June 2005 Gastroenterology / Nutrition Chris L. Ludlow, DVM, MS, DACVIM Royal Canin, USA An Update on Pancreatitis Introduction There is much that is not known regarding pancreatitis in dogs and cats. While the incidence of pancreatitis in dogs and cats is unknown, one study of findings at necropsy reported the incidence in dogs was 1.5% and in cats was 1.3%. This number likely underestimates how common the disease is. One reason for this uncertainty is the difficulty in diagnosing the disease. The inability to accurately diagnose pancreatitis leads to difficulties in assessing the severity of the disease. This in turn leads to difficulty in determining response to therapy. This leaves many unanswered questions about pancreatitis and its treatment. A better understanding of the current ideas regarding pathogenesis and progression of pancreatitis serves as a basis for understanding newer concepts in treatment. Also, newer diagnostic tests may help us recognize the disease. Pathogenesis Pancreatitis is often defined as "autodigestion" of the pancreas. Normally pancreatic digestive enzymes exist in the pancreas in inactive forms (zymogens) that are sequestered in lysosomes. These enzymes are not activated until their secretion into the intestinal lumen. The initiating event in acute pancreatitis is the inappropriate activation of trypsin in the pancreas. Initially activation occurs in the acinar cells in small cytoplasmic vacuoles. This leads to pancreatic autodigestion and resulting inflammation, hemorrhage and potentially necrosis. Trypsin is an auto-catalyzing enzyme, so its presence in the acinar cells continues to cleave trypsinogen (along with other zymogens) to the active form, leading to a self-perpetuating process. Autodigestion is prevented in a number of ways. Zymogens (inactive forms of the enzymes) are packaged in lysosomes to be kept separate from the cytoplasm. They are packaged with protease inhibitors to bind activated enzymes in the lysosome. Alpha-1 protease inhibitor and 1-macroglobulin are two serum proteins that are able to bind with and inactivate trypsin to stop this process. Levels of these proteins in the pancreas are dependent on adequate pancreatic blood flow and rate of binding to trypsin. They may be rapidly consumed in pancreatitis. This may become an issue in hypotensive patients, either due to hypovolemia or shock, where blood flow to the pancreas is reduced. In animal models, pancreatitis can be readily exacerbated by decreased pancreatic blood flow. Recently other pancreatic protease inhibitors have been discovered in humans. One of note is serine protease inhibitor Kazal type 1 (SPINK1, or pancreatic secretory trypsin inhibitor 1). Genetic abnormalities in the production of this protein has been linked to a predisposition to developing pancreatitis in people. Findings such as this may explain one of the mechanisms of breed predisposition to the disease. In addition to the effects of proteases, inflammatory cytokines resulting from pancreatic damage alter blood flow and membrane permeability. They are chemotactic for leukocytes, which in turn produce more inflammatory mediators and result in worsening of the process locally. Progression of pancreatitis from the most common mild, self-limiting localized form to more severe forms with systemic involvement is the most common cause of mortality in people and animals. This occurs in about 20% of humans with pancreatitis. The incidence in animals is not known. Progression was thought to be mediated by the release of proteases into the systemic circulation and their effect ability to damage or activate other proteins (e.g. clotting factors) leading to systemic collapse and DIC. More recent work has revealed the importance of inflammatory mediators and cytokines in the systemic manifestations of pancreatitis. Marked production of these may lead to the development of the systemic inflammatory response syndrome (SIRS), rapidly lead to circulatory and respiratory collapse, and ultimately multiple organ failure (MOF). In humans, most fatalities from pancreatitis are due to SIRS and MOF. Early in the disease this process is thought to be due to the marked inflammation in the pancreatic and peripancreatic tissue. In later stages of the disease, this process may occur secondary to infection associated with pancreatic necrosis and sepsis secondary to bacterial translocation from the gut. Many current studies have centered on different strategies to prevent or aggressively attenuate the SIRS. Diagnosis As previously stated, diagnosis of pancreatitis in dogs and cats may be difficult. There are no noninvasive and inexpensive markers that have high sensitivity and specificity. At present, without a pancreatic biopsy for definitive histologic diagnosis (which we rarely have), the diagnosis is made by supportive data and exclusion of other diseases. Clinical signs Clinical manifestations of pancreatitis are nonspecific. Recent studies have shown that the presenting signs of pancreatitis are very different in dogs and cats. Dogs present with the more classic signs of vomiting (90%), abdominal pain (58%), dehydration (46%) and diarrhea (33%). Fever is common in more sever forms of the disease. In contrast, cats rarely present with fevers, even in the more sever cases. Clinical signs in cats tend to be much more nonspecific including lethargy (100%), anorexia (97%), dehydration (92%), hypothermia (68%), vomiting (35%), and diarrhea (15%). Laboratory diagnosis Findings on routine laboratory tests are nonspecific. In dogs, CBC findings including a leukocytosis with a left shift is present in about one half of the cases. In cats, leukocytosis is present in about one third, while leukopenia can be seen in up to 15% of the cases and may indicate a worse prognosis. Serum chemistry abnormalities are nonspecific and may include elevations in liver enzymes and bilirubin in both species. Azotemia may be present due to dehydration, but renal failure may rarely result from pancreatitis. Hypocalcemia is more common in cats than dogs (50% vs. 5%) and suggests a worse prognosis in cats. Electrolyte abnormalities are common in both breeds. Pancreatic specific tests Pancreatic enzymes have been used for years to diagnose pancreatitis. It is important to recognize their limitations. Neither measurement of serum amylase or lipase activity is very sensitive or specific. Lipase may originate from other tissues than the pancreas (lipase activity remains in dogs and cats after pancreatectomy). Routine testing cannot differentiate these lipases from pancreatic lipase. Also, nonpancreatic disease including renal disease, hepatic disease, different types of cancer, heat stress and administration of corticosteriods may result in elevations of lipase. Sensitivity and specificity of serum lipase in the diagnosis of pancreatitis in dogs has been reported as 73% and 55%. Considering this, lipase should only be used as a screening tool for pancreatitis in dogs, and only elevations of 3-5 times the upper limit of normal should be considered suggestive of pancreatitis. In cats, lipase had been shown to be normal in cats with spontaneously occurring pancreatitis. This would suggest the use of lipase in diagnosing pancreatitis in cats is very limited. Measurement of serum amylase has similar limitations. Amylase activity remains in dogs after pancreatectomy, indicating other sites of synthesis. Dogs with spontaneously occurring pancreatitis have been shown to have amylase in the normal range, and nonpancreatic diseases may result in elevations. Sensitivity and specificity in dogs has been reported to be 62% and 57%. In cats, amylase has been shown to decrease in experimental pancreatitis. In cats with spontaneously occurring disease, no difference in amylase has been seen vs. normal cats or cats with nonpancreatic disease. This suggests that serum amylase measurement in cats is of no use. Serum trypsin-like immunoreactivity (TLI) Serum TLI measures primarily trypsinogen but also detects trypsin and some trypsin bound to proteinase inhibitors. It has been shown to be a very useful tool in the diagnosis of exocrine pancreatic insufficiency in dogs and cats. Its use in pancreatitis is less reliable. Elevations tend to occur early in the disease and resolve quickly. It has been shown to be elevated in dogs with experimental and spontaneously occurring pancreatitis, with the sensitivity and specificity of 33% and 65% in one study. This would suggest it has little benefit over lipase. In cats, sensitivity and specificity varies depending on cutoff values (33% and 90% in one study using 100 g/L as a cutoff value). While these numbers are poor, the lack of other diagnostic tests may make it worthwhile to use this test in cats. TLI has been shown to elevate in nonpacreatic diseases including renal failure and intestinal disease, which may result in false positives. Serum pancreatic lipase immunoreactivity (PLI) As mentioned previously, lipase may arise from tissues other than the pancreas. While the activity of these enzymes is the same, their structure differs. Measurement of PLI allows for differentiation of these enzymes and specific quantification of pancreatic lipase. This is a relatively new test that appears to have utility in diagnosing pancreatitis. It also appears to be less affected by nonpancreatic disease (one study showed elevations with renal failure, but not above the diagnostic cutoff value for pancreatitis). In dogs, one study demonstrated a sensitivity of >80%. In cats, this test has shown initial promise. In experimentally induced pancreatitis, rises occur similar to TLI, but elevations tend to persist longer. It has been suggested that PLI may be more sensitive than other diagnostic tools including imaging. While further studies evaluating PLI are warranted, it appears to have the potential to be a very useful tool in cats. At this time, measurement is only available at the GI Lab at Texas A&M University. Other laboratory tests Other lab tests have been evaluated for the diagnosis of pancreatitis. These include trypsin activation peptide (TAP), various trypsin-protein complexes, C-reactive protein, and other markers of inflammation. At this time, none of these has been shown to be clinically useful beyond standard tests. TAP may be a useful indicator of the severity of pancreatic disease, and its measurement is becoming easier and more available. At present, it can be evaluated in both serum and urine. Further evaluation of this test is warranted. Diagnostic imaging In humans, the gold standard for the diagnosis of pancreatitis is the contrast-enhanced CT scan (CECT). It is also very useful in determining the severity (necrosis) and identifying abscessation, cyst formation, and neoplasia. The use of CT in dogs has been very limited and additional studies will be needed to determine the amount of information that can be obtained. In one study in cats, the sensitivity of CT was no better than that of ultrasonography. Radiology has been used for years, but unfortunately radiographic findings in pancreatitis are very nonspecific. Increased use of abdominal ultrasound is showing promising results. Sensitivity of ultrasound in dogs has been reported as high as 68%, though this is highly dependent on the operator's skill level. Results in cats have not been as good, with a reported sensitivity of up to 35%. When changes are present, a specificity of up to 85% in diagnosing pancreatitis has been reported. Identifiable changes include pancreatic edema, fibrosis, calcification, and peripancreatic fluid accumulation. Abscessation, cyst formation, and neoplasia may also be detected. Therapy Therapy for pancreatitis in dogs and cats still remains largely supportive. At present there are no drugs specifically designed to relieve inflammation in the pancreas. For now, in animals therapy for pancreatitis centers on aggressive fluid therapy, antibiotics, and dietary therapy. Aggressive fluid therapy is critical for systemic cardiovascular support to prevent MOF. Remember that the blood supply to the gut is often compromised in hypotensive, hypovolemic patients. Also remember that many of the protective mechanisms for the pancreas are presented to or removed from the pancreas by the circulatory system (antiproteases, leukocytes, washout of toxic metabolites and inflammatory mediators). Considering these to concepts, it is clear why aggressive fluid support is critical to pancreatic recovery. Antibiotic therapy Antibiotic therapy has been the standard for many years. This is in the face of paucity of evidence showing bacterial involvement in canine or feline pancreatitis. In fact, most evidence points to the fact that bacterial involvement in pancreatitis, especially early in the disease process, is rare. In humans, antibiotic therapy is primarily used in cases where pancreatic necrosis is identified. In these patients, proper antibiotic therapy significantly improves outcomes. The issue continues to be when to initiate antibiotic therapy. One study showed that the use of prophylactic antibiotics in humans increased the risk of pancreatic necrosis and resultant infection. In animals, pancreatic necrosis, abscessation, and formation of cysts are rarely reported. The prevalence of these occurrences, and of infection in "routine" pancreatitis, is unknown. Thus it becomes even more difficult to know when to institute antibiotic therapy in animals. Certainly when evidence of systemic inflammation is present (fever, leukocytosis with a left shift, etc.), antibiotic therapy is warranted. But one must question the routine use of antibiotics in milder forms of pancreatitis. If antibiotics are to be used, proper selection is critical. Typically bacterial found in pancreatic lesions are of the gram-negative enteric form. Anaerobes have also been reported. Antibiotic penetration into the pancreas must be considered as well. In humans, clindamycin, quinolones, imipenem, and metronidazole are often used. Clindamycin, metronidazole, and ciprofloxacin have been shown to achieve therapeutic levels in the canine pancreas. Dietary therapy The paradigm of dietary therapy had been one of withholding food for "pancreatic rest". This is based on the concept that nutrients in the stomach or duodenum serve as a stimulus for pancreatic secretions, thus exacerbating intrapancreatic activation of enzymes and increasing the volume of pancreatic secretions (e.g. bicarbonate, water). This usually lasts until vomiting has subsided for 12-24 hours and may result in a prolonged period of food being withheld in animal patients. However, the concept of pancreatic rest is being challenged for a number of reasons. First, there is conflicting information regarding the degree that feeding stimulates pancreatitic secretions. Factors such as nutrient content of the meal, form of the nutrients (e.g. intact proteins vs. amino acids), and the rate at which the meal is given all must be considered. Whether the meal stimulates protease production vs. other secretions may also be of relevance. While there is good evidence that meal feeding may increase pain associated with pancreatitis, there is no definitive evidence that, regardless of the meal, feeding has a negative effect on the ultimate outcome of pancreatitis in humans or animals. What is clear from human studies is that, in the case of more serious, protracted cases of acute pancreatitis (about 20% of the human cases), nutritional intervention has repeated been shown to have a beneficial effect on patient outcome. Documented benefits of nutritional therapy include improvement in nitrogen balance, reduction in inflammatory mediators and incidence of SIRS and MOF, improvement in immune function (both systemically and at the level of the gut), decreased patient morbidity and mortality, decreased surgical intervention, increased intestinal blood flow, decreased absorption of endotoxin and cytokines from the gut, and decreased risk of pancreatic infection and sepsis secondary to bacterial translocation from the gut. While the greatest benefits of nutritional therapy occur when it is instituted early, studies show it is still beneficial when started later in the disease process. At present, nutritional therapy is the standard of care in human patients with severe acute pancreatitis. While the benefits of nutritional therapy are clear in humans, little information is available from naturally occurring animal disease. Experimentally models of pancreatitis using dogs and cats have shown similar benefits to what is seen in other species. The route of nutritional support is important. Total parenteral nutrition was the first choice for support in humans for many years owing to the fact that nutrition could be provided without stimulating pancreatic secretions. Disadvantages included expense, increased risk of complications over enteral nutrition, and gut atrophy with the subsequent risk of bacterial translocation and infection. Recently, it has been shown that enteral feeding downstream from the duodenum (jejunostomy tubes) results in no more pancreatic secretions that TPN. Comparison of enteral vs. parenteral nutrition in humans with pancreatitis shows the marked benefits of the enteral route. Enteral feeding through a jejunostomy tube (J-tube) allows for physiologic benefits and avoids the disadvantages of TPN. These may be easily placed in humans through the use of an endoscope. Endoscopic placement of J-tubes in dogs has been described, but is technically difficult and time consuming. Weighted tubes are typically required to prevent the tube from migrating proximally in the intestine, thus losing the benefits of downstream feeding. Should the patient require abdominal surgery for any reason, J-tubes may be easily placed at that time. One study in humans showed that low volume continuous enteral nutrition (CEN) provided through a nasogastric tube did not result in exacerbation of pancreatitis. This offers the advantage of not requiring anesthesia and ease of tube placement. Further investigation into this route of nutrition, especially with elemental or low fat enteral formulas, is worth looking at. There may also be a place for the combination of CEN combined with peripheral parenteral nutrition (PPN). This would increase the chance of meeting nutritional requirements while at the same not over-stimulating the pancreas. This would also provide nutrients for the GI tract and help prevent atrophy and bacterial translocation. The form of the nutrition may be equally important as the route. Studies in animals and humans have shown that not all nutrients stimulate the pancreas equally. Intact proteins and fats tend to have the greatest effect on pancreatic secretions. This may be minimized by the use of diets that do not contain intact components. Studies have shown that elemental diets (amino acids, fatty acids, simple sugars) have much less of a stimulatory effect on the pancreas. While no elemental diets currently exist for animals, there are several human diets available. It is important to consider that, while these are not formulate for animals and would not be nutritionally complete, they would provide nutrition for the GI tract and at least partially meet requirements. There is also evidence that specific nutrients may help to modulate the inflammatory process and reduce complications associated with pancreatitis. These include glutamine and n-3 fatty acids, both of which have been shown to be beneficial in experimentally induced pancreatitis. There are human critical care diets supplemented in these nutrients. These types of diets can be readily used in animals. Other therapies Therapies used to minimize pancreatic secretions, though in theory promising, have not proven to be of no benefit in human and animal studies. Anticytokine therapy shows promise in many areas of disease and may have applications in pancreatitis. Antiprotease therapy has been tried, both in the form of specific synthetic antiproteases and the use of plasma to replace naturally occurring antiproteases. Depletion of 1-antitrypsin macroglobulin has been demonstrated in both human and animal patients with pancreatitis. While medically sound in theory (replacing antiproteases to bind any active protease released into the systemic circulation), these treatments have proven to be no benefit in pancreatitis in humans or animals. One study in humans experiencing acute pancreatitis showed faster resolution of signs and lower morality when dexamethasone and Dextran 40 was added to standard therapy. Perhaps it is time to reconsider the role of corticosteriods in pancreatitis during the initial acute inflammatory stages. Surgical intervention continues to be a subject of debate. In human medicine, surgical therapy is now reserved for those patients with CT evidence of pancreatic necrosis, cyst formation, abscessation, or those patients that are deteriorating in the face of adequate medical therapy. Animal studies have shown no benefit in surgical intervention, though the numbers of animals have been small and criteria for surgery not well defined. A Clinical Approach to Feline Hepatic Disease (Oh no! Not another yellow cat!) Clinical signs related to hepatic disease are common presenting complaints in cats. Rule outs include a variety of etiologies including metabolic (idiopathic hepatic lipidosis), inflammatory (suppurative cholangitis/cholangiohepatitis; lymphocytic, lymphocytic-plasmacytic cholangitis/ cholangiohepatitis), neoplasia (lymphoma, mastocytosis, primary hepatic/bile duct neoplasia) and toxic. Of these, hepatic lipidosis and inflammatory hepatic diseases are common. These diseases may present as acute or chronic, mild to severe and life threatening, and with clinical signs ranging from vague to obvious. With routine laboratory data it is not difficult to reach a presumptive diagnosis of hepatic disease in feline patients. However, the process of making a definitive diagnosis, or at least reaching a point where the majority of diseases have been ruled out, is often more difficult. While this process may be frustrating, it is possible to accomplish with careful interpretation of history, clinical signs and routine laboratory data. Then additional procedures or tests may be carefully chosen to arrive at a specific diagnosis and therapeutic plan. The purpose of the following is to attempt to simplify the decision making process in a step-by-step manner, focusing on distinguishing the difference between metabolic and inflammatory diseases, and to discuss recent recommendations for therapy. OVERVIEW AND PATHOPHYSIOLOGY Hepatic Lipidosis Feline hepatic lipidosis (HL) is characterized by accumulation of excessive lipid in hepatocytes and resultant hepatic dysfunction. It is the most common hepatopathy in cats. The etiology of HL is unknown, but likely involves pathways of protein and lipid metabolism unique to the cat. Metabolic abnormalities implicated include insulin deficienciey (relative or absolute), essential AA deficiencies, deficiency of lipotrophic compounds, errors of fatty acid oxidation, or hepatic oxidative stress. About one half of the cases of HL in cats are considered idiopathic in that no underlying disease process is identified. Underlying diseases that have been recognized in cases of HL include inflammatory liver diseases, pancreatitis, small intestinal disease, diabetes mellitus, renal disease and neoplasia. Time from onset of anorexia to development of clinical hepatic lipidosis is variable, but is likely to be weeks rather than days. One study where cats were fed an unpalatable purified diet that was poorly consumed showed elevations in liver enzymes occurring at 3-4 weeks with the onset of clinical lipidosis occurring 1-2 weeks after that. All cats in the study developed fatty livers, but not all cats developed clinical lipidosis. The pathogenesis of HL is probably multifactorial, but is likely related to one or more of the following disturbances in lipid metabolism. Mobilization of triglycerides to the liver. While HL is common in obese cats, increased hepatic lipid storage due to obesity is an unlikely cause. Studies have shown that obese cats do not have increased hepatic lipid stores compared to nonobese cats. However, during periods of starvation, due to hormonal changes, fatty acids are mobilized and hepatic fatty acid levels are increased due to interference with lipid metabolism. It has been shown that cats fed <25% of maintenance energy requirements undergo lipid accumulation in the liver and may be at risk for the development of hepatic dysfunction Impaired VLDL metabolism. When lipoprotein synthesis and release are impaired, lipid accumulation will occur. Due to their high protein requirement, during periods of starvation lipoprotein synthesis in cats may be decreased in the face of increased fatty acid mobilization. This etiology is supported by the fact that cats with HL treated with high protein diets respond more rapidly than those fed low protein diets. Metabolic products may also interfere with formation and release of VLDL. Intermediates of the urea cycle (arginine deficiency in particular) have been investigated as mediators for the development of HL. While there does seem to be some benefit in supplementation of these intermediates in the treatment of HL, no one single factor has been identified as a causative agent. Impaired fatty acid oxidation. Decreased oxidation of fatty acids, especially in the face of increased mobilization, may lead to accumulation of lipid in the liver. Carnitine, now considered a "conditionally essential" amino acid, is required to shuttle fatty acids into mitochondria for oxidation. It is difficult to demonstrate carnitine deficiencies since blood levels may not reflect cellular carnitine levels. Studies in cats with HL have failed to demonstrate such a deficiency. However, these deficiencies may be "relative" in that increased levels may be required in cats undergoing starvation and increased fatty acid mobilization. This is supported by the fact that cats supplemented with carnitine have been shown to have an improved response to therapy. Hepatic peroxisome dysfunction may also lead to decreased fatty acid oxidation and lipid accumulation. Additionally, this may predispose to the formation of free radicals that may further damage cellular structures. Cats are in general susceptible to oxidative stress. Increases in free radicals perpetuate peroxisomal damage, further impairing fatty acid oxidation. Inflammatory hepatic disease Suppurative (neutrophilic) cholangitis/cholangiohepatitis (SCCH). This disease is characterized by infiltration of the biliary structures by large numbers of neutrophils. With chronicity, lymphocytes and plasma cells appear. Periportal fibrosis and bile duct hyperplasia are common. These changes then lead to bile duct obstruction. A high percentage of cases (75%+) are associated with bacterial, fungal or protozoal infections, or fluke infestation. Cats developing this disease often have underlying disorders of the biliary system that would facilitate the development of a septic disorder (IBD, pancreatitis, extrahepatic bile duct obstruction, or cholelithiasis). The combination of cholestasis with the introduction of an infectious organism leads to the characteristic infiltration of inflammatory cells and damage to the biliary system. This disease has been associated with the syndrome "triaditis" referring to chronic inflammation in the liver, intestine (83%), and pancreas (50%). Lymphocytic/lymphocytic-plasmacytic cholangitis/cholangiohepatitis (L/LPCCH) This disease process is characterized by infiltration of the biliary structures by lymphocytes ± plasma cells. It is thought to be a chronic nonseptic inflammation likely due to an autoimmune process. Bile ducts may be lost and bridging portal fibrosis may be present. Inflammation and fibrosis may result in increased portal vascular pressure and bile duct obstruction. Other disease processes are often associated with this complex including IBD and pancreatitis. These diseases may serve as the underlying inflammatory disease, or may be associated with the autoimmune process. It may also be difficult to distinguish this disease from some forms of lymphoma. CLINICAL DIAGNOSIS History and Physical Examination Signalment is a poor discriminator between metabolic and inflammatory liver diseases. In general, there is no gender predilection though males may be more at risk for SCCH. Adult cats are primarily affected in all cases, covering a wide age range with the youngest group with inflammatory disease being cats with SCCH. Most cats with L/LPCCH are over 9 years. Historically, a prolonged period of illness is common to all of the described diseases. Severity of illness is highly variable with HL. In the inflammatory group, cats with SCCH tend to be sickest and have the shortest duration of signs, while cats with L/LPCCH have the mildest clinical signs. Anorexia is a common finding in all categories as well. Anorexia may range from a few days to weeks. Prolonged periods, often linked to some type of "stressor" event, are common in HL. Cats with L/LPCCH generally have the best appetites. Obesity at onset of disease with marked weight loss is a common historical finding with HL. Vomiting, diarrhea, weight loss and depression are common historical findings with all the above diseases. Physical examination findings in feline hepatic diseases vary in relation to duration and severity. In cats with HL, prominent findings include loss of muscle mass, icterus and ptyalism. Hepatomegaly is a common but inconsistent finding. Cats with inflammatory disease will often show similar signs. Cats with SCCH are often febrile and most are icteric. Cats with L/LPCCH most often show weight loss and icterus. As with HL, hepatomegaly is a common (50%) finding with inflammatory disease. Laboratory Abnormalities Complete blood count Findings on complete blood counts are often nonspecific. Nonregenerative anemia and stress leukograms are consistent among all disease categories. Inflammatory leukograms with left shifts and toxic neutrophils are most consistent with SCCH (>50%), while leukocytosis due to lymphocytosis is most consistent with L/LPCCH. Low PCV is associated with decreased survival in cats with HL. Liver enzymes Liver enzymes maybe helpful not only for the diagnosis of liver disease in cats, but also in discriminating between inflammatory and metabolic causes. It is important to keep in mind that there are differences in the properties of liver enzymes in the cat versus those in the dog. The half-life of alanine aminotransferase (ALT), a liver specific indicator of hepatocellular damage, is shorter in cats than dogs. While the degree of elevation in ALT correlates to the severity of cell damage, it does not indicate the reversibility of liver damage or functional status of the liver. Serum alkaline phosphatase (SAP) originates from bile duct epithelial cells and is a marker of cholestasis. Again, the half-lives of feline and canine SAP are markedly different (6 hours vs. 72 hours), and any elevation of SAP in a cat should be considered significant. The steroid inducible isoenzyme of feline SAP has little to no activity and is rarely recognized. Gamma glutamyltranspeptidase (GGT) is another marker of cholestasis, and in most feline hepatic diseases changes in GGT mirror changes in SAP. While it is important to remember that changes in liver enzymes are inconsistent, there are trends that may be useful in differentiating categories of hepatic disease. With HL, enzyme elevations are moderate with SAP activity tending to be elevated to a larger magnitude than ALT (mean ALT 3-4 times normal, mean SAP 4-6 times normal). Some variability is derived from the existence of underlying disease associated with HL. While GGT changes typically parallel those of SAP in feline liver disease, in HL GGT tends to be elevated to a much smaller magnitude than SAP (GGT often <1.5 times normal). With inflammatory liver disease, the degree of elevations of ALT and SAP tend to be more equal. There are trends seen in the different categories of inflammatory liver disease. The magnitude of liver enzyme elevations are highest associated with SCCH (mean 6 times normal), followed by LPCCH (mean 4.5 times normal) with LCCH having the smallest magnitude of increase (mean 3 times normal). It is important to remember that these are means and there is considerable variability in these values. Serum and urine bilirubin Increased serum bilirubin may result from prehepatic (hemolysis), hepatic (primary hepatocellular disease), or posthepatic (biliary obstruction) causes. There must be considerable hemolysis (increased bilirubin load) or hepatocellular dysfunction (>75-80% hepatocellular involvement) to result in hyperbilirubinemia. The cat has a high renal threshold for bilirubin, so any bilirubinuria should be considered significant. Therefore, in the absence of hemolysis, hyperbilirubinemia or bilirubinuria are highly specific but insensitive indicators of hepatocellular dysfunction since levels are not increased until dysfunction is marked. If present, there is no benefit in running additional hepatic function tests. The relative amounts of conjugated and unconjugated bilirubin are variable in hepatic disease, and are of little diagnostic value in discriminating origin of hyperbilirubinemia or etiology of hepatic dysfunction. Any hepatic disease resulting in cholestasis may cause elevations of bilirubin. Bilirubin levels are variable in all hepatic disease and are a reflection of severity of hepatic dysfunction and cholestasis. In HL, bilirubin levels tend to be modestly elevated (mean 2-4 mg/dL). With inflammatory liver disease, highest bilirubin levels are typically seen with SCCH (mean 5.6 mg/dL) with L/LPCCH levels somewhat lower (mean 2-3 mg/dL), though a wide range exists with all these diseases. Serum Bile Acids Measurement of serum bile acids (SBA) is a sensitive test to identify hepatocellular dysfunction. The test is based on the premise that bile acids released from the gall bladder into the small intestine are then resorbed in the ileum and returned to the liver, with a very small percentage passing into the colon. In the normal animal, these bile acids are very efficiently removed from the portal circulation and recycled by the liver. In the diseased liver, bile acids are inefficiently removed and increased levels are found in systemic circulation. Serum bile acid levels are measured after a 12-hour fast and then 2 hours after the animal has ingested a small meal of a moderate to high fat diet that will stimulate CCK and gall bladder contraction. Increases of fasting or postprandial serum bile acids indicate hepatic dysfunction. Elevations of SBA in feline hepatic disease are a sensitive indicator of hepatic dysfunction, but are not specific to the type of disease. In HL, SBA levels are commonly elevated, with postprandial elevations most reliable. There is wide variation in levels, but they are typically marked. In inflammatory hepatic disease, elevations are also variable and in general are less common and less severe than those seen with HL. Measurement of SBA is of no value in hyperbilirubinemic individuals since elevated bilirubin is a less sensitive marker of hepatic dysfunction. Recently the measurement of urine bile acids has been evaluated in feline liver disease. Findings are similar to serum bile acid results in that abnormalities have been described but changes in urine bile acid levels are not specific to the type of liver disease. Unfortunately the test does not discriminate between lipidosis, inflammatory liver disease of neoplasia. One advantage of urine bile acid measurement is that the timing of the test related to a fasting period or postprandial period was not critical. Other Laboratory Abnormalities Many other laboratory abnormalities may exist in feline hepatic disease. They are associated with metabolic derangements seen in these cats. Hyperglobulinemia is commonly seen in inflammatory hepatic disease, while it is rarely seen in HL. This may serve as a discriminator between these diseases. If present in cats with HL, it should be a warning sign that some type of inflammatory disease is the underlying etiology. It is most common in cats that have suppurative disease, especially when it has been present chronically (>50%). Hypokalemia is a common finding in any serious feline disease and not unique to hepatic disease. It has been associated with decreased survival in cats with HL. Abnormalities of coagulation have been reported in HL and inflammatory hepatic disease. Hypophosphatemia has also been reported. Coagulopathies are generally associated with vitamin K associated factor deficiencies secondary to cholestasis and decreased fat-soluble vitamin absorption rather than to hepatic failure and decreased coagulation factor synthesis. Coagulopathies may occur in as much as 50% of cats with liver disease be responsive to parenteral vitamin K. Hypoalbuminemia and hypoglycemia are usually mild and may be associated with decreased hepatic function or sepsis. Elevations of blood ammonia are inconsistent and difficult to assess. In general, they do not provide useful additional information for diagnosis or discrimination of these diseases. Recent evaluation of vitamin B12 in cats with GI disease has shown B12 deficiency to be relatively common. The half-life of vitamin B12 in cats is much shorter that in dogs and humans, making them particularly susceptible to deficiency. B12 is important in triglyceride metabolism and for recycling of antioxidant systems in the liver. Measurement of serum levels may be helpful in identifying underlying GI disease and for making decisions to provide supplemental B12. OTHER DIAGNOSTICS Radiology Abdominal radiography offers little ability to discriminate between different types of liver disease, but is helpful to rule out extrahepatic disease and to evaluate other abdominal structures. With both HL and inflammatory disease, liver size may be normal to large. Ultrasonography is very helpful in distinguishing etiology of hepatic disease. With HL, increases in lipid content in the liver results in generalized increased echogenecity. Hepatic parenchyma echogenecity is often comparable to that of falciform fat. Liver margins are commonly rounded. It is also very important to evaluate the rest of the abdomen for other concurrent disease (pancreatitis, lymphadenopathy, thickened intestines, etc.) that may prove to be the underlying cause of HL. In the case of inflammatory hepatic disease, liver echogenecity is normal or, if marked infiltrative disease is present, decreased. Focal lesions may also be visualized. Equally important, the biliary structures may be evaluated. Distension of the gall balder is a common finding in cats with anorexia of any etiology, and not necessarily associated with biliary obstruction. It is important to evaluate for dilation of the intrahepatic, cystic and common bile ducts, which are better indicators of extrahepatic biliary obstruction. In addition, hepatic vasculature may be evaluated to help rule out portosystemic shunts and congestion secondary to right heart failure. Ultrasonography may also be used to guide needles for fine needle aspirates (FNA's) for cytology and tru-cut biopsy instruments. Cytology Cytology provides an excellent option to obtain a cellular diagnosis and avoids many of the risks of biopsies. Fine needle aspirates are best obtained under the guidance of ultrasound in order to avoid large blood vessels and the gall bladder, and to accurately aspirate focal structures. Techniques for blind aspiration have been described. Once the aspirate has been acquired, aspirated material is spread on a microscope slide and air dried for Diff Quick or modified Wright's staining. Cytologic diagnosis is useful in feline hepatic disease, but care must be exercised not to over interpret cytology results. In the case of neoplasia, cytology may lead to a definitive diagnosis, especially in lymphoma. However, a diagnosis of HL must be interpreted cautiously. Fatty changes in hepatocytes are a relatively common finding in cats with a number of metabolic diseases or who have experienced anorexia from any cause. Often the underlying disease may be missed if a diagnosis of HL is based wholly on the results of an FNA. It is important to interpret FNA results in light of history, clinical signs, and laboratory abnormalities. If all findings are compatible with HL, no further diagnostics may be required. If there are findings that are inconsistent with HL, diagnostics to further evaluate the liver and other organ systems are warranted. In the case of inflammatory liver disease, cytology is less helpful. Since inflammatory cells are not typically present in very high numbers and there is usually significant peripheral blood contamination of FNA's, interpretation of inflammatory infiltrates is difficult. In these cases, biopsies are required. Cytology may also be performed on impression smears of biopsy specimens and in order to provide quicker results. Hepatic biopsy Hepatic biopsies are often required to make a definitive diagnosis or to detemine the cause of the underlying disease. Many different techniques have been described and are beyond the scope of this discussion. Hepatic biopsies of cats with HL reveal marked infiltration of fat in the hepatocytes. This is seen as marked vacuolization. Vacuoles may be differentiated from glycogen by a number of different lipophilic stains. It is especially important to perform hepatic biopsies on cats with cytologic diagnosis of HL if there are inconsistencies in the history or on laboratory values that suggest other underlying disease. In the case of inflammatory liver disease, biopsies help to differentiate the forms of disease and may also provide an etiological diagnosis in the case of infectious disease. Special stains may be required. Biopsies are also helpful in determining the degree of fibrosis/cirrhosis that may help in prognostication. TREATMENT General Supportive Therapy Fluid/acid base balance. Liver disease in itself may cause a number of metabolic derangements. Coupled to anorexia and decreased water intake, these problems are common in cats presenting for liver disease. Restoration of fluid volume and correction of electrolyte balance should be the first goal in the treatment of hepatic disease. Acid/base disturbances may range from metabolic alkalosis (vomiting), metabolic acidosis (shock and hypovolemia), to respiratory alkalosis (hyperventilation from hepatic encephalopathy). It is important to begin initial fluid therapy and then make adjustments based on laboratory results. In general, fluids containing lactate should be avoided since lactate is dependent on the liver for metabolism, which may be decreased. Once initial abnormalities have been addressed, 0.45% NaCl with 2.5% dextrose make a good maintenance fluid. It is important to minimize sodium load since animals with hepatic disease are often predisposed to ascites. Glucose support is critical since the diseased liver may have reduced capacity to store and synthesize glucose. Hypoglycemia may exacerbate signs of hepatic encephalopathy and increase ammonia levels in the CNS. Diet Therapy. Adequate nutritional support is critical in all feline patients, and especially so in those with hepatic disease. The liver is a metabolically active organ and requires protein and energy to function. Specific dietary therapy will be discussed with HL. Specific therapy Hepatic lipidosis. Aggressive nutritional therapy is the mainstay in treatment of HL. Mortality in cats treated without nutritional therapy approaches 90%, while in cats treated with aggressive nutritional therapy is 25-40%. It is also critical to remember that approximately 50% of cats with HL have another precipitating disease that must be addressed if recovery is to occur. When considering dietary therapy for HL, the two primary nutrients of concern are calories and protein. Cats suffering from HL are usually profoundly anoretic and in a negative calorie balance. Adequate energy intake helps to prevent protein (AA) catabolism (decreasing weight loss and the risk of hepatic encephalopathy), decrease peripheral lipid breakdown, and inhibit hepatic triglyceride accumulation. Calories provide adequate energy for the liver to process fatty acids and mobilize them from the liver. They are protein sparing since endogenous proteins are utilized for gluconeogenesis and energy due to the fact that lipid metabolism is abnormal in these cats. Since most HL cats are anorectic, energy dense diets are preferable. Foods containing high fat content (25-40% DM) are well tolerated and do not contribute to hepatic lipid accumulation. In general, recommendations for caloric intake include 50 kcal/kg/day or feeding at a level of 1.1-1.2(RER). Protein should not be restricted unless signs of hepatic encephalopathy are present. Protein contents of up to 30-45% are well tolerated. Digestibility should be high (>85%). It may be necessary to provide potassium (2-6 mEq/day potassium gluconate) if there have been prolonged periods of anorexia. It is important to remember that these are estimations and are variable from cat to cat. This variation is usually not clinically relevant since cats fed even 25% of MER are resistant to the development of HL. Fat restriction is not required and in fact will increase caloric density and palatability. Protein restriction is not recommended in cats with HL unless signs of hepatic encephalopathy (HE) are present. These will be discussed later. Protein is required for hepatic metabolic processes and is especially important in hepatic VLDL formation to allow mobilization of fatty acids from the hepatocytes. Protein should be in a highly digestible form to maximize usage and minimize protein breakdown products that may contribute to hepatic encephalopathy. In general, highly palatable, highly digestible diets have been advocated in cats with HL. Select Care Feline Development, Hill's Prescription Diets p/d and a/d, and Iam's Nutrient Response canned diet are excellent choices. There are many other premium diets on the market that provide similar nutrient profiles. Other dietary supplements have been advocated in cats with HL. These include carnitine (250 mg/day), arginine (1000 mg/day), citrulline, taurine, fish oils and zinc. The basis of these recommendations is that these particular nutrients will feed in at biochemical pathways often deficient or affected by hepatic disease. Carnitine and arginine have been previously discussed. Citrulline is an intermediate in the urea cycle and supplementation at a dose of 1 gram/day was thought to improve clinical response in a group of cats with experimentally induced HL. Taurine, a sulfur containing amino acid, may be deficient in anorectic cats and may play a role in hepatic fatty acid metabolism. Taurine is required for bile acid conjugation in cats. Supplementation at a dose of 250-500 mg/day has been recommended by some, but no studies exist to support supplementation. The use of zinc and fish oils is highly speculative and are not generally recommended. The use of particular dietary supplements is much less important than adequate calorie and protein intake. Once a particular diet has been chosen, the next difficulty encountered is getting it into the cat. Cats with hepatic disease are frequently anorectic. Due to depression and nausea, force-feeding may be quite difficult. In this situation, placement of a feeding tube is required. Choices include nasoesophageal tubes, pharyngostomy tubes, and gastrostomy tubes. Nasoesophageal tubes offer the advantages of being quick and minimally stressful to place and do not require general anesthesia. Disadvantages include limitations on forms of diet available (must be a liquid due to the small diameter of the tube) and if vomiting is present, which is common, the tube may frequently become displaced. Some cats will not eat while NE tubes are in place, so it may become difficult to assess when the cat is ready to eat on its own. Pharyngostomy tubes offer no advantages over the improved gastrostomy and esophagostomy tube placement techniques. In the past few years many different techniques have been described for the nonsurgical placement of gastrostomy and esophagostomy tubes in cats and dogs. These include techniques using endoscopy and several alternatives for blind placement. These procedures are quick and very safe. Gastrostomy and esophagostomy tubes offer the advantage of larger tube diameters that allows a wider variety of diets to be used. They are well tolerated by cats and may be left in place for long periods of time (months). Most cats will begin eating with gastrostomy tubes in place. Cats with HL will typically require nutritional support for 3-6 weeks, so gastrostomy and esophagostomy tubes are well suited in these cases. Gastrostomy and esophagostomy tubes may be used in cats with vomiting, but supplying caloric requirements may be difficult if vomiting is severe. Use of antiemetics is indicated in these cases and will be discussed later. Disadvantages include the requirement of general anesthesia, but very little time is required to place gastrostomy or esophagostomy tubes so anesthesia time is minimal. Other complications of tube placement (organ/omentum entrapment or perforation, peritonitis, hemorrhage, esophagitis) are rare. Since cats with HL have typically been anorectic for prolonged periods, it is important to start nutritional therapy with small amounts and gradually increase over a period of 3-4 days. Initially 4-6 feedings are given throughout the day and gradually the frequency is decreased to an ideal of 3 feedings per day as the amount is increased. Care must be taken to watch for emerging signs of hepatic encephalopathy once feeding is initiated. Once hydration and caloric/protein requirements are being met, the cat may be discharged and managed at home. SCCH. Treatment for this disease is centered on treating underlying suppurative diseases and improvement of biliary function. Therapy for inflammatory disease is based on identification of the underlying etiologic agent, so attempts should be made to isolate/identify organisms. Cultures of bile and/or hepatic biopsy tissue will assist in identification of organisms. Organisms frequently identified include E. coli, Clostridia, Bacteroides, Actinomyces, and -hemolytic Streptococcus. If no organisms are identified, specific titers may be needed to identify infectious organisms (eg. toxoplasmosis). When no specific organisms are identified or patient/owner limitations prohibit definitive diagnosis, empirical therapy consisting of aminoglycosides, fluoroquinolones, amoxicillin (+/- clavulanic acid) and metronidazole has been used. It is important to remember that antibiotic penetration of bile and biliary structures may be difficult. Prolonged (3-6 months) antimicrobial therapy is usually recommended. The dosage of metronidazole is usually reduced (7.5 mg/kg BID) due to concerns of decreased hepatic drug metabolism. Clindamycin may be used (25 mg/kg divided BID) if toxoplasmosis is suspected, but is not a first choice due to the high incidence of complications (vomiting, anorexia). For management of cholestasis, removal of underlying extrahepatic bile duct obstructions (mass lesions, choleliths, etc.) should be the initial therapy. Biliary function may be addressed by use of drugs that improve bile flow and reduce inflammation. Ursodeoxycholic acid (Actigal®) is the drug of choice. Ursodeoxycholic acid is a hydrophilic bile salt that provides a number of beneficial actions in the treatment of inflammatory hepatic disease. It is a choleretic, stimulating biliary bicarbonate secretion resulting in "thinning" of biliary secretions and improving bile flow. Actigal also has antiinflammatory, "hepatoprotective" properties. Bile salts, which have been secreted into the GI tract, will be dehydroxylated and deconjugated by bacteria in the GI tract resulting in more hydrophobic bile salt forms. These will be returned to the liver via enterohepatic circulation where they will accumulate due to hepatic dysfunction and cholestasis. As they accumulate, they will integrate into hepatocyte membranes due to their hydrophobic nature, disrupt hepatocyte membranes and further decrease hepatocyte function. Ursodeoxycholic acid,a hydrophilic bile salt, will eventually substitute for hydrophobic bile salts via competitive uptake at ileal receptors. It also appears to have immune modulating properties resulting in reduced infiltration of inflammatory cells. Nutritional therapy and management of fluid and acid/base abnormalities are critical to prevent development of HL and complications associated with malnutrition. This should be undertaken as described in the HL section. In addition, a number of nutrients and "nutraceuticals" have been recommended in inflammatory liver disease. It is important to remember that the efficacy of these has not been established in feline liver disease. Vitamin E is a potent antioxidant that has been recommended for use in preventing bile salt related damage to hepatocytes. Vitamin E levels have been documented to be reduced in humans with chronic inflammatory liver disease. Therapy has been empirically recommended for inflammatory liver disease in dogs and cats. In one study in dogs with chronic hepatitis, supplementation with vitamin E resulted in elevated blood and liver levels, but did not alter the clinical outcome of the cases. Not studies have been completed in feline inflammatory liver disease. It has been recommended in the treatment of HL, but to date no studies showing a vitamin E deficiency in cats with HL or its effects on treatment have been published. S-andenosyl-methionine (SAMe) is "a nucleotide-like molecule". It is made by cells and is involved in intermediary metabolism. Specifically, in liver disease, it is involved in detoxification. It is also reported to stabilize membranes, regulate cell messengers, and promote GSH (an intracellular free radical scavenger) production. It may also enhance bile acid conjugation to taurine. There have been studies in humans on its use in prevention of hepatopathies in certain toxic conditions and in chronic liver disease. Results showed improved survival, though not statistically significant. Preliminary experimental studies with this compound in animals suggest that it may have hepatoprotective properties in some hepatopathies (corticosteroid induced). No toxicity has been demonstrated. Unfortunately controlled trials in animals evaluating clinical efficacy are lacking. Doses of 35-60 mg/kg has been recommended for the treatment of liver disease in cats, but no studies demonstrating efficacy have been published. Cats showing signs of oxidative damage (eg. Hienz body anemia) may gain more benefits. Silymarin is a derivative of European milk thistle. It is a mixture of flavinolignans. It has been shown to protect against a number of hepatotoxins in experimental rat models. Its primary action appears to in as an antioxidant. It may also have membrane-stabilizing effects. Human studies done to date are difficult to interpret due to study designs. It may have its biggest effects in acute liver disease. Better studies are required to evaluate efficacy. It appears to be relatively safe, but potency may vary depending on manufacturer. L/LPCCH. The cornerstone for therapy of this disease complex is based on modulation of the immune reaction. Many drugs have been proposed. This is initially accomplished by first attempting to rule out and treat any disorders associated with this disease complex (eg. IBD, pancreatitis). Once this is done, immunosuppressive drugs are most commonly used. Actigal has been proven to be very effective at reducing inflammation and improving liver enzyme levels in human cholestatic disorders. Early indications are that it has similar effects in cats. Immunosuppressive doses of corticosteroids (prednisolone 2 mg/kg BID) are usually the next therapy of choice. They may provide some degree of choleresis and may also reduce inflammation. While they may also stimulate the appetite, they are protein catabolic and will stimulate peripheral mobilization and accumulation of fatty acids in the liver, so corticosteroid therapy is contraindicated in the case of concurrent HL. Metronidazole may also be used at the reduced dose and may have cell mediated immunity immunosuppressive effects. Other immunosuppressive and antifibrotic agents (azathioprine, methotrexate, colchicine, D-penicillamine) have been used with anecdotal success, but in general are not effective. Difficulties lie in that there have been no good prospective controlled studies to evaluate the effectiveness of these different therapeutic protocols and the variable nature of this disease complex. At this point in time, there is NO evidence that any of these protocols improve quantity or quality of life. As with the other described hepatic disease, nutritional and fluid support is critical in L/LPCCH. Concurrent complicating disorders Vomiting. Vomiting is a common complication in cats with hepatic disease. Centrally acting agents or activation of peripheral pathways secondary to stretching of the hepatic capsule or GI ulceration may mediate this. Decreased GI motility may be associated with hepatic disease. Vomiting is also associated with institution of nutritional support. Therapy consists of both centrally acting antiemetics and prokinetic agents. Metoclopramide (0.2-0.5 g/kg TID PO or SQ) may be effective. At this dose, the centrally acting antiemetic effect predominates. The serotonin (5-HT3) receptor antagonist may be effective at controlling vomiting but are generally more expensive. Ondansetron® has been used (0.1-0.2 mg/kg q 6-12 hrs). Cisapride (Propulsid®) at 2.5-5 mg TID PO may be effective at stimulating GI motility. GI ulceration. Ulcerations in the proximal GI tract have been associated with hepatic disease. Mechanisms may include alterations in GI blood flow resulting in variceal formation or segmental GI ischemia, and increased gastrin levels resulting in increased gastric acid secretion. Complications from GI hemorrhage include anemia and worsening of HE. Hemorrhage in the GI tract serves as a very high protein meal for the production of protein breakdown products associated with HE. Treatment consists of reducing gastric acid secretion and fluid support to prevent hypoperfusion. Famotidine (Pepcid®), a potent H2 receptor antagonist, at 5 mg/day is the drug of choice. Cimetadine should be avoided due to inhibition of cytochrome P450 and associated interference with hepatic metabolism of other drugs, which may be already decreased due to hepatic disease. Omeprazole, a proton-pump inhibitor, is a very effective antisecretory but also has effects on cytochrome P450. Protectants may help to treat ulcers already present. Sucralfate is a sucrose aluminum salt that will form a "patch" over ulcers. Doses of 250 mg TID-QID have been used to treat GI hemorrhage. Ascites and edema. Fluid accumulation may be due to hypoalbuminemia (typically <1.5 mg/dL), portal hypertension, and sodium retention secondary to increased RAAS function. This is less common than in dogs. Treatment consists of sodium restricted diets, diuretics (furosemide 0.25 mg/kg BID), and in extreme cases therapeutic abdominocentesis. Abdominocentesis should be reserved for cases where respiration is being restricted. Complications include protein, potassium, and fluid loss. In cases of marked hypoalbuminemia, plasma transfusions may be helpful for the short term. Coagulopathies. Coagulopathies are an infrequent complication of chronic hepatic disease. These are not due to decreased coagulation factor synthesis, which appear to be spared even in severe liver disease, but due to a decrease in vitamin K related factors. When cholestasis is marked, it is possible to develop deficiencies in fat-soluble vitamins. Treatment with parenteral vitamin K (1.25-5 mg) may be of benefit. Hepatic encephalopathy. The development of HE is the most serious, life threatening complication associated with hepatic disease. Compounds produced from the bacterial degradation of gut protein may have profound effects on the central nervous system. These products include ammonia, aromatic amino acids, methionine and mercaptans, short chain fatty acids and inhibitory neurotransmitters (GABA). Increased levels of aromatic amino acids may also be associated with muscle catabolism. Clinical signs of HE in the cat are typically subtler than in dogs. They most commonly include depression and salivation. Cortical blindness, seizures and coma have also been reported. Therapy for HE should be immediate and aggressive to prevent the more serious manifestations. Treatment consists of NPO initially, followed by dietary protein restriction, medication to decrease production and absorption of toxic compounds, as well a treatment of dehydration, hypoglycemia and hypokalemia that may exacerbate HE if present. Initial medical therapy consists of lactulose, a nonabsorbable disaccharide (0.5 ml/kg TID PO). Since lactulose is not absorbed in the small intestine, it will pass into the colon where it is fermented by bacteria. This leads to a decrease in pH from production of short chain fatty acids (SCFA's). This decrease in pH causes ammonia (NH3), which is easily absorbed, to be driven to the ammonium ion (NH4+), which is poorly absorbable thus trapping ammonia in the gut to be excreted in the feces. Lactulose causes an osmotic diarrhea increasing fecal excretion of ammonia. It also decreases bacterial production of ammonia, and may increase ammonia excretion by promoting bacterial uptake and protein synthesis. Antibiotics may be of use to reduce bacterial numbers and thus decrease bacterial protein degradation. Recommended antibiotics include neomycin (5 mg/kg PO TID) and metronidazole (7.5 mg/kg PO BID). Once the initial signs of HE are resolved, a high biologically available, low protein diet is started. In cats protein restriction levels are usually in 20-24% range. Protein restriction continues only as long as hepatic dysfunction is severe enough to produce encephalopathic signs. Once liver function has improved, the dietary protein level may be increased to speed hepatic regeneration. Long term management of HE may include diets high in fiber. Decreased fecal pH may be accomplished by the addition of a soluble fiber source to the diet, stimulating bacterial fermentation and SCFA production. Dietary fiber may also increase bacterial mass and resulting in increased bacterial consumption of NH3 resulting in a net excretion of nitrogen products. CONCLUSION Presentation of an icteric cat is a common occurrence in veterinary practice that doesn't need to be met with shudders and groans. While more advanced imagining and biopsies are often necessary to arrive at a definitive diagnosis, careful history taking, physical examination, and interpretation of routine laboratory data make it possible to arrive at a rational presumptive diagnosis and initiate appropriate supportive therapy. It is then possible to give owners options for further diagnostics with a relatively high confidence level of what will be found. By taking this approach, the diagnostic work up of the icteric cat may be one of the most enjoyable and rewarding in veterinary medicine. Dietary and Medical Management of Chronic Gastrointestinal Disease Introduction Gastrointestinal (GI) disease is a common presenting complaint in veterinary practice. It may be mild and self-limiting, or very severe and potentially life threatening. GI disease may be a very acute event, or be more chronic and intermittent in nature. Often the duration may not be clear since the recurrent nature of these many diseases may appear at first as acute, unrelated diseases. With time, the chronic recurrent nature becomes apparent. This category of diseases includes infectious disease (bacterial, viral, fungal, protozoal), allergic disease (food hypersensitivity), disorders of the immune system response (inflammatory bowel disease) and neoplasia (lymphoma, primary GI tumors). While medical therapy may differ, nutritional management of GI disease can be understood by considering some broad concepts of GI disease. Clinical signs of GI disease The presenting clinical signs of gastrointestinal disease are usually obvious and straightforward. Before clinical signs are considered, it is important to take into consideration the patient's age, breed and history. The most common clinical signs are vomiting and diarrhea. They may be acute or chronic in nature. Vomiting may be associated with many diseases that are not of GI origin including liver and pancreatic disease, renal disease, neurological disease, and other metabolic diseases. Diarrhea is defined as any increase in fecal moisture content. It may originate from disease of the small intestine or the large intestine, and diarrhea from these two sites differs in character. The table on page one characterizes the differences between diarrhea originating in the small or large bowel. Weight loss is another common sign associated with GI disease, and usually indicates small intestinal involvement. It may be due to decreased calorie intake, inability to digest and absorb nutrients, or both. Other less obvious signs include nausea, increased gut sounds, abdominal distension and discomfort, and flatulence. If there is significant protein loss via the digestive tract, the animal may present with an accumulation of fluid in the abdominal cavity (ascites) due to the loss of the serum protein albumin. Diagnostic approach to chronic GI disease As stated before, many systemic diseases may present with clinical signs common to GI disease. The first step in the diagnostic work up is the obtaining of a complete history followed by a thorough physical examination. The next step is to rule out other systemic diseases before focusing on the GI tract. A complete blood count, chemistry profile, thyroid hormone assay and urinalysis are considered to be a minimum database in this regard. Preliminary diagnostic tests to evaluate the GI tract include a fecal examination, both a direct microscopic exam and a flotation (ideally ZnSO4 with centrifugation) for parasites. Exocrine pancreatic function testing (TLI) may be indicated in some cases. Thyroid hormone levels should be evaluated in middle aged to older cats. Abdominal radiography and ultrasonography can help rule out extra-intestinal causes of vomiting, diarrhea and abdominal pain. If no diagnosis has been made, it may be necessary to pursue further diagnostic steps including GI biopsies either via endoscopy or exploratory surgery. This is a step-by-step process and at any point in time dietary or medical therapy may be attempted before moving on to the next step. The severity of the signs and the patient's condition dictate how aggressive a work up is necessary. Chronic vomiting and diarrhea There are many causes for chronic vomiting and diarrhea. Chronic is typically defined as more than 3 weeks in duration or recurrent in nature. As with the acute form of these signs, the first step is ruling out systemic illness. Chronic disease always presents for a first time, so initially the diagnostic work up is exactly the same as the acute. As the signs become more clearly chronic and/or recurrent, it becomes evident that acute therapy is not adequate and more information is needed. Once it is clear this is a chronic-recurrent disease, it becomes imperative to get a definitive diagnosis, if possible, since symptomatic therapy has proven to be unsuccessful. Gastric and intestinal biopsies become critical to characterize the underlying disease. The easiest way to look at the chronic vomiting and diarrhea disorders is to look at chronic vomiting and small intestinal disease separate from chronic large bowel disease. It is further helpful to break the gastric and small bowel diseases down into those that are thought to be primarily responsive to diet and those that are not but benefit from appropriate nutrition. Infectious or neoplastic diseases are those that are not directly responsive to diet. That is not to say that proper diet therapy will not help control clinical signs of vomiting and diarrhea, or possibly even speed resolution of the disease itself. Diet therapy is targeted at providing nutrients that are highly digestible and do not increase the workload on the digestive tract. In many respects this is the same strategy as that used to treat acute vomiting and diarrhea. It is important that nutrients are present in adequate quantities since there is likely compromised GI function and subsequently poor digestion and absorption of nutrients, in some cases over an extended period of time. In the case of chronic diseases, nutrition is critically important since adequate nutrition is critical in the immune response and healing process. Lets now consider some diseases that are more directly diet responsive. Dietary hypersensitivity By definition, a food allergy must have an immunologic basis. This may be difficult to prove in many circumstances. Most commonly it is established by response to diet trials and reintroduction of food antigen to demonstrate recurrence of the clinical signs. Food antigens are most commonly water-soluble proteins that are resistant to heat and digestion. They are typically 10-70 kilo Daltons in size. More than 6000 food antigens have been identified in humans. In small animals, several common pet food ingredients have been identified with food allergy. The most commonly reported food antigens in dogs are beef, dairy products, and wheat. In cats, beef, dairy products, and fish are the most commonly reported. Any dietary protein may be a food allergen. Based on current studies, allergies to chicken and corn are less common, though they are commonly implicated in food allergies. Hypersensitivity to rice is extremely rare. Dietary hypersensitivity to food additives, though commonly suspected, are rare due to the fact that food additives rarely fit the size and molecular make up of intermediate sized water soluble proteins. Cross-reactivity between proteins can occur, though the incidence is unknown and cross-reactions are not well documented in small animals. Remembering our definition of a dietary hypersensitivity as an adverse reaction to food with a proven immunologic basis, it is clear the definitive diagnosis is of a food allergy is rarely made. In most clinical settings, immunologic proof of the immunologic basis is not possible. Instead, we are left to diagnose food allergies based on the presumption from a history that is compatible and seems more consistent with a dietary hypersensitivity than food intolerance, combined with some type of testing. There are currently two approaches to a more definitive diagnosis of dietary hypersensitivity. These are immunological testing and a dietary elimination trial. Dietary allergies are most commonly diagnosed based on response to food elimination diets. Current alternatives include novel protein diets or protein hydrolyzed diets. The ideal novel protein elimination diet is characterized by a protein source not previously fed to the animal that is highly digestible. Excessive numbers of protein sources should be avoided. Options include commercially available or homemade diets. It is important to recognize that many homemade elimination diets are not nutritionally complete and balanced. While this may not lead to overt nutrient deficiencies over the course of an elimination diet trial, the effects of malnutrition on immune function are well documented. The role of immunosuppression in the "lack of a allergic response" is not known. It is also important to obtain a very thorough dietary history to identify a "novel" protein. Few good clinical trials have been done to evaluate the accuracy of elimination diet trials, and response has been highly variable. The principle behind hydrolyzed diets is that any dietary protein, if hydrolyzed into small enough peptides (ideally <10 kilo Daltons (?)), will lose the property of being recognized by the immune system and/or stimulating an allergic response. Even if the peptide does bind to IgE, if small enough it will not be able to cross link IgE molecules bound to the surface of a mast cell and will not lead to mast cell degranulation and release of vasoactive amines. This principle has been used for years in human medicine. Hydrolyzed diets are truly "hypoallergenic". Since peptide size is so small, previous exposure to the parent protein source is not important. Therefore, any protein source may be used. Disadvantages of hydrolyzed diets include expense because they are difficult to produce. Hydrolysis of a protein alters palatability, so pet acceptance may be reduced. Early attempts at hydrolyzed diets resulted in an increase incidence of diarrhea. Improvements in diets have reduced the incidence of this complication. Once a diet has been chosen, it is critical to impress upon the owner that the diet is to be feed exclusively. No snacks or treats may be offered, and no other foods may be supplemented. Current recommendations are to feed the elimination diet for at least 12-16 weeks before ending the diet trial. Diet trials of only 8 weeks may miss up to 40% of diet allergic animals. This illustrates why one of the most common reasons for elimination diet trial failures is owner compliance. Gastrointestinal signs my resolve slightly faster; improvement is often noted within 2-4 weeks (possibly as soon as 4-5 days). If there is a response to the diet, the client has 2 alternatives (assuming the diet is complete and balanced). One is to continue to feed the elimination diet. If a novel protein diet is used, it is possible that the animal will eventually develop an immunologic reaction to the new protein. The other alternative is to begin to re-introduce protein sources to identify the culprit causing the problem. Inflammatory bowel disease Inflammatory bowel disease is characterized by a diffuse infiltration within the mucosal and the lamina propria (deeper lining) of the intestinal tract (small intestine, large intestine or both) by various populations of inflammatory cells. Changes in the small intestine are more common in cats, while in dogs changes are common throughout the GI tract. This immune cell population has been investigated in dogs with IBD and compared to dogs with other chronic enteropathies. Dogs with IBD have increased numbers of IgG+ plasma cells, CD3 and CD4 T cells, macrophages and neutrophils in the lamina propria. There are also increased numbers of intraepithelial CD3 T cells. These findings may lead to better understanding of the inflammatory process(es) present in patients with IBD and lead to more effective therapies. Identifying an increase in inflammatory cells on intestinal biopsy does not automatically warrant a diagnosis of IBD. Inflammatory cells may be present in increased numbers as a response to any number of inciting factors (e.g. bacteria, viruses, parasites, food antigens, foreign body, neoplasia etc). In man, IBD is thought to be caused by a number of factors including genetic predispositions, dietary influences, bacteria, immune-mediated mechanisms, allergic disease, altered mucosal permeability, and psychological problems. The cause of IBD in small animals remains elusive. Many different pathophysiological mechanisms have been proposed, and it is likely that the disease we call IBD may involve one or more of these mechanism, and even more likely multiple mechanism at the same time. Immune response to microorganisms in the gut has long been proposed as a potential underlying cause in inflammatory bowel disease. Never the less, to date no organism has been found to reliably cause the characteristic inflammatory response in the GI lining, and no organism has been consistently isolated in cases of IBD. This, combined with the consistent response to therapy with immunosuppressive, medications make infection an unlikely single cause of IBD. Microbes may contribute to the disease more indirectly by causing damage to the lining of the GI and increasing mucosal permeability, resulting in increased antigen exposure to GALT. This may be a function of pathogens or even the normal microflora. Pathogens and alterations of the normal microflora may also have significant impacts on the morphology and function of the mucosal and lamina propria. IBD has been associated with small intestinal bacterial overgrowth, though this must be interpreted with caution since alterations in microbial numbers and populations may be altered by pre-existing pathology in the GI lining. Which change comes first (SIBO vs. GI inflammation) is usually difficult to determine. The role of diet in the etiology of IBD is even more difficult to determine. Certain nutrients are capable of causing direct damage to the lining of the GI tract, and this may increase mucosal permeability and lead to the inflammatory response. Many nutrients have been determined to have significant impacts on GI morphology and physiology, and may even serve to modulate immune function in the GI tract. Diet therapy has always been one of the cornerstones in treatment of IBD, and several diet therapies have been shown in humans to be effective in controlling cases of steroid refractory IBD. One must still consider whether the reaction to food antigen is the inciting event in IBD, or a result of increased antigen presentation to the GALT secondary to increased permeability due to gut inflammation. Autoimmunity has been found as an underlying immune defect in humans, with autoantibodies having been found in people with IBD. These may either result from a classic immune response to self-antigens, or possibly a process that is initiated as a result from cross reactivity between foreign antigens and self-antigens. Foreign gut antigens (various bacterial antigen) have been identified that share antigenic similarity to self and are cross-reactive in laboratory testing. Regardless of the source of the antigen, the immune response initiates an inflammatory response that results in increased gut permeability, increased antigen penetration to deeper levels of the GI lining, and an ensuing immune response. This may result in a self-perpetuating inflammatory process. Regardless of the source of antigenic stimulus, it is becoming increasing likely that an underlying immune defect in individuals with IBD is a loss if immunoregulation and the subsequent failure to develop tolerance to antigen present in the GI tract. This failure of tolerance results from a loss of or defect in T suppressor cell function and subsequent immune amplification of the response to antigens. When suppressor function is abnormal, antigen of any source (diet, pathogens, normal microflora) are processed as an offending antigen and there is a subsequent immune response that leads to activation of inflammatory pathways. This inflammation leads to characteristic increases in permeability, increased antigen exposure, and potentially an overwhelming of functioning T suppressor cells resulting in further loss of tolerance. Abnormalities in T suppressor cells have been identified in humans with IBD. Evidence that the mucosal epithelial cells play a significant role in antigen processing and presentation to the GALT further stresses the role of mucosal lining may play in the loss of tolerance. As previously stated, increases in mucosal permeability result in increased presentation of antigen to GALT. While this commonly occurs secondary to inflammation) and GI mucosal damage (alterations in GI permeability have been identified in a number of acute and chronic GI diseases), it may also be a primary defect. The incidence of this is in animals is not know. In humans with IBD, permeability is also increased. Again, this may be a primary defect or secondary to GI damage. Interestingly thought, studies have shown that relatives of individuals affected with IBD that are not suffering from signs of GI disease may also have increased GI mucosal permeability. The role that this plays in the development of IBD has not been clearly defined. It is likely that the pathogenesis of IBD involves a hypersensitivity reaction to an antigen (be it a bacteria, food ingredient, self antigen etc.). A type I hypersensitivity likely plays a role in the eosinophilic forms of the disease. Histologic changes in other forms may be consistent with type II and III hypersensitivity reactions. These reactions may be to dietary antigens, parasites, or microbes. Diagnosis A dietary elimination trial may be indicated if the possibility of an adverse reaction to food is being considered. This will be discussed with dietary therapy. Is an elimination diet trial indicated in dogs and cats with chronic GI signs, or a waste of time and only forcing the pet and the owner to tolerate the signs longer? The answer is clearly yes. In one study, 29% of cats with chronic GI signs responded completely to diet therapy and were diagnosed as food sensitive. Fifty percent of these cats had histological changes consistent with mild to severe IBD and had they not gone through a food trial they would have likely been treated with corticosteroids. Unfortunately, histology is a poor predictor of an adverse reaction to food. Definitive diagnosis of IBD requires biopsies of the GI tract and histopathologic confirmation of characteristic inflammation. Biopsies may be acquired endoscopically or surgically. Be sure to biopsy multiple segments of the GI tract if possible. Results of histopathology must be interpreted carefully since mild mononuclear inflammation may be present in the absence of clinical signs and overt GI disease. Remember that the reverse is true. Severe clinical signs may be present in the face of mild inflammation. The degree inflammation can vary significantly between segments of the GI tract, and those biopsied may not reflect the severity of other segments. This is why multiple biopsies are critical. Medical therapy for IBD At the current time there are no significant changes in therapy for IBD. Immunosuppression is still the corner stone of treatment. Corticosteroids are the most commonly used drugs. Prednisone is recommended at 2-4 mg/kg qd-BID. The initial dose is high and tapered in intervals after 2-3 weeks if response is seen. Injectable steroids (Depo-medrol SQ 20 mg q3-6 weeks) may be more effective and convenient is cats, but present more difficulties if side effects occur. Recently, Budesonide has been investigated as a corticosteroid alternative. It is a corticosteroid with high topical anti inflammatory activity within the gastrointestinal lumen and low systemic activity (minimal side effects) due to rapid hepatic first pass metabolism. The dose in small dogs is 3 mg PO q24h; large dog is 3 mg PO q12h; and in cats is 1 - 3 mg/day PO. Significant suppression of PA axis occurs however no significant changes in ALP, USG or clinical signs are typical. Other immunosuppressive agents include azathioprine, chlorambucil and cyclosporine. Azathioprine (dogs: 2 mg/kg PO q24h for 14 days then 2 mg/kg PO qod, cats: 0.3 mg/kg PO q48h) can be used as adjunct therapy in severe or refractory IBD cases but is typically more effective in dogs than cats. It can also be used to decrease the dose of prednisone required to maintain remission. It is important to remember that it has a lag effect of several weeks. Side effects include bone marrow suppression, pancreatitis, liver failure, anorexia, and hepatic failure. Cats much more sensitive to side effects than dogs. Chlorambucil (2 mg/m2 PO q24h initially then q48h) is preferred over azathioprine for cats. For primarily large bowel disease, aminosalicylates are the drugs of choice. Sulfasalazine (dogs: 12.5 - 30 mg/kg PO q8h until feces normal for 4 weeks; then same dose PO q12h for 2 - 4 weeks; then decrease dose by 50% every 2 weeks until discontinue; cats: 10 - 20 mg/kg PO q24h / oral suspension (50 mg/ml) easier dosing for cats) is a 5-aminosalicylic acid (mesalamine) joined to sulfapyridine through an azo bond. Most reaches colon intact where bacteria break down the azo bond and 5-ASA exerts its topical anti inflammatory, anti-leukotriene effect Side effects include KCS (can be irreversible), anorexia, vomiting, and anemia (cats). Newer mesalamine drugs that reduce toxicity, have been developed to deliver mesalamine to colon without linkage to sulfa. Olsalazine (Dipentum® dogs: 10-22 mg/kg PO q8h) is 2 molecules of 5-ASA linked by azo bond. Antibiotic therapy has also been recommended in some cases. In theory, the may eradicate bacterial antigens, reduce bacterial overgrowth, and reduce pro-inflammatory bacterial toxins. Frequently recommended options include metronidazole and tylosin. Other therapies are being investigated in humans with Crohn's disease and ulcerative colitis. Oral Tacrolimus has been used effectively in refractory human cases of inflammatory bowel disease. It has better oral absorption than cyclosporine. Studies have looked at it use in both steroid dependent and steroid resistant cases. 83% of patients reduced or discontinued concurrent steroids. Oral tacrolimus is being studied as an immunosuppressive agent for transplants in dogs and cats. Methotrexate beneficial in some refractory human patients but it clinical efficacy has not been evaluated in dogs and cats. Care must be taken with its use, as it may be very toxic to the GI tract in cats. Cyclosporine is used in refractory human cases of IBD. Improvement has been noted 18-43%. Fistulas associated with Crohn's disease resolved 100% of time. Mycophenolate (specific and reversible lymphocyte purine synthesis inhibitor) caused remission in 40% of refractory CD bit not UC. 30% could not tolerate drug and 30% did not respond. It appears to be more selective than AZA specific and reversible lymphocyte purine synthesis inhibitor. Nicotine patches caused reduction in UC but no objective changes in controlled trial. Growth hormone causes an increase in IGF-1 which is trophic for intestinal mucosal and has been shown superior to placebo for CD in single trial (colostrum may be used to increase IGF-1). Probiotic therapy (replacing endogenous flora) causes a decrease in inflammation. In one study using E. coli (Nissle 1917), it was shown to be as effective as 5-ASA drugs in creating and maintaining remission in UC. Preliminary studies have shown that a yeast (S. boulardii) can be an effective treatment for UC Dietary therapy for IBD Ultimately, the goal of treatment for IBD is control of the disease with dietary therapy alone. There are no scientific studies in dogs and cats that support the role of treatment with diet therapy in IBD. Having stated this, it is common convention to use dietary therapy. The rationale is that dietary components (antigens) may be contributing to the immunologic response in the GI tract. Dietary therapy is the goal in treatment of IBD. However, its success as a stand-alone treatment is widely debated. Treatment is targeted at providing a diet that is less likely to produce an antigenic response, much in the fashion as in a dietary hypersensitivity. There are several factors involved. The most important quality is digestibility, especially of dietary protein. This is to reduce antigenicity and to help with decreased GI digestive and absorptive function. The use of novel proteins requires a complete dietary history to avoid using an antigen the pet has been exposed to. The use of hydrolysed proteins is somewhat controversial since their low molecular weights may exacerbate diarrhea, especially in early stages of treatment. Grant Guillford (New Zealand) recommends a "sacrificial protein" diet be fed for the first 4 weeks or so of treating IBD (while dog is on high dose steroid) followed by a second or "new" protein source when the dose of prednisone is being reduced. He believes this strategy may help prevent the relapses seen in dogs with IBD. This concept is somewhat controversial. Dietary therapy for large bowel signs more typically involves the use of increased fiber diets. Fiber has been shown to have a number of important qualities that help to maintain normal colon function and stool consistency. Fiber is "unavailable carbohydrate" or indigestible polysaccharide or the portion of the plant cell wall that is resistant to animal digestive enzymes. There is both "soluble" and "insoluble" fiber and they act in somewhat different ways. Soluble fiber has great water holding capacity, form viscous solutions (slow gastric emptying time because of gel-forming capacity) and are easily degraded (fermented) by colonic microflora in comparison to insoluble fiber. They slow gastrointestinal transit (allowing more time for absorption of water) and decrease gastrointestinal absorption of sugar, fats, bile acids etc. Colonic bacteria can ferment soluble fiber, which leads to the production of bacterial by-products, which contributes to increased fecal weight. Bacterial fermentation of fiber yields short chain fatty acids (SCFA) (acetate, propionate, and butyrate). These are absorbed form the colon and contribute to energy balance of the host, acidify the colonic environment, and have an osmotic action and draw water into the stools thus increasing stool bulk. Examples of soluble fiber include oats, oat bran, barley, citrus fruits, beans, lentils, psyllium (like in Metamucil), guar gum, gum arabic, hemicellulose, and carboxymethylcellulose. Insoluble fiber absorbs less water, is less viscous and is less degraded by colonic bacteria (yield no energy to host). They increase stool bulk by mechanical distension and by increasing the water-holding capacity of the fecal matrix. This helps both diarrhea (water-holding) and constipation (laxative action). They help normalize erratic colonic myoelectric activity and may bind potential colonic irritants. Examples of insoluble fiber include cellulose, wheat bran, cereal bran, alfalfa, peanut husks, and lignin. Pea fiber, beet pulp, tomato pomace and apple pomace are both soluble and insoluble sources of fiber. The soluble to insoluble ratio of these fiber sources are approximately 8:92, 54:46, 11:89 and 26:74 respectively. While both types of fiber (soluble and insoluble) have beneficial actions in the colon, it is likely that a mixed fiber source is the best therapy. Some have advocated the use hypoallergenic diets for the treatment of colitis. This may be a viable alternative for patients that do not respond to increased dietary fiber or have signs of gastric or small intestinal disease. Fructooligosaccharide (FOS) is a naturally occurring carbohydrate consisting of the sugar sucrose to which 2 or 3 fructose sugar molecules have been attached. FOS is found in various foods including wheat, onion, garlic, etc. They may be manufactured by allowing certain microbial or plant enzymes to react with sucrose. Mammalian pancreatic or intestinal digestive enzymes do not digest FOS. The growth of bacteria is highly dependent upon nutrient source. Some bacteria can metabolize FOS (e.g. Bifidobacteria and Bacteroides sp.) whereas other bacteria cannot (e.g. Clostridium perfringens). When FOS is used as a carbohydrate source, bacteria like Bifidobacteria grow and increase in number vs. Clostridial numbers decrease. Thus FOS may have a role in the management of small intestinal bacterial overgrowth (SIBO), Clostridial diarrhea, and other forms of intestinal disease related to altered gut flora. Cobalamin has recently been shown to be a common deficiency in animals with chronic GI disease, especially in cats. The half-life in cats is much shorter than in dogs or people (weeks vs. months-years). Cats with gastrointestinal disease and severe cobalamin deficiency appear to benefit from parenteral administration of cobalamin. Cats tend to gain weight and show a decrease in diarrhea, vomiting and anorexia. Recommendations are for one dose (250ug) parenterally weekly for six weeks, one dose every two weeks for six weeks, then dose monthly. Often cobalamin supplementation will need to be continued long term in cats or as long as the intestinal disease is present. Doses and frequency of administration can be adjusted by monitoring serum cobalamin levels. Oral B vitamin complex compounds are typically very low in cobalamin (~4-10ug/ml) and will not be well absorbed in cats with GI disease. Lymphangiectasia Intestinal lymphangiectasia is chronic small intestinal disease in dogs characterized by dilation of lymphatic vessels (lacteals). In the small intestine, these are responsible for the absorption and distribution of lipids. In lymphangiectasia, these vessels become distended and begin to leak or even rupture. This results in the leakage of lymphatic fluid into the small intestine. This fluid is rich in fats and proteins. Ultimately clinical signs may be related to chronic diarrhea and complications associated with protein loss into the digestive tract- protein losing nephropathy. Clinical signs include loss of lean tissue, ascites and thoracic effusions, edema, weight loss. In some cases GI signs are completely absent, and only signs related to hypoproteinemia are seen. Lymphangiectasia may be either primary (congenital), or more likely secondary to lymphatic obstruction resulting from other inflammatory or neoplastic diseases of the small intestine (e.g. IBD, lymphoma) or even systemic lymphatic hypertension. There is a strong breed disposition in German Shepherd Dogs, Lundehunds, and Yorkshire Terriers. Diagnosis of lymphangiectasia is based on identifying signs of protein-losing enteropathy (PLE). These may be distinguished from renal protein loss by evaluation of which proteins are being lost. In protein-losing nephropathy associated with glomerular disease, or less commonly tubular disease, protein loss in usually in the form of albumin to a much greater degree than globulins since the "leaks" in the nephron are much smaller and prevent significant loss of large proteins like globulins. In PLE, damage to the mucosal surface or lacteals results in large "leaks", and typically albumin and globulins are lost equally, leading to panhypoproteinemia. This is characteristic for GI protein loss and not specific for lymphangiectasia. PLE can be further confirmed using tests to specifically evaluate for GI protein loss. These include measuring the loss of radioactive albumin into the GI tract. More commonly, measurement of alpha-1-protease inhibitor is done. This protein is relatively the size of albumin, and will be lost into the GI tract in cases of PLE. Unlike other proteins, it is an anti-protease and is resistant to enzymatic degradation in the lumen of the GI track. Therefore, much of it passes through the GI tract intact. Levels of this protein in the feces are consistent with the degree of protein loss. Definitive diagnosis must be made based on histologic examination of the GI tract through either endoscopic or full-thickness intestinal biopsies. Endoscopy is often preferred over laprotomy since panhypoproteinemia may increase the risk of surgical dehiscence. Therapy for lymphangiectasia is based at resolving the underlying disease leading to lymphatic obstruction. Dietary management is focused on providing high quality, highly digestible nutrients while at the same time restricting fat intake to minimize lymphatic dilation. Ideally fat (long-chain triglyceride) content should be below 10-12% DM, and in some cases may need to be below 5% to control protein loss. In severely restricted fat diets it may be difficult to meet calorie requirements, but it is critical to do so to spare protein. Non-fat calorie sources may also need to be supplemented (pastas, breads, rice, potato). Protein should be as high of quality as possible and often it is necessary to supplement low fat sources to the diet. A critical discriminator in outcome is appetite. Anorexia is a poor prognostic indicator. In some cases, dietary fiber has been shown to be help control GI signs without significantly impacting nutrient digestibility. Gluten sensitive enteropathy This is a chronic small intestinal disease seen primarily in Irish Setters, though there is suspicion that gluten sensitivity has been seen in other breeds. Wheaton Terriers may have a type of this disease. The disease usually develops by 12 months of age, though the age of onset is later in Wheatons. It is characterized by changes in the lining of the small intestine that results in decreased nutrient absorption and protein loss. Diagnosis of this disease is based on changes on intestinal biopsies and response to dietary changes. The underlying problem is a hypersensitivity to gliaden (in the Irish Setter), a protein found in wheat, barley, rye, and oats. Treatment is simply avoidance of these grains and gliaden. Otherwise treatment is aimed at minimizing protein loss. Special Ingredients in the Dietary Management of Gastrointestinal Disease Introduction Alternatives for dietary management of GI disease Highly digestible, low fat, low residue Moderate protein levels Moderate to reduced fat Low levels of dietary fiber High digestibility- 85% + Typically used in acute GI disease or maintenance for animals intolerant to most maintenance diets Acute gastroenteritis Pancreatitis Exocrine pancreatic insufficiency "Hypoallergenic" diets Novel (restricted) protein Protein hydrolysate May or may not fit nutrient profile above Typically have high digestibility Are not typically protein or fat restricted Low to moderate fiber levels Typically used in more chronic GI disease IBD Dietary hypersensitivity High fiber diets Moderate protein May or may not be fat restricted Due to higher fiber content, digestibility is lower Other nutrients may be increased to compensate for lower digestibility Fiber has activity at all levels of the GI tract, but most effects are seen in the large bowel Fiber may Alter motility/GI transit Alter nutrient absorption Alter GI microflora "Regulate" GI water movement "Normalize" fecal consistency Provide energy source for GI tract Primarily colonocytes Provide short chain fatty acids Local GI effects Systemic effects Can diets (or nutrients) have specific effects at the level of the GI tract? Nutrient content of the diet may have direct effects on GI function Alter GI secretions Alter GI hormones Alter GI flora Alter motility Tremendous interaction of nutrients makes measuring the effect of a single nutrient difficult Specific ingredients have been evaluated for their direct effects on the GI tract and its flora Prebiotics Probiotics Glutamine Different fiber types Short chain fatty acids Arginine Prebiotics Definition Dietary components that alter the microbial population of the gut Nondigestible food ingredient that selectively stimulates the growth and activity of beneficial bacteria in the gut Are preferentially utilized by specific species of GI bacteria Preferential use based on bacterial enzyme activity E.g. high levels of fructosidase in bifidobacteria releases fructose for energy metabolism Most common are the oligosaccharides (OS) Fructooligosaccharides (FOS) Short chains of fructose bound to glucose by 2-1 linkages Mannanoligosaccharides (MOS) Arabinoglactans Long branched polysaccharides composed of galactose and arabinose Inulins Sucrose bound by 2-1 linkage to fructose Different inulins characterized by degree of polymerization Maltodextrins Act as fermentable fiber sources resulting in typical fermentation products Found in a large number of plants Some are commonly used in pet food Some st ructures are chemically altered Functions Manipulation of GI microflora Preferentially utilized by "good" bacteria in the GI tract Bifidobacteria Lactobacillus sp. Reduces the number of bad bacteria Clostridium sp. Pathogenic aerobes Coliforms Reduce pathogen attachment to mucosal cells MOS Modulate the immune system MOS Increase GI IgA Increase systemic IgG Increase neutrophil activity Alter nutrient digestibility No changes in ileal digestibility Increase in fecal nitrogen Decrease protein digestibility Increased bacterial nitrogen (ammonia) utilization Alter colonic pH and SCFA levels OS are fermentable Fermentation products depend on OS in diet FOS tends to be rapidly fermented and produce higher levels of butyrate Reduce fecal putrefactive compounds Alterations in bacterial microflora result in increased utilization of these compounds May have effect on fecal odor These compounds have been linked to colon cancer May exacerbate inflammatory conditions Canine and feline studies OS and bacterial populations In healthy dogs there was a trend toward lower aerobe counts and higher Lactobacillus counts, but results were not statistically significant FOS and MOS Healthy dogs supplemented with AG tended to have Higher concentrations of aerobic bacteria Higher levels of bifidobacteria Higher levels of Lactobacillus sp. Lower levels of Clostridium sp. None of these results were statistically significant Healthy dogs supplemented with glucooligosaccharides and maltodextrins had no significant difference in bacterial concentrations Trends toward increase in bifidobacteria and lower bacteroides Dogs with small intestinal bacterial overgrowth supplemented with FOS Control group had an increase in bacterial numbers FOS group was unchanged FOS group had decrease in aerobic bacteria There was a wide fluctuation in bacterial numbers over the course of the study Healthy cats supplemented with FOS No significant difference in aerobes, anaerobes or total bacteria Wide fluctuations in bacterial numbers and species between cats and within cats on a day to day basis OS and immune function Healthy dogs supplemented with AG No affect on serum concentrations of any Ig Things to consider when interpreting studies Type of OS used Amount in diet How reported g/day % DM How much Duration of feeding Duration of retention in colon Or duration of fermentation in test tube "Normal" bacterial flora in dogs and cats varies widely Previous diet Geographic Housing conditions Culture methodology Health vs. disease Probiotics Definition Live microbial food supplement that beneficially affects the host by improving its intestinal microbial balance Most commonly lactobacillus and bifidobacteria May be added as fermented milk products or lyophilized forms In pet food, probably requires special handling of food to allow probiotic survival Must be applied after processing Requires a lower water content Special packaging to reduce moisture Must be used on an ongoing basis Colonization ceases once supplementation is stopped Function Prevention and management of GI disease Prevention of diarrheal diseases Viral Clostridium sp. Antimicrobial associated Control of inflammatory disease Cancer prevention Immune stimulation Enhance response to vaccines Mechanisms Establish a balanced microbial flora Resist colonization by pathogens Produce antimicrobial peptides Reduce fecal enzymes Digestion of residual nutrients Lactose Reduce potential mutagens Canine and feline studies Lactobacillus added to dry dog food fed for 3 weeks to healthy dogs Established that the bacteria survived passage through the GI tract No changes in fecal characteristics Decrease in Clostridium sp. Probiotic increased serum IgG and neutrophil levels Lactobacillus added to dry dog food fed to healthy dogs Showed that higher doses of probiotic are associated with higher fecal levels No adverse effects were noted Lactobacillus added to dry cat food fed to healthy cats for 5 weeks No changes in health or fecal characteristics Transient decrease in Clostridium sp. Increase in neutrophil activity Lactobacillus added to dry cat food was fed to cats with naturally acquired Campylobacter infection Decrease in bacterial numbers in the supplemented group After 4 weeks, no difference between groups Supplemented groups dropped faster Lowered rate of reinfection Things to consider when interpreting studies Probiotic used Ideally would use a bacteria that is normally found in the subject Amount supplemented Duration of the supplementation Processing of the food Not all foods claiming to have a probiotic supplemented have the bacteria in the finished product Processing destroys the bacteria Health vs. disease Glutamine What is glutamine? Nonessential amino acid Most abundant in the plasma and ECF In health, plasma levels are constant Normally synthesized animals from glutamic acid and ammonia in many tissues Normally degraded by most organs A few particular organs are glutamine "utilizers" (poor synthetic capabilities) GI tract Pancreas Kidney Immune cells In healthy state, there is an overall net production of glutamine In illness or catabolic state, glutamine redistribution and utilization may overcome production ability Conditionally essential Arabella Supplementation into pet foods is not approved by AAFCO Functions Scavenge and transport ammonia to peripheral tissues Important function in the intestine Source of energy for the enterocyte Maintain mucosal integrity Synthetic processes Hexosamine synthesis for tight junction formation Mucus production Increase intestinal blood flow Immune cell function Precursor for purine and pyrimidine synthesis Upregulates cytotoxic T cell function Required for some cytokine synthesis Nitrogen and acid buffering in the kidney The role of glutamine in illness In illness, glutamine metabolism is altered Increased levels of counter regulatory hormones Plasma glutamine levels fall Increased glutamine uptake by enterocytes Muscle glutamine depletion May lead to muscle wasting In the gut Glutamine depletion may lead to Vomiting Diarrhea Villous atrophy Mucosal necrosis Depletion may lead to increased intestinal permeability Increased endotoxin absorption Bacterial translocation Depletion may also lead to decreased mucosal mass Decreased cell replication and mucosal atrophy Appears to be dose and timing dependent Supplementation had been shown to be trophic to the small intestine in many species In cancer Tumor cells may show increased levels of glutamine uptake Glutamine is necessary for cytokine synthesis GI protection from chemotherapy? May enhance chemotherapy drug effects In critical illness/sepsis/MOF Protect GI mucosal integrity Improve immune function Improve nitrogen balanceMaracle Glutamine supplementation Usually in the form of heat-stable dipeptides Canine dose is highly variable depending on the study evaluated 0.24-0.3 g/kg/day in enteral and parenteral solutions Cat doses may be higher 1 g/kg/day Canine and feline studies Few have been published in the literature Reduced GI complications (mucositis) in dogs undergoing radiation therapy In cats with methotrexate induced enteritis Glutamine was supplemented to a purified diet at the rate of 7% (1.08 g/kg/d) for 21 days prior to MTX Did not Improve biochemical parameters Improve intestinal permeability Alter bacterial translocation Intestinal morphology Enterocyte proliferation Cats being fed the purified diets in general did not do well compared to those eating a complex diet In healthy dogs, IV glutamine had no effect on duodenal mucosal protein synthesis May have been a dose proportional effect Short term of supplementation May have had a different outcome in dogs with GI disease Things to consider when interpreting studies Dose of supplementation Duration of supplementation Diet administered Health vs. disease Acute vs. chronic disease Segment of the GI tract evaluated

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