GI Dz

Question 1

Evidence for sildenafil in megaoeosphagus and proposed MOA

Answer 1

Sildenafil: PDE activity increases NO at LES resulting in relaxation (reducing basal tone)
2017 placebo controlled blinded study in CONGENITAL megaoesophagus. Reduced regurg in treatment group (12) compared to placebo (9). Only 15 day trial.

2022 randomised cross over trial found no difference in clearance times on VFSS but a reduction in # of regurgitations (though owner reported QoL scores not altered)
Used compounded LIQUID (?absorption), ADULT dogs.

Question 2

DDX for megaoesophagus

Answer 2

STRUCTURAL
stricture, FB,
neoplasia,
LES achalasia (2 small recent studies)
ENDOCRINE
hypoTH/cortisol,
NEUROMUSCULAR
MG, GOLLP
Myositis (SLE, polymyositis), lead poisoning,
tetanus, snake envenomation,
tick paralysis,
hiatal hernia, dysautonomia

Question 3

Recent studies on NSAID induced gastric ulceration in dogs

Answer 3

10/14 dogs treated chronically with NSAIDs had GI erosions (regardless of if COX2 selective). All were subclinical. Used video capsule endoscopy.

JVIM 2021 - serum gastrin increased over time in meloxicam treated dogs. And correlated with video endoscopic findings of ulcer index. Serum gastrin measured during fasting.

168 cases of gastric ulceration - most common assoc were NSAIDs, GCS, working dog breed, GI neoplasia, and GI mechanical disease

Question 4

Different prokinetics (4) and their MOA

Answer 4

Metoclopramide - 5HT4R agonist, stimulate smooth muscle contraction of stomach and proximal SI.

Erythromycin/Azithromycin (macrolides) - motilin-like activity stimulate MMC (subABx doses) to enhance gastric emptying

Ranitidine - Acetylcholinesterase inhibitor → increases ACh at muscarinic Rs.
Capromorelin - influences GI motility via ghrelin pathway → activation of efferent vagal nerves.

Question 5

REcent evidence for efficacy of prokinetics in cats

Answer 5

U/s assessment of prokinetics in healthy cats: Prospective, random, DB, PC. Metoclopramide and erythromycin both shortened emptying times.
Exanetide (a GLP-1 agonist) prolonged emptying.
Despite metoclopramide not working as an antiemetic it still has efficacy as prokinetic in cats

Another study of azithromycin in healthy cats - faster emptying after both erythromycin and azithromycin

Both in healthy cats - so need to look into use in disease

Question 6

Pathophysiological mechanisms in intestinal disease (10)

Answer 6

• Luminal disturbance (dysbiosis/EPI)
• Enterocyte Dysfunction
• Villous atrophy (crypt infection, malnutrition)
• Brush border dz (cubam R deficient, ileal resection)
• Microvilli damage (damage by pathogens, immature enterocyte repolacement)
• Barrier disruption (allows entry of antigens, protein loss)
• Inflammation
• Hypersensitivity
• Dysmotility (usually 2ry but allows bacterial fermentation of contnets)
• Lymphangiectasia or portal hypertension (reduced nutrient delivery to blood)

Question 7

Mechanisms of diarrhoea (4) and potential causes

Answer 7

Dysmotility
Osmotic
Secretory
Permeability

Malabsorption –> osmotic diarrhoea
Inflammation –> increased permeability
- Infections/toxins –> secretory diarrhoea

Question 8

Diagnostic work up for intestinal disease

Answer 8

CBC, Bio, UA - systemic cause

Direct faecal smear, cytology and float –> look for infectious causes (giardia, parasites, rare protozoal/fungal dz)

Faecal culture - low sensitivity, poor specificity as presence not always indicative of disease
PCR - similar limitations, possible use in Salmonella/Clostridial dz

B12 - see other entries, indicative of malabsorption

Folate - reduced with proximal SI damage (may increase with SIBO)

Calprotectin/Calgranulin - inflammatory marker, can differentiate responders from partial/non in CIE. Also increase in acute inflam (calgranulin not affected by steroids)

Alpha1 protease inhibitor - marker of PLE.

Breath tests - H2 measured as indication of time to reach bact populations (only bact release H gas)

Imaging - rads, u/s

Endoscopy -
Capsule video - some functional issues, seems sensitive for detection of bleeding in sites where traditional cannot reach
Histopath - Often agreement b/w histopathologists is poor, it is important to correlate results with clinical findings and reassess or acquire surgical biopsies if not consistent
Squash preps - complimentary info about presence of pathogens

Question 9

What are CIBDAI and CCEAI

Answer 9

Canine IBD Activity Index
–> measurement of severity of GI signs but high values do not confirm a diagnosis of IBD

Canine chronic enteropathy activity index
–> scores all of the same signs but includes additional characteristics (albumin, ascites, pruritus, oedema) which has made it correlate better with prognosis than CIBDAI
** Improvement in CCEAI did not correlate with changes in histopathology or mucosal permeability in one study

Question 10

TLR changes in IBD compared to health

Answer 10

In normal dogs, TLR 5 is highly expressed in SI as it stimulates production of IL12 and 27 → anti inflammation and Treg promotion –> IL10 and TGF-B

Higher TLR2 expression documented in studies of canine IBD (but not all cases - primarily IRE). In GSD dogs with IBD the expression of TLR4 was demonstrated to be significantly higher than dogs without IBD, and reduced TLR5 expression

A mutation in TLR has also been identified in GSD that can result in hyperresponsiveness to flagellin - this mutation was associated with CE development and has been identified in other affected dogs.

Question 11

Prevailing theory of chronic enteropathy pathogenesis

Answer 11

In CE lumen commensals are recognised as pathogens (possibly due to mutations of epithelial or APC receptors) → increased IL-23 which promotes Th17 cell differentiation (and reduces anti-inflammatory Tregs and Th1)

most forms of CE involve a complex interplay among host genetics, host immune system, the intestinal microenvironment (primarily bacteria and dietary constituents), and the immune system
→ disruption of normal mucosal epithelial architecture results in reduced SI function → malabsorption and dysbiosis → osmotic and secretory and dysmotility diarrhoea

Mutation of TLR5 reported in GSD that results in hyperreactivity to flagellin antigen, similar mutation reported in other breeds. HOWEVER - this is a POLYGENETIC disease with many environmental and biome factors contributing to disease phenotype

Question 12

JVIM 2019 Narrative CE therapy review - what had grade I, III and IV level of evidence as treatments

Answer 12

I = Elimination diets in short and long term remission of CE in dos
(only short term studies in cats)
Tylosin - weak but still grade I
Pred and budesonide short-term remission in canine CE. As well as probiotic combination

III - metronidazole adjunct with prednisolone for short term remission in cats
Enroflox for granulomatous colitis
Pred for short-term remission of cats
Cyclosporine for Tx of steroid refractory dz

IV - FMT for refractory IBD in dogs, single-strain probiotics and other immunosuppressives

Question 13

JSAP 2022 proposal for rational ABx use in CE propsed what?

Answer 13

strong argument against the empirical use of ABs when routinely managing dogs with suspected chronic enteropathy. The use of ABs should be reserved for patients in which all other conditions are excluded and other empirical treatments have been exhausted

AB administration causes changes in the composition and richness of the intestinal microbiota in dogs and cats and that this dysbiosis can be detrimental to overall host health

Question 14

What alternative therapies have grade I evidence for use in canine CE

Answer 14

• VSL#3 multistrain probiotic randomised controlled trial over 8 weeks
  Both groups treated with prednisolone + metronidazole/probiotic both clinically improved
  On histopathology only probiotic group increased tight junction protein expression (may suggest enhanced epithelial barrier)

RCT of 34 dogs: comparison of prednisolone and diet vs pred and probiotic
Both treatments increased the numbers of total bacteria and individual species residing within adherent mucus in a similar fashion. Although both treatments were associated with rapid and progressive clinical remission, significant improvement in histopathologic inflammation was not observed in either group.

Question 15

Where are inflammatory and neoplastic lesions in feline intestinal wall layers

Answer 15

Mucosa/lamina propria which is why endoscopic biopsies are often sufficient

Question 16

ACVIM consensus on biopsies in feline GI dz

Answer 16

No clearly demonstrated superiority in quality existsfor biopsy specimens obtained by laparotomy (full thickness) vsendoscopic biopsy specimens, because poor technique can affectsample quality and hamper diagnostic evaluation for both methods.It has been shown that all inflammatory and neoplastic lesions arepresent in the lamina propria and hence, if mucosal samples ofsufficient quality are procured endoscopically, a diagnosis ispossible without obtaining full-thickness biopsy specimens.However, because of limited access to the jejunum by endoscopy,jejunal lesions cannot be reliably sampled although this smallintestinal segment is frequently abnormal

Level 2 evidence

Question 17

IHC findings in feline LGITL

Answer 17

CD3 +
CCD 56 -
pSTAT5 +
High Ki67 (proliferative cell fraction)

Question 18

Limitations of PARR in feline LPE/LGITL differentiation

Reported Sens/Spec

Answer 18

Consensus: clonality must be interpreted in conjunction with clinical, histopathological, and immunohistochemical results and cannot be used as a sole means to reclassify cases

Sensitivity of newer primers reported to be 95.5%
HOWEVEr - specificity is what is more important as we need to differentiate the true negatives –> initial reports of 95-100% were based on comparison to healthy cat controls not CE - more recent CE comparison suggest Spec of 30-50%.

• Pseudoclonality in low numbers of lymphocytes
• clonality is not synonymous with malignancy and can occur with any strong antigen stimulation promoting selective proliferation of lymphocyte clones.
• lack of standardisation in method and interpretation in vet med

Question 19

Effects of soluble fibre on motility and nutrient absorption

Answer 19

slow GI transit time and reduce nutrient absorption in the small intestine. But, they may also have an AA sparing effect through the preferential shunting of the SCFA, propionate, into the TCA cycle over AAs

can provide a laxative effect for dogs with constipation and a water-holding, stool-bulking effect for those with large intestinal diarrhoea

Question 20

Effects of CE on vitamin D and benefit of supplementation evidence (JSAP CE Diet management review)

Answer 20

vitamin D deficiency is a common finding in dogs with CE, tends to correlate with disease activity and histologic disease severity, and is a negative prognos-tic indicator in dogs with CE or PLE

The Benefit of vitamin D supplementation in dogs with CE requires more investigation as, at the time of this writing, there are no published, randomised, controlled trials evaluating the effect of vitamin D supplementation on outcome in dogs with CE. However, it is the authors’ opinion that supplementation improves morbidity.
This is also supported by studies in people with IBDin which vitamin D supplementation improves clinical and bio-chemical disease activity

Question 21

When to consider diet fat reduction

Answer 21

dogs with GI motility disorders, lymphangiectasia or pancreatitis.

higher fat diets may slow gastric emptying and worsen clinical signs

Question 22

Benefit of medium chain triglycerides

Answer 22

MCT-containing oils can provide more digestible and absorbable energy while reducing lymphatic transport in dogs with lymphangiectasia

some dogs with lymphangiectasia causing PLE (ie requiring very low fat diets) may experience volume intolerance. While after digestion, long-chain triglycerides (LCTs) are transported via chylomicrons into lymphatic vessels, resulting in swelling and inflammation of the lymphatics and additional protein leakage. MCTs undergo more rapid and more complete digestion within the intestinal lumen and are absorbed largely as free fatty acids

MCTs cannot be used as the sole source of fatty acids long-term as they do not provide the essential fatty acids, omega-3 and omega-6 essential fatty acids

Question 23

Minerals that may be deficient in CE

Answer 23

Zn
Fe
Ca
Mg

Question 24

Pathogenesis of PLE

Answer 24

A syndrome with multiple aetiologies - think compromised mucosa and lymphatic obstruction.

Increased permeability of capillaries increasing the production of fluid and cuasing interstitial oedema

Dilation of lacteals → loss of normal valve like pumps that promote flow of lymph into lymphatics → external pressures merely pumping lymph into lumen → more inflammation and protein loss → interstitial oedema

Processes of lymph fluid loss, active protein exudation, and leaky cell junctions could be present at some juncture in every affected bowel

Question 25

Normal intestinal loss/absorption of lymph

Answer 25

Normally the lymphatic endothelial cells have loose junctions that serve as valves to allow entry of lymph due to the higher pressure in the lumen compared to lymphatics. Post-prandial lumen osmolality is much higher than fasted, which can result in reversal of the oncotic gradient driving movement of osmotically active particles into the lymph (along with the hydrostatic gradient)

Question 26

Categories (4) and differential dx for PLE

Answer 26

Erosive causes of mucosal injury - inflammatory bowel disease, infectious enteritis, neoplasia, NSAIDs

Non-erosive causes of mucosal injury - FRE, hypoadrenocorticism, crypt disease

Infectious causes of PLE - Hookworms, Strongyloides

Lymphatic disease - idiopathic lymphangiectasia, secondary lymphangiectasia, lymphangitis (granulomatous/inflammatory)

Question 27

Pathogenesis of thromboembolic dz in PLE

Answer 27

due to AT loss,
altered vit K absorption,
plt hyperaggregation,
hyperfibrinogenaemia and vascular compromise

Question 28

Mechanisms to diminish protein leak in PLE

Answer 28

(1) Optimising Starling forces - An iso or mildly hyperosmotic lumen could theoretically be achieved by feeding small, frequent, high-protein/low-fat meals every 2-3 hours so that the bowel is in the fed state more of the time. Reducing the time in fasted, hypo-osmotic lumen, state.

(2) Modifying intestinal peristalsis - hypomotile bowel can develop lymph stasis as peristalsis passively facilitates lymph fow. If dysmotility is present treatment with metoclopramide may be considered but in combination with appropriate feeding plan (as hypermotility could serve to worsen protein/lymph loss).

(3) Bypass of the affected intestinal area, if PLE is confirmed to be segmental

Question 29

Most common reported findings in histo of PLE (JVIM review)

Answer 29

• 66% LPE
• 50% lymphangiectasia
• 8% lymphangitis, lipogranulomas
• 7.2% crypt disease

Lymphangiectasia secondary to other disease may be underreported especially in LPE where inflammation can stimulate formation of new lymphatics

Question 30

Predisposed breeds and Pathogenesis of primary lymphangiectasia - and causes of secondary

Answer 30

Yorkshire Terrier, Lundehunds, SCWT, Terriers, Rottweilers

primary disease process with lymphatic abnormalities predominating → lymph leakage → inflammation and granuloma formation (though the inflammation could theoretically be causative)

secondary occurs from lymphatic obstruction directly by neoplasia, fibrosis, or indirectly by inflammation, or right heart failure.

Question 31

Features of crypt dz, affected breed/s and how does it cause PLE

Answer 31

Yorkshire terriers
Dilated cystic crypts, contain sloughed epithelial cells.

Lesions in the crypts without concurrent neoplasia, lymphangiectasia or inflammation
→ villous collapse and fusion due to loss of epithelial regeneration
→ rupture of cysts into lumen results in marked protein loss.
Unlikely immune mediated. No evidence of infectious cause has been found on FISH or parvovirus testing

Question 32

Evidence for diet in PLE management

Answer 32

1) mainstay in human disease (although this has different clinical picture to dogs)

2) Low fat reduces lymphatic pressure and flow preventing lacteal dilation and leakage

3) 12 Yorkies had better response to diet alone compared to immunosuppression

4) JSAP 2021- perspective study of steroid resistant PLE in 10 dogs. 8/10 dogs achieved complete remission and 7 of these remain in prolonged remission.
Diets provided by royal canin - free to owners, possible conflict of interest

5) GCS adverse effects are disadvantageous and counterintuitive in PLE (muscle catabolism, hypercoagulability, hyperlipidaemia)

6) lack of evidence that primary lymphangiectasia, crypt disease or granulomatous lymphangitis are immune mediated

Question 33

Pathogenesis and histo findings in AHDS

Answer 33

Numerous potential causes and exact pathogenesis is unknown - typically young small breed dogs.
Lesions are restricted to SI and LI (not stomach) so HGE name was dropped
mucosal necrosis and neutrophilic inflammation reported in a study of 10 dogs

Question 34

Evidence that ABx are not indicated in AHDS

Answer 34

disruption of normal flora;
potential to stimulate clostridial toxin release,
selection for resistant E.coli, clinical

resolution without ABx well documented (provided no systemic signs of illness) - a study where the incidence of bacteraemia was low in AHDS (not different to healthy controls) indicating effective clearance of translocating bacteria despite barrier dysfunction.

Question 35

Challenges with Faecal PCR interpretation and indications of whent to use

Answer 35

Isolation is not causation and similar rates in healthy and D+ animals.
Lack of clear indications to perform faecal PCR

PCR indications: recent possibility of exposure;
acute haemorrhagic diarrhoea with risk of sepsis;
outbreak scenarios;
concern for zoonotic risk

Question 36

Recent publications on clostridium perfringens toxin A involvement in AHDS

Answer 36

JSAP 2021 - retrospective assessment of Clostridial alpha toxins in faeces of dogs with AHDS (groups 15, 16, 10). Not higher prevalence than dogs without diarrhoea or with other causes.
JVIM 2019 - netE and netF pore forming Clostridial toxins. Found in 48% of AHDS and 12% of healthy dogs. No difference in presentation b/w AHDS dogs with and without + result.

seems unlikely to be causative, more likely associated and may contribute to CS, though a difference in presentation has not been identified b/w dogs with or without the presence of toxin

Question 37

MST for canine intestinal adenocarcinoma

Answer 37

MST 10 months with surgical resection but may be much shorter in metastatic disease (40% 1 year survival).
→ MST without LN metastasis and surgical removal is 15months, compared to 3 months if LN metastasis present at surgery

Feline MST is 5-15months with surgery (<2 weeks without), high perioperative mortality rates are reported

Question 38

Reasons LPE is difficult to differentiate from LGITL in cats

Answer 38

Diagnostic challenge as both present in similar way.
Physical examination, ultrasound and gross examination are of limited use
B cell lymphomas have distinct cellular morphology and can be recognised microscopically but T cell lymphoma can be difficult to differentiate from IBD.
Feline intestinal lymphoma is most commonly T cell moore et al, small cell arises from the base of the villus
In both IBD and lymphoma there is expansion of lymphocytes from the mucosa associated lymphoid tissues (MALT)
Can occur concurrently
Most biopsies collected via endoscopy which can be challenging as histo limited to mucosa and cannot assess transmucosal spread which is one of the diagnostic criterion for diagnosis of lymphoma
The most common sites of feline lymphoma is ileocolic junction and jejunum which is difficult to sample
Clinical signs often do not correlate with the extent or severity of intestinal lesions

Question 39

Proposed cause of chronic colitis in dogs/cats

Answer 39

Similar to CE there is an inflammatory infiltrate into the lamina propria as a result of: defective mucosal barrier; abnormal immune response to lumen antigens changes to the microbiome

Mutations in NODs and TLRs have been reported in association with development of idiopathic disease:
- TLR 2 (recognition of bact lipopeptides)
- TLR 4 (recognition of LPS and Cpg DNA)
- TLR 9 (intracellular virus recognition)
Increased expression/altered function of these has been associated with greater inflammatory response and need for immunosuppression.
→ production of IL 23 which stimulates Th17 and induction of innate immune cell recruitment (IL17, TNFa)
→ reduced production of IL 12 and 27 which induce Tregs and thus IL10/TGF-B

Question 40

Recent publications on use of fibre in acute LI Dz

Answer 40

JVIM 2022: high fibre diet in ACUTE LI D+ in 52 shelter dogs. USed Purina Proplan in prospective random control. Concurrent Tx with FBZ and Metronidazole in all study dogs may confound results. High fibre diet resulted in 100% normal fecal score within 9 days compared to 55% in control group. Small study 11 in each group.

JAVMA 2022 - random, placebo controlled trial comparing easily digestible diet with metronidazole or fibre added in ACUTE non-infectious LI D+. diet +/- psyllium had shortest recovery time. Addition of metronidazole prolonged time to recovery and increased DI.

Question 41

Evidence for use of fibre in chronic colitis

Answer 41

JSAP CE diet review - recommend trial of high fibre diet in dogs with LI signs followed by hydrolysed trial if no/partial response. If concurrent motility abnormalities can also use low fat diet.

JVIM 2019 CE therapeutics - does not specifically mention colitis. Improved tight junctions in dogs given probiotic with pred (not metro) but similar response rate. Similar in pred/diet and pred/probiotic RCT. No difference in outcome in dogs treated with diet +/- synbiotic
No strong evidence to support use of metronidazole in Tx of IBD, studies supporting use are grade III evidence

BMC Vet research - prospective study of fibre efficacy in chronic LI dz using a fibre enriched commercial diet. 68% CR, 32% PR. Total duration of study as 56d. Improved consistency, frequency and reduced haematochezia.

Vet Sci 2020 - 30 chronic colitis dogs unresponsive to prior interventions fed digestible, hydrolysed high fibre diet + probiotic → all improved by day 30 (unclear which component of therapy resulted in benefit)

Question 42

New publications on AMR in AIEC granulomatous colitis

Answer 42

JVIM 2022 - 9/24 GC cases were FQ sensitive, remainder resistant. All but 1 FQ-resistant E.coli were MDR.
FQ sensitive dogs had complete response to enro, FQ-R dogs Tx with meropenem or doxycycline, 50% had long term CR, 33% PR and 2/12 no response. 2 dogs tx not based on sensitivity results, one PR at 3mo, the other CR (given ceph which does not penetrate macs).
ABx Tx guided by sensitivity had improved prognosis.
Resistance by mutation in DNA gyrase (site of FQ activity) and less commonly plasmid acquired

JSAP 2021 - 5 cases retrospective review of outcome. CR in ⅘ long term with FQ tx
2 dogs relapsed with MDR E.coli but targeted ABX was associated with long-term partial remission

JVIM - 2019 CE therapeutics: grade III evidence to support use of enrofloxacin for AIEC. Based on information from initial small case series demonstrating response. Descriptive cohort study only - but complete remission and resolution of histopathological changes reported with prolonged

Question 43

Infectious causes for LI D+

Answer 43

Bacterial - as for SI D+ same potentially pathogenic spp.
WHIPWORM - Trichuris vulpis - more common in dogs than cats. Preference for caecum/colon. Intermittently shed eggs. Most dogs are asymptomatic. May cause low K+ due to alteration of colonic mucosal
Pythium insidiosum - aquatic pathogen can cause diffuse granulomatous disease of GIT or ulcerative skin lesions
Prototheca - algae that can cause systemic disease
Exotic causes:
- Histoplasmosis capsulatum: saprophytic soil fungus in Nth America. Causes granulomatous GI disease in young dogs and cats

Question 44

Feline megacolon - proposed pathogenesis, DDX and radiographic findings suggestive of dz

Answer 44

→ functional disturbance in smooth muscle of colon though histopathology is most often normal. Begins with descending colon but progresses to involve entirety.
→ dilated megacolon (end stage dz)

DDX: colonic hypertrophy due to obstruction from neoplasia, pelvic deformity/trauma, rectal stricture; FB

Dilation due to dysfunction from: hypokalaemia, hypercalcaemia; sacral spinal cord malformations, dysautonomia, drugs (opioids, cholinergic agonists, phenothiazines); dehydration, renal dz, hospitalisation

Rads: colon height >1.48x LENGTH of L5 (sens 77%; Spec 85%)
<1.28x is a strong indicator of normal (Sens 96%; spec 87%.
Not definitive differentiation of constipation and obstipation and severity thus far not shown to correlate with Tx response.

Question 45

Evidence for use of adjunctive Tx in AGASAC

Answer 45

Chemo - lack of controlled studies demonstrating efficacy. Not indicated as sole therapy. Many studies have not shown benefit in adjunctive chemo over surgery alone. Retrospective studies will have bias due to the nature of clinician bias towards recommending chemo in dogs with more aggressive histological or clinical features. Do not know if chemo will delay recurrence due to lack of prospective appropriate case-matched trials.
RT - recommended as adjuvant to Sx.
Overall lack of prospective, controlled trials to determine BEST adjunctive regime.

JVIM 2020 - toceranib use in AGASAC with various other adjuncts.
Clinical benefit in 69% - 20.7% PR, 40% stable dz
Not all had sx, some had concurrent chemo.

JAVMA 2019 - toceranib alone in stage 4 dz. 13/15 dogs had clinical benefit. PFI 350d which is an improvement on historical controls.

JAVMA 2018 - outcome in dogs with stage I dz Tx with surgery only.
MST >1200d; median time to recurrence 354d in 7/34 cases. 9/34 developed mets median time 589d

Question 46

Different types of laxative and examples

Answer 46

Bulk forming - psyllium, draws water in.

Emollient (docusate) - increases miscibility of water and lipid –> enhancing lipid absorption and preventing water

Lubricant (mineral oil) - reduce colonic water absorption

Hyperosmotic (lactulose, PEG)

Stimulant (bisacodyl) - increase colonic motility