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Veterinary Internal Medicne - 2022 - Cridge - New Insights Into The Etiology Risk Factors and Pathogenesis of

This review article provides an overview of the etiology, risk factors, and pathogenesis of pancreatitis in dogs, highlighting that while many cases are considered idiopathic, there are identifiable risk factors that can inform clinical practice. It discusses dietary influences, drug and toxin associations, and hereditary predispositions, emphasizing the complexity of the disease and the need for further research to clarify causative relationships. The authors advocate for improved awareness of these factors to aid in the prevention and management of pancreatitis in canine patients.

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0% found this document useful (0 votes)
33 views19 pages

Veterinary Internal Medicne - 2022 - Cridge - New Insights Into The Etiology Risk Factors and Pathogenesis of

This review article provides an overview of the etiology, risk factors, and pathogenesis of pancreatitis in dogs, highlighting that while many cases are considered idiopathic, there are identifiable risk factors that can inform clinical practice. It discusses dietary influences, drug and toxin associations, and hereditary predispositions, emphasizing the complexity of the disease and the need for further research to clarify causative relationships. The authors advocate for improved awareness of these factors to aid in the prevention and management of pancreatitis in canine patients.

Uploaded by

jrjailsoon74
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© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
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Download as PDF, TXT or read online on Scribd
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19391676, 2022, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jvim.16437 by CAPES, Wiley Online Library on [02/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Received: 4 January 2022 Accepted: 12 April 2022
DOI: 10.1111/jvim.16437

REVIEW

New insights into the etiology, risk factors, and pathogenesis


of pancreatitis in dogs: Potential impacts on clinical practice

Harry Cridge1 | Sue Yee Lim2 | Hana Algül3 | Jörg M. Steiner2

1
Department of Small Animal Clinical Sciences,
College of Veterinary Medicine, Michigan Abstract
State University, East Lansing, Michigan, USA While most cases of pancreatitis in dogs are thought to be idiopathic, potential risk
2
Gastrointestinal Laboratory, Department of
factors are identified. In this article we provide a state-of-the-art overview of
Small Animal Clinical Sciences, College of
Veterinary Medicine and Biomedical Sciences, suspected risk factors for pancreatitis in dogs, allowing for improved awareness and
Texas A&M University, Texas, USA
detection of potential dog-specific risk factors, which might guide the development
3
Gastrointestinal Cancer and Inflammatory
Research Laboratory, Technical University of of disease prevention strategies. Additionally, we review important advances in our
Munich, Munich, Germany understanding of the pathophysiology of pancreatitis and potential areas for thera-
Correspondence peutic manipulation based thereof. The outcome of pathophysiologic mechanisms
Harry Cridge, Department of Small Animal and the development of clinical disease is dependent on the balance between
Clinical Sciences, College of Veterinary
Medicine, Michigan State University, stressors and protective mechanisms, which can be evaluated using the critical
East Lansing, MI, USA. threshold theory.
Email: [email protected]

KEYWORDS
[Correction added on 28 May 2022, after first
online publication: The phrase “uncoupled protein colocalization, critical threshold theory, ER stress, impaired autophagy, mitochondrial
response” has been replaced with “unfolded dysfunction, oxidative stress, pathologic calcium signaling
protein response” on pages 1 (abbreviations), 10,
11 (Figure 6), and 12 (Figure 8).]

1 | I N T RO DU CT I O N data, which might not be directly relevant to spontaneous disease.


Clinical observations are also not without limitations, and the com-
The etiology and pathogenesis of spontaneous pancreatitis are poorly plexity of spontaneous disease often limits determination of causa-
understood in both humans and dogs and data is largely extrapolated tion. Furthermore, discrepancies in diagnostic standards and evolution
from experimental models and observations in clinical disease. Experi- of these criteria over time likely further complicate interpretation of
mental models provide mechanistic insights; however, spontaneous observational data in companion animal species. In this review we will
disease is likely far more complex and dependent on multiple genetic utilize a combination of data types to review the latest understanding
and environmental factors, some of which might be unknown. Addi- of the etiology, risk factors, and pathogenesis of pancreatitis in dogs
tionally, animal models provide species-specific or etiology-specific and their relation to clinical disease.

Abbreviations: AP, acute pancreatitis; cPLI, canine pancreatic lipase immunoreactivity; cTLI,
canine trypsin like immunoreactivity; DGGR, 1,2-O-dilauryl-rac-glycero glutaric acid-(60 - 2 | ETIOLOGY AND POTENTIAL RISK
methylresorudin) ester; DM, diabetes mellitus; ER, endoplasmic reticulum; HAC,
hyperadrenocorticism; ICAM-1, immunoglobulin-like cell adhesion molecule 1; IL, interleukin; FACTORS FOR PANCREATITIS
KBr, potassium bromide; LAMP-1, lysosomal membrane protein 1; LAMP-2, lysosomal
membrane protein 2; LFA-1, leukocyte function antigen-1; MPTP, mitochondrial permeability
transition pores; NEFA's, nonesterified fatty acids; NF-κB, nuclear factor-kappa beta; OR,
The etiology of pancreatitis is much better understood in humans than
odds ratio; PB, phenobarbital; PSTI, pancreatic secretory trypsin inhibitor; ROS, reactive in dogs. A systematic review and meta-analysis revealed that gall-
oxygen species; SPINK1, serine protease inhibitor Kazal type 1; STAT3, signal transducer and
stones were the most frequent cause of acute pancreatitis in humans,
activator of transcription 3; TNF-α, tumor necrosis factor alpha; UPR, unfolded protein
response. followed by alcoholic pancreatitis (with geographical differences).1

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any
medium, provided the original work is properly cited and is not used for commercial purposes.
© 2022 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.

J Vet Intern Med. 2022;36:847–864. wileyonlinelibrary.com/journal/jvim 847


19391676, 2022, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jvim.16437 by CAPES, Wiley Online Library on [02/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
848 CRIDGE ET AL.

TABLE 1 Suggested risk factors for pancreatitis in dogs The third most common cause is idiopathic acute pancreatitis (AP), which

Category Potential risk factor is suspected to be the most common cause in dogs.1 It is important to
note that research into the etiology of pancreatitis in dogs is limited. The
Dietary factors High fat diet2–4
term cryptogenic AP, might also, more accurately reflect the level of
Ingestion of unusual food items5,6
diagnostic investigation commonly performed into specific etiologies in
Ingestion of table scraps5
dogs. In other words, pancreatitis in dogs might be classified as idio-
Ingestion of trash5
pathic, not because there is no underlying cause, but because the poten-
Drugs/toxins L-asparaginase7,8
tial underlying causes have not been sufficiently studied.
Phenobarbital and potassium bromide9–11a Many factors have been identified as potential risks for AP in
Azathioprine12–14 dogs. These factors are often established based on a temporal associ-
Potentiated sulfonamides15 ation with the onset of clinical signs, and it is important to consider
Organophosphates12,16 that these risk factors might not represent a causative relationship.
Corticosteroids,12,17b These risk factors can be broken down into: dietary factors, lipid dis-
Furosemide 12 orders, drug and toxins, endocrinopathies, hereditary/breed predispo-

Atovaquone/proguanil (Malarone)18 sitions, and miscellaneous causes (see Table 1).


19b
N-methyl-glucamine (Meglumine),
Clomipramine20
2.1 | Dietary factors
Zinc21
Endocrinopathies Hyperadrenocorticism12,22,23a
High fat diets induce or worsen the severity of pancreatitis in dogs lead-
Hypothyroidism12a
ing to the belief that high-fat diets are a predisposing factor to AP.2,46
12,24,25ac
Diabetes mellitus,
Unfortunately consensus criteria regarding what constitutes a high fat
Hereditary/breed SPINK 1 mutation,26,27b diet is lacking. However, a low-fat diet is considered to contain less than
predispositions Acute: Terrier breeds, miniature poodles, 20% fat on a metabolizable energy basis.47 Animal models document
dachshunds, cocker spaniel, Alaskan
associations with high protein and fat diets in the development of
malamute, laika, miniature schnauzer12,28–31
AP.48–51 Further potential evidence for the role of high-fat diets in the
Chronic: Cavalier King Charles spaniel,
development of AP comes from the results of a study evaluating keto-
collies, boxers32
genic diets in the management of idiopathic epilepsy.3 In that study 3/9
Lipid disorders Hypertriglyceridemia28,29,33
dogs fed a ketogenic diet (57% fat, 5.8% NFE, 25% crude protein; as
Miscellaneous Babesiosis34–36
dry matter) developed pancreatitis whereas only 2/31 dogs fed the
Canine monocytic ehrlichiosis37
control diet (16% crude fat, 54% NFE, 25% crude protein; as dry mat-
Schistosomiasis (Heterobilharzia
ter) developed pancreatitis.3 This study is published in abstract form
americana)38–40
and information needed to calculate the fat content on an energy basis
Honeybee envenomation41
is unavailable. Additionally, the method of pancreatitis diagnosis is not
Organic acidemias42
reported. A more recent study prospectively evaluated the effect of
Immunoglobulin G4-related disease43,44
dietary composition on serum concentrations of canine pancreatic
Increasing age12 lipase immunoreactivity (cPLI).52 In that study there was no difference
5,12
Obesity/overweight status in serum cPLI concentration between a maintenance dog food (4.01 g
5,12
Neutered status of fat/100 kcal, 16% crude fat) and a low fat dog food (1.55 g of
Previous surgery5 fat/100 kcal, 5% crude fat), but it is important to note that the dogs
45 were all healthy dogs and that none of the diets are considered high in
Hepatitis/cholangitis
fat.52 While the study investigated the effect of dietary fat content on
Note: Potential risk factors for AP in dogs. Many of these factors are
implied by a temporal association alone and causation has not been serum cPLI concentration, this study cannot be extended to infer the
established for many of these factors. Additionally, various definitions effects of high fat diets on the development of pancreatitis. In another
and indicators of AP were utilized in the referenced studies and study 2/50 dogs receiving a struvite dissolution diet (5.7 g/100 kcal,
clinical signs of AP were not always noted, thus some of these risk
26.3% crude fat) were noted to develop pancreatitis.4 A control group
factors might represent risk factors for subclinical pancreatic injury
rather than primary clinical AP. The relationship between the was not used as part of the study design and the basis for a diagnosis
proposed risk factors and pancreatitis is often challenging to of pancreatitis is not reported. Given the current literature definitive
determine clinically and for some risk factors the direction of conclusions on the significance of high levels of dietary fat in the devel-
causation cannot be determined.
aa
opment of pancreatitis cannot be made. Controlled clinical trials are
May be due to secondary lipid abnormalities.
b
Contradictory evidence exists.
required to evaluate this potential relationship. Further studies are also
c
Reverse direction of causation has been suggested. required to determine the influence of the type of fat on AP in dogs,
19391676, 2022, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jvim.16437 by CAPES, Wiley Online Library on [02/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
CRIDGE ET AL. 849

given differences in endoplasmic reticulum stress noted in in vitro stud- therapeutic target. Of note, many dogs with hypertriglyceridemia do
ies.53 The role that diet plays in the development of AP is also compli- not develop pancreatitis, and risk modifying factors are unfortunately
cated by its association with other predisposing factors including poorly understood.
obesity and hypertriglyceridemia. Two retrospective studies have iden-
tified potential relationships between being overweight and develop-
ment of AP.5,12 In a retrospective study 39/101 dogs diagnosed with 2.3 | Drugs/toxins
AP were overweight and being overweight is associated with a 1.3
increased risk of AP.5,12 Unusual food items (odds ratio [OR]: 4.3), table Several drugs and toxins are implicated in the development of AP. In
scraps (OR: 2.2) and access to the trash (OR: 13.2) increases the risk of human patients several different classification systems have been
pancreatitis in dogs.5,6 It should be noted that this study is an associa- developed for drug associated pancreatitis. Initial systems were based
tion study and thus the level of evidence for a causative relationship on 3-tiers with the relative weighting being determined by the num-
should be considered weak. Additional factors other than dietary fat ber of cases and data from drug re-exposure (if performed).60,61
alone might modulate the disease risk toward pancreatitis and severe More-recently, the Badlov classification system, utilizing a 4-class sys-
disease in a given dog. Potential factors might include the level of intra- tem, was introduced.62 Class I drugs are classified as those with at
54,55
pancreatic and visceral fat present and its composition. This phe- least 1 case report documenting recurrence of AP with re-exposure to
nomenon is observed in people with alcoholic pancreatitis.56 While a the drug.62 Class II drugs are classified as those with a consistent
certain daily consumption of alcohol is a significant risk factor for devel- latency (ie, time from initiation of treatment to development of dis-
oping acute pancreatitis, certainly only the minority of human patients ease) in 75% or more of reported cases.62 Class III drugs are classified
56
with such alcohol consumption develop pancreatitis. Phosphate sta- as drugs with 2 or more case reports, but no consistent latency period
tus (eg, hypophosphatemia) is a risk modifying factor in alcohol induced or rechallenge reports.62 Class IV drugs are similar to Class III drugs.
57
pancreatitis in people. Unfortunately, these risk modifying factors are Except they have only 1 documented case report.62 It is the authors'
poorly understood in dogs fed a high fat diet. opinion that further detailed reports of cases of potential drug-
associated pancreatitis are needed before the development of a veter-
inary classification scheme.
2.2 | Lipid disorders L-asparaginase is associated with pancreatitis in up to 16.2% of chil-
dren being treated for acute lymphocytic leukemia or undifferentiated
Hypertriglyceridemia is commonly investigated as a cause of AP given leukemia.63 L-asparaginase depletes the body of L-asparagine, thus reduc-
the results of ex vivo and in vivo studies. Triglycerides are hydrolyzed ing protein synthesis, which also affects the pancreas and might predis-
by pancreatic lipase, thus high levels of triglycerides might result in pose to AP.64 Eleven of 52 dogs evaluated at various stages of a CHOP
excessive production of free fatty acids which are toxic to pancreatic protocol for canine large-cell lymphoma developed clinical signs compati-
58
acinar cells. Addition of triglycerides to a perfused canine pancreas ble with pancreatitis; however, the serum cPLI concentrations were not
results in structural changes including edema, hemorrhage, and weight consistently increased, suggesting that the gastrointestinal signs that
gain suggestive of pancreatic injury.59 Clinical studies evaluating the occurred were likely due to gastrointestinal toxicoses secondary to che-
correlation between hypertriglyceridemia and AP have been focused motherapy rather than drug-induced AP.7 In the same study, 14% of dogs
on the miniature schnauzer. Miniature schnauzers with a history of that received concurrent L-asparaginase and vincristine had serum cPLI
pancreatitis are more likely to have hypertriglyceridemia than those concentrations ≥400 mg/dL; however no clinical signs of pancreatitis
without a history of pancreatitis (77% vs 33%) and there is an associa- were noted.7 There was no statistically significant difference in serum
tion between hypertriglyceridemia and elevated serum cPLI concen- cPLI concentrations before and after vincristine therapy, suggesting that
28,29
trations. Additionally, severe hypertriglyceridemia (≥862 mg/dL) L-asparaginase was the cause of any subclinical increase of cPLI.7 A fur-
is associated with a 4.5 increased risk of an elevated cPLI concentra- ther case study reported suspected L-asparaginase induced pancreatitis
tion.29 While the relationship between hypertriglyceridemia and AP 2 days after therapy. In that case report the diagnosis of AP was made
has been described as bidirectional, there is a low prevalence of hyp- based on the presence of consistent clinical signs in conjunction with an
33
ertriglyceridemia (18%) in dogs with AP. This prevalence is lower increased serum cPLI concentration, although abdominal ultrasonography
than in earlier studies and likely reflects the study design, which con- was normal.8 Further studies are required to determine the incidence and
trolled for causes of secondary pancreatitis in addition to medication clinical significance of AP in dogs treated with L-asparaginase.
and dietary factors that could affect serum triglyceride concentra- Several studies suggest a relationship between anticonvulsant
tions. Although the prevalence of hypertriglyceridemia was signifi- therapy and AP. Between 10.3% and 37.0% of dogs with idiopathic
cantly different between the AP (18%) and the control (7.5%) group in epilepsy being treated with potassium bromide (KBr) have biochemical
that study, the magnitude of hypertriglyceridemia was low (median variables and a clinical history consistent with pancreatitis.9 This study
67 mg/dL vs 54 mg/dL).33 The results of these studies suggest that was performed prior to the commercial development of cPLI assays. A
severe hypertriglyceridemia is unlikely to occur secondary to AP group of researchers measured cPLI concentrations in 337 serum
alone, and if severe hypertriglyceridemia is documented in a dog, it samples that had been submitted for measurement of serum pheno-
likely reflects a predisposing factor to AP and could be considered a barbital (PB) levels, KBr levels, or a combination of both in dogs.10 In
19391676, 2022, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jvim.16437 by CAPES, Wiley Online Library on [02/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
850 CRIDGE ET AL.

that study, there was an increased risk of an elevated cPLI concentra- immune mediated diseases. In this study, 5/10 dogs showed serum cPLI
tion in dogs being treated with KBr, PB, or a combination of PB and concentrations ≥400 mg/dL; however, no clinical signs of pancreatitis
10
KBr. Given the study design, no information was available regarding were noted.17 The potential contribution of the primary disease process
clinical signs or diagnostic imaging findings, potentially limiting its to the cPLI concentration is unclear. A recent abstract also documented
application. An additional study documented that 6.8% of dogs receiving no effect of chronic administration of supraphysiologic doses of cortico-
PB or KBr have an elevated cPLI concentration.11 One potential con- steroids on cPLI concentration in 15 dogs.72 Administration of corticoste-
founding factor is that long term treatment of dogs with PB with or with- roids prior to referral also had no effect on serum cPLI activities in a
out KBr is associated with the development of hypertriglyceridemia in recent study of dogs with intervertebral disc disease.73 The effect of
33% of dogs, which might be an independent risk factor for pancreatitis. 65
exogenous corticosteroids on 1,2-O-dilauryl-rac-glycero glutaric acid-(60 -
The combined results of these studies suggest that a clinically relevant methylresorudin) ester (DGGR) lipase assays has also been evaluated.74 In
proportion of dogs receiving PB, KBr, or a combination of both might 17 dogs being treated with corticosteroids for several reasons DGGR
develop increases in serum cPLI concentrations. lipase activity increased following initiation of treatment and reduced dur-
Azathioprine is implicated in the development of AP based on data in ing drug tapering.74 The magnitude of increase in DGGR lipase activity
humans in addition to ex vivo models and isolated reports in dogs. Expo- was however low, potentially reducing the clinical significance of this find-
sure of an ex vivo perfused canine pancreas to azathioprine results in ing.74 The combined results of the above studies suggest that exogenous
marked effects on pancreatic function, as determined by secretory vol- corticosteroids are unlikely to result in clinically important AP in dogs,
ume, bicarbonate and trypsin output.66 Acute pancreatitis has been docu- although markers of subclinical pancreatic injury/inflammation might be
mented in 2 case reports of dogs receiving azathioprine in conjunction noted in some cases, and might be more importantly influenced by con-
13,14
with prednisone for various immune mediated disorders. Acute pan- current disease. Additionally, corticosteroids are being increasingly utilized
creatitis was suspected to be related to the azathioprine and not the at anti-inflammatory doses in the management of AP in dogs. In 1 study a
prednisone in both reports due to improvement in clinical signs after dis- 1 mg/kg dose of prednisolone was shown to reduce C-reactive protein
continuation of the drug; however, repeat exposure was not performed concentrations, shorten time to clinical improvement, and decrease mor-
and as such causation is difficult to prove. These reports were published tality in spontaneous AP in dogs.75 A recent review, evaluating data from
before the development of commercial cPLI assays. Azathioprine was also multiple species, suggested that corticosteroids might have a positive
noted in the history of 2 dogs, but in conjunction with corticosteroids, in effect on outcome in the treatment of acute or acute on chronic pancrea-
a retrospective study evaluating risk factors for AP in dogs.12 While addi- titis in dogs.76
tional studies are needed to fully determine the risk profile of azathioprine Several early studies documented a potential relationship between
with regard to AP, the authors suggest that dogs that develop gastroin- organophosphates and the development of AP. Sublethal doses of organ-
testinal upset or abdominal discomfort while receiving azathioprine, ophosphate anticholinesterase ex vivo results in AP in dogs as determined
should be evaluated for pancreatitis. by histopathology.16 Additionally in vitro acetylcholinesterase inhibitors
Knowledge regarding the role of exogenous steroids in the etiology result in marked increases in pancreatic amylase output.77 Five dogs were
of AP is perpetually evolving. Early studies documented an increase in also noted to have a recent exposure to organophosphate insecticides
serum lipase activity after steroid administration; however, postmortem prior to the development of AP in a large retrospective study.12 Organo-
examination rarely revealed evidence of pancreatitis, leading to the sug- phosphates might therefore be a risk factor for the development of pan-
gestion that serum lipase activity was an unreliable marker of AP in dogs creatitis in dogs, but more studies are needed to confirm this suspicion.
receiving corticosteroids.67,68 Histopathology might however miss focal Potentiated sulfonamides, furosemide, clomipramine, atovaquone/
areas of inflammation and this limitation should be considered. In another proguanil (Malarone), and n-methyl-glucamine (Meglumine) are associated
study 18/101 dogs received corticosteroids within 7 days of diagnosis of with the development of AP in isolated dogs.12,15,18–20 Another prospec-
AP and in a study of dogs with “pancreatic abscesses” (peri-pancreatic tive study reported that none of 20 dogs treated with meglumine and
fluid accumulations) 9/36 received corticosteroids prior to admission.12,69 allopurinol developed increased cPLI concentrations or clinical signs con-
Given these seemingly contradictory results several additional studies sistent with pancreatitis.78 Isolated reports of toxins such as zinc causing
have been performed utilizing cPLI assays. Six young female dogs with AP have been reported.21 Various antibiotics, chemotherapeutics, and endo-
X-linked hereditary nephritis receiving 2.2 mg/kg/d prednisone PO for crine therapies were also noted within 7 days of presentation, in a large ret-
4 weeks had no significant change in serum cPLI concentration.70 rospective study of AP; however, case details were sparse thus limiting the
Another study evaluated the effects of 4 mg/kg prednisolone daily for clinical utility of these data.12 Given the infrequent nature of these reports
2-3 weeks in 6 healthy beagle dogs. This study revealed an increase in many drug reactions are suspected to be idiosyncratic. Nonetheless a thor-
cPLI concentration after prednisolone therapy; however, no ultrasono- ough drug and toxin history should be taken in cases of suspected AP.
graphic signs of pancreatitis were noted with the exception of 1 day
when a single dog was assessed to have a hypoechoic pancreas.71 Addi-
tionally, laparoscopic pancreatic biopsies noted no histologic evidence of 2.4 | Endocrinopathies
71
pancreatitis. The same caveat as above exists regarding the sensitivity
of histopathology in the diagnosis of AP. The same research group evalu- Numerous endocrinopathies have been reported as risk factors for
ated the effects of 2.2 mg/kg prednisolone daily in dogs with various AP, including hyperadrenocorticism (HAC), hypothyroidism, and
19391676, 2022, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jvim.16437 by CAPES, Wiley Online Library on [02/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
CRIDGE ET AL. 851

F I G U R E 1 (A) Thresholds in the development of pancreatitis. A graphical representation of the critical threshold theory in which the balance
between stressors and protective mechanisms determines whether clinical disease is present (threshold 1) and if so, its severity (threshold 2).
Dog 1 and dog 2 have been exposed to the same stressor; however, dog 1 has greater protective mechanisms and as such, the disease burden
falls below threshold 1 and the dog develops subclinical pancreatic injury. In contrast, dog 2's disease burden is above threshold 1 and the dog
develops clinically evident AP. Similarly, dogs 2 and 3 have the same level of protective mechanisms, but the stressors are greater in dog 3. The
disease burden for dog 3 is therefore above threshold 2 and the dog develops clinically severe AP. As depicted in (B) this balance is also likely
influenced by factors such as supportive care, genetic and environmental factors, and amplification systems. While thresholds 1 and 2 are
represented as dashed lines in the figure, we suspect that the thresholds are more fluid and vary between individuals. This figure was adapted
with permission from Barreto et al. Gut. 2021;70:194-203. (B) A balance between protective mechanisms, stressors, and modulating factors
determines the risk of pancreatitis in each individual dog. A schematic representation of the fine balance between stressors and protective
mechanisms that determine whether pancreatic injury and inflammation occurs in an individual dog. Note that genetic and or environmental
factors on one side and supportive care on the other can modulate the risk toward or away from pancreatic injury, respectively

diabetes mellitus (DM).12,22–25,79,80 A retrospective study docu- suspect that increased pancreatic lipase concentrations in dogs
mented a preexisting or subsequent diagnosis of HAC in 12/101 with HAC reflect subclinical pancreatic injury/inflammation that
12
dogs with AP. It is important to note that this study did not has yet to reach a threshold, required to cause clinical pancreatitis
include a control group. Although large prospective studies have (see Figure 1A). Additional studies are needed to evaluate whether
not been performed to evaluate this relationship, recent studies there is a relationship between AP and HAC in dogs and the direc-
suggest a potential relationship between HAC and higher cPLI con- tion of the relationship. Hypothyroidism was documented in
centrations and DGGR lipase activities in the absence of clinical 4/101 dogs diagnosed with AP in a retrospective study, and it has
pancreatitis.22,23 Given that most studies evaluating exogenous been hypothesized that secondary hyperlipidemia might be
steroids document only minor elevations in pancreatic lipase we responsible for this relationship.12 A previous diagnosis of
19391676, 2022, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jvim.16437 by CAPES, Wiley Online Library on [02/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
852 CRIDGE ET AL.

hypothyroidism was also noted in a retrospective study of dogs pancreatitis was based solely on a semiquantitative point of care assay
with extrahepatic bile duct obstruction secondary to AP.80 in approximately 30% of dogs, which might have affected the results
Many studies have identified pancreatitis concurrently with DM of the study.86 Additional potential explanations for the lack of an
in dogs and this might represent shared risk factors for disease or a association between the SPINK1 variant and clinical disease is that
causative relationship between the 2 diseases.12,25,30,81 Pancreatitis the mutation might not be sufficient in isolation to cause pancreatitis
has also been shown to increase the hazard risk of death in dogs with and might require concurrent environmental or other genetic factors.
81
DM. Proposed mechanisms by which pancreatitis could theoretically Additional studies are therefore required to determine the potential
lead to DM include: islet cell damage, glucose toxicity, initiation of role of SPINK1 variants and other gene mutations in AP in dogs.87
autoimmune injury, inflammation induced insulin resistance, and the Cavalier King Charles spaniels, collies and boxers are predisposed to
action of cytokines and adipokines.24 One study indicated that 5/18 chronic pancreatitis (CP).32
dogs with diabetes mellitus had histopathologic features consistent
with advanced chronic pancreatitis, which was the presumed cause of
DM in those dogs.82 Additionally, in a study utilizing glucagon stimula- 2.6 | Autoimmune pancreatitis IgG4-related
tion tests in 6 dogs with presumed chronic pancreatitis, 5/6 had disease
reduced ß cell response and glucose intolerance.83 Proposed mecha-
nisms in which DM could in theory lead to pancreatitis include the The English Cocker spaniel is suggested to have a distinct form of CP
development of auto-antibodies or anti-insulin antibodies.24 Although characterized by ductal destruction, interlobar fibrosis, and T lympho-
the relationship might be bidirectional, many clinicians suspect that cyte infiltrations on histopathology.88 Immunohistochemistry has also
the predominant direction of the relationship is pancreatitis leading to shown a predominance of IgG4 positive plasma cells in multiple tis-
DM.24 Further discussion on the relationship between pancreatitis sues, including the pancreas, suggesting the presence of a multiorgan
and DM is available.24 immune mediated disease similar to IgG4-related disease in human
patients.89 Many of these dogs have concurrent keratoconjunctivitis
sicca, xerostomia, proteinuria, and other immune-mediated disor-
2.5 | Breed associated risk and potential ders.90 The diagnostic criteria for IgG4-related disease(s) in dogs
hereditary pancreatitis needs further clarification and consensus before a definitive diagnosis
can be confirmed.43,91 Also serum IgG4 concentrations have been
Certain breeds are reported to be at greater risk for the development noted to be high in other dogs with pancreatitis.44 However, strict
of AP. These predispositions likely reflect a combination of direct diagnostic criteria are required to prevent misclassification of other
genetic predispositions, a predisposition to a secondary factor such as inflammatory or neoplastic diseases as IgG4-related disease.43 It is
hypertriglyceridemia, or other disease modifying factors. The most hoped that ongoing study will further help to characterize this form of
consistently reported at-risk breeds for acute pancreatitis include the CP in dogs.
miniature schnauzer, miniature poodle, Yorkshire terrier, and other
terrier breeds.5,12,84 Other predisposed breeds include dachshunds,
poodles, cocker spaniels, Alaskan malamutes, and laika.30 Two poten- 2.7 | Miscellaneous risk factors
tial explanations are suggested for the high incidence of AP in minia-
ture schnauzers. One potential explanation is that AP occurs Many miscellaneous risk factors have been proposed for AP in dogs,
secondary to hypertriglyceridemia, which occurs commonly in this including weight/neuter status, infectious diseases (eg, Babesia spp.,
breed.28,29 A second potential explanation is that AP might be herita- Heterobilharzia americana, Leishmania infantum), hepatitis, honeybee
ble in the breed due to mutations in the serine protease inhibitor envenomation, snake envenomation, hypercalcemia and organic
Kazal type 1 gene (SPINK1). The product of the SPINK1 gene, pancre- acidemias.5,12,41,42,45 Although dogs of any age can be affected by AP,
atic secretory trypsin inhibitor (PSTI), is suspected to play a protective most dogs are middle-aged to older.12,30,31,92 Overweight animals and
role in the prevention of premature zymogen activation.85 A prospec- those who are neutered are also reported to be predisposed to
tive study evaluated the presence of SPINK1 gene variants in 39 Mini- AP.5,12,84,93 It is however, important to note that many of these fac-
ature Schnauzers with pancreatitis, 25 healthy Miniature Schnauzers, tors are influenced by additional factors, such as diet, lifestyle, and
and 23 healthy dogs of other breeds.26 In that study 3 variants were exercise level.94 A retrospective study revealed clinicopathologic evi-
identified, including 2 missense mutations in the second exon (N20K dence of AP in 16 dogs and histological evidence of AP in 4 dogs diag-
and N25T) in addition to a poly T insertion in the 3rd intron nosed with a Babesia rossi infection.34 An additional study
(IVS3 + 26-27ins[T]33-39,15_61dup11) and these variants were documented that 28% of dogs with a B. rossi infection had an
shown to correlate with the development of pancreatitis in this increased serum cPLI concentration.36 Other babesia species (eg,
breed.26 However, a subsequent study detected a high prevalence of B. gibsoni) have been implicated in the development of AP, albeit at a
SPINK1 variants in Miniature Schnauzers with and without pancreati- lower prevalence.35 Potential mechanisms include hypotension, sec-
tis and a relationship between the SPINK1 variant and clinical pancre- ondary immune-mediated hemolytic anemia, hemoconcentration, and
atitis could not be established.27 In this study however, diagnosis of alterations in lipid metabolism.34 Canine monocytic ehrlichiosis has
19391676, 2022, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jvim.16437 by CAPES, Wiley Online Library on [02/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
CRIDGE ET AL. 853

also been reported to be a predisposing factor to AP in dogs, with early pancreatitis, which was responsible for 50% of pancreatic
20% of cases in a recent study having subclinical elevations in cPLI.37 injury.109 Interestingly, however, the knockout mice demonstrated
Necropsy studies of canine schistosomiasis (ie, Heterobilharzia ameri- similar levels of local and systemic inflammation when compared to
cana infection) also document a high prevalence of parasitic infiltra- the wild-type cohort.109 The results of this experimental study
38
tion of the pancreas. Gross lesions consistent with pancreatitis were suggested that the inflammatory response and approximately 50% of
also noted during exploratory laparotomy in a dog subsequently diag- acinar cell damage during pancreatitis was independent of premature
39
nosed with schistosomiasis. Several studies also noted elevated pan- trypsinogen activation.109 This prompted reconsideration of the tradi-
creatic lipase concentrations in systemically ill dogs such as those with tional trypsin-centric pathogenesis and allowed for consideration of
cardiac disease, gastric-dilatation and volvulus, intervertebral disc dis- potential alternate or complementary pathways. One potential caveat
ease, parvovirus, and foreign bodies.73,95–99 In the authors' opinion to this is that mice have various trypsinogen isoforms, and the clinical
elevations in pancreatic lipase concentrations in such dogs likely significance of each isoform might vary. A further study documented
reflect a secondary pancreatic injury that might not be clinically rele- that intra-acinar activation of trypsinogen was able to induce AP but
vant, although this can be difficult to definitively determine. But, in not CP, suggesting that different pathogenic mechanisms might exist
some diseases (eg, chronic enteropathies) increased serum cPLI con- between acute and chronic disease.108 Although trypsin-independent
100
centrations have been associated with a worse outcome. mechanisms for pancreatitis have been suggested, they likely act in
Previous surgery, other than neutering, is associated with an parallel with trypsin-dependent mechanisms, therefore therapeutic
increase in risk of AP (OR: 21.1), likely due to hypotension, tissue manipulation of trypsin and other proteases might still be of benefit.
manipulation, or a combination of both.5 A high prevalence of AP has Reduced trypsinogen activation peptide concentrations, reduced pan-
also been noted in a recent retrospective study of dogs and cats with creatic necrosis, and reduced mortality is seen in rats treated with the
cholecystitis, although the direction of the relationship is unknown.45 protease inhibitor nafamostat.110 Multiple studies have also investi-
Therefore, many factors in a dogs history should be considered when gated protease inhibitors in humans, with varied, but most often dis-
evaluating a dog with suspected AP. appointing, results.111–113 Concern also exists regarding the
vasoconstrictive properties of these drugs and the potential perpetua-
tion of pancreatic necrosis.114 Additionally, proteases other than tryp-
3 | PATHOGENESIS OF ACUTE sin, might play protective roles in the pathophysiology of pancreatitis.
PANCREATITIS Chymotrypsin is a protease that regulates trypsin activity and is noted
in early pancreatic injury.109 Chymotrypsinogen knockout mice have
Over 100 years ago it was proposed that pancreatitis was caused by been shown to have an increased severity of induced pancreatitis,
autodigestion of the pancreas from premature activation of digestive when compared to a wild type cohort, thus protease inhibitors used in
zymogens.101 Since that time several experimental and clinical studies pancreatitis should ideally target trypsin, but spare chymotrypsin.115
have documented a key role of intra-acinar trypsinogen activa- Somatostatin analogues have the potential of inhibiting exocrine
tion.102–108 Despite the long-standing concept of premature trypsino- secretions of the pancreas, including trypsinogen, thus these drugs
gen activation, the initiating cellular mechanisms and the potential have also been considered in disease management. Unfortunately, the
role of alternate or complementary pathways have long been the somatostatin analogue, octreotide, is shown to have no benefit in an
source of ongoing research. While discussing these concepts we will experimentally induced (bile injection model)pancreatitis in dogs.116
relate the results of experimental data to implications for clinical prac- Indeed, it is suspected that zymogen granule release is inhibited early
tice by highlighting potential therapeutic targets. Development of during the pathogenesis of pancreatitis, a process that would be
such therapeutics will be critical in improving the outcome of this dis- expected to be even further propagated by somatostatin or its thera-
ease for which clinicians have traditionally been restricted to provid- peutic analogues.117 Given the results of the above studies, and the
ing only supportive and symptomatic care. presence of trypsin-independent mechanisms of pancreatic injury and
In this section we will also review studies that suggest the pres- inflammation, it is likely that detailed preclinical study would be
ence of trypsinogen independent pathways of acinar cell injury and needed before protease inhibitors or somatostatin analogues are con-
pancreatic and systemic inflammation. We will then discuss several sidered for clinical use in dogs.
proposed mechanisms that might initiate both trypsin-dependent and A major alternative or complementary pathway to the trypsino-
independent cellular damage. It is important to consider that the gen activation pathway of AP includes activation of nuclear factor-
described pathogenic mechanisms do not always result in clinical dis- kappa beta (NF-κB), which has been documented in pancreatitis for
ease and that the critical threshold theory (Figure 1A) is useful to help over 20 years.118 Intra-acinar NF-κB activation occurs alongside, and
describe the relationship between pathologic stressors and clinical dis- independent of, trypsinogen activation.109,119,120 The critical role of
ease expression and severity (Figure 1B). NF-κB in the inflammatory response is evidenced by experimental
In 2011, a study utilizing trypsinogen isoform-7 gene knockout studies in knockout mice, where absence of NF-κB activation results
mice and wild type mice to determine the role of trypsinogen in in reduced pancreatic inflammation relative to wild type mice.121–123
experimentally-induced pancreatitis (cerulein model) was publi- The level of NF-κB activation correlates with the severity of pancrea-
shed.109 Trypsinogen activation led to in vitro acinar cell death during titis in mice.124 Nuclear factor-κB is also involved in the systemic
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854 CRIDGE ET AL.

F I G U R E 2 Systemic inflammatory
response syndrome in AP. IL-6
transsignaling involves the interaction
between IL-6 and a soluble IL-6
receptor which increases
gp130-dependent STAT3 activation.
Nuclear translocation of STAT3 results
in release of cytokines such as CXCL1
which leads to acute lung injury.
Cytokine secretion in macrophages
depend on nuclear translocation
of RelA

inflammatory response to pancreatitis.125,126 While these studies lay activate bradykinin-kinin systems, thus increasing capillary perme-
strong evidence for a proinflammatory action of NF-κB in pancreatitis, ability and in turn leading to hypovolemia and edema.
some data suggests that NF-κB might play a multifaceted role in AP, Neutrophils and macrophages also play a key role in both the
127–129
and might be protective in some circumstances. These discrep- local as well as systemic inflammatory response in acute pancreati-
ancies can also be explained with different approaches in the preclini- tis.139,140 Neutrophil invasion into the pancreas is suspected to occur
cal models (overactivation vs genetic deletion). Additionally, currently due to the release of CXC ligand 2 (CXCL2) and other chemo-
used inhibitors are not specific for the NF-κB pathway. Furthermore, attractants in early AP.141,142 Experimental depletion of neutrophils
inhibition of single subunits of the pathway might be compensated for results in reduced pancreatic injury and increased survival, highlighting
by other components of the NF-κB family of proteins, such as RelB or the critical nature of neutrophils in disease pathogenesis.143,144 Neu-
c-Rel. Given the results of these studies targeted inhibition of the trophils also play a role in the development of systemic complications
proinflammatory properties of NF-κB could be of therapeutic benefit of AP including acute lung injury.145,146 Neutrophil extravasation into
but requires further study. Other key components of the inflamma- the tissues is dependent on rolling, activation, adhesion, and migration
tory response include tumor necrosis factor alpha (TNF-α), interleukin of neutrophils from the capillaries. Leukocyte function antigen-1
(IL)-1, IL-1ß, IL-2, IL-6, IL-8, and IL-18.93,130–134 Association studies (LFA-1), which binds to immunoglobulin-like cell adhesion molecule
correlating cytokines and chemokines with AP severity have been per- 1 (ICAM-1) during vascular adhesion, plays an important role in the
formed to identify surrogate biomarkers as predictors for severe recruitment of neutrophils to the pancreas and other tissues, CXCL2
AP. In humans serum levels of IL-6 and the IL-6 dependent acute formation, and subsequent tissue injury (Figure 3).147 This pathway is
phase protein C-reactive protein are the most reliable predictors of amenable to therapeutic intervention and LFA-1 inhibitors such as
severe AP.135,136 fuzapladib sodium hydrate prevent extravasation of neutrophils into
Interleukin 6 has both anti-inflammatory and proinflammatory prop- the tissue and have been approved for the treatment of pancreatitis
erties depending on the signaling type. Classic signaling requires the pres- in dogs in Japan. Data from a proof-of-concept study utilizing an
ence of an IL-6 receptor on a limited number of target cells and mediates experimental model of pancreatitis in dogs was recently presented at
its anti-inflammatory properties.137 Transsignaling however involves the the ACVIM Forum.148 This data suggests that fuzapladib improved
interaction of IL-6 with a soluble IL-6 receptor (sIL-6R) which then medi- survival rate in this experimental model, in a dose-dependent fashion.
ates gp130 activation, and IL-6's proinflammatory actions.137 IL-6 trans- A subsequent clinical trial in Japan revealed improved clinical scores,
signaling has effects on many cell types and can further increase the and a faster resolution of serum C-reactive protein increases in dogs
expression of signal transducer and activator of transcription 3 (STAT3) in treated with fuzapladib.148 A multicenter clinical trial in spontaneous
138
pancreatic acinar cells. Increased STAT3 expression further pro- pancreatitis in dogs is ongoing in the United States.
motes the inflammatory cascade via release of cytokines and Multiple mechanisms have been proposed to explain trypsinogen
chemokines.138 Cytokine secretion in macrophages is dependent and NF-κB activation during the early stages of pancreatitis. These mech-
on nuclear translocation of RelA.138 Thus IL-6 has also been shown anisms include deranged calcium signaling, colocalization of zymogens
to have a direct impact on the course of disease (Figure 2). Cyto- and lysosomes, impaired autophagy, endoplasmic reticulum stress and
kines and chemokines in the circulation induce further secretion of maladaptive unfolded protein response, mitochondrial dysfunction, and
acute-phase proteins in the liver, activate complement factors, and oxidative stress. For simplicity and given the focus of this review, we will
19391676, 2022, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jvim.16437 by CAPES, Wiley Online Library on [02/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
CRIDGE ET AL. 855

F I G U R E 3 Neutrophil
extravasation into the pancreas and
therapeutic manipulation with
fuzapladib sodium hydrate. Fuzadib
sodium hydrate inhibits leukocyte
function antigen-1, which prevents
neutrophils from extravasating from
capillaries into the surrounding tissue,
which inhibits the systemic
inflammatory response syndrome
(SIRS). ICAM-1, immunoglobulin-like
cell adhesion molecule 1;
LFA-1, leukocyte function antigen-1

F I G U R E 4 Persistent cytosolic calcium accumulation in AP. Under physiologic conditions there is a transient spike in apical calcium
concentration, which results in release of digestive zymogens from the apical border of the pancreatic acinar cell. During AP there is a global and
persistent increase in cytosolic calcium concentration, which causes calcium overload, premature trypsinogen activation and subsequent acinar
cell damage. Deranged calcium signaling is associated with mitochondrial dysfunction

discuss each of these mechanisms sequentially; however, there is likely a NF-κB.163,164 Calcineurin knockout mice have been shown to have
complex interaction between these mechanisms in spontaneous disease. reduced zymogen activation and acinar cell injury in response to an
Deranged calcium signaling is suspected to play a role in the path- experimental model of pancreatitis.165 Additionally, genetic mutations
ogenesis of AP. Under physiologic conditions a stimulus results in a in calcium channels such as transient receptor potential vanilloid sub-
149
transient spike in calcium in the apical region of the acinar cell. family member 6 (TRPV6) have been shown to be associated with
However, during pancreatitis there is a global and persistent increase nonalcoholic chronic pancreatitis (CP) in human patients.166 Given
150,151
in cytosolic calcium. Calcium overload then causes the prema- these findings, manipulation of calcineurin has garnered considerable
ture activation of trypsinogen, in addition to the development of vac- attention as a potential therapeutic target for the treatment of pan-
152,153
uoles, and acinar cell damage (Figure 4). Pathological calcium creatitis in humans. Pharmacologic inhibition of calcineurin via cyclo-
overload is associated with release of calcium from the endoplasmic sporine A and tacrolimus has protective effects in a rodent model of
reticulum (ER) and acidic calcium stores, which acts as a positive feed- pancreatitis.163,165 The protective effects of calcineurin inhibition
back mechanism.154,155 A variety of receptors are involved in patho- appear to be dependent on the source of its expression.167 Studies
155–157
logic calcium signaling. Calcium overload causes mitochondrial are ongoing to investigate cyclosporine therapy in both canine and
permeability transition pores (MPTP) to open, leading to a loss of feline CP (personal communication JMS). Given the immunosuppres-
mitochondrial membrane potential and mitochondrial dysfunc- sive properties of cyclosporine it might have multiple beneficial
tion.158,159 Mitochondrial dysfunction is a key acinar event in early effects in pancreatitis, particularly in those with suspected immune-
160,161
pancreatitis. Loss of mitochondrial function leads to ATP deple- mediated etiology.168 Research into drugs manipulating calcium sig-
tion. Removal of cytosolic calcium is ATP-dependent, therefore mito- naling and mitochondrial dysfunction are ongoing in experimental
chondrial dysfunction might further the global and persistent increase models and might offer future promise in the management of pancre-
in cytosolic calcium, thus forming a self-perpetuating increase in cyto- atitis.169–171
solic calcium, which is characteristic of pathological calcium signaling Under physiologic conditions, digestive enzymes are packaged as
during pancreatitis.151,160–162 Pathologic calcium signaling ultimately inactive enzymes, called zymogens, and are stored in granules. Lyso-
results in downstream activation of calcineurin, trypsinogen, and somal enzymes are packaged into lysosomes, thus preventing the
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856 CRIDGE ET AL.

F I G U R E 5 Colocalization theory.
Under physiologic conditions, digestive
zymogens and lysosomes do not
interact with each other within
pancreatic acinar cells. During AP an
apical block results in redistribution of
lysosomes, which then colocalize with
digestive zymogens. Colocalization
allows the lysosomal enzyme
cathepsin-B to activate the digestive
zymogens within the pancreatic acinar
cell, resulting in cell damage.
Basolateral release of granules might
occur leading to damage to the
interstitial space

interaction of zymogens and lysosomal enzymes until zymogens enter autophagic in nature.186 Lysosomal dysfunction results in degradation
the duodenum. During pancreatitis, lysosomes redistribute and colo- of lysosomal membrane proteins 1 (LAMP-1) and 2 (LAMP-2). Lyso-
calizes with zymogen granules in the subcellular compartment, somal membrane proteins play an important role in lysosomal stability.
resulting in the formation of large vacuoles.172,173 This colocalization The role of LAMP-2 in pancreatitis is demonstrated in knockout mice,
allows the lysosomal enzyme cathepsin B to prematurely activate which were shown to have impaired autophagy and developed pan-
trypsinogen (Figure 5).174 Maximal activation of trypsinogen by creatitis.187 Ultimately these processes result in acinar cell vacuola-
cathepsin B is reported to occur at an acidic pH, but might also occur tion, trypsinogen activation, inflammation and necrosis.162
174,175
at a higher pH. This hypothesis was further evaluated in a Pharmacological manipulation of impaired autophagy was studied in
cathepsin B gene knockout mouse cohort.176 In these mice, trypsin mice.188 Inhibition of a transcriptional regulator of autophagy allevi-
activity and pancreatic necrosis in response to cerulein stimulation is ated pancreatic acinar cell injury in experimental pancreatitis.188,189
markedly reduced relative to the wild-type cohort, suggesting that Further studies are needed to determine whether pharmacological
cathepsin B plays a key role in the induction of pancreatitis.176 manipulation of autophagy offers promise in the management of
Absence of the cathepsin B gene did not however completely prevent AP. Impaired autophagy might also be interrelated with other
the onset of pancreatitis.176 Similar results have been noted in several pathomechanisms of AP including mitochondrial dysfunction and
177,178
studies using cathepsin B inhibitors. While colocalization is a endoplasmic reticulum (ER) stress.190
popular theory and is well supported by the literature, there are some The exocrine pancreas is rich in ER, which plays a key role in pro-
studies that suggest that we do not fully understand this process. For tein synthesis. Endoplasmic reticulum stress is a key acinar event dur-
example, colocalization of cathepsin B with secretory vesicles is seen ing early pancreatitis and is associated with accumulation of unfolded
in regulated secretion from the exocrine pancreas and redistribution proteins in the ER.191–193 Under physiologic conditions, ER stress is
of lysosomal enzymes into the zymogen-rich subcellular compartment countered by an unfolded protein response (UPR), thus preventing cell
fails to result in pancreatitis in some studies.175,179 Thus, it is injury.194 This physiologic response involves autophagic processes.194
suspected that cathepsin B redistribution is involved in pancreatitis, During excess and prolonged ER stress, the UPR becomes maladap-
but alone, it might not be sufficient to induce disease and might be tive and upregulated NF-κB triggers proinflammatory genes
influenced by other factors, such as cathepsin D.180 Cathepsin B gene (Figure 6).122,124,194 Thus, dysregulated UPR results in the initiation of
mutations have also been associated with some forms of pancreatitis acinar cell injury and apoptosis.194 Interestingly, drugs such as HMG-
in humans, but the role of cathepsin B has yet to be studied in coA reductase inhibitors, have been shown to act on the UPR and
181,182
dogs. Further studies are needed to understand apparent dis- reduce ER stress.195 Observational studies also document a lower
crepancies in the results of prior studies, and to determine whether incidence of pancreatitis in humans treated with HMG-coA reductase
these pathways could act as therapeutic targets. inhibitors (OR: 0.29).196 Furthermore preexisting statin therapy is
Autophagy is cytoprotective and involves the catabolic removal associated with a reduced severity of pancreatitis in humans.197 To
of various obsolete cellular components preventing cell damage and the authors' knowledge no studies have been performed investigating
promoting survival in response to insults.183 Basal autophagy has the use of HMG-coA reductase inhibitors in dogs with pancreatitis.
been shown to play an important role in the homeostasis of pancre- Oxidative stress has long been implicated in the pathogenesis of
atic acinar cells.184 Genetic disruption of Atg5 induced pancreatic pancreatitis and free-radical concentrations have been correlated with
degradation also supports the role of autophagy in exocrine pancre- the degree of inflammatory response and disease severity.198–201
185
atic homeostasis. During pancreatitis impaired autophagy occurs as Antioxidants have been shown to reduce pancreatic damage in experi-
a result of lysosomal dysfunction.162 Colocalization of organelles is mental models; but this contrasts with the results of clinical trials in
19391676, 2022, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jvim.16437 by CAPES, Wiley Online Library on [02/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
CRIDGE ET AL. 857

F I G U R E 6 Endoplasmic reticulum
stress and the unfolded protein
response. Under physiologic
conditions endoplasmic reticulum
stress is countered by the unfolded
protein response, which prevents
cellular injury. However, in AP
excessive and prolonged ER stress
results in a maladaptive UPR and
subsequent upregulation of NF-κB,
resulting in acinar cell injury

with pancreatitis before therapeutic manipulation is considered. Stud-


ies are being performed at the primary author's institution to evaluate
reactive metabolite concentrations, plasma antioxidant potential, and
urinary F2-isoprostane concentrations in dogs with spontaneous AP.
An additional factor implicated in determining the clinical course
of AP is the role of nonesterified fatty acids (NEFA's).54,55 Lipolysis of
visceral fat by pancreatic lipase results in the formation of NEFA's,
which results in systemic inflammation and organ failure (Figure 7).54
Nonesterified fatty acids have been shown to alter the severity of AP,
independent of the necroinflammatory response.207 Free fatty acids
have also been shown to induce hypocalcemia.208 The mechanism of
NEFA-induced organ failure is suspected to involve inhibition of mito-
chondrial complex I and V and release of intracellular calcium.209 The
systemic effects of NEFAs have been evidenced by induction of mito-
chondrial damage in the kidney.209,210 Therapeutic manipulation of
these pathways has been considered in the management of
AP. Calcium supplementation and Ringer's lactate to counter the
hypocalcemia induced by NEFA's reduces C-reactive protein concen-
trations and the systemic inflammatory response during early pancrea-
titis.211 Additionally, inhibition of lipases is considered a therapeutic
target, with the aim of reducing the generation of NEFA's. Orlistat, a
lipase inhibitor, reduces organ failure and mortality in experimental
F I G U R E 7 Pancreatic enzyme leakage and the role of fatty acids in
AP.207 Other case reports have suggested that orlistat might induce
the pathogenesis of AP. Leakage of pancreatic enzymes, particularly
pancreatitis in some people and thus more studies are needed to
classical pancreatic lipase, into the intrapancreatic and peri-pancreatic fat
results in the generation of nonesterified fatty acids. These nonesterified investigate the effects of lipase inhibitors on disease outcome before
fatty acids lead to systemic inflammation and organ failure; thus, the level they can be considered for clinical use.212
of visceral adipose tissue might influence the clinical course of AP Having discussed potential initiating mechanisms of pancreatitis,
Source: This figure was adapted with permission from de Oliveira et al. J it is important to note that, the development of pancreatitis and the
Clin Invest. 2020;130(4):1931-1947
disease severity is dependent on a balance between stressors and
protective mechanisms, with several genetic and environmental fac-
spontaneous disease.202–204 A decisive study might help to explain tors modifying the individuals risk profile (Figure 1B).139 Protective
205
the lack of efficacy of antioxidants in some clinical trials. Booth mechanisms of the pancreas include: synthesis and storage of diges-
et al. showed that reactive oxygen species (ROS) promoted apoptosis tive enzymes as inactive zymogens, physical separation of lysosomal
of pancreatic acinar cells, and inhibition of ROS resulted in pathologic enzymes from zymogens, pancreatic secretory trypsin inhibitor, sub-
necrosis, suggesting an unexpected protective role of ROS within the optimal pH for autoactivation in zymogen granules, unidirectional flow
pancreatic acinar cells during pancreatitis.205 Contrasting findings in pancreatic ducts, and circulating antiproteases in the vascular
were noted regarding oxidative stress in neutrophils, suggesting a dual space.93 Acinar cell injury results in the release of inflammatory medi-
205,206
role of ROS in pancreatic injury. This dual role likely complicates ators, which are then amplified by pancreatic stellate cells resulting in
manipulation of oxidative stress pathways. Given these results, further a necroinflammatory amplification loop that furthers acinar cell injury
studies are needed to investigate the role of oxidative stress in dogs as well as a systemic inflammatory response.139 A critical threshold of
19391676, 2022, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jvim.16437 by CAPES, Wiley Online Library on [02/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
858 CRIDGE ET AL.

F I G U R E 8 Proposed pathogenesis of pancreatitis. This figure outlines the key pathophysiologic mechanisms proposed in the development of
clinically evident acute pancreatitis. UPR, unfolded protein response; *, context specific proinflammatory role
Source: This figure was adapted with permission from Barreto et al. Gut. 2021;70:194-203

acinar cell injury is likely required prior to the development of clinical disorders have been identified as potential risk factors for pancreatitis
disease (Figures 1A,B and 8).139 This critical threshold theory is impor- in dogs, and where biochemical markers or imaging are suggestive of
tant when interpreting abnormalities in pancreatic lipase or imaging pancreatic inflammation in the absence of clinical signs, this might
findings suggestive of pancreatitis, in the absence of clinical disease. reflect secondary acinar cell damage below the critical threshold
This theory would suggest that while various pathophysiologic mecha- required for clinical disease.
nisms might be at play in each dog, clinical disease only develops if a In recent years, important insights have been gained into the
certain clinical threshold is reached, and severe pancreatitis occurs pathophysiologic mechanisms of pancreatitis, many of which appear
only when another threshold is reached. This theory might provide a to have complex interactions and situation specific expressions. The
useful model for pancreatitis in dogs. It is important to note that these use of animal models, and more specifically knockout mice, has been
thresholds are likely not true thresholds, but rather theoretical ones critical to determine these interactions and elucidate potential expla-
and that the actual thresholds might vary widely between dogs. nations for apparently contradictory studies. The mechanistic insights
from these studies offer promise in the identification of therapeutic
targets, but species specific or etiology specific mechanisms might
4 | C O N CL U S I O N S mean that the results of experimental studies might not be directly
relevant to dogs with spontaneous disease.
While most cases of pancreatitis are thought to be idiopathic, our
knowledge regarding the etiology of pancreatitis in dogs is more lim- ACKNOWLEDG MENT
ited than it is for humans and a thorough diagnostic work-up evaluat- No funding was received for this study.
ing potential risk factors is not always performed. Thus, the term
cryptogenic AP might be more appropriate in most cases. A thorough CONFLICT OF INTEREST DECLARATION
medical, surgical, drug, and dietary history is indicated in all dogs with Dr Steiner and Dr Lim are associated with the Gastrointestinal labora-
suspected pancreatitis, and the results of which might be of particular tory at Texas A&M University, which offers Spec cPL testing on a fee-
importance in dogs with recurrent episodes of pancreatitis. If a tem- for-service basis. Dr Steiner acts as a paid consultant and Speaker for
poral association is noted between a drug and pancreatitis the rela- Idexx Laboratories, which offers Spec cPL testing on a fee-for-service
tionship might be causative or associative. Where it is deemed likely basis. Dr Steiner is also a paid consultant of ISK, who manufactures
that a drug or other risk factor is associated with pancreatitis, objec- fuzapladib. No other authors have a conflict of interest.
tive markers such as cPLI might be useful to identify reduction in pan-
creatic inflammation with risk factor elimination. However, repeat OF F-LABEL ANTIMI CROBIAL DECLARATION
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