Feline hepatobiliary disease: What's new in diagnosis and therapy? (Proceedings)


Feline hepatobiliary disease: What's new in diagnosis and therapy? (Proceedings)

Apr 01, 2010

Toxic Hepatopathy

Pathogenesis and Etiology – Toxic hepatopathy is a direct injury to hepatocytes or other cells in the liver attributable to therapeutic agents or environmental toxins. Cats are particularly sensitive to phenolic toxicity because of limited hepatic glucuronide transferase activity. The discriminatory eating habits of cats may account for the relatively uncommon occurrence of hepatotoxicity from ingested environmental toxins such as pesticides, household products, and other chemicals. Medical therapies (acetaminophen, acetylsalicylic acid, megesterol, ketoconazole, phenazopyridine, tetracycline, diazepam, griseofulvin) and environmental toxins (pine oil + isopropanol, inorganic arsenicals, thallium, zinc phosphide, white phosphorus, Amanita phalloides, aflatoxin, phenols) may contribute to liver pathology. A severe idiosyncratic hepatotoxicity has been reported with diazepam administration in several groups of cats. Clinical signs in affected cats include anorexia, vomiting, weight loss, ascites, encephalopathy, and death. The histology is characterized by severe central lobular necrosis and mild vacuolation.

Mechanisms of Hepatotoxicity - The liver is an important site of drug toxicity and oxidative stress because of its proximity and relationship to the gastrointestinal tract. Seventy-five to 80% of hepatic blood flow comes directly from the gastrointestinal tract and spleen via the main portal vein. Portal blood flow transports nutrients, bacteria and bacterial antigens, drugs, and xenobiotic agents absorbed from the gut to the liver in more concentrated form. Drug-metabolizing enzymes detoxify many xenobiotics but activate the toxicity of others. Hepatic parenchymal and non-parenchymal cells may all contribute to the pathogenesis of hepatic toxicity. The major mechanisms of hepatotoxicity include: Bile Acid-Induced Hepatocyte Apoptosis, Cytochrome P4502E1-Dependent Toxicity, Peroxynitrite-induced Hepatocyte Toxicity, Adhesion Molecules and Oxidant Stress in Inflammatory Liver Injury, Microvesicular and Nonalcoholic Steatosis.

Diagnosis of Hepatotoxicity – Clinical evidence includes supportive history, normal liver size to mild generalized hepatomegaly, elevated serum liver enzyme activities (predominantly ALT and AST), hypoalbuminemia and hypocholesterolemia, and recovery or death depending upon severity and magnitude of exposure. There are no pathognomonic histologic changes in the liver, although necrosis with minimal inflammation and lipid accumulation are considered classic findings.

Treatment of Hepatotoxicity – Few hepatotoxins have specific antidotes, and recovery relies almost exclusively on symptomatic and supportive therapy. If recognized, acetaminophen toxicity may be treated with acetylcysteine (sulfhydryl group donor), ranitidine or cimetidine (cytochrome P450 enzyme inhibition), ascorbic acid (anti-oxidant), and androstanol (consititutive androstane receptor [CAR] inhibition).

Hepatic Lipidosis

Pathogenesis and Etiology – Feline hepatic lipidosis is now a well-recognized syndrome characterized by intracellular accumulation of lipid with clinicopathologic findings consistent with intrahepatic cholestasis. The precise incidence of the syndrome is unknown but pathology surveys have revealed 5% of animals affected with this lesion. While some cases result from diabetes mellitus, the majority of cases are felt to result from the nutritional and biochemical peculiarities of the cat. It has been suggested, for example, that the cat is not very capable of regulating intermediary metabolism during starvation. Although the biochemistry of this lesion has not been completely worked out, there are several biochemical and nutritional peculiarities that predispose the cat to this syndrome. Some of the known biochemical peculiarities of the cat are: essentiality of dietary arginine; low levels of hepatic ornithine; high dietary protein requirements; lack of hepatic enzymatic adaptation to low dietary levels of protein; relative insufficiency of intestinal pyrroline-5-carboxylate synthase activity; relative insufficiency of intestinal and hepatic glutamate reductase; relative insufficiency of intestinal ornithine transcarbamylase; peculiarities in lipoprotein metabolism; and, differences in orotic acid metabolism.

Clinical Features – Most studies suggest that there are no breed, sex, or age predilections. A recent retrospective study by Center and her colleagues suggests that female and middle-age cats are at greater risk for the illness. Obesity may be a predisposing factor, although the syndrome readily develops in fit animals. It has been suggested that obesity followed by a period of anorexia and weight loss are particularly at risk. Cats affected with this syndrome are often presented with a complaint of anorexia, often of several weeks duration. These cats are also commonly presented with jaundice. Other reported clinical signs include vomiting, weakness, weight loss, and diarrhea. Physical examination often reveals dehydration, cachexia, jaundice, and hepatomegaly. All of these findings are also reported in cats with acute pancreatitis and other hepatobiliary disease.

Diagnosis – Hyperechoic changes in the hepatic parenchyma at ultraonography have been cited as a pathognomonic finding, but these changes may be seen in other feline hepatic disorders. Diagnosis should be substantiated by aspiration cytology, or better still, tissue biopsy (percutaneous, trans-abdominal ultrasound guidance, laparoscopy, or open laparotomy). Aspiration cytology has weak sensitivity and specificity, and may miss other diagnoses.

Therapy – Nutritional support is the cornerstone of therapy of this disorder. Most studies suggest that enteral feeding (by "forced" or encouraged feeding, pharyngostomy, gastrostomy, or enterostomy feeding tube) of commercially available cat foods will effect recovery in 90-95% of affected animals. Biourge and his colleagues have characterized some of the metabolic changes that take place during fasting in obese cats. They have been particularly interested in the effects of protein, lipid, or carbohydrate supplementation on hepatic lipid accumulation during rapid weight loss in obese cats. They found that small amounts of protein administered to obese cats during fasting significantly reduced accumulation of lipids in the liver, prevented increases in alkaline phosphatase activity, eliminated negative nitrogen balance, and appeared to minimize muscle catabolism. Carbohydrate supplementation reduced hepatic lipid accumulation, but metabolic abnormalities still developed. Lipid supplementation alone did not ameliorate hepatic lipidosis and even resulted in more severe lipid accumulation than under conditions of fasting alone. The use of benzodiazepine agonists (e.g. diazepam, oxazepam, elfazepam) and 5-HT2 agonists (e.g., cyproheptadine) as appetite stimulants has been encouraged in anorexic cats. These compounds particularly the benzodiazepine agonists, should be used with caution as they may exacerbate pre-existing hepatic encephalopathy. Benzodiazepine agonists have been shown to worsen hepatoencephalopathy in other animal species through activation of the neuronal benzodiazepine/GABA receptor-chloride channel complex.