The Feline Centre Department of Clinical Veterinary Science University of Bristol, UK
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 recognised 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 recognised 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 rechallenged 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 recognised.
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 faeces, 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 faeces may reveal the organism but PCR tests are now being more widely used for diagnosis. Faecal 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 faecal 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). A confident, accurate histopathological diagnosis was made in around a third of the cats with alimentary lymphosarcoma but lymphosarcoma was overlooked in around another third.
An overlap between IBD and alimentary lymphoma in cats has been suggested with some cases of IBD suspected of progressing to alimentary lymphoma. Progression of IBD to lymphoma in man is well recognised with prolonged antigen stimulation believed to be a contributory factor. In one study the immunophenotype of lymphocytes from cases of intestinal lymphoma was found to be the same as the immunophenotype of intra-epithelial lymphocytes (IELs) which suggests that IELs can be the origin of lymphomas (Roccabianca 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. Haematology 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 he 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).
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