UpdateUpdate inin GI:GI: WhatWhat’’ss NewNew andand UsefulUseful
WalterWalter J.J. Coyle,Coyle, MD,MD, FACP,FACGFACP,FACG OctoberOctober 20122012 DisclosuresDisclosures
II havehave nono disclosuresdisclosures relatedrelated toto thisthis talktalk
Specifically,Specifically, II havehave nono interestsinterests inin anyany probioticprobiotic oror prepre--bioticbiotic brandsbrands MovementMovement ofof thethe TalkTalk
EosinophilicEosinophilic esophagitis:esophagitis: WhatWhat isis itit andand howhow dodo II treattreat it?it? GERD:GERD: WhatWhat’’ss New?New? CeliacCeliac Sprue:Sprue: TheThe epidemicepidemic CRCCRC screening:screening: FollowFollow thethe guidelinesguidelines WhatWhat’’ss new?new?
MovementMovement ofof thethe TalkTalk PartPart IIII
StoolStool Transplants:Transplants: TheThe NewNew RageRage RosaceaRosacea andand SIBO:SIBO: NewNew evidenceevidence ChronicChronic nausea:nausea: aa newnew linklink TheThe HumanHuman Microbiome:Microbiome: HotHot topictopic ProPro andand PrePre biotics:biotics: aa rationalrational approachapproach C.C. difficiledifficile :: ItIt willwill notnot gogo away!away! ConclusionsConclusions
QuestionQuestion NumberNumber 11
2727 yearyear oldold malemale A. PepticPeptic stricturestricture presentspresents withwith intermittentintermittent solidsolid foodfood B. SchatzkiSchatzki ’’ss ringring dysphagiadysphagia forfor years.years. HeHe C. EosinophilicEosinophilic esophagitisesophagitis hashas hadhad 22 foodfood D. AdenocarcinomaAdenocarcinoma ofof thethe impactions.impactions. HeHe hadhad distaldistal esophagusesophagus childhoodchildhood asthma.asthma. E. AchalasiaAchalasia The most likely The most likely diagnosisdiagnosis is?is? EosinophilicEosinophilic EsophagitisEsophagitis
Common,Common, maymay bebe increasingincreasing HigherHigher inin males,males, youngeryounger ptspts withwith h/oh/o atopyatopy StrongStrong associationassociation withwith foodfood andand aeroallergensaeroallergens THETHE ALLERGICALLERGIC ESOPHAGUSESOPHAGUS Adults:Adults: presentpresent withwith dysphagia,dysphagia, atypicalatypical GERDGERD symptoms:symptoms: UsuallyUsually havehave yearsyears ofof symptomssymptoms Children:Children: FailureFailure toto thrive,thrive, nauseanausea oror vomiting.vomiting.
EosinophilicEosinophilic EsophagitisEsophagitis
LinearLinear FurrowsFurrows
RingsRings
Diagnosis:Diagnosis: BiopsyBiopsy atat endoscopyendoscopy EosinophilicEosinophilic EsophagitisEsophagitis
Eos.Eos. AbscessesAbscesses
Long,Long, oftenoften complexcomplex stricturesstrictures
CarefulCareful dilationdilation
EosinophilicEosinophilic EsophagitisEsophagitis
MucosalMucosal teartear afterafter scopescope passagepassage
TryTry medicalmedical treatmenttreatment firstfirst EosinophilicEosinophilic Esophagitis:Esophagitis: TreatmentTreatment
PPIsPPIs havehave shownshown efficacyefficacy inin upup toto 50%50% ofof ptspts TopicalTopical steroidssteroids usefuluseful butbut recentrecent PC/RandPC/Rand studiesstudies havehave shownshown lessless efficacyefficacy thenthen openopen labellabel studiesstudies FluticosoneFluticosone oror budesonide:budesonide: SwallowedSwallowed (not(not inhaled)inhaled) AllergyAllergy consultation:consultation: MayMay bebe helpfulhelpful inin findingfinding foodfood oror aeroallergenaeroallergen thatthat isis mainmain culpritculprit
Am J Gastroenterol 2010; 105:747–756 GERD:GERD: WhatWhat’’ss HotHot VisceralVisceral AdiposityAdiposity IncreasesIncreases thethe RiskRisk ofof GERDGERD
Subcutaneous adiposity Visceral adiposity
Courtesy of Brian Jacobson ObesityObesity--SeparationSeparation ofof thethe LESLES andand DiaphragmaticDiaphragmatic CrusCrus
HRM Inspiration LES
Crural separation Diaphragm
Visceral Adiposity Intragastric Intragastric Pressure Pressure
Normal Obese
Pandolfino JE, et al. Gastroenterology 2006; 639-349 GERDGERD andand BMI:BMI: WomenWomen
An increase in BMI of 3.5 was associated with increased risk of frequent GERD symptoms, even in women with normal baseline weight 4 P<0.001 3.5 Multivariate 3 odds in women 2.5 with at least 2 weekly GERD Odds Ratio 1.5 symptoms 1 (n=2306) or no 0.5 symptoms 0 (n=3904) <20 20 22 25 27 30 ≥35
N Engl J Med 2006;354:2340-2348. ObesityObesity asas aa RiskRisk Factor:Factor: BarrettBarrett’’ss EsophagusEsophagus
Risk of Barrett’s Esophagus in Obesity with GERD Symptoms
Obesity Odds Ratio 95% CI
With GERD Symptoms 34.4 6.3-188.0
Without GERD Symptoms 0.7 0.2-2.4 n = 167 with histologically confirmed Barrett’s esophagus
Smith KJ, et al. Cancer Epidemiol Biomarkers Prev. 2005;14:2481-2486. n = 2602
Hvid-Jensen et al., NEJM 2011;365(15):1375-1385 Lower Incidence of EAC with Larger Studies
Wani et al Clin Gastroenterol Hep. 2011; 9:200-220 GERDGERD
PPIsPPIs areare nono longerlonger viewedviewed asas innocuousinnocuous medsmeds MalabsorptionMalabsorption ofof nutrientsnutrients Iron, calcium, Vitamin B12B12 IncreaseIncrease riskrisk forfor fracturesfractures IncreaseIncrease riskrisk forfor infectionsinfections includingincluding ClostridiumClostridium difficiledifficile InteractionInteraction withwith clopidogrelclopidogrel (less(less anan issueissue now)now)
PPIPPI useuse andand HipHip fracturefracture
CaseCase--controlcontrol studystudy ofof patientspatients olderolder thanthan 5050 yearsyears inin aa largelarge UKUK databasedatabase PPI users had a 4 /1000 risk for hip fx vs 1.8 /1000 in non- users of acid related meds Absolute risk still low SevenSeven casecase controlcontrol oror cohortcohort trialstrials havehave shownshown aa smallsmall absoluteabsolute increasedincreased riskrisk ofof fracturesfractures RecentRecent metameta--analysisanalysis (DDW(DDW absabs only)only) showedshowed aa slightslight increaseincrease inin hiphip fxfx withwith PPIPPI therapytherapy JAMA 2006;296:2947-29 Calcif Tissue Int. 2008;83:251-259 LongLong termterm PPIPPI useuse
AGAAGA nownow recommendsrecommends CalciumCalcium // VitVit DD inin longlong termterm usersusers atat riskrisk forfor osteoporosisosteoporosis NoNo guidelinesguidelines forfor monitoringmonitoring B12B12 oror ironiron BeBe aware,aware, checkcheck whenwhen clinicallyclinically indicatedindicated BeBe awareaware ofof medsmeds thatthat absorbabsorb betterbetter withwith acidacid Digoxin,Digoxin, amoxicillin,amoxicillin, ketoconazole,ketoconazole, iron,iron, calciumcalcium OrganicOrganic (heme(heme derived)derived) ironiron nownow availableavailable
PPIsPPIs andand InfectionsInfections
StudiesStudies havehave linkedlinked acidacid suppresionsuppresion medsmeds includingincluding PPIsPPIs withwith C.C. difficiledifficile infectioninfection HigherHigher recurrencerecurrence ofof CC diffdiff ifif onon PPIPPI atat timetime ofof RxRx
MayMay increaseincrease riskrisk forfor hospitalhospital acquiredacquired pneumoniapneumonia
Am J Gastro 2007;102:2047-56 CMAJ 2004;171:33-38 JAMA. 2004;292:1955-60 Ann Intern Med. 2008;149:391-98 Arch Intern Med 2010;170:772-8 42% more likely to recur if on PPIs
Arch Intern Med. 2010;170(9):772-778 PPIs:PPIs: WaltWalt’’ss RecsRecs
RightRight drug,drug, rightright disease,disease, rightright patientpatient IfIf youryour patientpatient needsneeds thethe PPIPPI forfor PUD,PUD, GIGI bleeding,bleeding, BarrettBarrett ’’ss esophagus,esophagus, thenthen useuse thethe PPIPPI Lowest dose that works Use Calcium and Vit D in long term users IfIf itit isis symptomaticsymptomatic GERDGERD only,only, otherother optionsoptions LifestyleLifestyle changes,changes, H2H2 blockers,blockers, antacidsantacids InformedInformed consentconsent toto patientpatient untiluntil finalfinal datadata NB.NB. MoreMore GIGI bleedingbleeding inin CogentCogent studystudy inin nonnon--PPIPPI usersusers CeliacCeliac Disease:Disease: WhatWhat’’ss New!New!
CommonCommon gene:gene: DQ2DQ2 andand DQ8:DQ8: UpUp toto 25%25% ONLYONLY predisposespredisposes oneone toto CeliacCeliac ActualActual diseasedisease inin 1%1% inin US:US: IcebergIceberg analogyanalogy GlutenGluten enteropathyenteropathy VSVS GlutenGluten intoleranceintolerance GlutenGluten avoidanceavoidance isis inin vogue!!!vogue!!! Diagnosis:Diagnosis: GoldGold standardstandard remainsremains SBSB biopsybiopsy Serology:Serology: TissueTissue TransglutaminaseTransglutaminase andand EndomysialEndomysial antibodyantibody excellentexcellent sens/specificitysens/specificity ALWAYSALWAYS checkcheck serumserum IgAIgA (IgA(IgA deficiency)deficiency)
CeliacCeliac BurdenBurden VaryingVarying FormsForms ofof CeliacCeliac DiseaseDisease
• ClassicalClassical celiacceliac diseasedisease ofof childhoodchildhood • LateLate onset,onset, nonnon--specificspecific GIGI symptomssymptoms • DermatitisDermatitis herpetiformisherpetiformis • ExtraExtra --intestinalintestinal presentationspresentations (many)(many) • AssociatedAssociated conditionsconditions (many)(many) • SilentSilent oror asymptomaticasymptomatic celiacceliac diseasedisease (relatives)(relatives) • LatentLatent oror potentialpotential celiacceliac diseasedisease
DermatitisDermatitis HerpetiformisHerpetiformis
• Pruritic papulovesicular lesions IgA deposits at dermal-epidermal junction • Almost all have abnormal intestinal biopsies Few have GI symptoms • Treatment directed against skin doesn’t help gut lesions (e.g., dapsone) • Gluten free diet helps both gut and skin
AssociatedAssociated AutoimmuneAutoimmune ConditionsConditions
• DiabetesDiabetes mellitusmellitus -- TypeType II ~~ 33 toto 88 %% havehave celiacceliac diseasedisease • AutoimmuneAutoimmune thyroidthyroid diseasedisease (~5%) • AddisonAddison ’’ss diseasedisease • AlopeciaAlopecia areataareata • SjogrenSjogren ’’ss syndromesyndrome • OthersOthers
AssociatedAssociated HepatobiliaryHepatobiliary ConditionsConditions
• PrimaryPrimary sclerosingsclerosing cholangitischolangitis • AutoimmuneAutoimmune cholangitischolangitis • PrimaryPrimary biliarybiliary cirrhosiscirrhosis • ElevatedElevated transaminasestransaminases (up to 5 X normal) NonspecificNonspecific histologichistologic changeschanges NormalizeNormalize onon GFDGFD withinwithin aa yearyear inin 7575--95%95% EvaluationEvaluation ofof unexplainedunexplained elevatedelevated AST,AST, ALTALT includesincludes testingtesting forfor celiacceliac diseasedisease
Rubio-Tapa, A, et al, Hepatology, 46, 1650, 2007 ChangingChanging PicturePicture ofof DiseaseDisease
• ClassicalClassical formform lessless prevalentprevalent nownow • AverageAverage ageage ofof diagnosisdiagnosis inin 55th decadedecade
• ManyMany areare overweightoverweight • SeroprevalenceSeroprevalence M=F,M=F, diagnosisdiagnosis M CeliacCeliac IssuesIssues andand DilemmaDilemma PtPt presentspresents forfor CeliacCeliac testingtesting onon glutengluten freefree dietdiet PtPt hashas negativenegative serologyserology (maybe(maybe eveneven normalnormal SBSB biopsy)biopsy) andand insistsinsists theythey havehave celiacceliac RoleRole forfor geneticgenetic testingtesting GlutenGluten intoleranceintolerance vsvs GlutenGluten enteropathyenteropathy HealthHealth Maintenance:Maintenance: BoneBone healthhealth LiverLiver diseasedisease VitaminVitamin andand mineralmineral deficienciesdeficiencies Am J Gastroenterol advance online pub, 1 March 2011 Gluten Causes Gastrointestinal Symptoms in Subjects Without Celiac Disease: A Double-Blind Randomized Placebo-Controlled Trial Jessica R. Biesiekierski , B Appl Sci 1 , Evan D. Newnham , MD, FRACP 1 , Peter M. Irving , MD, MRCP 1 , Jacqueline S. Barrett ,PhD, BSc, MND 1 , Melissa Haines , MD 1 , James D. Doecke , BSc, PhD 2 , Susan J. Shepherd , B Appl Sci, PhD 1 , Jane G. Muir ,PhD, PGrad Dip(Dietetics) 1 and Peter R. Gibson , MD, FRACP 1 Am J Gastroenterol advance online publication, 11 January 2011; doi: 10.1038/ajg.2010.487 Results Am J Gastroenterol advance online publication, 11 January 2011; doi: 10.1038/ajg.2010.487 Results Discussion No prior randomized controlled trials demonstrating that the entity of “gluten intolerance” does actually exist This study supports the existence of non-celiac gluten sensitivity based on the following symptoms: Bloating Dissatisfaction with stool consistency Abdominal pain Tiredness Gluten:Gluten: TheThe newnew badbad boyboy Future studies Gluten may have the following deleterious effects in non-celiac patients: Increase fermentation, and thus, distension Increase cholinergic activation, and thus, increased smooth muscle contractility Increase enteric NS stimulation by gluten digestion creating neurally active peptides Symptoms may not be related to gliadin proteins of gluten Carbohydrates – fructans (in wheat) Novak Djokavic claims his energy improved on gluten- free diet and coincided with his winning streak “A gluten-free diet can have implications far beyond the physical, especially in tennis, which taxes the mind like few other sports.” ColonColon CancerCancer ScreeningScreening ReviewReview ofof thethe GuidelinesGuidelines WhatWhat’’ss new?new? HowHow areare wewe doing?doing? QuestionQuestion NumberNumber 33 WhatWhat isis thethe lifetimelifetime A.A. 2%2% riskrisk forfor coloncolon B.B. 4%4% cancercancer inin thethe C.C. 6%6% UnitedUnited States?States? D.D. 8%8% E.E. 10%10% ColonColon CancerCancer SecondSecond mostmost commoncommon causecause ofof cancercancer deathdeath PrototypicalPrototypical diseasedisease forfor screeningscreening Intermediate probability of disease Significant impact on public health Well defined, modifiable disease progression Current Guidelines USPSTF ACS ACR ACG USMSTFCC Age 50-75 50 50/45 AfAm Colonoscopy 10 yrs 10 yrs 10yrs Flex Sig 5 yrs 5-10 yrs FS/FOBT 5 yrs/ 3 yrs DCBE 5 yrs CT Insuff Evid 5 yrs 5 yrs Colonography FOBT Yearly Yearly Yearly FIT Yearly Yearly Pt refuses Stool DNA ? Colo FSig FOBT FIT DCBE CTC sDNA USPSTF Q10yr; Q5yr; Annually; Annually; NM Insufficient Insufficient 2008 Age 50-75 Age 50-75 Age 50-75 Age 50-75 evidence evidence ACS-MSTF Q10yr; Q5yr; Annually; Annually; Q5yr; Q5yr; Age ≥ 50; 2008 Age ≥ 50 Age ≥ 50 Age ≥ 50 Age ≥ 50 Age ≥ 50 Age ≥ 50 interval uncertain ACG 2009 ACS/MSTF Q5-10yr; Annually; Annually; NM Q5yr; Q3 yr; Age ≥ 50 Age ≥ 50 Age ≥ 50 Age ≥ 50 Age ≥ 50 AAFP 2010 USPSTF USPSTF USPSTF NM NM USPSTF USPSTF NCCN 2010 ACS/MSTF ACS/MST ACS/MSTF ACS/MSTF NM ACS/MSTF Not first-line; F Uncertain interval Kaiser Avg risk Avg risk Avg risk Avg risk NR NR NR adults adults adults adults Aetna ACS/MSTF ACS/MST ACS/MSTF ACS/MSTF ACS/MSTF Exper. and Exper. and F Investigat. Investigat. United ACS/MSTF ACS/MST ACS/MSTF ACS/MSTF ACS/MSTF NM Exper. and F Investigat. RecentRecent Evidence:Evidence: ColonoscopyColonoscopy ReducesReduces MortalityMortality NationalNational PolypPolyp StudyStudy (2012)(2012) Removal of adenomas resulted in 53% lower risk of CRC related death within 10 years (up to 23 years) CanadianCanadian studiesstudies CRC related deaths decreased with gastroenterologist performed colonoscopy complete to cecum (even right sided) GermanGerman studystudy Diminished CRC incidence after colonoscopy Zauber AG et al. NEJM 2012 FITFIT AntibodyAntibody teststests forfor thethe globinglobin productproduct TestTest performanceperformance cancan bebe modified/adjustedmodified/adjusted BetterBetter compliancecompliance thanthan FOBTFOBT Easier (brush stool inin toilettoilet water)water) Not impacted by diet One, two, or three samples required AnyAny positivepositive testtest == colonoscopycolonoscopy CannotCannot makemake aa classclass recommendationrecommendation Individual tests vary considerably; similar sensitivity to HS FOBT and better specificity N ENGL J MED 2012; 366:697-706 Colonoscopy versus FIT in Colorectal- Cancer Screening 26,703 colo invites; 26,599 FIT invites Male and females, randomized, prospective 24.6% had colo vs 34.2% had FIT (P<.001) CRC: 30 pts (.1%) vs 33 (.1%) Adenomas: 514 (1.9%) vs 234 (.9%) P<.001 FIT test may compare well to colo for cancer detection. Poor for detection of polyps. N ENGL J MED 2012; 366:697-706 AverageAverage RiskRisk Screening:Screening: RecommendationsRecommendations OR ≥50 years old Colonoscopy (every 10 years) Preferred: ACG and MSGITF OR Option: USPSTF, ACS, AGA Barium enema (every 5 years) Flexible Stool cards FUTURE? sigmoidoscopy (yearly); FIT?? Stool DNA AND (every 3–5 years) CT colonography Capsule Colonoscopy NewNew RecommendationsRecommendations forfor AfricanAfrican--AmericansAmericans YoungerYounger meanmean ageage atat diagnosisdiagnosis (60(60––6666 years)years) HigherHigher incidenceincidence ratesrates HigherHigher mortalitymortality ratesrates MoreMore proximalproximal distributiondistribution ofof cancerscancers andand adenomasadenomas RecentRecent AmericanAmerican CollegeCollege ofof GastroenterologyGastroenterology recommendationsrecommendations toto beginbegin averageaverage--riskrisk screeningscreening atat ageage 4545 http://seer.cancer.gov/csr/1975-2000. Access February 23, 2006. Agrawal S, et al. Am J Gastroenterol. 2005;100:515–523. Ghafoor A, et al. CA Cancer J Clin. 2002;52:326–341. ScreeningScreening ComplianceCompliance isis LowLow Cancer Prevention and Early Detection, Fact s and Figures 2008 StoolStool Transplants:Transplants: EveryoneEveryone isis doingdoing it!it! StoolStool Transplants:Transplants: HowHow ToTo StoolStool transplants:transplants: ““preparedprepared”” fecesfeces byby NGTNGT oror enemaenema oror colonoscopycolonoscopy UsuallyUsually familyfamily member;member; 3030--5050 gg freshfresh stoolstool StoolStool homogenizedhomogenized forfor deliverydelivery NoNo infectiousinfectious complicationscomplications toto datedate ScreenScreen forfor Hepatitis,Hepatitis, HIV,HIV, etcetc…… 7373--100%100% responseresponse reportedreported inin CC DiffDiff Gastro 2006;130 Clin Infect Dis 2003;36 StoolStool Transplant:Transplant: EvidenceEvidence 20032003 casecase seriesseries ofof refractoryrefractory CC diffdiff patientspatients StoolStool viavia NGNG fromfrom healthyhealthy familyfamily membermember 1515 ofof 1818 becamebecame recurrencerecurrence--freefree 20092009 casecase seriesseries ofof refractoryrefractory CC diffdiff patientspatients 1111 ofof 1515 becamebecame recurrencerecurrence--freefree 20102010 casecase seriesseries ofof refractoryrefractory CC diffdiff patientspatients StoolStool viavia colonoscopycolonoscopy 1212 ofof 1212 withwith immediateimmediate andand sustainedsustained responseresponse Clin Infect Dis 2003;36: 540-544 QJM 2009;102:781-784 Yoon, J of Clin Gastro 2010, 44:562-66 ColonoscopyColonoscopy StoolStool TransplantsTransplants ComingComing toto youryour neighborhoodneighborhood soonsoon…….. Stool transplants done here. Donations accepted. CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2010;8:471–473 FecalFecal TransplantTransplant WorkgroupWorkgroup GoodGood reviewreview andand providesprovides ““cookbookcookbook”” reciperecipe forfor performingperforming fecalfecal transplanttransplant CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2011;9:1044–1049 CoyleCoyle’’ss CorollaryCorollary It is better to be a stool donor than a recipient. Stool donor cards will be made available after this lecture. Stool Donor Card Share your stool; stop C diff Clinical Gastro Hep 2008; 759-764 MethodsMethods Prosp.Prosp. study;study; 113113 ptspts withwith rosacearosacea 6060 controlscontrols DermDerm AssessmentAssessment byby twotwo docsdocs 77 pointpoint scalescale AllAll subjectssubjects completedcompleted globalglobal scorescore BaselineBaseline labs,labs, UreaseUrease BT,BT, H2H2 BreathBreath teststests LactuloseLactulose BT:BT: 11st,, ++ testtest ifif doubledouble peakpeak seenseen GlucoseGlucose BT:BT: 22nd (1(1 wkwk later),later), ++ testtest singlesingle peakpeak HpHp ++ pts,pts, treatedtreated thenthen rere--testedtested byby H2H2 BTBT IfIf bothboth HpHp ++ andand SIBO+:SIBO+: rxrx SIBOSIBO 1st1st Results:Results: SIBOSIBO pospos andand negneg ptspts Clinical Gastro Hep 2008; 759-764 RosaceaRosacea andand thethe MicrobiomeMicrobiome DiscussionDiscussion SIBOSIBO commoncommon inin RosaceaRosacea ptspts EspEsp thosethose withwith papulopustulespapulopustules RxRx ofof SIBOSIBO resultsresults inin dramaticdramatic improvementimprovement ofof rashrash 78%78% resolved/17%resolved/17% improvedimproved (95%(95% total)total) AffectAffect isis sustainedsustained (9(9 months);months); relapserelapse cancan bebe rere--treatedtreated Hypothesis:Hypothesis: SIBOSIBO increasesincreases intestintest absorptionabsorption ofof bacterialbacterial products,products, espesp endotoxin,endotoxin, proinflamproinflam cytokinescytokines SIBOSIBO moremore importantimportant thenthen coloniccolonic bacteriabacteria (SIBO(SIBO negneg rosacearosacea ptspts diddid notnot respondrespond asas well)well) QuestionQuestion numbernumber 4.4. WhatWhat isis thethe causecause ofof discoloration?discoloration? A. StrepStrep toxictoxic shockshock syndromesyndrome B. GrayGray TurnerTurner signsign fromfrom pancreatitispancreatitis C. CannabinoidCannabinoid hyperemesishyperemesis syndromesyndrome D. HeparinHeparin--inducedinduced cutaneouscutaneous hemorrhagehemorrhage CannabinoidCannabinoid HyperemesisHyperemesis SyndromeSyndrome FirstFirst reportedreported inin AustraliaAustralia Chronic,Chronic, heavyheavy marijuanamarijuana useuse MoreMore commoncommon inin malesmales RecurrentRecurrent episodesepisodes ofof abdominalabdominal painpain andand vomitingvomiting CompulsiveCompulsive hothot bathingbathing andand showersshowers forfor reliefrelief ofof symptomssymptoms Rx:Rx: QuitQuit thethe Weed!Weed! Singh E, Coyle W. Am J Gastro 2008;103:1048-49 Mayo Clin Proc. 2012;87(2):114-119 Mayo Clin Proc. 2012;87(2):114-119 TheThe MicrobiomeMicrobiome andand ProbioticsProbiotics TheThe HumanHuman MicrobiomeMicrobiome Definitions:Definitions: Microbiome:Microbiome: AggregateAggregate ofof allall gutgut speciesspecies Microbiota:Microbiota: IndividualIndividual bacterialbacterial speciesspecies inin thethe biomebiome OverOver 100100 trilliontrillion organismsorganisms (10(1014)) PassengersPassengers inin thethe mobilemobile coloniccolonic petripetri dishdish OverOver 500500 speciesspecies identifiedidentified soso farfar (70(70 divisions)divisions) 90%90% ofof thethe cellscells inin ourour bodybody ourour microbial!microbial! 100100 foldfold moremore genesgenes inin ourour gutgut thenthen inin usus OurOur floraflora areare anan integralintegral partpart ofof ourour geneticgenetic landscapelandscape andand evolutionevolution TheThe Microbiome:Microbiome: WhoWho’’ss there?there? EarlyEarly gutgut colonizationcolonization hashas fourfour phasesphases PhasePhase 1:1: SterileSterile gutgut PhasePhase 2:2: InitialInitial acquisition:acquisition: vagina,vagina, feces,feces, hospitalhospital PhasePhase 3:3: BreastBreast feedingfeeding oror bottlebottle--feedingfeeding (different)(different) Breast fed more bifidobacteria (up to 90% of flora) Bottle fed more diverse; more Bacteroides , and Clostridial species PhasePhase 4:4: StartStart ofof solids;solids; movemove toto adultadult floraflora Bifidobacteria remain key flora into adulthood Ley, Peterson, Gordon. Cell 2006 ;124:837 Ley, et al. PNAS. 2005, 102: 11070 Edwards, et al. Br J Nutr. 2002 CC--SectionSection andand GutGut FloraFlora DanishDanish Registry:CRegistry:C--sectionsection vsvs NVDNVD inin 2.12.1 milmil DanesDanes 3232 millionmillion personperson yearsyears ofof followfollow--upup 1.291.29 RRRR forfor IBDIBD (most(most notablenotable << ageage 14)14) ScottishScottish studystudy onon risingrising incidenceincidence ofof IBDIBD CC--sectionsection associatedassociated withwith increasedincreased riskrisk ofof IBDIBD 1.261.26 RRRR (boys(boys only)only) MoreMore UCUC thanthan CDCD Bager, et al. Inflam Bowel disease, 2012;18:857-62 Andersen et al. Inflam Bowel disease, 2012;18:999-1005 BreastfeedingBreastfeeding andand IBDIBD SystemicSystemic review:review: FoundFound 88 articlesarticles relatedrelated ChildrenChildren whowho areare breastbreast fedfed protectedprotected fromfrom IBDIBD DecreasedDecreased riskrisk forfor IBDIBD (OR(OR .69,.69, CICI .51.51--.94,.94, P=02)P=02) OnlyOnly protectiveprotective inin earlyearly yearsyears IsIs itit microbiomemicrobiome oror somesome factorfactor inin breastbreast milk?milk? Barclay et al. J Pediatrics, 2009;155:421-426 The Human Gut Flora DiBiase, et al. Mayo Clin Proc 2008;83:460-469 Microbes and Humans Dethlefsen Nature 2007; 449:812-818 StudiedStudied 11,53211,532 childrenchildren inin Avon,Avon, UKUK (91(91--93)93) MappedMapped antibioticantibiotic useuse (<6m,6(<6m,6--14m,1514m,15--23m)23m) BodyBody massmass documenteddocumented atat 6wks,6wks, 10m,10m, 20m,20m, 38m38m andand 77 yrsyrs MultivariateMultivariate analysis:analysis: rolerole ofof tob,tob, mothermother’’ss BMI,BMI, otherother medications,medications, etcetc…… International J of Obesity; 2012: 1-8 AntibioticsAntibiotics inin childrenchildren andand obesityobesity Blaser, et al. Nature 2012 Proposed Mechanisms in Obesity DiBiase, et al. Mayo Clin Proc 2008;83:460-469 GutGut FloraFlora andand MetabolismMetabolism MicrobialMicrobial genomesgenomes enhanceenhance ourour metabolicmetabolic activityactivity MayMay indirectlyindirectly oror directlydirectly effecteffect ourour metabolismmetabolism TheThe coloncolon isis veryvery activeactive metabolicallymetabolically 2020--7070 gmsgms ofof carboscarbos andand 55--2020 gmsgms ofof protein/dayprotein/day Over 100 kcal per day! MassMass ofof coloniccolonic microbiomemicrobiome == singlesingle kidneykidney MetabolicallyMetabolically asas activeactive asas thethe liverliver Hooper, et al. Annu Rev Nutr, 2002 ProbioticsProbiotics Definition:Definition: LiveLive microorganismsmicroorganisms whichwhich whenwhen ingestedingested inin adequateadequate amountsamounts conferconfer aa healthhealth benefitbenefit onon thethe host.host. MajorityMajority ofof probioticsprobiotics areare GramGram +,+, lacticlactic acidacid producersproducers (ie.(ie. Firmacutes)Firmacutes) Bifidobacterial species and Lactobacillus species Survive transit through stomach and duodenum OthersOthers include:include: nonnon--pathogenicpathogenic streptococci,streptococci, enterococci,enterococci, EE colicoli NissleNissle 1917,1917, SaccharomycesSaccharomyces boulardiiboulardii (yeast)(yeast) Fooks, et al. Int Dairy J, 1999 Sheil, et al. In Gastrointestinal Microbiology, 2006 QuestionQuestion NumberNumber 55 WhichWhich probioticprobiotic hashas beenbeen shownshown toto A. LactobacillisLactobacillis acidopholusacidopholus decreasedecrease mucosalmucosal B. BifidobacterBifidobacter infantisinfantis ILIL--66 levels?levels? C. SaccharomycesSaccharomyces boulardiiboulardii D. LactobacillusLactobacillus rhamnosusrhamnosus GGGG ProbioticsProbiotics VSLVSL #3#3 44 lactobacillilactobacilli L. plantarum, casei, acidopholus, delbrueckii spp 33 bidifobacteriabidifobacteria B. infantis, breve, longum 11 streptococcusstreptococcus Streptococcus salivarius ssp. thermophilus Rand, PC studies have shown efficacy in pouchitis and IBS Some efficacy in mild/mod UC in new study ProbioticsProbiotics 1212 differentdifferent speciesspecies MostlyMostly LactobacillusLactobacillus andand BidifobacterBidifobacter speciesspecies ClinicalClinical datadata withwith thesethese combinationscombinations lackinglacking ProbioticsProbiotics DigestiveDigestive AdvantageAdvantage Ganeden BC30 Bacillus coagulans Erythritol Cellulose Other minor ingredients SomeSome datadata forfor IBSIBS MostlyMostly bloatingbloating Postgrad Med, Vol. 121, Issue 2, March 2009 ProbioticsProbiotics BifidobacteriumBifidobacterium infantisinfantis 3562435624 akaaka BifantisBifantis ““PatentedPatented”” strainstrain ofof probioticprobiotic inin AlignAlign DecreasedDecreased symptomssymptoms inin twotwo largelarge trialstrials inin subjectssubjects withwith IBS*IBS* *Whorwell P, et al. Am J Gastro 2006; 101 O’Mahoney L, et al. Gastro 2005;128 ProbioticsProbiotics SaccharomycesSaccharomyces boulardiiboulardii OtherOther minorminor ingredientsingredients ShownShown inin RandRand // PCPC trialstrials toto helphelp preventprevent recurrentrecurrent C.C. difficiledifficile infectioninfection DecreasesDecreases antibioticantibiotic associatedassociated diarrheadiarrhea Am J Gastroenterol. 2006 Apr;101(4):812-22 McFarland, et al. JAMA 1994;271:1913-8 Probiotics:Probiotics: E.E. colicoli NissleNissle 19171917 DiscoveredDiscovered inin 19171917 byby ProfessorProfessor AlfredAlfred NissleNissle WellWell studiedstudied SomeSome datadata forfor useuse inin IBD,IBD, IBS,IBS, andand AbAb associatedassociated diarrheadiarrhea ExcellentExcellent safetysafety profileprofile ProbioticsProbiotics inin FoodFood (Actimel)(Actimel) L.L. caseicasei ImmunitasImmunitas™™ ClaimClaim itit isis scientificallyscientifically provenproven toto bebe effectiveeffective ““EachEach bottlebottle containscontains 1010 billionbillion livelive”” bacteriabacteria ““thatthat survivesurvive andand remainremain activeactive inin thethe digestivedigestive tract.tract.”” ProbioticsProbiotics inin FoodFood (Activia)(Activia) ContainsContains BifidusBifidus regularisregularis BifidobacteriumBifidobacterium animusanimus ScientificScientific trialstrials showshow increasedincreased transittransit timetime inin adultsadults andand womenwomen ““HelpsHelps withwith slowslow transittransit inin womenwomen andand thethe elderlyelderly”” Bioscience and Microflora, 2001;20:43-48, Aliment Pharn Ther 2002;16:587-93 ProbioticsProbiotics forfor ImmuneImmune SystemSystem Lactobacillus rhamnosus GG (ATCC 53103) Patented by Gorbach and Goldin Various studies have shown it to be better than placebo for diarrheal illnesses Proven to survive the stomach, produces lactic acid and binds to human colonocytes BMJ 2007; 335 : 340-345 ProbioticsProbiotics andand prebioticsprebiotics inin maintenancemaintenance ofof remissionremission inin CrohnCrohn’’ss diseasedisease Study Groups Relapse Rate (%) n Intervention Comparator Dur Intervention Comparator p Guslandi 32 S. Bouliardii Mesalamine 6 6 38 0.04 (2000) + Mesalamine Campieri 40 VSL #3 Mesalamine 12 20 40 NR (2000) Prantera 45 LGG Placebo 12 17 11 0.3 (2002) Schultz 11 LGG Placebo 6 60 67 NS (2004) Bousvaro 75 LGG Placebo 24 31 17 0.18 s (2005) Marleau 98 L. johnsonii Placebo 6 49 64 0.15 (2006) Van 70 L. johnsonii Placebo 3 15 14 0.91 Gossum (2007) Chermes 30 Synbiotic Placebo 24 25 20 NS h (2007) 2000 Clostridium difficile Clostridium difficile and altered and altered microbiota microbiota Clostridium difficile Clostridium difficile ConfirmedConfirmed BIBI NAP1NAP1 strainstrain Gerding, et al. GASTRO 2009;136:1913–1924 MetronidazoleMetronidazole failuresfailures Leffler and Lamont in GASTRO 2009;136:1899–1912 NewNew CC DifficileDifficile RxRx GuidelinesGuidelines Infect Control Hosp Epidemiol 2010; 31(5):431-455 BurdenBurden OfOf CDICDI inin USUS Gerding, et al. GASTRO 2009; 136:1913–1924 TreatmentTreatment DCDC offendingoffending antibioticantibiotic (s)(s) ifif possiblepossible AvoidAvoid antiperistalticantiperistaltic agentsagents (incl(incl narcs)narcs) SupportiveSupportive carecare (hydrate,(hydrate, electrolytes)electrolytes) AntimicrobialAntimicrobial therapy:therapy: OralOral metronidazole:metronidazole: 250250 mgmg qidqid oror 500500 mgmg TIDTID forfor 1010 days;days; lowlow cost,cost, effectiveeffective OralOral Vancomycin:Vancomycin: 125125--250250 mgmg QIDQID forfor 1010 daysdays High cost Ann Intern Med 2006;145 Gastro 2009; 136:1913–1924 Recurrence:Recurrence: ProbioticProbiotic TreatmentTreatment ofof CC difficiledifficile ProbioticsProbiotics SaccharomycesSaccharomyces boulardii:boulardii: 500500 mgmg bidbid forfor 44--66 wkswks BestBest evidenceevidence ofof allall probioticsprobiotics SeveralSeveral DBDB // PCPC trialstrials showshow goodgood efficacyefficacy Lactobacilli:Lactobacilli: 11 gg qidqid forfor 44--66 weeksweeks EvidenceEvidence notnot asas convincingconvincing POPO nontoxicogenicnontoxicogenic CC Diff:Diff: experimentalexperimental EffectiveEffective butbut onlyonly casecase reportsreports toto datedate Gastro 2006;130 Ann Intern Med 2006; 145 Am J Gastroenterol 2006; 101:812–822. FidaxomicinFidaxomicin MacrocyclicMacrocyclic antibioticantibiotic Cure:Cure: 88.2%88.2% vsvs 85.8%85.8% vancomycinvancomycin RecurrenceRecurrence Rate:Rate: 15.415.4 %% vsvs 25.325.3 %% FDAFDA approved.approved. FidaxomicinFidaxomicin NEJM 2011;364:422-431 FidaxomicinFidaxomicin FDAFDA approvedapproved MayMay 20112011 MacrolideMacrolide Ab:Ab: AkaAka DificidDificid Dose:Dose: 200200 mgmg BIDBID forfor 1010 daysdays EstimatedEstimated cost:cost: $2800$2800 forfor fullfull coursecourse WaltWalt’’ss RecRec:: NotNot firstfirst line,line, tootoo expensiveexpensive SaveSave forfor recurrentrecurrent C.C. difficiledifficile infectionsinfections ProbioticsProbiotics andand DiarrheaDiarrhea 135135 hospitalizedhospitalized ptspts givengiven antibioticsantibiotics DB,DB, PC,PC, RandRand trialtrial ProbioticProbiotic YogurtYogurt (Actimel)(Actimel) oror PCPC BIDBID Diarrhea:Diarrhea: 34%34% PCPC vsvs 12%12% activeactive (NNT:5)(NNT:5) CC DiffDiff:: LessLess oftenoften inin RxRx armarm (NNT:(NNT: 6)6) FirstFirst randrand trialtrial toto showshow preventionprevention ofof CC diffdiff withwith probioticsprobiotics Hickson M, et al. BMJ, 2007:335-80 ProbioticsProbiotics andand PancreatitisPancreatitis NotNot allall goodgood news!news! 296296 hospitalizedhospitalized ptspts withwith acuteacute pancreatitispancreatitis givengiven probioticsprobiotics DB,DB, PC,PC, RandRand trial;trial; GivenGiven inin tubetube feedingsfeedings ProbioticProbiotic :: EcologicEcologic 642642 ((L.L. acidophilus,acidophilus, casei,casei, salivarius,salivarius, lactislactis andand B.B. bifidum,bifidum, lactislactis.).) Morbidity:Morbidity: NoNo differencedifference inin infectionsinfections Mortality:Mortality: 2424 (16%)(16%) vsvs 99 (6%)(6%) inin PCPC 99 ptspts inin RxRx armarm developeddeveloped ischemicischemic bowelbowel Besselink M, Gooszen H, et al Lancet 2008:371:651-659 PrebioticsPrebiotics PrebioticsPrebiotics IngestedIngested substancessubstances thatthat selectivelyselectively stimulatestimulate thethe proliferationproliferation and/orand/or activityactivity ofof desirabledesirable bacterialbacterial populationspopulations presentpresent inin thethe hosthost intestinalintestinal tract.tract. UsuallyUsually targettarget bifidobacteriabifidobacteria andand lactobacillilactobacilli BifidogenicBifidogenic oror bifidusbifidus factorsfactors exploredexplored inin thethe 50s50s UsuallyUsually areare nonnon--digestibledigestible oligosaccharidesoligosaccharides (NDOs)(NDOs) Lactulose,Lactulose, galactogalacto--oligosaccharides,oligosaccharides, lactosucroselactosucrose…… Crittenden and Playne. In Gastrointestinal Microbiology, 2006, pg 285-314. PrebioticsPrebiotics Inulin:Inulin: plantplant polymerspolymers mainlymainly comprisingcomprising fructosefructose units,units, useuse havehave aa terminalterminal glucoseglucose IndigestableIndigestable fiberfiber GutGut floraflora produceproduce H2,H2, CO2,CO2, methanemethane gasgas fromfrom inulininulin PrebioticsPrebiotics Inulin:Inulin: plantplant polymerspolymers mainlymainly comprisingcomprising fructosefructose units,units, useuse havehave aa terminalterminal glucoseglucose IndigestableIndigestable fiberfiber GutGut floraflora produceproduce H2,H2, CO2,CO2, methanemethane gasgas fromfrom inulininulin ““BreakfastBreakfast ofof FlatulanceFlatulance”” PrebioticsPrebiotics Feed your flora!!! PrebioticsPrebiotics IsIs isis possiblepossible toto designdesign aa food,food, sugar,sugar, protein,protein, oror fatfat thatthat wouldwould alteralter youryour gutgut floraflora toto promotepromote weightweight loss?loss? MoreMore likelylikely possibilitypossibility isis toto givegive aa prebioticprebiotic thatthat decreasesdecreases youryour ““EnergyEnergy HarvestHarvest”” ofof coloniccolonic bacteriabacteria ie.ie. loselose weightweight byby makingmaking youryour gutgut floraflora lessless efficientefficient atat digestingdigesting youryour leftleft overover foodfood DesigningDesigning Probiotics:Probiotics: TheThe Future?Future? GASTROENTEROLOGY 2009;136:2015–2031 ConclusionsConclusions FutureFuture studiesstudies mustmust focusfocus onon thethe mechanismsmechanisms ofof influenceinfluence ofof ourour gutgut flora.flora. StudiesStudies mustmust bebe placeboplacebo controlledcontrolled andand highhigh quality.quality. TrulyTruly needneed translationaltranslational sciencescience toto workwork atat thethe levelslevels ofof thethe petripetri dish,dish, genomics,genomics, andand clinicalclinical outcomes.outcomes. MuchMuch moremore toto come!come! GIGI Update:Update: SummarySummary LongstandingLongstanding dysphagia:dysphagia: ThinkThink EoEEoE PPIs:PPIs: UseUse themthem thoughtfullythoughtfully BeBe smartsmart aboutabout CeliacCeliac disease:disease: KnowKnow thethe teststests ColonColon cancercancer screening:screening: DODO IT!IT! ColonoscopyColonoscopy savessaves liveslives NewNew rolerole forfor FITFIT testingtesting GIGI Update:Update: SummarySummary StoolStool transplants:transplants: NotNot readyready forfor primeprime timetime ThinkThink SIBOSIBO withwith RosaceaRosacea PotPot andand vomiting:vomiting: AskAsk aboutabout hothot bathsbaths Microbiome:Microbiome: researchresearch willwill explodeexplode C.C. difficiledifficile:: thethe pestpest isis herehere toto staystay QuestionsQuestions BreakBreak TimeTime THETHE CALLCALL First Rule: Never go to “check” a puppy out The Visit Review of Bloodline Rule two: Never believe that parents have anything to do with the pup Rule Three: Never bring the puppy home TheThe InfectionInfection TheThe DecisionDecision ProbioticsProbiotics andand C.C. DifficileDifficile 124124 AdultsAdults withwith CC difficiledifficile (Rand,(Rand, PC)PC) 6464 11st episode,episode, 6060 recurrentrecurrent CDADCDAD StandardStandard AbAb withwith S.S. boulardiiboulardii oror PBOPBO Outcome:Outcome: RecurrenceRecurrence ofof CDADCDAD 11st Episode:Episode: 19.3%19.3% vsvs 24.2%24.2% (P=.86)(P=.86) RecRec CDAD:CDAD: 34.6%34.6% vsvs 64.7%64.7% (P=.04)(P=.04) S.S. boulardiiboulardii reducesreduces riskrisk forfor recurrencerecurrence inin subjectssubjects withwith recurrentrecurrent CC difficiledifficile McFarland, et al. JAMA 1994;271:1913-8 PPIsPPIs andand ClopidogrelClopidogrel MostMost PPIsPPIs areare metabolizedmetabolized partlypartly viavia CYPCYP 2C192C19 CYPCYP 2C192C19 criticalcritical forfor activationactivation ofof clopidogrelclopidogrel VeryVery mixedmixed datadata whetherwhether PPIsPPIs decreasedecrease efficacyefficacy ofof clopidogrel:clopidogrel: ie.ie. ConcernConcern isis stentstent patencypatency PromptedPrompted FDAFDA warningwarning TheThe onlyonly Rand/PCRand/PC controlledcontrolled studystudy ShowedShowed nono effecteffect fromfrom PPIsPPIs onon stentstent occlusionocclusion StudyStudy stoppedstopped duedue toto fundingfunding shortageshortage COGENTCOGENT TRIALTRIAL -3761 subjects -CV Event Rate: 4.9% vs 5.7% N Engl J Med 2010;363:1909-17 COGENTCOGENT TRIALTRIAL -3761 subjects -GI event rate: 1.1% vs 2.9% N Engl J Med 2010;363:1909-17 COGENTCOGENT TrialTrial COGENTCOGENT eventevent ratesrates End point Placebo, n PPI, n p All CV events 67 69 NS MI 37 36 NS Revascularization 67 69 NS GI events 67 38 0.007 Bhatt D. TCT 2009; Sept 24, 2009; San Francisco, CA. PPIsPPIs andand clopidogrelclopidogrel US Food and Drug Administration: Drug Safety Information Nov 2009 N Engl J Med 2010;363:1909-17. InflammatoryInflammatory BowelBowel DiseaseDisease NewerNewer ConceptsConcepts TreatmentTreatment TopTop downdown VSVS StepStep upup CurrentCurrent Model:Model: PathogenesisPathogenesis ofof CrohnCrohn ’’ss DiseaseDisease andand UCUC GENETIC ENVIRONMENTAL SUSCEPTIBILITY TRIGGERS & MODIFIERS IMMUNE RESPONSE BickstonBickston SJSJ,, etet al.al. CurrCurr GastroenterolGastroenterol RepRep.. 2003;5:518.2003;5:518. EnvironmentEnvironment andand IBDIBD GeographicGeographic distributiondistribution IncreaseIncrease incidenceincidence inin emigrantsemigrants toto NorthNorth SmokingSmoking GermGerm freefree animalsanimals dodo notnot getget IBDIBD InfluenceInfluence ofof thethe microbiomemicrobiome ?? InfectiousInfectious ((M.M. paratuberculosis,paratuberculosis, E.coliE.coli,, Measles)Measles) –– AntibodyAntibody testingtesting DietDiet andand DiversionDiversion ofof fecalfecal streamstream Inflammatory Bowel Disease EnvironmentalEnvironmental TriggersTriggers AntibioticsAntibiotics Infections DietDiet NSAIDsNSAIDs IBDIBD SmokingSmoking StressStress NormalNormal IntestineIntestine vs.vs. IntestineIntestine WithWith IBDIBD NormalNormal bowel:bowel: controlledcontrolled inflammationinflammation EnvironmentalEnvironmental triggerstriggers (medications(medications infections,infections, diet?)diet?) Normally:Normally: inflammationinflammation IBD:IBD: failurefailure toto IsIs down-regulateddown-regulated down-regulatedown-regulate inflammationinflammation InflamedInflamed bowelbowel NormalNormal bowel:bowel: ChronicChronic uncontrolleduncontrolled controlledcontrolled inflammationinflammation inflammationinflammation == IBDIBD ManagementManagement GoalsGoals inin IBDIBD Define disease extent and severity and type Evaluate for extra-intestinal disease and complications Induction of clinical remission – Short term side effects balanced vs. disease severity Maintenance of remission – Medical vs. Surgical – STEROID SPARING************************ Education and improvement of quality of life “Step up” vs “Top down therapy” TherapeuticTherapeutic OptionsOptions inin IBDIBD Crohn’s Disease Ulcerative Colitis – 5-Aminosalicylates – 5-Aminosalicylates – Antibiotics – Corticosteroids – Corticosteroids – 6-MP/AZA – 6-MP/AZA – Cyclosporine – Methotrexate – Biologics (only – Biologics (TNFs) infliximab to date) – Tacrolimus – Probiotics? – Probiotics? – Surgery – Surgery TopTop downdown vsvs StepStep upup RxRx ShouldShould wewe useuse TNFsTNFs earlierearlier SummarySummary forfor IBDIBD PathogenesisPathogenesis remainsremains obscureobscure stillstill RoleRole ofof MicrobiomeMicrobiome keykey SerologySerology hashas limitedlimited rolerole inin diagnosisdiagnosis HelpfulHelpful inin borderlineborderline casescases TreatmentTreatment optionsoptions havehave increasedincreased IndividualizedIndividualized therapytherapy bestbest TopTop downdown appropriateappropriate forfor somesome patientspatients QuestionQuestion NumberNumber 33 WhichWhich ofof thethe followingfollowing A. PrimaryPrimary sclerosingsclerosing extraextra --intestinalintestinal cholangitischolangitis manifestationsmanifestations ofof IBDIBD B. ErythemaErythema nodosumnodosum doesdoes notnot respondrespond toto C. SacroileitisSacroileitis treatmenttreatment ofof thethe IBD???IBD??? D. AcuteAcute arthritisarthritis E. AA andand CC F. BB andand DD