SIDELINES IN IBD
| WOMEN’S ISSUES AND IBD—Sunanda Kane, MD, MSPH, Associate Professor of Medicine, University of Chicago
Pritzker School of Medicine, Chicago, IL
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| Women’s concerns: ability to have children; attractiveness; feelings about body; feeling alone; intimacy issues
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| Menstrual cycle and bowel function fluctuations: speaker’s study—100 women with inflammatory bowel disease
(IBD) compared to women with irritable bowel syndrome (IBS) and healthy controls; found definite pattern of fluctuation
in IBD symptoms; over 3 mo, women could accurately predict mini-flares of disease; in general, women had
baseline gastrointestinal (GI) symptoms during premenstrual syndrome (PMS) and around time of menses; women with
IBD had symptoms higher than baseline; when women with IBD call about disease flare, physician should ask about
stage of menstrual cycle before prescribing steroid or infliximab (Remicade)
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| Oral contraceptives (OCs) and risk for IBD: controversial; some data from European studies suggest that OCs increase
incidence of Crohn’s disease (CD) and risk for disease activity; data do not apply, due to lower content of estrogen
in OCs in United States; data in United States do not show that OCs increase risk of developing IBD or having flare;
study—women on OCs whose IBD in remission had no increased risk for disease activity; after 500 days, ≈50% risk for
flare (not due to OCs)
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| IBD and fertility: in ulcerative colitis (UC), same fertility rate overall; patients who have had pouch procedure at increased
risk for infertility; voluntary childlessness higher in IBD patients; 60% of men taking sulfasalazine have reversible
sperm abnormalities (not dose-related; stop drug); fecundity—once woman has pouch procedure, ability to
conceive child decreases by 80%; woman ovulating regularly, but egg cannot get to uterus because of scarring of fallopian
tubes; in vitro fertilization and artificial insemination work well
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| Effect of pregnancy on IBD: if woman has inactive disease at time of conception, no greater risk for disease flare than
nonpregnant woman; of women who have active disease at time of conception, one third improve, one third worsen, and
one third remain same (true for UC and CD); HLA disparity—women carrying babies more disparate in HLA antigens
than themselves have to downregulate immune system, putting their autoimmune disease into remission; if mother and
fetus mismatched at DR and DQ loci, disease activity better; if disparate at only 1 locus, disease activity same; if same at
both loci, increased risk for flare
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| Effect of IBD on pregnancy outcomes: no increased risk for congenital abnormalities or decreased gestational age;
birth weights tend to be lower in women with CD (unknown whether due to disease or environment [more CD patients
smoke]); other studies—increased risk for low birth weight (with CD or UC); cesarean delivery rate higher in IBD; 1
study found 4-fold higher risk for congenital malformation in mothers with UC (never replicated)
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| Homocysteine and low birth weight: in other chronic conditions, increased homocysteine in third trimester highly
correlated with low birth weight; homocysteine marker for chronic inflammation; therapeutic intervention with extra
folic acid can reverse finding and change outcomes; study—prospectively enrolled 10 pregnant women with IBD and
matched them to 10 healthy controls; performed third-trimester homocysteine levels and genetic testing for methylenetetrahydrofolate
reductase (MTHFR; gene involved in metabolism of homocysteine and folic acid); correlated birth outcomes
to levels of homocysteine and found no differences between IBD patients and controls
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| Management principles for IBD during pregnancy: goal to establish remission before conception and to maintain
remission during pregnancy; greatest risk to pregnancy is active disease, not IBD therapy
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| Assessment of disease activity in pregnant IBD patients: laboratory studies; in pregnancy, erythrocyte sedimentation
rate and C-reactive protein normally increased, and hemoglobin and albumin normally decreased (not helpful); ultrasonography
safe; x-rays can be done if pelvis shielded (radiation risk 1 in 30,000); endoscopy safe if used for appropriate
indications (no increased risk for premature rupture of membranes or premature labor if done with flexible sigmoidoscopy
using upper scope); depending on trimester, may want obstetrician in room; no need for sedation if performing flexible sigmoidoscopy
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| Safety of IBD medications during pregnancy: sulfasalazine—no increased risk for fetal malformations; readily
crosses placenta, but only minimal amounts in breast milk; interferes with folic acid metabolism; pregnant woman needs
2 mg of folic acid daily; mesalamine—2 studies show that can safely use 3.4 to 3.6 g mesalamine for CD or UC; no data
on higher doses; corticosteroids—no data showing that women with IBD who need large doses of steroids have increased
risk for cleft palate in fetus; multiple human studies failed to find increased risk for adverse fetal outcomes; if
necessary to use steroids during pregnancy, use prednisone; placenta produces enzyme that metabolizes prednisone, so
fetus receives only 10% of prednisone dose; safety of long-term use of high doses during breast-feeding uncertain;
speaker recommends woman not breast-feed if on >15 to 20 mg of steroid daily; immunomodulators—study of 462
pregnant IBD patients exposed to 6-mercaptopurine (6-MP); definition of adverse outcome conception failure (spontaneous
abortion, early delivery, adverse outcome, or neonatal infection out to 3 or 6 mo); odds ratio for adverse outcome
<1.0 (not statistically significant), so no need to stop 6-MP; other medications—limited data for olsalazine and cyclosporine;
infliximab and azathioprine/6-MP have benefit; methotrexate and thalidomide contraindicated
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| Safety of IBD medications during breast-feeding: women at risk for disease flare in immediate postpartum period;
better to have women taking medication, because breast milk unhealthy during flare due to increased content of
proinflammatory cytokines; oral and topical mesalamine, sulfasalazine, and corticosteroids (<20 mg) safe; limited data on
azathioprine and 6-MP; small ongoing studies show infliximab safe; methotrexate, metronidazole, ciprofloxacin, and cyclosporine
contraindicated
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| Effect of smoking on CD in women: women smokers undergoing surgery 5 times more likely to have recurrence
than nonsmokers and recur more quickly; women smokers have hastened onset of disease, increased need for immunomodulators,
and highest risk for complications
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| Abnormal Papanicolaou (Pap) test in IBD: increased risk for abnormal Pap test (risk even higher if on immunomodulator);
recommendation that women with IBD on immunomodulators should have Pap tests more often; these
women good candidates for human papillomavirus (HPV) vaccine (all abnormal Pap tests positive for HPV)
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| Effect of menopause on IBD: with surgical menopause, no increased risk for disease flare
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| COLON CANCER SCREENING IN IBD—Glenn W. W. Gross, MD, Associate Professor of Medicine and Surgery, and
Chief, Division of Gastroenterology and Nutrition, University of Texas Health Science Center at San Antonio
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| Epidemiology: compared to age-matched population, relative risk for colorectal cancer (CRC) in UC 20 for pancolitis and
increased by factor of 4 in left-sided UC; risk in pancolitis begins to increase after 10 yr of active disease; when risk begins to
increase in left-sided UC controversial; risk increases by 0.5% to 1% annually, with median duration from symptom onset to
CRC of ≈20 yr; not everyone believes that cancer risk elevated; study—61 yr of data; 378 UC patients from Olmstead
County showed standard incidence ratio (observed to expected CRC cases) of 1.1, ie, barely increased above background
risk; with pancolitis, 2.5 times background rate; cumulative CRC incidence 2% at 25 yr; lower risk attributed to geographic
and socioeconomic factors, intensive surveillance, and mesalamine use
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| Risk factors: risk increased with—extent and duration of disease; primary sclerosing cholangitis (PSC); severity of inflammation;
backwash ileitis; family history of CRC; younger age at onset; PSC—2.5% to 6% of UC patients have PSC;
3- to 10-fold increase in relative risk for CRC in these patients, compared to non-PSC patients with UC; median duration
from diagnosis of PSC to detection of dysplasia or cancer <3 yr, with higher cumulative incidence of CRC; these cancers
tend to be diagnosed at later stage and have higher mortality; CD—data sparser; in study of Swedish patients with CD,
overall relative risk for CRC 2.5; with Crohn’s colitis alone, relative risk 5.6; with combination of ileal disease and colitis,
3.2; with small bowel disease alone, no increased risk for CRC; relative risk for small bowel cancer increased 27- to
40-fold
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| Biology of CRC in IBD: cancers seen in IBD patients biologically different from sporadic CRC, which arises from initially
benign adenomas; in IBD, cancer arises from dysplasia in flat mucosa or dysplasia-associated lesion or mass
(DALM); occur in setting of chronic inflammation, tend to be more broadly infiltrating, and, on average, occur 2 decades
earlier; 75% of sporadic CRCs distal to splenic flexure (more evenly distributed in IBD); multicentric cancers more common
in IBD population; finding of anaplastic and mucinous tumors (more dire pathology) relatively rare in sporadic
CRCs (more common in IBD); biologic markers—early loss of p53 heterozygozity and early DNA aneuploidy rare in
sporadic CRCs (common in IBD); c-K-ras mutations common in sporadic CRCs (rare in IBD); despite biologic differences,
5-yr survival or biologic behavior same for both types of cancers in large population
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| Pathology of neoplasia in IBD: surveillance strategy based on concept that dysplasia in flat mucosa or DALM precedes
CRC (rationale for pattern surveillance biopsies in IBD); interobserver agreement on diagnosis of dysplasia
sometimes as low as 33%; having second pathologist concur with initial diagnosis critical for therapeutic decisions
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 | Dysplasia: tissue classified as negative, indefinite, and positive for dysplasia; negative—encompasses normal mucosa, active
colitis, and quiescent colitis; indefinite—includes probably negative, unknown, and probably positive; positive—
includes low-grade dysplasia (LGD) or high-grade dysplasia (HGD); reactive atypia—challenge for pathologists to
distinguish from LGD and HGD in patients with background of inflammation; features of dysplasia—increased epithelial
proliferation and mitoses; increased nuclear size and nuclear/cytoplasmic ratio; nuclear pleomorphism; presence
of back-to-back glands; hyperchromaticity; altered nuclear polarity; differentiating dysplasia from reactive inflammatory
changes—dysplasia affects all portions of crypt and surface epithelium uniformly, whereas reactive changes more
prominent at crypt base, with maturation toward surface
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| Dysplasia-associated lesion or mass: significant risk for cancer; mandates colectomy; variable appearance; IBD patients
also may have typical or sporadic adenomas (in normal or colitic mucosa); since adenoma defined as at least
LGD, these lesions DALM; typical adenomas safely treated endoscopically; important to distinguish adenoma-like or
sporadic DALM from non–adenoma-like DALM
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| Adenoma-like DALMs—occur in older patients without adjacent or remote dysplasia; solitary smaller lesions with
shorter duration and extent of disease; tend to look like regular polyps, ie, pedunculated, less sessile, p53-negative, and
β-catenin positive
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| Non–adenoma-like DALMs: younger patients; associated dysplasia around or elsewhere in colon; multifocal larger lesions;
longer duration and extent of disease; plaque-like, flat, ulcerated, p53-positive, and β-catenin-negative
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| Pseudopolyps: irregular islands of postinflammatory or regenerative tissue; nondysplastic lesions with no risk for CRC; may
mimic adenomas or DALMs; if unsure, biopsy
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| Adenocarcinoma: in IBD, appearance variable, eg, ulcerations, depressions in mucosa, polypoid or nodular, plaque-like;
may occur in strictures (of concern in UC; biopsy); endoscopic findings—severe inflammation, pseudopolyps, shortened or
tubular colon
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| Clinical implications of dysplasia in IBD: meta-analysis—10 studies involving 1225 UC patients; if DALM
found with LGD or HGD, immediate colectomy revealed CRC in 43%; if HGD at initial examination, CRC in 42% to
67%; HGD at interval examination, CRC in 32%; LGD at initial examination, CRC in 19%; if no colectomy performed but
surveillance continued for LGD, one third progressed to HGD, DALM, or cancer; if no dysplasia found on initial examination,
2% to 4% progressed to HGD, DALM, or cancer; conclusions—immediate colectomy essential for all patients diagnosed
with LGD or HGD; diagnosis of dysplasia does not preclude presence of invasive cancer; inform patients about
limitations of endoscopic surveillance so they can take part rationally in making decisions about management; LGD—
conflicting data; 21-yr surveillance program in 332 patients found that 54% of patients with LGD developed HGD or cancer
within 5 yr of diagnosis; opposing recommendation that LGD should be followed by continued more intense surveillance;
adenoma-like DALMs—treated endoscopically; studies show that if typical-looking adenoma present and biopsy
does not show dysplasia around adenoma or elsewhere, can safely continue to follow usual pattern of surveillance
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| Current surveillance guidelines from major societies: American College of Gastroenterology (ACG) and
American Society of GI Endoscopy (ASGE)—for pancolitis, begin at 8 to 10 yr, repeat every 1 to 2 yr; for left-sided
colitis, ACG recommends starting at 8 to 10 yr and repeat every 1 to 2 yr (insufficient data to support later start); ASGE and
American Gastroenterological Association (AGA) recommend starting at 15 yr for left-sided colitis; for Crohn’s colitis,
ACG had no position (insufficient data), while AGA recommended starting at 8 yr and repeating every 1 to 2 yr; ASGE recommended
considering surveillance after 8 to 10 yr; Crohn’s and Colitis Foundation of America (CCFA) consensus
panel—recommended starting at 8 to 10 yr in all cases and repeating every 1 to 2 yr, with caveat that during first 10 yr of
surveillance, after 2 negative examinations, can decrease interval to every 3 yr; current recommendation—takes 33 biopsies
to detect dysplasia of any grade and up to 64 biopsies to detect highest grade of dysplasia present; take 2 to 4 biopsies
every 10 cm throughout colon; grouping multiple random biopsies in single container not advisable; CCFA consensus
panel recommends ≤4 biopsies in specimen jar; strictures or anything abnormal looking should be biopsied; typical-appearing
adenomas removed by polypectomy, with biopsies around lesions; pseudopolyps biopsied or removed if abnormal
looking; isolated proctitis screened as in non-IBD population; patient with high-risk factors and patient with UC and PSC
should be screened annually; if HGD or non–adenoma-like DALM found, recommendation clear for colectomy; for adenoma-like
DALM without local or remote dysplasia, endoscopic colectomy with continued surveillance; if LGD in flat mucosa,
colectomy acceptable; if not comfortable with recommendation, intensive surveillance recommended
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| Outcome of long-term surveillance programs: no prospective randomized controlled data that surveillance prolongs
life, decreases CRC mortality, or improves quality of life, compared to observation or colectomy; however, retrospective
and indirect evidence in UC and CD suggests surveillance decreases cancer mortality and leads to earlier diagnosis at
more treatable stage
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Suggested Reading
Chambers WM et al: Cancer surveillance in ulcerative colitis. Br J Surg 92:928, 2005; Chang L et al: Gender, age, society,
culture, and the patient's perspective in the functional gastrointestinal disorders. Gastroenterology 130:1435, 2006;
Drossman DA et al: A prospective assessment of bowel habit in irritable bowel syndrome in women defining an alternator.
Gastroenterology 128:580, 2005; Heitkemper M et al: Irritable bowel syndrome in women: a common health problem.
Nurs Clin North Am 39:69, 2004; Heitkemper MM et al: Relationship of bloating to other GI and menstrual symptoms in
women with irritable bowel syndrome. Dig Dis Sci 49:88, 2004; Hommes DW et al: Endoscopy in inflammatory bowel
diseases. Gastroenterology 126:1561, 2004; Itzkowitz SH et al: Diagnosis and management of dysplasia in patients with
inflammatory bowel diseases. Gastroenterology 126:1634, 2004; Jelovsek JE et al: Functional bowel and anorectal disorders
in patients with pelvic organ prolapse and incontinence. Am J Obstet Gynecol 193:2105, 2005; Kiesslich R et al: Methylene
blue-aided chromoendoscopy for the detection of intraepithelial neoplasia and colon cancer in ulcerative colitis.
Gastroenterology 124:880, 2003; Lim CH et al: Ten year follow up of ulcerative colitis patients with and without low grade
dysplasia. Gut 52:1127, 2003; Novi JM et al: Risk of irritable bowel syndrome and depression in women with interstitial cystitis:
A case-control study. J Urol 174:937, 2005; Pezzone MA et al: A model of neural cross-talk and irritation in the pelvis:
implications for the overlap of chronic pelvic pain disorders. Gastroenterology 128:1953, 2005; Ringel Y et al: Sexual
and physical abuse are not associated with rectal hypersensitivity in patients with irritable bowel syndrome. Gut 53:838, 2004;
Robert JJ et al: Modulation of sleep quality and autonomic functioning by symptoms of depression in women with irritable
bowel syndrome. Dig Dis Sci 49:1250, 2004; Rutter M et al: Severity of inflammation is a risk factor for colorectal neoplasia
in ulcerative colitis. Gastroenterology 126:451, 2004; Rutter MD et al: Cancer surveillance in longstanding ulcerative
colitis endoscopic appearances help predict cancer risk. Gut 53:1813, 2004; Rutter MD et al: Thirty-year analysis of a
colonoscopic surveillance program for neoplasia in ulcerative colitis. Gastroenterology 130:1030, 2006; Singh H et al: Risk
of developing colorectal cancer following a negative colonoscopy examination evidence for a 10-year interval between
colonoscopies. JAMA 295:2366, 2006; Spiegel BM et al: Clinical determinants of health-related quality of life in patients
with irritable bowel syndrome. Arch Intern Med 164:1773, 2004; Syngal S et al: Surveillance of patients at high risk for colorectal
cancer. Med Clin North Am 89:61, 2005; Tillisch K et al: Sex specific alterations in autonomic function among patients
with irritable bowel syndrome. Gut 54:1396, 2005; Epub 2005 May 28.Ullman T et al: Progression of flat low-grade
dysplasia to advanced neoplasia in patients with ulcerative colitis. Gastroenterology 125:1311, 2003; Velayos FS et al:
Predictive and protective factors associated with colorectal cancer in ulcerative colitis: a case-control study. Gastroenterology
130:1941, 2006; Vieth M et al: Sporadic adenoma in ulcerative colitis: endoscopic resection is an adequate treatment. Gut
55:1151, 2006; Epub 2006 Jan 19.Williams RE et al: Prevalence and characteristics of irritable bowel syndrome among
women with chronic pelvic pain. Obstet Gynecol 104:452, 2004; Williams RE et al: Recognition and treatment of irritable
bowel syndrome among women with chronic pelvic pain. Am J Obstet Gynecol 192:761, 2005
Educational Objectives
| The goal of this program is to educate the listener about women’s issues in inflammatory bowel disease (IBD) and colorectal
cancer (CRC) screening in IBD. After hearing and assimilating this program, the clinician will be better able to:
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| 1. Describe IBD concerns that affect women in general.
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| 2. Employ management principles for IBD in pregnant patients.
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| 3. Identify the risk factors for CRC in IBD patients.
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| 4. Discuss the clinical implications of dysplasia in IBD.
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| 5. Employ current guidelines for CRC screening.
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Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. For this issue, Dr. Gross reported
nothing to disclose. Dr. Kane reported that she has received research support from Procter & Gamble, Salix Pharmaceuticals,
Inc., and GlaxoSmithKline, is a consultant for Abbott, Centocor, Ferring Pharmaceuticals Inc., Shire, TAP
Pharmaceutical Products Inc, and UCB, and is on the Speakers’ Bureau of Centocor, GlaxoSmithKline, Novartis, Procter &
Gamble, Shire, Salix Pharmaceuticals, Inc., and TAP Pharmaceutical Products Inc.
Acknowledgements
Dr. Kane was recorded at State-of-the-Art Diagnosis and Treatment of IBD, held April 1, 2006, in Long Beach, CA,
and sponsored by the Cedars-Sinai Medical Center and the Crohn’s and Colitis Foundation of America, Greater Los
Angeles and Orange County Chapters. Dr. Gross was recorded at The 31st Annual Texas Program, held September
15-17, 2006, in San Antonio, TX, and sponsored by the Texas Society for Gastroenterology and Endoscopy and the
American College of Gastroenterology. The Audio-Digest Foundation thanks the speakers and the sponsors for their
cooperation in the production of this program.
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