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Chronic Enteropathies: How Should I Treat Them?

ACVIM 2003

Kenneth W. Simpson, BVM&S, PhD, MRCVS, DipACVIM, DipECVIMIthaca, NY

IDIOPATHIC INFLAMMATORY BOWEL DISEASE

Idiopathic inflammatory bowel disease is the term used to describe a diverse group of intestinal disorders which are characterised by cellular infiltrates of the intestinal mucosa. Diagnosis

is based on the description of histological findings in intestinal biopsies and the exclusion of known causes of intestinal inflammation e.g., endoparasites, dietary sensitivity. The mostcommon inflammatory infiltrates are lymphocytes and plasma cells or eosinophils. Neutrophils or granulomatous inflammation are encountered less commonly.

Lymphoplasmacytic enteritis

Lymphoplasmacytic enteritis is the most common type of inflammatory bowel disease in dogs and cats. It is characterised by the accumulation of excessive numbers of lymphocytes andplasma cells in the lamina propria of the intestine. The degree of cellular accumulation is variable and is subjectively categorised as mild, moderate and severe. Moderate to severe

lymphoplasmacytic enteritis is often associated with a protein losing enteropathy. A severe form of the condition has been reported in Basenjis. The extent of inflammation appearsvariable and ranges from the duodenum to the small and large bowel.

C l in i c a l f i n d i n g s

Chronic small bowel diarrhea accompanied by weight loss or vomiting are the most frequent findings in dogs whereas vomiting is the most common clinical sign in cats. Vomitus oftencontains bile. Hairballs are frequent in cats. Other findings include changes in appetite, excessive borborygmi and abdominal discomfort. The severity of disease is variable, ranging fromintermittent diarrhoea and vomiting in mild cases to intractable small bowel diarrhea, inappetance and weight loss in severe ones. The severity of the disease is thought to reflect thedegree of cellular infiltrate. Physical findings range from normal to thickened intestines mesenteric lymphadenopathy, marked weight loss, and ascites or oedema in animals with severeprotein losing enteropathy.

D i a g n o s i s

A diagnosis of idiopathic lymphoplasmacytic enteritis is made by excluding systemic, parasitic, infectious, pancreatic and structural causes of chronic diarrhea and demonstrating excessive

numbers of lymphocytes and plasma cells in intestinal biopsies.

T r e a t m e n t

Treatment of IBD is usually based on dietary modification, antibiotics and immunosuppression. Treatment is to some extent based on the severity of the disease. Mild to moderateintestinal inflammation may be associated with dietary sensitivity or intolerance, or potentially idiopathic small intestinal bacterial overgrowth. A therapeutic dietary trial can be performedwith either: 1) a highly digestible diet which is restricted in fat and gluten-free, 2) a diet limited to a single novel protein source or 3) a diet containing protein hydrolysate, to determine ifdietary sensitivity or intolerance are present. A response is usually observed within 2 wks. Similarly a therapeutic trial (21days) with Tylosin (10mg/kg PO TID), metronidazole (15mg/kg

PO BID) or oxytetracycline (10-20mg/kg PO TID) for antibiotic responsive enteropathy /small intestinal bacterial overgrowth may be warranted. In patients who fail these trials and inthose with moderate to severe infiltrates, or hypoproteinaemia the administration of immunosuppressive agents is usually required to achieve a response. Oral prednisolone (1-2mg/kg POBID) is the initial drug of choice. It is usually administered at an immunosuppressive dose for 2-3 wks and then decreased by 50% every 2-3wks, and then continued on an alternate daybasis for 2-3 months. If clinical response is poor or the adverse effects of prednisolone predominate azathioprine can be added to the regimen. In dogs it is usually given every day(2mg/kg PO SID) for five days and then on alternate days to prednisolone. Cats are more sensitive to azathioprine (0.3mg/kg PO SID) and may be better managed with chlorambucil

(6mg/m2 PO PO EOD (@2mg/5.3kg cat) and prednisone (5mg PO /cat/day). Supplemental cobalamin (1ml SC q 2-3wks) and folate / B complex vitamins should also be given if serumconcentrations are low. Metronidazole (15mg/kg PO BID 10-14d then SID 10-14d) can also be used in conjunction with corticosteroids and has effects on bacteria and possibly the immunesystem. Successful treatment is accompanied by a decrease in clinical signs and an increase in plasma proteins. Once a patient has had 2-3 months remission from signs it may be

possible to gradually withdraw immunosuppressive therapy. If signs recur daily medication i s continued until signs resolve then gradually reduced. In patients who respond poorly totherapy or relapse after an initial response lymphoma should be ruled out.

P r o g n o s i s

The prognosis for lymphoplasmacytic enteritis is variable and depends on its severity. Many patients require prolonged treatment with glucocorticoids and diet. As no accurate criteria existfor predicting response it is wise to give a guarded prognosis.

Eosinophilic enteritis

Eosinophilic enteritis is characterised by the excessive accumulation of eosinophils in the lamina propria. It is speculated that it may result from an immunologic reaction to parasites ordiet. the disease may also involve other areas of the gastrointestinal tract.

C l in i c a l f i n d i n g s

Chronic small bowel diarrhoea accompanied by vomiting or weight loss are the principal clinical signs. Large bowel signs or vomiting predominate in some cases. Physical findings range

from normal to focally or diffusely thickened intestines and marked weight loss.

D i a g n o s i s

Intestinal biopsy. Clinicopathologic abnormalities may include peripheral eosinophilia. Mast cell neoplasms, hypoadrenocorticism and endoparasites can produce a similar spectrum ofclinical signs and should be ruled out. The degree of eosinophilia can be extreme in cats and may be associated with eosinophilic infiltrates in the spleen, liver, lymph nodes and bonemarrow. Intestinal protein loss is less common than lymphoplasmacytic enteritis.

T r e a t m e n t

Some patients may respond to a strict exclusion diet, though prednisolone (2mg/kg PO SID) is usually required. In dogs signs usually resolve within a couple of weeks and prednisolone

can be tapered. Feeding an easily digestible diet that is restricted to a single novel protein source or is hydrolyzed may help to maintain clinical remission. Prophylactic administration of ananthelminthic such as fenbendazole (50mg/kg PO SID 3 days) is warranted to treat potential visceral larval migrans which has been associated with eosinophilic gastroenteritis. Cats withhypereosinophilic syndrome often respond very poorly to treatment with immunosuppressive agents, diet and anthelminthics.

P r o g n o s i s

The prognosis is guarded as relapse is common. The prognosis in cats with hypereosinophilic syndrome is poor.

OTHERINFLAMMATORYENTEROPATHIES

Other enteropathies which are characterised by neutrophilic or granulomatous inflammation have also been described infrequently small animals. Some of these may be associated withbacterial infections such as Streptococcus, Campylobacter, Yersinia and Mycobacteria and fungal infections such as Histoplasma. Special stains and culture of mucosal biopsies and

intestinal lymph nodes and other abdominal organs should be undertaken in cases of granulomatous enteritis to detect infectious organisms. Serology, chest radiographs and bone marrowbiopsies may help to diagnose systemic fungal disease. The prognosis for idiopathic granulomatous or neutrophilic enteropathies is guarded to poor.

GI Lymphoma

Lymphosarcoma (LSA) is characterised by the mucosal and sub-mucosal infiltration of neoplastic lymphocytes which cause malabsorption. Focal forms of lymphosarcoma may causeobstruction. The tumor is often thought to be related to feline leukemia virus in cats though cats with GI lymphoma are usually FeLV negative, and is of unknown etiology in dogs. In catsLSA has been classified as lymphocytic or lymphoblastic, with the lymphocytic form responding well to chemotherapy. In some animals lymphoplasmacytic enteritis may progress to LSA.

C l in i c a l f i n d i n g s

Weight loss, chronic small bowel diarrhea and progressive inappetance are common features of intestinal LSA. Vomiting may also be noted. Physical examination may reveal diffuselythickened or nodular intestines mesenteric lymphadenopathy. Acute abdominal pain and shock may be present if intestinal perforation has occurred. Hepatosplenomegaly andgeneralised lymphadenopathy are less frequently detected. Signs of hypoproteinemia may be evident.

D i a g n o s i s

Middle aged or older dogs and cats are most commonly affected. Routine biochemistry often reveals a protein losing enteropathy in dogs with LSA. Anaemia which is either normocytic

normochromic non-regenerative or microcytic and hypochromic, and neutrophilia may also be present. Ultrasound is useful for evaluating intestinal thickness and detecting mesentericlymphadenopathy. Diagnosis can be made by demonstrating neoplastic lymphocytes in aspirates or biopsies from enlarged intestinal or peripheral lymph nodes, but is more often made byintestinal biopsy. Endoscopic biopsies may miss the lesion or show lymphoplasmacytic enteritis. Serum concentrations of cobalamin are often very low in cats with GI lymphoma and serum

folate concentrations may also be reduced.

T r e a t m e n t a n d p r o g n o s i s

Dogs respond poorly to therapy. Cats with lymphocytic lymphoma may show a dramatic and lasting response (av. 17-20 mo.) to treatment with chlorambucil (6mg/m2 PO PO EOD

(@2mg/5.3kg cat) and prednisone (5mg PO /cat/day). Supplemental cobalamin (1ml SC q 2-3wks) and folate / B complex vitamins should also be given. Lymphoblastic lymphoma is muchless responsive.

Lymphangiectasia

Intestinal lymphangiectasia is characterised by the abnormal distension of lymphatic vessels within the mucosa. Lymphangiectasia is a consequence of a localised or generalised lymphatic

abnormality or increased portal pressure e.g., right-sided heart failure, caval obstruction or hepatic disease. Lymphatic abnormalities are often associated with lipogranulomatousinflammation which is visible as small white granules on the intestinal mesentery. Tumour infiltration of lymphatics or lymph nodes can also cause lymphangiectasia. In some caseslymphangiography reveals a generalised lymphatic abnormality. Dilatation of lymphatics is assoc iated with the exudation of protein rich lymph into the intestine and severe malabsorption

of long chain fats. Yorkshire Terriers and Soft Coated Wheaten Terriers and the Lundehound seem to be over represented, suggesting a possible familial cause in some dogs.

C l in i c a l f i n d i n g s

Intestinal lymphangiectasia is fairly common in dogs, but rare in cats. The clinical findings are essentially a consequence of the intestinal loss of protein and range from weight loss tochronic diarrhoea, ascites, oedema and chylothorax.

D i a g n o s i s

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Usually presents as a protein losing enteropathy, Endoscopic appearance of white blebs on the mucosa- dilated lymphatics, endoscopic biopsies are often adequate. Surgical biopsy should

be undertaken carefully with appropriate precautionary measures for dehiscence.

T r e a t m e n t

The cause of lymphangiectasia is usually not determined. Treatment is usually supportive and symptomatic. Dietary recommendations are the similar to those for other causes of small

bowel diarrhoea, but fat restriction may have to be more severe. Medium chain triglyceride (MCT oil, coconut oil 0.5-2ml/kg body weight per day added to food) can be added to the dietto provide an easily assimilable source of calories. Prednisolone is often necessary (1-2mg/kg PO BID) and may work by decreasing lipogranulomatous inflammation. Prednisolone istapered to the lowest effective dose once remission is achieved. Adjunct therapy with metronidazole or tylosin can also be given.

P r o g n o s i s

The response to therapy is variable with some patients staying in remission for several years while others pursue a path towards fulminant hypoproteinaemia. The prognosis is alwaysguarded.

SMALL INTESTINAL BACTERIAL OVERGROWTH / ANTIBIOTIC RESPONSIVE ENTEROPATHY

Small intestinal bacterial overgrowth (SIBO) = an abnormal accumulation of bacteria in the small bowel.

T h e i n t e s t i n a l f lo r a o f h e a l t h y d o g s a n d c a t s

Humans have total bacterial counts less than 5 (log10 cfu/ml or gram) small intestinal juice/tissue and anaerobic bacterial counts less than 4 5 (log10 cfu/ml or gram). Gram positiveaerobic bacteria such as Streptococci and Staphylococci predominate; anaerobic bacteria such as Clostridia and Bactericides are extremely uncommon.

Those findings in humans are not applicable to healthy dogs and cats.

At least 24 papers have been published which describe the small intestinal bacterial flora of healthy dogs or cats. The majority of studies indicate that both the healthy dog and cat

harbor a large number of diverse bacteria in the small intestine. The total bacterial counts in the proximal small intestine of healthy dogs ranges from 0-9.43 (log10 cfu/ml or gram) andanaerobes from 0 to 8.18 (log10 cfu/ml or gram). Similarly cats have total duodenal bacterial counts ranging from 2 to 8.3 (log10 cfu/ml or gram), and anaerobic bacteria from 2 to 8.05(log10cfu/ml). Common aerobic bacterial species in dogs and cats include Streptococcusspecies, Staphylococcusspp, Bacillusspp,Escherichia coli, Corynebacterium spp, Enterobactercloacea, Pseudomonasspp, and Pasturella multocida. Clostridiumspp, Bifidobacteriumspp, Eubacteriumspp and Bacteroidesspp are common anaerobes. Lactobacillusspp, are alsocommon.

S I BO i n d o g s a n d c a t s

The syndrome of small intestinal bacterial overgrowth has been used to describe patients with signs such as diarrhea and weight loss that are associated with a gastrointestinal abnormality

which is considered to cause small intestinal bacterial proliferation. It has also been applied to patients with similar clinical signs without an obvious cause for bacterial proliferation thatrespond to antibiotics.

The literature on the normal flora of dogs and cats indicates that SIBO can be defined as: bacterial counts > 9.43 (log10 cfu/ml or gram) in dogs, > 8.3 (log10 cfu/ml or gram) in cats

OR anaerobic bacterial counts > 8.18 (log10cfu/ml or gram) in dogs, > 8.05 (log10 cfu/ml or gram) in cats. Interestingly a disease, which fulfills those criteria, has yet to be described inthe dog and cat.

D i s e a se s o t h e r t h a n SI BO w h i c h m a y i m p r o v e w i t h a n t i b i o t i c t h e r a p y

I. Occult pathogens: Giardia, coccidia, Salmonella, Campylobacter, enteropathogenic E. Coli?

II. Unknown pathogens e.g., Helicobacterspp.

III. Increased host susceptibility to endogenous flora:

1. Breakdown of immune tolerance to indigenous microflora: Conventionally reared IL-10 knockout mice develop IBD whereasgerm free mice, do not. A similar loss of tolerance toa normal bacterial flora, or increased susceptibility to the potentially harmful effects of abnormal flora may also explain why Basenji dogs with immunoproliferative smallintestinal disease respond to antibiotic therapy.

2. Increased susceptibility to endogenous flora arising from mucosal IgA deficiency could explain the antibiotic responsive chronic diarrhea in GSD.

3. Altered balance between damage and repair: Decreased synthesis of mucosal enzymes in the face of increased degradation e.g., EPI

D o e s i d i o p a t h i c SI BO o c c u r i n d o g s a n d c a t s ?

In 1983 Batt et al. described small intestinal bacterial overgrowth in German Shepherd dogs which had no obvious underlying cause of SIBO. This study compared bacterial counts fromGerman Shepherd dogs with diarrhea, with those obtained in six healthy dogs. Those investigators proposed that SIBO was present based on the presence of >5 (log10 cfu/ml) of bacteriain dogs with diarrhea. Unfortunately the intestinal fluid aspirated from the dogs was variably diluted or frozen before culture. The abnormal clinical signs and the associated intestinalmucosal changes in affected dogs were responsive to antibiotic therapy, suggesting that the bacterial flora was an important cause of the diarrhea. However, whether the clinical signs

were caused by excessive numbers of bacteria or an enteropathy which renders the intestine more susceptible to damage by a normal flora, is unresolved.

Subsequent investigators have used the cut-off value described by Batt et al., despite clear evidence indicating higher bacterial numbers in healthy dogs and cats.

Further confusion over the reality of idiopathic SIBO in dogs was caused by a report which described a group of healthy GSD with duodenal bacterial counts >5 (log10 cfu/ml) as having

SIBO.The authors explicitly stated that 'All dogs appeared clinically normal" and '...one would not expect that these dogs had alimentary tract disease by observing or working with them.'The lack of clinical signs in these dogs is in stark contrast to the syndrome of SIBO in humans, experimental animals, and the GSD originally described by Batt et al. that was characterizedby diarrhea, weight loss and altered concentrations of cobalamin and folate. The authors refuted the suggestion that they had cultured intestinal fluid from healthy dogs. More recently in a

study of 107 dogs, 52 were diagnosed as having idiopathic SIBO (intestinal bacteria greater than >5 (log10 cfu/ml)) and no identifiable underlying cause. Such a high prevalence ofidiopathic SIBO serves to further question the validity of the 5 (log10 cfu/ml) cut-off vale for the diagnosis of SIBO.

T r e a t m e n t

Treatment of suspected SIBO is directed at correcting underlying anatomic or structural abnormalities, treating EPI, and controlling the abnormal flora with antibiotics. Suitable antibioticsinclude oxytetracycline (20mg/kg TID PO), tylosin (10mg/kg TID PO), or metronidazole (15 mg/kg BID PO). In dogs with idiopathic SIBO/ intolerance antibiotic therapy is usually given for28 days. Dietary modification also appears to be important and anecdotal evidence supports the use of highly digestible, low fat diets.

P r o g n o s i s

Many animals with undefined antibiotic responsive enteropathies relapse when antibiotics are stopped and require further courses, or long term maintenance therapy Prognosis forsecondary SIBO depends on the underlying disease.

SPEAKERINFORMATION(click the speaker's name to view other papers and abstracts submitted by this speaker)

Kenneth W. Sim pson, B VM&S, PhD, MRCVS, DipACVIM, DipECVIM-CA

Clinical Sciences, NYS, CVMCornell UniversityVMC 2001Ithaca, NY 14853

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