Elevated canine pancreatic lipase immunoreactivity concentration in dogs with inflammatory bowel dis

PAPER

Elevated canine pancreatic lipase immunoreactivity concentration in dogs with inflammatory bowel disease is associated with a negative outcome OBJECTIVES: To investigate whether elevated canine pancreatic lipase immunoreactivity (CPLI) concentrations in dogs with inflammatory bowel disease (IBD) is associated with a worse clinical outcome.

METHODS: Serum CPLI assays were performed on serum stored from

A. KATHRANI, J. M. STEINER*, J. SUCHODOLSKI*, J. EASTWOOD, H. SYME, O. A. GARDENy AND K. ALLENSPACH Journal of Small Animal Practice (2009) 50, 126–132 DOI: 10.1111/j.1748-5827.2008.00693.x

cases diagnosed with IBD. Thirty-two dogs with CPLI results within the reference range were designated as the control group and 15 dogs had CPLI above the reference range. Clinical signs, age, serum lipase and amylase activities, serum albumin and cobalamin concentrations, abdominal ultrasound examination, histopathology on small intestinal biopsies, management of IBD and outcome were compared between the two groups.

RESULTS: No significant differences were found in clinical activity score (P50 54), number of antibiotic-responsive disease cases

(P50 480), number of steroid-responsive disease cases (P50 491),

serum amylase activity (P50 058), serum cobalamin concentration

(P50 61), serum albumin concentration (P50 052), abdominal

ultrasound score (P50 23) and histopathology scores for IBD

(P50 74) between the two groups. Dogs with increased CPLI

concentration were significantly older and had a higher serum lipase activity than dogs with a CPLI concentration within the normal reference range (P50 001, P50 001, respectively). Moreover, dogs

with increased CPLI concentration responded poorly to steroid treatment (P50 01) and were significantly more likely to be

euthanased at follow-up (P50 02).

CLINICAL SIGNIFICANCE: CPLI should be measured in cases of canine IBD as elevated CPLI was associated with a worse outcome.

Department of Veterinary Clinical Sciences, Royal Veterinary College, University of London, London AL9 7TA *The Gastrointestinal Laboratory, Department of Small Animal Clinical Science, College of Veterinary Medicine, Texas A&M University, College Station, TX 77843-4474, USA yRegulatory T Cell Laboratory, Infection and Immunity Research Group, Royal Veterinary College, University of London, London AL9 7TA This study was in part presented at the ACVIM Forum 2007 in Seattle, USA

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INTRODUCTION Inflammatory bowel disease (IBD)-associated chronic pancreatitis (CP) has been described in people (Barthet and others 2006), although clinical symptoms of IBD-CP are only reported in approximately 2 per cent of patients. However, the actual frequency of this condition could be much higher because hyperamylasemia and exocrine pancreatic insufficiency (EPI) are found in 6 to 16 per cent and 21 to 80 per cent of IBD patients, respectively, and histological changes are observed in 38 to 53 per cent of post-mortem pathological examinations in these patients (Ball and others 1950, Chapin and others 1956, Angelini and others 1988, Katz and others 1988, Hegnhoj and others 1990, Tromm and others 1991, Heikius and others 1996). Therefore, it appears that IBD-CP in people could occur as a clinically silent but significant disease. To the authors’ knowledge, no long-term follow-up study has been conducted to ascertain whether IBD-CP in people is associated with a different outcome.

IBD-CP has not been reported in dogs, but CP may have been generally underrecognised in dogs as studies have suggested that it may be more common than traditionally thought (Newman and others 2006, Watson and others 2007). One study reviewed histology of the pancreas in more than 100 dogs presenting for post-mortem examinationforavarietyofreasons(Newman and others 2006). This study found that only 8 per cent of these pancreata were normal, while 52 5 per cent had lymphocyticplasmacytic infiltrates and 49 5 per cent had pancreatic fibrosis, changes which are consistent with chronic inflammation.

Another recent study examined 200 dogs post-mortem and found the prevalence of CP to be 34 per cent omitting the autolysed cases (Watson and others 2007). This data suggest that up to half of all dogs euthanased for any reason might have a degree of CP. Diagnosing pancreatitis, especially CP is very challenging in dogs. Clinical signs are non-specific and easily confused with those of IBD. Elevated serum amylase and lipase activities occur in non-pancreatic conditions and have a relatively low specificity and sensitivity for pancreatitis (Hess Journal of Small Animal Practice

and others 1998). Abdominal radiographs are subjective and non-specific for canine pancreatitis (Steiner 2003). The sensitivity of abdominal ultrasound for diagnosing pancreatitis is highly operator dependent and reported to be up to 68 per cent in dogs (Steiner 2003). Pancreatic biopsy remains the gold standard for diagnosing pancreatitis. Multiple biopsies may need to be taken as studies have shown that focal inflammation can easily be missed if only one site is used (Newman and others 2004). Although canine trypsin-like immunoreactivity is the test of choice for canine EPI, the sensitivity of this test for pancreatitis is poor at less than 40 per cent (Steiner and others 2001).

Recently, a commercial assay for canine pancreatic lipase immunoreactivity (cPLI) concentration has been validated for use in dogs. Serum cPLI concentration is highly specific for exocrine pancreatic function.

Steiner and others (2001) reported a sensitivity of 81 8 per cent using serum cPLI to diagnose pancreatitis in dogs. The current study used cPLI concentrations in a population of dogs with IBD to assess the possibility of IBD-associated pancreatitis being present.

The aims of this study were to investigate the prevalence of elevated serum cPLI concentrations in dogs with IBD and to evaluate the clinical characteristics of dogs with IBD and a high cPLI serum concentration.

MATERIALS AND METHODS This study was conducted at the Queen Mother Hospital for Animals, Department of Veterinary Clinical Sciences, Royal Veterinary College, University of London.

Forty-seven dogs with complete diagnostic work-up and histologically confirmed IBD were enrolled retrospectively into the study. Serum collected and stored during the initial diagnostic investigation before treatment was used for the cPLI assay (Spec cPLä; Gastrointestinal Laboratory, Texas A&M University). According to the cPLI results, dogs were then classified into two groups; those dogs with serum cPLI concentrations above the upper limit of the reference range of 200 lg/l and those with cPLI concentrations less than 200 lg/l.

For all cases, the diagnostic work-up was reviewed. All cases had complete medical

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records consisting of a detailed history at first examination and at subsequent re-examinations, haematology and biochemistry results, detailed ultrasound report and detailed histopathology reports. All known causes of gastrointestinal inflammation were ruled out by routine haematology and biochemistry, faecal analysis, ultrasound and measurement of serum trypsin-like immunoreactivity concentration. Definitive diagnosis of IBD was based on histological evidence of an inflammatory infiltrate within the lamina propria of endoscopically obtained small intestinal biopsies. The response to treatment was used to further categorise the IBD as food-responsive diarrhoea (FRD), antibiotic-responsivediarrhoea(ARD)orsteroid-responsive diarrhoea (SRD). Comparisons were made of the following parameters between the two groups: clinical signs, age, serum lipase and amylase activities, serum albumin and cobalamin concentrations, abdominal ultrasound findings, histopathological findings on endoscopic intestinal biopsies, response to treatment and clinical outcome.

Canine chronic enteropathy activity index All dogs were assigned a clinical score using the canine chronic enteropathy activity index (CCECAI) (Allenspach and others 2007). This index is based on nine criteria: attitude/activity, appetite, vomiting, stool consistency, stool frequency, weight loss, serum albumin concentration, ascites and peripheral oedema and pruritus. The total composite score for all criteria was determined to be clinically insignificant (score 0 to 3), mild (score 4 to 5), moderate (score 6 to 8), severe (score 9 to 11) or very severe (.12).

Abdominal ultrasound Abdominal ultrasound findings were scored as 0 if unremarkable and 1 if findings were consistent with pancreatitis.

Ultrasound findings that could be consistent with IBD were not scored.

Histopathology of intestinal endoscopic biopsies Histopathology scores for the small intestinal biopsies were based on a previously published scoring system (Jergens and others 1992): a score of 1 was given if mild 127

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inflammatory infiltrates and microarchitectural changes were present, a score of 1 5 if a mild to moderate inflammatory infiltrate and microarchitectural changes were present, a score of 2 if a moderate inflammatory infiltrate and microarchitectural changes were present, a score of 2 5 if a moderate to severe inflammatory infiltrate and microarchitectural changes were present and a score of 3 if severe inflammatory infiltrates and microarchitectural changes were present. Although in some cases, colonic biopsies were taken in addition to small intestinal biopsies, these were not scored as the predominant clinical signs were related to the small intestine.

Treatment for IBD Treatment was tailored for individual animals depending on the response to treatment received before referral and the extent of clinical signs at the time of presentation.

For those dogs where multiple treatments had failed or for dogs presented with severe clinical signs, corticosteroid treatment was initiated after diagnosis. Dogs that had received minimal treatment before referral and where clinical signs were mild to moderate were treated in a sequential manner with diet, antibiotics and corticosteroids.

Based on the long-term response to treatment, IBD dogs were further classified as FRD, ARD or SRD. FRD cases were defined as those with a good clinical response to a novel protein or hypoallergenic diet for a period of at least three months. Cases that failed to respond to a six week diet trial were subsequently treated with 10 to 20 mg/kg metronidazole twice a day or 20 mg/kg amoxicillinclavulanic acid twice a day for a period of at least three weeks. Dogs where clinical signs resolved with antibiotic treatment were defined as ARD. Dogs that failed to respond to diet followed by antibiotic treatment were then treated with starting dose of 1 to 2 mg/kg prednisolone twice a day and were designated as SRD. Follow-up Follow-up information was available for all 47 dogs for a period ranging from three to 18 months after IBD was diagnosed.

Approximately 50 per cent of the followup data were based on re-examinations at the investigating centre, approximately 128

35 per cent from either written or telephone communications with the referring veterinarian and the remainder from telephone communications with the owner.

Follow-up scores were assigned categorically into three groups as follows: good response to treatment based on resolution of clinical signs, poor response to steroid treatment requiring ciclosporin to control clinical signs and euthanasia. The reason for euthanasia in all cases was worsening clinical signs despite steroid treatment.

The minimum duration of follow-up was three months as those cases responding to dietary management alone with complete resolution of clinical signs at that point were considered to have foodresponsive diarrhoea (FRD) and further follow-up was not indicated.

Statistical analysis Normally distributed data are reported as means 6 sd. The Kolmogorov-Smirnoff test was used to assess normality. Data that were not normally distributed are reported as medians (ranges) unless otherwise indicated. Fisher’s exact tests were used to determine associations between categorical variables. Student’s t tests were used to compare normally distributed numerical values and Wilcoxon signed rank tests were used to compare numerical values in case they were not normally distributed. Logistic regression models with one predictor were used to evaluate differences between the two groups of dogs. Cross-tabulations were performed using a Fisher’s exact or chi-squared test. Correlations were evaluated with the Spearman rank correlation test. Odds ratios were determined using logistic regression models with a single predictor. Multi-variate logistic regression analysis for predicting negative outcome was performed for risk factors identified by univariate logistic regression analysis.

Statistical significance was set at P,0 05.

All statistical tests were carried out using SPSS 15.0 for windows.

RESULTS Serum cPLI concentration Fifteen dogs had high serum cPLI concentrations (mean 427 lg/l, sd 240, range Journal of Small Animal Practice

206 4 to 1001 lg/l, laboratory reference range ,200 lg/l, see Fig 1), while 32 dogs had serum cPLI concentrations within the reference range (mean 53 lg/l, sd 9 8, range 13 to 200 lg/l).

Age Dogs with a high cPLI concentration were found to be significantly older (mean 6 sd: 97 3 6 39 3 months) than dogs with normal cPLI (mean 6 sd: 60 9 6 38 6 months, P=0 001).

Canine chronic enteropathy activity index The median CCECAI of dogs in the high cPLI group (median: 7, range: 2 to 17) was not significantly different when compared with that for dogs in the normal cPLI group (median: 7, range: 3 to 15, P=0 5).

Serum lipase and amylase concentration There was a statistically significant difference between the two groups for serum lipase activity: high cPLI group (mean 6 sd: 849 0 6 1087 58 U/l), normal cPLI group (mean 6 sd: 286 42 6 332 63 U/l, P=0 001, reference range 72 to 1015 U/l).

Three dogs in the high cPLI group (1638, 2000 and 4245 U/l), but only one dog in the normal cPLI group (1782 U/l) had increased serum lipase activities.

There was no statistically significant difference in serum amylase activity between the two groups (high cPLI group, mean 6 sd: 1058 93 6 423 14 U/l; normal cPLI group, mean 6 sd: 812 35 6 466 94 U/l, P=0 058, reference range 176 to 1245 U/l).

Serum albumin and cobalamin concentration There was no statistically significant difference in mean serum albumin or cobalamin concentrations between the two groups (mean 6 sd albumin concentrations: high cPLI group 27 6 9 g/l, normal cPLI group 31 6 6 g/l, P=0 052, reference range 28 to 39 g/l; mean 6 sd cobalamin concentrations: high cPLI group 420 8 6 326 9 ng/ml, normal cPLI group 460 9 6 311 94 ng/ml, P=0 61, reference range .200 ng/ml).

Six dogs in the high cPLI group had decreased serum albumin concentrations

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(10, 14, 16, 20, 22 and 27 g/l) and six dogs in the normal cPLI group had a decreased serum albumin concentration (13, 16, 17, 23, 24 and 26 g/l). Two dogs in the high cPLI group (177 and 127 ng/ml) and three dogs in the normal cPLI group (165, 109 and 177 ng/ml) had decreased serum cobalamin concentrations.

Abdominal ultrasound scoring The proportion of dogs showing abnormal ultrasonographic findings in the pancreas was not significantly different between the two groups (P=0 23). Three dogs in the high cPLI group had pancreatic changes on ultrasound (hyperechoic appearance to right limb of pancreas, hyperechoic pancreas and body of pancreas mildly thickened with mixed echogenicity, whereas right and left limbs of pancreas appeared normal). No dogs in the normal cPLI group had evidence of pancreatic changes on ultrasound. Two dogs in the high cPLI group and two dogs in the normal cPLI group had ultrasonographic evidence of thickened intestines, which was felt to be consistent with IBD.

Histological scoring There was no statistically significant difference in the median histopathology scores between the two groups (high cPLI group: median 2, range 1 to 3; normal cPLI group: median 2, range 1 to 3, P=0 74).

Treatment scoring In the high cPLI group, four dogs had FRD, three dogs had ARD and eight dogs had SRD. In the normal cPLI group, 16 dogs had FRD, five dogs had ARD and 11 dogs had SRD (Fig 2). There was a significantly greater number of FRD cases in the normal cPLI group (P=0 007). There was no statistically significant difference in the number of ARD cases between the two groups (P=0 480). In addition, there was no statistically significant difference in the frequency of steroid treatment between the two groups (P=0 491).

Follow-up scoring Four out of 15 dogs with IBD and high serum cPLI concentration were euthanased, but only one out of the 32 dogs with IBD

Serum cPLI concentrations 1200

900

600

300

0

High cPLI group

Normal cPLI group

FIG 1. Box and whisker plots representing mean serum canine pancreatic lipase immunoreactivity (cPLI) concentration between a group of 15 dogs with high cPLI concentration and a group of 32 dogs with normal cPLI concentration. The central line in the box represents the median and the top and bottom of the box represent the 75th and 25th percentiles, respectively, and the whiskers represent the 95th and 5th percentiles. Outlying data points are represented by open circles. Mean 6 sd cPLI concentration in the high cPLI group: 427 6 240 mg/l, mean 6 sd cPLI concentration in normal cPLI group: 53 6 9 8 mg/l, reference range less than 200 mg/l Journal of Small Animal Practice

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and normal serum cPLI concentration was euthanased, which was statistically significant (P=0 02). All dogs that were euthanased in the two groups had SRD. A statistically significant number of dogs with SRD and high cPLI had poor response to treatment requiring the addition of ciclosporin to control clinical signs (three dogs) compared with those SRD cases with normal cPLI concentration (one dog) (P=0 01) (Fig 3).

Multi-variate logistic regression analysis Multi-variate logistic regression analysis for predicting survival identified high cPLI concentration as the only parameter, which significantly affected survival in dogs with IBD (P=0 027, see Table 1).

DISCUSSION In this study, 15 out of 47 dogs with confirmed IBD had increased serum cPLI concentrations. Although this could be suggestive of IBD-associated pancreatitis, this presumptive diagnosis is based on a single laboratory parameter. Although histopathology of the pancreas remains the gold standard for the diagnosis of pancreatitis, unfortunately, none of the cases included in this study had pancreatic biopsy to confirm this diagnosis. However, in a previous study, it was shown that in healthy dogs, pancreatic lipase immunoreactivity is only expressed in pancreatic acinar cells, suggesting that dogs with a high serum cPLI concentration have pancreatic pathology (Steiner and others 2002). Also, dogs with EPI were shown to have a severely decreased serum cPLI concentration further supporting the notion that an increase in serum cPLI concentration is because of exocrine pancreatic pathology (Steiner and others 2006).

Although the manufacturers of the cPLI assay currently state that values above 400 lg/l are diagnostic for pancreatitis, in this study, dogs with values above 200 lg/l were assigned to the high cPLI group rather than the normal group. Unfortunately, there are no published data that defines the specificity of the cPLI assay and further work needs to be carried out to overcome this limitation.

In this study, dogs with SRD and high cPLI concentration were less likely to respond to steroid treatment and 129

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FIG 2. Bar graph representing the number of food-responsive diarrhoea (FRD), antibiotic-responsive diarrhoea (ARD) and steroid-responsive diarrhoea (SRD) cases in the high canine pancreatic lipase immunoreactivity (cPLI) concentration group and in the normal cPLI concentration group

significantly more likely to be euthanased at follow-up. In some cases that failed to respond to steroids, ciclosporin was helpful in controlling clinical signs. None of the cases in this study were suspected of having concurrent pancreatitis at the time IBD was diagnosed or during their management but concurrent pancreatitis could have been overlooked as cPLI was only determined retrospectively for the purpose of this study. Failure to provide appropriate management for pancreatitis might have worsened the outcome in these cases, although strategies for managing pancreatitis are often non-specific.

Unfortunately, post-mortem examinations were not carried out on the euthanased cases, therefore additional disease exacerbating or causing refractoriness to treatment could not be ruled out. As all intestinal histopathology was based on endoscopic rather than full-thickness biopsies, underlying neoplasia (that is in the muscularis layer) could have been missed in some biopsies and potentially have been a contributing factor to poor outcome in the small number of cases in both groups that were euthanased. However, there was no clinical index of suspicion for lymphoma in any of the cases that were euthanased. Another limiting factor is that 130

interpretation of endoscopic biopsies has been shown to be very subjective and commonly differs between pathologists (Willard and others 2002). In the current study, the histopathology score was based on reports produced by various pathologists, which could inevitably have biased the scoring system. Similarly, the ultrasound examinations were performed by various radiologists, while this study might have benefited from review of the stored images by a single radiologist using a set of predefined criteria to reduce variability and increase statistical validity, assessing still images retrospectively can also introduce inconsistencies compared with assessing reports written at the time of an examination.

Dogs with FRD were more likely to be in the normal PLI group and as FRD occurs predominantly in younger dogs (Hall and others 2000, Allenspach and others 2007), this could explain why dogs in the normal cPLI group were significantly younger than the high cPLI group.

Although dogs with an increased cPLI concentration had a statistically significant higher serum lipase activity than dogs with normal cPLI concentration, there was considerable overlap in serum lipase activities between the two groups. Only three of the 15 dogs with a high cPLI concentration had Journal of Small Animal Practice

serum lipase activities above the reference range further supporting previous studies that showed serum lipase activity is not sensitive or specific for pancreatic inflammation and can therefore be difficult to interpret. Two separate studies report a sensitivity of approximately 50 per cent for serum lipase activity in acute canine pancreatitis (Strombeck and others 1981, Hess and others 1998) and another study found a specificity of about 50 per cent (Polzin and others 1983).

Even though both age and serum lipase activity were shown to be significantly different between dogs in the high cPLI group and those in the normal cPLI group, using multi-variate logistic regression, the only factor that affected survival in dogs with IBD was a high serum cPLI concentration. Category of disease including having steroid-responsive disease had no effect on survival. Previous studies have suggested that albumin and cobalamin are negative prognostic indicators in IBD (Allenspach and others 2007) but this was not found in the current study possibly because follow-up times were shorter or because insufficient dogs were included.

Albumin concentration was only just not significant (P=0 052) and unfortunately, a power analysis for albumin was not calculated.

Currently, any effect steroids might have on the pancreas is poorly understood and controversy surrounds the diagnosis of steroid-induced pancreatitis. To the authors’ knowledge, only one report exists in the human literature in which recurrence of pancreatitis was shown after rechallenge with steroid treatment (Levine and McGuire 1988). In this study population, no significant difference in the frequency of steroid treatment between the high and the normal cPLI groups was found; this could imply steroid treatment had no effect on the exocrine pancreas in these dogs. Dogs with high cPLI concentrations were more likely to respond poorly to steroid treatment, which could also suggest that steroid treatment in the face of pancreatitis might contribute to a higher mortality rate.

Although it has been shown that serum cPLI concentration is not altered by oral prednisone (Steiner and others 2003), a prospective study would be needed to investigate if prednisolone treatment in canine

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FIG 3. Bar graph representing the number of food-responsive diarrhoea (FRD), antibiotic-responsive diarrhoea (ARD) and steroid-responsive diarrhoea (SRD) cases in the high canine pancreatic lipase immunoreactivity (cPLI) concentration group and in the normal cPLI concentration group that responded well to treatment, poorly to treatment or were euthanased

IBD is a risk factor for the development and worsening of existing pancreatitis.

Recent evidence in the human literature suggests that most cases of Crohn’s diseaseassociated pancreatitis are idiopathic and could be related to the pathogenesis of IBD itself (Seyrig and others 1985, Barthet

and others 1999). Although the aetiology of IBD-CP is unknown, the clinical, morphological and histological features are reminiscent of autoimmune pancreatitis (AIP) (Barthet and others 1999, Sahel and others 2004). AIP is a rare but defined cause of CP in people. It is commonly

Table 1. Table representing P values from parameters affecting survival in IBD dogs using multi-variate logistic regression analysis Parameter Age Canine chronic enteropathy activity index Serum amylase activity Serum lipase activity cPLI Histopathological score on intestinal biopsies Ultrasound score Category of disease Steroid-resistant disease Albumin Cobalamin

Level of significance (P value) 0 267 0 761 0 683 0 706 0 027 0 845 0 636 0 951 0 464 0 052 0 204

IBD Inflammatory bowel disease, cPLI Canine pancreatic lipase immunoreactivity Serum cPLI concentration is the only parameter shown to be a significant factor influencing the outcome of dogs with IBD (P,0 05)

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subclinical and is the only form of CP in people that generally responds to corticosteroid administration (Hirano and others 2007). So far, AIP has not been definitively described in the dog. Further studies evaluating pancreata from dogs with confirmed IBD at necropsy for histological signs consistent with AIP in people may be useful. Pancreatic autoantibodies have been detected in approximately 30 per cent of human patients with Crohn’s disease and ulcerative colitis (Seibold and others 1996) and are one of the criteria for the diagnosis of AIP in people (Pickartz and others 2007). However, it is not known if there is a direct pathogenic role for these antibodies. Pancreatic autoantibodies have also been found in dogs with EPI (Wiberg and others 2000). Ascertaining if such antibodies are present in canine IBD patients might lead to a better understanding of any autoimmune-mediated aetiology for canine IBD-associated pancreatitis.

In conclusion, this study suggests that a proportion of dogs with IBD have high cPLI concentrations. Although the significance of this is unknown, it may be suggestive of IBD-associated pancreatitis. If this holds true then this disease entity is mainly subclinical and the diagnosis easily missed by routine investigations used in dogs suspected to have IBD. This study highlights the importance of assessing cPLI in dogs with IBD as high cPLI might adversely affect outcome and might require different management.

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Journal of Small Animal Practice 48, 609-618 WIBERG, M. E., SAARI, S. A., WESTERMARCK, E. & MERI, S. (2000) Cellular and humoral immune responses in atrophic lymphocytic pancreatitis in German shepherd dogs and rough-coated collies. Veterinary Immunology and Immunopathology 76, 103-115 WILLARD, M. D., JERGENS, A. E., DUNCAN, R. B., LEIB, M. S., MCCRACKEN, M. D., DENOVO, R. C., HELMAN, R. G., SLATER, M. R. & HARBISON, J. L. (2002) Interobserver variation among histopathologic evaluations of intestinal tissues from dogs and cats. Journal of the American Veterinary Medical Association 220, 1177-1182

Vol 50 March 2009 Ó 2009 British Small Animal Veterinary Association