Professor T.J. Gruffydd-Jones
The Feline Centre, Division of Companion Animals, Department of Clinical Veterinary Science, University of Bristol, Bristol, UK
Objectives of the Presentation
Review of the clinical features, diagnosis and treatment of inflammatory bowel disease (IBD) and inflammatory liver disease, with discussion of possible breed and familial predisposition.
Overview of the Issue
Feline Inflammatory Bowel Disease
Inflammatory bowel disease (IBD) is one of the most common intestinal disorders of cats and a major diagnosis in cats presented with chronic weight loss and gastrointestinal signs.
IBD is not a specific diagnosis. It represents a syndrome of characteristic chronic intestinal inflammation of unknown cause. It is therefore essentially a diagnosis of exclusion which requires elimination of other recognized causes of chronic gastrointestinal disease. IBD is considered to represent a heterogenous disorder which is reflected in the variable nature of the inflammatory infiltrate, and the variable clinical manifestations and progress of the disease.
The variable presentation of IBD, difficulty in defining specific criteria for diagnosis and the unpredictable response and progress of cases makes this a difficult challenge for practitioners.
The aetiology of IBD, by definition is not known. The nature of the lesions based on the histopathological appearance and immune characterization suggests some form of immune dysregulation. The immune system of the gut is exposed to many potential antigens, such as enteropathogens, and others which are beneficial such as food antigens and the indigenous natural intestinal microflora. The gut must discriminate between these adverse and beneficial antigens in developing an appropriate immune response. The most plausible explanation for why IBD develops is that it reflects failure of the normal regulatory immune responses that confer tolerance to the beneficial antigens. Many changes, particularly in immune and microbiological correlates, have been described and these reflect the diversity of factors that may contribute to the dysregulation that leads to IBD. These differ and vary between individual cases accounting for the heterogenous nature of the syndrome. A major dilemma is whether some of these changes are a cause of IBD or occur as a consequence of IBD developing.
There is strong evidence that genetic factors play a role in susceptibility to IBD in humans and in experimental laboratory animal models of IBD. The importance of genetic factors in cats is uncertain but there is circumstantial evidence that they may be important. Pedigree cats are over-represented in the cases seen in our clinic, in particular some breeds such as Abyssinians. We have diagnosed IBD in several individuals from closely related families.
The most striking immunohistological change in cats with IBD is expanded and intensified expression of MHC Class II (Waly et al., 2004). This is crucial to antigen presentation and suggests that abnormalities in presentation play a role in aetiology.
Two studies have now described changes in cytokine mRNA in cats with IBD (Nguyen Van et al., 2005; Janeczko et al., 2008) and both of these have shown a mixed picture of increases in both immunoregulatory cytokines and pro-inflammatory cytokines IFN-α. These changes may reflect immune-dysregulation. In the later study the most notable correlation with the severity of IBD was with IL-8 and this may have potential as a marker for IBD.
Small intestinal bacterial overgrowth (SIBO) has been incriminated in IBD in dogs and there has been speculation that this may be a factor in cats too. The belief that some cases respond to metronidazole therapy has been interpreted as lending credence to this theory. However detection of SIBO in cats is controversial as reliable criteria for diagnosis have not been established and it is recognized that particularly high numbers of bacteria exist in the small intestine of healthy cats compared to other species.
In a recent study the numbers of bacteria in duodenal mucosal biopsies of cats with IBD were investigated using fluorescence in situ hybridization with probes to 16SrDNA (Janeczko et al., 2008). This showed significant changes in some bacteria with increased numbers of E.coli and Clostridial spp. Associated with IBD. In contrast, numbers of Desulfovbria spp. which may be regarded as potentially pathogenic, were increased in cats with IBD whilst numbers of Bifidobacteria spp. and Bacteroides spp., which are potentially beneficial bacterial, were lower than in normal cats using similar techniques (Inness et al., 2007). This still leaves the question of whether any changes in bacteria drive the pathogenesis of IBD or reflect secondary changes as a consequence of damage to the gut.
The distinction between food sensitivity and IBD is blurred and there may be overlap between these two disorders. Indeed hypersensitivity to dietary antigens may well play an important role in the pathogenesis of IBD. Feeding of an exclusion diet is a mainstay of treatment for IBD. Some cats diagnosed as mild cases of IBD will respond to dietary therapy alone-which raises questions as to whether they might represent food sensitivity rather than IBD. Interpretation of response to the use of exclusion diets is complicated by the recognition that a significant proportion of cats with chronic gastrointestinal signs will respond to such management but do not relapse if re-challenged with their original diet. These cases are regarded as food responsive rather than food sensitive.
IBD can occur in cats of any age. Some studies have suggested that it is more common in older cats with nearly 70% of cases being reported to occur in cats over nine years of age in one study. However IBD has been reported in cats less than one year of age. A slight predisposition in male cats was reported in an early series of cases, but no clear sex predisposition is recognized.
Originally most cats with IBD were presented with predominantly small intestinal signs of weight loss, vomiting and diarrhoea of a small intestinal nature. However, more recently, an increasing proportion of cats are presented with predominantly large bowel signs of frequent passage of small quantities of feces, often with mucus and fresh blood, and associated with marked tenesmus.
The main challenge in diagnosis is to eliminate other possible causes of chronic gastrointestinal signs. An important priority is to rule out parasitic causes, most notably Giardia and Tritrichomonas, and appropriate diagnostic tests should be selected to do this. Tritrichomonas has emerged as an important differential diagnosis to consider in cats with large bowel signs, particularly in young pedigree cats from multicat households. Direct examination of wet preparations of freshly voided feces may reveal the organism but PCR tests are now being more widely used for diagnosis. Fecal analysis should include bacteriological culture and screening for other parasites such as coccidia. Trial treatment with fenbendazole, or occasionally metronidazole, is sometimes used as an alternative to fecal testing to eliminate Giardia as a possible factor.
The two main challenges in histological interpretation are variations in the assessment of the significance of changes and differentiation from alimentary lymphosarcoma. The WSAVA have now drawn up guidelines for the criteria for diagnosing IBD which should help to improve consistency of diagnosis. Architectural changes in villous/crypt structure, including villous stunting, ulceration and crypt hyperplasia, may be as important as the presence of abnormal inflammatory infiltrates. In most cases the inflammatory infiltrate is predominantly lymphocytic/plasma cells. The distribution of lesions throughout the gut has not been clearly defined. Some cases show widespread lesions with infiltration throughout the gut, but in other cases infiltration may be more localized. Pinch mucosal biopsies obtained by peroral endoscopy have the advantage of being obtained using a minimally invasive technique but may not always be diagnostic or yield the correct diagnosis. The size of the biopsy, fragmentation and orientation can influence the histopathological value. A recent study comparing endoscopic and full thickness biopsies showed that the latter are more reliable for diagnosing alimentary lymphosarcoma (Evans et al., 2006).
The mainstays of treatment for IBD are
dietary management-exclusion diets
The traditional approach to dietary management is to feed a single source of protein, preferably a novel protein source that the cat has not received previously and there are many possible options including commercial diets and home prepared diets. Concerns have grown in recent years about the potential role of cereal proteins, particularly wheat, in inducing hypersensitivity responses. The cereal content of the diet should be considered and the use of rice as a carbohydrate source is popular. If dietary management is likely to be successful some improvement is generally expected within two weeks of introducing a new diet. A newer approach to dietary management has been based on feeding hydrolysed proteins in which the molecular size of the proteins is reduced in the hope that this will reduce antigenicity.
Prednisolone is the most popular initial choice as an immunosuppressive agent, generally starting with a dosage of two to four milligrams per kilogram daily. If a good response is achieved this is gradually reduced over a period of generally six to 12 weeks, halving the dosage every one to three weeks. Alternative immunosuppressive drugs may be used but are generally reserved for refractory cases. Our first choice is usually chlorambucil given orally at a dose of 2 mg every four days to cats over two kilograms in weight, and once weekly to cats under two kilograms. This treatment option can be effective for lymphoma and is a good choice if no clear differentiation can be made between severe IBD and lymphoma. Hematology should be monitored periodically in cats receiving chlorambucil to check for myelosuppression. Other options that have been used as alternatives to prednisolone include budesonide (3 mg/m2 daily), cyclosporine (1-4 mg/kg twice a day) and cyclophosphamide (50 mg/m2 every other day).
Metronidazole is the antibiotic used most frequently. It is sometimes used as a first line treatment, occasionally in preference to prednisolone, but more often it is reserved for cases which fail to respond to initial treatment with dietary management and prednisolone, or when the IBD appears to be severe. It is questionable whether bacterial overgrowth occurs in IBD (see earlier) but metronidazole may modify the gut flora with potentially beneficial effects.
Little reliable information is available about the expected response to treatment and prognosis for IBD. In one study signs resolved in eight of 47 cases treated with prednisolone, and there was a partial improvement in a further 31. Eight cats failed to improve or deteriorated and in some of these the owners elected for euthanasia (Hart et al., 1994).
Feline Inflammatory Liver Disease
Hepatic lipidosis ("fatty liver syndrome") is the most common form of liver disease seen in cats in the USA, but the second most common is inflammatory liver disease-which is the most common liver disease seen in the UK.
The classification of inflammatory liver diseases in cats has been controversial but in recent years WSAVA established an expert panel which has provided guidelines for pathological classification. Two main forms are recognized-neutrophilic and lymphocytic. Some cases are seen with intermediate features. It has been suggested that the two main forms may be different stages of the same pathological process-although there are several observations that contradict this theory.
In the neutrophilic form of inflammatory liver disease the infiltration of the liver and biliary tree is primarily neutrophilic. It has been described as suppurative although this term may be misleading. The cause is uncertain but may be related to ascending infection of the bile duct from the gut. There is sometimes a link with pancreatitis and IBD-if all three features are present this is referred to as "triaditis".
There are no well recognized predispositions for neutrophilic cholangitis. Most affected cats are presented with jaundice, often as markedly depressed, sick cats with a relatively acute illness. Aggressive antibiotic therapy is usually successful in treating the disease.
In this form the infiltrate is predominantly lymphocytic with plasma cells. Fibrosis frequently occurs and can be severe in chronic cases. The nature of the infiltrate suggests that an immune-mediated mechanism plays a role in the pathogenesis of the disease.
Lymphocytic cholangitis occurs more often in young cats with more than 50% of cases in cats under four years of age. There is a predisposition in Persian cats but no sex bias (Lucke and Davies, 1984). This form of inflammatory liver disease is seen much more frequently than suppurative cholangitis in our clinic.
The aetiology of this liver disease is unknown, although an immune-mediated mechanism is believed to contribute to the pathogenesis.
The two main presenting signs in lymphocytic cholangitis are jaundice and progressive ascites. Occasionally both clinical signs are present. In contrast to suppurative cholangitis cats with lymphocytic cholangitis often do not appear ill in themselves. Appetite is often maintained and some cases show a noticeable polyphagia. There may be quite severe weight loss but other cases retain reasonable bodily condition. It is unusual for pyrexia to be present. Hepatomegaly may be detectable on abdominal palpation and in some cases this can be striking. Mild generalized lymph node enlargement is a common finding. This is most apparent on palpation of the superficial lymph nodes but may also involve the mesenteric lymph nodes. In the later stages of the disease with extensive cirrhosis and portal hypertension, hepatic encephalopathy may develop.
There is usually an increase in liver enzymes (ALT, ALP and GGT) and bile acids which can be severe. Bilirubin levels may be increased, frequently corresponding with jaundice. Serum globulin levels are often raised and this may reflect an increase in γ globulins detectable on serum protein electrophoresis. The most consistent change on hematology is lymphopenia. There may be some neutrophilia and mild anaemia. If ascitic fluid is present, abdominal paracentesis will show this to be clear to yellow tinged. It is generally thick with a high protein content, the majority of which is globulin. The cellular content is generally low with a non-specific mixture of inflammatory cells.
Radiography may be complicated by the presence of ascites but may reveal hepatomegaly. The liver may have a heterogenous appearance on ultrasonography with irregular margins. If there is extensive cirrhosis, the liver may have a hyperechoic appearance.
Histopathology is required to make a definitive diagnosis. Fine needle liver aspirates may reveal a lymphocytic infiltrate but will not show the characteristic changes in liver architecture, the location of the infiltration or the pattern of fibrosis. Percutaneous core biopsy techniques generally provide diagnostic samples. However the prominent presence of blood vessels on the surface of the liver, together with possible compromise of liver dependent clotting factors, leads to a significant risk of post biopsy hemorrhage and therefore biopsy at laparotomy provides the advantage of enabling better haemostatic control. Laparotomy also enables larger biopsies to be obtained, selection of biopsy sites including assessment and biopsy if appropriate of other abdominal organs.
Corticosteroids are the mainstay of treatment used on the basis of countering immune mediated damage to the liver. There is considerable clinical experience to support their beneficial effect. Prednisolone is frequently used at an initial immunosuppressive oral dosage of 1-2 mg/kg b.i.d. which is gradually reduced over an extended period of 6-12 weeks according to the progress of the case. Other immunosuppressive agents are occasionally used such as cyclosporine, chlorambucil, methotrexate and cyclophosphamide but there is limited experience of their use and value. Colchicine may be used at a dosage of 0.03 mg/kg sid in an attempt to combat fibrosis although there have been no controlled trials to confirm any beneficial effect. Choleretics, SAMe and nutritional support may be helpful.
There is limited information available about the prognosis for cats with lymphocytic cholangitis but the majority of cats respond well to treatment. The mean survival in 25 cats in which portal hepatitis was described was 37 months with 16 cats surviving for more than a year. Our experience is that the prognosis is better in cats that are presented with jaundice compared to those with ascites. Lymphocytic cholangitis has been seen to resolve spontaneously in occasional cases. Some cats will need repeated courses of prednisolone or may need to be maintained on long-term lower dosages. Response to treatment is based initially on resolution of clinical signs. Monitoring of liver biopsies can be used to assess response to treatment but is usually declined by owners and subsequent progress has to be based on monitoring laboratory features particularly liver enzymes and bile acids.
Inflammatory Bowel Disease
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2. Hart JR, Shaker E, Patnaik AK & Garvey MS. (1994) Lymphocytic-plasmacytic enterocolitis in cats: 60 cases (1988-1990). J Am Anim Hosp Assoc. 30: 505-514.
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4. Janeczko S, Atwater D, Bogel E, Greiter-Wilke A, Gerold A, Baumgart M, Bender H, McDonough PL, McDonough SP, Goldstein RE & Simpson KW. (2008) The relationship of mucosal bacteria to duodenal histopathology, cytokine mRNA, and clinical disease activity in cats with inflammatory bowel disease. Vet. Microbiol. 128: 178-193.
5. Sturgess CP, Manoussaka MS, Stokes CR & Gruffydd-Jones TJ. (2003) Antibody responses to commensal intestinal bacterial flora in normal cats, and cats with inflammatory bowel disease. (Abstract) J Vet Intern Med. 16: 383.
6. Nguyen Van N, Tatlinger K, Helps CR, Tasker S, Gruffydd-Jones TJ & Day MJ. (2005) Quantitative measurement of cytokine mRNA levels in duodenal biopsies in cats with inflammatory bowel disease (IBD). Immunology 116: 96.
7. Waly NE, Stokes CR, Gruffydd-Jones TJ, Day MJ. (2004) Immune cell populations in the duodenal mucosa of cats with inflammatory bowel disease. J Vet Intern Med. 18: 816-825.
Inflammatory Liver Disease
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