In this study, little evidence of seasonality was found. 26

In Hong Kong, a review of Department of Health records showed a relationship between the incidence of cholera and ciguatera fish poisoning (CFP). The observation in Hong Kong that the annual peak activity of cholera followed the annual peak activity of CFP outbreak by 2 to 3 months was first observed in 1998. The pattern was used to accurately predict the peak level of Vibrio cholerae for 3 years after 1998. Why a relationship exists between the cholera and CFP outbreaks is still unknown. 27

Several case reports of ciguatera poisoning during pregnancy have been published, reporting fetal symptoms beginning simultaneously with the mother's symptoms. These consisted of tumultuous fetal movements and an intermittent, peculiar fetal shivering. None of the liveborn infants appeared to have lasting effects from exposure to the toxin (1 fetus was aborted during the acute phase of the poisoning), although, this could not be ruled out in 1 infant exposed shortly before birth. Ciguatera is also, apparently, excreted in breast milk, and GI problems and pruritic symptoms have been reported in infants whose mothers continued to breast-feed during their illness. Cessation of breast-feeding appears to resolve the problem. 16

There is no antidote for ciguatera poisoning, and supportive therapy includes appropriate rehydration, observation, and symptomatic relief. 4 Although emesis and gastric lavage have been recommended if vomiting has not occurred, 16 to 30 hours may elapse before the first signs of intoxication appear, possibly making these maneuvers ineffective. A cathartic may be used to remove toxin from the lower GI tract. Because calcium is a competitive inhibitor of ciguatoxin, infusions of calcium salts have been beneficial. 28 Intravenous (IV) mannitol (eg, Osmitrol ) was introduced as a treatment for ciguatera poisoning in the late 1980s. Correctly diagnosed and adequately hydrated cases often respond to an infusion of mannitol, given at 1 g/kg over approximately 30 minutes. In instances where symptoms recur within the first 24 hours after treatment, a second infusion is usually effective. Mannitol is not consistently beneficial, however, and appears best when used in the acute phase of more severe intoxications. Reasons for a poor response are not known. A recent double-blind clinical trial of IV mannitol indicated no significant benefit over IV saline, with both interventions producing an improvement in symptoms. 29 Consequently, mannitol can no longer be recommended for treatment of ciguatera poisoning. 30

Other therapeutic agents have included atropine (eg, AtroPen , neostigmine (eg, Prostigmin ), steroids, pralidoxime Cl ( Protopam ), vitamins B 12 and C, antihistamines, amitriptyline, morphine, and gabapentin. 30 , 31 , 32 , 33

Persons living in or traveling to ciguatera-endemic areas should adhere to the following general precautions: 1) avoid consuming large, predatory reef fish, especially barracuda; 2) avoid eating the head, viscera, or roe of any reef fish; 3) avoid eating fish caught at sites known to be ciguatoxic. Health care providers everywhere who treat patients with GI or neurological symptoms after eating large, predatory fish should consider a diagnosis of ciguatera intoxication. 20

Detection

Ciguatoxic fish appear normal in all ways, including smell and taste. There are no distinguishing routine laboratory features of ciguatera toxin; however, testing of the toxin source is available in some endemic areas. The stick enzyme immunoassay provides promise as a simple widespread test for clinical laboratories and the fishing industry. Other tests include the mouse intraperitoneal injection and radioimmunoassay (RIA) and the guinea pig atrium assay. 19 , 34 RIA has been used to screen amberjack in Hawaii, 35 but this method is time consuming. An electrophoretic technique to evaluate potentially toxic fish has been described but requires further evaluation. 36

Bibliography

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