Wu HL, et al. reviewed fishes with poisonous gallbladders fishes in China.2 There are currently 12 known species of fish with poisonous bile in China, including the crucian carp (Carassius auratus), black carp (Mylopharyngodon piceus), silver carp(Hypophthalmichthys molitrix,Cyprinus carpio and big head carp (Aristichthys nobilis); all of which belong to the freshwater fish family Cyprinidae. Poisoning caused by grass carp gallbladder accounts for more than 80% of all cases, because it has a relatively big gallbladder.
Ichthyogallotoxin has been studied extensively in grass carp bile.5 The compound 5α-cyprinol sulfate (5α-cholestane-3α, 7α, 12α, 26, 27-pentol 26-sulfate) has been implicated in cases of human poisoning and has been isolated from carp bile. The molecular formula of the water soluble and thermostable 5α-cyprinol sulfate is C27H48O8S. Toxicity is dose-dependent, depending on quantity of bile and size of the ingested fish gall bladder.6 Mohri et al.7 reported that essentially all of the bile toxicity could be explained by the properties of cyprinol sulfate, based on the LD50 values. The LD50 of 2.5 mg / 20 g mouse was reported. After day 5, some mice died for every 24 h with a dose of 1.0 mg intraperitoneal administration7.
Damage to multiple organs after ingestion of fish gallbladder such as,the gastrointestinal, renal, hepatic, cardiac, and neurological systems have been reported previously8. The habit of swallowing fish gallbladder to cure chronic diseases exists in the rural areas of southeastern and southern China, including Hong Kong and Taiwan. Due to differences in socio-cultural beliefs3༌carp fish (Labeo rohita), known as Rohu in India, is commonly consumed as aphrodisiac. Our observations from this patient were similar to that of previous reports. The patient swallowed raw bile of grass carp in the belief that her cough would be alleviated and developed anuria due to ARF instead. The initial symptoms8 were similar to that of gastroenteritis, such as abdominal pain, nausea, vomiting and watery diarrhea, occurring 0.5-4 h after consumption of the offending agent. Edema, oliguria, or anuria may occur within 2–3 days after poisoning, sometimes even as late as 3–6 days, as reported by some authors8. Remarkable increase in urea, serum creatinine, urine-NAG with non-glomerular proteinuria was observed in our patients. ARF caused by fish gall bladder consumption have been reported in several case series,9,10 with a morbidity rate of 55–100% and overall mortality rate of 91.7% in all gall bladder consumers. Although some reports have showed improvement of renal function within 2–3 weeks11, the recovery time was 5 weeks in our patient. Raised liver enzymes or jaundice occurs in 75–87% of patients.9 Jaundice usually occurs on day 2 to 3, but can occur as late as day 5. Liver and kidney damage often occur simultaneously12 and mild hepatitis caused by carp gallbladder is usually self-limited. Our patient’s liver function recovered on day 19, which was consistent with previous reports. These patients can also die of fulminant hepatic failure.3 Other manifestations include cardiac complications (palpitations, hypertension, and myocardial damage) and neurological involvement (convulsion and coma), which varies individually.
The exact mechanisms of the toxic effects are not clear. However, necrosis of the renal proximal tubules (PT) may play an important role in the development of ARF.13 Degeneration of the renal tubular epithelial cells, dilatation of some tubular lumen, epithelial shedding, and segmental naked basement membrane formation was revealed by renal biopsy (shown in Fig. 2). The pathological severity correlated with clinical symptoms of sudden oliguria or anuria as well as increased urine NAG, a marker of tubular injury.14 In an animal study,13 glomerular filtration rate (GFR) decreased 24 h after ingestion of 0.3 mL of grass carp bile, suggesting that nephrotoxic substances might cause cellular damages by inhibiting the cytochrome oxidase, promoting calcium influx, and inducing lysosome membrane instability.9 In a porcine study,15 Choi K, et al. suggested that nitric oxide (NO) generation and the phospholipase C pathway affect the release of renal dipeptidase (RDPase) from the PT which may be involved in the development of ARF in vivo after carp bile ingestion. The significance of the interstitial edema and inflammation characterized by infiltration of lymphocytes and monocytes observed in the renal biopsy can be explained by the serious inflammatory response to cell necrosis induced by increased cell membrane permeability and the resultant enzyme release. In addition to renal toxicity, fish bile may cause a series of inflammatory responses evidenced by increased inflammatory mediators and cytokines, eventually leading to pathological changes of cell degeneration and necrosis. Another study16 showed that plasma endothelin levels correlated with the severity of carp gallbladder poisoning. In our patient,c-reactive protein༌procalcitionin and serum amyloid A were increased. However, the role of inflammation in carp gallbladder toxicity requires further elucidation.
In our patient, we also found decreased leukocytes, neutrophils, lymphocytes, hemoglobin and platelets; and sinus bradycardia in the ECG, which to our knowledge has not been previously reported. In 1993, Lim PS, et al.17reported a case of sinus bradycardia that persisted for 2 days even after atropine was administered for symptomatic relief. Some authors have demonstrated experimentally that bile acids can affect the cardiovascular functions of animals both in vivo and in vitro, inducing bradycardia and systemic hypotension.18 It was also found18, in vitro, that the bile salts caused a potent hemolysis.In our patient, the decreased values of leukocytes, neutrophils, lymphocytes, and platelets resolved spontaneously, though anemia lasted for more than 3 weeks. Sinus bradycardia persisted for 2 days. We hypothesize that there may be an undiscovered hematotoxin or cardiotoxin in fish gallbladder, which needs further investigations.
There is no specific antidote for carp gallbladder poisoning. However, gastric lavage is necessary in the early 72 h using 1–5% soda or warm water. Protecting the gastric mucosa by administering raw eggs and cattle milk may be effective11. Conventional hemodialysis is an effective temporary treatment for anuria or oliguria. Liu Z, et al.19 revealed continuous venovenous hemodiafiltration could effectively remove inflammatory mediators, metabolites, bilirubin and toxins in severe cases while maintaining homeostasis. Supportive treatment, like gastric mucosal protectant and liver protectant are equally important for targeted organ protection. Our patient did not receive gastric lavage like 1–5% soda or warm water due to the earlier misdiagnosis of gastroenteritis and delayed presentation at our center after poisoning. Nutritional support was provided appropriately and was tolerated in our patient, which aided her clinical recovery.