The role of roughage provision on the absorption and disposition of the mycotoxin deoxynivalenol and its acetylated derivatives in calves: from field observations to toxicokinetics.

A clinical case in Belgium demonstrated that feeding a feed concentrate containing considerable levels of deoxynivalenol (DON, 1.13 mg/kg feed) induced severe liver failure in 2- to 3-month-old beef calves. Symptoms disappeared by replacing the highly contaminated corn and by stimulating ruminal development via roughage administration. A multi-mycotoxin contamination was demonstrated in feed samples collected at 15 different veal farms in Belgium. DON was most prevalent, contaminating 80% of the roughage samples (mixed straw and maize silage; average concentration in positives: 637 ± 621 µg/kg, max. 1818 µg/kg), and all feed concentrate samples (411 ± 156 µg/kg, max. 693 µg/kg). In order to evaluate the impact of roughage provision and its associated ruminal development on the gastro-intestinal absorption and biodegradation of DON and its acetylated derivatives (3- and 15-ADON) in calves, a toxicokinetic study was performed with two ruminating and two non-ruminating male calves. Animals received in succession a bolus of DON (120 µg/kg bodyweight (BW)), 15-ADON (50 µg/kg BW), and 3-ADON (25 µg/kg) by intravenous (IV) injection or per os (PO) in a cross-over design. The absolute oral bioavailability of DON was much higher in non-ruminating calves (50.7 ± 33.0%) compared to ruminating calves (4.1 ± 4.5%). Immediately following exposure, 3- and 15-ADON were hydrolysed to DON in ruminating calves. DON and its acetylated metabolites were mainly metabolized to DON-3-glucuronide, however, also small amounts of DON-15-glucuronide were detected in urine. DON degradation to deepoxy-DON (DOM-1) was only observed to a relevant extent in ruminating calves. Consequently, toxicity of DON in calves is closely related to roughage provision and the associated stage of ruminal development.

Acute lymphocytic cholangitis and liver failure in an Amur tiger (Panthera tigris altaica).

An adult male Amur tiger (Panthera tigris altaica) with confirmed inflammatory bowel disease developed acute severe icterus, bilirubinuria, bilirubinemia, and elevated bile acids after a diet change. Liver biopsies showed moderate lymphoplasmacytic cholangiohepatitis (lymphocytic cholangitis). The tiger developed neurologic signs including ataxia, tremors, and seizures, as well as epistaxis. Therapy consisted of antibiotics, a steroid anti-inflammatory, vitamins, pro-coagulants, and liver-supportive medicines. The tiger improved from acute liver failure within 3 wk, while the epistaxis began at 3.5 wk and did not resolve until 10.5 wk. The long-term maintenance plan consists of oral prednisolone, metronidazole, ursodiol, and an all muscle-meat beef diet.

Liver failure in a dog following suspected ingestion of blue-green algae (Microcystis spp.): a case report and review of the toxin.

A 2.5 yr old spayed female Weimaraner presented after ingestion of blue-green algae (Microcystis spp.). One day prior to presentation, the patient was swimming at a local lake known to be contaminated with high levels of blue-green algae that was responsible for deaths of several other dogs the same summer. The patient presented 24 hr after exposure with vomiting, inappetence, weakness, and lethargy. Blood work at the time of admission was consistent with acute hepatic failure, characteristic findings of intoxication by Microcystis spp. Diagnosis was suspected by analyzing a water sample from the location where the patient was swimming. Supportive care including fluids, fresh frozen plasma, whole blood, vitamin K, B complex vitamins, S-adenosyl methionine, and Silybum marianum were started. The patient was discharged on supportive medications, and follow-up blood work showed continued improvement. Ingestion is typically fatal for most patients. This is the first canine to be reported in the literature to survive treatment after known exposure.

Hepatic encephalopathy: etiology, pathogenesis, and clinical signs.

Hepatic encephalopathy (HE) is a manifestation of clinical signs that may result from a variety of liver diseases. In small animals, HE is most commonly a result of portosystemic shunting. The pathogenesis is not completely understood, although it is likely multifactorial. Theories of pathogenesis include altered ammonia metabolism and glutamine and glutamate transmission, an increase in gamma-aminobutyric acid agonists and benzodiazepine-like substances, alterations of the serotonergic system and amino acid metabolism, elevated taurine levels, contributions from inflammatory mediators, and toxic effects of manganese. An understanding of the underlying mechanisms that result in HE may lead to new treatments in the future.

Hepatic encephalopathy: diagnosis and treatment.

Hepatic encephalopathy (HE) is a neurologic syndrome resulting from the synergistic action of multiple pathologic factors, which are discussed in a companion article. Early recognition of the clinical signs can improve treatment outcome, as well as reduce the incidence of risk factors. Multimodal treatment of HE is usually indicated. Studies on the pathogenesis and treatment of HE in people may shed new light on further treatment modalities in small animal patients.

Xylitol toxicosis in dogs.

The sugar alcohol xylitol is a popular sweetener used in gums, candies, and baked goods. While xylitol has a wide margin of safety in people and most mammalian species, when ingested by dogs it is believed to stimulate excessive insulin secretion leading to severe hypoglycemia, potentially followed by acute hepatic failure and coagulopathies. Additional clinical findings may include thrombocytopenia, hypokalemia, and hyperphosphatemia. The prognosis for recovery in dogs that develop uncomplicated hypoglycemia is generally good with prompt and aggressive veterinary care.

Successful treatment of hepatic failure secondary to diazepam administration in a cat.

A 2-year-old castrated male domestic shorthair cat developed acute hepatic failure following oral diazepam administration for behavioral problems. The patient survived with intensive supportive care and was discharged after 5 days in hospital. Successful treatment of diazepam-associated fulminant hepatic failure in cats has rarely been described in the veterinary literature.

Nephrotoxic effects from chronic toxic cyanobacterial blooms in fishes with different trophic levels in a large Chinese lake.

Physiological and biochemical responses in kidneys of fishes with different trophic levels to toxic cyanobacterial blooms were studied. We sampled four fishes: the phytoplanktivorous Hypophthalmichthys molitrix and Aristichthys nobilis, the omnivorous Carassius auratus, and the carnivorous Culter ilishaeformis. Alterations of the antioxidant (GSH) and the major antioxidant enzymes (CAT, SOD, GPx, GST) were monitored monthly. Catalase and glutathione S-transferase were significantly higher during blooms than before and after blooms. All fishes showed ultrastructural alterations during blooms, which mainly are inosculation of foot processes in epithelial cell of glomeruli and mitochondria swelling in the proximal tubules. The results suggested that kidney impairment from chronic exposure of toxic cyanobacterial blooms might be the first step, and then followed by hepatic failure. Compared with livers in terms of physiological status, the weaker antioxidant ability of kidney made it more susceptible to chronic MCs exposure, besides its effective accumulation of MC metabolites.

Amanitin toxicosis in two cats with acute hepatic and renal failure.

Amanitin is a toxic cyclopeptide present in several species of poisonous mushrooms. Amanitin toxicosis was diagnosed in 2 cats from separate premises. Both cats initially had lethargy and vomiting, and they rapidly developed depression and neurological signs over 24-48 hours. Marked elevation of alanine aminotransferase was the primary finding, with subsequent serum chemistry values compatible with hepatic and renal failure. Histopathological findings consisted of submassive to massive acute hepatic necrosis, renal proximal tubular epithelial necrosis, and foci of necrosis and inflammation in the gastrointestinal tract. Amanitin exposure was confirmed postmortem by detection of α-amanitin in the kidney by liquid chromatography-mass spectrometry. A similar clinical course and pathological changes are reported in human and canine amanitin intoxication; however, gastrointestinal lesions are not typically described.

Syndrome of inappropriate antidiuretic hormone secretion concurrent with liver disease in a dog.

A 5-year-old female Chihuahua was presented for acute collapse. Laboratory examinations showed markedly elevated levels of hepatobiliary enzymes. Empiric antibiotic therapy for bacterial infection of the liver was ineffective. The clinical signs worsened with the development of hyponatremia with hypoosmolality and elevated urine sodium levels. The dog was suspected of having acute cholangiohepatitis associated with an immune-mediated disease. Subsequently, it was diagnosed with syndrome of inappropriate antidiuretic hormone secretion (SIADH) on the basis of the specific disease criteria. Further tests showed normal function of the adrenal and thyroid glands, and MRI and cerebrospinal fluid (CSF) analysis did not show any intracranial diseases. Immunosuppressive therapy and water restriction resolved the clinical signs and improved the SIADH in this dog. This case indicates that SIADH can occur concurrently with suspected immune-mediated liver disease in dogs.

CCNU (lomustine) toxicity in dogs: a retrospective study (2002-07).

OBJECTIVE: To describe the incidence of haematological, renal, hepatic and gastrointestinal toxicities in tumour-bearing dogs receiving 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU). DESIGN: The medical records of 206 dogs that were treated with CCNU at the Melbourne Veterinary Specialist Centre between February 2002 and December 2007 were retrospectively evaluated. RESULTS: Of the 206 dogs treated with CCNU, 185 met the inclusion criteria for at least one class of toxicity. CCNU was used most commonly in the treatment of lymphoma, mast cell tumour, brain tumour, histiocytic tumours and epitheliotropic lymphoma. Throughout treatment, 56.9% of dogs experienced neutropenia, 34.2% experienced anaemia and 14.2% experienced thrombocytopenia. Gastrointestinal toxicosis was detected in 37.8% of dogs, the most common sign of which was vomiting (24.3%). Potential renal toxicity and elevated alanine transaminase (ALT) concentration were reported in 12.2% and 48.8% of dogs, respectively. The incidence of hepatic failure was 1.2%. CONCLUSIONS: CCNU-associated toxicity in dogs is common, but is usually not life threatening.

Xylitol toxicity in dogs.

Xylitol, a sugar substitute used in sugar-free gum, oral care products, and baked goods, is gaining popularity in the United States. Xylitol consumption is considered harmless to people but is known to cause life-threatening toxicoses in dogs. Dogs that ingest doses of >0.1 g/kg of xylitol are at risk for developing hypoglycemia, while dogs that ingest >0.5 g/kg may develop acute liver failure. Treatment includes dextrose supplementation for hypoglycemia and aggressive monitoring, treatment, and supportive care for dogs experiencing hepatotoxicosis. The prognosis for dogs with uncomplicated hypoglycemia is good, whereas the prognosis for dogs that develop severe hepatotoxicosis is guarded to poor.

Nutrition of critically ill horses.

Nutritional supplementation is becoming the standard of practice in equine medicine, although there are minimal data on nutritional support in critically ill horses and its association or effect on morbidity and mortality or length of hospital stay. Horses can be fed orally and when that is not possible, intravenously or parenterally. Enteral feeding is less expensive, more physiologic, improves immunity, and is easier and safer. This article reviews available information on the development of a nutritional plan for critically ill horses, and describes methods for and complications of enteral and parenteral feeding.

Adjuvant CCNU (lomustine) and prednisone chemotherapy for dogs with incompletely excised grade 2 mast cell tumors.

The use of adjuvant 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU; lomustine) to treat incompletely excised canine mast cell tumors (MCTs) has not been evaluated. Medical records of 12 dogs with grade 2 MCT treated with incomplete surgical excision and adjuvant CCNU and prednisone chemotherapy were reviewed. Local recurrence rate, metastasis rate, and survival time were evaluated. None of the dogs developed local recurrence or regional/ distant metastases. Two dogs developed fatal liver failure. The 1- and 2-year progression-free rates of surviving dogs were 100% and 77%, respectively. Postoperative adjuvant CCNU appears to be a useful alternative to radiation therapy for incompletely excised canine cutaneous MCTs.

Factors associated with outcome in foals with neonatal isoerythrolysis (72 cases, 1988-2003).

BACKGROUND: Neonatal foals with isoerythrolysis (NI) often die, but the risk factors for death have not been identified. OBJECTIVES: To identify factors associated with outcome in foals with NI and to identify factors associated with death from liver failure or kernicterus in the same population. ANIMALS: Seventy-two foals with NI examined at referral institutions. METHODS: Retrospective case series. Information on signalment, clinical examination findings, laboratory testing, treatment, complications, outcome, and necropsy results were obtained. RESULTS: The overall survival rate was 75% (54 of 72). Liver failure (n=7), kernicterus (n=6), and complications related to bacterial sepsis (n=3) were the 3 most common reasons for death or euthanasia. The number of transfusions with blood products was the factor most strongly associated with nonsurvival in a multivariate logistic regression model. The odds of liver failure developing in foals receiving a total volume of blood products >or= 4.0 L were 19.5 (95% confidence intervals [CI]: 2.13-178) times higher than that of foals receiving a lower volume (P= .009). The odds of kernicterus developing in foals with a total bilirubin >or= 27.0 mg/dL were 17.0 (95% CI: 1.77-165) times higher than that of foals with a lower total bilirubin (P= .014). CONCLUSIONS AND CLINICAL IMPORTANCE: Development of liver failure, kernicterus, and complications related to bacterial sepsis are the most common causes of death in foals with NI. Foals administered a large volume of blood products are at greater risk for developing liver failure.

The bioreactor with CYP3A4- and glutamine synthetase-introduced HepG2 cells: treatment of hepatic failure dog with diazepam overdosage.

A novel recombinant human hepatic cell line, CYP3A4- and glutamine synthetase (GS, an enzyme which converts ammonium ion and glutamate to glutamine)-introduced HepG2 (HepG2-GS-CYP3A4), was established. Its usefulness in a large-scale culture with a circulatory bioreactor in vitro and in dog models of ischemic hepatic failure with acute diazepam (DZP, a substrate of CYP3A4) overdosage was further examined. HepG2-GS-CYP3A4 expressed about 9 times larger amounts of CYP3A4 protein than a control. After incubation with HepG2-GS-3A4 cells in a circulatory bioreactor for 24 h, ammonia and DZP concentrations in the culture medium significantly decreased by about 40%. Furthermore, this system improved the survival time and decreased serum concentrations of DZP, ammonia, and transaminase in dogs with ischemic hepatic failure plus acute DZP overdosage. The mean survival time with bioreactor with HepG2-GS-3A4 was 42.7 +/- 3.6 h, which was significantly longer than that without reactor, with reactor (no cells), and with HepG2-GS (23.4 +/- 2.8, 22.1 +/- 2.4, and 31 +/- 3.7 h, respectively). Therefore, it is concluded that this bioartificial liver could be a good tool for the treatment of dogs with hepatic failure and that it could potentially be a bridging procedure to liver transplantation.

A mouse model provides evidence that genetic background modulates anemia and liver injury in erythropoietic protoporphyria.

Erythropoietic protoporphyria is an inherited disorder of heme biosynthesis caused by partial ferrochelatase deficiency, resulting in protoporphyrin (PP) overproduction by erythrocytes. In humans, it is responsible for painful skin photosensitivity and, occasionally, liver failure due to accumulation of PP in the liver. The ferrochelatase deficiency mouse mutation is the best animal model available for human erythropoietic protoporphyria. The original description, based on mice with a BALB/cByJCrl genetic background, reported a disease resembling the severe form of the human disease, with anemia, jaundice, and liver failure. Using congenic strains, we investigated the effect of genetic background on the severity of the phenotype. Compared with BALB/cByJCrl, C57BL/6JCrl mice developed moderate but increasing anemia and intense liver accumulation of PP with severe hepatocyte damage and loss. Bile excretory function was not affected, and bilirubin remained low. Despite the highest PP concentration in erythrocytes, anemia was mild and there were few PP deposits in the liver in SJL/JOrlCrl homozygotes. Discriminant analysis using six hematologic and biochemical parameters showed that homozygotes of the three genetic backgrounds could be clustered in three well-separated groups. These three congenic strains provide strong evidence for independent genetic control of bone marrow contribution of PP overproduction to development of liver disease and biliary PP excretion. They provide a tool to investigate the physiological mechanisms involved in these phenotypic differences and to identify modifying genes.