Spring 1998 Edition

The Society's Web Page is now operational. Interested Web enthusiasts may obtain information about the C.G.S. membership, grant and membership applications, articles of incorporation, Society resources, officers and directors, and related Societies (American Gastroenterology Association, American Physiological Society, and Gastrointestinal Research Group) by accessing the C.G.S. Web Page at: http://www.vet.upenn.edu/cs_phila/sam/cgs.htm. (Most Web browsers, e.g., Netscape and Explorer, have bookmark functions for easier access to favorite WebSites.) Society Newsletters, including this Newsletter, will be published on the Society Web Page.

Society ListServe

An InterNet ListServe will soon be operational. For those members with access to the Internet, the ListServe will permit group discussion of Society issues, interesting gastroenterology cases, and updates in clinical and basic research.

Society Meetings

1997 Conference of Research Workers in Animal Diseases - The 78th Annual meeting of the Conference of Research Workers in Animal Diseases was held in November at the Congress Hotel in Chicago. CGS Director Dr. Gerald Duhamel presided over the Gastroenteric Diseases section of the meeting. Twenty-six oral abstracts and sixteen posters were presented in the G.I. section, and seven abstracts were evaluated for the Society's research abstract award. Susan J. Hartmann of the Iowa State University College of Veterinary Medicine received the Society's award for her research abstract entitled, "Application of a reverse transcription-polymerase chain reaction (RT-PCR) for detection and differentiation of transmissible gastroenteritis virus in feces".

1998 North American Veterinary Conference - The Society sponsored a Scientific Symposium and Endoscopy Laboratory at the 1998 NAVC meeting in Orlando. The Endoscopy Laboratory was a big hit, and an outstanding Scientific Symposium was presented by Drs. Edward Hall, Bob Sherding, and David Twedt. Drs. Michael Leib and Robert DeNovo have agreed to present the CGS Scientific Symposium at the 1999 North American Veterinary Conference.

1998 ACVIM Forum - The Society will host an exciting half-day symposium at the 1998 ACVIM Forum in San Diego. Drs. Neil Granger and Rustin Moore have been invited to present overviews of their work in ischemia/re-perfusion injury of the gastrointestinal tract. Both speakers have excellent publication track records in the area of ischemia/re-perfusion injury. The CGS symposium will be held on Saturday May 23 from 8:00 am - 12:30 pm. The Liver Study Group will hold their half-day symposium on Saturday afternoon (2:00 - 6:00 pm). Drs. Alan Hofmann and David Williams have been invited to present overviews of their work in bile acid metabolism. Their presentations will be followed by a panel discussion of the medical management of chronic liver disease in dogs and cats. Please mark both meetings in your calendars. Please also mark your calendars for the CGS membership luncheon meeting on Sunday May 24, 12:30-2:00. Dr. Larry McDaniel at Ralston Purina Company has graciously agreed to sponsor the CGS luncheon meeting.

Related Societies and Their Meetings

American Gastroenterological Association (AGA) - The 1998 AGA meeting will be held May 17-20 in New Orleans. The PhD, MD/PhD and DVM Task force (Rick Boland, Colin Burrows, Hannah Carey, Helen Cooke-Chair, Allan Walker, Norm Weisbrodt) will once again sponsor an AGA Clinical Symposium on Current Topics in Comparative Gastroenterology. The focus of this symposium will be Viral Hepatitis and Hepatic Carcinogenesis, featuring John Cullen, VMD, PhD of North Carolina State University ("Animal Models of Hepatitis B Virus Infection") and Bud Tennant, DVM of Cornell University ("Woodchuck Hepatitis Virus Infection: Role in Hepatocarcinogenesis"). The Symposium will be held on Tuesday May 19, and will be chaired by Colin Burrows and Robert Washabau.

American Motility Society (AMS) - The 1998 biennial meeting of the American Motility Society will be held in Philadelphia in October. The meeting is primarily concerned with clinical and research aspects of gastrointestinal motility and nerve-gut interactions. If interested, please contact Society members Robert Washabau, Allen Roussel, or Al Merrit for more details.

European Society of Comparative Gastroenterology - The 1997 meeting was held in September in conjunction with the European Society of Veterinary Internal Medicine in Lyon, France. Mucosal inflammation, Helicobacter infection, and chronic hepatitis were the major focus areas of the Congress. Membership in the ESCG may be sought by writing: Dr. Patrick LeCoindre, ALGEC, 50 rue Jeanne d'Arc, 69003, Lyon, France. ESCG membership confers full membership in the European Society of Veterinary Internal Medicine because the ESCG is a fully-affiliated society. Dave Twedt also writes that: "The European Journal of Comparative Gastroenterology is the official journal of the ESCG. The journal is beginning its second year of publication producing two issues per year. The journal publishes original research, review articles, and clinical case histories on medical and surgical aspects of small animal gastroenterology. The journal is soliciting articles for publication and I encourage you to take a look at it. All of the figures and endoscopic photos have been very high quality. The journal is refereeed, but I'm not sure it is listed as an approved journal for ACVIM Internal Medicine specialty certification publication requirements. Due to the rapid turn around time, it might be worth investigating for some of our residents in need of a rapid publication. Further information can be obtained from the editor, Dr. Massimo Gualtieri, Instituto di Clinica Chirurgica Vet., Via Celoria, 10-20133, Milano, Italy, or via the InterNet at http://www.softeam.it/scivac. The Editorial Board includes CGS members Robert Washabau and myself, and you should feel free to contact us if you have any questions."

American Association for the Study of Liver Disease (AASLD) - Dr. Cyndie Webster attended the fall (1997) meeting of the AASLD and offered the following report: "This year I attended the postgraduate course entitled, "Liver Injury Update: Clinical Implications and Mechanistic Role of Cells of the Liver", in hopes I might gain some insight into the clinical management of my veterinary patients with liver disease. The session started out with a discussion of the relative contribution of necrosis and apoptosis in liver cell death in acute and chronic disease. This may seem a minor point, but actually could have therapeutic implications. Necrosis can be likened to cellular murder, a completely random event in response to an irreversible injury. Apoptosis, also called programmed cell death, is more like cellular suicide in which a cell "decides" to set in place a series of genetically controlled steps which culminate in cell death. It was the general consensus of the attendees that apoptosis is likely the major form of cell death in chronic liver disease. My own research involves studying the mechanisms whereby bile acids induce hepatocyte apoptosis. Since serum and hepatic bile acid concentration increase in most hepatopathies, it is likely that hydrophobic toxins contribute to ongoing pathology in cholestatic liver disorders. For the last several years there has been intense investigation geared toward elucidating the steps involved in apoptosis. A particularly exciting area of investigation is the development of inhibitors of the apoptotic cascade. Recent experiments in animal models have shown that drugs, which disrupt the apoptotic pathways in mice, protect again hepatocyte cell death associated with exposure to known hepatotoxins. These anti-apoptotic drugs, known as caspase inhibitors, are the subjects of intense interest in the pharmaceutical industry.

There was a session on NSAID hepatotoxicity was interesting in light of the recent reports on carprofen toxicity in dogs. The gist of the talk was that all NSAID's should be considered as potential hepatotoxins, although some classes appear to be associated with an increased incidence of toxic injury. Reactions are primarily idiosyncratic and mediated either by immunologic mechanisms (e.g. phenylbutazone) or by metabolic aberrations (e.g. diclofenac). The drugs cause different patterns of histologic injury (cholestatic or cytotoxic). The reactions are most often acute with the onset of injury within the first twelve weeks of therapy. Occasionally chronic injury after prolonged use has also been reported. With diclofenac there is an increased susceptibility in females and in patients treated for osteoarthritis. Soon to be published reports of carprofen toxicity in dogs suggest that the majority of cases are associated with idiosyncratic acute hepatocellular injury with a predisposition seen in Labrador Retrievers most of whom were on the medication for treatment of osteoarthritis.

There was a session on the treatment of autoimmune hepatitis (AIH) in man. There was a caution against tapering prednisone too quickly since a change in the dosage of as little as 2 mg can make the difference between continued clinical remission and relapse. In addition, there is some excitement over the development of a second generation corticosteroid, budesonide, for treatment of AIH. The following reasons were cited: 1. high affinity for the glucocorticoid receptor (15X greater than prednisolone), 2. rapid first pass hepatic clearance (which would decrease extrahepatic side effects) and 3. metabolites which are devoid of corticosteroid activity.

Day 2 of the postgraduate course started with a discussion of cryptogenic hepatitis. Even with sophisticated techniques to eliminate drug/toxin, viral, autoimmune, genetic and metabolic causes, 17% of chronic hepatic disease is man is classified of unknown etiology, i.e. cryptogenic hepatitis (CH). I don't know about everyone else out there, but about 90% of my cases of chronic hepatitis in dogs and cats are cryptogenic. In man there is some evidence to suggest that people with CH may have autoimmune disease that has escaped diagnosis by conventional markers (autoantibodies, increased globulins) either because of a decline in the markers or because there is an immune response to antigens which have not yet been identified. The latter is highly possible in dogs and cats where the only auto-antibody we have a reliable test for is ANA. Keep in mind that the majority of human patients with AIH (80%) are ANA positive. Most of my patients and the majority of the reports in the veterinary literature suggest that most canine and feline patients are not ANA positive. There is also some evidence that patients with CH respond equally well to corticosteroids as do patients with AIH. Biopsies from patients with CH are somewhat variable, most show some inflammatory activity with a mixture of plasma cells and lymphocytes, piecemeal necrosis and steatosis.

There were several talks about the role of endotoxin in hepatic injury. Endotoxin is believed to play a major role in alcohol induced liver injury, but endotoxemia occurs in a variety of hepatic disorders in man. The source of the increased endotoxin is not known. One theory is the "leaky gut" hypothesis which suggests that the intestinal mucosa becomes more permeable to endotoxin in liver disease. No one was able to offer an explanation as to why this occurs. The second reason suggested for the endotoxemia was decreased Kupffer cell clearance of endotoxin. Regardless of its source, it has been demonstrated in several animal models that removal or neutralization of endotoxin reduces the degree of toxin induced hepatocellular damage. Endotoxin, however, is not a direct hepatotoxin. It is believed that it mediates injury by activating hepatic macrophages, i.e. the Kupffer cells. Activated Kupffer cells release soluble mediators, such as tumor necrosis factor-a (TNF), which then in turn damage hepatocytes. TNF has been shown to be directly toxic to hepatocytes and can cause either hepatocyte necrosis or apoptosis. TNF receptor binding also activates intracellular mechanisms which lead to increased concentrations of a transcription factor called NF-kB. NF-kB acts on genes which control the production of inflammatory cytokines. The anti-inflammatory activity of corticoteroids may be largely associated with inhibition of NF-kB signaling. There is a tremendous amount of interest on the part of biotechnology and pharmaceutical industries to develop anti-inflammatory therapeutic agents which specifically interfere with NF-kB activation.

Non-alcoholic steatohepatitis (NASH) includes a spectrum of fatty disease of the liver in man which ranges from simple steatosis, to steatohepatitis, to the presence of portal fibrosis/cirrhosis with fat. NASH may be the third most common diagnostic category of people referred to specialists for evaluation of liver enzyme elevations. Many of these patients are otherwise asymptomatic, although some have nonspecific lethargy or mild right upper abdominal pain. Many of the patients are overweight and some are diabetic. About 1/2 are hyperlipidemic. Several patients with NASH were diagnosed with concurrent small intestinal bacterial overgrowth and treatment with metronidazole reversed the histologic lesions. Treatment of NASH is controversial. Weight reduction is recommended although it needs to be gradual since sudden weight loss can lead to worsening of disease and even severe hepatic failure. Sounds like our kitties with IHL. Recent studies have suggested that treatment with ursodeoxycholate or vitamin E might improve NASH. Studies on the pathogenesis of NASH suggest that the deposition of fat in the liver, regardless of cause, is associated with increased oxidant liver injury secondary to lipid peroxidation. Lipid peroxidation leads to the generation of free radicals which stimulate hepatic inflammation and fibrosis. It is also known that fatty livers are uniquely sensitive to endotoxin and cytokine mediated injury.

An interesting session was held on microvesicular steatosis In this condition numerous small lipid vesicles accumulate in the liver. It was stressed that this is the histological hallmark of a severe hepatic metabolic disease affecting mitochondrial function. Macrovesicular steatosis defined histologically as a single large lipid vacuole, appears to be a more clinically benign lesion. Cats with idiopathic hepatic lipidosis (IHL) get primarily macrovesicular steatosis although many cats have a mixed pattern. The speaker suggested that mixed patterns do not always behave benignly. Patients with liver failure due to microvesicular steatosis frequently have concurrent azotemia and pancreatitis. The latter is also quite common in cats with IHL. In human patients with microvesicular steatosis once hepatic failure has occurred , the accompanying anorexia and vomiting leads to further restriction of carbohydrate intake. This accentuates the energy deficient state caused by the mitochondria injury leading to increased peripheral lipolysis and increased mobilization of fats to the already fat overloaded liver. The liver is unable to handle the influx and the result is increased oxidant damage and exacerbation of mitochondrial damage. This may be the reason why cats with IHL that receive intensive nutritional support have a better chance of surviving. It may be that we are not necessarily supplying them with any deficient nutrient, but simply preventing exacerbation of their disease so that they can recover from whatever it is that causes the hepatic problem in the first place. There was a discussion of drugs which induce microvesicular steatosis. Among them are aspirin and tetracycline. In the liver aspirin is quickly hydrolyzed to salicylic acid and subsequently activated to salicyclic-CoA. Extensive formation of salicylic-CoA sequesters extramitochondrial CoA leaving insufficient CoA to activate long chain fatty acids and thereby decreasing beta-oxidation. In order to get clinically significant impairment of mitochondrial function with aspirin, however, requires a second injury. Tetracyclines inhibit both mitochondrial beta-oxidation and hepatic secretion of low density lipoproteins. Clinically significant steatosis is seen more commonly with intravenous use. Patients frequently have associated renal failure and pancreatitis. Glucocorticoids are also known to produce macrovesicular steatosis in man and should never be used in cats with IHL.

One talk argued that many of the manifestations of chronic hepatitis are related to adverse effects of cytokines. Of particular interest was the observation that cytokines can induce a centrally mediated anorexia perhaps through the effects of a variety of neuropeptides. Recent research has suggested that TNF induced expression of leptins may be involved in development of anorexia. Leptin, the product of the obese gene, is a peptide hormone produced in fat cells. It binds to receptors in the hypothalamus leading to inhibition of the feeding behavior and increased metabolic rate. It is interesting to speculate that this hormone may have a role in the anorexia we see accompanying IHL in cats."

Society Projects

Dr. Kenneth Simpson offers the following update on the CGS-sponsored Helicobacter project: "I would like to thank all of you who have been collecting biopsies and serum for the CGS Helicobacter study. It is now time to start analyzing the samples. Please could you send the standardized forms, H & E and silver stained slides, frozen biopsies, and serum samples to me as soon as possible. Dr. Jim Fox has offered the services of two of his pathologists to blindly evaluate histopathology slides for inflammation and Helicobacter colonization. Frozen biopsies will be evaluated for the presence of H. felis, H. heilmannii and H. pylori by PCR. Serum samples will be analayzed for gastrin and antibodies to Helicobacter species. Please E-Mail me at KWS5@cornell.edu to get an airborne express account number to cover shipping costs and to let me know that you intend to send samples. Thank you."

Society Support

The CGS gratefully acknowledges the support of Dr. Deborah Davenport and Hill's Pet Nutrition in the amount of $10,000. Thanks Debbie!

Society Grant Applications

As of March 1, the CGS has received only three research grant applications for the 1998 funding cycle. The application deadline has now been extended to April 13. Please encourage your residents, graduate students, and post-doctoral fellows to apply for funding through the CGS. Promoting gastrointestinal research is one of the major goals of the Society, and funding is available for 1- or 2-year grant proposals. Instructions for grant applications are enclosed in this mailing. Please mail completed proposals to Dr. David A. Williams at Texas A & M University.

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