Blister beetle toxicosis has been reported in a variety of species, most commonly horses, but this toxicosis has not been previously documented in camelids (6
). The toxic principle in blister beetle poisoning is cantharidin, a bicyclic terpenoid vesicant and acantholytic agent whose mechanism of action at the molecular level is not known (12
In Oklahoma alone, 67 species of blister beetle have been identified with Epicauta occidentalis
being involved in most of the confirmed equid intoxications (14
). The cantharidin content of the hundreds of species of blister beetles in North America varies widely; the toxin is only synthesized by males but is transferable from males to females. The blister beetle Epicauta immaculata
can contain an average of 5.2 mg of cantharidin per beetle (15
). The lethal dose of cantharidin in horses is approximately 1 mg/kg BW but may be less (1
); thus the ingestion of as few as 90 beetles can result in the death of a 454 kg horse.
There are no published controlled studies documenting the LD50 of cantharidin in ruminants or pseudoruminants. An unpublished study (John Reagor, plant toxicologist, retired from Texas Veterinary Medical Diagnostic Laboratory, 2012) found that as little as 0.5 mg/kg was lethal in cattle, indicating ruminants may be more susceptible than horses to cantharidin. The paucity of detailed descriptions of cantharidin toxicity in ruminants may indicate a lack of diagnostic scrutiny when toxicity is suspected or confirmed, or that sublethal or lethal cantharidin toxicosis is underdiagnosed in these species.
Clinical signs of cantharidin toxicity vary in severity and are dose-dependent (12
). The clinical presentation of blister beetle ingestion is best described in equids (1
). Signs frequently encountered include abdominal pain, fever, depression, oral mucosal ulcerations, immersion of the muzzle in water, diarrhea, dysuria, stiff gait, increased heart and respiratory rates, congested mucous membranes, sweating, lethargy, and anorexia (1
). Polyuria, pollakiuria, gross hematuria, ptyalism, melena, and synchronous diaphragmatic flutter from hypocalcemia may also be seen (1
). Lethal doses of cantharidin can result in signs of hypovolemic shock or sudden death (2
). In cattle the most consistent clinical signs in natural intoxication were mass feed refusal and decreased milk production (7
). Additional clinical signs reported were salivation, oral ulceration, diarrhea, bruxism, abdominal pain, polyuria, reluctance to move, ataxia, and recumbency (7
). The alpacas in this report had clinical presentations very similar to those observed in horses, with evidence of colic being the predominant sign. Diarrhea, dysuria, hematuria, polydipsia, hyporexia, hypomotility of the GIT, and depression were also apparent in alpaca #2. Interestingly, this animal had no oral lesions and continued to eat intermittently despite severe distal esophageal and forestomach ulceration. The absence of oral lesions and the distribution of the esophageal lesions might suggest that passive or partial regurgitation of the toxin in ruminating species exacerbates the severity of the GIT mucosal lesions. Signs consistent with hypovolemic shock were apparent 7 h following the onset of abdominal pain in alpaca #1.
Clinicopathologic findings in these alpacas varied. Consistent findings on initial presentation included neutrophilic leukocytosis, azotemia, hyperglycemia, and increased creatine kinase; these laboratory findings parallel those often found in equine cantharidin toxicosis. Marked hemoconcentration, a frequent finding in the early stages of cantharidiasis in equids (3
), was also present in the first case. Hypoproteinemia from hypoalbuminemia in the second alpaca may be credited to protein-losing gastropathy or enteropathy. Hypocalcemia is the most consistent biochemical finding in horses with cantharidin toxicity (17
) and was the most notable abnormality on the initial biochemistry panel performed in the second alpaca. Anecdotally, approximately 75% of horses with blister beetle toxicosis become hypocalcemic. Hypomagnesemia often accompanies hypocalcemia in equids (1
), but was not apparent in either alpaca initially; alpaca #1 was hypermagnesemic, which might be explained by oliguria. Common urinalysis findings in equids with blister beetle toxicity include hyposthenuria and microscopic hematuria (3
); while microscopic and subsequently gross hematuria were present in alpaca #2, hyposthenuria was never evident.
A unique finding in both alpacas was the absence of motile protozoa on C1 fluid analysis. In conjunction with the normal C1 pH this finding was highly suggestive of a severe disturbance of the forestomach flora unrelated to an acidotic event. The possibility exists that protozoal death is also dependent on the amount of cantharidin ingested.
Myocardial necrosis has been reported in cases of blister beetle toxicosis in equids (2
). At necropsy, 4 horses out of 21 with cantharidin toxicity had ventricular myocardial necrosis (4
), a higher proportion compared with 1 out of 24 equids necropsied in another report (2
). Recently, antemortem diagnosis of myocardial damage has also been documented via increased cTNI in 46% of horses with cantharidiasis (19
). Cardiac arrhythmias were not documented in any of the animals included in that prospective study (19
). The second alpaca in this case study had increased cTNI with a concurrent arrhythmia, and myocardial degeneration and necrosis with mineralization were confirmed in the right ventricle at necropsy.
The toxic effects of cantharidin and its analogues in mammalian tissues have been ascribed to an affinity and specificity for a cantharidin-binding protein subsequently identified as protein phosphatase type 2A (PP2A) (20
). Cantharidin inhibits PP2A and protein phosphatase type 1 (PP1) activity (20
), and it has been suggested that this may be the in vivo
mechanism whereby by these compounds exert their toxic effects (21
). Interestingly, inhibition of PP1 has also been demonstrated to decrease PTH secretion from bovine parathyroid cells in vitro
). This may help explain the low serum PTH concentration despite documented ionized hypocalcemia in case #2 and warrants further investigation. Recent research has established that cantharidin also has inhibitory effects on osteoclast differentiation and bone resorption activity but did not elucidate what if any effects this might have on calcium homeostasis in vivo
). Either or both of these mechanisms could be responsible for the hypocalcemia associated with cantharidiasis in clinical cases.
Definitive diagnosis of cantharidin toxicosis can be made via GC/MS or high-pressure liquid chromatography, but GC/MS is more sensitive and specific (10
). Urine and gastric contents are the diagnostic specimens of choice (10
). Urine samples collected more than 72 h after ingestion of the toxin could result in a false negative test result (10
); similarly, urine samples obtained after intensive IV fluid therapy may contain undectectable concentrations of cantharidin due to dilution. Of interest in case #2 is that 5 d following presentation cantharidin was still detectable in C1 contents suggesting this as an alternative diagnostic sample in ruminants or pseudoruminants that survive for more than 3 d. Although serum has been used to make a postmortem confirmation of cantharidiasis in a human (29
), a sensitive assay for blood has not been developed (16
). Detection of cantharidin even at very low concentrations is likely significant (11
) regardless of sample type. Aqueous (ocular) fluid was tested for the presence of cantharidin in case #2 in an attempt to identify a readily accessible, non-urine fluid specimen that might have diagnostic value at necropsy. The inability to detect cantharidin in the ocular fluid was not surprising given that cantharidin is irritating to tissues and clinical signs of ocular disease were not observed in this animal.
There is no specific antidote for cantharidin toxicosis, so therapy is generally supportive (3
). Treatment goals include elimination of the toxin and its source, decreasing toxin absorption, pain management, maintenance of fluid and electrolyte balances, and gastroprotection (3
). Oral di-tri-octahedral smectite was used as an adsorbent in alpaca #2. Based on a recent study, activated charcoal (1 g/kg BW, PO via orogastric tube, as a slurry) may have been a better selection (17
). Given the severity of the forestomach and esophageal ulcerations, case #2 might have benefitted from a C1 gastrotomy for removal of GI contents and C1 compartment lavage to minimize toxin absorption. However, the degree of mucosal damage already present could have compromised surgical recovery and the subacute nature of the intoxication may have mitigated the benefit of a gastrotomy.
Pain management options in blister beetle poisoning include nonsteroidal anti-inflammatories (NSAIDs), α2 agonists, and opioids (17
). Nonsteroidal anti-inflammatories were considered suboptimal as GI mucosal ulceration was already present in addition to apparent renal compromise in case #2. Butorphanol was chosen instead, as cantharidin antagonizes the antinociceptive effects of α2 agonists (30
) and the μ-opioid agonist morphine (31
) in mice, but had no adverse effect on the analgesic effects of κ-opioid receptor agonists (30
Prognosis in cases of cantharidin toxicity varies from poor (3
) to good (17
) and is likely dependent on the amount of toxin ingested in addition to timely recognition and aggressive treatment. Horses that survive more than 2 d following toxin ingestion are reported to have a good prognosis for survival (4
). Persistent tachycardia, tachypnea, and increased creatine kinase appear to be poor prognostic indicators in affected horses (13
). Prognosis in ruminants is difficult to ascertain as very few reports describe experimental or natural cantharidiasis in these species. Deaths have been reported in cattle (7
), sheep (10
), a goat (11
), and in this current case study in 2 alpacas.
Prevention centers around minimizing exposure to suspect alfalfa hay, cubes, or wafers (32
). One management strategy utilized by equine owners is to inspect each flake of alfalfa hay for the presence of blister beetles (32
). However, hay may still be contaminated even if beetles are not found as cantharidin is released when the beetles are crushed (12
). All affected hay should be discarded rather than fed to ruminants as these species are susceptible to cantharidin intoxication (33
). Pelleted alfalfa is unlikely to result in exposure to cantharidin as the toxin is drastically diluted during the course of processing (1
In summary, this is the first report to describe cantharidiasis in a camelid species. Additionally, attempted treatment of blister beetle poisoning in a ruminant or pseudoruminant species has not previously been reported. Livestock owners, including those with cattle, sheep, goats, alpacas, and llamas, should therefore be made aware of the potential for blister beetle toxicity especially if they feed alfalfa hay.