CROHN DISEASE

Eric Ji-Yuan Mao, MD • Samir A. Shah,

MD, FACG,
FASGE, AGAF
BASICS
DESCRIPTION
A chronic, relapsing inflammatory GI tract disorder, most
commonly involving
the terminal ileum (80%)
• Hallmark features of Crohn disease (CD)
– Transmural inflammation resulting in fibrosis, stricture,
and fissures with
sinus tract, abscess, or fistula formation
– Noncaseating granulomas (30%), crypt abscesses
– Skip lesions: segmental distribution of disease; may
affect multiple bowel
segments, interspersed with areas of normal mucosa; can
also be
continuous, mimickingulcerative colitis (UC).
– Diverse presentations: ileocolitis (50%); isolated colitis
(20%) are most
common.
• Early disease
– Ulcerations: focal lesions with surrounding edema,
resembling aphthous
ulcers
– Perianal disease (pain, anal fissures, perirectal
abscess) may precede
intestinal disease.
– May present as wasting illness or anorexia
• Developed disease
– Mucosal cobblestoning; luminal stenosis; creeping fat;
fissures between
mucosal folds result in strictures/adhesions and/or fistulae.
EPIDEMIOLOGY
Incidence
• 8 to 15 cases/100,000 North American adults; incidence
rising in North
America and Western Europe
• Bimodal age distribution: Predominant age is 15 to
25 years, with a second

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smaller peak at 50 to 70 years.
• Women slightly more affected than men; increased
incidence in northern
climates
• Increased risk in whites versus non-whites: 2- to 5-fold
• Increased risk in Ashkenazi Jews: 3- to 5-fold
Prevalence
U.S. adults: 100 to 200 cases/100,000
ETIOLOGY AND PATHOPHYSIOLOGY
• General: Clinical manifestations result from activation of
inflammatory cells,
whose by-products produce nonspecific tissue injury.
• Mechanism of diarrhea: excess fluid secretion and
impaired fluid absorption;
bile salt malabsorption in inflamed ileum, with steatorrhea,
bacterial
overgrowth
• Multifactorial: Genetics, environmental triggers, commensal
microbial
antigens, and immunologic abnormalities result in inflammation
and tissue
injury.
Genetics
15% of CD patients have a first-degree relative with
inflammatory bowel disease
(IBD); first-degree relative of an IBD patient has 3- to
30-fold increased risk of
developing IBD by age 28 years. ~200 different genes
associated with IBD.
• Mutations in susceptibility loci
– Ileal CD: IBD1 gene (chromosome 16)
– Early-onset CD (age =15 years): mutations in 5q31 to
33 (IBD5), 21q22,
and 20q13
– Extraintestinal manifestations of CD: mutations in
HLA-A2, HLA-DR1,
HLA-DQw5
– Others: IL-10, IL-23 receptors; ATG16L1; IRGM
• Associated genetic syndromes: Turner and
Hermansky-Pudlak syndromes,
glycogen storage disease type 1b
RISK FACTORS
• Environmental factors
– Cigarette smoking doubles the risk of CD; tobacco
cessation reduces flares

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and relapses.
– Dietary factors: higher incidence if diet high in
refined sugars, animal fat,
protein (meat, fish)
– Salmonella or Campylobacter increase risk of
developing IBD.
– Clostridium difficile infection may trigger flare and
make treatment more
difficult.
• Immunologic abnormalities: an aggressive immune
response against
commensal enteric bacteria
– Tumor necrosis factor (TNF): upregulation of inflammatory
Th1 cytokines
– Tissue inflammation may result from increased secretion of
cytokines.
COMMONLY ASSOCIATED CONDITIONS
• Extraintestinal manifestations
– Arthritis (20%): seronegative, primarily involving large
joints; axial
arthritis or ankylosing spondylitis (AS) and sacroiliitis (SI)
– Skin disorders (10%): erythema nodosum, pyoderma
gangrenosum,
psoriasis
– Ocular disease (5%): uveitis, iritis, episcleritis
– Kidney stones: calcium oxalate stones (from
steatorrhea and diarrhea) or
uric acid stones (from dehydration and metabolic acidosis)
– Fat-soluble vitamin deficiency (A, D, E, K)
– Osteopenia and osteoporosis; hypocalcemia
– Hypercoagulability: venous thromboembolism prophylaxis
essential in
hospitalized patients
– Gallstones: cholesterol stones resulting from impaired
bile acid
reabsorption
– Primary sclerosing cholangitis (5%): more common in
men with UC;
asymptomatic, elevated alkaline phosphatase as marker
– Autoimmune hemolytic anemia
• Conditions associated with increased disease activity
– Peripheral arthropathy (not SI and AS)
– Episcleritis (not uveitis)
– SI, AS, and uveitis are associated with HLA-B27.
– Oral aphthous ulcers and erythema nodosum
– Other complications: GI bleed, toxic megacolon, bowel
perforation,

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peritonitis, malignancy, sclerosing cholangitis, rectovaginal
fistula

DIAGNOSIS
HISTORY
Hallmarks: fatigue, fever, weight loss, prolonged diarrhea,
perianal disease,
crampy abdominal pain (+/- bleeding). Children may
present with failure to
thrive.
• Factors exacerbating CD: concurrent infection,
smoking, NSAIDs, and
possibly stress
PHYSICAL EXAM
Presentation varies with location of disease.
• General: signs of sepsis/disease activity (fever,
tachycardia, hypotension) or
wasting/malnutrition
• Abdominal: focal or diffuse tenderness, distension,
rebound/guarding; rectal
bleeding
• Perianal: fistulae, fissures
• Skin: erythema nodosum; psoriasis
DIFFERENTIAL DIAGNOSIS
• Acute, severe abdominal pain: perforated viscus,
pancreatitis, appendicitis,
diverticulitis, bowel obstruction, kidney stones, ovarian torsion
• Chronic diarrhea with crampy pain (colitis like): UC,
radiation colitis,
infection, drugs, ischemia, microscopic colitis, IBD, celiac disease,
malignancy (lymphoma, carcinoma), carcinoid
• Wasting illness: malabsorption, malignancy, psychiatric
illness
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
• CBC, chem 10, LFTs, erythrocyte sedimentation rate,
C-reactive protein,
serum iron, vitamin B12, vitamin D-25 OH, stool
calprotectin
• If diarrhea, stool specimen for routine culture, fecal
leukocytes, C. difficile,
and ova and parasites
• With severe flares, KUB to rule out toxic megacolon

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• Colonoscopy with ileoscopy provides the greatest
diagnostic sensitivity and
specificity for colonic disease and distal small bowel disease.
• Small bowel: Sensitivity of CT or magnetic resonance
enterography (MRE)
better than small bowel follow through. MRE has no radiation
exposure
(important in younger patients). Capsule endoscopy allows
small bowel
visualization but no biopsy (1)[A].
– Signs of small bowel disease: narrowed lumen with
nodularity and/or string
sign; cobblestone appearance, fistula and abscess formation,
bowel loop
separation (transmural inflammation)
• Gastroduodenal: upper GI endoscopy
– Signs of gastroduodenal disease: antral narrowing and
segmental
stricturing; inflammatory mucosa
• Perirectal complications: combination of endoscopic
ultrasound (EUS) or
MRI with exam under anesthesia
• Contraindications to endoscopy: perforated viscus,
recent myocardial
infarction, severe diverticulitis, toxic megacolon, or inability to
undergo
bowel preparation.
• In most cases, unprepared limited sigmoidoscopy allows
adequate
visualization to assess severity, extent, and aspirate stool
for C. difficile, obtain
biopsies to assess histologic severity, and exclude other
disorders (e.g.,
cytomegalovirus).
Follow-Up Tests & Special Considerations
Evidence of complications
• Stricture: obstructive signs—nausea, vomiting, pain,
weight loss, diarrhea, or
inability to pass gas/feces
• Abscess/phlegmon: localized abdominal peritonitis with
fever and abdominal
pain; diffuse peritonitis suggests perforation or abscess rupture
(may be
masked by steroids, opiates).
• Fistula:
– Enteroenteric: asymptomatic or a palpable, commonly
indolent abdominal
mass
– Enterovesical: pneumaturia, recurrent UTI
– Retroperitoneal: psoas abscess, ureteral obstruction
– Enterovaginal: vaginal passage of gas or feces;
clear, nonfeculent drainage

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from ileal fistula (may be misdiagnosed as primary vaginal
infection)
Diagnostic Procedures/Other
How to distinguish CD from UC
• CD: small bowel disease, rectal sparing; skip lesions;
granulomas, perianal
disease, and/or fistulae; no gross bleeding: RLQ pain is
common.
– Anti-Saccharomyces cerevisiae antibody (ASCA),
Cbir-1, OmpC, I2 (70%
sensitive)
• UC: diffuse, continuous involving the rectum; loss of
vascularity, friable
tissue; perinuclear antineutrophil cytoplasmic antibody
(pANCA); LLQ pain;
typically only affects colon; rectal bleeding common
ALERT
CD can mimic UC with continuous bowel involvement; 10–15%
of cases are
difficult to differentiate.

TREATMENT
• Disease severity: Crohn Disease Activity Index (CDAI)
– Asymptomatic: spontaneously, after medical/surgical
intervention, or while
on steroids (CDAI <150)
– Mild to moderate CD: ambulatory patients able to
tolerate PO intake
without dehydration, obstruction, or >10% weight loss; no
abdominal
tenderness, toxicity, or mass (CDAI 150 to 220)
– Moderate to severe CD: patients who have failed
initial treatment or who
continue to have mild symptoms such as fever, weight loss,
and abdominal
pain (CDAI 220 to 450)
– Severe: persistent symptoms despite therapy with
glucocorticoids and/or
biologics or fulminant disease (peritonitis, cachexia, intestinal
obstruction,
abscess) (CDAI >450)
– Step-up approach: Begin treatment with milder therapy
(5-ASA,
antibiotics) followed by more aggressive agents (steroids,
immunomodulators, anti-TNF agents) as needed.
– Top-down approach: Early management with
immunomodulators and/or
anti-TNF agents before patients receive steroids, become
steroid dependent,

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or require surgery.
GENERAL MEASURES
• Oral lesions: triamcinolone acetonide in benzocaine and
carboxymethyl
cellulose or topical sucralfate for aphthous ulcers, cheilitis, and/or
granulomatous sialadenitis
• Gastroduodenal CD: no clinical trials, slow-release
mesalamine may be
beneficial. Case reports show success of anti-TNF
therapies. Symptomatic
relief possible from proton pump inhibitors, H2-receptor
blockers, and/or
sucralfate.
• Ileitis: supplement fat-soluble vitamins, iron, B12,
folate, and calcium
• Treatment toxicity: pancreatitis, bone marrow toxicity,
lymphoma,
nonmelanoma skin cancer, infections (TB, histoplasmosis,
others),
malignancy
MEDICATION
First Line
• Asymptomatic patients: observation alone
• Mild CD
– 5-Aminosalicylates have minimal role in CD
management. They can be
used for colonic CD without deep ulcerations or
fibrostenosing disease.
– Antibiotics are controversial. Controlled trials have not
consistently
demonstrated efficacy.
– Glucocorticoid therapy: controlled ileal release
budesonide (9 mg/day for 8
to 16 weeks and then discontinued over 2- to 4-week
taper) for distal ileum
and/or right colon involvement (2)[A]
– Adjunctive therapy: antidiarrheals (loperamide); bile
acid-binding resin
(cholestyramine 4 to 12 g/day); probiotics (either alone or in
combination
may reduce inflammation/symptoms in acute CD)
– Induction/maintenance: 5-ASA is not recommended (2)[C].
Controlled ileal
release budesonide, 9 mg/day is effective for maintenance
for up to 6
months.
• Moderate to severe CD
– Induction: prednisone 40 to 60 mg/day or
controlled-release budesonide
(for isolated, moderate ileitis) or anti-TNF agents as initial
induction agent

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or for lack of response to corticosteroid or immunomodulator
(2)[A]
– Maintenance: no role for mesalamine. If steroids
required for induction, use
immunomodulator (2)[B] or biologic (anti-TNF agent) (2)[B] for
maintenance.
– Except for budesonide, do not use steroids for
maintenance (1)[A].
• Severe disease: immunomodulators, anti-TNF agents ±
steroids
– Azathioprine or 6-mercaptopurine: thiopurine
methyltransferase (TPMT)
and LFTs prior to initiation. Check CBC/LFTs q2–3mo.
– Methotrexate: effective for steroid-dependent and
steroid-refractory CD
Folic acid 1 mg/day; follow LFTs.
– Anti-TNF: active disease, fistulae, steroid sparing,
extraintestinal disease;
infliximab, adalimumab, certolizumab pegol
 Check for evidence of TB and HBV infection prior to
initiation of antiTNF therapy.
Avoid live vaccines.
Monitoring: Consider anti-drug Ab levels to assess for
immunogenicity.
Serum concentrations of anti-TNF agents may also
correlate with disease
activity.
• Combination therapy
– Azathioprine + infliximab is more effective than either
alone if no previous
treatment with either.
– Rare complication: hepatosplenic T-cell lymphoma
(fatal, mostly seen in
young males)
• Antiadhesion molecules: prevent inflammatory cells from
entering GI tract
– Vedolizumab: gut-specific, can be used in anti-TNF
failures or anti-TNF
naive patients as induction and maintenance; given IV, no
risk of
progressive multifocal leukoencephalopathy (PML)
– Natalizumab: non–gut-specific, PML risk (1/1,000); can
minimize risk by
testing for John Cunningham (JC) virus antibody. However, can
avoid risk
of PML now with vedolizumab
• Therapeutic drug monitoring: Optimize biologics and
avoid side effects.
Measure trough levels of drug, and if drug not present,
assess for antibody to
the drug. If low or absent drug level and no antibodies,
increase dose or
frequency. If no drugs and high antibody levels, switch
agents. If drug present

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and no antibodies, switch treatment if active disease (3)[C].
• New therapies:
– Ustekinumab: monoclonal antibody directed against
IL-12 and IL-23;
approved for psoriasis. Studies show efficacy in CD.
– JAK kinase inhibitors under trial and other small
molecules (SMAD-7
inhibitor) under investigation

ADDITIONAL THERAPIES
COMPLICATIONS
• Peritonitis: bowel rest and antibiotic therapy (7 to
10 days parenteral
antibiotics, followed by 2- to 4-week course of PO
ciprofloxacin and
metronidazole); surgery as indicated
– Consider holding steroids which mask sepsis.
• Abscess: antibiotics, percutaneous drainage, or surgery
with resection of
affected segments
• Small bowel obstruction: IV hydration, nasogastric (NG)
suction, total
parenteral nutrition (TPN) for malnutrition, resolution typically in
24 to 48
hours; surgery for nonresponders

ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
Vaccinations
• Check titers; avoid live vaccines (MMR,varicella, zoster)
in patients on
immunosuppressive therapy (steroids, 6MP, AZA, MTX, or
anti-TNF).
• Regardless of immunosuppression: HPV, influenza,
pneumococcal,
meningococcal, hepatitis A, B; Tdap
• Cancer prevention
– Colonoscopy with targeted biopsies every 1 to 3
years after 8 to 10 years of
CD with colonic involvement; consider chromoendoscopy if
available (4)
[C].

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– Annual PAP smears if immunocompromised
– Annual skin exam if immunocompromised
• Bone health
– Calcium and vitamin D supplementation with each
course of corticosteroids
or if vitamin D deficient
– Bone density assessment if previous steroid use,
maternal history of
osteoporosis, malnourished, amenorrheic, postmenopausal
PATIENT EDUCATION
Crohn and Colitis Foundation of America (800) 343-3637;
www.ccfa.org

REFERENCES
1. Baumgart DC, Sandborn WJ. Crohn’s disease. Lancet.
2012;380(9853):1590–
1605.
2. Talley NJ, Abreu MT, Achkar JP, et al. An
evidence-based systematic review
on medical therapies for inflammatory bowel disease. Am J
Gastroenterol.
2011;106(Suppl 1):S2–S25.
3. Vande Casteele N, Feagan BG, Gils A, et al.
Therapeutic drug monitoring in
inflammatory bowel disease: current state and future
perspectives. Curr
Gastroenterol Rep. 2014;16(4):378.
4. Laine L, Kaltenbach T, Barkun A, et al. SCENIC
international consensus
statement on surveillance and management of dysplasia in
inflammatory
bowel disease. Gastroenterology. 2015;148(3):639–651.
 CODES
ICD10
• K50.919 Crohn’s disease, unspecified, with unspecified
complications
• K50.00 Crohn’s disease of small intestine without
complications
• K50.10 Crohn’s disease of large intestine without
complications

CLINICAL PEARLS
• Cigarette smoking doubles the risk of developing CD;
tobacco cessation may

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reduce frequency of flares and need for surgery.
• MRE allows assessment of luminal and extraluminal
CD without radiation
exposure.
• Assess for TB and HBV infection prior to initiating
anti-TNF therapy.
• Test for C. difficile infection when evaluating diarrhea
in all CD patients.
• Hospitalized CD patients require deep vein thrombosis
prophylaxis