22ND FECAVA. Eurocongress. 31. VÖK Jahrestagung. 31ST VOEK Annual Meeting June 2016 Hofburg, Vienna.

Transcription

1 22ND FECAVA Eurocongress 31. VÖK Jahrestagung 31ST VOEK Annual Meeting June 2016 Hofburg, Vienna Proceedings Proceedings

2 22. FECAVA Eurocongress 31 st Annual Congress of the Association of Austrian small animal veterinarians Gastroenterology Hofburg, Vienna June 22-25,

3 Table of content Speakers... 4 Acute liver disease and hepatoencephalopathy making a big difference in a small amount of time... 5 Chronic inflammatory liver disease different or all the same... 9 The good and the bad microbiota and antibiotic-responsive diarrhea Canine IBD including steroid resistant IBD

4 Speakers Prof. Karin Allenspach, Dr.med.vet.FVH PhD DECVIM-CA USA Dr.med.vet., PhD Jörg M. Steiner, DACVIM, DECVIM-CA, AGAF USA 4

5 Acute Liver Disease and Hepatoencephalopathy --- Making a Big Difference in a Small Amount of Time Jörg M. Steiner, med.vet., Dr.med.vet., PhD, DACVIM, DECVIM-CA, AGAF GI Laboratory, Texas A&M University, College Station, TX, USA Introduction Liver disease is common in both dogs and cats, but acute liver disease is far less common than chronic hepatic disease in either species. Also, it should be noted that many patients with an acute onset of clinical signs suggestive of liver disease actually do have chronic liver disease. This is because chronic liver disease often remains subclinical for quite some time and clinical signs only occur when the disease process becomes more severe or has destroyed a significant portion of hepatic function, leading to acute signs of liver failure. One such example would be chronic hepatitis due to phenobarbital administration. Most of these patients have no clinical signs for years even though biochemically hepatic disease is evident. Only when hepatic function has been compromised significantly do these patients present with an apparently acute onset of clinical signs, such as anorexia, vomiting, ascites, hepatoencephalopathy (HE), and even bleeding diathesis. Thus, hepatoencephalopathy and other clinical signs of hepatic failure are not necessarily associated with acute hepatic disease, but are instead associated with hepatic failure. Acute Liver Disease Acute Hepatitis Both infections and toxicities can lead to acute hepatitis. While infections, for example with infectious canine hepatitis or leptospirosis lead to hepatic necrosis and secondary inflammation due to the infectious organism, toxic causes through chemicals or medications lead to hepatocellular necrosis due to the toxic substance with secondary inflammation. Clinical Signs Acute hepatitis may be associated with fever, anorexia, vomiting, depression, and dehydration. In severe cases, clinical signs of liver failure maybe seen in addition, such as HE, jaundice, ascites, and/or bleeding diathesis. Also, the underlying disease process may affect other organ systems and may thus be associated with additional clinical signs. For example, most cases of canine leptospirosis are associated with renal failure, acute hepatitis, and/or pneumonitis. Diagnosis A serum chemistry profile in patients with acute hepatitis usually shows severe increases of all serum hepatic enzyme activities, most importantly alanine amino transferase (ALT). Biochemical changes can also indicate hepatic failure and may include hyperbilirubinemia, hypoalbuminemia, decreased BUN concentration, or hypoglycemia. Hyperammonemia, thrombocytopenia, and alterations on a coagulation profile may also be observed. Ultimately, a diagnosis of acute hepatitis is dependent on a biochemical diagnosis of hepatic injury with or without hepatic failure, a history of a potential etiology, and the histopathologic confirmation of hepatic necrosis and inflammation. Histopathology may also be helpful in suggesting a specific etiology (e.g., frequent mitotic figures in canine patients with leptospirosis). Also, serology is useful to diagnose leptospirosis as an underlying cause of the acute hepatitis. 5

6 Treatment The therapeutic goals in patients with acute hepatitis are to treat a confirmed or suspected underlying cause, administer supportive care, and employ symptomatic therapy for hepatic failure. If leptospirosis is confirmed or heavily suspected the patient should be treated with ampicillin (22 mg/kg IV q 6-8 hrs) or preferably doxycycline (5 mg/kg IV or PO q 12 hrs). In cases of suspected acetaminophen or phalloidin intoxication the patient should be treated with silymarin (50 mg/kg PO q 24 hrs). Also, N-acetylcysteine and vitamin C may be useful to treat patients with acetaminophen intoxication. Patients with mild hyperbilirubinemia, but no evidence of fulminant hepatic failure may benefit from treatment with ursodeoxycholic acid. Patients with bleeding diathesis need to be treated with fresh frozen plasma. Patients with HE need to be treated as described below. Hepatoencephalopathy (HE) The liver has a large functional reserve. However, at the same time, some hepatic function is required to sustain life. The exact proportion of hepatic function that needs to be lost before clinical signs ensue is unknown and also depends on the type of function. The liver is a metabolic powerhouse and there are a variety of different functions, such as synthetic functions for albumin, coagulation factors, acute phase proteins, and many other proteins. The liver also synthesizes non-protein substances such as urea, bilirubin, or bile acids. Another important function of the liver is to metabolize substances that are no longer needed by the body or are there in excess, such as bilirubin from hemoglobin from senescent red cells or cholesterol. Finally, the liver is also responsible for metabolizing organic compounds, such as toxins and medications. Naturally, any one of these functions needs a minimal functional reserve. When this minimal functional reserve for one of these functions is reached, biochemical changes can be observed that may or may not be associated with clinical signs. For example, failure to extract bilirubin from the blood or to conjugate it in hepatocytes will lead to hyperbilirubinemia and, if severe enough, to jaundice. Similarly, failure of the liver to convert ammonia into urea will lead to hyperammonemia and, if severe enough, hepatic encephalopathy. Pathophysiology HE is the result of a dysfunction of several neurotransmitter systems in the brain, including the glutamate, the dopamine/noradrenaline, the gamma-aminobutyric acid, and the benzodiazepine neurotransmitter systems. All of these systems are dependent on metabolites from the gastrointestinal tract that are modified in the liver before reaching the brain. Glutamate is an important excitatory neurotransmitter in the brain. The level of glutamate in the brain is directly related to blood ammonia concentration. Ammonia is produced in the intestinal lumen through the metabolism of nitrogenous compounds by members of the intestinal microbiota. Ammonia freely enters mucosal cells and then into the circulation. Under physiologic conditions ammonia is removed very efficiently by the liver and is converted to urea, which is then excreted through the kidneys. However, in patients with liver failure ammonia accumulates in the blood and freely enters into the brain through the blood-brain barrier. The small amount of ammonia that usually enters the brain is detoxified by the production of glutamine in astrocytes. As the amount of ammonia increases that enters the brain, this process is overwhelmed and ammonia and glutamine enter presynaptic neurons. This ultimately leads to a depletion of the excitatory neurotransmitter glutamate at postsynaptic neurons. It should also be pointed out that HE can be potentiated by alkalosis and hypokalemia 6

7 as both of these conditions will increase the mucosal uptake of ammonia. Thus, alkalosis and hypokalemia should be avoided or treated in patients with HE. It is important to note that other neurotransmitters are also believed to play an important role in the pathogenesis of HE, though their exact role is poorly understood. For example, the aromatic amino acids tyrosine, tryptophane, and phenylalanine are physiologically absorbed by the intestinal mucosa. If they are not adequately removed by the liver they accumulate in the brain. In the brain increased concentrations of these amino acids overwhelm the synthetic pathway to generate dopamine and noradrenaline, leading to the generation of false neurotransmitters that, while binding to the receptors of catecholamines, do not have the same function. Clinical Sings As the name of the clinical syndrome, hepatoencephalopathy, suggests, clinical signs of HE are mostly neurologic and are divided into 4 stages. Patients with stage 1 HE may show depression, decreased mental alertness, staring, and unawareness of surroundings. Patients with stage 2 HE may show ataxia, circling, head pressing, and blindness. Patients with stage 3 HE may show stupor and are usually unarousable. Finally, patients with stage 4 HE are comatose. In many patients stages of HE will alter over time and it is not unusual for a patient to have stage 2 or 3 HE for a few days and then improve to stage 1 HE spontaneously a few days later. It is not exactly known why this happens, but it may be related to the decreased food intake in patients with higher stage HE patients, which leads to a decrease of nitrogenous waste products in the GI tract and in turn to a decreased plasma ammonia concentration. Seizures can also be seen in patients with HE, but are fortunately not very common. In addition to neurological signs patients with HE may also show PU/PD, salivation, vomiting, ascites, or bleeding diathesis as these clinical signs can also be observed in patients with liver failure. It is interesting to note that humans with HE often have severe headaches long before any other clinical signs are observed, but it is unknown whether dogs and cats suffer the same sensation. Diagnosis A diagnosis of hepatoencephalopathy is made biochemically or based on clinical signs and biochemical support. Many dogs and cats with biochemical evidence of HE don t have any apparent clinical signs. Also, sometimes the clinical signs are not correctly interpreted by the owner of the patient. For example, many owners of dogs with portosystemic vascular anomalies that have HE don t recognize that their dog is depressed until the shunt has been surgically corrected and the dog shows a much higher level of activity or playfulness. The measurement of plasma ammonia is complicated by the fact that it is not very stable. Thus, plasma ammonia has to be measured within 30 minutes of collection of the sample and the sample has to be kept on ice until measurement. Fortunately, several in-clinic ammonia analyzers are now available that are relatively accurate for the measurement of ammonia. Plasma concentrations of less than approximately 50 µg/l are considered normal, while values higher than 50 µg/l are considered abnormal and are considered to represent evidence of HE. Plasma concentrations above 100 µg/l should prompt aggressive treatment of HE. Treatment The treatment of hepatoencephalopathy has two major goals, cessation of clinical signs and biochemical normalization. Thus, observation of the patient, while important, is not sufficient to track treatment response and repeated measurement of plasma ammonia concentration is crucial. The rare patient that is presented actively seizing is very challenging to treat as such a patient may need to be treated with an antiepileptic agent. This is highly controversial as most antiepileptic agents are detoxified by the liver and some have been 7

8 hypothesized to have counterproductive effects in seizing patients. Also, the patient must be immediately assessed for hypoglycemia, as severe hypoglycemia could also occur in patients with hepatic failure and could also lead to neurological signs and seizures. If hypoglycemia has been ruled out, the patient may be treated with flumazenil (0.01 mg/kg IV; flumazenil has a very short half-life of approximately 1 hour). This benzodiazepine antagonist is aimed at decreasing the tone of the benzodiazepine neurotransmitter system in the brain and thus at reducing the seizure threshold. However, overall this treatment approach is not believed to be very effective. Though generally believed to be contraindicated, diazepam may be cautiously employed. A single dose in a seizing patient can be given and if efficacious maybe repeated if another seizure episode is encountered. However, diazepam should be avoided whenever possible. If a patient continues to seize, anesthesia with propofol may be unavoidable until plasma ammonia concentration can be decreased. In a patient that is not seizing, the primary goal of treatment is to decrease plasma ammonia concentration below 50 µg/l. This is achieved by a warm water enema with removal of as much colonic content as possible. After conclusion of the procedure, lactulose (20 60 ml) is instilled into the colon with a red-rubber catheter. These simple steps often lead to dramatic decreases in plasma ammonia concentration and improvement of mentation of the patient. Once the patient has improved an oral treatment protocol of lactulose (starting dose 5-15 ml PO q 8-12 hrs) and neomycin (20 mg/kg PO q 6-8 hrs) or another antibiotic is started immediately. The amount of lactulose should be adjusted so that liquid diarrhea is avoided, but stools are kept semi-formed. In addition, the diet should be changed to a low-protein diet to decrease the amount of nitrogenous waste products that are generated in the small intestine. 8

9 Chronic Inflammatory Liver Disease --- Different or All the Same Jörg M. Steiner, med.vet., Dr.med.vet., PhD, DACVIM, DECVIM-CA, AGAF GI Laboratory, Texas A&M University, College Station, TX, USA Introduction Liver disease is common in both dogs and cats. Acute liver disease can be caused by infectious diseases or intoxications. Chronic liver disease occurs much more commonly than acute liver disease. The most common chronic hepatic diseases are chronic hepatitis or cholangitis, copper-associated hepatopathies, iatrogenic liver disease, and hepatic vascular anomalies, which, with the exception of hepatic vascular anomalies, will be discussed in more detail in the following. Chronic Hepatitis and Cholangitis Chronic hepatitis is a heterogeneous group of chronic liver diseases in the dog that are associated with an inflammatory infiltration of the liver. Similarly, cholangitis is a heterogeneous group of diseases of the liver and the biliary tract in cats that lead to inflammatory infiltration of the liver and the biliary tract. There are many different etiologies of chronic hepatitis/cholangitis, including infectious (e.g., infectious canine hepatitis or leptospirosis), drug-induced (e.g., anticonvulsants), or familial-predisposition (e.g., in the Doberman pincher, Bedlington terrier, Cocker Spaniel, West Highland White terrier, and others). However, most cases of chronic hepatitis/cholangitis are idiopathic. Clinical presentation Clinical signs in dogs and cats with chronic hepatitis/cholangitis are often non-specific. Lethargy, anorexia, weight loss, and vomiting are most common. Cats with cholangitis may also show fever and abdominal pain. Other signs such as diarrhea, polydipsia, polyuria, icterus, ascites, and bleeding diathesis may also be seen when the liver is failing. The most common finding in dogs and cats with chronic hepatitis/cholangitis is an increase in serum liver enzyme activities, such as ALT and SAP. In more severe cases hypoalbuminemia, hyperbilirubinemia, hypocholesterolemia, and a decrease in BUN may also be observed. Approximately half of all cats with cholangitis have hyperglobulinemia, but this is not a common feature in dogs with chronic hepatitis. Fasting and post-prandial serum bile acids concentrations may be increased depending on the severity of the disease process. In patients with hepatic failure coagulation parameters may be abnormal either due to a lack of synthesis of coagulation factors or due to disseminated intravascular coagulation. Abdominal radiographs are usually within normal limits. However, in patients with end-stage cirrhosis the liver may appear small. Abdominal ultrasound often reveals changes in hepatic echogenicity and irregular hepatic margins. In more severe cases ascites and acquired intrahepatic shunts may be visualized. Diagnosis A diagnosis of chronic hepatitis/cholangitis is based on histopathology. Cytological evaluation of a fine needle aspirate is not sufficient for the diagnosis of chronic hepatitis/cholangitis. Biopsy samples for histopathology can be collected by true-cut biopsy, laparoscopy, or exploratory laparotomy. True-cut biopsy is least invasive but only allows for collection of small biopsy samples. In contrast laparoscopy allows for collection of much 9

10 bigger samples and allows for visual inspection of the liver surface and also for direct control of bleeding. One study has suggested that biopsy by laparoscopy is superior to true-cut biopsy. However, more studies are needed in order to make a conclusive assessment. Regardless of the way the biopsy is collected one biopsy sample should always be submitted for bacteriologic culture. Therapy Therapy of chronic hepatitis/cholangitis can be directed at the underlying cause, the hepatic inflammation, or can be supportive or symptomatic in nature in patients with liver failure. Therapeutic measures directed at the underlying cause may consist of antibiotic therapy in dogs with leptospirosis or cats with suppurative cholangitis. In other cases it may involve switching anticonvulsant therapy in dogs with chronic hepatitis due to anticonvulsant therapy. In patients, in which an infectious etiology has been excluded (either by culture of bile or hepatic tissue and/or based on failure to respond to antibiotic therapy), antiinflammatory/immunosuppressive therapy may be instituted. There are no controlled studies that evaluate the benefit of corticosteroid therapy in dogs with chronic hepatitis. However, a large retrospective study suggested a beneficial effect of corticosteroids in such patients. The author prefers to use corticosteroids when the bacterial culture of the hepatic biopsy is negative and the patient has not responded to an empiric antibiotic trial. If corticosteroids are being used, the patient should be started on a high dose of prednisone or prednisolone of 1-2 mg/kg twice a day for 5 days, then 1 mg/kg twice a day for 6 weeks, after which the dose should be slowly tapered. If corticosteroid side effects become unbearable other antiinflammatory/immunosuppressive agents such as azathioprine could also be considered. Patients treated with antiinflammatory/immunosuppressive agents should be carefully monitored as some patients may not benefit from corticosteroids and may instead deteriorate. Supportive therapy can include the use of ursodeoxycholic acid, SAME, or other antioxidants. While there are no controlled studies in dogs or cats, trials in human patients would suggest a beneficial effect of ursodeoxycholic acid in patients with chronic hepatitis. S- adenosyl-l-methionine (SAME) has been suggested for the ancillary therapy of dogs and cats with chronic hepatitis/cholangitis. Initial studies did show that SAME replenishes glutathione, but few data in clinical patients are available. Other agents, such as vitamin E, silymarin or milk thistle have been suggested by some, but there is little evidence for their efficacy. Several agents are thought to have antifibrotic properties, including colchicine, prednisolone, azathioprine, and others. Unfortunately, none of these agents have been shown to be efficacious in either dogs or cats with chronic hepatitis/cholangitis. Also, colchicine has significant side effects and should thus not be used in these patients. In patients with hepatic failure a low protein diet should be fed. In addition oral lactulose and potentially neomycin or another antibiotic can be used to treat hepatic encephalopathy. Copper-Associated Hepatopathies Copper toxicosis is characterized by excessive copper accumulation in hepatocytes and is a hereditary liver disease that is mainly seen in the Bedlington terrier but also in the West Highland White terrier, Sky terrier, Doberman pinscher, and recently the Labrador Retriever. A similar disease has been rarely described in Siamese cats. Hereditary background In the Bedlington terrier, copper toxicosis has been shown to follow an autosomal recessive pattern. Linkage studies have identified linkage of copper toxicosis with the marker 10

11 CO4107. A genetic test for copper toxicosis is now available for the Bedlington terrier ( This test can be used to identify dogs that are affected and that will benefit from anti-copper therapy in order to prevent the development of liver damage and clinical disease. The test also serves as a tool to assist dog breeders with their breeding strategy. Pathophysiology Copper toxicosis in the Bedlington terrier is similar to Wilson s disease in humans. Copper is physiologically stored in hepatocytes. In dogs with copper toxicosis, hepatic copper content increases until a critical threshold is reached. Tissue injury occurs depending on hepatic copper content and ranges from acute hepatic necrosis to hepatic cirrhosis and secondary inflammation. Dogs with copper toxicosis can also undergo a severe hemolytic crisis after a stressful event such as whelping. Excess copper, stored in the liver, can get released into the circulation resulting in hemolytic anemia, acute renal failure, and DIC. Clinical Signs Anorexia, vomiting, and diarrhea are common clinical signs. Chronically affected dogs can also develop jaundice, ascites, and hepatic encephalopathy. A stress related acute hemolytic crisis can develop in any dog with copper toxicosis. Diagnosis Diagnosis requires evaluation of hepatic biopsy specimens with a special copper stain. Measurement of hepatic copper concentration is preferable and a copper content exceeding 850 μg/g dry weight is considered indicative for copper storage disease. Treatment In dogs with copper toxicosis the homeostasis of copper storage and release is disturbed. Therefore, the main therapeutic approach is to prevent excessive copper storage. In order to maintain a low copper intake, some protein sources such as shellfish, liver, kidney, and heart should be excluded from the diet. Many commercial dog foods also have a high copper content and thus should be carefully evaluated before being fed on a long-term basis. Zinc has the ability to block enteric copper absorption and can thus be used as a supplement (100 mg zinc PO BID for 3 months followed by 50 mg PO BID) in a low copper diet. Early dietary management in dogs that carry the genetic defect for copper toxicosis can prevent or delay the onset of clinical signs. However, if copper storage disease has already developed copper chelating agents such as D-penicillamine (10-15mg/kg PO BID) should be administered to attempt to lower hepatic copper content. Trientine can be used in patients that have side effects from D-penicillamine. Iatrogenic Liver Disease Anticonvulsants Anticonvulsants are probably the most common cause of iatrogenic liver disease in dogs, but rarely in cats, as cats are placed on anticonvulsant therapy much less frequently than dogs. Phenobarbital, primidone, or phenytoin all can cause chronic liver disease. Clinical signs of dogs with anticonvulsant-induced liver disease are similar to those seen in dogs with other chronic liver diseases, such as anorexia, lethargy, weight loss, jaundice, ascites, and bleeding diathesis. In addition, dogs may show ataxia and sedation. Diagnosis of anticonvulsant-induced hepatic disease can be suspected in patients with a history of anticonvulsant administration and clinical signs of liver disease and/or increased serum activities of hepatic enzymes. It should be noted that anticonvulsant therapy with phenobarbital, primidone, or phenytoin all induce hepatic enzyme activities and not all 11

12 increases in serum hepatic enzyme activities indicate hepatic injury. However, severe increases of hepatic enzyme activities, clinical signs of liver disease, and markers of hepatic disease, such as increased serum bile acids concentrations or a decreased serum albumin concentration may be useful for arriving at the diagnosis. Also, abdominal ultrasound is useful in revealing changes of the hepatic parenchyma. Treatment of anticonvulsant-induced hepatic disease includes switching the patient to another anticonvulsant such as potassium bromide and potentially supportive and symptomatic therapy as described above. Many other drugs can be associated with hepatic injury. However, most are considered to cause idiosyncratic reactions, occur acutely, cannot reasonably be predicted, and are associated with necrosis (e.g., diazepam in cats) rather than an inflammatory responde. 12

13 The Good and the Bad --- Microbiota and Antibiotic-Responsive Diarrhea Jörg M. Steiner, med.vet., Dr.med.vet., PhD, DACVIM, DECVIM-CA, AGAF GI Laboratory, Texas A&M University, College Station, TX, USA Introduction The microbiota is the collection of all microorganisms in the GI tract, including viruses, bacteria, and fungi. A physiologic microbiota is essential for gastrointestinal and overall health of the host. Intestinal dysbiosis describes a situation where the intestinal microbiota is altered in either composition or numbers, which can lead to clinical signs of gastrointestinal disease. There are several different terms that describe similar clinical conditions: antibiotic-responsive diarrhea (ARD), tylosin-responsive diarrhea, small intestinal bacterial overgrowth (SIBO), and intestinal dysbiosis. For the purpose of this presentation antibiotic-responsive diarrhea and intestinal dysbiosis will be used interchangeably. It is however conceivable that a patient with clinical intestinal dysbiosis does not respond to appropriate antibiotic therapy. Etiology Antibiotic-responsive diarrhea or intestinal dysbiosis is caused by an abnormal proliferation of bacteria and/or the change in bacterial species present in the intestinal lumen. However, dysbiosis/ard should not be considered a primary disorder in most if not all patients with this disorder. There are several protective mechanisms that prevent a patient from dysbiosis/ard. Gastric acid, intestinal motility and antibacterial activity of pancreatic juice all limit the bacterial numbers in the small intestine. Gastric acid directly destroys bacteria that are ingested with the diet and also decreases the ph of the ingesta, leading to a lower ph in the proximal small intestine. However, the lack of gastric acid secretion alone is not sufficient for dysbiosis/ard to develop. Propulsive movements of the small intestine are probably the most important protective factor since there is no physical barrier between the large intestine and the small intestine that would prevent retrograde cultivation of the small intestine by the large intestinal microbiota. The antibacterial properties of pancreatic juice are not well understood. Pancreatic digestive enzymes may be partly responsible for the antibacterial action of pancreatic juice. Any disease process that affects one or more of the protective mechanisms discussed can ultimately lead to intestinal dysbiosis/ard. Clinical Findings Intestinal dysbiosis in dogs and cats leads to chronic small bowel diarrhea that is often intermittent. Weight loss can be present in some cases. Other clinical signs maybe due to the primary underlying disease process, such as partial obstruction, exocrine pancreatic insufficiency, or others. Diagnosis Part of the controversy about intestinal dysbiosis/ard is due to the fact that this disorder is difficult to diagnose. Traditionally, the gold standard for assessment of the intestinal bacterial ecosystem is bacterial culture, but it is now recognized that this does not allow for accurate characterization of the intestinal microbiota. Serum folate concentration - folic acid is synthesized by enteric bacteria and is available for absorption. In dogs with intestinal dysbiosis/ard for a long period of time, serum folate 13

14 concentration can increase. While an increased serum folate concentration is fairly specific for intestinal dysbiosis, it is not very sensitive. In one study only 50% of all dogs with intestinal dysbiosis had increased serum folate concentrations. Serum cobalamin concentration - Many species of bacteria utilize cobalamin and compete with the body for dietary supplies. Unlike an increased serum folate concentration a decreased serum cobalamin concentration is not specific for intestinal dysbiosis. Any severe small intestinal disease involving the ileum can lead to cobalamin deficiency. Also, a lack of intrinsic factor and digestive proteases in dogs with exocrine pancreatic insufficiency can cause cobalamin deficiency. A decreased serum cobalamin concentration is rather insensitive for intestinal dysbiosis and in one study only 25% of dogs with intestinal dysbiosis had decreased serum cobalamin concentrations. A combination of a decreased serum cobalamin and an increased serum folate concentration is highly specific for intestinal dysbiosis but rather insensitive. These two parameters are to date the most practical diagnostic tools for the diagnosis of intestinal dysbiosis/ard. The GI Lab at Texas A&M University has recently developed PCR based assays that are able to measure the fecal abundances of some key bacterial groups. A mathematical algorithm is used to report these changes as a single numerical value; the so called dysbiosis index (DI). A negative DI indicates normobyosis, whereas a positive DI indicates dysbiosis. The DI was specifically trained to diagnose the dysbiosis associated with chronic enteropathy in dogs and an increased DI in dogs with chronic enteropathy provides additional information during the diagnostic work-up of these dogs. The limitations for the diagnosis of intestinal dysbiosis/ard are part of the reason why the term antibiotic-responsive diarrhea has been coined. If a patient with intermittent chronic diarrhea responds to antibiotic therapy the diagnosis of antibiotic-response diarrhea can be made. This maybe somewhat unsatisfactory as these patients may also respond to other therapeutic trials and as the term ARD does not define an underlying cause. However, the term ARD does represent a practical clinical diagnosis. Treatment The therapeutic goal in dogs with dysbiosis/ard is the identification and treatment of a possible inciting cause. For example, serum TLI concentration should be evaluated. If a primary cause cannot be identified one of several therapeutic strategies or a combination thereof should be employed. Prebiotics Prebiotics are substances that preferentially support the resident bacterial ecosystem of the intestine. Basically, prebiotics are non-digestible food components (dietary fiber) that are being fermented by intestinal bacteria. This can lead to normalization of the intestinal microbiota. In one study, the use of fructooligosaccharides (FOS) in the diet showed a lasting advantageous effect. While this has not been evaluated as of yet, other prebiotics, such as inulin or beet-pulp, may also prove to be beneficial. In one study dogs with intestinal dysbiosis diagnosed based on clinical signs and serum folate and cobalamin concentrations were divided into two groups. One group was treated with an antibiotic for 6 weeks and the other group was switched to a diet containing FOS. Both groups of dogs responded equally with normalization of fecal quality among improvement of other parameters, but many of the dogs treated with the antibiotic showed a relapse after the antibiotic therapy was stopped, while the beneficial effect of the diet was maintained. Probiotics 14

15 Several studies have been conducted in dogs that show that certain probiotics carry health benefits in dogs with gastrointestinal disorders. Scenarios for which there is good evidence of a beneficial effect of probiotics are the prevention of stress-related diarrhea, treatment of stress-related diarrhea, and acute non-specific diarrhea. The effects of probiotics in dogs and cats with intestinal dysbiosis/ard have not been sufficiently studied. Synbiotics Synbiotics are combinations of prebiotics and probiotics. There are three different approaches to synbiotic use. Some boutique pet foods are fortified with a prebiotic and are sprayed with a probiotic. Even though most of these pet foods use bacterial spores that show much greater resilience to environmental factors than bacteria themselves, this mode is likely unrealistic as the load of bacteria is small and the bacterial spores may not be stable enough to reach the patient. Another approach is to use a pet food fortified with a prebiotic and also use a probiotic nutraceutical concurrently. This is likely the most realistic synbiotic approach. The use of a nutraceutical that contains both a pre- and a probiotic may be realistic in cats and small dogs, but in large dogs the amount of prebiotic in the supplement is likely not sufficient to show any prebiotic effect. Fecal transplantation In humans with chronic intestinal disease there has been some experience with fecal transplantation. Experience in dogs and cats with intestinal dysbiosis/ard are limited and great care would need to be taken not to transplant enteropathogens, especially when donors are chosen that are subclinically infected. Antibiotics Tylosin (25 mg/kg q 12 hrs for 6 weeks) is the antibiotic of choice. Tylosin is extremely safe and is not used in humans for the most part thus, creating resistant bacterial strains is not a big concern. In one study, a group of dogs was treated with 400 mg/kg daily for a period of 2 years and none of them developed any side-effects. The superb efficacy of tylosin has been well-demonstrated in studies from Finland. Some of the newer studies would suggest that smaller dosages may also be beneficial, but these findings will need to be verified. Other antibiotics, such as metronidazole can also be used. Some patients respond to therapy rapidly and do not have a recurrence. However, other patients do not respond to antibiotic therapy alone. If there is no marked improvement after 2 weeks of appropriate antibiotic therapy further work-up is necessary. Some patients may respond to therapy with a complete resolution of clinical signs but may have a recurrence of clinical signs as soon as antibiotic therapy is discontinued. These patients require further diagnostic work-up. In some of these patients a specific underlying cause of the intestinal dysbiosis can be identified and treated accordingly. However, in some patients no specific cause can be identified and prolonged, maybe even lifelong, antimicrobial therapy is required. Ancillary Therapy If serum cobalamin concentration is decreased below the lower limit of the reference interval or in the very low end of the reference interval, cobalamin should be supplemented. 15

16 CANINE IBD INCLUDING STEROID RESISTANT IBD Karin Allenspach, Dr med vet FVH PhD DECVIM-CA Royal Veterinary College University of London, United Kingdom Introduction The traditional approach to the treatment of canine IBD relies on 3 components that can be used individually or most often combined: dietary modifications, antibiotic treatment, and specific antiinflammatory and immune-suppressive drugs. Although most specialists agree that dietary therapy is a central component, the routine use of antibiotics in the treatment of dogs tentatively diagnosed with IBD is subject to controversy. In many instances, immune suppressive doses of corticosteroids are administered for various lengths of time. There is evidence accumulating on what percentages of dogs seen in referral practice will be food-responsive, and the phenotype of these cases has been fairly well characterized. Probiotics are used more commonly in private practice and in acute cases rather than in chronic IBD, however, the question remains how much benefit can be gained form dietary treatment, probiotics or both treatment combined. Food responsive Diarrhoea In a prospective study of 57 dogs with chronic intestinal disease of more than 3 weeks duration, 36 dogs responded totally or significantly to one week a food trial with a salmon and rice based commercial elimination diet alone (dry formulation) 1. The high proportion of food responsive disease (FRD) (63%) was surprising considering that many of these dogs had been referred to from veterinarians who had previously attempted dietary and medical treatment without satisfactory outcome. This observation has recently been confirmned in a large retrospective study at the Royal veterinary College in London. Upon presentation, our food responders were significantly younger than the dogs that did not respond to dietary therapy and required medical therapy (median age 2 years vs. 6 years). Furthermore, dogs who were food responsive were significantly more commonly presenting with predominantly large intestinal signs, and most dogs could be switched back to their normal diet after treatment with elimination diet for 14 weeks. Only 8/36 cases had a relapse after challenge with the original diet and would therefore qualify as true food allergic cases. Moreover, dogs with FRD showed histologically mild to severe disease, which did not correlate to clinical severity disease, nor the number of infiltrating lymphocytes or CD3 cells 2. In a new study recently reported at the RVC, 20 dogs with FRD were included. Endoscopic duodenal biopsies were collected before and 6 weeks after the start of a dietary trial were assessed by means of qualitative and quantitative histopathological, immunohistochemical and ultrastructural criteria. After treatment, FRD dogs had improved ultrastructural lesions on electron microscopy, such as lesions of the mitochondria and brush border 3. Antibiotic responsive Diarrhoea An antibiotic trial typically involves oral administration of tylosin 10 to 15 mg/kg q8h PO, oxytetracycline 20 mg/kg q8h PO, or metronidazole 10 mg/kg q8h PO. A positive response suggests ARD. The dog typically is maintained on antibiotics for 28 days. If signs reoccur after stopping, then long-term antibiotic therapy with tylosin 5 mg/kg q24h PO is used, or low-dose metronidazole (1 to 2 mg/kg q12h PO). If the response to antibiotics is poor, then the patient may need steroids or other immunosuppressives to control the clinical signs. Treatment of granulomatous colitis in boxer dogs consists of enrofloxacin therapy at 5 mg/kg q12h PO for 6 to 8 weeks that eradicates the adherent-invasive E. coli strains that seem in part responsible for the development of the disease. 16

17 Anti-inflammatory and immune-suppressive treatment for IBD Current treatment protocols for canine IBD most often involve the use of immunosuppressive doses of corticosteroids for several weeks followed by slow tapering to reduce the intestinal mucosal inflammation and achieve clinical remission. The usual protocols for prednisolone usage recommend dosages of 1-2 mg/kg BID for approximately 2-4 weeks, followed by a slow tapering period over weeks to months. However, a number of dogs treated with immune suppressive doses of corticosteroids will show either no response at all to the drug or will relapse after weeks to months of treatment. A recent retrospective study including 80 dogs with IBD revealed 13/80 or 16% of cases with intractable disease. In people, failure to respond to medical treatment with steroids can be observed in 20 to 30% of patients with IBD. Other immunosuppressive agents such as azathioprine, chlorambucil, cyclophosphamide at the usual dosages are used alone or in combination with corticosteroids. When used in combination, they may (a) decrease the required dosage of corticosteroids and the associated side-effects, or (b) allow the dogs to be weaned off CS as soon as possible. Moreover, these drugs are also used cases of steroid-refractory canine IBD. They may have a delayed onset of action (weeks to months until maximal effect). Cyclosporine in IBD We performed a pilot study to evaluate the pharmacokinetics and clinical efficacy of cya in dogs with severe steroid-refractory clinical IBD. A total of 14 dogs were included into the clinical efficacy study. All of these dogs had been treated with 2mg/kg per day of prednisolone p.o. for a period ranging from a minimum of 6 weeks with only minimal clinical effect before being tapered off. The severity of disease was assessed using the CIBDAI described by Jergens et al., with a score of 0-3 indicating clinically insignificant disease, a score of 4-5 indicating mild IBD, a score of 6-8 indicating moderate IBD and a score of >9 indicating severe clinical IBD. After the first endoscopical examination, all dogs received treatment with cya 5mg/kg p.o. once daily for a total of 10 weeks and CIBDAI scores were assessed every second week after starting treatment during the entire study period. A recheck endoscopical examination was performed in 9 dogs after 10 weeks of treatment. In addition, serum concentration of cya was measured in 8 dogs by FPLI during 24hrs after giving the first dose of cya to assess the drug pharmacokinetics. Clinical severity as scored by CIBDAI was very high (over 9) in the majority of cases at the beginning of treatment with CyA, indicating severe clinical disease. After 10 weeks of treatment with cya, the median CIBDAI was significantly reduced. Eight dogs showed a complete response within 4 weeks of treatment (reduction in CIBDAI to a score of 0-2). Two dogs did not respond to treatment with cya during the first 10 weeks of the study and were euthanized 6 and 10 weeks respectively after starting treatment with cya. One dog responded well to cya for 14 weeks but then experienced a relapse with clinical signs of intractable vomiting and was euthanized at that time. Side effects attributed to cya during the study transiently occurred over the first two weeks of treatment. Reported side effects were vomiting and partial anorexia in 4/14 dogs, gingival ulceration in one dog and alopecia followed by hypertrichosis in one dog. Pharmacokinetics of cya in severe canine IBD were comparable to values in normal dogs and atopic dogs, indicating that cya can be expected to be effective in severely ill IBD cases from the first day of treatment. CyA was effective in reducing clinical signs of severe IBD in a majority of dogs in this pilot study and may therefore be a valid option for steroid-resistant dogs with IBD. 17

18 Treatment for Severe Protein Losing Enteropathy Canine patients with serum albumin concentrations below 1.5 g/dl are at risk of developing ascites, pleural effusion, subcutaneous edema, and thromboembolism. Hypercoagulability has been shown to occur in a high percentage of dogs with PLE, and prophylactic treatment with low-dose aspirin is recommended (0.5 mg/kg q24h PO), especially when treating the dogs with immunosuppressive doses of steroids. Cyclosporine may be a better treatment option for dogs with PLE, because some dogs with steroid-resistant IBD were rescued by sole treatment with cyclosporine for 10 weeks. In addition, the use of enteral nutrition via feeding tubes can help in anorexic animals, and elemental diets and partial parenteral nutrition may be indicated at the beginning of the treatment in some dogs with severe PLE. Finally, these patients also may be at risk of complications associated with intestinal biopsy by celiotomy; therefore plasma transfusion, human albumin infusion, or synthetic colloid may be indicated during the perioperative period, and endoscopic biopsies should be obtained instead of full thickness biopsies whenever possible. References 1. Allenspach K, B. Wieland, A. Gröne, F. Gaschen. Chronic enteropathies in dogs: Evaluation of risk factors for negative outcome Journal of Veterinary Internal Medicine 2007;21: German AJ, Day MJ, Ruaux CG, et al. Comparison of direct and indirect tests for small intestinal bacterial overgrowth and antibiotic-responsive diarrhea in dogs. JVetInternMed 2003;17: Craven M, Simpson JW, Ridyard AE, et al. Canine inflammatory bowel disease: retrospective 4. Allenspach K, Rufenacht S, Sauter S, et al. Pharmacokinetics and clinical efficacy of cyclosporine treatment of dogs with steroid-refractory inflammatory bowel disease. J Vet Intern Med 2006;20: