Chronic enteropathy in cats

Introduction

Inflammatory bowel disease (IBD) and small cell lymphosarcoma (ScLSA) of the gastrointestinal tract (GIT) are common diseases in cats that cause similar clinical signs. IBD refers to a group of idiopathic and chronic inflammatory disorders characterized by persistent or recurrent gastrointestinal signs, and is a diagnosis of exclusion. The etiology and pathogenesis of IBD is likely multifactorial, involving the interaction of host genetics, immune system and the intestinal microenvironment. The etiology of ScLSA is similarly complex, poorly understood and again likely multifactorial. The emergence of GIT ScLSA has created a diagnostic and treatment challenge for the feline patient with chronic enteropathy. Efforts to standardize the reporting of endoscopy and histopathology findings, in addition to advanced diagnostics such as Immunohistochemistry (IHC) and polymerase chain reaction (PCR), represent a great help to the feline practitioner.

Feline chronic enteropathy

Evaluating a feline patient with chronic signs of GIT disease (vomiting, diarrhea, weight loss and/or variation of appetite) should start with a thorough, sequential, noninvasive diagnostic work-up and a well-implemented therapeutic trial tailored to each specific patient. The goal is to exclude extra-GI disorders, GIT parasites, food- or antibiotic-responsive enteropathy, and intestinal structural abnormalities before narrowing down the differential diagnosis to IBD or ScLSA (Table 1) (Figure 1) (Figure 2) (Figure 3). Differentiating ScLSA from IBD is difficult and requires relatively invasive and costly diagnostics 1 2 3 4 5 6 7 8. 

The lack of diagnostic and therapeutic standards for cats with chronic enteropathy creates great challenges for the practitioner. Because IBD is poorly understood and has vague diagnostic criteria, the syndrome is probably over/ misdiagnosed 1. Multiple specialty associations have made excellent efforts over the last decade to provide guidelines and standards for history taking, physical examination, laboratory diagnostic tests, imaging procedures, endoscopic and biopsy procedures, histopathologic interpretation, therapeutic trials, and patient response and outcome in dogs and cats with chronic GIT disease 1 4 5 6 7. By methodically fulfilling the criteria for the clinical diagnosis of IBD (Table 2), the clinician may avoid expensive and invasive testing in addition to unnecessary long-term anti-inflammatory therapy 1.

Lymphosarcoma (LSA) is the most common hematopoietic neoplasia in cats and can occur in multiple anatomic locations, but the GIT is the most frequently affected site 8. ScLSA of the feline GIT is an emerging disease with a poorly understood but likely multifactorial pathogenesis. Risk factors may include chronic inflammation, Helicobacter infection, retroviruses (FeLV, FIV), and exposure to cigarette smoke 8 9 10 11. ScLSA and IBD are both characterized by infiltration of the GIT with small lymphocytes and have overlapping findings in history, physical exam, bloodwork, imaging and histopathology. In spite of the similarities, the course of the disease, treatment options and the prognosis are different for these two conditions, highlighting the importance for an accurate diagnosis (Table 3). 

Diagnostic biopsy dilemmas

Intestinal biopsy for histological evaluation is often recommended once a thorough diagnostic work-up and therapeutic trials fail to identify the cause of a chronic enteropathy. Although histologic evaluation is the test of choice for diagnosis of IBD or LSA, multiple factors can make this problematic. These factors include inadequate sample size, poor sample processing, segmental disease, the coexistence of ScLSA and inflammation in the same patient, the overlap in histologic features between the two entities, and differences of opinion among pathologists 1 3 5. The potential for progression of IBD to LSA further complicates the diagnosis 9.

Among the key challenges associated with GIT biopsy is the need to obtain tissue at the correct location and of adequate depth. The inability to assess architectural integrity of all tissue compartments in endoscopic biopsy specimens and the fact that some patients have segmental pathology have fueled the debate regarding the best method required (i.e., endoscopy or full-thickness surgical biopsy) to differentiate IBD from ScLSA 5.

A few studies supported the use of full-thickness biopsy by showing that LSA (unlike IBD) frequently infiltrates beyond the mucosa into the deeper layers, destroying normal tissue architecture 5. Furthermore, the common sites of feline intestinal LSA are the ileocecocolic junction and the jejunum, and neither site is routinely sampled at gastroduodenoscopy. A decade ago, a prospective study on 22 cats that underwent gastroduodenoscopy immediately prior to laparotomy or laparoscopic surgery concluded that endoscopic biopsies are inadequate for differentiating IBD from GIT LSA, and that full-thickness intestinal samples should be obtained for accurate diagnosis 2. However, the study had a serious limitation in that the endoscope could not traverse the pylorus in 8 cats, and therefore some duodenal samples were obtained blindly. It is likely that endoscopically obtained samples would have performed better if the duodenum had been successfully intubated.

The ACVIM* has stated that biopsy is not appropriate in every animal with chronic GIT disease, but where biopsy is indicated an endoscopic method is the preferred choice 1. This statement acknowledges the advantages of surgical biopsy, such as the ability to collect full-thickness samples and to observe and sample other abdominal organs. On the other hand, endoscopy permits the operator to see mucosal changes and direct biopsy acquisition at these locations (Figure 4) with collection of multiple tissue samples from various intestinal sites. Endoscopy also permits diagnosis of selected lesions (e.g., ulceration, erosion, lymphangiectasia). A large retrospective study on GIT samples collected from a total of 63 cats (50 surgical samples and 13 endoscopic samples) revealed clear evidence that both false negatives and positives are possible for the histopathological diagnosis of ScLSA even when evaluating full-thickness samples 5. One retrospective study revealed that standard gastroduodenoscopy resulted in misdiagnosis in 44% of the study population; for 8 of the 18 cats diagnosed with LSA, neoplastic cells were found in the ileal tissue alone, and the authors suggested performing both upper and lower GIT endoscopy to improve the accuracy of samples 14.

* American College of Veterinary Internal Medicine

IHC and PCR

Confirming a diagnosis of GIT ScLSA against IBD based on traditional histopathology can be challenging for the many reasons mentioned above. Multiple advanced diagnostic tests have been researched to help the pathologist reach an accurate diagnosis. Of these, IHC and PCR have gained the most attention 5 6 7 8 16.The detection of a clonal population of cells in a lesion represents an important criterion for the diagnosis of neoplasia. PCR is a methodology that can be used to detect clonality in lymphocytes. IHC assesses the phenotypic uniformity of a lymphocytic infiltrate, making it a useful adjunct to histopathology in further characterizing a lesion. Multiple studies showed that the sensitivity and specificity of IHC and PCR make them valuable adjunctive tools for accurately differentiating ScLSA from IBD, even from small amounts of tissue such as endoscopically obtained biopsies 5 6 7 8 16 (Figure 5) (Figure 6). In addition, immunophenotyping and clonality testing might be of prognostic value in cases of feline GIT LSA 15 16. 

One study looked at the impact of adding IHC and PCR results to the traditional histopathology for diagnosis of GIT LSA or IBD 5. The study cats were classified as either IBD (19 cases) or intestinal LSA (44 cases), based on routine histologic examination alone. When IHC and PCR results were used in conjunction with the histopathology, 10 of the original 19 IBD cases were reclassified as lymphoma and 3 of 44 ScLSA cases were reclassified as IBD. The study demonstrates that a significant number of cats with intestinal ScLSA or IBD are misdiagnosed when using traditional histopathology alone, even with surgical sampling. Based on the results, the author suggested a novel diagnostic approach utilizing a stepwise testing strategy; this involves initially evaluating intestinal biopsy specimens with a histomorphologic assessment, followed by IHC, and finally PCR. This systematic approach will likely decrease the likelihood of misdiagnosis, and help guide the clinician to formulate an appropriate therapy and more accurate prognosis.

IBD treament

Treatment for presumptive or diagnosed IBD includes dietary modification, cobalamin supplementation (when indicated), antimicrobials with immunomodulatory properties, and immunosuppressive therapy.

Dietary modification

The use of a highly digestible diet with a novel source of protein (e.g., rabbit, venison) or a hydrolyzed diet is recommended for cats with suspected or confirmed IBD. Clinical signs may improve within 4-8 days after dietary modification. Some studies have shown that diet trials can help improve clinical signs but that immunosuppressive therapy was necessary to sustain remission 17. If the patient is inappetent, an appetite stimulant (e.g., mirtazapine 1/8-1/4 of a 15 mg tablet per cat Q48-72 h or cyproheptadine 1-2 mg per cat Q12 h) may be necessary. Sometimes glucocorticoids may need to be started before a dietary change can be accomplished.

Probiotics and symbiotics

The efficacy of probiotics for adjunct treatment of feline IBD or ScLSA has not been established; however, studies in cats have shown that probiotics can improve the intestinal environment and immune system function 18. Once started, probiotics may need to be continued indefinitely, but selecting the best product is difficult due to a large variation in quality control among commercial products. Symbiotics contain prebiotic sugars (e.g., inulin, fructo-oligosaccharides) and probiotic bacteria, and a recent review article revealed that cats with chronic diarrhea had improved fecal scores after being fed a proprietary symbiotic for 21 days 19.

Cobalamin

Cobalamin (Vitamin B12) is a cofactor for normal nucleic acid synthesis and is absorbed by specific receptors in the ileum. Pathology in this area may result in hypocobalaminemia, and subcutaneous supplementation (Table 4) may result in improvement of clinical signs and optimal response to immunosuppressive therapy 12. Oral supplementation may be an alternative, but efficacy and dosing guidelines have not been established for cats. 

Immunosupressive therapy

Corticosteroids are the cornerstone of therapy for both IBD and ScLSA. In cats, prednisolone is preferred over prednisone due to its higher bioavailability. Several tapering regimens are available for the treatment of IBD (Table 4), with the goal of achieving the lowest effective dose that keeps the patient free from clinical signs. Rarely, prednisolone can be discontinued and the patient maintained on a novel diet and possibly an antimicrobial (e.g., metronidazole). Flavored additives of animal origin should be avoided if a compounded form of prednisolone is used, as they may interfere with disease remission.

Individual cats can vary in their response to prednisolone, and if therapy is ineffective the clinician should consider using a different type of corticosteroid (e.g., dexamethasone or methylprednisolone), although drawbacks with the latter include unpredictable bioavailability and development of diabetes mellitus. Budesonide is an orally administered glucocorticoid that has a high first-pass removal from the liver, potentially causing fewer systemic side effects; its efficacy in cats with IBD has not been established, but empirical dosages of 0.5-0.75 mg Q24 h per cat have been suggested 20.

Some clinicians reserve the use of chlorambucil in conjunction with steroids for patients with severe or relapsing IBD 21. Usually, it is given every 48-72 hours depending on the patient’s weight (Table 4) 20. Initially, a CBC should be monitored every 2-4 weeks for declining neutrophil or platelet counts, which can indicate bone marrow toxicity.

Cyclosporine has been used anecdotally to treat IBD in cats with some success at a dose of 5 mg/kg once to twice daily 20. Side effects may include vomiting, diarrhea and anorexia, which may require a change in dose or frequency. Hepatopathies, urinary tract infections and recrudescence of dormant toxoplasmosis can also occur. Azathioprine is not generally recommended in cats due to reports of severe bone marrow suppression and idiosyncratic fatal leukopenia and thrombocytopenia 23.

Antimicrobioals

Metronidazole can be used as a sole agent in patients with mild inflammation, or in conjunction with a glucocorticoid. Neurotoxicity (disorientation, ataxia, seizures, blindness) is the main adverse effect and is usually reversible upon discontinuation of the drug 20.

ScLSA treatment

The optimal diet for cats with ScLSA should be similar to those with IBD (e.g., highly digestible nutrients, with single ingredients if possible), with an appetite stimulant if appropriate. Prednisolone is commonly started at an immunosuppressive dose and then tapered to every other day once remission has been achieved. Chlorambucil is used with a corticosteroid at the start of therapy, typically either continuously (e.g., Q48-72 h) or as a bolus (20 mg/ m² PO every 2-3 weeks) 24; the duration of clinical remission appears similar with either protocol. Again, CBCs should be monitored and the drug discontinued if segmented neutrophil and platelet counts are persistently below 1,500 and/or 75,000 cells/µL, respectively 25. If a cat fails or no longer responds to glucocorticoidchlorambucil therapy, rescue protocols (e.g., cyclophosphamide) may be attempted 24.

Prognosis

The prognosis for cats with small cell lymphoma can be favorable, with some reporting a 92% response rate for a median of > 2.5 years 26. Feline IBD can be well managed with a combination of dietary modification and immunosuppression; however, the client must be informed that the objective of treatment is to improve clinical signs and that a cure is unlikely. A guarded prognosis may be warranted for severely debilitated patients or those with major histologic gastrointestinal lesions, eosinophilic enteritis or hypereosinophilic syndrome 27. In IBD cases, refractory to treatment, the clinician should question the client’s compliance with therapy (e.g., was the diet changed or the medication administered?), presence of comorbidites (e.g., pancreatitis, cholangitis) and the accuracy of the original diagnosis 27. In the latter case, the clinician should discuss collecting gastrointestinal biopsies for histologic assessment and immunohistochemistry/PCR for antigen receptor rearrangement as necessary 5.