Accepted Manuscript Title: Prognostic factors in dogs with protein-losing enteropathy Author: K. Nakashima, S. Hiyoshi, K. Ohno, K. Uchida, Y. Goto-Koshino, S. Maeda, N. Mizutani, A. Takeuchi, H. Tsujimoto PII: DOI: Reference:
S1090-0233(15)00181-1 http://dx.doi.org/doi:10.1016/j.tvjl.2015.05.001 YTVJL 4508
To appear in:
The Veterinary Journal
Accepted date:
2-5-2015
Please cite this article as: K. Nakashima, S. Hiyoshi, K. Ohno, K. Uchida, Y. Goto-Koshino, S. Maeda, N. Mizutani, A. Takeuchi, H. Tsujimoto, Prognostic factors in dogs with protein-losing enteropathy, The Veterinary Journal (2015), http://dx.doi.org/doi:10.1016/j.tvjl.2015.05.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31
Prognostic factors in dogs with protein-losing enteropathy K. Nakashima a,1, S. Hiyoshi a,1, K. Ohno a,*, K. Uchida b, Y. Goto-Koshino a, S. Maeda a, N. Mizutani a, A. Takeuchi c, H. Tsujimoto a a
Department of Veterinary Internal Medicine, Graduate School of Agricultural and Life Sciences, the University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan b Department of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, the University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan c Department of Preventive Medicine and Public Health, School of Medicine, Keio University, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan
*Corresponding author. Tel: +81 3 58415402. E-mail address: [email protected] (K. Ohno). 1
These authors contributed equally to the work.
Highlights - Prognostic factors for dogs with protein-losing enteropathy were investigated. - Small-cell lymphoma had shorter survival than chronic enteritis and lymphangiectasia. - Clonal expansion of lymphocytes was associated with shorter survival time. - Response to initial treatment within 50 days was associated with longer survival time. -The canine inflammatory bowel disease activity index was a valuable prognostic factor.
1
Page 1 of 20
32
Abstract
33
Canine protein-losing enteropathy (PLE) is associated with severe gastrointestinal
34
disorders and has a guarded to poor prognosis although little information is available
35
regarding factors affecting prognosis. The purpose of this study was to identify prognostic
36
factors for survival of dogs with PLE. Ninety-two dogs diagnosed with PLE from 2006 to
37
2011 were included in a retrospective cohort study. Survival analysis was performed using the
38
Kaplan−Meier method and log-rank test. Variables recorded at the time of diagnosis were
39
statistically analyzed for possible prognostic factors in a univariate and multivariate Cox
40
proportional hazard model.
41 42
In the multivariate analysis, the predictors for mortality in dogs with PLE were more
43
highly scored in terms of canine inflammatory bowel disease activity index (CIBDAI) (P =
44
0.0003), clonal rearrangement of lymphocyte antigen receptor genes (P = 0.003), and
45
elevation of blood urea nitrogen (BUN) (P = 0.03). Using histopathological diagnosis, both
46
small- and large-cell lymphomas were associated with significantly shorter survival times
47
than chronic enteritis (CE) and intestinal lymphangiectasia (IL). Normalisation of CIBDAI
48
and plasma albumin concentration within 50 days of initial treatment was associated with a
49
longer survival time. In conclusion, CIBDAI, clonal rearrangement of lymphocyte antigen
50
receptor genes, histopathological diagnosis, and response to initial treatments could be
51
valuable in separating underlying causes and important in predicting prognosis in dogs with
52
PLE.
53 54 55
Keywords: Canine; Chronic enteropathy; Gastrointestinal lymphoma; Intestinal lymphangiectasia; Prognosis
2
Page 2 of 20
56
Introduction
57
Protein-losing enteropathy (PLE) in dogs is characterized by hypoalbuminaemia due to
58
excessive loss of plasma proteins through the gastrointestinal mucosa. PLE can be associated
59
with various diseases and chronic enteritis (CE), intestinal lymphangiectasia (IL), and
60
gastrointestinal (GI) lymphoma are common underlying diseases in canine PLE (Dossin and
61
Lavoue, 2011; Dandrieux et al., 2013). Because PLE results from severe GI disorders, the
62
prognosis is usually considered guarded to poor (Dossin and Lavoue, 2011).
63 64
In dogs with CE, hypoalbuminaemia has previously been reported as a poor prognostic
65
factor (Craven et al., 2004; Allenspach et al., 2007) although little information is available on
66
survival and prognostic factors in canine PLE. One small data set indicated that the 3-year
67
survival rate was 70% in CE dogs with hypoalbuminaemia (Allenspach et al., 2007). Another
68
report estimated that PLE dogs with hypercoagulability had a death rate of 66% within 5
69
months (Goodwin et al., 2011). With canine IL, there are no data about long-term survival
70
rate and prognosis. On the other hand, the prognosis is poor for dogs with GI lymphoma, even
71
for those undergoing multidrug chemotherapy (Rassnick et al., 2009).
72 73 74
The purpose of this retrospective study was to identify prognostic factors for survival of dogs with GI disorders associated with hypoalbuminaemia.
75 76
Materials and methods
77
Case selection
78
Dogs diagnosed with PLE from 1 April 2006 to 31 January 2011 were identified from
79
medical records of the Veterinary Medical Center of the University of Tokyo (VMC-UT).
80
Inclusion criteria for the PLE dogs included hypoalbuminaemia (
S1090-0233(15)00181-1 http://dx.doi.org/doi:10.1016/j.tvjl.2015.05.001 YTVJL 4508
To appear in:
The Veterinary Journal
Accepted date:
2-5-2015
Please cite this article as: K. Nakashima, S. Hiyoshi, K. Ohno, K. Uchida, Y. Goto-Koshino, S. Maeda, N. Mizutani, A. Takeuchi, H. Tsujimoto, Prognostic factors in dogs with protein-losing enteropathy, The Veterinary Journal (2015), http://dx.doi.org/doi:10.1016/j.tvjl.2015.05.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31
Prognostic factors in dogs with protein-losing enteropathy K. Nakashima a,1, S. Hiyoshi a,1, K. Ohno a,*, K. Uchida b, Y. Goto-Koshino a, S. Maeda a, N. Mizutani a, A. Takeuchi c, H. Tsujimoto a a
Department of Veterinary Internal Medicine, Graduate School of Agricultural and Life Sciences, the University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan b Department of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, the University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan c Department of Preventive Medicine and Public Health, School of Medicine, Keio University, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan
*Corresponding author. Tel: +81 3 58415402. E-mail address: [email protected] (K. Ohno). 1
These authors contributed equally to the work.
Highlights - Prognostic factors for dogs with protein-losing enteropathy were investigated. - Small-cell lymphoma had shorter survival than chronic enteritis and lymphangiectasia. - Clonal expansion of lymphocytes was associated with shorter survival time. - Response to initial treatment within 50 days was associated with longer survival time. -The canine inflammatory bowel disease activity index was a valuable prognostic factor.
1
Page 1 of 20
32
Abstract
33
Canine protein-losing enteropathy (PLE) is associated with severe gastrointestinal
34
disorders and has a guarded to poor prognosis although little information is available
35
regarding factors affecting prognosis. The purpose of this study was to identify prognostic
36
factors for survival of dogs with PLE. Ninety-two dogs diagnosed with PLE from 2006 to
37
2011 were included in a retrospective cohort study. Survival analysis was performed using the
38
Kaplan−Meier method and log-rank test. Variables recorded at the time of diagnosis were
39
statistically analyzed for possible prognostic factors in a univariate and multivariate Cox
40
proportional hazard model.
41 42
In the multivariate analysis, the predictors for mortality in dogs with PLE were more
43
highly scored in terms of canine inflammatory bowel disease activity index (CIBDAI) (P =
44
0.0003), clonal rearrangement of lymphocyte antigen receptor genes (P = 0.003), and
45
elevation of blood urea nitrogen (BUN) (P = 0.03). Using histopathological diagnosis, both
46
small- and large-cell lymphomas were associated with significantly shorter survival times
47
than chronic enteritis (CE) and intestinal lymphangiectasia (IL). Normalisation of CIBDAI
48
and plasma albumin concentration within 50 days of initial treatment was associated with a
49
longer survival time. In conclusion, CIBDAI, clonal rearrangement of lymphocyte antigen
50
receptor genes, histopathological diagnosis, and response to initial treatments could be
51
valuable in separating underlying causes and important in predicting prognosis in dogs with
52
PLE.
53 54 55
Keywords: Canine; Chronic enteropathy; Gastrointestinal lymphoma; Intestinal lymphangiectasia; Prognosis
2
Page 2 of 20
56
Introduction
57
Protein-losing enteropathy (PLE) in dogs is characterized by hypoalbuminaemia due to
58
excessive loss of plasma proteins through the gastrointestinal mucosa. PLE can be associated
59
with various diseases and chronic enteritis (CE), intestinal lymphangiectasia (IL), and
60
gastrointestinal (GI) lymphoma are common underlying diseases in canine PLE (Dossin and
61
Lavoue, 2011; Dandrieux et al., 2013). Because PLE results from severe GI disorders, the
62
prognosis is usually considered guarded to poor (Dossin and Lavoue, 2011).
63 64
In dogs with CE, hypoalbuminaemia has previously been reported as a poor prognostic
65
factor (Craven et al., 2004; Allenspach et al., 2007) although little information is available on
66
survival and prognostic factors in canine PLE. One small data set indicated that the 3-year
67
survival rate was 70% in CE dogs with hypoalbuminaemia (Allenspach et al., 2007). Another
68
report estimated that PLE dogs with hypercoagulability had a death rate of 66% within 5
69
months (Goodwin et al., 2011). With canine IL, there are no data about long-term survival
70
rate and prognosis. On the other hand, the prognosis is poor for dogs with GI lymphoma, even
71
for those undergoing multidrug chemotherapy (Rassnick et al., 2009).
72 73 74
The purpose of this retrospective study was to identify prognostic factors for survival of dogs with GI disorders associated with hypoalbuminaemia.
75 76
Materials and methods
77
Case selection
78
Dogs diagnosed with PLE from 1 April 2006 to 31 January 2011 were identified from
79
medical records of the Veterinary Medical Center of the University of Tokyo (VMC-UT).
80
Inclusion criteria for the PLE dogs included hypoalbuminaemia (
