Clinical and clinicopathologic features of dogs that consumed foodborne hepatotoxic aflatoxins: 72 cases (2005-2006)

OBJECTIVE: To characterize clinical signs, clinicopathologic features, treatments, and survival in dogs with naturally acquired foodborne aflatoxicosis. DESIGN: Retrospective case series. ANIMALS: 72 dogs that consumed aflatoxin-contaminated commercial dog food. PROCEDURES: Medical records of affected dogs were reviewed. Between December 2005 and March 2006, dogs were identified as having foodborne aflatoxin hepatotoxicosis on the basis of the history of consumption of contaminated food or characteristic histopathologic lesions (subject dog or a recently deceased dog in the same household or kennel). Recorded information included signalment, clinical features, clinicopathologic test results, treatments, and survival. Data were analyzed by survival status. RESULTS: Most dogs were of large breeds from breeding kennels. No significant differences were found in age or weight between 26 (36%) survivor dogs and 46 (64%) nonsurvivor dogs. Severity of clinical signs varied widely; 7 dogs died abruptly. In order of onset, clinical features included anorexia, lethargy, vomiting, jaundice, diarrhea (melena, hematochezia), abdominal effusion, peripheral edema, and terminal encephalopathy and hemorrhagic diathesis. Common clinicopathologic features included coagulopathic and electrolyte disturbances, hypoproteinemia, increased serum liver enzyme activities, hyperbilirubinemia, and hypocholesterolemia. Cytologic hepatocellular lipid vacuolation was confirmed in 11 dogs examined. In comparisons of clinicopathologic test results between survivor and nonsurvivor dogs, only granular cylindruria (7/21 dogs) consistently predicted death. Best early markers of aflatoxicosis were low plasma activities of anticoagulant proteins (protein C, antithrombin) and hypocholesterolemia. Despite aggressive treatment, many but not all severely affected dogs died. CONCLUSIONS AND CLINICAL RELEVANCE: Serum liver enzyme activities and bilirubin concentration were unreliable early markers of aflatoxin hepatotoxicosis in dogs. Hypocholesterolemia and decreased plasma protein C and antithrombin activities may function as exposure biomarkers.     

Disseminated intravascular coagulation complicating aflatoxicosis in dogs

An outbreak of chronic liver disease was investigated in a kennel of dogs. Anorexia, depression, polyuria, polydipsia, icterus and a terminal hemorrhagic diathesis were noted in clinically affected dogs. Thrombocytopenia, hypofibrinogenemia, elevated fibrinogen degradation products and prolonged activated partial thrombosplastin times (PTT) and one-stage prothrombin times (PT) were associated with the hemorrhagic crisis. Aflatoxicosis was confirmed by the presence of significant levels of aflatoxicosis was confirmed by the presence of significant levels of aflatoxin B in the commercial dog food being fed. A subacute hepatitis was found on necropsy. Disseminated intravascular coagulation was suspected as the cause of the hemorrhage in these cases and treatment was instituted.     

Pathological findings in a natural outbreak of aflatoxicosis in dogs

The gross and histopathological lesions of 10 cases in a natural outbreak of aflatoxicosis amongst dogs in the Republic of South Africa are reported. The 10 cases were classified as acute (1 case), subacute (7 cases) and chronic (2 cases) on the basis of the nature, degree and extent of the following histopathological fractures: hepatocellular fatty degeneration, necrosis or regeneration; proliferation of bile ductules; accumulation of bile within the canaliculi; fibroplasia; and, mucoid degeneration, necrosis or segmental atrophy of the larger intrahepatic bile ducts. Fatty degeneration was noted grossly in the livers of all 10 cases and bile stasis in 4. Varying degrees of fibrosis were present depending on the stage of the disease. In the 2 chronic cases in which nodular regeneration was also observed fibrosis was pronounced. Other macroscopic findings included icterus, anaemia, ascites, hydrothorax, hydropericardium, anasarca, pulmonary oedema, gastro-enterorrhagia and nephrosis.     

Aflatoxicosis in Iowa swine: eight cases (1983-1985)

During 1983, 1984, and 1985, aflatoxicosis was diagnosed in 8 Iowa swine herds after the herds were fed corn from the 1983 corn crop. As a result of the diagnosis, the associated environmental conditions, clinical signs of aflatoxicosis, macroscopic and microscopic lesions, aflatoxin concentrations detected in feeds, and management of affected swine were reviewed. Concentrations of aflatoxin in shelled corn and complete feed were as high as 2,020 ng and 1,200 ng of aflatoxin (B1 and B2)/g of feed, respectively. Clinical signs of aflatoxicosis included decreased feed consumption and weight loss. Some pigs died acutely, but death often was preceded by a period of clinical disease. Greater morbidity and mortality were observed in swine herds that consumed greater concentrations of aflatoxin.     

Aflatoxicosis in feedlot cattle

Aflatoxicosis was diagnosed in lightweight feedlot cattle fed aflatoxin-contaminated cottonseed or gin trash. Clinical signs of hepatic damage and death were recorded for more than 200 of the 14,000 animals in a feedlot. Aflatoxin concentration in feedlot products fed to these cattle ranged from 96 to 1,700 ng/g. Diagnosis was based on the correlation of characteristic microscopic liver lesions, high concentration of aflatoxin in cottonseed feed products, and isolation and detection of aflatoxin B1 and aflatoxin M1 in urine and liver from affected calves. This report describes a large-scale outbreak of aflatoxicosis and demonstrates the need for careful quality control of feed products susceptible to aflatoxin contamination.     

A Syndrome Resembling Idiopathic Noncirrhotic Portal Hypertension in 4 Young Doberman Pinschers

We describe 4 young male Doberman Pinschers (3 littermates and 1 unrelated dog) with a syndrome resembling idiopathic or noncirrhotic portal hypertension of humans. Each dog was evaluated for a hepatopathy resulting in portal hypertension, development of portosystemic collateral vessels, and hepatic encephalopathy. These dogs differ from previous reports of young dogs with hepatic insufficiency associated with portal hypertension and acquired portal systemic shunting by their lack of intrahepatic arteriovenous fistulae, portal vein atresia, or intrahepatic fibrosis. Clinicopathologic features included erythrocyte microcytosis, normal to mildly increased liver enzyme activities, increased concentrations of serum bile acids, reduced plasma indocyanine green clearance, and normal total bilirubin concentration. Abdominal ultrasonography disclosed a small liver and portosystemic collateral vessels. Radiographic imaging studies confirmed hepatofugal portal circulation and discounted hepatic arteriovenous fistulae. Histopathologic features in liver tissue from each dog were similar and consistent in all sections examined. Common findings included increased cross-sectional views of hepatic arterioles; hepatic lobular atrophy; scanty increase in connective tissue around some large portal triads; and absence of inflammation, disturbed lobular architecture, bile duct proliferation, or intrahepatic cholestasis.     

Field cases of aflatoxicosis in pigs

SUMMARY Five cases of aflatoxicosis in pigs in southern Queensland are described. One peracute case where aflatoxin concentrations of up to 5000μg aflatoxin B₁/kg were demonstrated in stomach contents was presumed to be caused by consumption of mouldy bread. High levels of toxins were also present in the livers. Two cases of acute toxicity were caused by feeding mouldy peanut screenings containing 22000μg aflatoxin B₁/kg. One case of subacute and one of chronic toxicity were caused by sorghum grain based rations with lower aflatoxin levels (4640 and 255 μg/kg). Peracute toxicity caused collapse and deaths within several hours, acute toxicity caused deaths within 12 h and with subacute toxicity deaths occured after 3 weeks on a toxic ration. Anorexia and ill thrift affecting only growing animals were seen with chronic toxicity. Extensive centrilobular liver necrosis and haemorrhage occured with peracute toxicity and in cases of acute poisoning there was hepatic centrilobular cellular infiltration, hepatocyte swelling and bile stasis. With subacute toxicity hepatocyte vacuolation together with bile stasis and bile ductule hyperplasia were seen.     

Incidence of hepatopathies in dogs administered zonisamide orally: A retrospective study of 384 cases

BackgroundAcute hepatopathy secondary to administration of zonisamide has been reported in 2 dogs, but overall incidence of hepatopathy is unknown.ObjectiveTo characterize the incidence of hepatopathy in dogs administered zonisamide PO.AnimalsThree hundred eighty‐four dogs administered zonisamide PO.MethodsMulticenter retrospective study. Medical records were searched for dogs prescribed zonisamide PO and which had follow‐up for at least 3 months (acute exposure) and >3 months (chronic exposure). Reported clinical signs, physical examination findings, and serum biochemical panels were reviewed for possible hepatotoxicosis. Serum alanine aminotransferase (ALT) and alkaline phosphatase (ALP) activity and albumin concentration were documented for all available cases.ResultsAcute clinical hepatopathy was found in 2 of 384 treated dogs (0.52%, 95% confidence interval [CI], 0.06‐1.9) after 13‐16 days of zonisamide treatment. One additional dog had elevated serum ALT activity with no clinical signs. Of these 3 dogs, 2 recovered after administration of zonisamide was stopped, and 1 was euthanized because of liver failure. Of the 117 cases chronically administered zonisamide, 10 had an increase in ALP, 6 had an increase in ALT, and 1 had hypoalbuminemia. No clinical signs of liver disease were noted in dogs chronically treated with zonisamide (median, 20 months; range, 5‐94 months).Conclusions and Clinical ImportanceAcute, potentially life‐threatening hepatopathy associated with oral administration of zonisamide to dogs is estimated to occur in less than 1% of dogs and was observed in the first 3 weeks of treatment. Subclinical abnormalities in ALT and ALP activity were noted in <10% of dogs during chronic administration of zonisamide, with no clinical signs of liver disease noted.     

Treatment of cyclophosphamide-induced hemorrhagic cystitis in five dogs

Sterile hemorrhagic cystitis developed in 5 dogs after treatment with cyclophosphamide. Four dogs were being treated with various antineoplastic protocols, and the fifth dog had recurrent immune-mediated thrombocytopenia. In all instances, clinical signs of hematuria and stranguria persisted after cyclophosphamide administration was discontinued. Three dogs required cystotomy to remove necrotic mucosa and calculi. The other 2 dogs were treated with intravesicularly administered dimethyl sulfoxide to decrease inflammation and to inhibit fibroplasia of the bladder wall. In 4 dogs, clinical signs resolved after treatment. The fifth dog, treated surgically, continued to have intermittent urinary incontinence attributable to residual bladder wall fibrosis.     

Mycotoxin interactions in poultry and swine

Mycotoxins are toxic compounds produced by fungi. When one mycotoxin is detected, one should suspect that others also are present in a contaminated feed ingredient or finished feeds. The toxicity and clinical signs of observed in animals when more than one mycotoxin is present in feed are complex and diverse. Some mycotoxins, such as the combination of aflatoxin with either ochratoxin A or T-2 toxin, interact to produce synergistic toxicity in broiler chicks. The effects observed during multiple mycotoxin exposure can differ greatly from the effects observed in animals exposed to a single mycotoxin. For example, fatty livers in poultry are used for presumptive diagnostic identification of aflatoxicosis. However, simultaneous presence of ochratoxin A prevents fatty livers. Of the mycotoxin combinations that have been investigated in poultry and swine, the aflatoxin + ochratoxin A and aflatoxin + T-2 toxin interactions appear to be the most toxic.     

Effectiveness of melatonin on aflatoxicosis in chicks

The efficacy of melatonin co-administration on aflatoxicosis in chicks was investigated. Ross PM3 breed chicks were divided into groups of 10 and given conventional feed. One of the groups was kept as a control (C), and the others were given 150 ppb aflatoxin (AF1), 300 ppb aflatoxin (AF2), 150 ppb aflatoxin plus 10 mg/kg/bwt melatonin (AF1+M), 300 ppb aflatoxin plus 10 mg/kg/bwt melatonin (AF2+M), 10 mg/kg/bwt melatonin (M), and 1% ethanol (E). After 21 day-treatment period, the chicks were sacrificed, liver and kidney tissues were collected, processed for immuno-histochemical staining, in situ TUNEL method, and biochemical analyses. Vacuolar degeneration, necrosis, bile duct hyperplasia in liver, and mild tubular degeneration in kidney were detected in AF groups. Pathological changes were markedly reduced in AF+M groups, and a microscopic view similar to group C was observed. Increased immunoreactivity against inducible nitric oxide synthase (iNOS) and nitrotyrosine was detected in AF groups compared to weak immunoreactivity in group C. Immunoreactivity in AF+M groups was markedly reduced compared to AF groups and was similar to group C in liver and kidney. Many apoptotic cells were detected in the livers of AF groups, whereas there were no apoptotic cells in AF+M groups. While reduced glutathione (GSH) levels in liver and kidney of AF groups were greatly reduced, malondialdehyde (MDA) levels increased. With melatonin co-administration, the levels of GSH and MDA approached to the values of group C. These results indicated that nitrosative tissue degeneration caused by aflatoxin could be greatly reduced by melatonin supplementation in chicks.     

An overview of aflatoxicosis of poultry: its characteristics, prevention and reduction

Aflatoxicosis represents one of the serious diseases of poultry, livestock and other animals. The cause of this disease in poultry and other food-producing animals has been attributed to the ingestion of various feeds contaminated with A. flavus. This toxigenic fungus is known to produce a group of extremely toxic metabolites, of which aflatoxin B1 (AFB1) is most potent. Avian species especially chicks, goslings, ducklings and turkey poults are most susceptible to AFB1 toxicity. The toxic effects of AFB1 are mainly localized in liver as manifested by hepatic necrosis, bile duct proliferation, icterus and hemorrhage. Chronic toxicity in those birds is characterized by loss of weight, decline in feed efficiency, drop in egg production and increased susceptibility to infections. The incidence of hepatocellular tumors, particularly in ducklings, is considered to be one of the serious consequences of aflatoxicosis. Even though prevention and avoidance are the best way to control aflatoxicosis, natural contamination of crops with A. flavus is sometimes unavoidable. Such aflatoxin-contaminated feeds can be decontaminated using various methods which mainly focus on physical removal or chemical inactivation of the toxins in the feeds. Moreover, dietary additives such as activated charcoal, phenobarbital, cysteine, glutathione, betacarotene, fisetin and selenium have also been reported to be effective in the reduction of aflatoxicosis in poultry.     

Aplasia of the gallbladder in a dog

A young, female Maltese dog was presented with intermittent vomiting of bile. Biochemical evidence of persistent mild hepatopathy had been present for 11 months. Exploratory celiotomy was performed. Absence of the gallbladder with malformation of the quadrate lobe of the liver was identified. There was histological evidence of bile duct proliferation and portal fibrosis.     

An overview of aflatoxicosis of poultry: Its characteristics,prevention and reduction

Aflatoxicosis represents one of the serous diseases of poultry, livestock and other animals. The cause of this disease in poultry and other food-producting animals has been attributed to the ingestion of various feeds contaminated with A. flavus. This toxigenic fungus is known to produce a group of extremely toxic metabolites, of which aflatoxin B₁ (AFB₁) is most potent. Avian species especially chickes, goslings, ducklings and turkey poults are most susceptible to AFB₁ toxicity. The toxic effects of AFB₁ are mainly localized in liver as manifested by hepatic necrosis, bile duct proliferation, icterus and hemorrhage. Chronic toxicity in those birds is characterized by loss of weight, decline in feed efficiency, drop in egg production and increased susceptibility to infections. The incidence of hepatocellular tumors, particularly in ducklings, is considered to be one of the serious consequences of aflatoxicosis. Even though prevention and avoidanve are the best way to control aflatoxicosis, natural contamination of crops with A. flavus is sometimes unavoidable. Such aflatoxin-contaminated feeds can be decontaminated using various methods which mainly focus on physical removal or chemical inactivation of the toxins in the feeds. Moreover, dietary additives such as activated charcoal, phenobarbital, cysteine, glutathione, betacarotene, fisetin and selenium have also been reported to be effective in the reduction of aflatoxicosis in poultry.     

Congenital dilatation of the bile ducts (Caroli's disease) in young dogs

We describe 8 young dogs with congenital dilatation of the intra- and extrahepatic bile ducts and diffuse cystic kidney disease, compatible with Caroli's disease in humans. The dogs were referred between 1980 and 2000 because of chronic disease at an age of 6 months to 3 years. These dogs included 3 Collies, 2 Frisian Stabyhouns, 2 Jack Russell Terriers, and 1 mixed-breed dog. The most common signs were vomiting (6/6), polyuria and polydipsia (4/6), and anorexia (4/6). Ascites was a common finding (4/6). Clinicopathologic abnormalities were available for 6 dogs. All had increased plasma alkaline phosphatase activity and fasting bile acids: increased alanine aminotransferase activity and urea and creatinine concentrations were present in 50% of dogs. Ultrasound examination of the liver showed severely dilated bile ducts without evidence of obstruction, and calcification in all cases but 1. Postmortem examination revealed severe dilatation of the larger intra- and extrahepatic bile ducts. The common bile duct and gall bladder were normal, and the bile system was patent. The ducts contained a clear viscid fluid often with calcified material. Microscopically, marked portal fibrosis was present, often with abnormally structured dilated bile ducts lined with columnar or cuboid epithelium and regularly small calcifications. The lesion was complicated by ascending cholangitis in 1 dog. The kidneys showed marked cortical and medullary fibrosis with a diffuse radial cystic pattern; only slight renal fibrosis was found in the oldest dog. Seven dogs were euthanized without treatment; the oldest dog was alive and well 5 months after diagnosis and was maintained on a protein-restricted diet.     

Major biological consequences of aflatoxicosis in animal production.

Aflatoxins, a family of closely related, biologically active mycotoxins, have been known as a prominent cause of animal disease for 30 yr. The toxins occur naturally on several key animal feeds, including corn, cottonseed, and peanuts. Occurrence of aflatoxin on some field crops tends to spike in years when drought and insect damage facilitate invasion by the causative organisms, Aspergillus flavus and A. parasiticus, which abound in the crop's environment. Acute aflatoxicosis causes a distinct overt clinical disease marked by hepatitis, icterus, hemorrhage, and death. More chronic aflatoxin poisoning produces very protean signs that may not be clinically obvious; reduced rate of gain in young animals is a sensitive clinical register of chronic aflatoxicosis. The immune system is also sensitive to aflatoxin, and suppression of cell-mediated immune responsiveness, reduced phagocytosis, and depressed complement and interferon production are produced. Acquired immunity from vaccination programs may be substantially suppressed in some disease models. In such cases the signs of disease observed are those of the infectious process rather than those of the aflatoxin that predisposed the animal to infection. Mixtures of aflatoxin with other mycotoxins can result in greatly augmented biological responses in terms of rate of gain, lethality, and immune reactivity. Because of its great biological activity, its wide-spread potential presence in areas where critical feed crops are grown, and its propensity to spike in problem years, aflatoxin promises to be a continuing problem in animal production.     

Chronic active hepatitis in 26 Doberman pinschers

Chronic active hepatitis with increased hepatic copper concentration was diagnosed in 25 female and 1 male Doberman Pinscher dogs. Common clinical signs included polyuria/polydipsia, weight loss, anorexia, icterus, and ascites. Increased liver enzyme activities and abnormal liver function test results were the most consistent clinicopathologic changes. The dogs were assigned to 3 groups on the basis of clinical course of the disease. Group 1 dogs (n = 12) had clinical signs of advanced liver failure and died within one week. Group 2 dogs (n = 7) had less severe clinical signs of liver disease and died within one month. Group 3 dogs (n = 5) did not have clinical signs of illness or had mild clinical signs of liver disease and died 1 to 42 months after initial evaluation. One dog could not be reevaluated and another dog was alive 3 months after initial examination. Treatments consisted of supportive care for dogs in group 1, and dietary manipulations and corticosteroids for dogs in groups 2 and 3. The association of increased liver copper concentration and chronic active hepatitis is not known.     

Circulatory disorders of the liver in dogs and cats

Summary

This paper presents a review of the literature on hepatic circulation and circulatory disorders of the liver in the dog and cat, and also includes a number of our own not previously published data. Circulatory disorders of the liver are frequently observed in dogs and cats. These disorders can be divided into congenital portosystemic shunts, disorders associated with outflow disturbances, and disorders associated with portal hypertension. Outflow disturbances result in passive congestion of the liver and in both species are mainly due to cardiac failure. Portal hypertension with resultant portosystemic collateral circulation and ascites mainly results from chronic liver disease, particularly cirrhosis. The main vascular disorder resulting in portal hypertension and ascites in the dog is primary hypoplasia of the portal vein.     

QUANTITATIVE HEPATIC SCINTIGRAPHY IN THE DOG

Quantitative hepatic scintigraphy is a noninvasive test for measurement of relative arterial and portal blood flow to the liver. This technique has been used to evaluate human patients with known or suspected liver tumors or diffuse hepatocellular disease. A computer program to assess the hepatic perfusion index (HPI) in the normal dog is described. Factors affecting study quality and accuracy include injection technique, cardiac function, patient position, respiration, gross patient motion, and user intervention during data processing. HPI for a group of 12 normal dogs was 0.9±0.4 (X±SD). Quantitative scintigraphy could be used to evaluate dogs with primary or secondary liver tumors, portacaval shunts, or chronic liver disease     

Possible drug-induced hepatopathy in a dog receiving zonisamide monotherapy for treatment of cryptogenic epilepsy

A 9-year old female spayed Rottweiler was diagnosed with cryptogenic epilepsy and started on zonisamide monotherapy (8.3 mg/kg, PO, q 12 hr). Three weeks after the 1st dose of zonisamide the dog presented for vomiting, inappetence and icterus. Serum biochemistry showed marked elevation of liver enzymes, consistent with hepatocellular damage and cholestasis. No underlying cause for liver disease was identified and a drug-induced hepatopathy was suspected. Zonisamide was discontinued and replaced by potassium bromide. Supportive therapy consisted of intravenous fluids, antiemetics, antibiotics and hepatoprotectants. The dog made a complete recovery and serial serum biochemical examinations showed complete normalisation of liver parameters 8 weeks after discontinuation of zonisamide. Based on a human Drug-induced Liver Injury Diagnostic Scale, the likelihood for zonisamide-induced hepatopathy was classified as "possible". Veterinary practitioners and owners should be educated about the potential for an idiosyncratic drug reaction to zonisamide. If signs of hepatotoxicity are recognised early and zonisamide is discontinued, complete recovery is possible.