Inflammatory Bowel Disease Internal Medicine Lecture Series November 21, 2007 Ron Barac, D.O.

Inflammatory BowelInflammatory BowelDiseaseDisease

Internal Medicine Lecture SeriesInternal Medicine Lecture Series

November 21, 2007November 21, 2007Ron Barac, D.O.Ron Barac, D.O.

Inflammatory Bowel Inflammatory Bowel DiseaseDisease

Crohn’s diseaseCrohn’s disease Ulcerative colitisUlcerative colitis

Pathogenesis of IBD is unknown!Pathogenesis of IBD is unknown!

Familial Patterns of IBDFamilial Patterns of IBD

10-25% occurrence of IBD in 10-25% occurrence of IBD in relativesrelatives

Strong concordance by disease Strong concordance by disease categorycategory

Genetic vs. environmental influences Genetic vs. environmental influences still unresolvedstill unresolved

Etiological theories of IBDEtiological theories of IBD GeneticGenetic SmokingSmoking DietaryDietary InfectionInfection ImmunologicalImmunological Psychogenic?Psychogenic?

Epidemiology of IBDEpidemiology of IBDFactorFactor Ulcerative Ulcerative

ColitisColitisCrohn’s DiseaseCrohn’s Disease

Incidence (per Incidence (per 100,000)100,000)

2-102-10 1-61-6

Prevalence (per Prevalence (per 100,000)100,000)

35-10035-100 10-10010-100

Racial incidenceRacial incidence High in whitesHigh in whites High in whitesHigh in whites

Ethnic incidenceEthnic incidence High in JewsHigh in Jews High in JewsHigh in Jews

SexSex Slight female Slight female preponderancepreponderance

Slight female Slight female preponderancepreponderance

Age of onsetAge of onset 15-2515-25

?55-65?55-6515-2515-25

?55-65?55-65

SmokingSmoking Fewer smokers than Fewer smokers than expectedexpected

More smokers than More smokers than expectedexpected

Crohn’s diseaseCrohn’s disease

First First documented documented case by case by Morgagni in Morgagni in 17611761

Crohn’s disease - DescriptionCrohn’s disease - Description

Chronic inflammation that may involve Chronic inflammation that may involve any part of the GI tract from mouth to any part of the GI tract from mouth to anus.anus.• associated with many extraintestinal featuresassociated with many extraintestinal features

Frequently manifested by abdominal pain Frequently manifested by abdominal pain and diarrheaand diarrhea

Often complicated by intestinal Often complicated by intestinal fistulization, obstruction or both.fistulization, obstruction or both.

Typically affects the ileum, colon, and/or Typically affects the ileum, colon, and/or perianal regionperianal region

Distribution is asymmetric/segmentalDistribution is asymmetric/segmental Tendency toward lifelong recurrence Tendency toward lifelong recurrence

Crohn’s Disease - PathologyCrohn’s Disease - Pathology Earliest/most frequent mucosal lesion: Earliest/most frequent mucosal lesion: crypt injurycrypt injury

secondary to neutrophil infiltrationsecondary to neutrophil infiltration Distribution of crypt lesions is typically more focalDistribution of crypt lesions is typically more focal Crypt injury is followed by microscopic ulceration of Crypt injury is followed by microscopic ulceration of

intestinal mucosa over a lymphoid follicleintestinal mucosa over a lymphoid follicle Macrophage/other inflammatory cells invade and proliferate Macrophage/other inflammatory cells invade and proliferate

in the lamina propria.in the lamina propria. Loose aggregates of macrophages ultimately organize into Loose aggregates of macrophages ultimately organize into

discrete noncaseating granulomas, which consist of discrete noncaseating granulomas, which consist of epithelioid cells with multinucleated giant cells.epithelioid cells with multinucleated giant cells.

While granulomas seem to be a pathognomonic feature of While granulomas seem to be a pathognomonic feature of Crohn’s disease, absence of granulomas does not rule out Crohn’s disease, absence of granulomas does not rule out the diagnosis.the diagnosis.

Crohn’s Disease – Clinical Crohn’s Disease – Clinical PresentationPresentation

Pain - colicky RLQ/suprapubic regionPain - colicky RLQ/suprapubic region DiarrheaDiarrhea Fever - usually low grade, higher spiking fevers Fever - usually low grade, higher spiking fevers

signify complicationssignify complications Weight loss - typically 10-20% of body weightWeight loss - typically 10-20% of body weight Gross bleeding - unusual, massive bleeding in only 1-Gross bleeding - unusual, massive bleeding in only 1-

2%2% Perineal disease - fissures/fistulas and/or abscessesPerineal disease - fissures/fistulas and/or abscesses

Crohn’s diseaseCrohn’s disease Flexible sigmoidoscopy:Flexible sigmoidoscopy:

• rectal sparing is commonrectal sparing is common• distal colon may be unremarkable or mildly distal colon may be unremarkable or mildly

erythematous in 50-70% of patientserythematous in 50-70% of patients Colonoscopy:Colonoscopy:

• contraindicated in acute Crohn’s diseasecontraindicated in acute Crohn’s disease• mucosal involvement is discontinuous with mucosal involvement is discontinuous with

intervening intervening “skip”“skip” areas of normal mucosa areas of normal mucosa Plain films of abdomenPlain films of abdomen UGI/small bowel seriesUGI/small bowel series

• 60-70% of patients have some ileum 60-70% of patients have some ileum involvementinvolvement

Barium enemaBarium enema

Crohn’s Disease Crohn’s Disease ComplicationsComplications

Fistula formationFistula formation• enterocutaneousenterocutaneous• enterovesicalenterovesical• enteroenteric/enterocolicenteroenteric/enterocolic• rectovaginal/rectovesicalrectovaginal/rectovesical

Intraabdominal abscessIntraabdominal abscess Bowel obstructionBowel obstruction Growth failure in pediatric/adolescent patientsGrowth failure in pediatric/adolescent patients MalignancyMalignancy

• gastrointestinalgastrointestinal• squamous cell CA of anussquamous cell CA of anus• squamous cell CA of vulvasquamous cell CA of vulva

Ulcerative ColitisUlcerative ColitisFirst recognized First recognized by Wilkes in by Wilkes in 18591859

Ulcerative ColitisUlcerative Colitis

Inflammatory disorder that affects the Inflammatory disorder that affects the rectum and extends proximally to rectum and extends proximally to affect a variable extent of the colon.affect a variable extent of the colon.

Cause of the disease and factors Cause of the disease and factors determining its clinical course are determining its clinical course are unknown.unknown.

Ulcerative Colitis - PathologyUlcerative Colitis - Pathology Inflammation predominantly confined to the Inflammation predominantly confined to the

mucosa/submucosamucosa/submucosa Characteristic histologic finding in UC is the Characteristic histologic finding in UC is the

crypt abscesscrypt abscess • crypt abscesses are crypt abscesses are notnot specific for UC though specific for UC though

Crypt abscesses are comprised of PMNs and Crypt abscesses are comprised of PMNs and degenerated or necrotic epithelial cells in the degenerated or necrotic epithelial cells in the crypts of Lieberkuhn.crypts of Lieberkuhn.

Coalescence of adjacent crypt abscesses Coalescence of adjacent crypt abscesses produce the mucosal ulcerations which typify produce the mucosal ulcerations which typify ulcerative colitis.ulcerative colitis.

Ulcerative Colitis – Clinical Ulcerative Colitis – Clinical PresentationPresentation

HematocheziaHematochezia Diarrhea - not always presentDiarrhea - not always present Pain - lower abdominal/crampy, Pain - lower abdominal/crampy,

relieved by BM’srelieved by BM’s Fever - only seen in severe casesFever - only seen in severe cases Weight lossWeight loss

Clinical assessment of disease Clinical assessment of disease severityseverity

Mild:Mild: (60% of patients) (60% of patients)• < 4 stools per day with or without blood, with < 4 stools per day with or without blood, with

no systemic disturbances and normal ESR.no systemic disturbances and normal ESR. Moderate:Moderate: (25% of patients) (25% of patients)

• > 4 stools per day but with minimal systemic > 4 stools per day but with minimal systemic disturbancesdisturbances

Severe:Severe: (15% of patients) (15% of patients)• > 6 stools daily with blood and evidence of > 6 stools daily with blood and evidence of

systemic disturbance as shown by fever, systemic disturbance as shown by fever, tachycardia, anemia, or an ESR > 30.tachycardia, anemia, or an ESR > 30.

Ulcerative ColitisUlcerative Colitis Flexible sigmoidoscopy:Flexible sigmoidoscopy:

• assess disease activity in acute UCassess disease activity in acute UC• Rectal involvement in 95% cases of UCRectal involvement in 95% cases of UC• Mucosal involvement is continuous and non-segmentedMucosal involvement is continuous and non-segmented• Mucosa is granular/friable with discrete ulcerationsMucosa is granular/friable with discrete ulcerations

Colonoscopy:Colonoscopy:• relatively contraindicated in acute UC due to increased risk of perforation.relatively contraindicated in acute UC due to increased risk of perforation.• useful in chronic UC to evaluate disease extent, evaluate strictures, and useful in chronic UC to evaluate disease extent, evaluate strictures, and

surveillance of colonic CAsurveillance of colonic CA Plain films of abdomenPlain films of abdomen Barium enema:Barium enema:

• contraindicated in acute UCcontraindicated in acute UC• useful in chronic UC – “lead pipe” colonuseful in chronic UC – “lead pipe” colon• colonic strictures should be considered malignant until proven otherwisecolonic strictures should be considered malignant until proven otherwise

Ulcerative Colitis Ulcerative Colitis ComplicationsComplications

Toxic megacolonToxic megacolon Free perforationFree perforation Massive colonic hemorrhageMassive colonic hemorrhage Colon cancer:Colon cancer:

• Major risk factors are Major risk factors are extent and duration of extent and duration of diseasedisease

• Colonoscopic surveillance with biopsies should Colonoscopic surveillance with biopsies should be done yearly in patients with universal colitis be done yearly in patients with universal colitis of 10 yrs. duration or left-sided colitis of 20 yrs. of 10 yrs. duration or left-sided colitis of 20 yrs. duration.duration.

Exclusion of Infectious ColitisExclusion of Infectious Colitis

Exclusion of infectious Colitis may be clinically, Exclusion of infectious Colitis may be clinically, endoscopically, and histologically endoscopically, and histologically indistinguishable from IBD.indistinguishable from IBD.• stool for ova and parasitesstool for ova and parasites• stool cultures for enteric pathogensstool cultures for enteric pathogens

Patients with proctitisPatients with proctitis• exclude STDs if there is a history of anal intercourseexclude STDs if there is a history of anal intercourse

Patients with diarrhea and recent antibiotic usePatients with diarrhea and recent antibiotic use• exclude pseudomembranous colitisexclude pseudomembranous colitis• check stools for check stools for C. difficileC. difficile toxin toxin

Extraintestinal Manifestations Extraintestinal Manifestations of IBDof IBD

33% of IBD patients will have one or more 33% of IBD patients will have one or more manifestations in their lifetime.manifestations in their lifetime.

Extraintestinal manifestations may be related to Extraintestinal manifestations may be related to bowel disease activity, may be independent of bowel disease activity, may be independent of bowel disease, or may occur as a consequence of bowel disease, or may occur as a consequence of bowel diseasebowel disease..• DermatologicDermatologic• RheumatologicRheumatologic• HepatobiliaryHepatobiliary• OcularOcular• RenalRenal

Dermatologic manifestationsDermatologic manifestations Erythema nodosumErythema nodosum

• most common skin manifestation of IBDmost common skin manifestation of IBD• occurs in 9% of UC, 15% of CDoccurs in 9% of UC, 15% of CD• directly related to bowel disease activity and directly related to bowel disease activity and

resolves with control of the diseaseresolves with control of the disease• erythema nodosum is non-specific for IBDerythema nodosum is non-specific for IBD

Pyoderma gangrenosumPyoderma gangrenosum• occurs in 2-5% UC, 1-2% of CDoccurs in 2-5% UC, 1-2% of CD• clinical course is independent of bowel diseaseclinical course is independent of bowel disease• treatment with intralesional/systemic steroidstreatment with intralesional/systemic steroids

Rheumatologic manifestationsRheumatologic manifestations Axial arthritisAxial arthritis

• Ankylosing spondylitisAnkylosing spondylitis 18-20% of patients with IBD, more common in males18-20% of patients with IBD, more common in males clinical course independent of bowel diseaseclinical course independent of bowel disease assoicated with HLA-B27 haplotypeassoicated with HLA-B27 haplotype ““bamboo” spine on plain x-raysbamboo” spine on plain x-rays

• SacroilitisSacroilitis independent of bowel diseaseindependent of bowel disease associated with HLA-B27 haplotypeassociated with HLA-B27 haplotype plain films show obliteration of sacroiliac joint spaceplain films show obliteration of sacroiliac joint space

Peripheral arthritisPeripheral arthritis• Activity parallels bowel disease activityActivity parallels bowel disease activity• Peripheral arthritis in IBD is mono-articular (affects large joints such Peripheral arthritis in IBD is mono-articular (affects large joints such

as knee, wrist, ankles), asymmetric, migratory, seronegative, and is as knee, wrist, ankles), asymmetric, migratory, seronegative, and is unassociated with deformity or erosive changes.unassociated with deformity or erosive changes.

Hepatobiliary ManifestationsHepatobiliary Manifestations Primary sclerosing cholangitisPrimary sclerosing cholangitis

• 4-6% of patients with UC4-6% of patients with UC• 70% of patients with PSC have UC70% of patients with PSC have UC• associated with DRW-52A haplotypeassociated with DRW-52A haplotype• clinical course is independent of bowel diseaseclinical course is independent of bowel disease• diagnosis made by ERCP; suggested by liver biopsydiagnosis made by ERCP; suggested by liver biopsy• cholangiocarcinoma is a complication of PSCcholangiocarcinoma is a complication of PSC

PericholangitisPericholangitis CholelithiasisCholelithiasis

• cholesterol stones may occur in CD patients with terminal ileal involvementcholesterol stones may occur in CD patients with terminal ileal involvement• Occurs in 15-30% of patients with small bowel CDOccurs in 15-30% of patients with small bowel CD• Resection or disruption of ileal absorptive surface causes alteration of Resection or disruption of ileal absorptive surface causes alteration of

enterohepatic circulation and bile salt depletionenterohepatic circulation and bile salt depletion Chronic active hepatitisChronic active hepatitis

Ocular ManifestationsOcular Manifestations UveitisUveitis

• Clinical course is independent of bowel Clinical course is independent of bowel disease activitydisease activity

• Associated with HLA-B27 haplotypeAssociated with HLA-B27 haplotype• Clinical presentation is painful, injected Clinical presentation is painful, injected

eye with opacity in the anterior eye with opacity in the anterior chamber.chamber.

EpiscleritisEpiscleritis

Renal ManifestationsRenal Manifestations NephrolithiasisNephrolithiasis

• Urate stones associated with ulcerative colitisUrate stones associated with ulcerative colitis• Oxate stones associated with Crohn’s diseaseOxate stones associated with Crohn’s disease

Obstructive hydronephritisObstructive hydronephritis• Associated with Crohn’s disease but not UCAssociated with Crohn’s disease but not UC• Caused by local extension of bowel Caused by local extension of bowel

inflammation to uretersinflammation to ureters PyelonephritisPyelonephritis

IBD IBD TREATMENTTREATMENT

AminosalicylatesAminosalicylates Used for both CD and UCUsed for both CD and UC Active component is 5-aminosalicyclic acid (5-ASA)Active component is 5-aminosalicyclic acid (5-ASA) Mode of actionMode of action

• inhibition of lipoxygenase enzyme in the alternate inhibition of lipoxygenase enzyme in the alternate arachidonic acid pathway resulting in decreased arachidonic acid pathway resulting in decreased production of leukotrienesproduction of leukotrienes

Examples:Examples:• sulfasalazine (Azulfidine), olsalazine (Dipentum), sulfasalazine (Azulfidine), olsalazine (Dipentum),

mesalamine (Pentasa, Asacol), topical mesalamine mesalamine (Pentasa, Asacol), topical mesalamine (Rowasa)(Rowasa)

Both oral/topical forms are effective in maintaining Both oral/topical forms are effective in maintaining remission in UC.remission in UC.

SulfasalazineSulfasalazine 5-ASA linked by an azo bond to sulfapyridine5-ASA linked by an azo bond to sulfapyridine Azo bond is split by bacteria in distal ileum/colon releasing the Azo bond is split by bacteria in distal ileum/colon releasing the

active 5-ASA moietyactive 5-ASA moiety 90% of the adverse effects of sulfasalazine are related to the 90% of the adverse effects of sulfasalazine are related to the

sulfapyridine moietysulfapyridine moiety Adverse effects include:Adverse effects include:

• Rash, fever, headachesRash, fever, headaches• Reversible male infertilityReversible male infertility• Folate deficiencyFolate deficiency• AgranulocytosisAgranulocytosis

Indications:Indications:• Mild to moderate UCMild to moderate UC• Mild to moderate Crohn’s colitis, ileocolitis, less effective in Crohn’s Mild to moderate Crohn’s colitis, ileocolitis, less effective in Crohn’s

ileitisileitis• Maintenance of remission in UCMaintenance of remission in UC

Sulfasalazine – Safety in Sulfasalazine – Safety in Pregnancy and Breast Pregnancy and Breast

FeedingFeeding Crosses placenta and appears in milkCrosses placenta and appears in milk No adverse effect on pregnancyNo adverse effect on pregnancy No teratogenicityNo teratogenicity No kernicterusNo kernicterus

MesalamineMesalamine Active moiety is 5-ASAActive moiety is 5-ASA Adverse effects:Adverse effects:

• Nausea, flatulence, diarrheaNausea, flatulence, diarrhea• Fever, rashFever, rash• Pancreatitis, pericarditis, colitisPancreatitis, pericarditis, colitis

Indications:Indications:• same as for sulfasalazinesame as for sulfasalazine

Systemic corticosteroids:Systemic corticosteroids:• Indicated in short term treatment of Indicated in short term treatment of

moderate/severe UC or CDmoderate/severe UC or CD• Not shown to maintain remission in either UC or Not shown to maintain remission in either UC or

CDCD• Preparations:Preparations:

Oral: prednisone, prednisoloneOral: prednisone, prednisolone Parental: hydrocortisone, corticotropin (ACTH)Parental: hydrocortisone, corticotropin (ACTH)

Topical corticosteroidsTopical corticosteroids• Indicated in treatments of proctitis or left-sided Indicated in treatments of proctitis or left-sided

colitiscolitis• Advantage is minimalization of systemic effects Advantage is minimalization of systemic effects

of steroidsof steroids• Preparation: hydrocortisone enemasPreparation: hydrocortisone enemas

STEROIDS

Budesonide (controlled ileal Budesonide (controlled ileal release)release)

• Corticosteroid with high 1Corticosteroid with high 1stst-pass hepatic -pass hepatic metabolismmetabolism

• Used as an alternative to prednisoneUsed as an alternative to prednisone• Effective in mild to moderately active Crohn’s Effective in mild to moderately active Crohn’s

ileitis and/or right colon involvementileitis and/or right colon involvement• Effective for prolongation of time to relapse Effective for prolongation of time to relapse

and maintenanceand maintenance• More effective than mesalamine for More effective than mesalamine for

maintenance of remission of patients with maintenance of remission of patients with steroid-dependent Crohn’s disease steroid-dependent Crohn’s disease

MetronidazoleMetronidazole Indications:Indications:

• fulminant UCfulminant UC• active CD (mild/moderate)active CD (mild/moderate)• perianal disease/fistulaeperianal disease/fistulae

Adverse effects:Adverse effects:• peripheral neuropathyperipheral neuropathy• disulfiram-like reactiondisulfiram-like reaction• teratogenicity precludes use in pregnancyteratogenicity precludes use in pregnancy

Immunosuppressive agentsImmunosuppressive agents 6-Mercaptopurine (6-MP) and Azathioprine are the only medications known to 6-Mercaptopurine (6-MP) and Azathioprine are the only medications known to

induce/maintain remission in CDinduce/maintain remission in CD Indications:Indications:

• steroid-dependentsteroid-dependent• refractory diseaserefractory disease• perianal diseaseperianal disease• refractory fistulaerefractory fistulae• maintenance of remissionmaintenance of remission

Disadvantage is delay in response to treatmentDisadvantage is delay in response to treatment• mean time of clinical response is 3-4 monthsmean time of clinical response is 3-4 months

Complications of treatment:Complications of treatment:• neutropenianeutropenia• bone marrow suppression – 2% casesbone marrow suppression – 2% cases• pancreatitis – 3.3%pancreatitis – 3.3%• lymphomalymphoma

Cyclosporine:Cyclosporine:• may have role in acute or severe UC/CDmay have role in acute or severe UC/CD• Has quick onset of action but limited by serious side effects.Has quick onset of action but limited by serious side effects.

InfiximabInfiximab• Chimeric mouse/human monoclonic antibody Chimeric mouse/human monoclonic antibody

against tumor necrosis factor alphaagainst tumor necrosis factor alpha• Used in moderate to severe Crohn’s and Used in moderate to severe Crohn’s and

ulcerative colitisulcerative colitis• Very active for fistulizing Crohn’s diseaseVery active for fistulizing Crohn’s disease• Useful for both induction & maintenance of Useful for both induction & maintenance of

remissionremission• Patients should be evaluated for latent TB prior Patients should be evaluated for latent TB prior

to treatment (can also be associated with to treatment (can also be associated with reactivation of HBV infection)reactivation of HBV infection)

• Possible association with rare lymphomas Possible association with rare lymphomas

Surgical Management of IBDSurgical Management of IBD

Ulcerative colitisUlcerative colitis• Proctocolectomy with ileostomyProctocolectomy with ileostomy• Ileoanal anastomosisIleoanal anastomosis

Crohn’s diseaseCrohn’s disease• StricturoplastyStricturoplasty• FistulectomyFistulectomy• Segmental resectionSegmental resection