Evidence-based management of canine chronic enteropathy
There was a great article by Mark Rishniw and Paul Pion a few years back:
J Feline Med Surg. 2011 Jul;13(7):487-97
Is treatment of feline hypertrophic cardiomyopathy based in science or faith? A survey of cardiologists and a literature search.
Rishniw M, Pion PD.
http://journals.sagepub.com/doi/abs/10.1016/j.jfms.2011.05.006
These are seriously bright guys and the article is a revealing ’emperor’s new clothes’ moment. Their cutting conclusion:
‘Evaluation of the therapeutic strategies chosen for these hypothetical cases of HCM suggests that cardiologists or clinicians with a strong interest in cardiology often prescribe treatments knowing that little documented evidence supports their decisions.‘
I presumptively contend that this is also the case in other areas of specialism. In an age of evidence-based medicine there’s still an awful lot of opinion-based treatment going on at all levels of the profession.
Which brings us to canine chronic enteropathy. As far as I’m concerned the truth of it in terms of EBM is summarised eloquently by Elias Westermark:
‘There is a paucity of research based knowledge about chronic diarrhoea in dogs. In the literature no studies can be found that confirms that round worm, whip worm, hook worm or giardia cause chronic diarrhoea in dogs. For this reason, it is questionable to study endoparasites when clarifying the reason for chronic diarrhoea in dogs. No study confirms that clostridium-, campylobacter- or salmonella species cause chronic diarrhoea signs in dogs. There is no research-based information to-date that endoscopy would be helpful in the diagnosis of dogs with chronic diarrhoea or to monitor how the disease progresses. Neither no reliable laboratory test can be recommended to be used in evaluating the seriousness of the disease or to monitor the progress of the disease. There is no evidence based information on what food should be recommended for dogs suffering from diarrhoea. Only a few studies have been published that show how effective antibiotics are in the treatment of diarrhoeal dogs. Many more studies are needed before it is possible to determine how effective corticosteroids are in the treatment of diarrhoea in dogs.’
This is the abstract from his recent and comprehensive review:
Top Companion Anim Med. 2016 Jun;31(2):78-84. doi: 10.1053/j.tcam.2016.03.001.
Epub 2016 Jun 11.
Chronic Diarrhea in Dogs: What Do We Actually Know About It?
Westermarck E.
https://www.ncbi.nlm.nih.gov/pubmed/27968758/
So, why do we see dogs having endoscopic biopsies, repeated faecal campylobacter cultures or treated with a wide variety of antibiotics? Well, chronic diarrhoea can become a very pressured situation; -especially for a referral service. There’s a lot of pressure for a ‘diagnosis’ and a lot of pressure to ‘do something’. I can buy that. It’s not a perfect world and it’s not good enough to shrug your shoulders all the time and say ‘we don’t know’. On the other hand I think we should be rigorous enough to look at what’s published and act on it where we can. And where we’re going to go ‘off piste’ then I believe we should be honest with ourselves and clients as to potential costs and adverse effects.
To be specific:
Endoscopy (in chronic diarrhoea):
A ‘diagnosis’ of ‘inflammatory bowel disease’ isn’t really a useful diagnosis any more than a diagnosis of ‘inflammatory skin disease’ would be tolerated by a self-respecting dermatologist. There’s a reason why ‘chronic enteropathy’ is replacing ‘inflammatory bowel disease’ as terminology of choice:
J Small Anim Pract. 2016 Nov;57(11):589-599. doi: 10.1111/jsap.12588. Epub 2016 Oct 16.
Inflammatory bowel disease versus chronic enteropathy in dogs: are they one and the same?
Dandrieux JR.
https://www.ncbi.nlm.nih.gov/pubmed/27747868
As things stand there is minimal correlation between specific histopathological findings and response to any specific treatment. In fact there is sometimes depressingly little agreement as to what even constitutes ‘normal’ or ‘abnormal’ in gut histopathology.
This is a sobering read:
Interobserver variation among histopathologic evaluations of intestinal tissues from dogs and cats.
Willard MD, Jergens AE, Duncan RB, Leib MS, McCracken MD, DeNovo RC, Helman RG, Slater MR, Harbison JL.
J Am Vet Med Assoc. 2002 Apr 15;220(8):1177-82.
https://www.ncbi.nlm.nih.gov/pubmed/11990964
Clue….they conclude ‘ Clinicians must be cautious about correlating clinical signs and histopathologic descriptions of intestinal biopsy specimens.’
Endoscopy requires general anaesthesia and it’s not cheap. So justification is required.
How about diagnosing GI lymphoma? OK, arguably maybe yes, if faced with a patient who has failed to respond to diet and antibiotic trials: but you’re certainly not going to pick up all lymphomas…or maybe even most of them. It’s a very operator-dependent skill, biopsy quality is variable and even good samples may not detect lymphoma when it’s present because endoscopes do not reach the jejunum and samples are not full-thickness. There’s a risk of performing anaesthesia and spending a lot of money without achieving an accurate diagnosis. These days we have the option of flow cytometry on ultrasound-guided FNAs from abdominal nodes. Despite the obvious risks, full-thickness biopsies may be a better bet if you really need to know.
It’s a feline paper but probably can be extrapolated to dogs:
J Am Vet Med Assoc. 2006 Nov 1;229(9):1447-50.
Comparison of endoscopic and full-thickness biopsy specimens for diagnosis of inflammatory bowel disease and alimentary tract lymphoma in cats.
Evans SE1, Bonczynski JJ, Broussard JD, Han E, Baer KE.
https://www.ncbi.nlm.nih.gov/pubmed/17078807
These authors conclude ‘EB specimens were useful for diagnosis of gastric lymphosarcoma but were not adequate for differentiating between IBD and lymphosarcoma in the small intestine. Because the most common sites of alimentary tract lymphosarcoma in cats are the jejunum and ileum, full-thickness biopsy specimens of those sites should be obtained via laparotomy or laparoscopy for accurate diagnosis.’
What about lymphangiectasia? There is some evidence that lymphangiectasia would be best managed with ultra-low fat diet. Well, firstly, lymphangiectasia is a descriptive term rather than a ‘diagnosis’. Secondly, correlation between ultrasonographic features suggestive of lymphangiectasia and histopathologic diagnosis of lymphangiectasia is >90%. You don’t need histopath really.
COMPARISON OF ULTRASONOGRAPHIC FINDINGS WITH CLINICAL ACTIVITY INDEX (CIBDAI) AND DIAGNOSIS IN DOGS WITH CHRONIC ENTEROPATHIES
In: Veterinary radiology & ultrasound the official journal of the American College of Veterinary Radiology and the International Veterinary Radiology Association, 2008 Jan-Feb., v. 49, no. 1, p. 56-64
LORRIE GASCHEN,PATRICK KIRCHER,ANJA STuSSI,KARIN ALLENSPACH,FREDERIC GASCHEN,MARCUS DOHERR, ANDREA GRUNE
https://www.ncbi.nlm.nih.gov/pubmed/18251296
In summary, there is, of course, a place for endoscopy in various scenarios but in chronic diarrhoea the decision to go ahead needs serious consideration.
Antibiotics:
So, you could do faecal samples …but worth having a think first about what you’re going to do if any of tests are positive! I won’t bore you with more papers -they’re summarised in Westermark as above. But there’s no evidence that bears examination for a role of Campylobacter, Salmonella or Giardia in chronic diarrhoea.
Repeated courses of erythromycin or metronidazole may sometimes be associated with improvement ….but are perhaps equally likely to be associated with changes in gut flora which may even perpetuate signs in the longer term. We are barely scratching the surface of what the health implications might be to messing with gut flora but I think it’s a safe bet they aren’t negligible. Since some of these potential adverse effects are very long term they may well not be recognised as sequelae to treatment choices.
Gut microbiota composition correlates with diet and health in the elderly
Marcus J. Claesson, Ian B. Jeffery, Paul W. O’Toole
Nature volume 488, pages 178–184 (09 August 2012)
https://www.nature.com/articles/nature11319/
OK, antibiotic-responsive diarrhoea is a thing. Sometimes you have to try something.
But….a decision to use them should be based on a risk-benefit analysis. A patient with a 6 month history of enteropathy, recurrent abdominal discomfort and weight loss is a different proposition from a fit and healthy dog with a 3 week history of diarrhoea. My experience is that pet owners with the latter scenario start off wanting ‘something’ but, after discussion of the potential adverse effects of antibiotics are often very happy to wait a bit longer. I sometimes tell them about my patient who died after idiosyncratic renal tubular necrosis following oxytetracycline.
If we’re going to use an antibiotic for chronic enteropathy then what’s the best option? I just don’t understand the widely-touted preference for metronidazole or oxytetracycline. This appears to be largely on the basis of ‘well, that’s what we do’. It’s suggested that potential immunomodulatory effects of metronidazole might be useful. And there’s evidence to support the hypothesis that this drug does affect immune function:
Int Immunopharmacol. 2008 Feb;8(2):341-50.
Evaluation of immunosuppression induced by metronidazole in Balb/c mice and human peripheral blood lymphocytes.
Fararjeh M, Mohammad MK, Bustanji Y, Alkhatib H, Abdalla S.
https://www.ncbi.nlm.nih.gov/pubmed/18182250
But absolutely no good randomised, controlled study data! Hypotheses are all very well but when faced with a complex, multi-factorial scenario where our understanding is, in all likelihood, rudimentary I’d like to see some actual evidence of benefit.
Metronidazole certainly does have well-established potential for toxicity.
Drug Saf. 2000 Nov;23(5):429-48.
Comparative tolerability of treatments for inflammatory bowel disease.
Stein RB, Hanauer SB.
https://www.ncbi.nlm.nih.gov/pubmed/11085348
‘Adverse reactions
The following adverse reactions may occur after administration of metronidazole: vomiting, hepatotoxicity, neutropenia and neurologic signs.’
http://www.noahcompendium.co.uk/?id=-467982
I reckon we might not always recognise peripheral neuropathy, headache or nausea in our patients.
…and is potentially carcinogenic:
Mutat Res. 2002 Jun;511(2):133-44.
Is metronidazole carcinogenic?
Bendesky A, Menéndez D, Ostrosky-Wegman P.
https://www.ncbi.nlm.nih.gov/pubmed/12052431
…and should be handled with care by owners:
‘Skin Contact: Remove contaminated clothing. Flush area with large amounts of water. Use soap. Seek
medical attention.’
There are one or two papers which do report the use of metronidazole in dogs with chronic diarrhoea. For example:
BMC Vet Res. 2016; 12: 217.
Rifaximin is an effective alternative to metronidazole for the treatment of chronic enteropathy in dogs: a randomised trial
Alessandro Menozzi,corresponding author1 Manuel Dall’Aglio, Fausto Quintavalla, Luca Dallavalle, Valentina Meucci, and Simone Bertini
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5053129/
And since this study involved small numbers of individuals, required only a three-week history of diarrhoea for enrolment, was entirely uncontrolled, and all dogs also received a novel diet, ranitidine, metoclopramide and sometimes vitamin B12 I’d be thinking the suggestion that any meaningful conclusions can be drawn is contentious.
Metronidazole is licensed in dogs.
But, on the other hand we DO have a nice series of controlled studies documenting the efficacy of tylosin in canine chronic enteropathy.
Acta Vet Scand. 2011 Apr 14;53:26.
Effect of tylosin on dogs with suspected tylosin-responsive diarrhea: a placebo-controlled, randomized, double-blinded, prospective clinical trial.
Kilpinen S1, Spillmann T, Syrjä P, Skrzypczak T, Louhelainen M, Westermarck E.
https://www.ncbi.nlm.nih.gov/pubmed/21489311
Acta Vet Scand. 2014 Aug 6;56:43
Efficacy of two low-dose oral tylosin regimens in controlling the relapse of diarrhea in dogs with tylosin-responsive diarrhea: a prospective, single-blinded, two-arm parallel, clinical field trial.
Kilpinen S, Spillmann T, Westermarck E.
https://www.ncbi.nlm.nih.gov/pubmed/25096196
Tylosin tablets are readily available in the UK (from Summit) although unlicensed in dogs. I don’t understand why evidence-based medicine doesn’t appear to translate into widely-recommended practice here.
Other options:
Check TLI. That’s a no brainer.
First thing is sort diet. STRICT 2 month hydrolysed diet or single protein-source ‘hypoallergenic’ diet. There is some evidence that hydrolysed gives better long term control of signs than a ‘GI diet’ containing a mix of protein sources.
Mandigers PJJ, Biourge V, van den Ingh TSGAM, Ankringa N,German AJ.
A randomized, open-label, positively-controlled field trialof a hydrolyzed protein diet in dogs with chronic small bowel enterop-athy.J
Vet Intern Med. 2010;24:1350-1357
https://onlinelibrary.wiley.com/doi/full/10.1111/j.1939-1676.2010.0632.x
Most of the dogs which are going to do well will do so on dietary management alone.
Vet Rec. 2016 Apr 9;178(15):368. doi: 10.1136/vr.103557. Epub 2016 Jan 25.
Long-term outcome in dogs with chronic enteropathies: 203 cases.
Allenspach K1, Culverwell C1, Chan D1.
https://www.ncbi.nlm.nih.gov/pubmed/26811439
There is evidence that some dogs with lymphangiectasia respond to ultra-low fat diets where steroids have failed. If ultrasonography suggests lymphangiectasia then this is probably a good strategy.
J Vet Intern Med. 2014 May-Jun;28(3):809-17. doi: 10.1111/jvim.12327. Epub 2014 Mar 27.
The clinical efficacy of dietary fat restriction in treatment of dogs with intestinal lymphangiectasia.
Okanishi H1, Yoshioka R, Kagawa Y, Watari T.
https://www.ncbi.nlm.nih.gov/pubmed/24673630
Ultra-low fat = boiled chicken or turkey breast + rice/potato. There is no commercial ultra-low fat diet in the UK as far as I’m aware.
If still not right, signs are severe enough or develops hypoalbuminaemia or weight loss then next step is to try glucocorticoids: prednisolone or budesonide. Although budesonide is unlicensed there are more papers documenting its effect than exist to support the use of prednisolone. However, pred probably remains first line choice.
Other immunosuppressives are anecdotally used in refractory cases but little or no objective data is available.
It’s worth noting that in a small case series…
J Small Anim Pract. 2017 Feb;58(2):103-108. doi: 10.1111/jsap.12625.
Dietary management of presumptive protein-losing enteropathy in Yorkshire terriers.
Rudinsky AJ1, Howard JP1, Bishop MA2, Sherding RG1, Parker VJ1, Gilor C1.
https://www.ncbi.nlm.nih.gov/pubmed/28160309
10/11 Yorkies with PLE responded to diet alone without glucorticoids. It should not necessarily be assumed that hypoalbuminaemia is a definite indication for steroids in all cases.
It may be worth measuring B12: although objective data confirming that supplementation is clinically helpful in cases with low blood b12 is lacking. If you choose to supplement on the basis of low B12 then oral tablets are as effective as injections (available through amazon or umpteen other online sources).
J Vet Intern Med. 2016 Jan-Feb; 30(1): 101–107.
Oral Cobalamin Supplementation in Dogs with Chronic Enteropathies and Hypocobalaminemia
L. Toresson,corresponding author 1 , 2 J.M. Steiner, 3 J.S. Suchodolski, 3 and T. Spillmann 1
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4913667/
In this study ‘dogs included had been treated with oral cyanocobalamin tablets1 (1 mg). Dogs with a body weight of 1–10 kg received ¼ tablet, dogs with a body weight of >10–20 kg received ½ tablet, and dogs with a body weight >20 kg received 1 tablet daily.’
In last ditch scenarios then you could consider using oclacitinib: on the basis that JAK inhibitors are used in human IBD.
Gastroenterol Clin North Am. 2014 Sep; 43(3): 603–617.
Update on Janus Kinase Antagonists in Inflammatory Bowel Disease
Brigid S. Boland, MD,1,2 William J. Sandborn, MD,1,2 and John T. Chang, MD1,2
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4129380/
Or even adipose-derived autogenous stem cell therapy:
Vet J. 2015 Dec;206(3):385-90.
Safety and efficacy of allogeneic adipose tissue-derived mesenchymal stem cells for treatment of dogs with inflammatory bowel disease: Clinical and laboratory outcomes.
Pérez-Merino EM1, Usón-Casaús JM2, Zaragoza-Bayle C2, Duque-Carrasco J3, Mariñas-Pardo L4, Hermida-Prieto M4, Barrera-Chacón R2, Gualtieri M5.
Great review guys!!!!
thanks a lot for putting all this together….
Thanks Eric, diarrhoea floats our boat 😉