Gambierdiscus toxicus is the dinoflagellate most associated with the production of ciguatoxins that are the cause of systemic symptomatology [
16]. These toxins are of a lipid nature, forming rings joined by ether bonds that gives them firmness in its structure. Three types of ciguatoxins have been identified, namely, CTX1B, 54-deoxyCTX1B and 52-epi-54-deoxyCTX1B, which accumulate more frequently in the muscle, liver, kidneys and spleen of bioaccumulated fish. These toxins present intrinsic resistance to cold, heat and exposure to acidic and basic media; therefore, cooking contaminated fish is not a guarantee for the prevention of toxic infection [
17].
The intoxication is the result of eating herbivorous fish that have fed on the dinoflagellates of the genus
Gambierdiscus that synthesize gambiertoxins. The biomagnification process of ciguatoxins in fish that have been fed with
Gambierdiscus sp. have been previously described, establishing an association between the size of the herbivorous fish that habitually feed on this type of dinoflagellates and the concentration of the ciguatoxins, which is species specific [
18].
Several factors influence the risk of suffering CFP, being more frequent when consuming fish of a large size or high longevity due to the fact that it is more likely that they have a greater accumulation of ciguatoxins given the associations made with these two factors previously [
19]. It should be noted that the bioaccumulated fish have a normal appearance, texture, smell and taste [
20].
As for the toxicokinetics of the ciguatoxins, it has been described that ciguatoxins are voltage-gate selective; the intestinal absorption of ciguatoxins is rapid, and it is quickly localized in soft tissues such as skeletal muscle, the heart and the nervous system. Ciguatoxins are transported together with plasma proteins, mainly seroalbumin, and can be found in toxic levels in body fluids such as breast milk and seminal fluid, in addition to their characteristic of liposolubility, making them able to cross the placental barrier and can cause fetal conditions and abortions during the acute phase of the poisoning. After a liver biotransformation, finally the toxin is excreted by bile in the feces [
21].
Toxicodynamics consists of an induction to the opening of the voltage-gated sodium channels dependent on ciguatoxins at the level of skeletal muscle, heart cells and mainly peripheral nerves. Once the sodium channels open, an intracellular flow of sodium is generated that causes water to enter the cell and produce edema generated at the level of the white tissues by the toxin mentioned previously. In search of intracellular homeostasis, compensatory mechanisms begin the expulsion of excess sodium internalized in the cell, exchanging it for extracellular calcium to such an extent that the intracellular calcium levels can become so high that they generate increased tissue contraction force muscle [
22].
2.1. Clinical Manifestations
The general signs and symptoms of CFP are as follows: headache, diarrhea, vomiting, osteotendinous hyporeflexia, hives, conjunctivitis, pain and decreased visual acuity. These clinical presentations may vary in the acute, chronic and relapsing phases of the illness [
23].
According to the article of Palafox and Buenconsejo-Lum in 2001 [
23], the clinical manifestations can be classified into three groups, which are (1) acute (within the first two weeks of exposure of ciguatoxin); (2) chronic (persisting beyond the two weeks of the initial intoxication); and (3) relapsing phases of the illness (occur years after the initial intoxication) [
23].
Looking at the first symptoms detected, they frequently appear 4–6 h after toxin consumption, but can occur within minutes with large toxin ingestions or can manifest in 24 h with smaller doses of the toxin [
24].
CFP presents a great variety of symptoms and symptomatological patterns, depending on the region where the contaminated meat has been ingested. It is said that the Caribbean areas have primarily gastrointestinal symptoms of the neurological type, whereas the opposite happens in the Pacific [
25]; these differences in symptomatology in different geographic regions are probably related to structural differences between the ciguatoxins of the Pacific, the Caribbean and India. Symptoms usually begin minutes after ingestion; however, cases of late onset, e.g., after more than 36 h, have been described. For unknown reasons it has been observed that people who ingest fish contaminated with ciguatoxins do not present any condition [
26]. More than 175 symptoms related to toxic infection have been described, and the following will emphasize the most common ones [
27].
Gastrointestinal tract: It is perhaps the most affected and associated with earlier onset; it is characterized by diarrhea, nausea, vomiting, metallic taste, abdominal pain and pain with defecation. The gastroenteritis of infectious origin appears easily; however, they have very nonspecific symptoms that do not usually orient the ciguatera disease with certainty, and can take a long time to disappear, usually between 1 and 2 days after ingestion [
28].
Neurological manifestations: Taking into account the pathophysiology of the toxin when producing sodium-channel opening, whereby large intracellular water flow causes edema at the level of the Schwann cells and the axons generate a decrease in the speed of the nerve conduction, and an increase of the refractory phase of the potential of the action, the patients present paresthesia in their limbs that could start from 30 min or days after the consumption of the contaminated fish, being able to persist for months or years. In addition, cases of odontalgias have been reported, so too ataxia, vertigo, allodynia and headache after consumption of ciguatoxins [
29,
30,
31].
Cardiovascular manifestations: These are the least frequent but the most feared, usually starting 2 and 3 days after consumption [
32]. The toxin has a direct effect on the papillary muscles and on the atrium, therefore predisposing the patient to presenting cardiac arrhythmias, extrasystoles and heart failure that can be potentially lethal. Orthostatic hypotension due to stimulation of the parasympathetic system and respiratory arrest due to phrenic nerve block has also been described [
33].
Other manifestations: The most frequent skin conditions of toxic infection are a rash associated with pruritus and are related to acne exacerbations [
14].
The main route of exposure of the toxin is orally; there are other ways of transmission, such as maternal–fetal, for which cases of abortions and preterm birth have been reported. In addition to the oral route is the sexual route, by the presence of the toxin in the seminal fluid, causing pain during ejaculation, vaginal burning and pelvic pain; these symptoms may persist for 2 to 3 weeks [
34].
2.2. Diagnosis
The diagnosis is clearly clinical, looking at the recent history of fish consumption, more so if they are species of reefs, and at the subsequent onset of a gastroenteric condition associated with neuropathic symptoms, mainly at the level of the peripheral nervous system. It should always be remembered that the consumption of fish in non-coastal areas does not exclude the diagnosis [
35].
The results of general paraclinics, such as a hemogram, arterial gases, and renal and hepatic function, generally yield results in the normal range. Nonspecific alterations in heart rhythms documented in electrocardiogram traces should generate suspicion about the cardiac compromise generated by the ciguatoxins [
36].
So far there is no specific paraclinical method for accurate diagnosis of ciguatera in humans. A practical product is commercialized to detect toxins in the meat of the fish to be consumed, called ciguaCheck [
36,
37]. In addition to this, in 2018, a highly sensitive fluorescent sandwich ELISA, which can detect, differentiate and quantify the four major CTX congeners (CTX1B, CTX3C, 51-hydroxyCTX3C, and 54-deoxyCTX1B [
38]) with a detection limit of less than 1 pg/mL, was successfully developed by Tsumuraya and Hirama [
39].
It is worth mentioning that the most traditional biological method that is available for use in most care centers, having considerable reliability without being highly specific, is not considered a routine diagnostic method due to its high cost; so, it is not cost effective. From a mouse bioassay, where the rodent was fed contaminated fish meat, it was learnt that one of its main disadvantages is the long observation time of the mice that consumed the contaminated fish meat [
40,
41].
2.3. Differential Diagnoses
Like ciguatera, there is a wide range of toxic infections related to consumption of seafood that are the same or mostly unknown and whose clinical manifestations can be very similar [
42].
Tetradotoxism caused by tetradotoxin, which is acquired by consuming puffer fish, is the most fatal marine toxin causing systemic block of the sodium channels, generating symptoms from approximately 20 min up to 3 h after ingestions, rapidly evolving into nausea, vomiting, headache, paresthesia, dysarthria, ataxia, quadriplegia, respiratory failure, coma and death. There is no evidence of an antidote, and treatment consists of limiting or minimizing absorption and treating complications that threaten the patient’s life [
43].
The scombroidosis caused by the consumption of fish that have not had a good refrigeration begins a process of decomposition with growth of bacterial colonies activating the enzyme histidine decarboxylase using as a substrate histidine, abundant amino acid in the muscle tissue of reef fish [
44], with the end product of the enzymatic activity being a large amount of histamine generated, which is absorbed and distributed at the systemic level of the person affected, generating symptoms such as flushes, rashes, pruritus, nausea, vomiting, diarrhea, headache, conjunctival, cough, bronchospasm, tachycardia and anaphylactic shock [
45].
