Tri ad i ti s: Truth and Consequences

Jonathan A. Lidbury, BVMS, MRCVS, PhDa,

Shankumar Mooyottu, DVM, PhDb, Albert E. Jergens, DVM, PhD
c,
*

KEYWORDS
 Pancreatitis  Cholangitis  Inflammatory bowel disease  Cat  Histopathologic
 Prognosis

KEY POINTS
 Clinical findings with triaditis as well as the individual disease components overlap and
may include hyporexia, weight loss, lethargy, vomiting, diarrhea, dehydration, icterus,
abdominal pain, thickened bowel loops, pyrexia, dyspnea, and shock.
 A definitive diagnosis of triaditis requires histologic confirmation of inflammation in each
organ, but this may not be possible because of financial or patient-related constraints.
 Evidence-based data indicate that histologic lesions of triaditis are present in 30% to 50%
of cats diagnosed with pancreatitis and cholangitis/inflammatory liver disease.
 How inflammation in 1 organ contributes to inflammation in other gastrointestinal organs is
not fully known but likely involves either a bacterial- or an immune-mediated process.
 Treatment of triaditis is based on the overall health status of the patient and the type and
severity of disease in component organs.

INTRODUCTION

“Triaditis” is a term applied to feline inflammatory gastrointestinal (GI) disease

describing concurrent inflammation of the small intestines, pancreas, and hepatobili-
ary system.1,2 Anecdotally, multiorgan GI inflammation in cats would appear to be a
clinically prevalent disorder that complicates treatment strategies and impacts
outcome for affected cats versus cats having single-organ inflammation alone. How-
ever, there is a paucity of evidence-based data on the etiopathogenesis, diagnosis,
and treatment of triaditis in cats. This article provides a thorough overview of the pu-
tative causes of simultaneous multiorgan inflammatory disease in cats as well as how
to diagnose and treat these disorders, and whether inflammation in multiple organs af-
fects long-term outcome.

a
Department of Small Animal Clinical Sciences, College of Veterinary Medicine & Biomedical
Sciences, Texas A&M University, 4474 TAMU, College Station, Texas 77843, USA; b Department
of Veterinary Pathology, College of Veterinary Medicine, Iowa State University, 2716 Vet Med,
1800 Christensen Drive, Ames, IA 50011, USA; c Department of Veterinary Clinical Sciences,
College of Veterinary Medicine, Iowa State University, L2565 Lloyd, 1809 South Riverside Drive,
Ames, IA 50011, USA
* Corresponding author.
E-mail address: ajergens@[Link]

Vet Clin Small Anim 50 (2020) 1135–1156

[Link] [Link]
0195-5616/20/ª 2020 Elsevier Inc. All rights reserved.
1136 Lidbury et al

TRIADITIS: PAST AND CURRENT PERSPECTIVE

A definitive diagnosis of triaditis requires histologic confirmation of inflammation in

each organ.3 However, triaditis, or inflammation of more than 1 GI organ, is often clin-
ically suspected in cats based on salient clinical, laboratory, imaging, and fine needle
aspiration (FNA) findings. Kelly and colleagues4 were the first to report an association
between cholecystitis, cholangitis, and pancreatitis in a cat with intermittent vomiting
and weight loss, closely followed by a series of reports in the mid-1990s from different
investigative groups evaluating multiorgan inflammation in cats (Table 1).2,5–12 Collec-
tively, these data report histologic lesions of triaditis in 30% to 50% of cats diagnosed
with pancreatitis and cholangitis/inflammatory liver disease (ILD). Caution is advised
when drawing conclusions about specific multiorgan inflammatory conditions from
these earlier reports for several reasons (Box 1). In a recent prospective study, inflam-
matory bowel disease (IBD) with cholangitis was noted to occur in 6 of 27 (22%) cats
with GI signs, IBD with pancreatitis in 2 of 27 (7%), and triaditis in 8 of 27 (30%), sug-
gesting that triaditis or inflammation of two-thirds of these organs is relatively com-
mon. However, some combination of histopathological changes of 2 or more of
these organs was also found in 20 of 39 (51%) asymptomatic cats undergoing ovar-
iohysterectomy, although interestingly none of the cats in this group had histologic
inflammation in 3 or more organs.12 This finding may truly reflect subclinical disease
or be due to the inability to histologically appreciate the spectrum of normal
morphology for the small intestine, liver, and pancreas.

DOES INFLAMMATION IN ONE COMPONENT ORGAN CONTRIBUTE TO TRIADITIS?

Pancreatitis
Even with comprehensive diagnostic evaluation, the cause for acute and chronic
pancreatitis in most cats remains unknown (Box 2). Following a triggering event,
pancreatic enzymes are activated within the pancreatic parenchyma, and cytokines
and other inflammatory mediators are released causing cell injury resulting in both
pancreatitis and systemic effects.13,14 The spectrum of acute inflammation varies
from acute necrotizing pancreatitis with necrosis predominating (>50% of pathologic
condition) compared with suppurative pancreatitis with neutrophilic inflammation ac-
counting for greater than 50% of pathologic condition.7 Acute pancreatic necrosis is
more common than suppurative inflammation and is a well-recognized GI disorder
causing significant morbidity and mortality in cats.7,10 However, because pancreatic
biopsy is seldom performed in the acute setting, these histologic distinctions are rarely
made antemortem.
Acute pancreatitis may progress to chronic pancreatitis characterized by lympho-
cytic inflammation, variable fibrosis, and acinar atrophy, potentially resulting in
exocrine pancreatic insufficiency. Bacterial infection and biliary tract obstruction
may exacerbate pancreatic injury. Fluorescence in situ hybridization (FISH) has
revealed the presence of bacteria in pancreata of 13 of 46 cats with pancreatitis.3
Bacterial colonization was more frequent in cats having moderate to severe pancre-
atitis (13/46) versus cats with mild pancreatitis (2/15) with bacteria visualized in
diverse tissues, including connective/periductal regions (n 5 9), within glandular pa-
renchyma (n 5 6), saponified fat (n 5 5), ducts (n 5 3), and in areas of necrosis
(n 5 3). Obstruction of the pancreatic and/or bile duct may also cause intrahepatic
cholestasis and impaired clearance of bacteria that translocate across the inflamed
intestines. It remains unclear whether enteric bacteria are a primary cause or a sec-
ondary consequence on pancreatitis and whether this may vary between individual
cats.
Table 1
Evidence-based literature describing multi-organ (pancreas, liver and/or intestines) histopathologic inflammation

#
Study Study Design Cats Pancreatitis ILD IBD Triaditis
Kelly et al Necropsy 1 1 1 ND
Weiss et al Retrospective, necropsy 18 9/18 (50%) 18/18 (100%) 15/18 (83%) 7/18 (39%)
CIN 6/33
Callahan et al Retrospective, necropsy 44 22/34 (65%) 44/44 (100%) 17/37 (46%) 10/31 (32%)
CNC - 33/44 CIN 30/37
ANC - 7/44 HL 14/44
Ferreri et al Retrospective, necropsy 63 ANP - 30/63 ND
CP - 33/63
Hill and Van Winkle Retrospective, necropsy 40 ANP - 32/40 5/40 (12%) 13/40 (32%) ND
ASP - 8/40 IC CIN 14/40
HL 19/40
Twedt et al Retrospective, 39 15/23 39/39 (100%) 11/24 7/14 (50%)
biopsy - 27, CP - 12/15 NC - 12/39 LPE - 8/11
necropsy - 12 LC - 7/39 LSA - 5/24
RH - 12/39
Brain et al Prospective, biopsy - 3 6 2/6 NC - 3/6 LSA - 1/6 ND
CC - 3/6
Marolf et al Prospective, biopsy 10 8/10 (80%) 9/10 (90%) ND
CP - 6/8 Cholangitis
Swift et al Prospective, 28 18/28 (64%) 15/18 (83%) 11/18 (61%) 10/28 (36%)

Triaditis
biopsy, necropsy HL, CH

(continued on next page)

1137
 1138
Lidbury et al
Table 1
(continued )
#
Study Study Design Cats Pancreatitis ILD IBD Triaditis
Forman et al Prospective, 21 18/21 (86%) 11/18 (61%) 10/18 (56%) ND
biopsy, necropsy M - 5/18 Cholangitis LSA - 3/18
M-S - 13/18 HL - 3/18
Fragkou et al Prospective, biopsy 47a 1/47 (2%) 6/47 (13%) 13/47 (28%) 8/27 (30%)

Abbreviations: ANC, acute neutrophilic cholangitis; ANP, acute necrotizing pancreatitis; ASP, acute suppurative pancreatitis; CC, cholecystitis; CIN, chronic inter-
stitial nephritis; CNC, chronic neutrophilic cholangitis; CP, chronic pancreatitis; HL, hepatic lipidosis; IC, intestinal changes; LC, lymphocytic cholangitis; LSA, lym-
phosarcoma; M, mild; M-S, moderate-severe; NC, neutrophilic cholangitis; ND, not determined; RH, reactive hepatopathy.
a
Includes cats with (n 5 27) and without (n 5 20) chronic GI signs.
 Triaditis 1139

Box 1
Reasons for caution when estimating the prevalence of triaditis from the available evidence

 Early studies were retrospective and necropsy based.

 Most publications focused on subsets of cats having different GI diseases rather than triaditis.
 Early studies used less sophisticated diagnostic indices for diagnosing tissue inflammation.
 Even with standardized templates for histopathological evaluation of the GI tract,
agreement between pathologists is suboptimal.
 Most studies failed to confirm active inflammation of all 3 organs.
 In necropsy studies, severe inflammatory disorders, such as neutrophilic cholangitis and
suppurative pancreatitis, may be overrepresented compared with less severe disease.
 Direct comparison between studies is difficult due to differences in study design.

Data from Refs.5,7,19,29,39,58

Inflammatory Liver Disease

Feline ILD is a group of acquired disorders that are centered on the biliary tract (chol-
angitis) with secondary involvement of the hepatic parenchyma (cholangiohepati-
tis).8,15–17 Morphologically, this group of heterogeneous inflammatory hepatic
disorders has arbitrarily been classified as being suppurative or nonsuppurative based
on the predominant inflammatory cell type (neutrophils, lymphocytes, and/or plasma
cells), and by the extent of bile duct hyperplasia and fibrosis.18 A refined

Box 2
Proposed causes of feline acute or chronic pancreatitis

 Pancreatic ischemia
 Hypotension
 Cardiac disease
 Concurrent biliary or GI tract disease
 Pancreatic ductal obstruction
 Neoplasia, choleliths, flukes
 Infectious agents
 Toxoplasma gondi
 Enteric bacteria
 Feline herpes virus
 Feline infectious peritonitis virus
 Virulent feline calicivirus infection
 Liver or pancreatic flukes
 Platynosomum fastosum
 Eurytrema procyonis
 Trauma
 Metabolic
 Lipodystrophy
 Hypercalcemia
 Immune-mediated disease
 Organophosphate intoxication (experimental)

Data from Refs.2,3,6,8,20,21,24,28,42.

1140 Lidbury et al

histopathological classification scheme by the World Small Animal Veterinary Associ-

ation has now divided cholangitis into 4 major types: neutrophilic cholangitis, lympho-
cytic cholangitis, chronic cholangitis caused by liver fluke infestation, and destructive
cholangitis.19 To the authors’ knowledge, destructive cholangitis has been described
in dogs but not cats and therefore will not be discussed further. Similarly, chronic chol-
angitis caused by liver fluke infestation will not be discussed. Infectious causes (ie,
toxoplasmosis, feline infectious peritonitis [FIP]) for inflammatory hepatobiliary dis-
ease remain much less common (w15% prevalence for ILD) but are important differ-
ential diagnoses for ILD.
There is no clear understanding of the steps leading to ILD and its different pheno-
types (including neutrophilic and lymphocytic cholangitis), but it is generally accepted
that infectious agents (eg, enteric bacteria) and immune mechanisms contribute to in-
flammatory lesions.19–21
Bacteria are frequently cultured from the bile and/or liver of cats with neutrophilic
cholangitis, with isolation of a single bacterial species in 80% of cats; these cats often
respond well to appropriate antimicrobial therapy.2,8,22–25 Thus, there is compelling
evidence that bacteria are the primary etiologic agent in this form of feline ILD. The
bacteria isolated are often those expected to be present in the intestinal tract, with
Escherichia coli being the most frequently isolated species followed by Enterococcus
spp, Bacteroides spp, Clostridium spp, and Streptococcus spp.2,8,22–25 Some contro-
versy exists as to the most likely mechanism by which these organism reach the liver.
In about 80% of cats, the common bile duct and pancreatic duct both enter the duo-
denum together at the major duodenal papilla. It has long been suspected that this
“common channel” creates a route via which bacteria can ascend from the duodenum
into the liver (and pancreas).3,22 However, more recent work suggests that bacterial
translocation across the intestinal wall and hematogenous spread via the portal circu-
lation are more likely routes for hepatic colonization.2 The role of Helicobacter spp in
causing neutrophilic cholangitis (and pancreatitis) in cats is questionable. Although
Helicobacter spp DNA has been found in the liver and bile of cats with ILD, it has
also been found in the livers of cats with non-ILD, and the livers of healthy cats.2,21,26
Lymphocytic cholangitis is thought to occur because of loss of immune tolerance
resulting in an adaptive immune response targeting the bile ducts and is typically
treated with immunomodulatory agents, such as prednisolone.3,22,27 Interestingly,
an association between ILD, pancreatitis, and nephritis has been found in cats, sug-
gesting a possible common immune-mediated cause.1 It is possible that bacteria
also play a role in the development of this form of feline ILD. Transient bacterial infec-
tion of the liver (or another organ) could lead to an aberrant host immune response that
persists once infection has cleared.22 Using molecular techniques, such as FISH or
polymerase chain reaction (PCR), a variety of bacteria, including E coli, Enterococcus
spp, Helicobacter spp, Micrococcus spp, and Streptococcus spp, have been found in
the livers of cats with lymphocytic cholangitis. However, it is hard to determine if these
organisms are the primary cause of this disease or a secondary consequence because
they can occur in mixed microbe populations as well as in liver tissue of healthy control
cats.2,20,28 In 1 recent study, the presence and distribution of bacteria within the livers
of 39 cats with ILD (both neutrophilic and lymphocytic cholangitis) and 19 control cats
with histologically normal livers were evaluated with eubacterial FISH.2 Although bac-
teria were observed in 21 of 39 ILD and 3 of 19 control hepatic sections, the preva-
lence of intrahepatic bacteria was higher in ILD (13/31; 41%) versus control (1/17;
6%) tissues. Moreover, bacteria in cats with ILD were primarily localized to portal ves-
sels, venous sinusoids, and parenchyma (12/13) than bile ducts (1/13). The spatial dis-
tribution of bacteria in liver tissue of cats with ILD supports the hypothesis that
 Triaditis 1141

colonization likely occurs by enteric translocation or by hematogenous means rather

than ascending infection of the bile duct. Concurrent pancreatic and intestinal disease
was frequent in all 13 cats with intrahepatic bacteria, suggesting a possible link be-
tween hepatic bacterial colonization and GI or pancreatic diseases that reduce intes-
tinal barrier function and promote hematogenous seeding of the liver with enteric
bacteria.
It is also possible that the bile ducts are injured because of loss of immune tolerance
to components of the GI microbiota or dietary constituents in cats with IBD. Possible
mechanisms are discussed later.

Inflammatory Bowel Disease

IBD denotes 1 form of chronic enteropathy characterized by persistent or intermittent
GI signs associated with histologic inflammation of the GI tract.29,30 Current hypothe-
ses support the notion that feline IBD results from interactions between host genetics,
intestinal environment (gut microbiome, dietary constituents), and mucosal immu-
nity.29,31 It is noteworthy that cats with IBD show an expanded and intensified expres-
sion of major histocompatibility complex class II, which may contribute to antigen
presentation and aberrant host responses.32 What the triggers are that drive chronic
intestinal inflammation and the variable phenotypic expression and individual
response to treatment remain unknown. As observed in humans33,34 and dogs with
IBD,35–37 shifts in gut bacterial populations (ie, reduced overall microbial diversity
with decreased beneficial species but increased harmful species, including the
Enterobacteriaceae) are found in cats with active disease. Mucosal bacteria have
been linked to both clinical signs and histopathologic lesions in cats with IBD. Using
FISH, increased total numbers of Enterobacteriaceae correlated to chronic duodenal
histopathologic lesions (ie, villus atrophy, fusion), number of GI signs, and upregulated
proinflammatory cytokine messenger RNA expression (ie, interleukin-1 [IL-1], -8, and
-12) in cats with IBD as compared with healthy cats. It is possible that these shifts
occur as a consequence of a primary insult rather than being the inciting cause of
IBD. Growing evidence also supports the importance of diet in the development of fe-
line IBD. In 1 study investigating 55 cats with variable signs of chronic enteropathy,
49% responded to dietary modification using an elimination diet alone.38 Upon chal-
lenge with the original diet, signs recurred in 16 of 55 (29%) of these cats but not in the
remaining 11 of 55 (20%) responders.
Histologically, IBD in cats is characterized by variable degrees of cellular infiltration
(most commonly lymphocytic-plasmacytic enteritis) and architectural alterations
causing mucosal disruption and increased intestinal permeability.29,30,39,40 Because
cats have high numbers of bacteria in their proximal small intestines, translocation
of enteric bacteria can occur across the inflamed intestines into the portal circulation
potentially seeding the liver and/or pancreas. Alternatively, reflux of enteric contents
into the pancreaticobiliary duct causing ascending infection in the liver and pancreas
could occur.41 Duodenal reflux may occur in response to an increase in duodenal
pressure during vomiting associated with IBD.

Interplay of Pancreatitis, Inflammatory Liver Disease, and Inflammatory Bowel

Disease
How inflammation in 1 organ contributes to inflammation in other GI organs is not fully
known. Different scenarios are proposed with current hypotheses supporting either a
bacterial- or an immune-mediated pathogenesis.
The first model proposed by Simpson3 (Fig. 1A) relates to the development of acute
(suppurative) pancreatitis and neutrophilic cholangitis. One variant of this is that the
1142 Lidbury et al

Fig. 1. (A) Proposed pathogenesis for triaditis emphasizing the roles of dysbiosis, enteric
inflammation (IBD), bacterial translocation, and secondary seeding of the liver and pancreas
causing neutrophilic cholangitis and acute pancreatitis, respectively. (B) Proposed pathogen-
esis for triaditis emphasizing the roles of dysbiosis, chronic intestinal inflammation, and
autoimmunity as stimuli for chronic lymphocytic cholangitis and chronic immune-
mediated pancreatitis. DAMPs, damage-associated molecular patterns; MAdCAM, mucosal
addressin cell adhesion molecule-1; MAMPs, microbe-associated molecular patterns; PAMPs,
pathogen-associated molecular patterns. (Modified from Ref.3)

inciting event is intestinal disease that results in enteritis and dysbiosis with enteric
translocation of bacteria across the inflamed intestinal mucosa. Translocation of bac-
teria could cause septicemia, resulting in hematogenous infection of the liver and/or
the pancreas. An alternative model suggests that the inciting event is acute pancrea-
titis that secondarily leads to acute enteritis and/or neutrophilic cholangitis, possibly
because of the proximity of these 3 organs. In this scenario, enteritis favors secondary
dysbiosis with potential sequelae of bacterial translocation, septicemia, and microbial
seeding of the liver and/or pancreas. In an experimental model of induced feline acute
pancreatitis, seeding of the pancreas with enterically translocated E coli has been
 Triaditis 1143

shown to occur supporting the hypothesis that acute pancreatitis could be the initial
event in the pathogenesis of triaditis.42–44
The other proposed mechanism (Fig. 1B) hinges on chronic intestinal inflammation
and the development of secondary immune mechanisms as a cause for triaditis.3 Ge-
netic and environmental factors are suggested to play a role in decreasing immune
tolerance to components of the GI microbiota and/or diet, resulting in chronic IBD.
In this scenario, dysbiosis, increased intestinal permeability, low-grade bacterial
translocation, and activation of innate and/or adaptive immunity contribute to
immune-mediated injury to the liver and pancreas. Chronic intestinal disease is often
associated with nonspecific reactive hepatitis in dogs and cats.45 Moreover, loss of
immune tolerance in the intestines could secondarily affect the liver and pancreas
causing lymphocytic cholangitis and/or chronic pancreatitis, respectively. In humans,
autoimmune pancreatitis46 and primary sclerosing cholangitis (PSC)47 may occur in
association with IBD. In PSC, 1 mechanism for targeting of bile ducts is “gut lympho-
cyte homing” of activated T cells generated in the intestine. Homing is mediated by
mucosal addressin-cell adhesion molecule I and chemokine (C-C motif) ligand 25,
which are normally expressed in the intestine but can also be aberrantly expressed
by the liver in this disease.3,48,49 In addition, in PSC, cholangiocytes can produce in-
flammatory cytokines in response to pathogen-associated molecular patterns and
other stimuli.50 Another potential mechanism is that in response to gut-derived micro-
bial molecules from the portal circulation, cholangiocytes become senescent and
secrete inflammatory cytokines and other molecules.48 It is likely that the GI tract
and the liver also communicate via bile acids and the host-microbiota metabolome.47
In humans, autoimmune pancreatitis can be part of a multisystemic condition that
often occurs in association with IBD and/or PSC.46,51 A variety of autoantibodies,
including those against carbonic anhydrase type II and pancreatic secretory trypsin
inhibitors, have been identified in people with autoimmune pancreatitis. It has been
proposed that molecular mimicry between microbial and host proteins could lead to
autoimmunity.52 For example, significant homology between human carbonic
anhydrase-II and a-carbonic anhydrase of Helicobacter pylori has been shown. There-
fore, in a genetically susceptible person it is possible the H pylori infection could lead
to autoimmune pancreatitis.53 It is possible that similar mechanisms could lead to loss
of immune tolerance and the development of triaditis in cats.
It is important to note that because triaditis is a syndrome with variation in the com-
binations of organs affected, the type, severity, and duration of clinical signs, and the
type of inflammatory infiltrates present, different mechanisms may be at play in indi-
vidual cats. It is also clear that there is still much unknown about the pathogenesis
of this syndrome.

HOW TO DIAGNOSE TRIADITIS

General Diagnostic Overview
Definitive diagnosis of triaditis requires integration of the patient’s history, clinical ex-
amination, results of laboratory testing, diagnostic imaging findings, and tissue bi-
opsies confirming histologic inflammation (Table 2). Sometimes because of financial
or patient-related constraints, a presumptive diagnosis is made based on the patient’s
history, clinical examination, results of laboratory testing, diagnostic imaging findings,
and cytologic evaluation of the liver/pancreas. However, this approach hinders the cli-
nician’s ability to make an accurate diagnosis. Ultrasound-guided FNA of hepatic pa-
renchyma and bile may be useful for confirming active bacterial infection causing
ILD8,25 (see Craig B. Webb’s article, “Evidence-Based Medicine: Ultrasound-guided
 1144
Lidbury et al
Table 2
Diagnostic testing options for triaditis

Diagnostic Test Pancreatitis ILD IBD

Clinical signs Decreased appetite, lethargy, Decreased appetite, lethargy, Decreased appetite, lethargy,
vomiting, weight loss, diarrhea vomiting, weight loss, icterus vomiting, weight loss, diarrhea
Physical examination Abdominal pain, mass or effusion Icterus, hepatomegaly,  fever Thickened bowel loops,
mesenteric lymphadenopathy
Laboratory tests
CBC Neutrophilia, neutropenia, Anemia, leukocytosis, Anemia, neutrophilia
thrombocytopenia neutrophilia  left shift
Biochemistry Low calcium and albumin Increased ALT, AST, ALP, total Low phosphorous  low
bilirubin, globulins5,8,71 albumin40
Specialized serology/biomarkers Elevated feline pancreatic lipase Bile acid test Low cobalamin  low folate29,74
immunoreactivity, fPL6,11,67
Diagnostic imaging
Radiographs Loss of serosal detail, abdominal  Mild hepatomegaly, choleliths Fluid-distended bowel loops
effusion
Ultrasound Increased pancreatic size, Hepatomegaly, hyperechoic liver, Thickened intestinal wall, 
hypoechoic parenchyma, enlarged common bile duct, normal wall layering, muscularis
hyperechoic mesenteric fat, choleliths, gall bladder wall thickening, mesenteric
abdominal effusion,9,13 abnormalities5,9,71 lymphadenopathy29
US interventions FNA of pancreas for cytology and FNA of liver  gall bladder for Possible FNA of mesenteric lymph
culture cytology and culture, needle nodes
(Tru-Cut) biopsy8,25
Tissue diagnosis Biopsy by laparoscopy, laparotomy Biopsy by US guidance (needle), Biopsy by GI endoscopy,
laparoscopy, laparotomy laparotomy

Data from Refs.5,6,8,9,11,13,25,29,40,67,71,74

 Triaditis 1145

Percutaneous Cholecystocentesis in the Cat,” in this issue). The presence of neutro-

phils or lymphocytes on cytologic evaluation of hepatic aspirates is suggestive of
neutrophilic or lymphocytic cholangitis (or small cell lymphoma), respectively. Howev-
er, hepatic FNA cytology has significant diagnostic limitations, and results should be
cautiously interpreted.54 Tissue biopsy by GI endoscopy, laparoscopy, or exploratory
laparotomy with histopathology confirms inflammation in the liver, pancreas, and/or
intestines.

Histopathologic Features of Tissue Inflammation

Histopathologic evaluation of liver, intestine, and pancreas is required for a definitive
diagnosis of triaditis in cats. However, many veterinary pathologists do not recognize
this as a distinct disease complex in cats.
Chronic interstitial pancreatitis is the most common histologic type seen in cats with
triaditis (Fig. 2).3,12 A multifocal distribution, with interlobular, intralobular, or dissect-
ing fibrosis, is a prominent feature of chronic pancreatitis. The interstitium is infiltrated
with lymphocytes, plasma cells, and occasionally, macrophages.55 When a neutro-
philic component is seen, it is described as chronic active pancreatitis, and cholangitis
and/or IBD are commonly present.12 Additional features of chronic pancreatitis
include cystic dilatation of acini, ductal ectasia, ductal epithelial hyperplasia, and
acinar atrophy in severely fibrosed areas.55
Histologically, hepatic inflammation in cats with triaditis can be broadly divided into
neutrophilic cholangitis and lymphocytic cholangitis.5,12
 In the acute form of neutrophilic cholangitis, the portal region is generally edem-
atous and populated with neutrophils. Inflammatory cells often infiltrate the bile
ducts and transmigrate through the degenerating or viable biliary epithelium to
the ductular lumen. Based on the severity and disease progression, the inflam-
matory infiltrate may cross the limiting plate and cause hepatocellular necrosis
in the periportal regions (cholangiohepatitis).

Fig. 2. Chronic interstitial pancreatitis. There are mild to moderate numbers of lymphocytes
expanding the interstitium between pancreatic exocrine acini and between pancreatic lob-
ules. There is a modest degree of fibrosis expanding the pancreatic interstitium.
Hematoxylin-eosin [HE] stained sections, original magnification 200.
1146 Lidbury et al

 In chronic neutrophilic cholangitis, the inflammatory infiltrate is mixed with lym-

phocytes and plasma cells, and the portal region is expanded with biliary hyper-
plasia and portal to bridging fibrosis (Fig. 3).
 Lymphocytic cholangitis is characterized by infiltration of lymphocytes in the por-
tal region accompanied with bile duct proliferation, bile duct epithelial degener-
ation, bile duct loss (ductopenia), and periportal to bridging fibrosis.5,15,20,22
Occasionally, lipogranulomas may be present in the portal regions that are help-
ful in differentiating lymphocytic cholangitis from hepatic lymphomas.20 Other
features of lymphocytic cholangitis that can help differentiate it from small cell
lymphoma include bile duct targeting, ductopenia, peribiliary fibrosis, and portal
B-cell aggregates.20
Because IBD is a diagnosis of exclusion, the histologic changes indicative of this
condition are interpreted cautiously and in a contextual manner.39,56,57 Despite the
standardization attempts made to characterize the GI inflammation, inconsistencies
associated with interobserver variability and specimen quality are of real concern.58
In some cases, differentiating between IBD and feline small intestinal lymphoma can
be challenging and may require specialized testing (eg, immunophenotyping or clon-
ality testing with PCR for antigen receptor rearrangement [PARR]).59 It should be noted
that there is evidence that clonality testing with PARR has a low diagnostic specificity
for feline intestinal small cell alimentary lymphoma, so results must be interpreted in
conjunction with histologic findings and immunophenotyping results.60,61 Histological-
ly, the extent of mucosal architectural changes, and to a lesser degree, the type and
degree of inflammatory infiltration are used to assess intestinal inflammation. An
increased number of inflammatory cells (lymphocytes, plasma cells, and/or eosino-
phils) are observed in the lamina propria depending on the subtype, with
lymphocytic-plasmacytic enteritis being the most common form of IBD in cats
(Fig. 4).30,39 In addition, an increased number of intraepithelial lymphocytes is seen

Fig. 3. Chronic-active neutrophilic cholangitis/pericholangitis: liver, portal region. The por-

tal area is expanded by edema, by peribiliary fibrosis, and by moderate numbers of lympho-
cytes admixed with fewer plasma cells and neutrophils. Multifocally, biliary epithelium is
infiltrated by a few neutrophils. There are multiple cross-sectional profiles of bile ducts
(biliary reduplication/hyperplasia). HE stained sections, original magnification 200.
 Triaditis 1147

Fig. 4. Chronic lymphocytic enteritis (IBD): small intestine, jejunum. Villi within the section
are stumpy and thicker than normal with more than 4 layers (up to 10–12 layers) of lympho-
cytes expanding the lamina propria. There is a diffuse infiltrate of lymphocytes and plasma
cells in all layers of the mucosa with subjectively increased numbers of intraepithelial lym-
phocytes. There are scattered neutrophils admixed with the mononuclear infiltrate. HE
stained sections, original magnification 100 magnification.

in the intestinal mucosa. Architectural changes generally noticed in the intestine (eg,
duodenum) include villous blunting, villous epithelial erosion, crypt ectasia, lacteal
dilation, and periglandular fibrosis.39 Architectural changes in the intestinal mucosa
are considered a more reliable criterion that correlates best with disease severity.39,62
In 1 study, the histologic lesions of IBD in cats with triaditis were found to be more se-
vere compared with cats with IBD alone.12

TREATMENT STRATEGIES FOR TRIADITIS

General Considerations
Treatment of triaditis is based on the overall health status of the patient and the type
and severity of disease in component organs. Global treatment recommendations are
found in Table 3. Because histopathologic confirmation of multiorgan inflammation is
often unavailable, therapy is often directed to the organ thought to be primarily
responsible for the clinical signs. When using this approach, the clinician should avoid
or use care when prescribing treatments that could adversely affect another compo-
nent or possible component of the cat’s disease. For example, in a cat with histolog-
ically confirmed IBD that has suspected but not histologically confirmed ILD, empiric
antibiotic therapy is often initiated before starting corticosteroids in case neutrophilic
cholangitis with an active bacterial infection is present. Integrating clinical findings,
laboratory testing, diagnostic imaging, and targeted FNA or biopsy results (if possible)
serve to prioritize treatment decisions. Immediate supportive care is required in cats
with persistent vomiting, abdominal pain, icterus, prolonged anorexia, severe hypovo-
lemia, hypotension, signs of sepsis, and/or pyrexia. These general nonspecific treat-
ments include hospitalization with intravenous (IV) fluid therapy for rehydration and
electrolyte correction, analgesics for abdominal discomfort, and antiemetics to control
 1148
Lidbury et al
Table 3
Treatment of pancreatitis, inflammatory liver disease, and inflammatory bowel disease

Treatment Pancreatitis3,67 ILD3,24,69–72 IBD29,38,40,57,63,74

Fluid therapy Parenteral crystalloids Parenteral crystalloids Uncommon
Colloid fluids
Plasma?
Analgesia Buprenorphine: 0.02 mg/kg IV, IM q6h Uncommon Uncommon
Fentanyl: transdermal patch 25 mg/h
as required
Antibiotics For confirmed bacterial infection, For confirmed bacterial infection For neutrophilic inflammation or
sepsis, severe neutrophilia  left (liver  bile) seen with neutrophilic abundant mucosal bacteria (FISH)
shift or suspicion of bacterial cholangitis; suspicion of bacterial
translocation; target E coli and translocation; targets E coli and
other enteric bacteria: other enteric bacteria:
Enrofloxacin: 2.5 mg/kg SC or PO q12h Enrofloxacin
Ticarcillin-clavulanate: 40 mg/kg IV Amoxicillin-clavulanate
q6h Ticarcillin-clavulanate
Antiemetics Maropitant: 1 mg/kg SC q24h Maropitant Maropitant
Ondansetron: 0.5–1.0 mg/kg PO q24h Ondansetron Ondansetron
Combination therapy has additive
effects
Immunosuppressive drugs Prednisolone for chronic pancreatitis: Lymphocytic cholangitis: LPE:
1–2 mg/kg PO q24h Prednisolone: 1–2 mg/kg PO q12h Prednisolone
Chlorambucil for severe IBD or LSA:
2 mg/cat PO 2–3 times/wk
Nutrition Naso-esophageal tube Naso-esophageal tube Hydrolyzed/restricted antigen diet
Esophagostomy tube Esophagostomy tube Soluble fiber for colitis
Mirtazapine: 2 mg PO q24 h Mirtazapine Mirtazapine
 Vitamins Cobalamin if deficient Vitamin K1 for coagulopathy: 0.5– Cobalamin: 250 mg SC weekly x 6 wk
1.5 mg/kg SQ q12 h for 3 doses +/ folate if deficient
+/ cobalamin if deficient
Vitamin E?
Nutraceuticals Uncommon SAMe: 20 mg/kg PO q24 h Probiotics/prebiotics?
Ursodiol: 10–15 mg/kg PO q24 h with n-3 fatty acids?
food
Surgery Biopsy (rarely performed) Biopsy with culture of liver  bile Full-thickness biopsy uncommon
EHBO  biliary stent or except to rule out LSA
cholecystoduodenostomy GI endoscopy (always obtain ileal
biopsies)
Co-morbidities ILD, IBD and/or diabetes mellitus IBD and/or pancreatitis ILD and/or pancreatitis
EPI with severe disease

Abbreviations: EHBO, extrahepatic biliary obstruction; IM, intramuscularly; LC, lymphocytic cholangitis; LPE, lymphocytic-plasmacytic enteritis; LSA, low-grade
alimentary lymphoma; NC, neutrophilic cholangitis; SC, subcutaneously.
Data from Refs.3,24,29,38,40,57,63,69–72,74,78

Triaditis
1149
1150 Lidbury et al

vomiting. Cats with hypocobalaminemia can be supplemented by parenteral means,

although recent work suggests that daily oral administration is also effective.63 Nutri-
tion is provided in persistently anorexic cats by use of nasoesophageal, esophageal,
or gastric feeding tubes.64–66

Treatment of Pancreatitis
Treatment of pancreatitis is mainly symptomatic and supportive. IV fluid therapy, an-
algesics, antiemetics, and enteral nutrition are the cornerstones of therapy. Fluid ther-
apy corrects the circulating fluid volume, restores and maintains microcirculation of
the pancreas (important because pancreatic ischemia can contribute to the develop-
ment of necrotizing pancreatitis), and restores and maintains plasma oncotic pres-
sure, especially if used with a synthetic colloid. Antiemetics (eg, maropitant and
ondansetron) control vomiting and continued fluid and electrolyte loss. The combina-
tion of maropitant and ondansetron provides an effective control of vomiting and
nausea in those patients who fail to respond to single antiemetic treatment alone. An-
algesics, including buprenorphine or fentanyl, are typically used for control of abdom-
inal pain during hospitalization. Transdermal fentanyl patches are very effective at
maintaining analgesia for longer periods of time (approximately 72 hours); however,
it may take up to 12 hours for therapeutic fentanyl concentrations to be achieved.3
The optimal diet to feed cats with pancreatitis is unknown; however, there is no evi-
dence that dietary fat restriction results in improved outcome. The authors often
feed these cats a highly digestible, moderate fat diet designed for intestinal disease,
or possibly, if concurrent IBD is present, an elimination diet. Some cats require place-
ment of a feeding tube to provide appropriate enteral nutrition. Antimicrobial therapy is
reserved for severe cases, such as those presenting with shock, fever, marked leuko-
cytosis, or suspected/confirmed sepsis.67 The considerations for selection of antimi-
crobials are similar to those later discussed for neutrophilic cholangitis. Use of
corticosteroids for acute pancreatitis is not recommended. For some cats with chronic
pancreatitis, however, especially if neutrophilic cholangitis has been ruled out, treat-
ment with anti-inflammatory doses of prednisolone seems to be beneficial. Whether
this is owing to a reduction in pancreatic inflammation or treatment of concurrent
IBD is uncertain.
The presence of comorbidities is common but only confirmed if biopsy of the
pancreas, liver, and small intestines are evaluated and cultures of the pancreas and
liver are performed. Although pancreatic biopsy remains the gold standard for diag-
nosing pancreatitis, the patchy distribution of histopathologic lesions limits routine
performance of this procedure by clinicians, especially in the acute setting.68 Persis-
tent biliary obstruction secondary to pancreatitis is another potential indication for sur-
gery when biliary stenting or cholecystojejunostomy is required. General anesthesia
allows for placement of an enteral feeding tube into the esophagus or stomach for
nutritional support.

Treatment of Inflammatory Liver Disease

Vitamin K1 is typically given to icteric cats before hepatic FNA, cholecystocentesis, or
hepatic biopsy. Antibiotics and supportive care are the primary treatments for neutro-
philic cholangitis. Antibiotics are ideally chosen based on bacterial culture and sus-
ceptibility testing. They should be active against gram-positive and gram-negative
aerobic and anaerobic bacteria (especially E coli and Enterococcus spp because
these are isolated most often).24,69 Bactericidal antibiotics that are active in bile and
can be administered IV are most suitable. Empirical first-choice options (these are
often given pending culture and susceptibility testing results) include a
 Triaditis 1151

fluoroquinolone, potentiated penicillin, a fluoroquinolone combined with a potentiated

penicillin or clindamycin, or ticarcillin-clavulanate; however, antimicrobial resistance is
frequent with Enterobacteriaceae, including E coli.24 Antibiotic therapy is typically
continued for 4 to 6 weeks.8 Other supportive measures are similar for cats with acute
pancreatitis and include IV fluid therapy and analgesics for control of abdominal pain.
Feline ILD is associated with oxidative stress and depletion of hepatic glutathione.70
Therefore, there is justification for administering oral antioxidants (ie, S-adenosylme-
thionine [SAMe], silybin, or vitamin E). There is also rationale for giving cats with chole-
stasis the synthetic bile acid and choleretic agent, ursodeoxycholic acid (UCDA).
Although there are few to no data documenting improved outcomes when these cyto-
protective drugs are given, their use is unlikely to be detrimental to the patient. How-
ever, it is important to prioritize medications that treat the underlying disease and
essential supportive care over them and to be cognizant that giving multiple oral med-
ications places a burden on the cat and its guardian.
The primary treatment of culture-negative lymphocytic cholangitis involves immu-
nosuppressive drug treatment with prednisolone for induction of remission and then
tapering over 6 to 8 week to the lowest effective dose. Supportive care, such as
feeding tubes, IV fluid therapy, antiemetics, and therapeutic abdominocentesis,
may also be indicated.71 One study showed that cats treated with prednisolone ther-
apy had prolonged survival27 and greater improvement in histopathologic inflamma-
tion compared with cats treated with UCDA, but no difference in hepatic fibrosis was
found.72 Chlorambucil is sometimes used for refractory cases or to reduce the corti-
costeroid dose needed to maintain remission.3 Again, there is a rationale to admin-
ister antioxidant agents, but no improvement in clinical outcome has been
documented with their use. Cats with complete biliary obstruction and some cats
with choleliths will require surgery.

Treatment of Inflammatory Bowel Disease

Sequential therapy using specially formulated diets, antimicrobials, and immuno-
suppressive drugs is the most common strategy used to achieve clinical remission
in cats with chronic enteropathies (including IBD), with a final diagnosis made
following histopathologic evaluation of intestinal biopsy samples.73 The type of
cellular infiltrate (lymphocytic-plasmacytic, eosinophilic, neutrophilic, or granulo-
matous) and severity of mucosal epithelial/architectural alterations (erosion/ulcera-
tion, villus atrophy/fusion, fibrosis) serve to guide treatment decisions. There is
strong evidence from clinical trials to support a recommendation to feed elimination
diets to cats with mild IBD.38,40 Clinical signs in food-responsive cats may resolve
quickly within 3 to 5 days on an elimination diet. It is not possible to ascertain which
form of diet (eg, antigen-restricted or hydrolyzed) is most effective in modulating GI
signs in cats. Cats with more severe mucosal inflammation that fail to achieve
remission to diet alone may respond to a combination of diet plus predniso-
lone.29,56 Vitamin B12 deficiencies are common in cats with chronic GI disease
and require parenteral or oral supplementation.63,74
Cats failing prednisolone therapy should be investigated further (eg, through immu-
nophenotyping and possibly clonality testing with PARR) to rule out misdiagnosis and
the possibility of small cell alimentary lymphoma. Cats with small cell alimentary lym-
phoma usually respond well to combination therapy with prednisolone and chloram-
bucil and supplementation with vitamins B12 and folate.75,76 Cats with neutrophilic
or granulomatous infiltrates on intestinal biopsy should be screened for infectious
agents (eg, bacterial, viral [FIP, feline leukemia virus, feline immunodeficiency virus],
fungal) before initiating immunosuppressive therapy.
1152 Lidbury et al

Box 3
Risk factors associated with negative outcomes in triaditis or component organ inflammation

 Acute pancreatitis: plasma ionized hypocalcemia; ionized hypocalcemia, lethargy, pleural

effusion, hypoglycemia, azotemia, parenteral nutrition administration, and persistent
anorexia67
 Chronic pancreatitis: development of diabetes mellitus and EPI3
 Lymphocytic cholangitis: presence of concurrent illness71
 IBD: severe histologic inflammation seen with triaditis?12; failed response to dietary
trials 1 prednisolone76

Abbreviation: EPI, exocrine pancreatic insufficiency.

Data from Refs.3,12,67,71,76

PROGNOSIS FOR CATS WITH TRIADITIS

There is a paucity of information defining prognosis for cats with triaditis. Overall, the
prognosis of each patient will depend on the severity of their disease and extent of
systemic involvement. For example, cats with severe acute pancreatitis or neutrophilic
cholangitis, especially with systemic signs (shock, septicemia, systemic hypotension,
disseminated intravascular coagulation), will require aggressive medical therapy to
survive the initial period of hospitalization. On the other hand, cats diagnosed with
mild to moderate lymphocytic-plasmacytic IBD, accompanied by increased serum
pancreas-specific lipase concentrations, typically respond well to treatment of IBD
with a hydrolyzed diet and prednisolone.40,77 Several risk factors linked to prognosis
have been identified for cats with triaditis or its inflammatory components (Box 3). A
compilation of additional evidence-based data, ideally based on clinical trials, will
improve the understanding of the complex interactions among inflammation in the
pancreas, liver, and/or intestines.

ACKNOWLEDGMENTS

The authors gratefully acknowledge Dr Kenny Simpson, Cornell University for his
insight into manuscript preparation and Dr Tyler A. Harm, Iowa State University for his-
topathologic images.

DISCLOSURE

The authors have no disclosures to report nor was funding required for production of
this article.

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