Stanley L. Marks, BVSc, PhD, DACVIM (Internal Medicine, Oncology), DACVN
School of Veterinary Medicine, University of California-Davis, Davis, CA, USA
The disciplines of nutrition and gastroenterology are intimately related by virtue of the primary role played by the gastrointestinal tract in the assimilation of food. The therapeutic approach to most gastrointestinal diseases involves a combination of pharmacologic and nutritional therapy. Unfortunately, the beneficial impact of nutritional therapy is often ignored in many patients, resulting in incomplete or delayed resolution of signs. Restriction or manipulation of individual dietary components is perhaps the single most important factor in the treatment of either acute or chronic gastrointestinal disturbances. This presentation will focus on the dietary management of chronic small- and large-bowel disease, management of exocrine pancreatic disease, and management of hepatic disease.
Chronic Small-Bowel Disease
Dietary modification is essential for the management of most patients with chronic small-bowel disease. Dogs with diarrhea associated with small-bowel disease should be managed with a diet that is highly digestible, moderately fat restricted, lactose free, gluten free, and "hypoallergenic." The theoretical concerns with dietary fibers "abrasive" effects on the inflamed intestinal tract and the presumed negative effects of fiber on small intestinal assimilation of nutrients should be reconsidered because the gelling and binding properties of fiber may be beneficial in certain small intestinal diseases.1 Less information is known about the nutritional recommendations for the management of chronic diarrhea associated with feline small-bowel disease. In contrast to dogs, cats with small-bowel disease seem to tolerate diets containing higher levels of fat,2 and high-fat diets (79% fat calories) do not appear to delay gastric emptying in the cat.3
A fat-restricted diet is important in the management of a variety of gastrointestinal diseases in dogs, even though fat is a valuable caloric source and enhances the palatability of the diet. Fat delays gastric emptying,4,5 and fat-restricted diets appear to be better tolerated in a variety of gastrointestinal diseases. The assimilation of dietary fat is a relatively complex process and malabsorbed fatty acids are hydroxylated by intestinal and colonic bacteria. These hydroxy-fatty acids stimulate colonic water secretion and exacerbate diarrhea and fluid loss.6 Fat malassimilation can also be associated with malabsorption of bile acids, resulting in deconjugation of unabsorbed bile acids and increased mucosal permeability and secretion.7
Dietary Lactose and Gluten
Intestinal disease frequently destroys or reduces mucosal brush-border enzyme activity, particularly lactase, the most superficial enzyme. Milk or other lactose-containing substances should therefore be avoided in patients with enteric disease. Failure to digest lactose results in bacterial degradation of the sugar to volatile fatty acids, which can cause an osmotic diarrhea. The use of yogurt for therapy of chronic diarrhea is not recommended because of its lactose content. In addition, orally administered bacteria in yogurt do not colonize the bowel and displace the "unfavorable" microorganisms in both normal and diseased intestines. Gluten is a component of wheat, oats, barley, and rye, all of which should be avoided in patients with inflammatory bowel disease (IBD) in the event that the diarrhea is due to a gluten enteropathy.
Adverse reactions to dietary staples are common in cats and dogs with chronic gastrointestinal disease, and can often be successfully managed by feeding selected protein diets.8-11 Because antigenic determinants on proteins are incriminated as the precipitating factor in many cases of IBD, it is usually recommended to feed a "hypoallergenic" diet that is generally free of additives and preservatives, and contains a single, novel protein source that is highly digestible.12 There are no protein sources that are inherently hypoallergenic. The protein source should be highly digestible because intact proteins are far more antigenic than polypeptides and amino acids.13
Inflammatory Bowel Disease (IBD)
The inflammatory bowel diseases (IBD) are the most common causes of chronic vomiting and diarrhea in dogs, and refer to a group of idiopathic, chronic gastrointestinal tract disorders, characterized by infiltration of the lamina propria by lymphocytes, plasma cells, eosinophils, macrophages, neutrophils, or combinations of these cells.12 The diagnosis of IBD requires the comprehensive exclusion of potential causes of gastrointestinal inflammation, including intestinal parasites, small intestinal bacterial overgrowth, bacterial enterocolitis, dietary intolerances or allergies, and neoplasia.12 Failure to eliminate known causes of gastrointestinal inflammation, which can mimic IBD, can result in frustration for the owner and clinician due to poor responsiveness of the animal to dietary or pharmacologic therapy.
Although the etiology of canine IBD is poorly understood, most of the evidence for proposed causes in dogs have been extrapolated from humans with ulcerative colitis and Crohn's disease.13-17 Proposed causes for human IBD include defective immunoregulation of the gut-associated lymphoid tissue that may be precipitated by permeability defects,14 infectious and parasitic agents,15,16 and dietary allergies.13,17 There is provocative evidence from clinical observations and animal models to incriminate normal luminal bacteria or bacterial products in the initiation and perpetuation of canine IBD.18,19 The clinical response to hypoallergenic diets suggests that dietary factors may influence the pathogenesis of canine IBD.8-11 The term "hypoallergenic" refers to a diet that is generally free of additives and preservatives, and contains a single, novel protein source that is highly digestible.
Because the presumed pathogenesis of canine IBD involves hypersensitivity to luminal dietary or microbial antigens, therapy is aimed at removing any antigenic source of inflammation,13,18,19 followed by suppression of the cell-mediated inflammatory response in the gastrointestinal tract. Unfortunately, the increased utilization of commercial, lamb-based, formulas has diminished its application in many "hypoallergenic" diets, necessitating the selection of more "exotic" protein sources, such as kangaroo, ostrich, rabbit, and venison. It is important that the ingredient list of a potentially hypoallergenic diet be thoroughly evaluated, because diets with several protein sources (lamb, beef, rice, and wheat) are commonly marketed with a claim to hypoallergenicity. All flavored vitamins and flavored heartworm preventatives, table scraps, and raw-hide chews should be avoided during the feeding of the controlled diet.
The concept of feeding a "sacrificial protein source" during the early phase of therapy is currently under investigation to minimize the likelihood of the animal becoming sensitive to the novel protein source, while the intestine is still inflamed and more permeable to indigestible dietary proteins.12 The first novel protein offered is referred to as a sacrificial protein because it is introduced while the gut mucosal barrier is abnormally permeable, increasing the likelihood of the patient acquiring an allergy to this protein. The sacrificial protein is fed for approximately 6 weeks, after which time a second novel protein source is offered. This diet change would coincide with the lowering of the prednisone dose from the immunosuppressive to the anti-inflammatory range. There are no data advocating the benefits of this dietary concept over the implementation of a rotational dietary approach in which two diets containing novel protein sources are alternatively fed every 3 to 5 days. Likewise, there is no documented benefit of either of the two previously mentioned dietary approaches to the feeding of a single novel protein source diet that is fed until the patient becomes intolerant to the protein source.
A small percentage of dogs with severe IBD will fail to respond to commercial "hypoallergenic" diets containing intact protein sources, despite aggressive pharmacologic therapy. These patients may benefit from diets containing hydrolyzed protein sources in which the molecular weight of the polypeptide molecule is below 18,000 daltons (Purina HA Canine Formula or Hill's Prescription Diet Canine z/d ULTRA and Feline z/d, and Royal Canin Hypoallergenic hydrolyzed HP or RS formula) or from home-cooked diets containing single novel protein and carbohydrate sources.
Chronic Large-Bowel Disease
The response to dietary therapy can vary dramatically from one patient to another, with some animals showing improvement on low-residue, "hypoallergenic" diets,9,20,21 and others improving on less digestible diets containing soluble or insoluble fiber sources.22
There is evidence to suggest that some forms of colitis may be associated with a dietary sensitivity similar to that observed with small-bowel disease.8 Proteins, lipoproteins, glycoproteins, lipopolysaccharides, and carbohydrates can induce an immunologic or inflammatory response similar to that observed in the small intestine. The theoretical benefit for utilizing highly digestible "hypoallergenic" diets for patients with colitis includes reducing the digestive challenge to the large intestine and minimizing the likelihood of dietary antigens actually reaching the colon, thus lessening the likelihood of an immunological reaction.21
Several studies in the veterinary literature suggest that some patients may benefit from diets providing novel, highly digestible, protein sources.9-11 One prospective study reported a resolution in clinical signs associated with idiopathic, chronic colitis in 13 dogs fed rice and cottage cheese.9 Only 2 of the dogs in this study tolerated a challenge with the original commercial diet that had been fed at the time of the onset of signs of colitis. A second prospective study reported resolution of clinical signs associated with lymphocytic-plasmacytic colitis in 6 cats fed lamb and rice, or horse meat.10 Four of those cats were successfully placed on a veterinary therapeutic diet after two weeks on the elimination diet. Subsequent reintroduction of a feline commercial diet resulted in recurrence of diarrhea in 3 cats, which resolved after the diet was removed. In a third prospective study, 20 dogs with a non-seasonal, pruritic skin disorder and gastrointestinal signs, were placed on one of two novel protein diets: a homemade diet of fish and potato or a commercial diet containing fish and soy.11 Gastrointestinal signs were reduced or eliminated while the dogs were on their dietary treatments. Recurrence of gastrointestinal signs was seen concurrently, with a recurrence of pruritus when the dogs were challenged with components of their original diets. The challenge results in these three studies strongly suggest a dietary role in the pathogenesis of this disorder and also illustrate the potential importance of dietary therapy.
Highly digestible commercial diets, without novel protein sources, have also been shown to be effective in the management of patients with large-bowel diarrhea. In one prospective study, 11 dogs with idiopathic, chronic colitis were treated for 4 months with a commercial, restricted-antigen diet containing protein sources limited to chicken and rice.21 All dogs were simultaneously treated with sulfasalazine (20 to 40 mg/kg/day). Previous dietary management had been attempted in 9 of the 11 dogs, but diet histories were not provided. Within 1 month of consuming the limited-antigen diet, 60% of the dogs required no sulfasalazine, or a reduced dosage than when originally presented. Within 2 months, 90% were stabilized with no drug therapy. In this study, it was difficult to differentiate between the dietary and drug-related effects of management, because the two were administered simultaneously. The authors also suggest it was likely that both the digestibility (although not determined in the study) and the limited allergen content of the diet were important factors that may have contributed to the successful management of the dogs.
A recent study investigated the prevalence of adverse reactions to foods in cats with chronic gastrointestinal problems.8 The diagnosis of food sensitivity was made by dietary elimination-challenge studies using commercial selected-protein diets (chicken or venison-based). Sixteen (29%) of the 55 cats with chronic, idiopathic gastrointestinal problems were diagnosed as food sensitive. The clinical signs of another 11 cats (20%) resolved on the elimination diet, but did not recur after a challenge with their previous diet. The most common allergens identified were beef, wheat and corn gluten. Weight loss occurred in 11 of the affected cats and large-bowel diarrhea was more common than small-bowel diarrhea. The clinical feature most suggestive of food sensitivity was concurrent occurrence of gastrointestinal and dermatological signs. Collectively, 50% of the cats fed the selected-protein diets had resolution of their clinical signs. This observation suggests that selected-protein diets should be considered an important part of the management of cats with chronic, idiopathic gastrointestinal disease.
High-fiber diets containing soluble, insoluble or mixed fiber are frequently recommended for the treatment of chronic colitis. The use of soluble (fermentable) fiber in preference to insoluble (non-fermentable) fiber is sometimes advocated, because most soluble fibers generate butyrate, the principal source of energy for the colonocyte, and other short-chain fatty acids.23 Short-chain fatty acids may lower the colonic luminal pH, impeding the growth of pathogens.23 The use of dietary fiber can have deleterious consequences. As dietary fiber increases, digestibility of essential nutrients decreases, which may result in nutritional imbalances, particularly if a marginal quality diet is being fed.
Fructooligosaccharides (FOS) are carbohydrates that resist digestion by the enzymes in the gastrointestinal tract and can be metabolized by the microbial species that colonize the distal small intestine and colon. The addition of FOS to feline diets at 0.75% (DM) did not affect duodenal flora, but it did increase the numbers of lactobacilli and reduce the numbers of E. coli in the fecal flora of healthy cats.24,25 Healthy German shepherds believed to have bacterial overgrowth were supplemented with FOS at 1.0% (AF) of their diet.26 Changes were recognized in the duodenal bacterial flora, but these changes were of less magnitude than seen in normal dogs for these parameters. The clinical significance of these studies in cats and dogs with colitis is unknown.
Recently, treatment of chronic, idiopathic large-bowel diarrhea with a highly digestible diet and soluble fiber was reviewed in a retrospective study of 37 dogs.27 Treatment with a soluble fiber source (Metamucil), added to a highly digestible diet, resulted in a very good to excellent response in 23 of the 27 dogs that received supplementation. Dogs classified as having a very good or excellent response to soluble fiber supplementation received no other additional therapy, except for occasional loperamide or diphenoxylate. Fiber supplementation was later reduced or eliminated in 11 dogs; diarrhea returned in 6 of them.
Polyunsaturated Fatty Acids
Manipulation of the dietary ratio of omega-6 to omega-3 polyunsaturated fatty acids (PUFAs) has the potential to reduce the inflammatory response in human ulcerative colitis and Crohn's disease patients.28,29 Diets enriched in ω-3 fatty acids can result in the incorporation of the ω-3 fatty acids into biological membranes, with a corresponding decrease in concentrations of the proinflammatory ω-6 fatty acids, such as arachidonic acid (20:4ω-6). The therapeutic potential of dietary precursor modulation by a fish-oil-supplemented diet (ω-3 fatty acids), such as eicosapentaenoic acid (C20:5, ω-3) and docosahexaenoic acid (C22:6, ω-3) in the therapy of ulcerative colitis has been shown to result in a 35% to 50% decrease in neutrophil production of LTB4.28 Significant improvement in symptoms and histologic appearance of the rectal mucosa has been observed in several small series of patients with Crohn's disease and ulcerative colitis given fish oil at 3 to 4 g daily for 2 to 6 months in uncontrolled studies.29 However, a larger, randomized, double-blind trial comprising 96 patients with ulcerative colitis failed to reveal any benefit in remission maintenance or treatment of relapse on 4.5 g of eicosapentaenoic acid daily, despite a significant reduction in LTB4 synthesis by blood peripheral polymorphonuclear cells.30 It should be emphasized, however, that the anti-inflammatory actions of the fish oils, in addition to inhibition of LTB4, include suppression of IL-1 and platelet activating factor synthesis and scavenging of free oxygen radicals.30
The impact of increased lipid peroxidation after fish oil supplementation should be considered when altering the ω-6: ω-3 fatty acid ratio.31 Antioxidant supplementation may be able to counteract the potentially adverse effects of ω-3 fatty acids. There are no reports in the veterinary literature demonstrating the efficacy of ω-3 fatty acid supplementation in managing canine or feline large intestinal disease. Studies in healthy dogs fed diets with ω-6: ω-3 fatty acid ratios of 5:1 and 10:1 demonstrated a decreased production of LTB4 in plasma, neutrophils and skin.32 Increases in certain long chain ω-3 fatty acids and decreases in arachidonic acid were identified in the small intestine and colonic mucosa of healthy Beagles fed the same ratios.33 Further research is necessary to establish a dosage of PUFAs and to determine the clinical benefits in dogs and cats with large-bowel diseases.
Diet Selection for Large-Bowel Disease
Three types of foods are frequently used in the management of large-bowel diarrhea: 1) highly digestible, low-residue foods, 2) fiber-enhanced foods, and 3) elimination or novel foods. One common approach is to feed a complete and balanced commercial diet containing moderate amounts of a highly digestible protein source to which the animal has not been previously exposed with moderate levels of dietary fat (12–15% or 15–20% DM for dogs and cats, respectively). There are a number of commercial diets available that meet these specifications. The supplementation of fermentable fiber sources, such as psyllium or oat bran, may be necessary in animals showing partial resolution of their clinical signs. Failure to respond to these recommendations may necessitate selecting another novel protein source diet, adding insoluble fiber to the diet, or further dietary fat restriction. A complete and balanced computer-generated homemade diet that is prepared by a veterinary nutritionist is a viable alternative for dogs and cats that do not show improvement with conventional dietary recommendations.
The traditional recommendation for managing dogs with pancreatitis is to give nothing by mouth for 2 to 3 days, followed by the gradual introduction of water and a fat-restricted diet; however, this recommendation should only be reserved for animals that are vomiting intractably. Fluid and electrolyte balance is maintained with crystalloids (usually lactated Ringer's solution) and colloid solutions, such as dextran 70 or hetastarch, are utilized to maintain oncotic pressure and help ensure adequate perfusion to the inflamed pancreas. Consumption of plasma protease inhibitors and saturation of available α2-macroglobulin by activated proteases is rapidly followed by acute disseminated intravascular coagulation, shock and death.34,35 Although a clinical trial in humans has failed to show the beneficial effects of fresh frozen plasma directed at replenishing α2-macroglobulin stores, there is anecdotal evidence of its benefit in dogs with pancreatitis.36 Transfusion of fresh frozen plasma (10–20 ml/kg) to replace natural protease inhibitors, such as α2-macroglobulin, is frequently associated with amelioration of the deleterious effects associated with inflammatory mediators and activated proteases. Dietary amino acids and fatty acids are the most potent stimulators of pancreatic enzyme secretion and are thus avoided during the initial recovery period. Small amounts of water or ice cubes should be offered after the patient has stopped vomiting. If there is no recurrence of clinical signs, a diet rich in carbohydrate (rice, pasta, potatoes) and restricted in fat and protein should be gradually reintroduced. With continued clinical improvement, gradual introduction of a fat-restricted maintenance diet should be attempted. Patients with relapsing pancreatitis or severe necrotizing pancreatitis require prolonged hospitalization and attention to their nutritional status. Patients with prolonged anorexia may require enteral feeding via jejunostomy tube or total parenteral nutrition to maintain their metabolizable energy requirements. The lack of commercially available, highly digestible, and severely fat-restricted (10–12% fat calories) diets may necessitate the use of computer-generated homemade diets in select patients.
The clinical picture and nutritional recommendations for cats with pancreatitis differ markedly from those in dogs. Most cats diagnosed with pancreatitis have a more chronic and indolent form of the disease, with vomiting or diarrhea being relatively uncommon presenting complaints.37,38 In addition, most cats with pancreatitis have concurrent hepatic or intestinal disease, contributing to the anorexia commonly observed.37,38 Because of the prolonged anorexia and frequent loss of body weight, fasting the cat for an additional 3–5 days to "rest" the pancreas could be detrimental, particularly if the cat has concurrent hepatic lipidosis. At the University of California-Davis VMTH, anorectic cats with pancreatitis are nutritionally supported via esophagostomy or gastrostomy tube feeding, while maintaining fluid and electrolyte balance parenterally. Despite the dogma recommending complete "pancreatic rest" in patients with pancreatitis, we have not appreciated any clinical deterioration in these patients associated with intragastric feeding. Most cats with chronic pancreatitis can be fed a commercial, complete and balanced diet formulated for maintenance of the animal. Unlike the dog, there is little clinical evidence to support the notion for excessive dietary fat restriction in cats with pancreatitis. Caution should be exercised in implementing human liquid enteral formulas for feline patients, as most of the formulas are deficient in protein, arginine, and taurine. Gastrostomy or esophagostomy tube feeding is avoided if the cat is vomiting intractably or has moderate ascites present. Jejunostomy tube feeding or total parenteral nutrition should be implemented in these situations.
Exocrine Pancreatic Insufficiency (EPI)
Nutrient malabsorption in EPI arises as a consequence of failure of intraluminal digestion, and impaired function of intestinal mucosal enzymes. Most dogs and cats with EPI can be managed with dietary modification and pancreatic enzyme supplementation. A suboptimal response to enzyme supplementation usually reflects associated small intestinal disease or bacterial overgrowth.
Fat absorption does not return to normal despite appropriate enzyme replacement therapy in dogs with EPI.39 Patients usually compensate by increasing their caloric intake, necessitating an increase of approximately 20% above their calculated maintenance requirements. Although fecal fat decreases when a fat-restricted diet is fed, excessive dietary fat restriction could decrease the absorption of fat, fat-soluble vitamins, essential fatty acids, and cholesterol. It has also been shown that a fat-restricted diet does not ameliorate signs of EPI.40 In fact, the feeding of a high-fat and high-protein diet in combination with porcine lipase maximized fat absorption in one experimental study in dogs with EPI.41 Studies in human patients also reveal that certain fiber sources (e.g., wheat bran, pectin) impair pancreatic enzyme activity; therefore, high-fiber diets should be avoided.42 Most dogs with exocrine pancreatic insufficiency do well when fed regular commercial maintenance diets. Patients exhibiting poor weight gain may benefit from dietary supplementation with medium-chain triglycerides, although studies are needed to confirm whether dietary fats containing medium-chain triglycerides are directly absorbed into the portal circulation, and whether digestion by lipase with incorporation into chylomicrons is circumvented. Fat absorption will not be improved by pre-incubation of the food with pancreatic enzymes, administration of antacids, or by addition of bile salts.
Many different preparations of pancreatic enzymes are commercially available; however, powdered formulations have been shown to be most effective in dogs.39 Tablets, capsules and enteric-coated preparations are less effective than powdered extracts and are not recommended.43 Enzyme replacement using an initial dose of 1 teaspoonful of powdered non-enteric-coated pancreatic extract with each meal per 10 kg of body weight is generally effective for dogs, whereas cats should receive one teaspoon per meal. Animals that do not show an optimum response to this dose do not usually benefit by increasing the amount of extract. The extract should be mixed with food immediately prior to feeding. Two meals a day are usually sufficient to promote weight gain of 0.5 to 1.0 kg per week in larger dogs; diarrhea generally resolves within 2–3 days, and coprophagia and polyphagia also often disappear within a few days. As soon as clinical improvement is apparent, owners can determine a minimum effective dose of enzyme supplement that prevents return of clinical signs. This varies slightly between different enzyme preparations, and also from dog to dog. Most affected animals need at least 1 teaspoonful of extract with each meal. An economical alternative to commercially available enzyme preparations is chopped raw bovine or porcine pancreas (3 to 4 ounces per meal for a 20-kg dog) given with the food. Porcine pancreas is as effective as bovine pancreas, but there is a potential risk of infection with Aujeszky's disease since the pancreas must be fed raw. Fresh pancreas can be stored frozen for at least 3 months without loss of enzyme activity. The owner should be reminded about maintaining proper kitchen hygiene to decrease the risk of possible transmission of zoonotic diseases such as salmonellosis. There is no difference in the therapeutic response between dogs that are treated with pancreatic powder or raw pancreas.44
Serum concentrations of cobalamin (vitamin B12) and vitamin E are often subnormal in dogs with EPI and do not necessarily increase in response to treatment with enzymes, even though the clinical response may otherwise be excellent. Vitamin E should be supplemented at a daily dose of 250 to 500 mg alpha-tocopherol (vitamin E) given in the food for 1 month. Low serum cobalamin concentrations in dogs have been associated with exocrine pancreatic insufficiency, severe intestinal disease, and putatively small intestinal bacterial overgrowth.45-47 Cobalamin is an essential cofactor for the activity of methylmalonyl-CoA mutase and methionine synthase.48 Anemia with hypoplastic erythropoietic centers in the bone marrow has been described as a consequence of cobalamin deficiency in the dog. Serum cobalamin can be assayed and if decreased, administered subcutaneously at a dose of 500 µg per dog, once weekly for 6 weeks, with the dosing schedule decreased to once every 6 to 12 months depending on serum cobalamin concentrations. Cats appear highly susceptible to cobalamin deficiency, partly as a result of the very rapid turnover of this vitamin compared with humans.49 Cats with decreased serum cobalamin concentrations should be supplemented with subcutaneously administered cobalamin at a dose of 1000 µg per cat, once weekly for 6 weeks, with reassessment of the serum cobalamin concentration approximately one month after discontinuing therapy. Cases of vitamin K deficiency-responsive coagulopathies have occasionally been documented in dogs and cats with EPI and severe IBD. Parenteral vitamin K1 (2.5 mg/kg) followed by oral vitamin K1 at 0.25 to 2.5 mg/kg q12 hours should be given when there is clinical or laboratory evidence of a coagulopathy.
The need for antibiotic therapy varies from patient to patient, but is usually indicated in dogs with small intestinal bacterial overgrowth (SIBO). Secondary SIBO can cause diarrhea, weight loss, and malabsorption. Pancreatic enzyme supplementation did not have a significant effect on the jejunal microflora in a group of dogs with naturally occurring EPI;50 however, a study completed in dogs with experimentally induced EPI revealed that clinical signs improved with pancreatic enzyme supplementation alone.51 Administration of tylosin (20–40 mg/kg BID for 2–3 weeks), oral oxytetracycline (10–20 mg/kg BID for 2–3 weeks), or oral metronidazole (10–20 mg/kg BID for 2–3 weeks) may improve overall response to therapy.
Failure to respond to the abovementioned therapeutic measures warrants consideration of concurrent lymphocytic-plasmacytic gastroenteritis, which, if confirmed via gastrointestinal biopsy, may resolve with concurrent prednisone therapy.
The complex relationship between nutrition and the liver is reflected by the magnitude of the difficulties encountered in managing patients with compromised hepatic function. Nutritional management is frequently delayed in small animal patients with liver disease owing to the insidious onset and lack of understanding of pathophysiologic mechanisms. In addition, therapeutic diets may need to be modified depending on the patient's nutritional status and underlying liver disorder. Sufficient carbohydrate and fat must be provided in the diet to minimize protein catabolism for energy needs and consequent ammonia formation. Although nutritional therapy only plays a supportive role in the management of most hepatic diseases, it is the primary treatment for feline idiopathic hepatic lipidosis.
Feline Idiopathic Hepatic Lipidosis
Feline idiopathic hepatic lipidosis (IHL) is a well-recognized syndrome characterized by accumulation of excess triglycerides in hepatocytes with resulting cholestasis and hepatic dysfunction. The prognosis for this life-threatening disorder has improved dramatically during the past several years, as a result of utilization of long-term (three to ten weeks) enteral feeding. Most cats with IHL are obese and usually present with a history of prolonged anorexia after a stressful event.52,53 The etiopathogenesis of this syndrome is poorly understood, but may relate to protein deficiency, excessive peripheral lipolysis, excessive lipogenesis, inhibition of lipid oxidation or inhibition of the synthesis and secretion of very low-density lipoproteins.52,53 Initial management should be directed toward correcting complications, such as dehydration, electrolyte abnormalities, hepatic encephalopathy, and infection. Correction of acid-base and electrolyte disturbances is also important in cats with IHL. Hypokalemia was present in 19 of 66 cats (29%) with severe hepatic lipidosis.53 Hypokalemia may develop due to inadequate potassium intake, vomiting, magnesium depletion, and concurrent renal failure. Hypokalemia was significantly related to nonsurvival in this group of cats. Hypokalemia is deleterious because it may prolong anorexia and exacerbate hepatic encephalopathy. Diets for cats with IHL should be potassium replete (0.8–1.0% potassium on a DM basis), or potassium supplementation (2–6 mEq potassium gluconate per day) should be considered. Resolution of hepatic lipidosis associated with pancreatitis, infection, and the use of drugs depends on the success in treating the underlying disorder. Early tube feeding via nasoesophageal, esophagostomy, or gastrostomy tube remains the cornerstone of therapy. Force feeding is contraindicated in this syndrome, because adequate nutrition is rarely provided by this method and the likelihood of inducing a conditioned food aversion is increased.
An adequate supply of energy is needed to prevent catabolism of amino acids for energy and inhibit peripheral lipolysis. Most cats with IHL can be fed commercially available therapeutic or maintenance diets containing up to 30% fat (DM). Cats with IHL will tolerate moderately high amounts of dietary protein (up to 45% protein on a DM basis), unless they are suffering from concurrent hepatic encephalopathy, in which case a protein-restricted diet intended for the management of patients with chronic renal failure (< 30% protein on a DM basis) may be needed until the encephalopathy can be resolved. Food aversion appears to be an important component of the anorexia of cats with hepatic lipidosis.52,53 Cats that refuse to eat a diet that they associate with nausea may continue to avoid that diet even after full recovery, due to their association with the unpleasant sensation. One should therefore tube feed these cats as soon as the diagnosis of hepatic lipidosis has been made, rather than offer several commercial diets that the cat can develop an aversion to. Cats should not be offered any food by mouth for approximately 10 days following placement of a feeding tube. Cats expressing an interest to eat can then be presented with food. The prognosis for IHL is influenced to a large degree by the ability of the clinician or owner to aggressively meet the cat's caloric requirements via enteral feeding. The use of appetite stimulants can be attempted, but usually results in failure to meet the cat's caloric requirement and frustration for the owner and cat. Caution should be exercised with the use of anabolic steroids and diazepam, because of the potential for hepatotoxicity.54
Carnitine transports long-chain fatty acids across the inner mitochondrial membrane into the mitochondrial matrix for oxidation. Carnitine also removes potentially toxic acyl groups from cells and equilibrates ratios of free CoA/acetyl-CoA between the mitochondria and cytoplasm. Jacobs and colleagues found that mean concentrations of carnitine in plasma, liver, and skeletal muscle were significantly greater in cats with IHL vs. control cats.55 These findings suggest that systemic carnitine deficiency does not appear to contribute to the pathogenesis of feline IHL. In contrast, Armstrong and colleagues showed that dietary L-carnitine supplementation protected obese cats from hepatic lipid accumulation during calorie restriction and rapid weight loss.56 Center and colleagues showed that diets supplemented with L-carnitine can safely facilitate rapid weight loss in privately owned obese cats.57 Based on these findings, a number of clinicians supplement L-carnitine at 7–14 mg/kg body weight/day to cats with IHL. Center and colleagues have recommended a higher dose of 250–500 mg L-carnitine/day to cats with IHL.57
Copper-Associated Hepatotoxicosis in Dogs
The abnormal accumulation of copper within hepatic lysosomes has been associated with hepatocellular damage in several breeds, most notably the Bedlington terrier, West Highland white terrier, Skye terrier, and Doberman pinscher.58 Studies of copper-associated hepatotoxicity in the Bedlington terrier have proven the disease to be an inherited, autosomal recessive trait, resulting in the aberrant expression of the copper-binding protein metallothionein. Copper accumulates in an age-related process within hepatocyte lysosomes, often reaching levels of 10,000 parts per million (ppm). Normal hepatic copper levels are considered to be less than 400 ppm.58 Confusion arises in other breeds, because copper can also accumulate in the liver secondary to cholestatic liver diseases. Most commercial dog foods contain an excess of copper, so deficiencies are uncommon. Absorption of copper is enhanced by amino acids and high dietary protein, and reduced by zinc, ascorbate, and fiber.
The management of copper toxicosis is directed at reducing copper stores in the body. Dietary restriction of copper probably plays a minor role in reducing hepatic copper concentrations in diseased dogs.59 Dietary restriction has the most potential for managing young dogs known to be affected with an inherited hepatic metabolism defect (e.g., Bedlington terriers and West Highland white terriers). A minimum dietary copper requirement has been established as 2.9 ppm available copper (DM basis) for growth. A minimum dietary copper allowance of 7.3 ppm for growth and adult maintenance has been established for typical dog foods. There are no proven nutritionally balanced commercial diets that are restricted in copper, although a diet such as Hill's Prescription Diet® Canine u/d® may be suitable for short-term management, because it does not contain organ meats and is markedly protein restricted. One can also prepare a homemade complete and balanced diet that is restricted in copper. Homemade diets should exclude liver, shell fish, and organ meats, which are all high in copper content.
Zinc salts are effective in preventing copper accumulation in the livers of humans with Wilson's disease.60 Zinc ions induce the synthesis of metallothionein, which binds copper tightly, thus rendering copper unabsorbable from the intestine and possibly detoxifying it in the liver.61 The copper is lost in the feces when the intestinal cell is sloughed. Zinc acetate or zinc gluconate is recommended, because the sulfate form is associated with gastric irritation and vomiting in humans. Zinc is administered one hour before meals at 5 to 10 mg/kg twice daily. Excess zinc will interfere with the absorption and utilization of iron and copper and can cause chronic copper deficiency manifested by hypochromic microcytic anemia and neutropenia.
Copper chelators bind copper either in the blood or tissues and promote its urinary excretion. D-penicillamine, the most frequent copper chelator recommended for use in dogs, should be given at a dose of 10 to 15 mg/kg, twice a day, on an empty stomach. Vomiting is the most common side effect in dogs and can be alleviated by reducing the dose and giving it more frequently. D-penicillamine therapy has also been associated with a pyridoxine deficiency in human patients.62 Although this problem has not been recognized to occur in dogs, the diet should be fortified with B-vitamin, or supplemental amounts should be given daily. Trientine (2,2,2-tetramine) is another chelating agent with comparable effects to D-penicillamine, but with fewer adverse effects.63 Trientine is usually dosed orally at 10–15 mg/kg body weight, twice daily. Modification of 2,2,2-tetramine to 2,3,2-tetramine increases potency as a copper-chelating agent. Use of 2,3,2-tetramine in affected Bedlington terriers reduced liver copper concentrations significantly after 200 days of treatment at a dose of 15 mg/kg body weight. This drug is not commercially available, but can be obtained from chemical supply companies in the form of N,N'-bis(2-aminoethyl)-1,3-propanediamine and prepared as a salt for oral administration. Periodic liver biopsies are suggested with the use of copper chelators to monitor hepatic copper levels and response to therapy. Anti-inflammatory agents, such as prednisone, may be of benefit in the management of chronic hepatitis in Bedlington terriers and West Highland white terriers.
Supplemental vitamin E (alpha-tocopherol) may be beneficial for these patients, because lipid peroxidation has been implicated in the pathogenesis of copper toxicosis. Vitamin E deficiency is permissive to hepatic injury associated with cholestasis, because both accumulation of hepatic copper and hydrophobic bile acids promote free radical injury.64 Vitamin E supplementation at 10 to 100 IU/kg per day is recommended as a nutritional supplement in all patients with chronic necroinflammatory liver disorders.64
S-Adenosyl-L-methionine (SAMe) plays a complex role in metabolism, where it functions as a methyl donor important in transmethylation reactions, as a precursor of sulphur-containing compounds, and in production of polyamines. It is well documented that the transulphuration pathway becomes impaired in chronic liver disease. SAMe has also been shown to have anti-inflammatory effects and has been used in the treatment of arthritis in human beings. Administration of SAMe protects against the hepatotoxicity induced by acetaminophen in animal models. In addition, oral SAMe administration in humans with cirrhosis replenishes hepatic glutathione reserves in depleted patients, which is suggested to improve tolerance of free radicals and reperfusion-type injury. SAMe is currently marketed for dogs and cats as enteric coated tablets (Denosyl SD4) and is being evaluated in these animals with chronic liver disease for its putative benefits.65,66
Portosystemic Vascular Shunts and Hepatic Encephalopathy (HE)
An understanding of the pathogenesis and precipitating factors for development of HE is integral to successful patient management. The goals of therapy in patients with HE are threefold: (I) early recognition and correction of precipitating causes of encephalopathy (e.g., gastrointestinal bleeding, constipation); (II) reduction of the intestinal production and absorption of toxins; and (III) provision of supportive and symptomatic care. Clinicians should refrain from the use of sedatives, narcotics, and anesthetic agents in patients with HE. Diuretics, in particular furosemide, should be judiciously utilized, because overzealous use may cause hypokalemic alkalosis and hypovolemia. Treatments based on the mechanism of intestinal production and absorption of toxins (ammonia, mercaptans, short-chain fatty acids, indole and skatole, and biogenic amines) include decreasing or modifying dietary protein, altering intestinal flora, and decreasing intestinal transit time. Supportive care includes correction of hypovolemia, electrolyte, and acid/base abnormalities.
The question of dietary protein restriction for companion animals with liver disease is a particularly frustrating one for veterinary practitioners, because the true protein requirement for dogs and cats with liver disease has not been defined. Protein source and quality is of equal importance, and should also be considered when formulating a diet for a patient with liver disease. Dogs with experimentally created portosystemic shunts had significantly prolonged survival and fewer signs of encephalopathy when fed a dairy-based diet as opposed to a meat diet. It is possible that heme, RNA, and other nitrogenous bases in the meat contributed to the exacerbation of hepatic encephalopathy and shortened survival.67 In addition, the presence of diarrhea and soft stools in the dogs that received the dairy-based diet was a possible cause of decreased nitrogen absorption secondary to shortened intestinal transit time and lowering of the colonic pH. The feeding of vegetable-based diets (soybeans) is also preferred to the feeding of meat-based diets in human patients with cirrhosis.68 The effect of vegetable diets on nitrogen metabolism can be accounted for mainly by the increased intake of dietary fiber and increased incorporation and elimination of nitrogen in fecal bacteria. Although eggs are an excellent protein source, they are relatively high in methionine and should therefore be avoided in patients with severe liver disease. Oral methionine is noncomatogenic in normal dogs, but is consistently comatogenic in dogs with portacaval shunts in the presence of elevated ammonia levels.69 Thus, both the type and amount of protein need to be considered when discussing the protein requirements of dogs with liver disease.
Numerous randomized, controlled trials of branched-chain amino acid-enriched supplements in human patients with hepatic encephalopathy have been performed.70,71 Meta-analysis of these studies by two different groups gave diametrically opposite results. Although they may be effective in restoring positive nitrogen balance, branched-chain amino acids do not seem therapeutically effective in either acute or chronic hepatic encephalopathy. In addition, branched-chain amino acid supplementation is extremely expensive.72
The administration of lactulose, a synthetic disaccharide that is hydrolyzed by colonic bacteria, principally to lactic and acetic acids, is considered to be one of the treatments of choice in hepatic encephalopathy.73 Lactulose exerts its beneficial effects by (1) lowering colonic pH with subsequent trapping of ammonium ions; (2) inhibiting ammonia generation by colonic bacteria through a process known as catabolite repression; (3) decreasing intestinal transit time because of its cathartic properties; and (4) suppressing bacterial and intestinal ammonia generation by providing a carbohydrate source. The dosage required to achieve these goals varies greatly, with a range of 2.5 to 25 ml three times daily in dogs, and 1.0 to 3.0 ml three times daily in cats. The dose should be reduced if watery diarrhea develops.
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