Title

Subtitle

Pancreatitis to EPI visuals

 

.... inflamed "Pancreatitis" pancreas

 

 .... atrophied "EPI" pancreas

 

Pancreatitis to EPI

Dr. Penny Watson, an esteemed canine and feline pancreatic researcher, contacted epi4dogs and offered to contribute to our website with regards to secondary EPI from chronic pancreatitis. Secondary EPI is not very well represented and we are honored that Dr. Watson is sharing her knowledge and research with us.

 Please feel free to check out a thread "Pancreatitis to EPI that was started on the FORUM  http://www.epi4dogs.com/apps/forums/topics/show/9204962-pancreatitis-to-epi-

In addition to contributing to epi4dogs, Dr. Watson is available for vet consultations. Her contact information is:

Penny Watson MA VetMD CertVR DSAM DipECVIM MRCVS
 
Senior Lecturer in Small Animal Medicine
Department of Veterinary Medicine
Madingley Road
Cambridge CB3 OES

Tel (+44+ - (0)1223 337621 Fax: (+44) - (0)1223 330848

Email:  [email protected]  

Dr. Penny Watson ... an esteemed Pancreatic Researcher

  (taken from)  http:[email protected]

 

  • SENIOR LECTURER IN SMALL ANIMAL MEDICINE
  • MEDICINE CLINICIAN & RESIDENT SUPERVISOR IN THE QUEEN'S VETERINARY SCHOOL HOSPITAL
  • DIRECTOR OF STUDIES IN CLINICAL VETERINARY MEDICINE AND TUTOR (EMMANUEL COLLEGE) 

 

Biography:

VetMD. University of Cambridge 2009

M.A. University of Cambridge 1990

Vet.MB. University of Cambridge 1989

B.A. Medical Sciences University of Cambridge 1986

RCVS Certificate in Veterinary Radiology October 1993

RCVS Certificate in Small Animal Medicine October 1995

RCVS Diploma in Small Animal Medicine September 1997

European College of Veterinary Internal Medicine Diploma  September 2000

Recognised RCVS Specialist in Small Animal Medicine March 2003

2004 to date. University Senior Lecturer in Small Animal Medicine, University of Cambridge.

1998 – 2004 Waltham Lecturer in Small Animal Medicine, University of Cambridge

Jointly responsible for running the small animal medicine service in the referral hospital and teaching students and clinical residents small animal medicine in all areas, but particularly gastroenterology; hepatology and clinical nutrition.

Co-supervisor of one successful PhD students and many successful ECVIM diploma candidates (residents)

1994-1997 Waltham Resident in Small Animal Medicine and Clinical Nutrition, University of Cambridge.

1993-1994: Locum University Assistant Physician, University of Cambridge

1989-1993: Private Veterinary Practice (large and small animal and equine) in Clwyd; Bedforshire and Cambridge. 

Research Interests

Penny Watson’s research focuses on liver and pancreas disease in dogs and cats, particularly chronic disease and fibrosis. There is a strong focus on comparative pathology and identifying the relevance to humans as well as small animals. Her work on canine chronic pancreatitis, in collaboration with Prof Michael Herrtage and pathologists in Cambridge (Tim Scase, Aude Roulois and Fernando Constantino-Casas) and Glasgow and funded by BSAVA Petsavers, has defined the prevalence of lesions at post mortem and breed-related differences in pancreatic pathology which suggest differences in aetiology between breeds. Concurrent clinical studies funded by the Pet Plan Charitable Trust identified the same breed relationships and showed the importance of chronic pancreatitis in causing clinical disease in dogs. Initial work in English Cocker spaniels suggest a disease similar to autoimmune chronic pancreatitis in humans. Ongoing studies in English Cocker spaniels, in collaboration with Fernando Constantino-Casas at Cambridge and Professor Michael Day at Bristol are investigating whether their disease is similar to human IgG4+ related disease. Genetic studies are also ongoing in the breed with Julien Bazelle (clinical resident), David Sargan and Jesus Aguirre-Hernandez.

Cavalier King Charles spaniels (CKCS) have also been identified in this research as having an increased risk of chronic pancreatitis and ongoing work in this breed is investigating potential mechanisms of multi-organ fibrosis and the role of platelet-derived mediators including serotonin. The initial part of this work is funded by BSAVA Petsavers and is being undertaken with Fernando Constantino-Casas and James Warland (clinical resident) and in collaboration with human medical colleagues including Professor John Iredale, Dr Jonathan Fallowfield and Mr Damian Mole at the MRC Centre for Inflammation Research in Edinburgh, together with veterinary colleagues Claire Rusbridge from London and Brendan Corcoran from Edinburgh.

Chronic hepatitis in dogs is another key research focus. Dr Nick Bexfield’s PhD funded by the Wellcome Trust and co-supervised by Penny Watson with Prof Jon Heeney and Laurence Tiley investigated the potential role of novel viruses in the disease and also described breed-related hepatitis in the English Springer Spaniel (ESS). Novel methods of viral discovery have so far failed to find a convincing aetiological agent.  Nick also demonstrated that the recently described canine hepacivirus does not appear to be associated with chronic hepatitis in dogs and has shown an association between the dog leukocyte antigen and chronic hepatitis in the ESS. Ongoing work continues to investigate the genetics of the disease in the ESS and to try to identify the cause with the help and support of the breed health co-ordinators.

Biliary tract disease in dogs and cats is also an active research interest. An Emesis Council award has enabled Ben Harris (clinical resident – residency completed in 2012) to undertake a study of the prevalence and importance of biliary tract infections in dogs, including fluorescence in situ hybridization of dog’s livers in collaboration with Tristan Cogan at Bristol and other colleagues from the veterinary schools at Dublin, Bristol, Liverpool and Glasgow and at Dick White Referrals. In addition, a project on feline biliary tract disease as a potential model for human disease is being developed in collaboration with Dr Sue Davies, Dr Graeme Alexander and Dr David Lomas (imaging) at Addenbrookes Hospital and colleagues at the veterinary schools in Edinburgh and Bristol and the Animal Health Trust.

Penny also has ongoing interests in a number of smaller student and resident clinical research projects, particularly in gastroenterology and clinical nutrition. Congenital portosystemic shunts have been a long term interest, particularly medical management, and she has published a number of book chapters and reviews on pancreatitis and liver disease in dogs and cats. 

 

EPI as an end stage of Chronic Pancreatitis

EPI as an end stage of chronic pancreatitis: could this be your dog and why is this important to recognise?

By: Dr. Penny Watson

 

Dr Penny Watson at the Department of Veterinary Medicine, University of Cambridge UK has spent much of her research career investigating chronic pancreatitis (CP) in dogs. As a result of her research, detailed below, she has demonstrated that CP is in fact common in dogs but often not recognised until very late in the disease. Chronic pancreatitis is defined as: ‘a continuing inflammatory disease of the pancreas characterized by the destruction of pancreatic parenchyma leading to progressive or permanent impairment of exocrine or endocrine function or both’. The gold standard for diagnosis of CP is pancreatic histology after biopsy but this is rarely indicated or performed in dogs or cats because it is too invasive and dangerous. Noninvasive diagnosis is difficult: vets have to suspect it in the first place and then the currently available diagnostic imaging, and blood tests have a lower sensitivity for CP than for acute disease. Dr Watson therefore believes that many dogs remain un-diagnosed which means they may not receive effective treatment with diet and painkillers. In ‘end stage’ chronic pancreatitis, a dog will develop EPI and often also diabetes mellitus as a result of destruction of the pancreas. Again, it is very important that vets and owners recognise that older dogs with diabetes mellitus may then develop EPI. If they do not recognise and treat the EPI, then the dog will lose a large amount of weight and may be euthanased as a result. Whereas recognising the presence of EPI in an older diabetic dog and treating it with enzymes can make a marked difference to the dog’s quality of life. The pancreas has an amazing reserve which means a dog has to destroy about 90% of its pancreas before it develops EPI. Dogs with EPI as a result of end stage CP therefore tend to be middle-aged to old and not as young as those with pancreatic acinar atrophy. They may have such mild clinical signs of their disease that it is not recognised. Typically, dogs with low grade CP will have a long history of occasionally going off their food, having colitis like diarrhoea and occasional vomiting. Some cases have had flare-ups of ‘acute’ pancreatitis or acute haemorrhagic gastroenteritis. They also tend to be different breeds from dogs with pancreatic acinar atrophy. In the UK, affected dogs particularly include cavalier king Charles spaniels, cocker spaniels and collies. English Cocker spaniels often have concurrent disease particularly in the kidneys and dry eye (detailed below) and there s growing evidence that the disease in English cocker spaniels is immune-mediated involving several organs, as detailed below. Dr Watson was interested to Dr Leigh Clark’s list of breeds with EPI on the EPI4dogs website and note collies, cockers and cavaliers listed there. In addition, a separate study in the UK looking at breeds with EPI diagnosed with a TLI blood test at the University of Liverpool also found a large number of older Cavaliers affected, suggesting end stage CP although the cause was not found out in that study (Batchelor et al. 2007). The evidence from Dr Watson’s work suggests that most if not all cavaliers and cockers with EPI have end stage CP. This is also likely in a number of other breeds but cannot be confirmed for sure without histology. However, any dog with concurrent diabetes mellitus and EPI has a high suspicion of underlying end stage chronic pancreatitis since dogs with pancreatic acinar atrophy do not typically suffer from diabetes mellitus.

 

So what do you do if you suspect your dog has chronic pancreatitis?

The best action is to discuss effective treatment with your vet. These dogs often do better on a low fat diet because it reduces the pain experienced after eating. They also may need painkillers during bouts. One breed – the English Cocker Spaniel – may also benefit from steroid treatment in some cases and it is also important in cockers for the vet to screen for concurrent kidney and eye disease (see below) and treat these too if present. Recognition and treatment of CP in this way should improve the dog’s quality of life.

 

Background research and papers for those interested

Dr Watson noticed an unexpectedly high prevalence of EPI due to end stage CP in clinical cases and published a small retrospective series of histopathologically confirmed disease in 2003 (Watson 2003). Prior to this, canine CP was believed to be rare and was not really recognised as a cause of EPI which was predominantly recognised only in young German Shepherd dogs with pancreatic acinar atrophy.

 

Dr Watson’s research continued to define the prevalence and clinical importance of CP in dogs. The great difficulty in diagnosing CP non-invasively (shared with human medicine) meant that sensitive and specific confirmation of disease required histological examination of the pancreas. It is usually not clinically justified to do something as invasive as a pancreatic biopsy in dogs. Therefore, to discover how common CP really was in old dogs, Dr Watson undertook a study of pancreatic pathology at post mortem in 200 old dogs euthanased for any reason from first opinion practice to define the prevalence and breed association of canine CP. This showed that the prevalence of CP in old dogs was 34%, which is remarkably high for a disease which was barely recognised at the time (Watson et al. 2007). In addition, there was a difference in pathological appearance between pedigree dog breeds suggesting different aetiologies. Some breeds showed a duct-centred pattern typical of duct blockage or autoimmune disease in humans and some showed intra-acinar inflammation and fibrosis typical of premature enzyme release in humans.

 

 The question remained as to whether pathological lesions were clinically significant, given that the pathology study had demonstrated they were so common and yet CP was not previously recognised as a common disease in dogs. Dr Watson therefore undertook a concurrent clinical study recruiting any case presented to the Hospital with compatible clinical signs for a variety of blood and imaging tests. Pancreatic biopsy was performed if clinically justified or disease was confirmed at post mortem if a biopsy was not taken. Sixty-one dogs were recruited, with a strong clinical suspicion of CP. Results of the first 14 histologically confirmed clinical cases were published in 2010 (Watson et al. 2010), confirming the breed relationships identified in the pathological studies, particularly in cavalier King Charles and English cocker spaniel)  and also demonstrating that many cases progress to end stage disease with EPI and or DM. This study also stressed the disease causes chronic pain in affected dogs and responds symptomatically to low fat diet and enzyme supplementation, together with insulin injections in diabetic dogs.

 

 Dr Watson has continued to investigate the disease in the English Cocker spaniel. Her work has shown that the disease in cockers showed a predominance of T-lymphocytes targeting ducts and veins, very similar to human autoimmune chronic pancreatitis and distinctively different histologically from the disease in most other dog breeds (Watson et al. 2011). Work presented at ACVIM in 2012 and 2013 further supports the autoimmune hypothesis and also demonstrates that these dogs often suffer from concurrent kidney disease; dry eye and anal sac disease and share a high risk genetic type with cockers with suffer from autoimmune haemolytic anaemia. This work provides support for the idea that cockers with CP may respond well to steroid treatment. However, it is important not to extrapolate this to other breeds because the pathology of the disease looks very different in them so likely has a different cause.

 

 Batchelor, D.J. et al., 2007. Breed associations for canine exocrine pancreatic insufficiency. Journal of Veterinary Internal Medicine, 21(2), pp.207–214.

Watson, P.J., 2003. Exocrine pancreatic insufficiency as an end stage of pancreatitis in four dogs. Journal of Small Animal Practice, 44(7), pp.306–312.

Watson, P.J. et al., 2011. Characterization of Chronic Pancreatitis in English Cocker Spaniels. Journal of Veterinary Internal Medicine, 25(4), pp.797–804.

Watson, P.J. et al., 2010. Observational study of 14 cases of chronic pancreatitis in dogs. Veterinary Record, 167(25), pp.968–976.

 

Watson, P.J. et al., 2007. Prevalence and breed distribution of chronic pancreatitis at post-mortem examination in first-opinion dogs. Journal of Small Animal Practice, 48(11), pp.609–618.

Pancreatitis and Leukocyte Antigen Halotypes

ASSOCIATION BETWEEN CHRONIC PANCREATITIS AND DOG LEUKOCYTE ANTIGEN HAPLOTYPES IN THE ENGLISH COCKER SPANIEL. J. Bazelle1, J. Aguirre-Hernández1, P. J. Watson1, L. J. Kennedy2. 1. Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge, UK. 2. Centre for Integrated Genomic Medical Research, University of Manchester, Manchester, UK

   There are strong breed predispositions with chronic pancreatitis in dogs. English Cocker Spaniels (ECS) are frequently affected and genetic predisposition is suspected in this breed. More recently, chronic pancreatitis in this breed has been associated with IgG4+ plasma cells infiltration, suggesting an immune-mediated mechanism. The purpose of this study was to investigate the association between chronic pancreatitis in ECS and the major histocompatibility complex class II loci (the dog leukocyte antigen loci DLA-DRB1, -DQA1, -DQB1).

   DNA was extracted from 40 cases and 82 controls. The second exon of the canine DLA-DRB1, -DQA1 and –DQB1 was amplified by PCR and purified. All fragments were sequenced and the sequences obtained were identified by comparing them to a canine genotype databse.

   Haplotypes distribution was found to be significantly different between cases and controls with higher frequency of the haplotype DLA-DQB1*00701 among cases, and the lower frequency, compared to controls, of the DLA- DQB1*02001 haplotype.

 

   These results confirmed DLA haplotypes are a contributory factor in the development of chronic pancreatitis in ECS. These results parallel the results of previous study indicating that DLA-DQB1*00701 was found more frequently in ECS affected by anal sac adenocarcinoma and primary immune-mediated haemolytic anaemia. This may indicate a predisposition of ECS for a multi-systemic immune-mediated disease, similar to IgG4+-related disease described in human patients. 

ACVIM Abstract by Dr. Watson

CHRONIC PANCREATITIS IN THE ENGLISH COCKER SPANIEL SHOWS A PREDOMINANCE OF IgG4+ PLASMA CELLS IN SECTIONS OF PANCREAS AND KIDNEY

PJ Watson1, F Constantino-Casas1, CJ Saul2 ; MJ Day3

1Department of Veterinary Medicine, University of Cambridge, UK; 2Chestergates Referral Hospital, Chester, UK; 3School of Veterinary Sciences, University of Bristol, UK

   Chronic pancreatitis (CP) in the English Cocker Spaniel (ECS) has been described as a histologically distinctive disease which is duct destructive and shows similarities to human autoimmune CP.  Human autoimmune CP is characterised by a predominance of IgG4+ plasma cells in the pancreas and is associated with IgG4+ disease in other organs including liver, kidney and salivary and tear ducts, prompting the new term ‘IgG4-related sclerosing disease’. It was hypothesised that CP in ECS would be predominantly associated with IgG4+ plasma cells, whereas CP in other breeds would be involve a mixed population of plasma cells.  It was also hypothesised that ECS would show multi-organ IgG4+ disease.

   Sections of pancreas from 5 ECS with confirmed CP; 4 dogs of other breeds with confirmed CP and 4 dogs without pancreatitis (one ECS and 3 other breeds) were available for immunolabelling together with sections of kidney with glomerulonephritis and interstitial nephritis from one of the ECSs with CP. Canine lymph node and duodenum acted as positive controls. Sections were immunolabelled with a rabbit anti-human polyclonal IgG at 1:5000 dilution and  a panel of 4 previously validated mouse monoclonal antibodies specific for canine IgG subclasses at a 1:400 dilution. 

   The canine IgG1 specific antibody was ineffective in formalin fixed tissue, as in previous studies, but the polyclonal IgG and the monoclonals specific for canine IgG2, IgG3 and IgG4 worked well. Two ECSs had IgG4+ CP with multifocal dense accumulations of plasma cells which were predominantly IgG4+ with 20-50 cells per high power field (hpf). Two ECSs had end-stage CP with marked fibrosis and very few plasma cells. One ECS had periductular plasma cell infiltrates with lesser numbers of IgG4+ plasma cells (6-10 per hpf) and a similar number of IgG2+ plasma cells. This dog also had renal disease with IgG4+ nephritis with 40-70 IgG4+ plasma cells per hpf and very few other IgG subtypes. The normal pancreas sections had very few plasma cells of any subtypes, occasionally seen individually and predominantly in blood vessels. Other breeds with CP had mild to moderate plasma cell infiltrations in inflammatory foci which were polyclonal with a predominance of IgG2+ cells.

 

   Two ECS showed histological findings typical of IgG4+ CP in man. One dog had less convincing pancreatic lesions, but renal histology typical of IgG4+ sclerosing disease in man. More investigations are indicated to investigate whether this is the only cause of CP in ECS, its prevalence and treatment. 

 

False read with concurrent EPI + Pancreatitis

  http://www.provet.co.uk/health/diagnostics/tlitest.htm

 Please note the last bullet point highlighted in red
     


TRYPSIN-LIKE IMMUNOREACTIVITY TEST
(TLI Test)


Description
The TLI test is highly sensitive and specific for the diagnosis of canine exocrine pancreatic insufficiency (EPI). This test measures the concentration of trypsin-like proteins in a blood sample by radioimmunoassay. These proteins diffuse into the blood stream in small amounts (0.01-0.1% of pancreatic trypsinogen).

  • In normal dogs the TLI concentrations are greater than 5.5µg/L (up to 35µg/L).
  • In dogs with exocrine pancreatic insufficiency TLI concentrations are less than 2.5µg/L.
  • In dogs with pancreatitis TLI can be normal or increased.
  • Dogs with bacterial overgrowth have a normal TLI test - unless exocrine pancreatic insufficiency is present as well.
  • False negative results may occur if a dog has concurrent pancreatitis (increasing TLI) and exocrine insufficiency.

 

Last updated : October 2013 

 

    Back

TRYPSIN-LIKE IMMUNOREACTIVITY TEST
(TLI Test)


Description
The TLI test is highly sensitive and specific for the diagnosis of canine 
exocrine pancreatic insufficiency (EPI). This test measures the concentration of trypsin-like proteins in a blood sample by radioimmunoassay. These proteins diffuse into the blood stream in small amounts (0.01-0.1% of pancreatic trypsinogen).

  • In normal dogs the TLI concentrations are greater than 5.5µg/L (up to 35µg/L).
  • In dogs with exocrine pancreatic insufficiency TLI concentrations are less than 2.5µg/L.
  • In dogs with pancreatitis TLI can be normal or increased.
  • Dogs with bacterial overgrowth have a normal TLI test - unless exocrine pancreatic insufficiency is present as well.
  • False negative results may occur if a dog has concurrent pancreatitis (increasing TLI) and exocrine insufficiency.

 

Last updated : October 2013

    Back

TRYPSIN-LIKE IMMUNOREACTIVITY TEST
(TLI Test)


Description
The TLI test is highly sensitive and specific for the diagnosis of canine 
exocrine pancreatic insufficiency (EPI). This test measures the concentration of trypsin-like proteins in a blood sample by radioimmunoassay. These proteins diffuse into the blood stream in small amounts (0.01-0.1% of pancreatic trypsinogen).

  • In normal dogs the TLI concentrations are greater than 5.5µg/L (up to 35µg/L).
  • In dogs with exocrine pancreatic insufficiency TLI concentrations are less than 2.5µg/L.
  • In dogs with pancreatitis TLI can be normal or increased.
  • Dogs with bacterial overgrowth have a normal TLI test - unless exocrine pancreatic insufficiency is present as well.
  • False negative results may occur if a dog has concurrent pancreatitis (increasing TLI) and exocrine insufficiency.

 

Last updated : October 2013

THANK YOU!!!!!

A very much appreciative THANK YOU to Dr. Penny Watson from all of us here at epi4dogs for sharing this interesting and insightful information on pancreatitis. It is very important to us to have the best and most current research information so that we may better care for our ailing companions. With your generosity, you have afforded us this benefit...... thank you !!! 

False positives with Acute Pancreatitis diagnosis

If your dog was diagnosed with ACUTE PANCREATITIS with a SNAP cPL blood assay... please read the following 2014 research report regarding the testing inaccuracies  by:

 

"Diagnostic accuracy of the SNAP and Spec canine pancreatic lipase tests for pancreatitis in dogs presenting with clinical signs of acute abdominal disease"

Please read the research in it's entirety here: 

http://onlinelibrary.wiley.com/enhanced/doi/10.1111/vec.12158/?campaign=wlytk-41806.6740046296&dmmsmid=87469&dmmspid=18667501&dmmsuid=2305163 

 CONCLUSION: 
This study indicated a poorer specificity of cPL for diagnosing AP than previously reported, although sensitivity was similar. There was reasonable agreement between SNAP cPL and Spec cPL results. Measurement of Spec cPL had a better agreement than SNAP cPL for a clinical diagnosis of AP, but overall both produced poor agreement. A positive SNAP cPL or Spec cPL may be indicative of pancreatic inflammation, however this cannot readily determine the primary reason for clinical presentation. Conversely, a negative SNAP cPL or Spec cPL < 200 μg/L appears to be moderately specific, with a small number of dogs (2/11; 18%) diagnosed with AP having false negative results.

 

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