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Disorders of Esophageal Motility

Robert J. Washabau, VMD, PhD, Dipl. ACVIMProfessor of Medicine and Department Chair Department of Veterinary Clinical ciences

Colle!e of Veterinary Medicine" #ni$ersity of Minnesota%&'( )oyd A$enue, t. Paul, Minnesota ''%*+

-%( -('/'(0&" -%( -(1/*0'%2ashabau3umn.edu

ESOPHAGEAL DYSMOTILITY

4sopha!eal dysmotility is a primary motility disorder of the esopha!us characteri5ed by reduced esopha!eal peristalsis, food retention,and re!ur!itation. It is not necessarily accompanied by esopha!eal dilation or permanent me!aesopha!us, and therefore is not referredto as idiopathic me!aesopha!us. 4sopha!eal dysmotility has been reported in youn! do!s as a conse6uence of delayed maturation,%/0

muscular dystrophy,+/7 myasthenia !ra$is,%* inflammatory myopathy,%%,%( transient dysfunction follo2in! anesthetic episodes,%& and breed/specific abnormalities.%1

8herapy is primarily supporti$e and follo2s therapy outlined for idiopathic me!aesopha!us see )o9 '-.%. 8he pro!nosis foresopha!eal dysmotility is !enerally more fa$orable than it is for idiopathic me!aesopha!us.

IDIOPATHIC MEGAESOPHAGUS

Etiology8he term idiopathic me!aesopha!us refers to concurrent esopha!eal dysmotility and dilation of un:no2n etiolo!y, and is the mostcommon cause of re!ur!itation in the do!.%',%- Aside from dysautonomia, me!aesopha!us is an uncommon findin! in the cat. 8hecanine disorder is characteri5ed by pro!ressi$e re!ur!itation, aspiration pneumonia and loss of body condition. e$eral forms of thesyndrome ha$e been described, includin! con!enital, ac6uired secondary, and ac6uired idiopathic me!aesopha!us.%-

PathophysiologyCon!enital idiopathic me!aesopha!us is a !enerali5ed hypomotility and dilation of the esopha!us causin! re!ur!itation and failure tothri$e in puppies shortly after 2eanin!. An increased breed incidence has been reported in the ;erman shepherd, ;reat Dane, Irish

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setter, <abrador retrie$er, Chinese har/Pei, and =e2foundland breeds, and autosomal dominant inheritance has been demonstrated inthe Miniature chnau5er and >o9 terrier breeds.%- 8he patho!enesis of the con!enital form is incompletely understood, althou!h se$eral

studies ha$e pointed to a defect in the $a!al afferent inner$ation of the esopha!us.

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Primary, but not secondary, esopha!eal peristalsis appears to be intact in this disorder. Con!enital idiopathic me!aesopha!us has been reported in se$eral cats%+ and in one!roup of cats secondary to pyloric dysfunction.%7

Ac6uired secondary me!aesopha!us may de$elop in association 2ith a number of other conditions. Myasthenia !ra$is accounts for ('/&*? of the secondary cases.%*,(*,(% In some cases of myasthenia !ra$is, re!ur!itation and 2ei!ht loss may be the only presentin! si!ns of thedisease, 2hereas in most other cases of ac6uired secondary me!aesopha!us re!ur!itation is but one of many clinical si!ns includin! peripheral muscle 2ea:ness. Ac6uired secondary me!aesopha!us has also been associated 2ith hypoadrenocorticism, lead poisonin!, lupusmyositis, and se$ere forms of esopha!itis.%- @ypothyroidism has been su!!ested as a secondary cause of idiopathic me!aesopha!us butretrospecti$e ris: factor analysis has not identified it as an important cause.%'

Ac6uired/idiopathic me!aesopha!us usually has no :no2n underlyin! etiolo!y and occurs spontaneously in adult do!s bet2een 0 to %'years of a!e 2ith no se9 or breed predilection. 8he disorder has been compared erroneously to !astroesopha!eal achalasia in humans.Achalasia is a hypertensi$e sphincteric disorder characteri5ed by failure of rela9ation of the lo2er esopha!eal sphincter and ineffecti$e peristalsis of the esopha!eal body.% A similar disorder has ne$er been ri!orously documented in the do! althou!h putati$e case reports areoccasionally reported.(( e$eral important differences bet2een idiopathic me!aesopha!us in the do! and achalasia in humans ha$e beendocumented.%,(,%0 Althou!h the precise etiolo!y has not yet been identified, some studies ha$e su!!ested a defect in the afferent neuralresponse to esopha!eal distension similar to 2hat has been reported in con!enital me!aesopha!us . (&

Clinial E!a"inationRe!ur!itation is the most fre6uent clinical si!n associated 2ith me!aesopha!us. 8he fre6uency of re!ur!itation $aries from intermittent

irre!ular episodes to multiple episodes per day. As 2ith other esopha!eal disorders, affected animals suffer from malnutrition and aspiration pneumonia. Physical e9amination may re$eal e9cessi$e sali$ation, mild to moderate cache9ia, cou!hin!, and pulmonary crac:les or2hee5es.

DiagnosisRoutine hematolo!y, serum biochemistry, and urinalysis should be performed in all cases to in$esti!ate possible secondary causes ofme!aesopha!us. ur$ey radio!raphs 2ill be dia!nostic for most cases of me!aesopha!us, but !enerally do not differentiate one cause$ersus another.(1 Contrast radio!raphs may be necessary in some cases to confirm the dia!nosis, e$aluate motility, and e9clude forei!n bodies or obstruction as the cause of the me!aesopha!us. 4ndoscopy 2ill confirm the dia!nosis and may further re$eal esopha!itis, a

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fre6uent findin! in canine idiopathic me!aesopha!us.%',%- Ris: factor analysis su!!ests that esopha!itis mar:edly increases the ris: for thede$elopment of me!aesopha!us.%',%- 4sopha!itis could be cause or conse6uence of esopha!eal dysmotility and me!aesopha!us.

If ac6uired secondary me!aesopha!us is suspected, additional dia!nostic tests should be considered, includin! serolo!y for nicotinicacetylcholine receptor antibody, pre and post/AC8@ cortisolB, serum creatine phospho:inase acti$ity, electromyo!raphy and ner$econduction $elocity, and muscle and ner$e biopsy.%- Additional medical in$esti!ation 2ill be dependent upon the indi$idual case presentation. @ypothyroidism has been cited as an important cause of idiopathic me!aesopha!us in the do!, althou!h ris: factor analysishas not re$ealed a clear association.%' 8hyroid function testin! e.!., 8@ assay, 8@ stimulation, free and total thyroid hormones should be performed only in indi$idual suspected cases.

Treat"ent )o9 '-.%Animals 2ith secondary ac6uired me!aesopha!us should be appropriately differentiated from other esopha!eal disorders 8able '-.%.Do!s affected 2ith myasthenia !ra$is should be treated 2ith pyridosti!mine %.*/&.* m!:! po bid, corticosteroids prednisone %.*/(.*

m!:! po or sc bid, or a5athioprine ( m!:! po sid initially, *.'/%.* m!:! po e$ery other day. Mycophenolate has been recommendedin the treatment of myasthenia !ra$is, but a recent report su!!ests that mycophenolate does not impro$e outcome o$er pyridosti!minealone.(' Do!s affected 2ith hypothyroidism should be treated 2ith le$othyro9ine (( !:! po bid, and do!s affected 2ith polymyositisshould be treated 2ith prednisone %.*/(.* m!:! po bid. If secondary disease can be e9cluded, therapy for the con!enital or ac6uiredidiopathic me!aesopha!us patient should be directed at nutritional mana!ement and treatment of aspiration pneumonia.

Affected animals should be fed a hi!h/calorie diet, in small fre6uent feedin!s, from an ele$ated or upri!ht position to ta:e ad$anta!e of!ra$ity draina!e throu!h a hypomotile esopha!us. Dietary consistency should be formulated to produce the fe2est clinical si!ns. omeanimals handle li6uid diets 6uite 2ell, 2hile others do better 2ith solid meals. Animals that cannot maintain ade6uate nutritional balance2ith oral inta:e should be fed by temporary or permanent tube !astrostomy. ;astrostomy tubes can be placed sur!ically or percutaneously

2ith endoscopic !uidance.

Pulmonary infections should be identified by culture and sensiti$ity, and an appropriate antibiotic selected for the offendin! or!anisms.8his may be accomplished by trans/ or endo/tracheal 2ash or by bronchoal$eolar la$a!e at the time of endoscopy.

mooth muscle pro:inetic e.!., metoclopramide or cisapride therapy has been ad$ocated for stimulatin! oesopha!eal peristalsis in affectedanimals, ho2e$er metoclopramide and cisapride 2ill not ha$e much of an effect on the striated muscle of the canine esopha!eal body.(-,(0,(+ 4sopha!eal '/@81 receptors are present in many animal species, but are apparently absent in canine esopha!eal striated muscle.(- )ethanechol '/%' m!do! po tid has been sho2n to stimulate esopha!eal propa!atin! contractions in some affected do!s and is

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therefore a more appropriate pro:inetic a!ent for the therapy of this disorder.%0 )ecause of the hi!h incidence of esopha!itis in canineidiopathic me!aesopha!us,%' affected animals should also be medicated 2ith oral sucralfate suspensions % ! tid for lar!e do!s, *.' ! tidfor smaller do!s, and *.(' to *.' ! bid/tid for cats.

ur!ical cardiomyotomy myotomy of the !astroesopha!eal sphincter has been recommended in the past as a therapeutic measure inthe belief that canine me!aesopha!us is similar to human achalasia. )ecause most studies ha$e reported normal !astroesopha!ealsphincter tone and appropriate rela9ation 2ith s2allo2in!,(& cardiomyotomy cannot be recommended for the treatment of this disorder.Indeed, animals treated 2ith myotomy !enerally ha$e had poorer outcomes than untreated animals.

PrognosisAnimals 2ith con!enital idiopathic me!aesopha!us ha$e a fair pro!nosis. With ade6uate attention to caloric needs and reco!nition ofepisodes of aspiration pneumonia, many animals 2ill de$elop impro$ed esopha!eal motility o$er se$eral months. Pet o2ners must becommitted to months of physical therapy and nutritional support.

8he morbidity and mortality of ac6uired idiopathic me!aesopha!us remain unacceptably hi!h. Many animals e$entually succumb to theeffects of chronic malnutrition and repeated episodes of aspiration pneumonia. A poor pro!nosis must be !i$en in such cases.

Animals 2ith ac6uired secondary me!aesopha!us ha$e a more fa$orable pro!nosis if the underlyin! disease can be promptly identified andsuccessfully mana!ed. Refractory cases result from chronic esopha!eal distension, myenteric ner$e de!eneration, and muscle atrophy

DYSAUTO#OMIA

Etiology

Dysautonomia is a !enerali5ed autonomic neuropathy that 2as ori!inally reported in cats in the #nited Ein!dom, but that has no2 beendocumented in do!s and cats throu!hout Western 4urope and the #nited tates.(7/&' 8he clinical si!ns reflect a !enerali5ed autonomicdysfunction but me!aesopha!us, esopha!eal hypomotility, and re!ur!itation are fairly consistent findin!s. (7,&%

PathophysiologyDe!enerati$e lesions are found in autonomic !an!lia, intermediate !ray columns of the spinal cord, and some sympathetic a9ons.&%,&&,&1 Despite an intensi$e search for !enetic, to9ic, nutritional, and infectious etiolo!ic a!ents, no definiti$e etiolo!y has e$er beenestablished.

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Clinial Signs8he most fre6uently reported clinical si!ns are depression, anore9ia, constipation, and re!ur!itation or $omitin!. >ecal and urinaryincontinence ha$e been reported less commonly. Physical e9amination findin!s consistent 2ith dysautonomia include dry mucousmembranes, pupillary dilation, prolapsed nictitatin! membranes, reduced or absent pupillary li!ht refle9, bradycardia, and arefle9ic anus.Paresis and conscious propriocepti$e deficits ha$e been reported in a small number of cases.&&

DiagnosisA clinical dia!nosis is made in most cases based on historical and physical e9amination findin!s. Additional findin!s consistent 2ith thedia!nosis 2ould includeF % esopha!eal dilation and hypomotility on sur$ey or barium contrast radio!raphs" ( delayed !astric emptyin!on barium contrast radio!raphs" & reduced tear production in chirmer tear tests" 1 atropine/insensiti$e bradycardia" and, ' bladderand colonic distention on sur$ey radio!raphs. 8here are fe2 differential dia!noses to consider in a do! or cat presentin! 2ith themyriad manifestations of the syndrome. 4arly in the course of the illness, ho2e$er, other differential dia!noses to consider are colonicor intestinal obstruction, other causes of me!aesopha!us, and lo2er urinary tract disease.

Treat"entupporti$e care e.!. artificial tears, ele$ated feedin!s, e9pressin! the urinary bladder, antibiotics, etc. is still the basis of therapy in thisdisorder, althou!h some do!s and cats are reported to sho2 mild impro$ement 2ith parasympathomimetic dru!s e.!. bethanechol ormetoclopramide. ;astrostomy tube feedin!s or total parenteral nutrition may sustain some animals until they re!ain neurolo!icfunction.

PrognosisIn !eneral, dysautonomia carries a !uarded to poor pro!nosis for lon!/term sur$i$al in both the do! and the cat. (* to 1*? of affectedcats are li:ely to reco$er, althou!h cats may ta:e ( to %( months to do so. &&/&' Reco$ery rates are lo2er still in the do!.&%,&& Complete

reco$ery is uncommon and many cats and do!s are left 2ith residual impairment, e.!. intermittent re!ur!itation, dilated pupils, and fecalor urinary incontinence.

ESOPHAGEAL DI$E%TICULA

Etiology4sopha!eal di$erticula are circumscribed sacculations in the 2all of the esopha!us that interfere 2ith the normal esopha!eal motility patterns. )oth con!enital and ac6uired forms ha$e been described.&-

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be treated sur!ically since food impaction mi!ht cause them to enlar!e.

PrognosisMost cases 2arrant a !uarded pro!nosis since se!mental esopha!eal hypomotility may persist after sur!ery. Animals are also at someris: for esopha!eal stricture follo2in! correcti$e sur!ery. In cases of traction di$erticula, the pro!nosis 2ill also be some2hatdependent upon the patho!enesis and resolution of the peri/esopha!eal inflammation.

%E&E%E#CES

%. Diamant =, 5c5epans:i M, and Mui @. Manometric characteristics of idiopathic me!aesopha!us in the do!F An unsuitable modelfor achalasia in man. ;astroenterolo!y -'F (%-/((&, %70&(. 8an )JE and Diamant =. Assessment of the neural defect in a do! 2ith idiopathic me!aesopha!us. Di! Dis ci &(F 0-/+', %7+0.&. @olland C8, atchell PM, and >arro2 )R@. Hesopha!eal compliance in naturally occurrin! canine me!aoesopha!us. Aus Vet J 0*F

1%1/1(*, %77&1. @olland C8, atchell PM, and >arro2 )R@. Va!al afferent dysfunction in naturally occurrin! canine esopha!eal motility disorder.Di! Dis ci &7F (*7*/(*7+, %771.'. @olland C8, atchell PM, and >arro2 )R@. Va!al esopha!omotor ner$e function and esopha!eal motor performance in do!s 2ithcon!enital idiopathic me!aesopha!us. Am J Vet Res '0F 7*-/7%%, %77-.-. @olland C8, atchell PM, and >arro2 )R@. electi$e $a!al afferent dysfunction in do!s 2ith con!enital idiopathicme!aoesopha!us. Autonomic =euroscienceF )asic Clinical 77F %+/(&, (**(.0. )e9field =@, Watson PJ, and @errta!e M4. 4sopha!eal dysmotility in youn! do!s. J Vet Intern Med (*F %&%1/%&%+, (**-.+. Peeters M4, Ven:er/$an @aa!en AJ, ;oede!ebuure A, et al. Dyspha!ia in )ou$iers associated 2ith muscular dystrophyF e$aluationof (1 cases. Vet uart %&F -'/0&, %77%.

7. Peeters M4 and #bbin:;J. Dyspha!ia/associated muscular dystrophyF a familial trait in the )ou$ier des >landres. Vet Rec %&1F 111/11-, %771.%*. Dic:inson PJ, tur!es )E, helton ;D, et al. Con!enital myasthenia !ra$is in smooth/haired miniature dachshund do!s. J VetIntern Med %7F 7(*/7(&, (**'.%%. 4$ans J, <e$es6ue D, and helton ;D. Canine inflammatory myopathiesF a clinicopatholo!ic re$ie2 of (** cases. J Vet InternMed %+F -07/-7%, (**1.%(. Ma55ei MJ, )issett A, Murphy EM, et al. 4osinophilic esopha!itis in a do!. J Am Vet Med Assoc (&'" -%/-', (**7.%&. @endric:s JC, Ma!!io/Price <, Dou!herty J>. 8ransient esopha!eal dysfunction mimic:in! me!aesopha!us in three do!s. J AmVet Med Assoc %+'" 7*/7(, %7+1.

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%1. tic:le R, parschu ;, <o$e =, et al. Radio!raphic e$aluation of esopha!eal function in Chinese har pei pups. J Am Vet MedAssoc (*%" +%/+1, %77(.%'. ;aynor A, hofer >, and Washabau RJ. Ris: factors associated 2ith the de$elopment of canine ac6uired me!aesopha!us. J Am VetMed Assoc (%%F %1*-/%1%(, %770.%-. Washabau RJ. Diseases of the 4sopha!us. InF 8e9tboo: of Veterinary Internal Medicine. 'th edition. 4ds. J 4ttin!er and 4C>eldman, W) aunders Company, Philadelphia, pp %%1(/%%'&, (***.%0. Diamant =, 5cepans:i M, and Mui @. Idiopathic me!aesopha!us in the do!F Reasons for spontaneous impro$ement and a possible method of medical therapy. Can Vet J %'F --/0%, %*01.%+. @oeni! M, Mahaffey M), Parnell P;, et al. Me!aesopha!us in t2o cats. J Am Vet Med Assoc %7-F 0-&/0-', %77*.%7. Pearson @, ;as:ell CJ, ;ibbs C, et al. Pyloric and oesopha!eal dysfunction in the cat. J mall Anim Pract %'F 1+0/'*%, %701.(*. helton ;D, Willard MD, Cardinet ;@, et al. Ac6uired myasthenia !ra$isF selecti$e in$ol$ement of esopha!eal, pharyn!eal, andfacial muscles. J Vet Intern Med 1F (+%/(+1, %77*.(%. helton ;D, chule A, and Eass P@. Ris: factors for ac6uired myasthenia !ra$is in do!s. J Ame Vet Med Assoc (%%F %1(+/%1&%,

%770.((. )oria PA, Webster CR<, and )er! J. 4sopha!eal achalasia and secondary me!aesopha!us in a do!. Can Vet J 11F (&(/(&1, (**&(&. Washabau RJ. Canine me!aesopha!usF patho!enesis and therapy. Proceedin!s of the American Colle!e of Veterinary InternalMedicine >orum %*F -0%/-0&, %77(.(1. Wray JD and par:es A@. #se of radio!raphic measurements in distin!uishin! myasthenia !ra$is from other causes of canineme!aesopha!us. JAP 10F ('-/(-&, (**-.('. De2ey CW, Cerda/;on5ale5 , >letcher DJ, et al. Mycophenolate mofetil treatment in do!s 2ith serolo!ically dia!nosed ac6uiredmyasthenia !ra$is. J Am Vet Med Assoc (&-" --1/--+, (*%*.(-. Cohen M<, usemichel AD, and )loom6uist W. '/@81 receptors in rat but not rabbit, !uinea pi!, or do! esopha!eal muscle. ;enPharm ('F %%1&/%%1+, %771.

(0. @all JA, Washabau RJ. ;astrointestinal pro:inetic therapyF dopaminer!ic anta!onist dru!s. Compendium Contin 4duc Pract Vet%7F (%1/((%, %770(+. Washabau RJ, @all JA. ;astrointestinal pro:inetic therapyF serotoner!ic dru!s. Compendium of Contin 4duc Pract Vet %7F 10&/1+*, %770.(7. )er!haus RD, HK)rien DP, Johnson ;C, et al. Ris: factors for de$elopment of dysautonomia in do!s. J Am Vet Med Assoc (%+F%(+'/%(7*, (**%&*. Det2eiler DA, )iller D, @os:inson JJ, et al. Radio!raphic findin!s of canine dysautonomia in t2enty/four do!s. Vet Radiol #ltrasound 1(F %*+/%%(, (**%.&%. @ar:in ER, and Andre2s ;A, and =ietfeld JC. Dysautonomia in do!sF -' cases %77&/(***. J Am Vet Med Assoc ((*F -&&/-&7,

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(**(.&(. @ar:in ER, =ietfeld J, and >ischer JR. Dysautonomia in a family of ;erman shorthaired pointers. JAA@A &+F ''/'7, (**(.&&. HK)rien DP and Johnson ;C. Dysautonomia and autonomic neuropathies. Vet Clin = Amer / mall Anim Pract. &(F ('%/(-', (**(.&1. harp =J@. >eline dysautonomia. emin Vet Med ur! 'F -0/0%, %77*.&'. Eidder AC, Johannes C, HL)rien DP, et al. >eline dysautonomia in the Mid2estern #nited tatesF a retrospecti$e study of ninecases. J >el Med ur! %*F %&*/%&-, (**0.&-. Pearson @, ;ibbs C, and Eelly D> . Hesopha!eal di$erticulum formation in the do!. J mall Anim Pract %7, &1%/&'', %70+.

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'o! ()*+ / 8herapy for canine idiopathic me!aesopha!us.Problem 8herapyRe!ur!itation of food 4le$ated feedin!s, li6uid to semi/li6uid densityMalnutrition @i!h biolo!ical, hi!h ener!y feedin!sPulmonary infections )road spectrum antibiotics4sopha!eal dysmotility )ethanechol4sopha!itis Hral ucralfate li6uid suspension

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Ta,le ()*+* Medial in-estigation and treat"ent of anine idiopathi "egaesophag.s*

ETIOLOGY MEDICAL I#$ESTIGATIO# T%EATME#T

Congenital Megaesophag.sMyasthenia !ra$is 4drophonuim response electrophysiolo!y Pyridosti!mine %.*/&.* m!:! po, bid =europathy 4sopha!eal manometry electrophysiolo!y 4le$ated, small fre6uent feedin!s" bethanechol '/%'

m!do! po tidA/.ired Idiopathi Megaesophag.s

=europathy 4sopha!eal manometry electrophysiolo!y 4le$ated, small fre6uent feedin!s, bethanechol '/%'m!do! po tid,

sucralfate *.'/%.* !rams po, tid, antibiotics asneededA/.ired Seondary Megaesophag.s

Myasthenia !ra$is =icotinic acetylcholine receptor antibody, Pyridosti!mine %.*/&.* m!:! po, bidedrophonium response, electrophysiolo!y prednisone %.*/(.* m!:! po or s6, bid@ypoadrenocorticism AC8@ stimulation Prednisone *.% m!:! po, bid,<ead to9icity @ematolo!y, blood lead concentrations Chelation 2ith calcium 4D8A4sopha!itis 4sopha!eal endoscopy ucralfate *.'/%.* !rams po, tid, cimetidine '/%*

m!:! po, tid, omepra5ole *.0 m!:! po, sid@ypothyroidism 8hyroid function tests <e$othyro9ine (( N!:! po, bidDysautonomia Clinical dia!nosis upporti$e carePolymyositispolymyopathy erum creatine phospho:inase, muscle Prednisone %.*/(.* m!:! po or s6, bid

biopsy electrophysiolo!yystemic lupus erythematosus Anti/nuclear antibody Prednisone %.*/(.* m!:! po or s6, bid

&ig.re ()*0

Inter1%elationships 'et2een Gastroesophageal %efl.!3 Esophagitis3 Esophageal Dys"otility3 and Idiopathi Megaesophag.s

Ca.se;astroesopha!eal Reflu9 O Reflu9 4sopha!itis O 4sopha!eal Dysmotility O Idiopathic Me!aesopha!us

Conse/.ene4sopha!eal Dysmotility O Idiopathic Me!aesopha!us O ;astroesopha!eal Reflu9 O Reflu9 4sopha!itis

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Gastri Motility Disorders

GAST%IC PHYSIOLOGYAnatomically, the stomach is composed of fi$e distinct anatomic componentsF cardia, fundus, corpus, antrum, and pylorus. Physiolo!ically,the stomach can be thou!ht of as a t2o/component modelF a pro9imal stomach cardia, fundus, first of the corpus characteri5ed by slo2tonic contractions, and a distal stomach distal Q of the corpus and antrum characteri5ed by phasic propa!atin! contractions . % lo2 2a$es2ithout action potentials !i$e rise to the sustained tonic contractions of the pro9imal stomach. Durin! s2allo2in!, !astroesophaealsphincter and intra!astric pressure decrease to accommodate emptyin! of solids and li6uids. 8his phenomenon, referred to asrecepti$e rela9ationS, ta:es place 2ith each s2allo2, and as a conse6uence, lar!e $olumes can be accommodated 2ith minimalincreases in intra!astric pressure. 8he pro9imal stomach becomes much less compliant 2ith fundic disease or fundectomy.

A pacema:er site in the pro9imal fundus of the !reater cur$ature !enerates action potentials and phasic contractions that propa!ate from thesite of ori!in circumferentially and distally to the pylorus.( Durin! feedin!, phasic contractions of the distal stomach tri!!er a repetiti$e cycle

of propulsion, trituration, and retropulsion that pro!ressi$ely reduce the si5e of the in!esta. 8hus, the peristaltic 6ualities of the distalstomach re!ulate the emptyin! of solid particles into the duodenum. Antral disease or antrectomy abolish this physiolo!ic effectresultin! in a dumpin! syndromeS due to accelerated !astric emptyin!, nutrient o$erload in the small intestine, and an osmotic typediarrhea.

;astric emptyin! is re!ulated by se$eral physiolo!ic parameters, includin!F % pyloric resistance and pressure differential bet2een thestomach and duodenum" ( 2ater content T li6uids are emptied more rapidly than solids" & nutrient composition T carbohydrates areemptied more rapidly than proteins 2hich in turn are more emptied more rapidly than lipids" 1 nutrient acidity T delayed at acid oral:aline p@" ' nutrient osmolality T delayed at hi!h osmolality" and, - hot or cold temperatures. Duodenal, GeGunal, and ileal bra:in!mechanisms also feedbac: inhibit !astric emptyin! throu!h acti$ation of mucosal sensory receptors for fatty acids, tryptophan,

osmolality, and acid. Intestinal bra:in! mechanisms ser$e to prolon! transit time and nutrient contact time.%

Durin! the fastin! state the stomach is ordinarily empty, aside from s2allo2ed sali$a, a small amount of mucus, and cellular debris thatcollects in the !astric lumen. In addition, there may be particles of indi!estible solids left o$er from the pre$ious meal. A special mechanisme9ists to empty this fastin! content called the mi!ratin! motility comple9 MMC. 8he ability of the MMC to completely empty thestomach of its residue is so stri:in! that it is sometimes referred to as the interdi!esti$e house:eeperS of the !astrointestinal tract. % 8he!astrointestinal hormone, motilin, is in$ol$ed in the re!ulation of this MMC pattern. Cats and rabbits do not ha$e a mi!ratin! motilitycomple9, and instead ha$e a less $i!orous emptyin! pattern :no2n as the mi!ratin! spi:e comple9 MC.&,1

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CLI#ICAL SIG#S O& DISEASE

Delayed !astric emptyin! most often results in the clinical si!ns of !astric distension, retention of food, and $omitin! see 8able '-/%.A !astric motility disorder should be considered 2hen there is a history of chronic $omitin!. Vomitin! may or may not be associated2ith feedin!. 8ypically, $omitin! of undi!ested or partially di!ested food is obser$ed + to %* hours after feedin!, at a time 2hen thestomach should be empty of in!ested solids. 8he character of the $omitus is dependent on time lapse since the last meal, de!ree of!astric trituration, amount of !astric secretions, and e9tent of hydrolytic di!estion. Hther si!ns of a !astric motility disorder mayinclude anore9ia, belchin!, polydipsia, pica, and 2ei!ht loss. Animals may occasionally assume a position of relief referred to as theprayin! postureS to relie$e !astric pain. 8he physical e9amination may be normal or may re$eal findin!s associated 2ith theunderlyin! disease process. Abdominal distension may be present, increased bo2el sounds may be noted 2ith abdominal auscultation,and nonspecific pain may be e$o:ed on abdominal palpation. Palpable abdominal masses are most consistent 2ith intestinal or other$isceral neoplasia, forei!n bodies, and intussusceptions. =euromuscular abnormalities may also be obser$ed in do!s 2ith se$ereelectrolyte or metabolic deran!ements secondary to chronic $omitin!.

PATHOPHYSIOLOGY 1 GAST%IC OUT&LO4 O'ST%UCTIO#

Anatomic lesions of the pylorus and adGacent duodenal se!ment impede !astric emptyin! because of mechanical obstruction.',- In!eneral, dia!nosis of mechanical obstruction is usually strai!htfor2ard and in$ol$es sur$ey and contrast radio!raphy, ultrasono!raphy,or !astroscopy. ur!ical remo$al of the forei!n obGect of the affected area is the preferred therapy. ;astrointestinal pro:inetic a!entsare !enerally contraindicated in treatin! patients 2ith mechanical obstruction.

Si"ple and Linear &oreign 'odies T ;astric forei!n body in!estion is a common occurrence, particularly in youn! puppies. Manydifferent types of forei!n bodies are in!ested in companion animals, from bones to cartila!e, coins and other metal obGects, strin!syarn,

and nylons. Many of these can be mana!ed 2ith endoscopy, but others may re6uire sur!ical remo$al.

Antral Pylori Hypertrophy T Pyloric stenosis or chronic hypertrophic pyloric !astropathy is a common cause of !astric outflo2obstruction.-/%% Most affected do!s are of male !ender, youn! to middle/a!ed, brachycephalic, or of small breeds. @istopatholo!icchan!es include hypertrophy of the circular muscles of the pylorus, hyperplasia of the antropyloric mucosa, or a combination of bothmuscular hypertrophy and mucosal hyperplasia, 2ith or 2ithout inflammation. Antral pyloric hypertrophy may occur as a con!enitallesion in youn! animals con!enital pyloric stenosis T reported in bo9er and )oston terrier breeds, or as an ac6uired lesion in olderanimals chronic hypertrophic pyloric !astropathy T reported in <hasa apso, hih 85u, Maltese, and Pe:in!ese breeds. Positi$e/contrast radio!raphic studies are useful in documentin! !astric outflo2 obstruction. #ltrasono!raphy can help identify a thic:

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hypoechoic layer of pyloric muscle and a thic:ened !astric 2all.%( 8he dia!nosis is confirmed by the endoscopic appearance of enlar!edmucosal folds surroundin! the pyloric orifice and by e9clusion of other causes by mucosal biopsies.%& ur!ery, for e9ample, pyloroplasty, is the treatment of choice for both lesions.

Gastri Phyo"yosis T ;astric phycomycosis is a systemic fun!al disease caused by the ubi6uitous fun!us Pythium.%1/%- 8hisinfectious disease is seen most often in the southeastern #nited tates, but solitary cases ha$e been seen throu!hout the #nited tates.8he or!anism elicits an intense inflammatory and fibrotic reaction often mimic:in! inflammatory carcinomas. Do!s may be presentedfor chronic debilitation and $omitin! because of pyloric mechanical obstruction. An abdominal mass is often palpable on physicale9amination, and positi$e/contrast radio!raphic studies re$eal a thic:ened !astric 2all.%0 Definiti$e dia!nosis is made by identifyin! theor!anism 2ith special stains in histolo!ical sections, fun!al culture, serolo!y, or PCR.%+ Phycomyosis lesions are best mana!ed bysur!ical resection follo2ed by systemic anti/fun!al therapy.

Chroni Gastritis T Chronic hypertrophic !astritis may be associated 2ith diffuse or focal macroscopic thic:enin! of the !astric

mucosa, leadin! to pro!ressi$e obstruction to outflo2. @istopatholo!ic chan!es include mucosal hypertrophy and hyperplasia of!astric !lands, 2ith inflammatory cells and cystic dilatation of mucous !lands.%+/(* @ypertrophic !astritis is probably the result ofchronic mucosal inflammation. Contrast radio!raphy is sometimes useful in demonstratin! lesions, but a definiti$e dia!nosis usuallyre6uires endoscopy and !astric biopsy. Dietary modification may be helpful in these patients.

Eosinophili Gastritis T 8his lesion characteri5ed by chronic eosinophilic infiltration of the !astric mucosa can also cause obstructi$e pyloric lesions. <esions usually consist of diffuse eosinophilic infiltrates, !ranulation tissue, and fibrosis in$ol$in! the mucosa and otherlayers of the !astric 2all. <ess fre6uently, discrete !ranulomatous nodules may be present.%+/(* 8he etiopatho!enesis is un:no2n,althou!h some cases may result from an underlyin! parasitic or aller!ic reaction. %+/(* Definiti$e dia!nosis is based on !astric biopsy.ur!ical correction of pyloric obstruction may be re6uired, but dietary manipulation hypoaller!enic or elimination diet and

!lucocorticoid therapy are the mainstays of therapy.

Gastri #eoplasia 5 Adenocarcinomas are the most common mali!nant !astric tumor in do!s, and metastasis is common.<ymphosarcomas are the most common !astric tumor in cats. Hther primary mali!nant tumors include leiomyosarcomas, plasmacytomas, and fibrosarcomas.((/(' Clinical si!ns include chronic $omitin!, hematemesis, melena, anore9ia, and 2ei!ht loss.4ndoscopy or e9ploratory laparotomy and biopsy are re6uired for definiti$e dia!nosis. 8he pro!nosis for mali!nant !astric neoplasia isusually poor because of the ad$anced nature of the lesion at the time of dia!nosis and because of complications associated 2ith !astricresection. 49trinsic pyloric lesions such as hepatic or pancreatic neoplasms can also cause !astric outflo2 obstruction $ia e9tramuralcompression of the pylorus

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PATHOPHYSIOLOGY 1 GAST%IC MOTILITY DISO%DE%S

Aelerated Gastri E"ptying T 8he best e9ample of an accelerated !astric emptyin! disorder is the $omitin! associated 2ith thehyperthyro9inemia of feline hyperthyroidism. @yperthyro9inemia induces a tachy!astria and accelerated !astric emptyin!. =ormal !astric emptyin! rhythm is restored follo2in! successful treatment of hyperthyroidism. Accelerated !astric emptyin!occasionally occurs in do!s follo2in! antral andor pyloric resections for the treatment of !astric cancer. A post/prandialdumpin! syndromeS de$elops in these animals characteri5ed by acute $omitin!, abdominal pain, and diarrhea.

%etrograde Transit T ;astroesopha!eal reflu9 and duodeno!astric reflu9 are the t2o best e9amples of retro!rade transit disorders.;astroesopha!eal reflu9 is an increasin!ly reco!ni5ed clinical disorder in the do!, althou!h clinical si!ns are more related to esopha!eal

dysfunction.(%,(- Duodeno!astric reflu9 may be the underlyin! patho!enesis of the so/called bilious $omitin!S syndrome in the do!.Affected animals tend to $omit small amounts of bile in the mornin! follo2in! an o$erni!ht fast

Delayed Gastri E"ptying T Delayed !astric emptyin! is no2 reco!ni5ed as an important cause of upper !astrointestinal tract si!ns. %+/(* Delayed!astric emptyin! has been reported in animals reco$erin! from !astric dilatation$ol$ulus >i!ure '-/&, infectious and inflammatory !astricdiseases, e9perimental !astric ulcer, and radiation !astritis. It has also been associated 2ith se$eral secondary conditions, includin! electrolytedisturbances e.!., hypo:alemia, metabolic disorders e.!., hypoadrenocorticism, uremia, diabetes mellitus, concurrent dru! usa!e e.!., anti/choliner!ics, and acute abdominal inflammation

GAST%IC P%O6I#ETIC THE%APY Dietary mana!ement should al2ays be used as an adGunct to ;.I. pro:inetic therapy. Dietary mana!ement is based on the :no2led!e

that li6uids are emptied from the stomach more rapidly than solids, and that carbohydrates are emptied more rapidly than proteins,2hich in turn are emptied more rapidly than lipids. A lo2/fat, lo2/protein diet of li6uid or semi/li6uid consistency should be fed atfre6uent inter$als to facilitate !astric emptyin!. Diets should be selected for lo2 acidity and lo2 osmolality and should be fed at 2arm

temperatures ((° T &+° C" 0(° T %**° >. ;astric pro:inetic a!ents should be considered in patients that fail to respond to dietary

mana!ement alone.

Dopa"inergi Antagonisti Dr.gs 8he dopaminer!ic anta!onists are a !roup of dru!s 2ith !astrointestinal pro:inetic and antiemetic effects at peripheral pro:inetic orcentral antiemetic dopamine D( receptors. 8he best representati$es in this classification, metoclopramide and domperidone, re$erse

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!astric rela9ation induced by dopamine infusion in do!s, and they abolish $omitin! associated 2ith apomorphine therapy. Althou!h therole of dopamine receptors in chemoreceptor tri!!er 5one/induced $omitin! is fairly 2ell established, there is no definiti$e e$idence thatinhibitory dopaminer!ic neurons re!ulate !astrointestinal motility. 8he pro:inetic effects of metoclopramide and domperidone thus maynot be readily or e9clusi$ely e9plained by dopamine receptor anta!onism. ome dopaminer!ic anta!onists e.!., metoclopramide ha$e

other pharmacolo!ic properties, e.!., '/@8& receptor anta!onism and '/@81 receptor a!onism. Domperidone also has α(/ and β(/

adrener!ic receptor anta!onistic effects. 8he characteri5ation of these dru!s as dopaminer!ic anta!onists is con$enient but may not properly describe their o$erall in $i$o effects.

Serotonergi Dr.gs Dru!s actin! on !astrointestinal '/hydro9ytryptamine '/@8 or serotonin receptors ha$e potent motility effects. As pro:inetic a!ents,the serotoner!ic dru!s bind '/@81 receptors on enteric choliner!ic neurons inducin! depolari5ation and contraction of !astrointestinalsmooth muscle. 8hese dru!s are not entirely selecti$e for the '/@81 receptor, ho2e$er. ome of the putati$e '/@81 receptor a!onistsalso ha$e '/@8% and '/@8& anta!onistic effects on enteric choliner!ic neurons, and direct non/choliner!ic perhaps '/@8(a effects on

colonic smooth muscle. Cisapride and te!aserod 2ere perhaps the best e9amples in this classification althou!h it has been 2ithdra2nfrom se$eral mar:ets, includin! the #nited tates, Canada, and se$eral 2estern 4uropean countries.

Motilin1Li7e Dr.gs

8he antibiotic properties of erythromycin and other macrolides 2ere disco$ered in the early %7'*Ls. ince that time, erythromycin has been 2idely used in treatin! patients 2ith !ram/positi$e and !ram/ne!ati$e bacterial and mycoplasmal infections. Physicians and$eterinarians noted that erythromycin therapy 2as accompanied by fre6uent !astrointestinal side effects includin! nausea and $omitin!.8his occurrence su!!ested to researchers that erythromycin mi!ht ha$e effects on !astrointestinal motility. It 2as subse6uentlydemonstrated that microbially/effecti$e doses of erythromycin stimulate retro!rade peristalsis and $omitin! in do!s, and that lo2ermicrobially/ineffecti$e doses of erythromycin stimulate mi!ratin! motility comple9es and ante!rade peristalsis similar to that induced by

the endo!enous !astrointestinal hormone, motilin.

Aetylholinesterase Inhi,itors and Cholino"i"eti Agents

Ranitidine and ni5atidine, classic histamine @( receptor anta!onists, stimulate !astrointestinal motility by inhibitin! acetylcholinesteraseacti$ity. As parasympathetic potentiatin! a!ents, ranitidine and ni5atidine stimulate !astric emptyin! and small intestinal and colonicmotility. 8he pro:inetic effects of ranitidine and ni5atidine appear to be more prominent in the pro9imal !astrointestinal tract i.e.,!astric emptyin!. Hther members of this classification, e.!., cimetidine and famotidine, apparently ha$e no effect on !astrointestinalmotility. )ethanechol is a cholinomimetic a!ent that binds muscarinic choliner!ic receptors and stimulates motility throu!hout the!astrointestinal tract.

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NITRIC OXIDE DONORS

Delayed !astric emptyin! is reco!ni5ed as an important cause of upper !astrointestinal tract patholo!y e.!., anore9ia and $omitin! incompanion animals.(% Delayed !astric emptyin! has been reported in infectious and inflammatory !astric diseases, diabetes mellitus,and radiation inGury in the do!.%7,(0 Delayed !astric emptyin! has also been associated 2ith se$eral secondary conditions, includin!electrolyte disturbances e.!., hypo:alemia, hypocalcemia, metabolic disorders e.!., hypoadrenocorticism, hyper!astrinemia, uremia,

concurrent dru! usa!e e.!., choliner!ic anta!onists, β/adrener!ic a!onists, opiates, acute stress e.!., sympathetic stimulation, spinal

cord inGury, and acute abdominal inflammation.%7,(0

Diabetes mellitus is the most common endocrinopathy of the domestic do!.(+ <on!/standin! un/dia!nosed or un/treated diabetesmellitus is associated 2ith si!nificant !astroparesis in the do!,(7,&* Gust as it in humans. 8he patho!enesis of !astroparesis in diabetesmellitus is comple9 and probably multi/factorial, in$ol$in! one or more of the cellular elements neurons, smooth muscle cells,interstitial cells of CaGal re!ulatin! !astric motility.&% An important pathophysiolo!ic mechanism appears to be the loss of neuronal

nitric o9ide synthase, the en5yme responsible for the production of nitric o9ide, an inhibitory neurotransmitter that is re6uired forrela9ation of smooth muscle and therefore a critical component of normal !astrointestinal motility. In the absence of nitric o9ide, thestomach cannot rela9, resultin! in bloatin!, satiety, nausea, and $omitin!.&(

Cisapride, metoclopramide, and erythromycin ha$e all been used 2ith $ariable effect in diabetic !astroparesis. 8herapy aimed instead atrestorin! nitrer!ic neurotransmission could ha$e intrinsic beneficial effects in canine diabetic !astroparesis. AM#/&*%, a nitric o9ide=H donor, is reco!ni5ed as an effecti$e treatment for diabetic !astroparesis in strepto5otocin/induced 8U diabetic rat models ofdelayed !astric emptyin!, and may e$entually pro$e useful in spontaneous canine diabetes mellitus.

%eferenes8

%. Meyer J@. Motility of the stomach and !astroduodenal Gunction. In Johnson <R edF Physiolo!y of the ;astrointestinal 8ract, (nded. =e2 or:, Ra$en Press, %7+0, pp. -%&/-&*.(. <ammers WJ4P, Ver Donc: <, tephen ), et al. Hri!in and propa!ation of the slo2 2a$e in the canine stomachF the outlines of a!astric conduction system. Am J Physiol (7-F ;%(**/;%(%*, (**+.&. de Vos WC. Mi!ratin! spi:e comple9 in the intestine of the fastin! cat. Am J Physiol (-'F ;-%7/;-(0, %77&.1. de Vos WC. Role of the enteric ner$ous system in the control of mi!ratin! spi:e comple9 in the feline intestine. Am J Physiol (-'F;-(+/;-&0, %77&.'. ;ualtieri M, Mon5e!lio M;. ;astrointestinal polyps in small animals. 4urop J Comp ;astro %77-" %F '/%'.-. Matthiesen D8, Walter MC. ur!ical treatment of chronic hypertrophic pyloric !astropathy in 1' do!s. J Am Anim @osp Assoc

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%7+-" ((F (1%/(17.0. )ellen!er CR, Maddison J4, MacPherson ;C, et al. Chronic hypertrophic pyloric !astropathy in %1 do!s. Aus Vet J %77*" -0F&%0/&(&.+. i:es R<, )irchard , Patnai: A, et al. Chronic hypertrophic pyloric !astropathyF a re$ie2 of %- cases. J Am Anim @osp Assoc%7+-" ((F 77/%*-.7. $an der ;aa! I. @ypertrophic !astritis in (% do!s. Uentralbl Veterinarmed %7+1" &%F %-%/%-0.%*. Walter MC, ;oldschmidt M@, tone 4A, et al. Chronic hypertrophic pyloric !astropathy as a cause of pyloric obstruction in thedo!. J Am Vet Med Assoc %7+'" %+-F %'0/%-1.%%. )iller D, Partin!ton )P, Miyabayashi 8, et al. #ltrasono!raphic appearance of chronic hypertrophic pyloric !astropathy in thedo!. Vet Radiol #ltrasound %771" &'F &*/&0.%(. <eib M, aunders ;E, Moon M<, et al. 4ndoscopic dia!nosis of chronic hypertrophic pyloric !astropathy in do!s. J Vet InternMed %77&" 0F &&'/&1%.%&. Miller RI. ;astrointestinal phycomycosis in -& do!s. J Am Vet Med Assoc %7+'" %+-F 10&/107.

%1. Pier AC, Cabanes >J, >erreiro <, et al. Prominent animal mycoses from $arious re!ions of the 2orld. Med Mycol (***" &+F 10/-(.%'. ;rooters AM. Pythiosis, la!enidiosis, and 5y!omycosis in small animals. In, Veterinary Clinincs of =orth America (**&" &&F-7'/0%+.%-. ;raham JP, =e2ell M, Roberts ;D, et al. #ltrasono!raphic features of canine !astrointestinal pythiosis. Vet Radiol #ltrasound(***" 1%F(0&/(+*.%0. ;rooters AM, ;ee ME. De$elopment of a nested polymerase chain reaction assay for the detection and identification of Pythiuminsidiosum. J Vet Intern Med (**(" %-F%10/%'1.%+. @all JA and Washabau RJ. Dia!nosis and treatment of !astric motility disorders. In, Veterinary Clinics of =orth America %777"(7(F &00/&7'%7. @all JA. Diseases of the stomach. In, 8e9tboo: of Veterinary Internal Medicine. 'th edition. 4d. 4ttin!er J and >eldman 4C, W)

aunders Company, Philadelphia, pp %%%+/%%1(.(*. Washabau RJ, @olt D4 (**&a. Pathophysiolo!y of ;astrointestinal Disease. In, 8e9tboo: of Veterinary ur!ery. &rd edition. 4d.D latter, W) aunders Company, Philadelphia, pp '&*/'''.(%. Couto C; et al. ;astrointestinal lymphoma in (* do!s. J Vet Intern Med %7+7" &F 0&/07.((. Eapat:in A et al. <eiomyosarcomas in do!s. J Amer Vet Med Assoc %77(" (*%F %*00/%7+1.(&. Ra:ich PM et al. Mucocutaneous plasmacytomas in the do!. J Am Vet Med Assoc %7+7" %71F+*&/+*7.(1. Mahony HM, Moore A, Cotter M, et al. Alimentary lymphoma in cats. J Amer Vet Med Assoc %77'" (*0F %'7&/%-*(.('. Washabau RJ. Diseases of the esopha!us. InF 8e9tboo: of Veterinary Internal Medicine. 'th edition. 4ds. J 4ttin!er and 4C>eldman, W) aunders Company, Philadelphia, (***, pp %%1(/%%'&.

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(-. Washabau RJ. ;astrointestinal motility disorders and !astrointestinal pro:inetic therapy. InF Vet Clin = Amer (**&" $ol, pp, W)aunders Company, Philadelphia.(0. =elson RW. Diabetes mellitus. In, 8e9tboo: of Veterinary Internal Medicine, 4ttin!er J and >eldman 4C, eds. -th edition. W)aunders, Philadelphia, (**', %'-&/%'7%.(+. 8a:eda M, Mi5utani , 8su:amoto E, et al. ;astric emptyin! in diabetic !astroparetic do!sF effects of DE/7'%, a no$el pro:inetica!ent. Pharmacolo!y (**%" -(F (&/(+.(7. Eoi5umi >, Ea2amura 8, Ishimori A. Correlation bet2een !astric emptyin! time and both plasma !astrin and pancreatic polypeptide in strepto5otocin diabetic do!s. Japanese Journal of ;astroenterolo!y %7+7" +-F %*&0/%*1&.&*. Camilleri M. Diabetic !astroparesis. =e2 4n!land Journal of Medicine (**0" &'-F +(*/+(7.&%. Pasricha PJ. 8he riddle, mystery, and eni!ma of !astroparesis. Journal of upporti$e Hncolo!y (**0" 'F &-+/&0*.&(. Amulet Pharmaceuticals AM#/&*% >act heet. =e2 Chemical 4ntity =C4 for Diabetic ;astroparesis.httpF222.amuletpharma.comAM#/&*%>[email protected]

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S"all Intestinal Motility Disorders

Intestinal Motility PatternsContractions in the small intestine ser$e three !eneral functions / mi9in! of the in!esta 2ith di!esti$e en5ymes and other secretions,circulation of the intestinal contents to facilitate contact 2ith the intestinal mucosa, and net propulsion of the intestinal contents in an aboraddirection. Intestinal contractions are !o$erned by four motility patterns T se!mentation, peristalisis, intestino/intestinal inhibition, and themi!ratin! motility comple9.

e!mentation / If a contraction is not coordinated 2ith acti$ity abo$e and belo2, intestinal contents are displaced both pro9imally anddistally durin! the contraction and may, in fact, propa!ate orad durin! the period of rela9ation. uch contractions appear to di$ide the bo2elinto se!ments, 2hich accounts for the term se!mentationS !i$en to the process. e!mentation ser$es to mi9 and locally circulate theintestinal contents. e!mentation primarily in$ol$es circular smooth muscle contraction.

Peristalsis / 8he small intestine is capable of elicitin! a hi!hly coordinated contractile response that is propulsi$e in nature. When the bo2elis distended by a bolus of food the bo2el responds 2ith contraction orad and rela9ation aborad to the point of distension. 8heneurotransmitters in$ol$ed in the orad contraction are acetylcholine ACh and substance P P, and the neurotransmitters in$ol$ed in thecaudad rela9ation are $asoacti$e intestinal peptide VIP and nitric o9ide =H. 8hese e$ents tend to mo$e the material in an aboraddirection. hort se!ment peristalsis of the bo2el is the norm in do!s and cats. If short se!ment peristalses occur se6uentially they can propel a bolus the entire len!th of the !ut in a short period of time. 8his peristaltic response, first characteri5ed by )ayliss and tarlin!, isreferred to as the <a2 of the IntestineS, and is less fre6uent than short/se!ment peristalses.

Intestino/intestinal Inhibition / If an area of the bo2el is !rossly distended, contractile acti$ity in the rest of the bo2el is inhibited. 8hisrefle9 pre$ents the mo$ement of in!esta into more distal se!ments of intestine that ha$e been se$erely distended or obstructed. 8his refle9

is mediated by the e9trinsic autonomic ner$ous system.(

Mi!ratin! Motility Comple9 / 8he mi!ratin! motility comple9 MMC propa!ates indi!estible materials, mucus, and secretions from thestomach to the colon durin! the fastin! state. 8he enteric ner$ous system re!ulates the periodicity and mi!ration of the MMC, but the!astrointestinal hormone motilin reinforces the MMC acti$ity. Cats do not ha$e MMCs, and instead ha$e a mi!ratin! spi:e comple9MC that is less $i!orous than the canine MMC.(,&

'reed Differenes in GI Transit Ti"e

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i!nificant differences in physiolo!y and pharmacolo!y ha$e been found in do! breeds. 8here are o$er 1** breeds of do!s reco!ni5ed2orld2ide and %'- breeds reco!ni5ed by the American Eennel Club. Amon!st these $arious do! breeds, se$eral important differences inmetabolism ha$e been noted, e.!., p/!lycoprotein/mediated metabolism, copper stora!e, and !ro2th rates,' Differences in ;I transit

characteristics ha$e also been noted. 8he ;I tract of lar!e breed do!s e.!., -* :! comprises (.+? of their total body 2ei!ht. In contrast,it comprises 0? of the total body 2ei!ht of small breed do!s e.!., ' :!. )reed related differences in fecal 2ater content could reflectdifferences in ;I transit time, intestinal fermentation, diet, metabolism, and dru! absorption. #sin! radio/opa6ue mar:ers %.' mm diameter administered in food, %( 2ee: old lar!e breed puppries e.!., ;reat Danes e9hibited a si!nificantly lon!er oro/cecal transit time HC88"&.1 hours as compared to small breed puppies e.!., Miniature poodle, (.' hours. 8he lon!er transit time appears to reflect both a lon!er!astric emptyin! time and a lon!er small intestinal transit time bet2een breeds. 8here also appear to be differences in intestinal permeability bet2een do! breeds. 8he lactuloserhamnose ratio reflects the relati$e absorption across the intestinal ti!ht Gunction transcellularabsorption $ersus the intestinal surface area paracellular absorption, 2hich occurs across the cell membrane of the enterocyte. 8he <Rratio is substantially !reater in the ;reyhound breed as compared to the ;olden Retrie$er breed. )reed and a!e characteristics must beta:en into account 2hen differentiatin! normal and abnormal transit times.

Definition of Ile.sIleus has been defined as the functional inhibition of propulsi$e bo2el acti$ity, irrespecti$e of patho!enetic mechanism.-,0 8here are se$eralunderylin! causes of ileus, includin! dysautonomia, post/operati$e ileus, opioid/induced bo2el dysfunction, muscular dystrophy, $isceralmyopathy, $iral enteritis, radiation enteritis, idiopathic pseudo/obstruction, and hypothyroidism. ome ileus disorders are more readilytreated than others.

DYSAUTO#OMIA

Etiology

Dysautonomia is a !enerali5ed autonomic neuropathy that 2as ori!inally reported in cats in the #nited Ein!dom, but that has no2 beendocumented in do!s and cats throu!hout Western 4urope and the #nited tates.+/%- 8he clinical si!ns reflect a !enerali5ed autonomicdysfunction but me!aesopha!us, esopha!eal hypomotility, !astric and small bo2el distension and hypomotility, and urinary bladderdistension are fairly consistent findin!s.+,%*,%- Aspiration pneumonia and me!acolon are seen less fre6uently.

PathophysiologyDe!enerati$e lesions are found in autonomic !an!lia, intermediate !ray columns of the spinal cord, and some sympathetic a9ons.%*,%(,%& Despite an intensi$e search for !enetic, to9ic, nutritional, and infectious etiolo!ic a!ents, no definiti$e etiolo!y has e$er beenestablished.

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Clinial SignsVomitin!, diarrhea, anore9ia, lethar!y, 2ei!ht loss, dysuria, and inspiratory dyspnea are the most fre6uent clinical si!ns reported in

do!s. In cats, dilated pupils, esopha!eal dysfunction, dry nose, reduced lacrimal secretions, prolapse of the third eyelid re!ur!itationand constipation are the most fre6uent clinical si!ns.%(

DiagnosisA clinical dia!nosis is made in most cases based on historical and physical e9amination findin!s. Additional findin!s consistent 2ith thedia!nosis 2ould includeF % esopha!eal dilation and hypomotility on sur$ey or barium contrast radio!raphs" ( delayed !astric emptyin!on barium contrast radio!raphs" & reduced tear production in chirmer tear tests" 1 atropine/insensiti$e bradycardia" and, ' bladderand colonic distention on sur$ey radio!raphs. 8here are fe2 differential dia!noses to consider in a do! or cat presentin! 2ith themyriad manifestations of the syndrome. 4arly in the course of the illness, ho2e$er, other differential dia!noses to consider are colonicor intestinal obstruction, other causes of me!aesopha!us, and lo2er urinary tract disease.

Treat"entupporti$e care e.!. artificial tears, ele$ated feedin!s, e9pressin! the urinary bladder, antibiotics, etc. is still the basis of therapy in thisdisorder, althou!h some do!s and cats are reported to sho2 mild impro$ement 2ith parasympathomimetic dru!s e.!. bethanechol ormetoclopramide. ;astrostomy tube feedin!s or total parenteral nutrition may sustain some animals until they re!ain neurolo!icfunction.

PrognosisIn !eneral, dysautonomia carries a !uarded to poor pro!nosis for lon!/term sur$i$al in both the do! and the cat. (* to 1*? of affectedcats are li:ely to reco$er, althou!h cats may ta:e ( to %( months to do so. %(/%- Reco$ery rates are lo2er still in the do!.%*,%( Complete

reco$ery is uncommon and many cats and do!s are left 2ith residual impairment, e.!. intermittent re!ur!itation, dilated pupils, and fecalor urinary incontinence

POST1OPE%ATI$E ILEUS

EtiologyPost/operati$e ileus has been defined as ileus that de$elops follo2in! abdominal sur!ery, resol$in! spontaneously 2ith ( to & daysS. %0 It may be e9acerbated by opioid administration durin! and follo2in! sur!ery. Multiple mechanisms ha$e been proposed for theetiopatho!enesis of post/operati$e ileus.%0

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Post/operati$e ileus is a si!nificant problem in human medicine and constitutes the most important reason for delayed dischar!e fromthe hospital after abdominal sur!ery. 8he economic impact of post/ ileus has been estimated to be X0'* million to X% billion in the#nited tates. imilar data are not yet a$ailable in $eterinary medicine.

Pathophysiology<aparotomy and manipulation of the $iscera are the main mechanisms underlyin! post/operati$e ileus, but other factors such asanesthetic a!ents and post/operati$e pain medication contribute to the delay in reco$ery of normal transit. 8he effect of !eneralanesthetic a!ents is short lastin! and therefore of only minor importance. 8he use of opioids to control post/operati$e pain has a much!reater impact on post/operati$e motility. Post/operati$e opioids ha$e si!nificantly impro$ed patient comfort in the early post/operati$e phase, but these dru!s potently inhibit !astrointestinal transit. 4fforts to reduce the dose of opioids or to anta!oni5e theireffects 2ith peripherally actin! opioid N/anta!onists such as methylnaltre9one or al$imopan are important to minimi5e the detrimentaleffect of opioids on !astrointestinal motility.

8he main cause of post/operati$e ileus relates to the sur!ical procedure itself.%0,%+

8he first or neuro!enic phase is neurally/mediatedand in$ol$es neural refle9es acti$ated durin! and immediately follo2in! sur!ery. 8he second or inflammatory phase is tri!!ered by theinflu9 of leu:ocytes in manipulated intestinal se!ments and is responsible for the sustained inhibition of !astrointestinal motility. %0

Clinial E!a"ination =ausea, $omitin!, intestinal distension, and abdominal pain are the most important clinical si!ns of post/operati$e ileus in do!s and cats.>e$er and leu:ocytosis may also be found dependin! upon the type and se$erity of abdominal sur!ery.

Diagnosis8he dia!nosis of post/operati$e ileus is usually strai!ht for2ard, and an e9clusion of other :no2n causes of ileus. <aboratory testin!

complete blood count, serum chemistry, urinalysis are sometimes performed to rule out metabolic disorders such as li$er disease andrenal failure. Abdominal ima!in! e.!., sur$ey radio!raphy and ultrasono!raphy should be performed to e9clude other causes of ileusand their complications, e.!., mechanical obstruction, peritoneal free air of fluid accumulation, and pancreatitis.

Treat"entHro!astric intubation / Intermittent oro!astric or naso!astric intubation may be of benefit particularly in those patients 2ith !aseous!astrointestinal distension.

4arly post/operati$e feedin! T 4arly post/operati$e feedin! has been recommended as a means of decreasin! the duration of post/

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operati$e ileus. >eedin! may stimulate a refle9 that coordinates propulsi$e acti$ity and elicits the secretion of !astrointestinalhormones, causin! an o$erall positi$e effect on bo2el motility.

<aparoscopic procedures T <aparoscopic procedures offer the theoretical ad$anta!e of decreased tissue trauma compared 2ith openabdominal procedures. 8his decrease in tissue trauma may lead to faster reco$ery of post/operati$e bo2el function. Animal studiesha$e found si!nificant decreases in the duration of post/operati$e ileus after laparoscopic $s. open abdominal procedures.%+

Pro:inetic a!ents T ;astrointestinal pro:inetic a!ents ha$e a clear place in the mana!ement of post/operati$e ileus. 8hese dru!s andand their clinical usa!e are discussed in !reater detail.

CHY/II Inhibitors T Mechanical stretch in intestinal obstruction induces mar:ed e9pression of CHY/II in intestinal smooth muscle cells,and stretch/induced CHY/II plays a critical role in the suppression of smoth muscle contractility in bo2el obstruction.%7 8herefore,CHY/II inhibitors may ha$e therapeutic potential in stretch/related disorders of the !ut.

Hpioid N/anta!onists / Hpioid N/anta!onists li:e al$imopan and methylnaltre9one may be useful in anta!oni5in! the effects of morphine/li:e opioid a!onists if that is part of the underlyin! patho!enesis of post/operati$e ileus.(*,(%

4lectrical stimulation T Althou!h not yet clinically applicable, !astrointestinal pacin! is achie$able in the canine stomach and smallintestine but not the colon.((/(- 8he ma9imal entrainable fre6uency of the !astric and small intestinal slo2 2a$es is about (*? hi!herthan the intrinsic fre6uency. In the future, stimulation parameters may be identified that 2ill entrain slo2 2a$es thereby normali5in!!astric and intestinal dysrhythmias.((/(-

Prognosis

8he pro!nosis for short term post/operati$e ileus is !enerally !ood to e9cellent. In animals 2ith complicated, refractory post/operati$eileus, the pro!nosis is less clear. More a!!ressi$e therapies may be needed in this patient population. In such cases, intestinal failuremay result culminatin! in intestinal transplantation as a last resort. (0,(+,(7

OPIOID1I#DUCED 'O4EL DYS&U#CTIO#

EtiologyHpioid/induced bo2el dysfunction may be part of a post/operati$e ileus syndrome, or it may relate solely to the use of opioid N,Z/a!onists as part of an anal!esic therapeutic re!imen. Hpioids are a mainstay in the treatment of acute and chronic pain. Althou!h

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opioids are $ery effecti$e for pain relief from cancer and other non/mali!nant diseases, their use is often limited by side effects. 8hemost common ad$erse side effects are constipation and $omitin!, but they also alter small bo2el function causin! opioid/induced bo2eldysfunction. Hpioid/induced bo2el dysfunction can occur immediately after the first dose and persist for the duration of therapy. 8he

peripherally actin! NTreceptor anta!onists methylnaltre9one and al$imopan are a ne2 class of a!ents desi!ned to re$erse opioid/induced side effects on the !astrointestinal tract 2ithout compromisin! pain relief.&%/&-

Pathophysiology4ndo!enous opioids include endorphins, en:ephalins, and dynorphins. 8hey act selecti$ely at opioid receptors composed of the N, Z,and [ sub/types. Hpioid N receptors are present in the central and peripheral ner$ous system, as 2ell as the ;I tract. 8here are manyspecies and site differences, but N receptors ha$e been reported on the interstitial cells of CaGal, smooth muscle, and epithelial cells. 8he predominant opioid effect appears to be at the local le$el and includes stimulation of absorption $illus epithelial cells, inhibition ofsecretion crypt epithelial cells, increased se!mentation circular smooth muscle, and reduced peristalsis lon!itudinal smooth muscle.49o!enously administered opioids ha$e the same o$erall effect of opioid inhibition of peristalsis and secretion leadin! to the syndrome

of opioid/induced bo2el dysfunction.&%,&(

Clinial E!a"inationConstipation and $omitin! are the primary clinical si!ns of opioid/induced bo2el dysfunction. <eft untreated, constipation can pro!ressto fecal impaction and mechanical obstruction.

Diagnosis8he patient usually has a 2ell documented history of opioid N/a!onist therapy, e.!., morphine, in the mana!ement of a pain syndrome.till, it 2ould be important to rule out other causes of ileus, metabolic disorders, and mechanical obstruction. 8herefore, the minimumdatabase should include laboratory data complete blood count, serum chemistry, urinalysis and ima!in! sur$ery abdominal

radio!raphy or ultrasono!raphy.

Treat"entIn most instances, discontinuation of the opioid NTa!onist is sufficient to ameliorate clinical si!ns. With persistence of clinical si!ns after dru! 2ithdra2al, la9ati$e re$ie2ed in Chapter '% and other therapies may be used to treat constipation, althou!h it should beemphasi5ed that a definiti$e role in the treatment of opioid/induced bo2el dysfunction has not yet been pro$ed. Any of the la9ati$ea!ents bul:, lubricant, osmotic, stimulant, emollient T Chapter '% could be used to attenuate the constipatin! effect of the opioid NT a!onist. Misoprostol, a synthetic prosta!landin 4 analo! could also be used to impro$e intestinal and colonic transit times.&-

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If the central anal!esic effect of the opioid NTa!onist is paramount, the patient could be treated concurrently 2ith an opioid NT anta!onist, methylnaltre9one or al$imopan, both of 2hich 2ill impro$e ;I transit 2ithout inhibitin! the central anal!esic effect of theopioid NTa!onist. In do!s, methylnaltre9one at a dose ran!e of %.*/'.* m!:! subcutaneously abolishes the effect of morphine on ;I

transit 2ithout interferin! 2ith the central anal!esic effect.&( afe and effecti$e doses of al$imopan ha$e not yet been reported in thedo!.

If morphine must be used pre/operati$ely, the epidural route $s. continuous lo2 dose infusion facilitates the time of appearance of thefirst !astric interdi!esti$e mi!ratin! comple9 the MMC in do!s 2ith paralytic ileus after open abdominal sur!ery.&0

Prognosis8he pro!nosis for acute opioid/induced bo2el dysfunction is !enerally !ood to e9cellent. Chronic opioid/induced bo2el dysfunctionmay persist and therefore has a more !uarded pro!nosis.

MUSCULA% DYST%OPHY

EtiologyDuchenne/type muscular dystrophy in the ;olden Retrie$er do! is an Y/lin:ed !enetic disorder that is characteri5ed primarily by pro!ressi$e muscular 2ea:ness. In$ol$ement of the ;I tract is fre6uent and may occur at any le$el from stomach to intestine andcolon.&+ 8he disorder is caused by mutations in the dystrophin !ene responsible for production of the dystrophin membrane protein.&7 8he absence of dystrophin is accompanied by alteration of the dystrophin/!lycoprotein comple9 DC; and results in pro!ressi$ede!eneration of the heart, s:eletal and smooth muscle 2ith subse6uent replacement by fibrosis and fatty infiltration.

Pathophysiology

8he !astroenterolo!ic clinical si!ns ha$e been attributed to motility disorders caused by smooth muscle dama!e, but histolo!ic e$idenceof alterations has not been a consistent findin!. In a more recent report, ;olden Retrie$er do!s affected 2ith Duchenne/type musculardystrophy had mar:ed de!enerati$e lesions in the smooth musclulature of the ;I tract, urinary, and reproducti$e systems. ;I smoothmuscle lesions 2ere associated 2ith the clinical findin!s of !astroparesis, !astric dilatation, and intestinal pseudo/obstruction.&+

Clinial SignsDyspha!ia, re!ur!itation, !astroparesis, abdominal pain, and intestinal distension ha$e been reported in affected animals.;astroenterolo!ic clinical si!ns may be the first si!n of dystrophic disease and may precede the appendicular musculos:eletal features.8he impairment of ;I function may be !radual and undetected by the pet o2ner, breeder, or $eterinarian.&+

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DiagnosisDefiniti$e dia!nosis may be confirmed on the basis of history and physical e9amination findin!s, serum creatine :inase acti$ity, !enomic

D=A analysis, muscle electrophysiolo!y, !ross morpholo!y, and histolo!ical features.&7 Ileus may be difficult to detect in the 2holeanimal and may re6uire the use of endoscopy, ultraono!raphy, and scinti!raphy.

Treat"entDespite maGor ad$ances in our understandin! of the pathophysiolo!y of the disease, therapy is still lar!ely supporti$e and symptomatic.;ene replacement therapy has not yet succeeded in restorin! muscle function or in prolon!in! life.

PrognosisAt the present time, the pro!nosis for cure is poor. With supporti$e and symptomatic therapy, some affected animals ha$e sur$i$ed outto '% months.&+

$ISCE%AL MYOPATHYHne case of $isceral myopathy in a si9 month old D@ cat has been reported in the $eterinary literature.1* 8he :itten had a -/day historyof anore9ia, intermittent $omitin!, and diarrhea, and se$erely dilated loops of hypomotile intestine 2ere found on sur$ey abdominalradio!raphy and ultrasono!raphy. Intestinal dilation 2as confirmed at the time of sur!ery, and a (*/cm section of GeGunum 2as resected.In the pro9imal GeGunum, there 2as mar:ed atrophy of the lon!itudinal muscle of the muscularis e9terna layer and diffuse se$erede!enerati$e $acuolar chan!e 2ithin the myocytes and endomysial cells. 8he circular muscle layer 2as of normal thic:ness andmorpholo!y. Villus stuntin! and fusion 2ere e$ident in the mucosa. In the distal GeGunum, the mucosa and submucosa 2ere normal, butthe lon!itudinal muscle layer 2as mar:edly atrophic 2ith focal de!eneration, calcification, loss of myocytes, and replacement by proliferatin! fibroblasts. )ased upon descriptions of human $isceral myopathy, the findin!s 2ere thou!ht to be consistent 2ith a

dia!nosis of $isceral myopathy causin! chronic intestinal pseudo/obstruction.

1*

8he cat 2as ali$e and doin! 2ell t2enty months aftersur!ery.

PA%$O$I%AL E#TE%ITISIleus is a fre6uent findin! in puppies affected 2ith par$o$iral enteritis. 1% 8he ultrasono!raphic appearance of the !astrointestinal tract2as characteri5ed in forty puppies 2ith confirmed canine par$o$iral enteritis.1% ono!raphic findin!s included fluid/filled small intestinesin 7(.'? of the cases see >i!ure '0/&, and of the stomach and colon in +*? and -(.'? of the cases, respecti$ely. ;enerali5ed atony2as present in 0'? of the cases, and 2ea: peristaltic contractions indicati$e of functional ileus 2ere obser$ed in the remainin! ('? ofcases. 8he duodenal and GeGunal mucosal layer thic:nesses 2ere si!nificantly reduced 2hen compared 2ith normal puppies 2ith mean

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duodenal mucosal layer measurin! %.0mm and GeGunal mucosal layer %.*mm. A mucosal layer 2ith diffuse hyperechoic spec:les 2as seenin the duodenum %'? and the GeGunum '*?. 8he luminal surface of the duodenal mucosa 2as irre!ular in ((.'? and the GeGunalmucosa in 1(.'?. Chan!es 2ere accompanied by !enerali5ed indistinct 2all layerin!.in all animals. A mortality rate of &*? 2as found

in this patient population.1%

%ADIATIO# E#TE%ITISRadiation produces a $ariety of chan!es in !astrointestinal tract motility and ileus is a common clinical findin!.1( Most of the chan!esobser$ed 2ith radiation enteritis occur in other patholo!ic states. 8hese include delayed !astric emptyin!, retro!rade !iant contractionsR;Cs and $omitin!, !iant mi!ratin! contractions ;MCs, and abdominal crampin! and diarrhea.1& 8he threshold for these contractilee$ents to occur and their control mechanisms are incompletely understood. Many studies su!!est that treatment i.e., '/@8 & anta!onists prior to e9posure may be the best method to pre$ent the contractions from occurrin!. 8he role of dose rate is unclear.Within hours of a si!nificant e9posure to radiation, these contractions be!in to occur and contribute si!nificantly to the early sta!es ofradiation illness.

IDIOPATHIC I#TESTI#AL PSEUDO1O'ST%UCTIO#

EtiologyChronic intestinal pseudo/obstruction is defined by the presence of chronic intestinal dilatation and dysmotility in the absence ofmechanical obstruction.11 In humans, chronic intestinal pseudo/obstruction has many causes 2hich ha$e been simplified intoabnormalities of enteric smooth muscle myopathies and the enteric ner$ous system neuropathies.1* uch $isceral myopathies andneuropathies are primary causes of chronic intestinal pseudo/obstruction, and myopathies are either familial, or sporadic and idiopathic.Pseudo/obstruction can also arise secondary to other underlyin! disorders, such as pro!ressi$e systemic sclerosis, amyloidosis,muscular dystrophy, !enerali5ed neuromuscular diseases, endocrinopathies, infectious disease, and dru! to9icity. 1*

PathophysiologyHnly ele$en cases of chronic intestinal pseudo/obstruction ha$e been reported in companion animals 7 do!s and ( cats.11/17 >our do!shad atrophy, fibrosis, and mononuclear cell infiltration of the muscularis e9terna similar to 2hat is obser$ed in pro!ressi$e systemicsclerosis in humans. 82o do!s had atrophy of the muscularis e9terna but not fibrosis, either 2ith or 2ithout mononuclear cellinfiltration, 2hereas one do! had hyperplasia of the circular muscle 2ithout atrophy, fibrosis, or inflammation. In only ( reported do!s2ith pseudo/obstruction, the patholo!y described as primarily affectin! the circular muscle the lon!itudinal muscle. Hnly ( reportmentions myocyte $acuolar de!eneration, but it 2as not a p"rominent feature and mar:ed myenteric ple9us $acuolar de!eneration 2as present, su!!estin! an underlyin! primary neuropathy. Hne of the cats reported 2ith pseudo/obstruction actually had diffuse intestinal

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lymphosarcoma 2ith no additional histopatholo!ic details.

Clinial Signs

As 2ith $isceral myopathy, the primary clinical si!ns seen 2ith chronic intestinal pseudo/obstruction are anore9ia, intermittent $omitin!,and diarrhea. i!ns may be referable to one se!ment of the !ut, but the disease us usually diffuse.

DiagnosisAbdominal ima!in! sho2in! intestinal dilatation 2ith no e$idence of mechanical obstruction is the hallmar: of the pseudo/obstruction.>ull/thic:ness intestinal histolo!y is re6uired to identify underlyin! causes of chronic intestinal pseudo/obstruction.

Treat"ent)ecause of the diffuse nature of the disease, sur!ical resection of diseased intestine is not !enerally recommended. Resection only benefits selected patients 2ith locali5ed disease. Medical therapy should other2ise be aimed at correctin! electrolyte and acidbase

disturbances, treatin! infection or sepsis, supportin! nutritional needs, suppressin! the inflammatory or immune response, and instituin! pro:inetic therapy see Chapter '&.11/17

PrognosisAside from the apparent reco$ery reported in one cat 2ith $isceral myopathy, most of the cases of chronic intestinal pseudo/obstructionhad a poor outcome.

HYPOTHY%OIDISM#ntreated or poorly re!ulated hypothyroidism has been associated 2ith important chan!es in !astrointestinal motility. Compared toeuthyroid do!s, thyroidectomi5ed do!s ha$e decreased fre6uency of electrical control acti$ity of the stomach and GeGunum, decreasedoccurrence of electrical response acti$ity spi:e potentials follo2in! stimulation, and decreased mechanical response to feedin!.'*

%E&E%E#CES%. Weisbrodt =W. Motility of the small intestine. In Johnson <R edF Physiolo!y of the ;astrointestinal 8ract, (nd ed. =e2 or:,Ra$en Press, %7+0, pp. -&%/--1.(. Mishra =E, Appert @4, @o2ard JM. 8he effects of distention and obstruction on the accumulation of fluid in the lumen of small bo2el of do!s. Ann ur! %+*F 07%/07', %701.&. de Vos WC. Mi!ratin! spi:e comple9 in the intestine of the fastin! cat. Am J Physiol (-'F ;-%7/;-(0, %77&.1. de Vos WC. Role of the enteric ner$ous system in the control of mi!ratin! spi:e comple9 in the feline intestine. Am J Physiol (-'F

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;-(+/;-&0, %77&.'. >leischer , har:ey M, Mealey E, et al. Pharmaco!enetic and metabolic differences bet2een do! breedsF their impact on caninemedicine and the use of the do! as a preclinical animal model. AAP Journal %*F %%*/%%7. (**+.

-. Camilleri M, )ueno <, de Ponti >, et al. Pharmacolo!ical and pharmaco:inetic aspects of functional !astrointestinal disorders.;astro %&*F %1(%/%&&1, (**-.0. Wood JD. =europathophysiolo!y of functional !astrointestinal disorders. World J ;astro %&F %&%&/%&&(, (**0.+. )er!haus RD, HK)rien DP, Johnson ;C, et al. Ris: factors for de$elopment of dysautonomia in do!s. J Am Vet Med Assoc (%+F%(+'/%(7*, (**%7. Det2eiler DA, )iller D, @os:inson JJ, et al. Radio!raphic findin!s of canine dysautonomia in t2enty/four do!s. Vet Radiol #ltrasound 1(F %*+/%%(, (**%.%*. @ar:in ER, and Andre2s ;A, and =ietfeld JC. Dysautonomia in do!sF -' cases %77&/(***. J Am Vet Med Assoc ((*F -&&/-&7,(**(.%%. @ar:in ER, =ietfeld J, and >ischer JR. Dysautonomia in a family of ;erman shorthaired pointers. JAA@A &+F ''/'7, (**(.

%(. HK)rien DP and Johnson ;C. Dysautonomia and autonomic neuropathies. Vet Clin = Amer / mall Anim Pract. &(F ('%/(-', (**(.%&. harp =J@. >eline dysautonomia. emin Vet Med ur! 'F -0/0%, %77*.%1. Eidder AC, Johannes C, HL)rien DP, et al. >eline dysautonomia in the Mid2estern #nited tatesF a retrospecti$e study of ninecases. J >el Med ur! %*F %&*/%&-, (**0.%'. Ca$e 8A, Enottenbelt C, Mellor DJ, et al. Hutbrea: of dysautonomia in a closed colony of pet cats. Vet Rec %'&F &+0/&7(, (**&.%-. =o$ellas R, impson E4, ;unn/Moore DA, et al. Ima!in! findin!s in %% cats 2ith dysautonomia. J >el Med ur! %(F '+1/'7%,(*%*.%0. )oec:9staens ;4, de Jon!e WJ. =euroimmune mechanisms in postoperati$e ileus. ;ut '+F %&**/%&%%, %**7.%+. <uc:ey A, <i$in!ston 4, 8ache . Mechanisms and treatment of postoperati$e ileus. Arch ur! %&+F (*-/(%1, (**&.%7. hi YU, <in /M, Po2ell DW, et al. Pathophysiolo!y of motility dysfunction in bo2el obstructionF role of stretch/induced CHY/(. Am J Physiol ;astrointest <i$er Physiol &**F ;77/;%*+. (*%%.(*. De@a$en/@ud:ins D<, De@a$en R, <ittle PJ, et al. 8he in$ol$ement of the N/opioid receptor in !astrointestinal pathophysiolo!yFtherapeutic opportunities for anta!onism at this receptor. Pharm 8o9icol %%0F %-(/%+0, (**+.(%. )ec:er ;, )luim @4. =o$el opioid anta!onists for opioid/induced bo2el dysfunction and post/operati$e ileus. <ancet &0&F %%7+/%(*-, (**7((. un , on! ;, <ei , et al. 4ffects and mechanisms of !astrointestinal electrical stimulation on slo2 2a$esF a systematic caninestudy.(&. @uibin , Chen JDU. 4ffects of intestinal electrical stimulation on postprandial small/bo2el motility and transit in do!s. Am J ur!%7(F e''/e-*, (**-.

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(-. Yu Y, <ei , Chen JDU. 4ffects and mechanisms of electrical stimulation of the stomach, duodenum, ileum, and colon on !astrictone in do!s. Di! Dis ci ''F +7'/7*%, (*%*.(0. 8odo , 85a:is A, Abu/4lma!d E, et al. Current status of intestinal transplantation. Ad$ ur! (0F (7'/&%-, %771.(+. )ines J4. Intestinal failureF a ne2 era in clinical mana!ement. J ;astro @epatol (1F +-/7(, (**7.(7. )el:ind/;erson J, ;raeme/Coo: >, Winter @. 4nteric ner$ous system disease and reco$ery, plasticity, and re!eneration. J Ped;astroenterol =utr 1(F &1&/&'*, (**-.&*. 8homas J. Hpioid/induced bo2el dysfunction. J Pain ymp Mana!ement &'F %*&/%%&, (**+.&%. )ec:er ;, )lum @4. =o$el opioid anta!onists for opioid/induced bo2el dysfunction and post/operati$e ileus. <ancet &0&F %%7+/%(*-, (**7.&(. >u:uda @, uena!a E, 8suchida D, et al. 8he selecti$e mu opioid receptor anta!onist, al$imopan, impro$es delayed ;I transit of

postoperati$e ileus in rats. )rain Research (**-.&&. uan C/. Methylnaltre9one mechanisms of action and effects on opioid bo2el dysfunction and other opioid ad$erse effects. AnnPharmacotherapy 1%F 7+1/77&, (**0.&1. Viscusi 4R, ;an 8J, <eslie J), et al. Periphierally actin! mu/opioid receptor anta!onists and postoperatie ileusF mechanisms ofaction and clinical applicability. Anesth Anal! %*+" %+%%/%+((, (**7.&'. <eslie J). Al$imopan for the mana!ement of postoperati$e ileus. Ann Pharmacotherapy &7F %'*(/%'%*, (**'.&-. Washabau RJ.&0. =a:ayoshi 8, Ea2asa:i =, u5u:i , et al. 4pidural administration of morphine facilitates time of appearance of first !astricinterdi!esti$e mi!ratin! comple9 in do!s 2ith paralytic ileus after open abdominal sur!ery. J ;astrointest ur! %%F -1+/-'1, (**0.&+. Iya5ato <;, )eretta DC, 4n!racia/>ilho JR, et al. In$ol$ement of or!anic systems in !olden retrie$er Y/lin:ed muscular dystrophy.)ra5 J Vet Path 1F +0/71, (*%%.&7. )ellini M, )ia!i ;, tasi C, et al. ;astrointestinal manifestations in myotonic muscular dystrophy. World J ;astro %(F %+(%/%+(+,(**-.1*. )ettini ;, Muracchini M, Della alda <, et al. @ypertrophy of intestinal smooth muscle in cats. Res Vet ci 0'F 1&/'&, (**&.1%. tander =, Wa!ner WM, ;oddard A, et al. Veterinary Radiolo!y #ltrasound '%" (*%*, -7T01, (*%*.1(. ummers RW, ;lenn C4, >latt AJ et al. Does irradiation produce irre$ersible chan!es in canine GeGunal myoelectric acti$ity\ Di!Dis ci (0" 0%-/0((, %77(.1&* Htterson M>. 4ffects of radiation upon !astrointestinal motility. World J ;astroenterol %&F (-+1/(-7(, (**0.11. @ar$ey AM, @all 4J, Day MJ, et al. Chronic intestinal pseudo/obstruction in a cat caused by $isceral myopathy. J Vet Intern Med

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%7F %%%/%%1, (**'.1'. Couraud <, Jermyn E, am P, et al. Intestinal pseudo/obstruction, lymphocyticleiomyositis and atrophy of the muscularis e9ternain a do!. Vet Rec %'7F +-/+0, (**-.

1-. Johnson C, >ales/Williams AJ, Reimer ), et al. >ibrosin! !astrointestinal leiomyositis as a cause of chronic intestinal pseudo/obstruction in an +/month old do!. Vet Pathol 11F %*-/%*7, (**0.10. 4ast2ood JM, McInnes 4>, White R=, et al. Caecal impaction and chronic intestinal pseudo/obstruction in a do!. J Vet Med '(F1&/11, (**'.1+. <amb WA, >rance MP. Chronic intestinal pseudo/obstruction in a do!. Aus Vet J 0%" +1/+-, %771.17. D$ir 4, <eise2it5 A<, Van Der <u!t JJ. Chronic idiopathic intestinal pseudo/obstruction in an 4n!lish bulldo!. JAP 1(F (1&/('(,(**%.'*. Daher R, a5bec: 8, Jaoude J), et al. Conse6uences of dysthyroidism on the di!esti$e tract and $iscera. World J ;astroenterol (%F(+&1/(+&+, (**7.

Ta,le (91+* Pathophysiologi "ehanis"s of post1operati-e ile.s

Mechanisms >actors In$ol$edAutonomic ner$ous system ympathetic inhibitory path2ays4nteric ner$ous system ubstance P, nitric o9ide@ormones and neuropeptides Vasoacti$e intestinal peptide" corticotrophin/releasin!

factor li!ands" calcitonin !ene/related peptide li!andsInflammation Macropha!e and neutrophil infiltration" cyto:ines and other

inflammatory mediatorsAnesthesia ;eneral anesthetics =arcotics Hpiates

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'o! (91+* Ca.ses of intestinal dys"otility in dogs and ats

Dysa.tono"ia

Post1operati-e ile.sOpioid1ind.ed ,o2el dysf.ntionM.s.lar dystrophy$iseral "yopathy$iral enteritis%adiation enteritisIdiopathi pse.do1o,str.tionHypothyroidis"

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Gastrointestinal Pro7ineti Agents

I#T%ODUCTIO#

;astrointestinal motility disorders represent a dia!nostic and therapeutic challen!e. Disorders of !astrointestinal motility may result indelayed transit, accelerated transit, impaired rela9ation, or inappropriate rela9ation. 8he delayed transit disorders are the mostimportant motility disorders of companion animals and may in$ol$e the esopha!us hypomotility and me!aesopha!us, stomachdelayed !astric emptyin!, small intestine post/operati$e ileus and intestinal pseudo/obstruction, or colon constipation andme!acolon.

DOPAMI#E%GIC D: A#TAGO#IST D%UGS ;Ta,le (:*+<Metolopra"ide and Do"peridone / 8he dopaminer!ic D( anta!onists are a !roup of dru!s 2ith !astrointestinal pro:inetic andantiemetic effects at peripheral pro:inetic or central antiemetic dopamine D( receptors.% 8he best representati$es in thisclassification, metoclopramide and domperidone, re$erse !astric rela9ation induced by dopamine infusion in do!s, and they abolish

$omitin! associated 2ith apomorphine therapy. Althou!h the role of dopamine receptors in chemoreceptor tri!!er 5one/induced$omitin! is fairly 2ell established, there is no definiti$e e$idence that inhibitory dopaminer!ic neurons re!ulate !astrointestinal motility.8he pro:inetic effects of metoclopramide and domperidone thus may not be readily or e9clusi$ely e9plained by dopamine receptoranta!onism. ome dopaminer!ic anta!onists e.!., metoclopramide ha$e other pharmacolo!ic properties, e.!., '/@8& receptor

anta!onism and '/@81 receptor a!onism. Domperidone also has α(/ and β(/adrener!ic receptor anta!onistic effects. 8he

characteri5ation of these dru!s as dopaminer!ic anta!onists is con$enient but may not properly describe their o$erall in $i$o effects.

Gastroesophageal Sphincter Disorders8he !astroesopha!eal sphincter pre$ents reflu9 of !astrointestinal contents into the esopha!eal body.(,& Reflu9 of !astric @] and pepsins, and of duodenal bicarbonate, bile salts, and proteases, induces chemical inGury and inflammation of the esopha!eal mucosa.&

;astroesopha!eal sphincter tone appears to be under the re!ulation of dopaminer!ic neurons as both metoclopramide and domperidoneincrease sphincter tone. 8he !astric pro:inetic effect of metoclopramide, althou!h moderate, may also help to reduce the fre6uency,se$erity, and duration of reflu9 episodes.

Gastric Emptying DisordersMetoclopramide increases the amplitude and fre6uency of antral contractions" inhibits fundic recepti$e rela9ation" and coordinates!astric, pyloric, and duodenal motility, all of 2hich result in moderate acceleration of !astric emptyin!. 1,' Metoclopramide appears toha$e continuin! clinical application as a !astric pro:inetic a!ent in the do! and cat, althou!h the serotoner!ic a!onists are clearly more potent. Domperidone appears to be less effecti$e as a !astric pro:inetic a!ent. Althou!h effecti$e in humans, domperidone actually

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decreases the fre6uency of corporeal, pyloric, and duodenal contractions and deteriorates antropyloroduodenal coordination in the do! by decreasin! the fre6uency of contractions spreadin! from the antrum or pylorus to the duodenum.'

Small Intestinal Transit DisordersMetoclopramide and domperidone are !enerally considered less effecti$e in the mana!ement of the small intestinal transit disorders.Metoclopramide enhances antropyloroduodenal coordination in the do! and may be effecti$e 2hen delayed !astric emptyin! is due to poor antropyloroduodenal coordination.- Domperidone has no documented effects on small intestinal transit.

Chemoreceptor trigger zone-induced emesis8he antiemetic effects of metoclopramide and domperidone are attributed to their central effects at the chemoreceptor tri!!er 5one.0 8he anti/emetic effect of metoclopramide is more important than its pro:inetic effect.%,0 Despite lon!standin! usa!e by small animal$eterinarians, metoclopramide is not a $ery potent !astrointestinal pro:inetic a!ent. Domperidone is %( to (' times more potent thanmetoclopramide and '* to -* times more potent than prochlorpera5ine in attenuatin! apomorphine/induced $omitin!.

SE%OTO#E%GIC (1HT4 AGO#IST D%UGS ;Ta,le (:*+<Dru!s actin! on !astrointestinal '/hydro9ytryptamine '/@8 or serotonin receptors ha$e potent motility effects.+ erotoner!ic dru!sthat bind '/@81 receptors on enteric choliner!ic neurons induce depolari5ation and contraction of !astrointestinal smooth muscle.8hese dru!s are not entirely selecti$e for the '/@81 receptor, ho2e$er. ome of the putati$e '/@81 receptor a!onists also ha$e '/@8% and '/@8& anta!onistic effects on enteric choliner!ic neurons, and direct non/choliner!ic perhaps '/@8(a effects on colonic smoothmuscle. Cisapride, mosapride, prucalopride, and te!aserod are the best e9amples in this classification. Cisapride and te!aserod ha$e been 2ithdra2n from se$eral international mar:ets because of their effects on myocardial /8 internal prolon!ation, althou!h bothremain a$ailable throu!h compoundin! pharmacies. Mosapride is a$ailable in Japan Pronamid / D Pharma, and prucalopride isa$ailable in 4urope Resolor / Mo$etis.

Cisapride / Cisapride 2as 2idely used in the mana!ement of canine and feline !astric emptyin!, intestinal transit, and colonic motilitydisorders throu!hout most of the %77*Ls.7,%* Cisapride 2as 2ithdra2n from the American, Canadian and certain Western 4uropean inJuly of (*** follo2in! reports of unto2ard cardiac side effects in human patients. Cisapride causes 8 inter$al prolon!ation andslo2in! of cardiac repolari5ation $ia bloc:ade of the rapid component of the delayed rectifier potassium channel IEr .%% 8his effect mayresult in a fatal $entricular arrhythmia referred to as torsades de pointes.%% imilar effects ha$e been characteri5ed in canine cardiacPur:inGe fibers, but in $i$o effects ha$e not been reported in do!s or cats. 8he 2ithdra2al of cisapride has created a clear need for ne2;.I. pro:inetic a!ents althou!h cisapride continues to be a$ailable from compoundin! pharmacies.

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Gastroesophageal Sphincter DisordersCisapride is indicated for the treatment of !astroesopha!eal reflu9 because it stimulates !astric emptyin! and increases

!astroesopha!eal sphincter pressure. Comparati$e studies ha$e sho2n that cisapride is more potent than metoclopramide in stimulatin!!astric emptyin! and increasin! !astroesopha!eal sphincter pressure. Cisapride can be used in conGunction 2ith chemical diffusion barriers e.!., sucralfate and !astric acid secretory inhibitors e,!., @( receptor anta!onists" @],E ] A8Pase inhibitors in the treatment of !astroesopha!eal reflu9.%(/%1 Cisapride stimulates distal esopha!eal peristalsis in those animal species e.!., cat, human bein!, !uinea pi! in 2hich the distal esopha!eal muscularis is composed of smooth muscle. 8he ob$ious e9ception is the do!, a species in 2hich theentire esopha!eal body is composed of striated muscle. It has been su!!ested that cisapride mi!ht impro$e esopha!eal peristalsis indo!s affected 2ith idiopathic me!aesopha!us. 8his 2ould not appear to be a rational clinical application of the dru!, because a smoothmuscle pro:inetic a!ent 2ould not be e9pected to ha$e much effect on striated muscle function. Indeed, the pro:inetic effect ofcisapride in the esopha!us of human bein!s or cats is confined to the distal esopha!eal body at the transition 5one from striated muscleto smooth muscle. Cisapride has no effect on pro9imal esopha!eal peristalsis in these species. >urther, '/@8 stimulates contraction of

canine !astroesopha!eal sphincter smooth muscle, but is 2ithout effect on canine esopha!eal body striated muscle.%'

8hus, cisapridecannot be recommended for the treatment of idiopathic me!aesopha!us in do!s. Indeed, cisapride/induced increases in!astroesopha!eal sphincter pressure could diminish esopha!eal clearance and 2orsen clinical si!ns in do!s affected 2ith idiopathicme!aesopha!us.

Gastric Emptying DisordersCisapride accelerates !astric emptyin! in do!s by stimulatin! pyloric and duodenal motor acti$ity, by enhancin! antropyloroduodenalcoordination, and by increasin! the mean propa!ation distance of duodenal contractions.',%- Cisapride appears to be superior tometoclopramide and domperidone in stimulatin! !astric emptyin!. Dosa!es of cisapride in the ran!e of *.*'/*.( m!:! enhance !astricemptyin! in do!s 2ith normal !astric emptyin!. Dosa!es in the ran!e of *.'/%.* m!:! are needed to enhance !astric emptyin! in do!s2ith delayed !astric emptyin! induced by ^(/adrener!ic a!onists, dopamine, disopyramide, or antral tachy!astria.7,%*

Small Bowel Motility DisordersCisapride stimulates GeGunal spi:e burst mi!ration, GeGunal propulsi$e motility, and antropyloroduodenal coordination follo2in! intestinallipid infusion in the do!.-,%0 8hus, cisapride 2ould appear to ha$e a rational place in the treatment of post/operati$e ileus and intestinal pseudo/obstruction. Well/desi!ned clinical trials and e$idence/based data 2ill be re6uired to determine the effecti$eness of cisapride inthe treatment of these disorders.

Colonic Motility Disorders

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Cisapride stimulates colonic motility,%+,%7 and 2ould appear to ha$e a rational place in the treatment of idiopathic constipation.Disruption of the normal colonic motility patterns results in constipation in domestic cats. Cisapride impro$es colonic motility in catsthat are mildly or moderately affected 2ith idiopathic constipation" cats 2ith lon!/standin! hypomotility and dilation are usually less

responsi$e. A recent e$idence/based data re$ie2 of cisaprideLs efficacy in the treatment of human constipation and constipation/ predominant irritable bo2el syndrome I) 2as carried out by the Cochrane Collaboration.(* 8he authors concluded that no clear benefit could be demonstrated 2ith cisaprideS.(*

Cis-platinum-Induced EmesisCisplatinum/induced emesis is mediated by '/@8& serotoner!ic receptors, either in the chemoreceptor tri!!er 5one cat or in $a!alafferent neurons do!. electi$e anta!onists of the '/@8& receptor e.!., ondansetron, !ranisetron, tropisetron, dolasetron abolish$omitin! associated 2ith cis/platinum chemotherapy. Cisapride anta!oni5es these '/@8& receptors and inhibits $omitin! associated 2ithcis/platinum chemotherapy. 8he potency of cisaprideKs '/@8& anti/emetic effect 4D'* _ *.- m!:! IV" 4D%** _ (.- m!:! IV is lessthan its '/@81 !astric pro:inetic effect. 8hus, cisapride could be recommended as an antiemetic a!ent for the cancer chemotherapy

patient only if ondansetron, !ranisetron, tropisetron, or dolasetron 2ere not immediately a$ailable or 2ere too cost/prohibiti$e.0

Metoclopramide is e6uipotent 2ith cisapride in inhibitin! cisplatinum emesis, but it has the distinct disad$anta!e of ad$erse centralner$ous system side effects, e.!. dro2siness, e9treme 2ea:ness, and body tremors. Cisapride has no effect on nausea and $omitin!mediated by dopaminer!ic D( receptors e.!. apomorphine, uremia or histaminer!ic @% receptors e.!. motion sic:ness.

Mosapride / Mosapride citrate, a substituted ben5amide, is a no$el '/@81 receptor a!onist that increases !astric emptyin! in rats anddo!s, and increases electrically/e$o:ed contractions in the isolated !uinea pi! ileum.(%/(( Mosapride stimulates acetylcholine releasefrom the myenteric ple9us $ia acti$ation of '/@81 receptors, but has no real affinity for D ( dopamine, '/@8%, '/@8( receptors, or ^%/adrenoceptors. Mosapride restores !astric motility in do!s 2ith $incristine/induced !astric hypomotility,(& and therefore may beclinically useful in other !astric emptyin! disorders. Mosapride is apparently 2ithout effect on distal !astrointestinal tract motility.Mosapride is mar:eted as Pronamid by D Pharma Animal @ealth in Japan.

Pr.alopride / Prucalopride is a potent partial ben5amide a!onist at '/@81 receptors, but is 2ithout effect on other '/@8 receptors orcholinesterase en5yme acti$ity. Prucalopride dose/dependently *.*(/%.(' m!:! stimulates !iant mi!ratin! contractions ;MCLs anddefecation in the do!.(1/(- 8he prucalopride effect is obser$ed most prominently in the first hour after administration, su!!estin! that the prucalopride effect is a direct effect on the colon rather than on total !ut transit time. Hral and intra$enous doses appear to bee6uipotent a!ain implyin! a hi!h oral bioa$ailability. Prucalopride also enhances defecation fre6uency in healthy cats.(0 Cats treated2ith prucalopride at a dose of *.-1 m!:! e9perience increased defecation 2ithin the first hour of administration. >ecal consistency isnot altered by prucalopride at this dosa!e.

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Prucalopride also appears to stimulate !astric emptyin! in the do!.(+ In lidamidine/induced delayed !astric emptyin! in do!s, prucalopride *.*%/*.%- m!:! dose/dependently accelerates !astric emptyin! of de9trose solutions. 8he prucalopride effect ise6uipotent follo2in! oral and intra$enous administration su!!estin! that prucalopride may ha$e a hi!h oral bioa$ailability. Prucalopride

is mar:eted as Resolor by Mo$etis in 4urope.

Tegaserod / 8e!aserod is a potent partial non/ben5amide a!onist at '/@81 receptors and a 2ea: a!onist at '/@8 %D receptors.(7,&* 8e!aserod has pro:inetic effects in the distal !astrointestinal tract. Intra$enous doses of te!aserod *.*&/*.& m!:! accelerate colonictransit in do!s durin! the first hour after intra$enous administration.(7 8he hi!hest doses of te!aserod *.% and *.& m!:! ha$e no!reater efficacy than lo2er doses *.*& m!:!, su!!estin! the possibility that te!aserod may stimulate canine colonic motility throu!h areceptor/independent mechanism, or that te!aserod may act at sites other than '/@81 receptors at hi!her doses.8he motor mechanisms responsible for te!aserod/induced canine colonic propulsion are unclear. @i!h amplitude propa!ated phasiccontractions are thou!ht to be responsible for mass mo$ements, but they 2ere not obser$ed durin! te!aserod infusion. Contraction,amplitude, and motility indices 2ere not different postprandially amon! treatment !roups, so the mechanism of the te!aserod effect 2ill

re6uire more detailed in$esti!ation in the do!.;astric effects of te!aserod ha$e not been reported in the do!, so this dru! may not pro$e as useful as cisapride in the treatment ofdelayed !astric emptyin! disorders. 8e!aserod at doses of &/- m!:! PH has been sho2n to normali5e intestinal transit in opioid/induced bo2el dysfunction in do!s,&% and it may be useful in other disorders of intestinal ileus or pseudo/obstruction.8e!aserod 2as appro$ed by the #.. >ood and Dru! Administration in eptember (**(, but later remo$ed from the American mar:et in(**0 because of reports of prolon!ation of the /8 inter$al and delayed cardiac repolari5ation. 8e!aserod is mar:eted as Uelnorm by =o$artis in 4urope.`

uture !esearch in "-#T !eceptor Pharmacology8he '/@81 receptor appears to hold the most interest and promise for future dru! de$elopment. '/@81 receptor acti$ation can causerela9ation or contraction dependin! on the re!ion, cell type, and animal species. In the do!, the effects of selecti$e '/@81 receptora!onists su!!est that these receptors are present on GeGunal mucosa, ileal mucosa, !astric choliner!ic neurons, and circular colonicsmooth muscle cells. De$elopment of '/@81 li!ands is some2hat constrained by the effects these dru!s ha$e on cardiac '/@81 receptors and the delayed rectifier potassium channel IEr . ome, but not all, '/@81 a!onists prolon! the 8 inter$al and delay cardiacrepolari5ation. Molecular biolo!y e9periments ha$e re$ealed differences in the carbo9yl terminus of smooth muscle and cardiac muscle'/@81 receptors, but these amino acids differences are distant from the receptor bindin! site. 8hus, receptor sub/types may e9ist butthey may not be important from a functional or therapeutic standpoint.

MOTILI#1LI6E D%UGS ;Ta,le (:*+<

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Erythro"yin / 8he antibiotic properties of erythromycin and other macrolides 2ere disco$ered in the early %7'*Ls. ince that time,erythromycin has been 2idely used in treatin! patients 2ith !ram/positi$e and !ram/ne!ati$e bacterial and mycoplasmal infections.

Physicians and $eterinarians noted that erythromycin therapy 2as accompanied by fre6uent !astrointestinal side effects includin! nauseaand $omitin!. 8his occurrence su!!ested to researchers that erythromycin mi!ht ha$e effects on !astrointestinal motility. It 2assubse6uently demonstrated that microbially/effecti$e doses of erythromycin stimulate retro!rade peristalsis and $omitin! in do!s, andthat lo2er microbially/ineffecti$e doses of erythromycin stimulate mi!ratin! motility comple9es and ante!rade peristalsis similar to thatinduced by the endo!enous !astrointestinal hormone, motilin.&(,&&,&1

Gastroesophageal Sphincter DisordersMotilin, erythromycin, and erythromycin analo!ues e.!., </(-0%*+ increase !astroesopha!eal sphincter pressure in cats and do!s. &' 4rythromycin also increases !astroesopha!eal sphincter pressure in cats in 2hich the basal pressure has been lo2ered e9perimentally byesopha!eal acid perfusion or follo2in! intra$enous isoproterenol administration.&' 8hese studies su!!est that erythromycin should beuseful in treatin! cats, and perhaps do!s, 2th !astroesopha!eal reflu9 and reflu9 esopha!itis.

Gastric Emptying Disorders4rythromycin accelerates !astric emptyin! by inducin! antral contractions similar to phase III of the interdi!esti$e state. &-/&7 8he stron!contractions associated 2ith phase III normally occur only durin! the fasted state 2hen they clear the stomach of lar!e indi!estiblesolids. After meals, intra$enous or oral erythromycin accelerates !astric emptyin! of solid meals in do!s. 4M'01 is ('* times more potent than erythromycin in inducin! phase III contractions in do!s and it has no anti/bacterial acti$ity.&0,&+ 4M'01 is as effecti$e ascisapride in normali5in! !astric contractility and emptyin! in do!s 2ith clonidine/induced !astroparesis in do!s. &0,&+

Colonic Motility Disorders4rythromycin accelerates re!ional colonic transit in the do!.1* 4rythromycin has been sho2n to stimulate canine but not feline colonicsmooth muscle contraction in $itro.1% 8hese results su!!est that erythyromycin may be useful in the treatment of canine colonic motility

disorders.

ACETYLCHOLI#ESTE%ASE I#HI'ITO%S A#D CHOLI#OMIMETIC AGE#TS ;Ta,le (:*+<

%anitidine and #i=atidine / Ranitidine and ni5atidine, classic histamine @( receptor anta!onists, stimulate !astrointestinal motility byinhibitin! acetylcholinesterase acti$ity.1(/11 As parasympathetic potentiatin! a!ents, ranitidine and ni5atidine stimulate !astric emptyin!and small intestinal and colonic motility. 8he pro:inetic effects of ranitidine and ni5atidine appear to be more prominent in the pro9imal!astrointestinal tract i.e., !astric emptyin!. Hther members of this classification, e.!., cimetidine and famotidine, apparently ha$e no

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effect on !astrointestinal motility.

'ethanehol / )ethanechol is a cholinomimetic a!ent that binds muscarinic choliner!ic receptors and stimulates motility throu!hout the

!astrointestinal tract.

Esophageal Motility Disordersmooth muscle pro:inetic a!ents, e.!., cisapride and metoclopramide, ha$e limited clinical application in the treatment of canineidiopathic me!aesopha!us. Cisapride and metoclopramide stimulate distal esopha!eal peristalsis in those animal species e.!., cat,human bein!, !uinea pi! in 2hich the distal esopha!eal muscularis is composed of smooth muscle. 8he domestic do! has e$ol$ed 2itha purely striated muscle esopha!eal muscularis 2hich has a different re!ulation and therapeutic responsi$eness.%& )ethanechol has beensho2n to stimulate esopha!eal propa!atin! contractions in some do!s affected 2ith idiopathic me!aesopha!us and is therefore a moreappropriate pro:inetic a!ent for the therapy of this disorder.1'

Gastric Emptying DisordersRanitidine and ni5atidine stimulate !astric antral contractions at !astric anti/secretory dosa!es ranitidine %.*/(.* m!:! PH )ID"ni5atidine (.'/'.* m!:! PH )ID and may be useful as !astric pro:inetic a!ents in do!s and cats. 1&,11,1-

Colonic Motility DisordersInfusions of ranitidine at doses of &.* m!:! induce canine colonic propa!atin! contractions in $i$o.1- Ranitidine and ni5atidine ha$ealso been sho2n to stimulate feline colonic smooth muscle contraction in $itro.10 8hese data su!!est that ranitidine and ni5atidine may be useful in the treatment of feline or canine colonic motility disorders.1(

#IT%IC O>IDE DO#O%S ;Ta,le (:*+3 &ig.re (:*(<Delayed !astric emptyin! is reco!ni5ed as an important cause of upper !astrointestinal tract patholo!y e.!., anore9ia and $omitin! incompanion animals.%1 Delayed !astric emptyin! has been reported in infectious and inflammatory !astric diseases, diabetes mellitus,and radiation inGury in the do!.1+,17 Delayed !astric emptyin! has also been associated 2ith se$eral secondary conditions, includin!electrolyte disturbances e.!., hypo:alemia, hypocalcemia, metabolic disorders e.!., hypoadrenocorticism, hyper!astrinemia, uremia,

concurrent dru! usa!e e.!., choliner!ic anta!onists, β/adrener!ic a!onists, opiates, acute stress e.!., sympathetic stimulation, spinal

cord inGury, and acute abdominal inflammation.1+,17

Diabetes mellitus is the most common endocrinopathy of the domestic do!.'* <on!/standin! un/dia!nosed or un/treated diabetesmellitus is associated 2ith si!nificant !astroparesis in the do!,'%,'( Gust as it in humans. 8he patho!enesis of !astroparesis in diabetes

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mellitus is comple9 and probably multi/factorial, in$ol$in! one or more of the cellular elements neurons, smooth muscle cells,interstitial cells of CaGal re!ulatin! !astric motility.'& An important pathophysiolo!ic mechanism appears to be the loss of neuronalnitric o9ide synthase, the en5yme responsible for the production of nitric o9ide, an inhibitory neurotransmitter that is re6uired for

rela9ation of smooth muscle and therefore a critical component of normal !astrointestinal motility. In the absence of nitric o9ide, thestomach cannot rela9, resultin! in bloatin!, satiety, nausea, and $omitin!.'1

Cisapride, metoclopramide, and erythromycin ha$e all been used 2ith $ariable effect in diabetic !astroparesis. 8herapy aimed instead atrestorin! nitrer!ic neurotransmission could ha$e intrinsic beneficial effects in canine diabetic !astroparesis. AM#/&*%, a nitric o9ide=H donor, is reco!ni5ed as an effecti$e treatment for diabetic !astroparesis in strepto5otocin/induced 8U diabetic rat models ofdelayed !astric emptyin!,'' and may e$entually pro$e useful in spontaneous canine diabetes mellitus.

P%OSTAGLA#DI# E+ A#ALOGUESMisoprostol is a prosta!landin 4% analo!ue that reduces the incidence of nonsteroidal anti/inflammatory dru!/induced !astric inGury.

8he main side effects of misoprostol therapy are abdominal discomfort, crampin!, and diarrhea. Do! studies su!!est that prosta!landins may initiate a !iant mi!ratin! comple9 pattern and increase colonic propulsi$e acti$ity.'- In $itro studies of misoprostolsho2 that it stimulates feline and canine colonic smooth muscle contraction. '0 ;i$en its limited to9icity, misoprostol may be useful indo!s and cats 2ith se$ere refractory constipation.

%eferenes8%. @all JA, Washabau RJ. ;astrointestinal pro:inetic therapyF dopaminer!ic anta!onist dru!s. Compend Contin 4duc Pract Vet %7(F(%1/((%, %770.(. )iancani P, )ar2ic: E, ellin! J, et alF 4ffects of acute e9perimental esopha!itis in mechanical properties of lo2er esopha!ealsphincter function. ;astroenterolo!y +0F+/%-, %7+1.&. 4ast2ood ;, Castell DH, @i!!s R@F 49perimental esopha!itis in cats impairs lo2er esopha!eal sphincter function in the cat.

;astroenterolo!y -7F%1-/%'&, %70'.1. @all JA, olie 8=, eim @), et al. 4ffect of metoclopramide on fed/state !astric myoelectric and motor acti$ity in do!s. Am J VetRes '0F %-%-/%-((, %77-.'. Hrihata M, arna E. Contractile mechanisms of action of !astropro:inetic a!entsF cisapride, metoclopramide, and domperidone.Amer J Physiol (--F ;--'/;-0-, %771.-. ummers RW, anda R, Prihoda M, et al.F A comparati$e study of the effects of four motor/stimulatin! a!ents on canine GeGunalspi:e bursts. cand J ;astroenterol (&F %%0&/%%+%, %7++.0. Washabau RJ and 4lie M. Anti/4metic 8herapies. In, Eir: R and )ona!ura J, eds. Current Veterinary 8herapy YII. %(th ed.

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PhiladelphiaF W) aunders Co., %77', -07/-+1.+. Janssen P, Prins =@, Meulemans A<, et al. Pharmacolo!ical characteri5ation of the '/@8 receptors mediatin! contraction andrela9ation of canine isolated pro9imal stomach smooth muscle. )rit J Pharm %&-F &(%/&(7, (**(.

7. Washabau RJ, @all JA. Clinical pharmacolo!y of cisapride. JAVMA (*0F %(+'/%(++, %77'.%*. Washabau RJ, @all JA. ;astrointestinal pro:inetic therapyF serotoner!ic dru!s. Compend Contin 4duc Pract Vet %71F 10&/1+*,%770.%%. Drici MD, 4bert =, Wan! WY, et al. Comparison of te!aserod and its main metabolite 2ith cisapride and erythromycin on cardiacrepolari5ation in the isolated rabbit heart. J Cardio$asc Pharmacol &1F +(/++, %777.%(. Clar: et al.F Comparison of potential cytoprotecti$e action of sucralfate and cimetidine / studies 2ith e9perimental felineesopha!itis. Amer J Med +&F '-, %7+0.%&. Washabau RJ. Diseases of the esopha!us. In, 4ttin!er J and >eldman 4C, eds. 8e9tboo: of Veterinary Internal Medicine. 'th ed.PhiladelphiaF W) aunders Co., (***, pp. %%1(/%%'&.%1. Washabau RJ, @olt D4. Pathophysiolo!y of ;astrointestinal Disease. In, latter D, ed. 8e9tboo: of Veterinary ur!ery. &rd

edition. PhiladelphiaF W) aunders Co., (**&, pp '&*/''(.%'. Cohen M<, usemichel AD, )loom6uist W, et al.F '/@8 1 receptors in rat but not rabbit, !uinea pi!, or do! esopha!eal muscle. ;enPharmacol ('F %%1&/%%1+, %771.%-. 4delbroe: M, chuur:es JAJ, de Ridder WJ4, et al.F 4ffect of cisapride on myoelectrical and motor responses ofantropyloroduodenal lipid and antral tachy!astria in conscious do!s. Di! Dis ci 1*F 7*%/7%%, %77'.%0. chemann M, 4hrlein @JF '/hydro9ytryptophan and cisapride stimulate propulsi$e GeGunal motility and transit of chyme in do!s.Di!estion &1F ((7/(&', %7+-.%+. @asler A@, Washabau RJ. Cisapride stimulates contraction in feline idiopathic me!acolonic smooth muscle. J Vet Intern Med%%-F &%&/&%+, %770.%7. Washabau RJ and ammarco J. 4ffect of cisapride on colonic smooth muscle function. Am J Vet Res '0F '1%/'1-, %77-.(*. Aboumar5ou: HM, A!ar2al 8, Anta:ia R, et al. Cisapride for intestinal constipation re$ie2. 8he Cochrane Collaboration, (*%%"httpF222.thecochranelibrary.com(%. Curran MP, Robinsoni DM. Mosapride / #se in !astrointestinal disorders. Dru!s -+0F7+%/77%, (**+.((. Mine 8, oshi:a2a , H:u , et al. Comparison of effect of mosapride citrate and e9istin! '/@81 receptor a!onists on!astrointestinal motility, in $i$o and in $itro. J. Pharm. 49p. 8her. (+&F %***/%**+, %770.(&. 8su:amoto A, Hhno E, 8su:a!oshi 8, et al. #ltrasono!raphic e$aluation of $incristine/induced !astric hypomotility and the pro:inetic effect of mosapride citrate in do!s. J. Vet. Intern. Med. (1&F 0(%, (*%*.(1. )rieGer MR, Van Daele P, )osmans J/P, et al. Dose/dependent effects after oral and intra$enous administration of R*7&+00 oncolonic motility in conscious do!s. ;astroenterolo!y %%(F A0*1, %770a.

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('. )rieGer MR, ;hoos 4, 4elen J, et al. erotonin '/@81 receptors mediate the R*7&+00/induced chan!es in contractile patterns inthe canine colon. ;astroenterolo!y %%(F A0*', %770d.(-. Prins =@, Van @aselen J>, <efeb$re RA, et al. Pharmacolo!ical characteri5ation of '/@8 receptors mediatin! rela9ation of canine

isolated rectum circular smooth muscle. )rit J Pharmacol %(0-F %1&%/%1&0, %777.(0. )rieGer MR, 4n!elen M, Jacobs J, et al. R*7&+00 enhances defecation fre6uency in conscious cats. ;astroenterolo!y %%(F A0*',%770c.(+. )rieGer MR, Meulemans A<, Wellens A, et al. R*7&+0 dose dependently accelerates delayed !astric emptyin! in conscious do!s.;astroenterolo!y %%(F A0*', %770b.(7. =!uyen A, Camilleri M, Eost <J. DU @8> 7%7 te!aserod stimulates canine colonic motility and transit in $i$o. J Pharmacol49per 8herap (+*F %(0*/%(0-, %770.&*. chi:o2s:i A, 8he2issen M, Mathis C, et al. erotonin type/1 receptors modulate the sensiti$ity of intramural mechanorecepti$eafferents of the cat rectum. =euro!astroenterol Mot %1F ((%/((0, (**(.&%. Weber 4, )raun 4, >or!iarini P, et al. 8e!aserod normali5es opioid/induced bo2el dysfunction in do!s. ;astroenterolo!y %(1"

A'0%, (**&.&(. @all JA, Washabau RJ. ;astrointestinal pro:inetic therapyF motilin/li:e dru!s. Comp Contin 4duc Pract Vet %7&F (+%/(++, %770.&&. Itoh U, u5u:i 8, =a:aya M, et alF ;astrointestinal motor/stimulation! acti$ity of macrolide antibiotics and analysis of their sideeffects on the canine !ut. Antimicrob A!ents Chemother (--F +-&/+-7, %7+1&1. arna , ;on5ale5 A, Ryan R. 4nteric locus of action of pro:ineticsF A)8/((7, motilin, and erythromycin. Amer J Physiol (0+F;011/;0'(, (***.&'. ;reen2ood ), Eiec:man D, Eirst @A, et alF 4ffects of <(-0%*+, an erythromycin analo!ue deri$ati$e, on lo2er esopha!ealsphincter function in the cat. ;astroenterolo!y %*-F-(1/-(+, %771.&-. a:o >, Marui , Inatomi =, et al. 4M'01, an erythromycin deri$ati$e, impro$es delayed !astric emptyin! of semi/solid meals inconscious do!s. 4ur J Pharm &7'F %-', (***.&0. 8ana:a 8, Mi5umoto A, Mochi:i 4, et al.F 4ffects of 4M'01 and cisapride on !astric contractile and emptyin! acti$ity in normaland dru!/induced !astroparesis in do!s. J Pharmacol 49p 8herap (+0F 0%(/0%7, %77+.&+. 8ana:a 8, Mi5umoto A, Mochi:i 4, et al. 4ffect of 4M'01 on postprandial pancreaticobiliary secretion, !astric motor acti$ity, andemptyin! in conscious do!s. Di! Dis ci 11F %%**/%%*-, %777.&7. 8su:amoto E, 8a!i , =a:a5a2a 8, et al. ;astropro:inetic effect and mechanism of E/+7-, a ne2 motilin analo!ue, durin! theinterdi!esti$e period in conscious do!s. Pharmacolo!y -&F 7'/%*(, (**%.1*. Chiba 8, 8homforde ;M, Eost <J, et al. Motilides accelerate re!ional !astrointestinal transit in the do!. Aliment Pharmacol 8her%1F 7''/7-*, (***.1%. Mel!areGo <8, imon DA, Washabau RJ. 4rythromycin stimlulates canine, but not feline, lon!itudinal colonic muscle contraction. J

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Vet Intern Med %'F &&&, (**%.1(. @all JA, Washabau RJ. ;astrointestinal pro:inetic therapyF acetylcholinesterase inhibitors. Compend. Contin. 4duc. Pract. Vet.%7'F -%'/-(%, %770.

1&. )ertaccini ;, Poli 4, Adami M, et alF 4ffect of some ne2 @s/receptor anta!onists on !astrointestinal motility. A!ents Actions %&F%'0/%-(, %7+'.11. Mi5umoto A, >u:imura M, I2ana!a , et al. Anticholinesterase acti$ity of histamine @( receptor anta!onists in the do!F their possible role in !astric motor acti$ity. J ;astrointestinal Motil (F (0&/(+*, %77*.1'. Diamant =, 5cepans:i M, Mui @F Idiopathic me!aesopha!us in the do!F Reasons for spontaneous impro$ement and a possiblemethod of medical therapy. Can Vet J %'F --/0%, %701.1-. Eishibayashi =, 8omaru A, Ichi:a2a , et alF 4nhancement by EW/'*7(, a no$el !astropro:inetic a!ent, of the !astrointestinalmotor acti$ity in do!s. Japn J Pharmacol -'F %&%/%1(, %771.10. Washabau RJ, Pitts MM, @asler A. =i5atidine and ranitidine, but not cimetidine, stimulate feline colonic smooth musclecontraction. J Vet Intern Med %*F %'0, %77-.

1+. @all J4, Washabau RJ. Dia!nosis and 8reatment of ;astric Motility Disorders. In, %eterinary Clinics o& 'orth (merica, %777" $ol.(7F &00/&7'.17. Washabau RJ. ;astrointestinal Motility Disorders and ;.I. Pro:inetic 8herapy. In, Veterinary Clinics of =orth America, WillardMD, ed. PhiladelphiaF W) aunders Co., (**&, %**0/%*(+.'*. =elson RW. Diabetes mellitus. In, 8e9tboo: of Veterinary Internal Medicine, 4ttin!er J and >eldman 4C, eds. -th edition. W)aunders, Philadelphia, (**', %'-&/%'7%.'%. 8a:eda M, Mi5utani , 8su:amoto E, et al. ;astric emptyin! in diabetic !astroparetic do!sF effects of DE/7'%, a no$el pro:inetica!ent. Pharmacolo!y (**%" -(F (&/(+.'(. Eoi5umi >, Ea2amura 8, Ishimori A. Correlation bet2een !astric emptyin! time and both plasma !astrin and pancreatic polypeptide in strepto5otocin diabetic do!s. Japanese Journal of ;astroenterolo!y %7+7" +-F %*&0/%*1&.'&. Camilleri M. Diabetic !astroparesis. =e2 4n!land Journal of Medicine (**0" &'-F +(*/+(7.

'1. Pasricha PJ. 8he riddle, mystery, and eni!ma of !astroparesis. Journal of upporti$e Hncolo!y (**0" 'F &-+/&0*.''. Amulet Pharmaceuticals AM#/&*% >act heet. =e2 Chemical 4ntity =C4 for Diabetic ;astroparesis.httpF222.amuletpharma.comAM#/&*%>[email protected] '-. >ioramonti J, taumont ;, )arcia/Villar 8, et al. 4ffect of sennosides on colonic motility in do!s. Pharmacolo!y &-" (&/&*, %7++.'0. Mosenco A, Melt5er E, Washabau RJ. Prostanoids stimulate duodenal and colonic smooth muscle contraction. J Vet Intern Med%0F 110, (**&.

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Ta,le (:1+* Mehanis"s3 sites of ati-ity3 indiations3 and doses of .rrently a-aila,le gastrointestinal pro7ineti agents*

Dru! ClassificationMechanism ites of Acti$ity Indications Dose Hther Properties

Dopa"inergi D2 antagonist Dr.gs

Metoclopramide ;4, stomach, intestine, Vomitin! disorders, *.(/*.' m!:! PH, IV 8ID" α(/adrener!ic anta!onist

CR8U !astroesopha!eal reflu9, *.*%/*.*( m!:!hr infusion β(/adrener!ic anta!onistdelayed !astric emptyin!, '/@81/serotoner!ic

a!onistileuspseudo/obstruction '/@8&/serotoner!ic

anta!onist

Domperidone ;4, CR8U Vomitin! disorders, *.*'/*.%* m!:! PH )ID α(/adrener!ic anta!onist

!astroesopha!eal reflu9 β(/adrener!ic anta!onist

Sertonergi (1HT4 agonist Dr.gs

Cisapride ;4, stomach, intestine, ;astroesopha!eal reflu9, *.%/*.' m!:! PH 8ID '/@8&/serotoner!icanta!onist

colon, CR8U delayed !astric emptyin!, doses as hi!h as '/@8%/serotoner!icanta!onist

ileuspseudo/obstruction, as *.'/%.* m!:! ha$e '/@8(/serotoner!ica!onist

constipation, chemotherapy/ been used in some do!sinduced $omitin!

Mosapride tomach Delayed !astric emptyin! *.('/%.* m!:! PH )ID =one

Prucalopride tomach, colon Delayed !astric emptyin!, *.*%/*.(* m!:! PH )ID =oneconstipation

8e!aserod Intestine, colon Constipation, *.*'/*.%* m!:! PH or IV, )ID '/@8%/serotoner!icanta!onist

ileuspseudo/obstruction

Motilin1li7e Dr.gs

4rythromycin ;4, stomach, ;astroesopha!eal reflu9, *.'/%.* m!:! PH IV 8ID '/@8&/serotoner!ic

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anta!onistintestine, colon delayed !astric emptyin!,

constipation do!s

Aetylholinesterase Inhi,itors and Cholino"i"eti AgentsRanitidine tomach, colon Delayed !astric emptyin!, %.*/(.* m!:! PH )ID/8ID @( histaminer!ic

anta!onistconstipation

=i5atidine tomach, colon Delayed !astric emptyin!, (.'/'.* m!:! PH ID @( histaminer!icanta!onist

constipation

)ethanechol 4sopha!us Canine idiopathic me!aesopha!us Do!F '/%' m!do! PH 8ID

#itri O!ide Donors

AM#/&*% tomach Diabetic !astroparesis =ot yet establishedProstanoids

Misoprostol Colon Constipation Do!F (/' µ!:! PH 8ID/ID

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Canine Infla""atory 'o2el Disease8 Pathogenesis3 Diagnosis3 Therapy

Definition of I'D 1 Inflammatory bo2el disease I)D may be defined usin! clinical, patho!enetic, ima!in!, histolo!ic, immunolo!ic,

pathophysiolo!ic, and !enetic criteria.

Clinical CriteriaI)D has been defined clinically as a spectrum of !astrointestinal disorders associated 2ith chronic inflammation of the stomach,intestine andor colon of un:no2n etiolo!y. A clinical dia!nosis of I)D is considered only if affected animals ha$eF % persistent& 2ee:s in duration !astrointestinal si!ns anore9ia, $omitin!, 2ei!ht loss, diarrhea, hematoche5ia, mucousy feces, ( failure torespond to symptomatic therapies parasiticides, antibiotics, !astrointestinal protectants alone, & failure to document other causesof !astroenterocolitis by thorou!h dia!nostic e$aluation, and 1 histolo!ic dia!nosis of beni!n intestinal inflammation. mall bo2eland lar!e bo2el forms of I)D ha$e been reported in both do!s and cats, althou!h lar!e bo2el I)D appears to be more pre$alent inthe do!.

Patho!enetic Criteria

Eno2n causes of intestinal diarrhea should first be consideredF food sensiti$ity reaction, bacterial infection, parasitic infection,fun!al infection, pancreatic insufficiency, intestinal neoplasia, lymphan!iectasia canine, and hyperthyroidism feline.

Most current hypotheses on the patho!enesis of I)D hold that the !ut has sustained reacti$ity to endo!enous bacterial andor foodanti!ens.

@istolo!ic CriteriaI)D has been defined histolo!ically by the type of inflammatory infiltrate neutrophilic, eosinophilic, lymphocytic, plasmacytic,!ranulomatous, associated mucosal patholo!y $illus atrophy, fusion, crypt collapse, distribution of the lesion focal or!enerali5ed, superficial or deep, se$erity mild, moderate, se$ere, mucosal thic:ness mild, moderate, se$ere, and topo!raphy!astric fundus, !astric antrum, duodenum, GeGunum, ileum, cecum, ascendin! colon, descendin! colon. As 2ith lar!e intestinalI)D, subGecti$e interpretation of small intestinal I)D lesions has made it difficult to compare tissue findin!s bet2een patholo!ists.ubGecti$ity in histolo!ic assessments has led to the de$elopment of se$eral I)D !radin! systems.

Immunolo!ic CriteriaI)D has been defined immunolo!ically by the innate and adapti$e response of the mucosa to !astrointestinal anti!ens. Althou!h the precise immunolo!ic e$ents of canine and feline I)D remain to be determined, a pre$ailin! hypothesis for the de$elopment of I)D

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is the loss of immunolo!ic tolerance to the normal bacterial flora or food anti!ens, leadin! to abnormal 8 cell immune reacti$ity inthe !ut microen$ironment. ;enetically en!ineered animal models e.!., I</(, I</%*, and 8 cell receptor :noc:outs that de$elopI)D in$ol$e alterations in 8 cell de$elopment andor function su!!estin! that 8 cell populations are responsible for the homeostatic

re!ulation of mucosal immune responses. Immunohistochemical studies of canine I)D ha$e demonstrated an increase in the 8 cell population of the lamina propria, includin! CD&] cells and CD1] cells, as 2ell as macropha!es, neutrophils, and I!A/containin! plasma cells. Many of the immunolo!ic features of canine I)D can be e9plained as an indirect conse6uence of mucosal 8 cellacti$ation. 4nterocytes are also li:ely in$ol$ed in the immunopatho!enesis of I)D. 4nterocytes are capable of beha$in! as anti!en/ presentin! cells, and interleu:ins e.!., I</0 and I</%' produced by enterocytes durin! acute inflammation acti$ate mucosallymphocytes. #p/re!ulation of 8oll/li:e receptor 1 8<R1 and 8oll/li:e receptor ( 8<R( e9pression contribute to the innateimmune response of the colon. 8hus, the patho!enesis and pathophysiolo!y of I)D appears to in$ol$e the acti$ation of a subset ofCD1] 8 cells 2ithin the intestinal epithelium that o$erproduce inflammatory cyto:ines 2ith concomitant loss of a subset of CD1] 8cells, and their associated cyto:ines, 2hich normally re!ulate the inflammatory response and protect the !ut from inGury.4nterocytes, beha$in! as anti!en/presentin! cells, contribute to the patho!enesis of this disease.

Pathophysiolo!ic CriteriaI)D may be defined pathophysiolo!ically in terms of chan!es in transport, blood flo2, and motility. 8he clinical si!ns of I)D,2hether small or lar!e bo2el, ha$e lon! been attributed to the pathophysiolo!y of malabsorption and hypersecretion, bute9perimental models of canine I)D ha$e instead related clinical si!ns to the emer!ence of abnormality motility patterns. 8he pathophysiolo!y of small intestinal I)D is e9plained by at least t2o interdependent mechanismsF the mucosal immune response, andaccompanyin! chan!es in motility.

Immune !esponsesA !eneric inflammatory response in$ol$in! cellular elements ) and 8 lymphocytes, plasma cells, macropha!es, and dendritic cells,secretomotor neurons e.!., VIP, substance P, and choliner!ic neurons, cyto:ines and interleu:ins, and inflammatory mediators e.!.,

leu:otrienes, prostanoids, reacti$e o9y!en metabolites, nitric o9ide, '/@8, I>=/, 8=>/^, and platelet/acti$atin! factor is typical ofcanine and feline inflammatory bo2el disease. 8here are many similarities bet2een the inflammatory response of the small and lar!eintestine, but recent immunolo!ic studies su!!est that I)D of the canine small intestine is a mi9ed 8h%8h( response 2hereas I)D of

the canine colon may be more of a 8h% type response 2ith elaboration of I</(, I</%(, I=>/, and 8=>/α.

Motility Chan!es49perimental studies of canine small and lar!e intestinal I)D ha$e sho2n that many of the clinical si!ns are related to motorabnormalities of the !astrointestinal tract. 4thanol and acetic acid perfusion of the canine ileum or colon induces a form of I)D

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syndrome indistin!uishable from the natural condition. Inflammation in this model suppresses the normal phasic contractions of thecolon, includin! the mi!ratin! motility comple9, and tri!!ers the emer!ence of !iant mi!ratin! contractions ;MCs. 8he appearanceof these ;MCs in association 2ith inflammation is a maGor factor in producin! diarrhea, abdominal crampin!, and ur!ency of

defecation. ;MCs are po2erful lumen/occludin! contractions that rapidly propel pancreatic, biliary, and intestinal secretions in thefastin! state, and undi!ested food in the fed state, to the colon to increase its osmotic load. Malabsorption results from direct inGury tothe epithelial cells and from ultrarapid propulsion of intestinal contents by !iant mi!ratin! contractions ;MCs so that sufficientmucosal contact time is not allo2ed for di!estion and absorption to ta:e place.

Inflammation impairs the re!ulation of the colonic motility patterns at se$eral le$els, i.e., enteric neurons, interstitial cells of CaGal, andcircular smooth muscle cells. Inflammation/induced chan!es in the amplitude and duration of the smooth muscle slo2 2a$e plateau potentials contribute to the suppression of rhythmic phasic contractions RPCs. 8hese alterations li:ely ha$e their ori!in in structuralas 2ell as functional dama!e to the interstitial cells of CaGal. At the same time that inflammation suppresses the RPCs, inflammationsensiti5es the colon to the stimulation of ;MCs by the neurotransmitter substance P. 8hese findin!s su!!est that P increases the

fre6uency of ;MCs durin! inflammation, and that selecti$e inhibition of ;MCs durin! inflammation may minimi5e the symptoms ofdiarrhea, abdominal discomfort, and ur!ency of defecation associated 2ith these contractions.

Inflammation suppresses the !eneration of tone and phasic contractions in the circular smooth muscle cells throu!h multiple molecularmechanisms. Inflammation shifts muscarinic receptor e9pression in circular smooth muscles from the M& to the M( subtype. 8his shifthas the effect of reducin! the o$erall contractility of the smooth muscle cell. Inflammation also impairs calcium influ9 and do2n/re!ulates the e9pression of the </type calcium channel, 2hich may be important in suppressin! phasic contractions and tone 2hileconcurrently stimulatin! ;MCs in the inflamed colon. Chan!es in the open/state probability of the lar!e conductance calcium/acti$ated potassium channels E Ca partially attenuate this effect. Inflammation also modifies the si!nal transduction path2ays of circular smoothmuscle cells. Phospholipase A( and protein :inase C PEC e9pression and acti$ation are si!nificantly altered by colonic inflammation

and this may partially account for the suppression of tone and phasic contractions. PEC α, , and ε isoen5yme e9pression is do2n/

re!ulated, PEC ι and λ isoen5yme e9pression is up/re!ulated, and the cytosol/to/membrane translocation of PEC is impaired. 8he </

type calcium channel, already reduced in its e9pression, is one of the molecular tar!ets of PEC. Inflammation also acti$ates the

transcription factor =>/κ ) 2hich further suppresses cell contractility.

;enetic CriteriaI)D may be defined by !enetic criteria in se$eral animal species. CrohnLs disease and ulcerati$e colitis are more common in certainhuman !enotypes, and a mutation in the =HD( !ene nucleotide/bindin! oli!omeri5ation domain( has been found in a sub/!roupof patients 2ith CrohnLs disease. ;enetic influences ha$e not yet been identified in canine or feline I)D, but certain breeds e.!.,

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;erman shepherds, )o9ers appear to be at increased ris: for the disease.

H$er$ie2 of Pathophysiolo!y of I)DF Inflammation impairs motility by inducin! chan!es in receptor, si!nal transduction, and ion

channel acti$ity in smooth muscle cells and enteric neurons. Chan!es include but not are limited to a shift in muscarinic receptore9pression from M& to M( receptor subtype, impaired calcium mobili5ation, do2n/re!ulation of </type calcium channel e9pression,chan!es in the open/state probability of the lar!e conductance calcium/acti$ated potassium channels E Ca, do2n/re!ulation of

phospholipase A( and protein :inase C α, , and ε isoen5ymes, and acti$ation of the transcription factor =>/κ ) in smooth muscle cells.

Inflammation also sensiti5es the colon to the stimulation of ;MCs by the neurotransmitter substance P. PEC _ protein :inase C, P<A(

_ Phospholipase A( , M _ muscarinic, =>/κ ) _ =uclear factor/κ ), E Ca _ Calcium/acti$ated potassium channel, P _ substance P, ACh _

acetylcholine.

ClinialPathogeneti I"aging

I*'*DHistologi I"".nologi

Pathophysiologi Geneti

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Clinial E!a"ination

8he clinical si!ns of lar!e intestinal I)D are those of a lar!e bo2el/type diarrhea, i.e., mar:ed increased fre6uency, reduced fecal

ACh

M: M0

Cao

:?

6 ?

o

Enteri#e.ron

i

iCa

6 ?

:?

I6 'P6C

P LAS"ooth M.sle

Cell

P 6 C

:

SP

#&6 '

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$olume per defecation, blood pi!ments and mucous in feces, and tenesmus. Anore9ia, 2ei!ht loss, and $omitin! are occasionallyreported in animals 2ith se$ere I)D of the colon or concurrent I)D of the stomach andor small intestine. Clinical si!ns usually 2a9and 2ane in their se$erity. A transient response to symptomatic therapy may occur durin! the initial sta!es of I)D. As the condition

pro!resses, diarrhea !radually increases in its fre6uency and intensity, and may become continuous. In some cases the first bo2elmo$ement of the day may be normal or nearly normal, 2hereas successi$e bo2el mo$ements are reduced in $olume and pro!ressi$elymore ur!ent and painful. Durin! se$ere episodes, mild fe$er, depression, and anore9ia may occur.

8here does not appear to be any se9 predilection, but a!e may be a ris: factor 2ith I)D appearin! more fre6uently in middle a!ed animals meana!e appro9imately - years 2ith a ran!e of - months to (* years. ;erman shepherd and )o9er do!s are at increased ris: for I)D, and pure/breedcats appear to be at !reater ris:. Cats more often present 2ith an upper !astrointestinal form of I)D, 2hereas do!s are at ris: for both small andlar!e bo2el I)D.

Physical e9amination is unremar:able in most cases. 8hic:ened bo2el loops may be detected durin! abdominal palpation if the small bo2el isconcurrently in$ol$ed. Di!ital e9amination of the anorecturm may e$o:e pain or re$eal irre!ular mucosa, and blood pi!ments and mucous may be

e$ident on the e9am !lo$e.

Diagnosis

Complete blood counts, serum chemistries, and urinalyses are often normal in mild cases of lar!e bo2el I)D. Chronic cases may ha$e one or moresubtle abnormalities. Hne re$ie2 of canine and feline I)D reported se$eral hematolo!ic abnormalities includin! mild anemia, leu:ocytosis,neutrophilia 2ith and 2ithout a left shift, eosinophilia, eosinopenia, lymphocytopenia, monocytosis, and basophilia. 8he same study reported se$eral

biochemical abnormalities includin! increased acti$ities of serum alanine aminotransferase and al:aline phosphatase, hypoalbuminemia,hypoproteinemia, hyperamylasemia, hyper!lobulinemia, hypo:alemia, hypocholesterolemia, and hyper!lycemia. =o consistent abnormality in thecomplete blood count or serum chemistry has been identified.

A scorin! inde9 for disease acti$ity in canine I)D 2as recently de$eloped that relates se$erity of clinical si!ns to serum acute/phase protein C/reacti$e protein, serum amyloid A concentrations. 8he canine I)D acti$ity inde9 CI)DAI assi!ns le$els of se$erity to each of se$eral!astroenterolo!ic si!ns e.!., anore9ia, $omitin!, 2ei!ht loss, diarrhea, and it appears to be a reliable inde9 of mucosal inflammation in canine I)D.Interestin!ly, both the acti$ity inde9 and serum concentrations of C/reacti$e protein CRP impro$e 2ith successful treatment, su!!estin! that serumCRP is suitable for the laboratory e$aluation of therapy in canine I)D. Hther acute/phase proteins 2ere less specific than CRP. Hne importantca$eat that should be emphasi5ed is that altered CRP is not prima &acie e$idence of !astrointestinal inflammation. Concurrent infections or otherinflammatory conditions could cause an acute/phase response, includin! CRP, in affected patients.

Treat"ent T Mana!ement of I)D consists of % dietary therapy, ( e9ercise, & antibiotics, 1 probiotics, ' anti/diarrheal a!ents, - restoration ofnormal motility, 0 anti/inflammatory or immunosuppressi$e therapy, and + beha$ioral modification.

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%. Dietary 8herapy

8he precise immunolo!ic mechanisms of canine and feline I)D ha$e not yet been determined, but a pre$ailin! hypothesis for the de$elopment of I)Dis the loss of immunolo!ic tolerance to the normal bacterial flora or food anti!ens. Accordin!ly, dietary modification may pro$e useful in themana!ement of canine and feline I)D. e$eral nutritional strate!ies ha$e been proposed includin! no$el proteins, hydroly5ed diets, anti/o9idant

diets, medium chain tri!lyceride supplementation, lo2 fat diets, modifications in the ome!a/-ome!a/& ω/-ω/& fatty acid ratio, and fiber

supplementation. Hf these strate!ies, some e$idence/based medicine has emer!ed for the use of no$el protein, hydroly5ed, and fiber/supplementeddiets.

>ood sensiti$ity reactions 2ere suspected or documented in 17? of cats presented because of !astroenterolo!ic problems 2ith or 2ithout concurrentdermatolo!ic problems in a prospecti$e study of ad$erse food reactions in cats. )eef, 2heat, and corn !luten 2ere the primary in!redientsresponsible for food sensiti$ity reactions in that study, and most of the cats responded to the feedin! of a chic:en/ or $enison/based selected/proteindiet for a minimum of 1 2ee:s. 8he authors concluded that ad$erse reactions to dietary staples are common in cats 2ith chronic !astrointestinal

problems and that they can be successfully mana!ed by feeded selected/protein diets. >urther support for this concept comes from studies in 2hich!astroenterolo!ic or dermatolo!ic clinical si!ns 2ere si!nificantly impro$ed by the feedin! of no$el proteins.

4$idence is accruin! that hydroly5ed diets may be useful in the nutritional mana!ement of canine I)D. 8he conceptual basis of the hydroly5ed dietis that oli!opeptides are of insufficient si5e and structure to induce anti!en reco!nition or presentation. In one preliminary study, do!s 2ithinflammatory bo2el disease sho2ed si!nificant impro$ement follo2in! the feedin! of a hydroly5ed diet althou!h they had failed to respond to thefeedin! of a no$el protein. Clinical impro$ement could not be solely attributed to the hydroly5ed nature of the protein source because the test diet

had other modified features, i.e., hi!h di!estibility, cornstarch rather than intact !rains, medium chain tri!lycerides, and an altered ratio of ω/- to ω/& polyunsaturated fatty acids. Additional studies 2ill be re6uired to ascertain the efficacy of this nutritional strate!y in the mana!ement of I)D.

>iber/supplemented diets may be useful in the mana!ement of irritable bo2el syndrome I) in the do!. I) is a poorly defined syndrome in thedo! that may or may not bear resemblance to I) in humans. Canine I) has been defined as a chronic lar!e/bo2el type diarrhea 2ithout :no2n

cause and 2ithout e$idence of colonic inflammation on colonoscopy or biopsy. Do!s fulfillin! these criteria 2ere successfully mana!ed 2ith solublefiber psyllium hydrophilic mucilloid supplementation of a hi!hly di!estible diet.

)* E+ercise

49perimental I)D in the do! is accompanied by si!nificant abnormalities in the normal colonic motility patterns. Physical e9ercise has been sho2nto disrupt the colonic MMCs and to increase the total duration of contractions that are or!ani5ed as non/mi!ratin! motor comple9es durin! the fedstate. 49ercise also induces ;MCs, defecation, and mass mo$ement in both the fasted and fed states. 8he increased motor acti$ity of the colon ande9tra ;MCs that result from physical e9ercise may aid in normal colonic motor function.

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&. Antibiotics

ome I)D cases are initiated by true enteric patho!ens, 2hile others are complicated by small intestinal bacterial o$er!ro2th. ome I)D cases maysho2 short term responsi$eness to one or more antibiotics, e.!., tylosin, metronida5ole, or o9ytetracycline.

1. Probiotics

Probiotics are li$in! or!anisms 2ith lo2 or no patho!enicity that e9ert beneficial effects e.!., stimulation of innate and ac6uired immunity on thehealth of the host. 8he ;ram/positi$e commensal lactic acid bacteria e.!., <actobacilli ha$e many beneficial health effects, includin! enhancedlymphocyte proliferation, innate and ac6uired immunity, and anti/inflammatory cyto:ine production. <actobacillus rhamnosus ;;, a bacteriumused in the production of yo!urt, is effecti$e in pre$entin! and treatin! diarrhea, recurrent Clostridia di&&icile infection, primary rota$irus infection,and atopic dermatitis in humans. <actobacillus rhamnosus ;; has been safely coloni5ed in the canine !astrointestinal tract, althou!h probioticeffects in the canine intestine ha$e not been firmly established. 8he probiotic or!anism, Enterococcus &aecium >-+, has been safely coloni5ed inthe canine !astrointestinal tract, and it has been sho2n to increase fecal I!A content and circulatin! mature ) CD(%]M@C class II] cells in

youn! puppies. It has been su!!ested that this probiotic may be useful in the pre$ention or treatment of canine !astrointestinal disease. 8hisor!anism may, ho2e$er, enhance Campylo,acter euni adhesion and coloni5ation of the do! intestine, perhaps conferrin! carrier status on coloni5eddo!s.

82o recent studies ha$e sho2n that many commercial $eterinary probiotic preparations are not accurately represented by label claims. ualitycontrol appears to be deficient for many of these formulations. #ntil these products are more ti!htly re!ulated, $eterinarians should probably $ie2

product claims 2ith some s:epticism.

'. Anti/Diarrheal A!ents

Prostaglandin Synthetase Inhi,itors

/ ulfasala5ine / %*/(' m!:! 8ID/ID, PH/ '/aminosalicylate / '/%* m!:! PH, 8ID/ID do!

./0-1pioid (gonists T 8hese dru!s stimulate circular smooth muscle contraction and, therefore,intestinal se!mentation. It has been sho2n morerecently that these dru!s also stimulate absorption, and inhibit secretion of, fluid and electrolytes./ <operamide *.*+ m!:! 8ID, PH/preferred dru!/ Dipheno9ylate *.*'/*.%* m!:! 8ID/ID, PH/a$ailable in <omotil

"-#T 2 Serotonin (ntagonists / Anta!onists of the neuronal '/@8& receptor inhibit Cl/ and @(H secretion from intestinal epithelial cells./ Hndansetron Uofran, ;la9o / *.'/%.* m!:! )ID, PH

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/ ;ranisetron Eytril, mithEline )eecham / *.'/%.* m!:! )ID, PH

3)-(drenergic (ntagonists / 8hese dru!s must be used carefully as they can acti$ate ^ (/adrener!ic receptors in the chemoreceptor tri!!er 5one andcause $omitin!./ Clonidine '/%* N!:! )ID/8ID, PH

-. Restoration of =ormal Motility

8he mi9ed µ,δ/opioid a!onist, loperamide, stimulates colonic fluid and electrolyte absorption 2hile inhibitin! colonic propulsi$e motility.

<operamide *.*+ m!:! PH 8ID/ID may be beneficial in the treatment of difficult or refractory cases of lar!e bo2el/type I)D.

0. Anti/InflammatoryImmunosuppressi$e 8herapy

Sul&asalazine T ulfasala5ine is a hi!hly effecti$e prosta!landin synthetase inhibitor that has pro$en efficacy in the therapy of lar!e bo2el I)D in thedo!. ulfasala5ine is a compound molecule of '/aminosalicylate meselamine and sulfapyridine lin:ed in an a5o chemical bond. >ollo2in! oral

dosin!, most of the sulfasala5ine is transported to the distal !astrointestinal tract 2here cecal and colonic bacteria metaboli5e the dru! to itscomponent parts. ulfapyridine is lar!ely absorbed by the colonic mucosa but much of the '/aminosalicylate remains in the colonic lumen 2here itinhibits mucosal lipo9y!enase and the inflammatory cascade. ulfasala5ine has been recommended for the treatment of canine lar!e bo2el I)D atdoses of %*/(' m!:! PH 8ID for 1/- 2ee:s. With resolution of clinical si!ns, sulfasala5ine dosa!es are !radually decreased by (' per cent at (/2ee: inter$als and e$entually discontinued 2hile maintainin! dietary mana!ement. alicylates are readily absorbed and induce to9icity in cats,therefore this dru! classification should be used 2ith !reat caution in cats. If used in cats, some authors ha$e recommended usin! half of therecommended do! dose i.e., '/%(.' m!:! PH 8ID. ulfasala5ine usa!e has been associated 2ith the de$elopment of :eratoconGuncti$itis sicca inthe do!, so tear production should be assessed subGecti$ely by the pet o2ner and obGecti$ely by the $eterinarian durin! usa!e.

1ther "-(minosalicylates T 8his dru! classification 2as de$eloped to reduce the to9icity of the sulfapyridine portion of the parent moleculesulfasala5ine and to enhance the efficacy of the '/aminosalicylate portion. Meselamine Dipentum, Asachol and dimeselamine Hlsala5ine are

a$ailable for use in the treatment of canine lar!e bo2el I)D. Hlsala5ine has been used at a dosa!e of '/%* m!:! PH 8ID in the do!. Despite theformulation of sulfa/free '/aminosalicylate preparations, instances of :eratoconGuncti$itis sicca ha$e still been reported in the do!.

Metronidazole T Metronida5ole %*/(* m!:! PH )ID/8ID has been used in the treatment of mild to moderate cases of lar!e bo2el I)D in bothdo!s and cats. Metronida5ole has been used either as a sin!le a!ent or in conGunction 2ith '/aminosalicylates or !lucocorticoids. Metronida5ole is

belie$ed to ha$e se$eral beneficial properties, includin! anti/bacterial, anti/proto5oal, and immunomodulatory effects. ide effects include anore9ia,hypersali$ation, and $omitin! at recommended doses and neuroto9icity ata9ia, nysta!mus, head title, and sei5ures at hi!her doses. ide effectsusually resol$e 2ith discontinuation of therapy but dia5epam may accelerate reco$ery of indi$idual patients.

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Glucocorticoids T Anti/inflammatory doses of prednisone or prednisolone %/( m!:! PH ID may be used to treat I)D in do!s that ha$e failed torespond to dietary mana!ement, sulfasala5ine, or metronida5ole, and as adGuncti$e therapy to dietary modification in feline I)D. Prednisone or

prednisolone is used most fre6uently, as both ha$e short durations of action, are cost/effecti$e, and are 2idely a$ailable. 46uipotent doses ofde9amethasone are e6ually effecti$e but may ha$e more deleterious effects on brush border en5yme acti$ity. Prednisone should be used for (/12ee:s dependin! upon the se$erity of the clinical si!ns. @i!her doses of prednisone e.!., (/1 m!:! PH ID may be needed to control se$ere formsof eosinophilic colitis or hypereosinophilic syndrome in cats. Combination therapy 2ith sulfasala5ine, metronida5ole, or a5othioprine may reduce theo$erall dosa!e of prednisone needed to achie$e remission of clinical si!ns. As 2ith sulfasala5ine, the dose of !lucocorticoid may be reduced by ('?at %/( 2ee: inter$als 2hile hopefully maintainin! remission 2ith dietary modification.

)ecause of steroid side effects and suppression of the hypothalamic/pituitary/adrenal a9is, se$eral alternati$e !lucocorticoids ha$e beende$eloped that ha$e e9cellent topical i.e., mucosal anti/inflammatory acti$ity but are si!nificantly metaboli5ed durin! first pass hepaticmetabolism. )udesonide has been used for many years as an inhaled medication for asthma, and an enteric/coated form of the dru! isno2 a$ailable for treatment of I)D in humans and animals. 8here is little e$idence/based medicine in support of the use of thismedication in canine or feline I)D, but doses of % m!cat or % m!do! per day ha$e been used 2ith some success in anecdotal cases.

(zathioprine T A5athioprine is a purine analo! that, follo2in! D=A incorporation, inhibits lymphocyte acti$ation and proliferation. It is rarelyeffecti$e as a sin!le a!ent, and it should instead be used as adGuncti$e therapy 2ith !lucocorticoids. A5athioprine may ha$e a si!nificant steroid/sparin! effect in I)D. Doses of ( m!:! PH 6 (1 hours in do!s and *.& m!:! PH 6 1+ hours in cats ha$e been used 2ith some success in I)D. Itmay ta:e se$eral 2ee:s or months of therapy for a5athioprine to become ma9imally effecti$e. Cats particularly should be monitored for side effects,includin! myelosuppression, hepatic disease, and acute pancreatic necrosis.

Cyclosporine T Cyclosporine has been used in the renal transplantation patient for its inhibitory effect on 8 cell function. In more recent times,cyclosporine has been used in a number of immune/mediated disorders, includin! :eratoconGuncti$itis sicca, perianal fistula anal furunculosis, andIM@A. Anecdotal reports su!!est that cyclosporine &/0 m!:! PH )ID may be useful in the treatment of some cases of refractory I)D. 4$idence/

based medicine studies 2ill be needed to establish efficacy, but anecdotal e9perience 2ould su!!est that cyclosporine may be useful in some of themore difficult or refractory cases of I)D.

Chloram,ucil T Chlorambucil ( m!m( PH e$ery other day has been used in place of a5athioprine in some difficult or refractory cases of felineI)D.

4* Beha$ioral Modi&icationInflammatory bo2el disease and irritable bo2el syndrome $ery li:ely ha$e underlyin! beha$ioral components. Abnormal personality traits and

potential en$ironmental stress factors 2ere identified in &+? of do!s in one study. Multiple factors 2ere present in affected households, includin!tra$el, re/location, house construction, separation an9iety, submissi$e urination, noise sensiti$ity, and a!!ression. %+' 8he role of beha$ior in the

patho!enesis and therapy of canine and feline !astrointestinal disorders remains lar!ely une9plored.

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Prognosis

Most reports indicate that the short/term pro!nosis for control of I)D is !ood to e9cellent. >ollo2in! completion of dru! therapy,

many animals are able to maintain remission of si!ns 2ith dietary mana!ement alone. 8reatment failures are uncommon and are usuallydue to % incorrect dia!nosis it is especially important to rule out alimentary lymphosarcoma, ( presence of se$ere disease such ashistiocytic ulcerati$e colitis and protein/losin! enteropathy or irre$ersible mucosa lesions such as fibrosis, & poor client compliance2ith appropriate dru!dietary recommendations, 1 use of inappropriate dru!s or nutritional therapy, and ' presence of concurrentdisease such as small intestinal bacterial o$er!ro2th or hepatobiliary disease. 8he pro!nosis for cure of I)D is poor, and relapsesshould be anticipated.

%eferenes

A more detailed re$ie2 of diseases of the intestine, includin! (71 refereences, may be found inF Washabau RJ. Diseases of the Intestine. In,8e9tboo: of Veterinary Internal Medicine, -th edition, 4ttin!er J and >eldman 4C, editors. W) aunders Co, Philadelphia, PA, (**'F %&0+/%1*+.

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&eline Hepato,iliary Disease8 4hat@s #e2 in Diagnosis and Therapy

To!i Hepatopathy

Patho!enesis and 4tiolo!y T 8o9ic hepatopathy is a direct inGury to hepatocytes or other cells in the li$er attributable to therapeutic a!ents oren$ironmental to9ins. Cats are particularly sensiti$e to phenolic to9icity because of limited hepatic !lucuronide transferase acti$ity. 8hediscriminatory eatin! habits of cats may account for the relati$ely uncommon occurrence of hepatoto9icity from in!ested en$ironmental to9ins suchas pesticides, household products, and other chemicals. Medical therapies acetaminophen, acetylsalicylic acid, me!esterol, :etocona5ole,

phena5opyridine, tetracycline, dia5epam, !riseoful$in and en$ironmental to9ins pine oil ] isopropanol, inor!anic arsenicals, thallium, 5inc phosphide, 2hite phosphorus, Amanita phalloides, aflato9in, phenols may contribute to li$er patholo!y. A se$ere idiosyncratic hepatoto9icity has been reported 2ith dia5epam administration in se$eral !roups of cats. Clinical si!ns in affected cats include anore9ia, $omitin!, 2ei!ht loss, ascites,encephalopathy, and death. 8he histolo!y is characteri5ed by se$ere central lobular necrosis and mild $acuolation.

Mechanisms of @epatoto9icity / 8he li$er is an important site of dru! to9icity and o9idati$e stress because of its pro9imity and relationship to the

!astrointestinal tract. e$enty/fi$e to +*? of hepatic blood flo2 comes directly from the !astrointestinal tract and spleen $ia the main portal $ein. Portal blood flo2 transports nutrients, bacteria and bacterial anti!ens, dru!s, and 9enobiotic a!ents absorbed from the !ut to the li$er in more concentrated form.Dru!/metaboli5in! en5ymes deto9ify many 9enobiotics but acti$ate the to9icity of others. @epatic parenchymal and non/parenchymal cells may allcontribute to the patho!enesis of hepatic to9icity. 8he maGor mechanisms of hepatoto9icity includeF )ile Acid/Induced @epatocyte Apoptosis,Cytochrome P1'*(4%/Dependent 8o9icity , Pero9ynitrite/induced @epatocyte 8o9icity, Adhesion Molecules and H9idant tress in Inflammatory <i$erInGury, Micro$esicular and =onalcoholic teatosis.

Dia!nosis of @epatoto9icity T Clinical e$idence includes supporti$e history, normal li$er si5e to mild !enerali5ed hepatome!aly, ele$ated serum li$eren5yme acti$ities predominantly A<8 and A8, hypoalbuminemia and hypocholesterolemia, and reco$ery or death dependin! upon se$erity andma!nitude of e9posure. 8here are no patho!nomonic histolo!ic chan!es in the li$er, althou!h necrosis 2ith minimal inflammation and lipidaccumulation are considered classic findin!s.

8reatment of @epatoto9icity T >e2 hepatoto9ins ha$e specific antidotes, and reco$ery relies almost e9clusi$ely on symptomatic and supporti$etherapy. If reco!ni5ed, acetaminophen to9icity may be treated 2ith acetylcysteine sulfhydryl !roup donor, ranitidine or cimetidine cytochromeP1'* en5yme inhibition, ascorbic acid anti/o9idant, and androstanol consitituti$e androstane receptor CARB inhibition.

Hepati Lipidosis

Patho!enesis and 4tiolo!y T >eline hepatic lipidosis is no2 a 2ell/reco!ni5ed syndrome characteri5ed by intracellular accumulation of lipid 2ithclinicopatholo!ic findin!s consistent 2ith intrahepatic cholestasis. 8he precise incidence of the syndrome is un:no2n but patholo!y sur$eys ha$ere$ealed '? of animals affected 2ith this lesion. While some cases result from diabetes mellitus, the maGority of cases are felt to result from the

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nutritional and biochemical peculiarities of the cat. It has been su!!ested, for e9ample, that the cat is not $ery capable of re!ulatin! intermediarymetabolism durin! star$ation. Althou!h the biochemistry of this lesion has not been completely 2or:ed out, there are se$eral biochemical andnutritional peculiarities that predispose the cat to this syndrome. ome of the :no2n biochemical peculiarities of the cat areF essentiality of dietaryar!inine" lo2 le$els of hepatic ornithine" hi!h dietary protein re6uirements" lac: of hepatic en5ymatic adaptation to lo2 dietary le$els of protein"relati$e insufficiency of intestinal pyrroline/'/carbo9ylate synthase acti$ity" relati$e insufficiency of intestinal and hepatic !lutamate reductase"relati$e insufficiency of intestinal ornithine transcarbamylase" peculiarities in lipoprotein metabolism" and, differences in orotic acid metabolism.

Clinical >eatures T Most studies su!!est that there are no breed, se9, or a!e predilections. A recent retrospecti$e study by Center and her collea!uessu!!ests that female and middle/a!e cats are at !reater ris: for the illness. Hbesity may be a predisposin! factor, althou!h the syndrome readilyde$elops in fit animals. It has been su!!ested that obesity follo2ed by a period of anore9ia and 2ei!ht loss are particularly at ris:. Cats affected2ith this syndrome are often presented 2ith a complaint of anore9ia, often of se$eral 2ee:s duration. 8hese cats are also commonly presented 2ith

Gaundice. Hther reported clinical si!ns include $omitin!, 2ea:ness, 2ei!ht loss, and diarrhea. Physical e9amination often re$eals dehydration,cache9ia, Gaundice, and hepatome!aly. All of these findin!s are also reported in cats 2ith acute pancreatitis and other hepatobiliary disease.

Dia!nosis T @yperechoic chan!es in the hepatic parenchyma at ultraono!raphy ha$e been cited as a patho!nomonic findin!, but these chan!es may

be seen in other feline hepatic disorders. Dia!nosis should be substantiated by aspiration cytolo!y, or better still, tissue biopsy percutaneous, trans/abdominal ultrasound !uidance, laparoscopy, or open laparotomy. Aspiration cytolo!y has 2ea: sensiti$ity and specificity, and may miss otherdia!noses.

8herapy T =utritional support is the cornerstone of therapy of this disorder. Most studies su!!est that enteral feedin! by forcedS or encoura!edfeedin!, pharyn!ostomy, !astrostomy, or enterostomy feedin! tube of commercially a$ailable cat foods 2ill effect reco$ery in 7*/7'? of affectedanimals. )iour!e and his collea!ues ha$e characteri5ed some of the metabolic chan!es that ta:e place durin! fastin! in obese cats. 8hey ha$e been

particularly interested in the effects of protein, lipid, or carbohydrate supplementation on hepatic lipid accumulation durin! rapid 2ei!ht loss inobese cats. 8hey found that small amounts of protein administered to obese cats durin! fastin! si!nificantly reduced accumulation of lipids in theli$er, pre$ented increases in al:aline phosphatase acti$ity, eliminated ne!ati$e nitro!en balance, and appeared to minimi5e muscle catabolism.Carbohydrate supplementation reduced hepatic lipid accumulation, but metabolic abnormalities still de$eloped. <ipid supplementation alone did not

ameliorate hepatic lipidosis and e$en resulted in more se$ere lipid accumulation than under conditions of fastin! alone. 8he use of ben5odia5epinea!onists e.!. dia5epam, o9a5epam, elfa5epam and '/@8( a!onists e.!., cyproheptadine as appetite stimulants has been encoura!ed in anore9iccats. 8hese compounds particularly the ben5odia5epine a!onists, should be used 2ith caution as they may e9acerbate pre/e9istin! hepaticencephalopathy. )en5odia5epine a!onists ha$e been sho2n to 2orsen hepatoencephalopathy in other animal species throu!h acti$ation of theneuronal ben5odia5epine;A)A receptor/chloride channel comple9.

&eline Cholangitis

Patho!enesis and 4tiolo!y T 8his syndrome has been classified in three different 2aysF

#ni$ersity of Minnesota Classification Dou! Weisse" %77- T <ymphocytic portal hepatitis and suppurati$e cholan!itis. 8his classification system

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implies that there are t2o different inflammatory conditions in$ol$in! the feline li$erF inflammatory li$er disease lymphocytic portal hepatitis andinflammatory biliary tract disease suppurati$e cholan!itis. <imitations of this classification system T It fails to reco!ni5e that acute i.e.,suppurati$e cholan!itis can pro!ress to more chronic forms i.e., lymphocytic of the disease. 8his system also implies that there is suppuration,2hich, in fact, is rarely seen. =eutrophilic infiltrates do occur, but rarely does it pro!ress to suppuration. >inally, itLs not entirely clear 2hetherlymphocytic portal hepatitis is a distinct clinical entity or Gust a histolo!ic lesion.

WAVA International <i$er tandardi5ation ;roup Classification Multi/Institutional ;roup" (**( T =eutrophilic cholan!itis, lymphocyticcholan!itis, lymphocytic portal hepatitis. 8his classification system implies that there are acute neutrophilic and chronic lymphocytic forms ofcholan!itis, and that there may be a separate form of portal hepatitis in cats. <imitations of this classification system T We still donLt :no2 iflymphocytic portal hepatitis is a disease or a histolo!ic lesion.

=eutrophilic cholan!itis T 8his disorder has been seen primarily in youn! to middle/a!ed male cats 2ith clinical si!ns of acute $omitin!, diarrhea,anore9ia, and lethar!y. Physical e9amination findin!s often re$eal fe$er, icterus, abdominal pain, and hepatome!aly '*? of cases. <aboratoryfindin!s fre6uently re$eal mild to moderate leu:ocytosis 2ith mild to moderate ele$ations in A<8, A8, ;;8, and A<P. )ased on recent studies, catsaffected 2ith this form of cholan!itis often ha$e related disease, e.!., pancreatitis and inflammatory bo2el disease. 8he dia!nosis of suppurati$e

cholan!iohepatitis is achie$ed by serum li$er en5ymolo!y" ultrasono!raphic characteri5ation of the li$er parenchyma" culture / bile, !allbladder,cholelith, li$er" ;ram stainin!" and, biopsy of the li$er andor e9trahepatic biliary system. Common bacterial isolates in affected cases include 4.coli, Clostridia, )acteroides, Actinomyces, ^/trep. 8he treatment of this syndrome has included appropriate antibiotic based on culture andsensiti$ity, cholelith remo$al 2here appropriate, bile duct decompression if necessary, fluid and electrolyte maintenance, and ursodeo9ycholatetherapy %*/%' m!:! P.H. ID.

<ymphocytic cholan!itis T Chronic lymphocytic cholan!itis is characteri5ed by a mi9ed inflammatory response e6ual numbers of lymphocytes or plasma cells and neutrophils 2ithin portal areas and bile ducts. Hther features of chronicity include mar:ed bile duct proliferation, brid!in! fibrosis, and pseudolobule formation. Chronic cholan!iohepatitis may pro!ress to pro!ressi$e biliary cirrhosis and the death of the patient. <ymphocytic cholan!itismay represent a persistent bacterial infection or an immune/mediated response may result in a chronic self/perpetuatin! disorder. Clinical si!ns areusually of a chronic, intermittent or persistent nature. With chronic cholan!iohepatitis, a lon!/standin! history o$er a period of 2ee:s or months is more

li:ely. Vomitin!, icterus, hepatome!aly and ascites are common findin!s. @epatic encephalopathy and e9cessi$e bleedin! are uncommon unless se$ereend/sta!e li$er disease is present. 8he best treatments for this syndrome are not clearly understood. It has been su!!ested that many cats re6uiremulti/component therapy, e.!., !lucocorticoids / %/( m!:! PH ID" metronida5ole / 0.' m!:! PH )ID" ursodeo9ycholate %*/%' m!:! PH ID"$itamin E % / %.'/' m! (/& 2ee:s" dietary manipulation for presumed I.).D." and, immune modulation 2ith a5athioprine or chlorambucil.

<ymphocytic portal hepatitis T A retrospecti$e re$ie2 of li$er biopsies of cats 2ith inflammatory li$er disease identified a subset of cats 2ithlymphocytic portal infiltrates 2hich had histopatholo!ic features distinct from cats 2ith acute or chronic cholan!itis. 8he term lymphocytic portalhepatitis has been proposed for this disorder. As opposed to findin!s in cholan!itis, there is a lac: of neutrophilic inflammation, bile duct in$ol$ement,infiltration of inflammatory cells into hepatic parenchyma, or periportal necrosis. <ymphocytic portal hepatitis is not associated 2ith inflammatory bo2eldisease or pancreatitis. Pre$ious reports of pro!ressi$e lymphocytic cholan!itis or lymphocytic cholan!itis referred to $aryin! de!rees of neutrophilic

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inflammation and the condition may actually ha$e been a chronic form of cholan!itis. <ymphocytic portal hepatitis is a common findin! in li$er biopsiesof older cats, su!!estin! that it is a common a!in! chan!e or that a sub/clinical form of disease is pre$alent. <ymphocytic portal hepatitis appears to

pro!ress slo2ly 2ith $aryin! de!rees of portal fibrosis and bile duct proliferation but no pseudolobule formation. Concurrent hepatic lipidosis is lessli:ely than 2ith cholan!itis.

Hepati #eoplasia

Patho!enesis and 4tiolo!y T Primary neoplasms of the feline li$er are uncommon. Cholan!iocellular carcinoma and hepatocellular carcinoma arethe most important of the primary feline li$er neoplasms, but they are of $ery lo2 incidence and therefore minor importance. Metatstatic li$erneoplasia are much more important in cats. 8he most common metastatic tumors to the li$er are lymphoma, systemic mast cell disease,heman!iosarcoma, and myeloproliferati$e disorders.

Clinical >eatures T Clinical si!ns are fairly non/specific, but may be similar to clinical si!ns reported in cats 2ith other li$er disorders, for e9ampleFlethar!y, anore9ia, 2ei!ht loss, and intermittent $omitin!. Abdominal effusion, Gaundice, and encephalopathy may be seen terminally.

Dia!nosis T <aboratory data are also usually non/specific. 4le$ations in serum li$er en5yme acti$ities and abnormalities in bile salt metabolismshould be ob$ious, but they are not remar:ably different from cats 2ith other li$er disorders. Ima!in! studies radio!raphy, ultrasono!raphy may

pro$ide e$idence of diffuse hepatome!aly or of discrete tumors in$ol$in! one or more li$er lobes. Definiti$e dia!nosis al2ays re6uires aspirationcytolo!y, or better yet, tissue biopsy. Aspirates andor tissue biopsies may be obtained by percutaneous trans/abdominal ultrasound !uidance,laparoscopy, or laparotomy techni6ues.

8herapy T 8he cell of ori!in of a metastatic tumor should al2ays be identified, if possible. Chemo/ or other therapies may then be selected based ona 2or:in! :no2led!e of the biolo!ic basis of the tumor. >ocal tumors of the li$er may be best mana!ed by hepatic lobe resection.

E!tra1Hepati 'ile D.t O,str.tion

Patho!enesis and 4tiolo!y T 49tra/hepatic cholan!itis, mali!nancy, pancreatitis, cholelithasis, and li$er flu:es Eurytrema procyonis, Platynosomum

concinnum are the maGor causes of e9tra/hepatic biliary obstruction in cats. Pro!ressi$e cholan!itis accounts for o$er '*? of the cases of hepatic ductobstruction, common bile duct obstruction, and pro!ressi$e hepatobiliary failure.

Clinical >eatures T Affected cats ha$e mar:ed persistent hyperbilirubinemia, and mar:ed ele$ations in serum A<8, A8, A<P, ;;8, and serum bile acids.#ltrasono!raphic e$idence of obstruction is ob$ious, and many cats under!o e9ploratory laparotomy and biliary decompression.

Dia!nosis T As 2ith other feline hepatobiliary disorders, dia!nosis of e9tra/hepatic bile duct obstruction re6uires careful inte!ration of history, physicale9amination, laboratory data, and ima!in! findin!s.

Pro!nosis and 8herapy T 8he pro!nosis for cats 2ith e9tra/hepatic biliary obstruction, re!ardless of underlyin! patho!enesis is !uarded to poor, and

8/10/2019 13 Mar Notes


perioperati$e morbidity and mortality is hi!h. 8he maGority of cats ha$e a prolon!ed disease course, and lon!/term complications include recurrin! boutsof cholan!itis, 2ei!ht loss, and biliary tract obstruction.

Congenital Portosyste"i Sh.nts

Patho!enesis and 4tiolo!y T Di$ersion of portal blood flo2 to the central circulation depletes the li$er of nutrients, hormones, and !ro2th factors.Portosystemic shunts in cats are !enerally e9tra/hepatic and most arise from the left !astric $ein. Portosystemic shuntin! results in poor hepatocyte!ro2th and function, and the li$er under!oes pro!ressi$e atrophy.

Clinical >eatures and Dia!nosis T Affected cats appear stunted, fail to !ro2, and ha$e e9cessi$e sali$ation perhaps as an early manifestation ofhepatoencephalopathy. Cats may manifest other beha$ioral and neurolo!ic abnormalities such as sei5ures, dementia, $isual disturbances, and ata9ia.Hnset of clinical si!ns 2ith feedin! and delayed reco$ery from anesthetic e$ents are reported more fre6uently 2ith canine portosystemic shunts.Affected cats may ha$e only subtle laboratory abnormalities mild increases in A<8 A8" mild hypoalbuminemia and hypocholesterolemia" lo2

blood urea nitro!en" and microcytosis. Dia!nosis is best achie$ed by couplin! a li$er function test bile salts andor =@& 6uantitations to a li$erima!in! techni6ue, e.!., ultrasono!raphy, scinti!raphy, or contrast portal $eno!raphy. <i$er biopsy typically re$eals portal $enous hypoplasia,arterial smooth muscle hypertrophy, hepatocellular atrophy 2ith lipo!ranulomas, and sometimes periportal sinusoidal dilatation.

Pro!nosis and 8herapy T 8he pro!nosis is !enerally !ood if reco!ni5ed early in the course of the disease. Cats are best mana!ed 2ith sur!icalattenuation or li!ation of the shuntin! $essel. ome cats, especially those 2ith incomplete attenuation of the shunt, may still re6uire medical therapyfollo2in! sur!ical repair.

%eferenes 5 A-aila,le .pon re/.est*

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