dealing with diarrhea wendy blount, dvm. contents of the gut are actually outside the body contents...

Dealing with Diarrhea

Wendy Blount, DVM

• Contents of the gut are actually outside the body

• This illustrates the importance to the integrity of the mucosal GI barrier, which must be selectively permeable

• GALT (gut associated lymphoid tissue) monitors what and what does not enter into the body

Gut Tissue Layers

• Mucosa• Submucosa/Lamina Propria• Muscularis– Longitudinal smooth muscle – Submucosal nerve plexus – Circular smooth muscle – Myenteric nerve plexus – Longitudinal smooth muscle

• Serosa - connects to mesentery, everywhere but esophagus and rectum

DDx Diarrhea

• Extra-intestinal causes (13%)– Everything that causes vomiting– Exocrine pancreatic insufficiency

• Intra-intestinal causes (87%)– 52% are food responsive– 12% IBD– 9% antibiotic responsive diarrhea– 3% prednisone responsive but no inflammation on histopath– 12% GI parasites

(Volkmann et al, 2012)

Acute vs. Chronic Diarrhea

• Most cases if acute diarrhea respond to empirical therapy

• HGE is a particular clinical picture that responds well if treated early

• We will spend most of the hour talking about chronic diarrhea

Diagnostics for Diarrhea

1. Empirical Treatment2. MDB– CBC, panel, electrolytes– Urinalysis– Fecal flotation and direct smear– Heartworm test for dogs, FeLV/FIV for cats– T4 and free T4 for cats

3. Abdominal x-rays and ultrasound, GI Lab tests4. Endoscopy (always do GI panel first)

Abdominal Radiographs and US

• Abdominal Radiographs– obstruction (foreign body, intusussception)– ileus– Mass

• Abdominal ultrasound - above plus– Increased intestinal thickness for IBD– Obliteration of the layers of the gut for neoplasia and

phycomycosis– Muscularis:mucosa > 1:1 suggests lymphoma– Lymphadenopathy can be seen with LSA or IBD

Symptoms – Large vs. Small Bowel Diarrhea

• Frequency of bowel movements– Not always abnormal with SI diarrhea– Usually frequent with SI diarrhea

• Volume of bowel movements– Large volume for SI– Small volume for LI

• Blood and mucus– Unusual for SI– Common for LI

Symptoms – Large vs. Small Bowel Diarrhea

• Straining– Academically considered more often with LI– But SI diarrhea can cause secondary inflammation

in the rectum which can result in straining• Weight loss– Common with SI– Rare with LI except Boxer Colitis, colon neoplasia

and colon Histoplasmosis

Symptoms – Large vs. Small Bowel Diarrhea

• MDB and GI Panel– More often normal with LI except Boxer Colitis– SI disease can be associated with low albumin– Low albumin and globulin can indicate GI bleeding– Low B12 indicates proximal intestinal disease– Folate indicates distal intestinal disease– Low TLI indicates EPI– High TLI indicates acute pancreatitis– High PLI indicates acute and/or chronic pancreatitis

Treatment of Diarrhea

1. Empirical Treatment– Fenbendazole 50 mg/kg x 3-10 days

• Rules out Giardia and whipworms

– Metronidazole as for vomiting• 250 mg – ¼ tab per 10 lbs PO BID• 500 mg – ¼ tab per 20 lbs PO BID

– Tylan powder 1/8 tsp (325 mg) per 35-65 pounds• 5-20 mg/kg BID

2. MDB & Intestinal Diagnostics3. Specific Treatment based on diagnostics

Inflammatory Bowel Disease

• Inflammatory reaction to food and/or bacteria• Uncommon in young dogs• Food intolerance or allergy more common in

young dogs, or parasites• Symptoms– Weight loss– Vomiting and/or diarrhea– Appetite decreased to increased, pica

Inflammatory Bowel Disease

• Clues on the lab work:– Mild increase in liver enzymes– Low albumin is a negative prognostic factor

Inflammatory Bowel Disease

• CIBDAI – Canine IBD Activity Index– Total Score from 0-18– Six things rated from 0-3:

1. Activity level2. Appetite3. Weight loss4. Vomiting5. Stool Consistency6. Stool frequency

Inflammatory Bowel Disease

Inflammatory Bowel Disease

Interpreting Histopathology1. inflammatory cells in the lamina propria• Lymphocytes, plasma cells, eosinophils

2. Blunting and fusion of the villi3. Crypt lesions (edema)4. LP fibrosis– Idiopathic IBD will look just like reaction to parasites or

food– Chronicity must be established to diagnose IBD– IBD does not invade the muscularis as lymphoma does

Inflammatory Bowel Disease

Treatment1. Empirical treatments has already failed2. Dietary Trial, with more antibiotics• Hypoallergenic or hydrolyzed diet• Can see response as early as 2 weeks

3. Immunosuppressives• Prednisone – 75-80% respond

– 1 mg/kg PO BID x 3 weeks, then 0.5 mg/kg PO BID x 3 weeks, then wean to lowest effective dose over months

• Others if pred is not effective or not tolerated• azathioprine, cyclosporine, budesonide, chlorambucil• Norsworthy uses a CCNU protocol for cats• May not be needed long term if there is response to diet

4. B12 and folate as indicated by GI panel

Inflammatory Bowel DiseaseTreatment– Simpson et al, 2012• 43 dogs with LP enteritis• 29 normal albumin and B12

– 23 responded to diet– 4 responded to antibiotics– 2 required corticosteroids

• 14 Low albumin and B12– 5 responded to diet– 5 responded to immunosuppression– 4 did not respond and were euthanized

Inflammatory Bowel DiseaseTreatment– Simpson et al, 2012 – LP enteritis

Dogs with normal albumin are likely to respond to diet, and likely do not need corticosteroids

Dogs with low albumin and B12 are not likely to respond to diet alone, likely need corticosteroids, and may have a poor prognosis

Inflammatory Bowel DiseaseTreatment– Mandigers et al, 2010• Compared results for hydrolyzed diet and intestinal diet

such as EN or I/D• Initial response the same – 88%• After 3 years

– 13/14 on hydrolyzed diet were still in remission– 1/6 on intestinal diet still in remission– 2/3 in both groups relapsed when fed the original diet

Hydrolyzed diet is superior to intestinal diet for empirical treatment of dogs with chronic diarrhea

Inflammatory Bowel DiseaseMonitoring– CIBDAI – 75% reduction is ideal– Histopath can be used to monitor – improves

with successful treatment– Repeating histopath can also reveal other

underlying causes, when therapy is not going well

– Prednisone and metronidazole, if needed, can be weaned down to the lowest effective dose

Inflammatory Bowel DiseaseAzathioprine– Start at 2 mg/kg PO SID x 1-2 weeks, then QOD• Lower for very large dogs

– Can take weeks to take effect– No studies to show efficacy, even though many

internist like to use it• If steroids not effective, or to spare side effects

– Side effects:• Pancreatitis• Bone marrow suppression• hepatotoxicity

Inflammatory Bowel DiseaseChlorambucil– Recent study shows it may be more effective

when added to pred than azathioprine (Dandrieus et al, 2013)

– Median survival much longer– dose

Inflammatory Bowel DiseaseBudesonide– More locally acting, less systemically absorbed

than prednisone– Similar response to therapy as prednisone– Systemic side effects may happen, but also may

be less likely– May be preferred for diabetics– 1-5 mg PO SID– 3 mg/m2 PO SID– More expensive than prednisone

Inflammatory Bowel DiseaseCyclosporine– 5 mg/kg PO SID– Use therapeutic drug monitoring to adjust dose– Can be used alone for steroid refractory IBD– Produced a 50% in CUBD AID in these refractory

patients

Inflammatory Bowel DiseaseB12 and Folate– Gastric acid releases B12 from dietary proteins and

microbes– Intrinsic factor binds to B12 to prevent its digestion• Intrinsic factor made by the pancreas in the cat and the

stomach in the dog

– B12 complex is absorbed in the ileum, folate in proximal SI

– About one third of dogs with chronic diarrhea will have low B12

– B12 <200 carries worse prognosis– Dose: 250-1500ug SC once weekly for 4-6 weeks, then

once monthly, and monitor to adjust dose

Boxer Colitis– Aka Histiocytic Ulcerative Colitis– Aka Granulomatous Colitis– Similar to Crohn’s Disease in people

Signalment:– Young dogs less than 4 years of age– Boxers, French Bulldogs, English Bulldogs– Less often mastiffs, malamutes, Dobermans– Genetic defect in ability to clear intracellular

bacteria

Boxer ColitisSymptoms:– Large bowel diarrhea– Marked cachexia, unlike other causes of colitis– Hypoabluminemia, unlike other causes of colitis– Mild anemiaColonoscopy– Erythemic, ulcerated mucosa, cobblestoned– Histopathology• Inflammatory – macrophages, lymphocytes, neutrophils• PAS positive organisms in macrophages – E coli• Goblet cells disappear, beneficial bacteria need mucus

Boxer ColitisFISH Analysis – Fluorescent In Situ Hybridization– Fluorescent probes attach to bacterial ribosomal

DNA– Can find bacteria even with lots of inflammation– On fixed histopath samples– False negatives if on antibiotics– Intramucosal E coli in boxer colitis– FISH negative after treatment

Boxer ColitisHistorically Unsuccessful Treatments:– Dietary therapy– Metronidazole– Sulfasalazine– Tylan– Prednisone– azathioprine

Boxer ColitisTreatment:– Enrofloxacin 10 mg/kg/day– If resistant to enrofloxacin, consider chloramphenicol

or TMPS– Boxer Colitis Panel can guide therapy in resistant

cases (Dr. Simpson at Cornell)• Culture and sensitivity of colonic mucosa with special broth

media• FISH Analysis• histopath

Monitoring– Clinical and histologic improvement

Antibiotic Responsive Diarrhea– Formerly known as SIBO (Small Intestinal

Bacterial Overgrowth)

Signalment:– Young large breed dogs, especially GSD– Defect in mucosal barrier and low IgA levels– Causes dysbiosis – changes in bacterial flora

Antibiotic Responsive DiarrheaSymptoms:– Small intestinal diarrhea– Most polyphagic, but can be anorexic– Response to antibiotics and relapse when

therapy stopped– Histopath normal to boring– Low B12, high folate (SI diarrhea in general)

Antibiotic Responsive DiarrheaTreatment:– Antibiotics for 4-6 weeks• Some resolve • Some need long term therapy

– Tylosin 5-20 mg/kg PO BID• #3 capsule holds 130mg• #1 capsule holds 240 mg• #0 capsule holds 345mg• #00 capsule holds 430mg

– Metronidazole 10 mg/kg PO BID– Oxytetracycline 10-20 mg/kg PO TID

Antibiotic Responsive DiarrheaTreatment:– Diet – low fat, highly digestible– B12 as indicated on GI panel– Probiotics, prebiotics

Hemorrhagic Gastroenteritis– See Vomiting section– Clostridium perfringens found on 10/11 dogs

with HGE, and 1/11 of control dogs

Probiotics– Used to be considered “alternative” medicine,

now considered conventional standard of care– Compete with pathogens– Produce antimicrobials– Produce protective organic acids– Enhance IgA secretion

ProbioticsWhich should you use?– Product should list organisms in the container– Check with www.consumerLabs.com for

potency and purity– Refrigeration is not necessarily needed, if

packaging is adequate

Not usually needed for acute diarrhea, tough studies show diarrhea stops 1 day earlier

ProbioticsImproved Toll like receptor expressionFor antibiotic responsive diarrhea– No response to probiotics alone after relapse

when antibiotics stoppedFor food responsive IBD– improvement in fecal score when treated with

probiotics as well as dietFor idiopathic IBD– Probiotics decreased CIBDAI and improved

histopathology

Fecal TransplantationFor chronic diarrhea (Weese, 2013) C difficile in people1. Screen donors for enteropathogens• Giardia, Salmonella, Campylobacter, Tritrichomonas,

Clostridium, Cryptosporidium, etc.

2. Collect fresh sample from donor3. Prepare fecal suspension – mix with saline, blend

and filter4. Warm water enema for recipient5. Give fecal suspension to recipient as a 45 minute

retention enema6. Both patients clinically normal for 3 months

Feline Hairballs– No longer considered just a nuisance to prescribe a

hairball remedy or diet for– May indicate underlying problems resulting in either

increased hair intake or decreased motility• Overgrooming

– Pruritus– behavior problem– Neuropathic or musculoskeletal pain– Abdominal pain (bladder, bowel)

• Upper GI motility disorder

Cats Are Carnivores– Dogs grind their food, cats do not• Cats have no lateral-medial movement of the jaws• Cat teeth lack occlusal surfaces for grinding – the molars

and premolars interdigitate• Cats crack their tooth into smaller pieces and swallow it

– Cats lack salivary amylase• Digestion begins in the feline stomach

– Cats need 5g/kg protein daily to maintain nitrogen balance

– Cats do not have tastebuds to taste sweet– GI tract length in cats is relatively shorter (4:1) than

dogs (6:1)

Cats Are Carnivores– The intestinal sugar transport system fo the cat is

not adaptable to varying dietary levels of carbs– Cats have low intestinal disaccharadiase levels

(sucrase, maltase, isomaltase)– Pancreatic amylase production is 5% of dogs– Paleolithic diet - 50% protein, 40% protein, <10%

carbs– Cats do not down regulate proteinases well– The only reason ever to restrict protein in a cat is to

prevent hepatic encephalopathy

Cats Are Carnivores– Cats have a short colon that limits their ability do

digest and absorb starches and fiber by fermentation• Cats express ingesta from entrails before eating them

Feline Triaditis– Inflammation in SI, liver and pancreas– Pancreatic and common bile duct join before

emptying into the duodenum – problem in one area affects the other 2

Feline Megacolon/Constipation– Constipation is a sign of dehydration– Constipated cats often vomit, especially after

defecating– Colonocyte lifespan is 4-7 days, so cats can recover

from colitis quickly

Feline Megacolon/Constipation– Treatment• REHYDRATE!!!• Dietary fiber - high soluble fiber for diarhea, high

insoluble fiber for constipation early on, then low residue diet as pathology continues

• Physical removal of hard feces – sedation/removal or even subtotal colectomy

• Royal Canin Fiber Response and Hill’s Constipation Diet work well

• Need huge amounts of canned pumpkin to get adequate fiber

• Don’t add Miralax until the animal is rehydrated

Subtotal Colectomy

NO!!

Subtotal Colectomy

• Cut ileum at an angle to match opening with the colon of larger diameter

• Avoid a blind pouch in the colon• Cut shorter at the antimesenteric side to avoid

avascular necrosis

Feline GI Lymphoma

• Small cell lymphoma, aka LGAL (Low Grade Alimentary Lymphoma)

• Second hand smoke is a significant risk for all feline lymphoma

• IBD a precursor to intestinal LSA• Full thickness biopsies often required for diagnosis• SI > colon > stomach• 80% small cell, 20% large cell• Mesenteric LN enlargement can not distinguish IBD from LSA• Clinical signs the same for LSA and IBD

Feline GI Lymphoma

• When do you run flow cytometry or PARR?• PARR = Lymphoma PCR• When not responding to therapy for either IBD

or lymphoma and you want to confirm the diagnosis

• PARR shows 35% false negatives• Flow cytometry– Homogenous cell size indicates lymphoma– Heterogenous cell size indicates IBD

Feline GI Lymphoma

• Treatment– VCP – 73% remission, median survival 239 days– CHOP Wisconsin – 64-75% remission, median

survival 563 days – Chlorambucil + prednisone – 76% remission,

median survival 19 months• 100% response for rescue chemotherapy

cyclophosphamide + pred

Feline GI Lymphoma

• Prognosis– Small cell lymphoma does very well with

treatment (median survival 2 years)– Large cell lymphoma poor prognosis

APUDomas– APUD – Amine Precursor Update and

Decarboxlylation• pka enterochromaffin or argentaffin cells• Make hormones – gastrin, cholecystokinin, secretin,

glucagon, vasoactive intestinal peptide, somatostatin, motilin, insuiin, etc.

– APUDomas secdrete one of these petides– Insulinoma, gastrinoma, carcinoid (serotonin),

multiple endocrine neoplasia (MEN)

Acknowledgements

• Adam Honeckman, DVM, ACVIM Casselberry, Florida

• Margie Scherck, DVM, ABVP Vancouver, British Columbia, Canada