DISORDERS OF THE LARGE INTESTINE

CAUSING DIARRHOEA IN EQUINES

DEFINITION OF DIARRHOEA

• Passage of fecal material that has increased water contentvarying from soft and formed stools with a mild tomoderate increase in water content

• Result in significant losses of water, electrolyte and bufferand is often accompanied by local and systemicinflammatory responses

• Diarrhoea in adult horses can be divided into thosecharacterized by inflammation of the cecum and largeintestine (typhlitis, colitis)

• Important problem in horse with colitis: impairedcardiopulmonary function, coagulopathy and othersequelae of activation of inflammatory mediator cascades

• Septicemia can be most life threatening .

Complications that occur in colitis patient…

• Overwhelming endotoxemia

• Laminitis

• Septicemia and organ colonization by bacteria

• Immune suppression and susceptibility to super infection with bacteria orfungi

• Severe tissue inflammation can result in loss of the mucosal epithelium

resulting in chronic malabsorption and protein losing enteropathy

DIFFERENCE BETWEEN ACUTE AND CHRONIC DIARRHOEA

Clinical Sign Acute diarrhoea Chronic diarrhoea

Onset Rapid Rapid or gradual

Sickness Very sick Variable degree of sickness

Duration Diarrhoea of few hrs/days Diarrhoea of >2 weeks

Causes Salmonellosis, clostridiosis, cyathostomiasis, antibiotic induced, blister beetle intoxication, peritonitis mycotic enterocolitis, equine viral arteritis rare

Salmonellosis, cyathostomiasis, sand induced, CIBD, NSAID –induced, giardiasis, peritonitis, enteric lymphosarcoma, Strongyle vulgaris induced arteriopathy

• Salmonellosis

• Intestinal Clostridiosis

• Cyathostomiasis

•NSAIDs

•Arsenic Toxicity

•Cantharidin Toxicity

•Antibiotic associated diarrhea

CAUSES

INFECTIOUS CAUSES TOXIC CAUSES

Salmonellosis

• Salmonella typhimurium

• Salmonellosis in horses is associated with:

1. Stress (transport)

2. Concurrent gastrointestinal disease

3. Antibiotic administration (oxytetracycline, particularly with concurrentstress)

4. Immunosuppression (post-operative colic)

Clinical findings

• Profuse foul smelling diarrhea and occasionallyabdominal pain

• Signs compatible with endotoximia and suffer fromcardiovascular shock and coagulopathy

• Tachycardia, moderate to severe dehydration

• Fever, depression and anorexia

• May have an absolute neutropenia

Salmonellosis Diagnosis

• Can be detected in feces by culture or PCR

• Culture is less sensitive than PCR and may require up to 5 sequentialsamples bcoz organism is shed in the feces intermittently and in smallnumbers

• 5-10g amount of feces should be submitted for culture in selective mediasuch as tetrathionate broth or selenite broth and brilliant green agar

• PCR is a very sensitive test that detects both viable and non-viableorganism

• Culture of a rectal mucosal biopsy

Intestinal Clostridiosis

• Clostridium perfringens (Type A and C) or Clostridium difficile

• Common cause of diarrhea in both adult horses and foals

• C. difficile is a sporulated obligate anaerobe responsible for most cases ofantibiotic-associated diarrhea

• Grain feeding may increase clostridia growth in the face of antibiotics

• As the clostridia overgrow unknown factors trigger the production andrelease of toxins (cytotoxins A and B produced by C. difficile and toxins alpha,beta, gamma, delta and epsilon produced by C. perfringens)

• Toxin A can activate epithelial cells, neutrophils, mast cells, monocytes andmacrophages to release a multitude of proinflammatory cytokines and vasoactive

mediator

• Toxin B exhibits enterotoxigenic (secretory) activity

• Type A and type C has phospholipase activity, necrotizing cytotoxic effects and

hemolytic effects

Clinical Findings

In foals predominantly gastrointestinal signs (colic, diarrhea)

In neonatal foals clostridiosis may present as septicemia

In some foals classic necrotizing enterocolitis will be manifested by gasor fluid distended intestine and thickened intestinal mucosa

In adult horses diarrhea is there but may have abdominal discomfort orfever

A spectrum of clinical signs exists from moderate illness to severetoxemic colitis

Clostridiosis Diagnosis

Method of diagnosis consists of culture of the organism from feces and testing for toxin production by PCR

It is recommended to transport samples chilled on ice (not frozen),immediately or by overnight delivery for best recovery of clostridialorganism

ELISA test for C. difficile (toxin A)

Latex - agglutination test for C. perfringens

Cyathostomiasis

• Caused by emergence of encysted small strongyle larvae (cyathostomes)from the mucosa of the large intestine

• Acute severe diarrhea may be associated with the sudden emergence oflarge numbers of encysted larvae

• Characterized by profound protein-losing diarrhea resulting from themucosal damage and inflammation

• Weight loss and peripheral edema are common

Cyathostomiasis diagnosis

• Fecal egg counts are often not useful because the larvae are not patent

• Definitive diagnosis requires microscopic examination of cecal or colonicmucosa either from biopsy specimens (rectal or laparoscopic biopsy)

• Increased serum concentrations of Beta 1 globulins may indicatecyathostomiasis but is not diagnostic

• Response to therapy may be the most practical diagnostic aid

• Herd monitoring should be done by performing fecal egg counts

• At least once a year fecal egg counts should be done before and 5-7 days aftertreatment to assess resistance

NSAIDs

• NSAIDs administration can cause gastric or colonic ulcers (right dorsalulcerative colitis)

• Inhibit the synthesis of prostaglandins by antagonizing the activity ofcyclooxygenase

• Inhibition of PGE synthesis can promote ulceration of the colonic epithelium

that leads to inflammation of the tissue

• NSAID administration can cause severe diarrhea in many species

TOXIC CAUSES

Arsenic Toxicity

• Cytotoxin that causes gastroenteritis by direct toxic activity on the

mucosa

• source of arsenic poisoning is usually pesticide or herbicide

contamination of feed or water

• Any cell type is sensitive to arsenic toxicity so absorption of the metal

during gastroenteritis may result in multiorgan dysfunction or failure

Diagnosis : NSAIDs

• Diagnosis of NSAID-induced diarrhea is based on history of NSAIDadministration and clinical signs suggestive of right dorsal ulceration

• Ultrasonographic examination of the right dorsal colon may revealthickening of the colon wall with edema

• Hypoalbuminemia may be severe (<1.5g/dL)

Arsenic Toxicity

• Antemortem diagnosis can be attempted by measuring blood and urinearsenic concentrations

• Postmortem diagnosis made by measuring liver and kidney arsenicconcentrations is usually definitive

Cantharidin Toxicity

• Substance contained in the bodies of members of the blister beetle

• Source is usually dried crushed beetles in hay

• Cytotoxin causing ulceration throughout the alimentary tract by directtoxic activity on the mucosa

• Excreted in the urine in its active form so renal tubular nephrosis andcystitis is common

• Myocardiocytes are also sensitive to cantharidin so signs of myocarditismay be noted

Cantharidin Toxicity Diagnosis

• Diagnosis of cantharidin toxicity is based on clinical features:• Diarrhea, oral ulceration• Polyuria with hypocalcemia, azotemia• Hematuria and proteinuria• Presence of blister beetles in the feed

• In suspected cases cantharidin concentrations can be measured inthe urine and GI contents

Antibiotic associated diarrhea

• Administration of a particularantibiotic causing diarrheadepends on several factorsincluding diet, residentgastrointestinal flora andconcurrent disease

• Antibiotics cause diarrhea byaltering the gastrointestinal floraresulting in overgrowth of apathogenic organism such assalmonella and clostridia

• C. difficile diarrhea is the mostcommon cause of antibiotic-induced diarrhea

• Altered growth of nonpathogenic organisms may contribute todiarrhea by reducing short chain fatty acid production which reduceselectrolyte absorption

• Other factors that may contribute to the pathogenesis of diarrheainclude direct actions of the antibiotic on the physiology of the largeintestine

• Lincomycin (orally) and Tetracycline (Parenterally) have beendemonstrated to induce severe diarrhea in horses

• Oral Trimethoprim – Sulfa, erythromycin, metronidazole & penicillinand parenteral ceftiofur have been implicated with onset of diarrheaincluding fatal colitis

PATHOPHYSIOLOGY

• Three factors work to maintain normal fluid and electrolyte transport inthe large intestine

1. Absorptive activity2. Secretory activity3. Epithelial barrier

• Most causes of diarrhea alter homeostasis by:1. Directly disrupting the epithelial barrier2. Directly affect secretion and absorption by the mucosa

• Result is fluid, electrolyte and protein loss

• Another consequence of epithelial barrier injury is bacterial endotoxinabsorption and bacterial translocation resulting in endotoxemia or sepsis

Direct mucosal damage due to colitis and mucosal inflammation

Massive influx of neutrophils and release of inflammatory mediators by neutrophils

And mucosal cells characterize the inflammatory response

Mucosal Inflammation

Release of inflammatory mediated vasoactive substances like platelet activating factor, prostaglandins, leukotrienes, kinins, chemokines and cytokines

They cause vasodilation and increase endothelial permeability

Thus exacerbating the mucosal edema and fluid loss associated with colitis

Release of toxic metabloites of oxygen and proteases by Neutrophils

► Chemokines and leukotrienes attract more neutrophils into the tissue, therebypotentiating the inflammatory response

► Kinins sensitize tissues to pain, contributing to the pain associated with colitis

► Prostaglandin synthesis is induced in the mucosa by inflammatory mediatorswhich has several important effects

► Prostaglandins are critical for epithelial repair after a variety of forms of mucosalinjury

► However prostaglandins also potently stimulate chloride secretion which has an

important role in the fluid and electrolyte loss associated with colitis

► Altered motility by prostaglandins and absorbed endotoxin may also influence the

clinical manifestation of colitis

► Neutrophils also impair mucosal healing during colitis by migrating in large

numbers through the epithelial monolayer disrupting the intracellular junctions

Essential Historical Information

• Duration

• Weight loss?

• Any other illness associated with onset of the diarrhea?

• Was onset associated with any specific drug use (e.g. antibiotics)?

• Have any drugs been given in an attempt to control the diarrhea?

• Was onset associated with any dietary changes?

• Have changes been made in an attempt to control the diarrhea?

• Fecal consistency and volume?

DIAGNOSIS OF DIARRHOEA

• Fluid loss can be profound in patients with acute diarrhea

• Physical examination – dehydration status, congested mucous membranes,capillary refill time

• Horses with colitis are often moderately to severely dehydrated with eitherpurplish or brick - red mucous membrane or congested

• PCV and TP measurement is often advisable

• Moderate to severe clinical signs of dehydration and hematologicalevidence of severe hemoconcentration (PCV>60) are unfavorableprognostic indicators

• Total serum protein is usually decreased with a chronic inflammatorydisorder of the colon

Assessment of Gastrointestinal Tract

If signs of colic are present the GI tract should be assessed to rule outan obstructive condition and ischemic disease(thrombosis/infarction)

Rectal examination:

A) Masses size and location: whether they are primarily within the peritoneal cavity, gut wall or gut lumen

B) Thickened bowel: consistent with chronic inflammatory bowel disease (CIBD) and lymphosarcoma

C) Degree of large colon fill: in some cases of chronic diarrhea the large colon cannot be readily palpated because it is so empty

• Peritoneal fluid analysis can be helpful to assess the GI tract

• Peritoneal fluid analysis may reveal an increase in protein or WBC>10,000/μl which is indicative of inflammatory process with inperitoneal cavity

• Transabdominal ultrasonography of large intestine provideinformation about the thickness of the colonic tissue indicating thedegree of inflammation and edema of the mucosa

Cardiovascular Status

• Dehydration and hemoconcentration can adversely affect peripheralperfusion and cause tachycardia

• Endotoxemia or sepsis causes hypotensive shock, peripheral vasodilationand coagulopathies which manifest as

- Tachycardia

- Edema

- Petechial hemorrhage

- Altered peripheral perfusion

Hematological and Biochemical Parameters

• Leukopenia and neutropenia with a left shift are poor prognosticindicators associated with endotoxemia or sepsis in horses with diarrhea

• Neutrophilic leukocytosis may follow neutropenia or be a primary finding

• Elevated plasma fibrinogen concentration may be noted if large intestinalinflammation is severe or if peritonitis is concurrent

# Plasma albumin concentration should be measured to evaluate gastrointestinal protein loss

# Reduced renal perfusion due to dehydration and endotoxemic hypotension may cause prerenal azotemia (assessed by serum BUN and creatinineconcentrations) which may progress to acute hemodynamic renal failure

# Urine output determination and urinalysis should be performed to further assess renal function, detect hematuria and determine whether renal losses of protein are significant

Serum Electrolyte Concentrations and Acid Base Status

# Evidence of hyponatremia, hypokalemia, hypochloremia, azotemia and metabolic acedemia

# Hypokalemia can cause weakness Hyperkalemia may be noted very early in the course of the disease or if renal failure is present

# Hypocalcemia can cause weakness, altered (reduced) GI motility

# Metabolic acidosis resulting form poor perfusion and metabolic alterations may be severe and require correction

General Concepts Regarding Fluid Needs in Dehydrated Horses

•Hydration and circulating fluid volume can be maintained byadministering fluid via a nasogastric tube and I/v fluidadministration

•Supplementation with KCl, calcium or bicarbonate:based on serumelectrolyte concentrations and acid base status

•Lactated ringers solution is appropriate

•In cases of endotoxemic shock associated with diarrhea 5%hypertonic saline: to support the cardiovascular system

•Colloidal fluids such as hetastarch or plasma are important tosupport plasma oncotic pressure and reduce intestinal edema inhorses with hypoalbuminemia

Determining

FactorFormula Used Amount for a 500

kg Horse

Fluid deficit % dehydration ×body weight (kg)

4-10% × 500 = 20-50 L

Maintenance 50 mL/kg/24 hr 50 × 500 = 25 L/24 hr

Rate of administration

50% in 1-2 hr; 50% throughout rest of day

Anti-inflammatory Treatment

• Flunixin meglumine: Potent inhibitor of prostaglandin and thromboxanesynthesis(0.25 mg/kg QID-1 mg/kg BID IV) effectively reduces endotoxin inducedelevations of serum thromboxane and ameliorates many of the cardiovascularand clinical signs associated with endotoxemia

• Limit the use of NSAIDs in horses with diarrhea by using the lowest dose that willeffectively inhibit endotoxin activities while sparing the colonic mucosa from thedetrimental effects of prostaglandin synthesis inhibition

• Plasma or serum products are available that are designed to inactivate endotoxinactivity with anti-endotoxin antibodies induced in donor horses by immunizationwith rough mutants of E coli or Salmonella typhimurium

• Hyperimmune plasma is a good source of plasma protein for horses with diarrhea(3-10ml/kg)

► Pentoxifylline (8 mg/kg PO, BID-TID) - methylxanthinederivative that inhibits cytokine production bymacrophages stimulated with endotoxin

► Studies in horses are limited and efficacy has not yetbeen proven in horses

► Polymyxin B (2500-6000 units/kg IV BID) binds andinactivates the lipopolysaccharide component ofendotoxin

Mucosal Protectants

• Sucralfate (22 mg/kg PO QID) has been advocated in patients with right dorsalulcerative colitis or diffuse colitis to aid in mucosal healing. It is not clearwhether sucralfate is efficacious in either case

• Psyllium (0.25-0.5 g/kg PO or by tube SID-BID) may be beneficial to enhancemucosal healing in patients with diarrhea

• Psyllium mucilloids are fermented to the volatile fatty acids butyrate,propionate and acetate - important for epithelial

repair in damaged mucosa

• Misoprostol (0.002 mg/kg PO QID) is a prostaglandin analog that promotesmucosal healing

• Indicated in right dorsal ulcerative colitis associated with NAISDadministration

• The benefits of misoprostol may be negated by the adverse effects whichinclude cramping, sweating, abortion in pregnant mares and furtherdiarrhea

• Corn oil (1-2 cups SID-BID) is a source of essential fats such as linoleic acidthat are important for mucosal health and healing by locally increasingprostaglandin production

SPECIFIC TREATMENT

• Metronidazole (15 mg/kg PO QID) appears to be an effective treatmentfor adult horses and foals with intestinal clostridiosis

• Hemorrhagic diarrhea in foals may be controlled with prophylactictreatment with metronidazole for the first 2 weeks of birth

• Broodmares should be vaccinated with C. perfringens type C/D toxoid at 6and 3 weeks prepartum

• Fluroquinolones are effective because of high lipid solubility and bactericidal

activity against salmonella bacteria

• Ivermectin and fenbendazole have relatively good anti - cyathostome

larvicidal activity in horses

• 5 days course of fenbendazole (10-50 mg/kg PO SID) followed by ivermectin

(200 microgram/kg PO SID) administration

• Concurrent treatment with dexamethasone (0.01-0.05 mg/kg PO or IM SID)

or prednisolone (2 mg/kg PO SID) has been advocated to prevent acute

exacerbation of diarrhea by larval death within the mucosa

• Moxidectin(0.4 mg/kg PO SID) reportedly has the best larvicidal activity

• Dimethyl sulfoxide (DMSO)- potential anti-inflammatory used in colitis cases(100-200 mg/kg/day)

• Antimicrobial like chloramphenicol, enrofloxacin, gentamicin, amikacin orthird generation cephalosporin are usefull for treatment

• Activated charcoal should be administered via nasogastric tube in horseswith diarrhea caused by cantharidin or arsenic toxicity

• Mineral oil should be avoided if cantharidin is a possible cause because thetoxin is lipid soluble and absorption may be enhanced by mineral oil in the GItract

• Good quality grass hay, pasture or grass hay/alfalfa mixtures are commonlyfed

• Feeding only pelleted feeds to rest the colon

• Caution should be observed to prevent exacerbation of diarrhea byfermentation of concentrates in pelleted diets