Case Report, Cholangitis

Hindawi Publishing Corporation
Case Reports in Veterinary Medicine

Volume 2012, Article ID 758784, 3 pages
doi:10.1155/2012/758784
Case Report
Destructive Cholangitis in an Adult Jack Russell Terrier
Atsushi Kodama,1 Hiroki Sakai,1, 2 Tsuyoshi Kimura,3 Sadatoshi Maeda,2, 3
Takashi Mori,2, 4 Toshiaki Masegi,1 and Tokuma Yanai1
1 Laboratory
of Veterinary Pathology, Faculty of Applied Biological Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan
of Veterinary Medicine, and Comparative Cancer Center, Faculty of Applied Biological Sciences, Gifu University,
1-1 Yanagido, Gifu 501-1193, Japan
3 Laboratory of Veterinary Clinical Radiology, Faculty of Applied Biological Sciences, Gifu University, 1-1 Yanagido,
Gifu 501-1193, Japan
4 Laboratory of Veterinary Clinical Oncology, Faculty of Applied Biological Sciences, Gifu University, 1-1 Yanagido,
Gifu 501-1193, Japan
2 Department
Correspondence should be addressed to Hiroki Sakai, shiroki@gifu-u.ac.jp

Received 7 June 2012; Accepted 16 August 2012
Academic Editors: M. Anttila, J. Lakritz, F. Martinho, and P. Roccabianca
Copyright 2012 Atsushi Kodama et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
A 4-year-old female Jack Russell terrier dog exhibited vomiting and severe jaundice of the visible mucous membranes and skin.
Ultrasonography revealed diuse areas of high echogenicity and focal areas of low echogenicity in the left lobe of the liver. On
macroscopic observation of the biopsied liver specimen, many scattered irregularly shaped red spots were observed on the liver
surface and on the cut surface. Histopathologically, there was loss of the interlobular bile duct and cholangitis accompanied by
infiltration of pigment-laden macrophages in the Glissons capsule. Therefore, in the present case the dog was diagnosed with
destructive cholangitis.
1. Introduction
Destructive cholangitis is characterized by the loss of bile
ducts in area for Glissons capsule. This condition induces
severe intrahepatic cholestasis, icterus, and eventually, hepatic failure. In humans, bile-duct loss occurs with primary
biliary cirrhosis, hepatic allograft rejection, and idiopathic
adulthood ductopenia [13]. The pathogenesis of bile-duct
loss includes immunological, infectious, ischemic, and toxic
factors [4]. On the other hand, bile-duct loss is rarely
reported in dogs [5, 6]. The present paper describes the
clinical and histopathological characteristics of destructive
cholangitis in a canine.
2. Case Presentation
A 4-year-old female Jack Russell terrier dog with a history of
vomiting for 1 week was admitted to the Animal Teaching
Hospital of Gifu University, Japan. The dog was slim,
and physical examination revealed severe jaundice of the

visible mucous membranes and skin. Routine hematological
examination revealed no abnormalities; however, serum
biochemical examination revealed increased total bilirubin
(T-Bil; 7.0 mg/dL) and C-reactive protein (CRP; 2.5 mg/dL)
levels. Ultrasonographic examination revealed areas of diffuse, high echogenicity and areas of focally low echogenicity
in the left lobe of the liver. A small gall bladder was observed,
but no biliary obstruction was detectable, and a clinical
diagnosis of hepatic jaundice was made by the clinician.
A histopathological sample from the right median lobe
of liver was collected by excisional biopsy with the dog
under general anesthesia, 7 days after the first examination.
Although the clinical status had improved gradually with
the administration of prednisolone and cyclosporine, the
dog died 46 days after the first examination. Postmortem
examination of the dog was not allowed by the owner.
The liver specimen was fixed in 10% neutral buered
formalin, processed for histology using routine methods,
Figure 1: Gross appearance of the dogs liver. The surface of the liver presented with many scattered, irregularly shaped red spots.
sectioned (4 m), and stained with hematoxylin and eosin

(HE). In addition, some sections were stained using Prussian
blue stain, Schmorl method, Halls method, and rhodanine
stain. Immunohistochemistry (IHC) on the formalin-fixed
paran-embedded sections was performed using antibodies
against cytokeratin 19 (mouse monoclonal antibody, Vision
Biosystems Novocastra, Tyne, UK) and canine distemper
virus (CDV; mouse monoclonal antibody, Cosmobio Co.,
Tokyo, Japan) at 1 : 100 dilution. Prior to incubation with
the cytokeratin 19 primary antibody, we carried out a
blockade of endogenous peroxidase activity (0.3% hydrogen
peroxidase in methanol for 20 minutes at room temperature)
and enzyme digestion (0.05% trypsin in PBS at 37 C for 5
minutes). For CDV antigen retrieval, boiling was performed
at 121 C for 15 minutes in an antigen retrieval solution
(Target Retrieval solution, DakoCytomation, Denmark).
Subsequently, the sections were incubated with a peroxidaselabeled secondary antibody (Envision+, DakoCytomation)
and visualized using diaminobenzidine. Mayers hematoxylin
was employed for counterstaining. For the negative controls,
the primary antibody was omitted and replaced with PBS.
Macroscopic examination of the liver specimen revealed
many scattered irregularly shaped red spots on the liver
surface and on the cut surface, resembling nutmeg liver
(Figure 1). Histopathologically, brown pigmentations were
observed in approximately the entire Glissons capsule and
part of the hepatic lobule at low magnification (Figure 2(a)).
There were many pigment-laden macrophages and some
neutrophils, lymphocytes, and plasma cells present in
most portions of Glissons capsule (Figure 2(b)). Although
interlobular arteries and veins of the liver were present,
interlobular bile ducts and bile ductules were not observed
(Figure 2(b)). Some clumps composed of irregularly disposed epithelioid cells containing light cytoplasm at the
boundary division between Glissons capsule and the hepatic
lobule were present. Septal bile ducts, which have their own
bile duct wall and are lined by a single layer of high columnar
epithelium and hepatic duct, were observed. In the hepatic
lobule, there was minimal parenchymal necrosis, brown
pigmented hepatocytes, and mild intrahepatic cholestasis.
The brown pigments stained blue with Prussian blue stain
(Figure 2(c)), dark green with Schmorl method, and they
did not stain with Halls method. There was no evidence of
positive staining with rhodanine or immunohistochemical
labeling for CDV. The epithelial cells at the boundary division between the Glissons capsule and the hepatic lobule and
the epithelial cells of the septal bile ducts and hepatic duct
were confirmed by positive immunohistochemical labeling
for cytokeratin 19 (Figure 2(d)). However, lumen formation
composed of cytokeratin 19-positive cells was not observed.
Canine cholangitis is classified into 4 types: neutrophilic
cholangitis, lymphocytic cholangitis, destructive cholangitis,
and chronic cholangitis associated with liver fluke infestation
[7]. Neutrophilic cholangitis and lymphocytic cholangitis are
characterized by infiltration of neutrophils or small lymphocytes in the area for Glissons capsule, especially in the biliary
epithelium. The main microscopic feature of destructive
cholangitis is the loss of the intrahepatic bile ducts in the
area for Glissons capsule, associated with the infiltration of pigment-phagocytic macrophages, neutrophils, and
eosinophils in the area for Glissons capsule. Chronic cholangitis associated with liver fluke infestation is an endemic
infection caused by the family Opisthorchiidae. The lesions
consist of dilated, large bile ducts with papillary proliferation
associated with various inflammatory infiltrates. In the
present case, there was loss of the interlobular bile duct and
cholangitis characterized by infiltration of macrophages
ingesting the hemosiderin in the Glissons capsule. Therefore,
the pathological findings of the lesion were similar to
destructive cholangitis in dogs.
3. Discussion
In humans, several drugs, such as flucloxacillin, chlorpromazine, and carbamazepine, and hepatotoxic agents have
been reported to cause bile-duct loss [8]. Some of these
compounds induce bile-duct injury at a specific anatomical
level of the intrahepatic biliary tree [4]. Paraquat induces
cytopathic changes in bile epithelial cells ranging from
those of bile ductules to large intrahepatic bile ducts and
4,4 diaminodiphenylmethane causes necrotic cholangitis in
small bile ducts [9]. Because the bile-duct loss occurred
specifically at the interlobular bile duct with cholangitis,
a drug or hepatotoxic-agent-induced cholangitis was suspected in the present case. However, the particular drug
responsible in this case was not elucidated because drug
use history or hepatotoxic agent exposure was not known.
(a)
(b)
(c)
(d)
Figure 2: Histopathological and immunohistological features of the liver. (a) Glissons capsule with brown pigmentations. HE. Bar = 250 m.
(b) Interlobular bile ducts and bile ductules were not observed, but many pigment-laden macrophages infiltrating Glissons capsule were
present. HE. Bar = 50 m. (c) The brown pigments contained within macrophages in Glissons capsule stained blue with Prussia blue
stain. Bar = 50 m. (d) There is no lumen formation composed of cytokeratin 19-positive cells in Glissons capsule. However, positivity
for cytokeratin 19 is shown in the epidermoid cells at the boundary division between the Glissons capsule and hepatic lobule (arrowheads).
IHC for cytokeratin 19. Bar = 50 m.
Although CDV is known to cause bile-duct loss in dogs, a

positive reaction for CDV was not detected in the present
case [7]. Similarly, the deposition of copper causes bile-duct
loss, but there was no copper deposition in this case [7]. In
addition, lesions indicative of immune-mediated or ischemic
bile-duct loss in humans were not evident [4].
Interestingly, in this case, bile-duct loss occurred at the
bile ductules and interlobular bile ducts, but did not occur
at the septal bile ducts that had bile-duct walls. In addition,
lumen formation was not apparent, although cytokeratin
19-positive cellsevidence of bile-duct regenerationwere
observed [10]. We hypothesize that the inhibition of lumen
formation in the bile ductules and interlobular bile ducts
may be associated with the development of the lesion in this
case.
References
[1] T. Kuroki, S. Seki, N. Kawakita et al., Expression of antigens
related to apoptosis and cell proliferation in chronic nonsuppurative destructive cholangitis in primary biliary cirrhosis,
Virchows Archiv, vol. 429, no. 2-3, pp. 119129, 1996.
[2] D. H. Adams and S. C. Aord, Eector mechanisms of
nonsuppurative destructive cholangitis in graft-versus-host
disease and allograft rejection, Seminars in Liver Disease, vol.
25, no. 3, pp. 281297, 2005.
[3] V. J. Desmet, Destructive intrahepatic bile duct diseases,

Recenti Progressi in Medicina, vol. 81, no. 6, pp. 392398, 1990.
[4] Y. Nakanuma, K. Tsuneyama, and K. Harada, Pathology and
pathogenesis of intrahepatic bile duct loss, Journal of HepatoBiliary-Pancreatic Surgery, vol. 8, no. 4, pp. 303315, 2001.
[5] T. S. van den Ingh, J. Rothuizen, and H. M. van Zinnicq Bergman, Destructive cholangiolitis in seven dogs, Veterinary
Quarterly, vol. 10, no. 4, pp. 240245, 1988.
[6] A. Gabriel, T. S. Van Den Ingh, C. Clercx, and D. Peeters, Suspected drug-induced destructive cholangitis in a young dog,
Journal of Small Animal Practice, vol. 47, no. 6, pp. 344348,
2006.
[7] T. S. van den Ingh, J. M. Cullen, D. C. Twedt, T. V. Winkle,
V. J. Desmet, and J. Rothuizen, Morphological classification
of biliary disorders of the canine and feline liver, in WASAVA
Standards For Clinical and Histological Diagnosis of Canine and
Feline Liver Diseases, WASAVA Liver Standardization Group,
Ed., pp. 6176, Saunders, Philadelphia, Pa, USA, 2006.
[8] S. Chitturi and G. C. Farrell, Drug-induced cholestasis, Seminars in Gastrointestinal Disease, vol. 12, no. 2, pp. 113124,
2001.
[9] A. P. Geubel and C. L. Sempoux, Drug and toxin-induced bile
duct disorders, Journal of Gastroenterology and Hepatology,
vol. 15, no. 11, pp. 12321238, 2000.
[10] P. Stosiek, M. Kasper, and U. Karsten, Expression of cytokeratin 19 during human liver organogenesis, Liver, vol. 10, no.
1, pp. 5963, 1990.
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Hindawi Publishing Corporation

Case Reports in Veterinary Medicine

Correspondence should be addressed to Hiroki Sakai, shiroki@gifu-u.ac.jp

and physical examination revealed severe jaundice of the

Case Reports in Veterinary Medicine

sectioned (4 m), and stained with hematoxylin and eosin

Case Reports in Veterinary Medicine

Although CDV is known to cause bile-duct loss in dogs, a

[3] V. J. Desmet, Destructive intrahepatic bile duct diseases,

Hindawi Publishing Corporation

Hindawi Publishing Corporation

Hindawi Publishing Corporation

Hindawi Publishing Corporation

Submit your manuscripts at

Hindawi Publishing Corporation

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