2477 Inflammatory Bowel Disease CHAPTER 326

Stricturing can occur in the colon in 4–16% of patients and produce

symptoms of bowel obstruction. If the endoscopist is unable to traverse

a stricture in Crohn’s colitis, surgical resection should be considered,

especially if the patient has symptoms of chronic obstruction. Colonic

disease may fistulize into the stomach or duodenum, causing feculent

vomiting, or to the proximal or mid-small bowel, causing malabsorption by “short circuiting” the absorptive surface and bacterial

overgrowth. Ten percent of women with Crohn’s colitis will develop a

rectovaginal fistula.

Perianal disease affects about one-third of patients with Crohn’s

colitis and is manifested by incontinence, large hemorrhoidal tags,

anal strictures, anorectal fistulas, and perirectal abscesses. Not all

patients with perianal fistula will have endoscopic evidence of colonic

inflammation.

GASTRODUODENAL DISEASE Symptoms and signs of upper GI tract

disease include nausea, vomiting, and epigastric pain. Patients usually

have a Helicobacter pylori–negative gastritis. The second portion of the

duodenum is more commonly involved than the bulb. Fistulas involving the stomach or duodenum arise from the small or large bowel and

do not necessarily signify the presence of upper GI tract involvement.

Patients with advanced gastroduodenal CD may develop a chronic gastric outlet obstruction. About 30% of children diagnosed with CD have

esophagogastroduodenal involvement. The classification of disease

activity is shown in Table 326-5.

Laboratory, Endoscopic, and Radiographic Features Laboratory

abnormalities include elevated ESR and CRP. In more severe disease,

findings include hypoalbuminemia, anemia, and leukocytosis. Fecal

calprotectin and lactoferrin levels have been used to distinguish IBD

from irritable bowel syndrome (IBS), to assess whether CD is active,

and to detect postoperative recurrence of CD. Fecal calprotectin is a

more sensitive marker of ileocolonic or colonic inflammation rather

than isolated ileal inflammation.

Endoscopic features of CD include rectal sparing, aphthous ulcerations, fistulas, and skip lesions. Colonoscopy allows examination and

biopsy of mass lesions or strictures and biopsy of the terminal ileum.

Upper endoscopy is useful in diagnosing gastroduodenal involvement

in patients with upper tract symptoms. Ileal or colonic strictures may

be dilated with balloons introduced through the colonoscope. Strictures ≤4 cm in length and those at anastomotic sites respond better

to endoscopic dilation. The perforation rate is as high as 10%. Most

endoscopists dilate only fibrotic strictures and not those associated

with active inflammation. Wireless capsule endoscopy (WCE) allows

direct visualization of the entire small-bowel mucosa (Fig. 326-8). The

diagnostic yield of detecting lesions suggestive of active CD is higher

with WCE than CT or magnetic resonance (MR) enterography. WCE

should be used in the setting of a small-bowel stricture. Capsule retention occurs in <1% of patients with suspected CD, but retention rates

of 4–6% are seen in patients with established CD. It is helpful to give

the patient with CD a patency capsule, which is made of barium and

starts to dissolve 30 h after ingestion. An abdominal x-ray can be taken

at around 30 h after ingestion to see if the capsule is still present in the

small bowel, which would indicate a stricture.

In CD, early radiographic findings in the small bowel include

thickened folds and aphthous ulcerations. “Cobblestoning” from longitudinal and transverse ulcerations most frequently involves the small

bowel. In more advanced disease, strictures, fistulas, inflammatory

masses, and abscesses may be detected. The earliest macroscopic findings of colonic CD are aphthous ulcers. These small ulcers are often

multiple and separated by normal intervening mucosa. As the disease

progresses, aphthous ulcers become enlarged, deeper, and occasionally

connected to one another, forming longitudinal stellate, serpiginous,

and linear ulcers (see Fig. 322-4B).

The transmural inflammation of CD leads to decreased luminal

diameter and limited distensibility. As ulcers progress deeper, they can

lead to fistula formation. The segmental nature of CD results in wide

gaps of normal or dilated bowel between involved segments.

CT enterography and MR enterography have been shown to

be equally accurate in the identification of active small-bowel

inflammation. MRI is thought to offer superior soft tissue contrast

and has the added advantage of avoiding radiation exposure changes

(Figs. 326-9 and 326-10). The lack of ionizing radiation is particularly

appealing in younger patients and when monitoring response to therapy where serial images will be obtained. Pelvic MRI is superior to pelvic CT for demonstrating pelvic lesions such as ischiorectal abscesses

and perianal fistulas (Fig. 326-11). An underutilized resource for

assessing small-bowel CD is small-bowel ultrasound (SBUS). SBUS

is at least as sensitive as MR enterography and CT enterography for

detecting small-bowel CD, with a sensitivity of 94%, specificity of 97%,

positive predictive value of 97%, and negative predictive value of 94%.

Use of oral contrast medium can increase the sensitivity and specificity

to detect small-bowel lesions to 100%. SBUS is best suited for distal

small-bowel assessment, as the sensitivity of detecting lesions within

the duodenum and proximal jejunum may be lower due to anatomic

position. The limitations of SBUS include availability and operator

dependence.

Complications Because CD is a transmural process, serosal adhesions develop that provide direct pathways for fistula formation and

reduce the incidence of free perforation. Perforation occurs in 1–2%

of patients, usually in the ileum but occasionally in the jejunum or

as a complication of toxic megacolon. The peritonitis of free perforation, especially colonic, may be fatal. Intraabdominal and pelvic

abscesses occur in 10–30% of patients with CD at some time in the

course of their illness. CT-guided percutaneous drainage of the abscess

is standard therapy. Despite adequate drainage, most patients need

resection of the offending bowel segment. Percutaneous drainage has

an especially high failure rate in abdominal wall abscesses. Systemic

glucocorticoid therapy increases the risk of intraabdominal and pelvic

abscesses in CD patients who have never had an operation. Other complications include intestinal obstruction in 40%, massive hemorrhage,

malabsorption, and severe perianal disease.

Serologic Markers Patients with UC and CD show a wide variation in the way they present and progress over time. Some patients

present with mild disease activity and do well with generally safe and

mild medications, but many others exhibit more severe disease and

can develop serious complications that will require surgery. Current

and developing biologic therapies can help halt progression of disease

FIGURE 326-8 Wireless capsule endoscopy image in a patient with Crohn’s disease

of the ileum shows ulcerations and narrowing of the intestinal lumen. (Courtesy

of Dr. S. Reddy, Gastroenterology Division, Department of Medicine, Brigham and

Women’s Hospital, Boston, Massachusetts; with permission.)

2478 PART 10 Disorders of the Gastrointestinal System

and give patients with moderate to severe UC and CD a better quality

of life. There are potential risks of biologic therapies such as infection

and malignancy, and it would be optimal to determine by genetic or

serologic markers at the time of diagnosis which patients will require

more aggressive medical therapy.

For success in diagnosing IBD and in differentiating between CD

and UC, the efficacy of these serologic tests depends on the prevalence

of IBD in a specific population. Increased titers of anti–Saccharomyces

cerevisiae antibody (ASCA) have been associated with CD, whereas

increased levels of perinuclear antineutrophil cytoplasmic antibody

(pANCA) are more commonly seen in patients with UC. However,

when evaluated in a meta-analysis of 60 studies, the sensitivity and

specificity of an ASCA-positive/pANCA-negative pattern for identification of CD were 55 and 93%, respectively. In addition to ASCA, multiple other antibodies to bacterial proteins (Omp-C and I2), flagellin

(CBir1), and bacterial carbohydrates have been studied and associated

with CD. These serologic markers tend to have low sensitivity and

specificity and may be elevated due to other autoimmune diseases,

infections, and inflammation including those outside of the GI tract.

The Prometheus IBD SGI Diagnostic blood test measures a panel of

serologic (S), genetic (G), and inflammatory (I) biomarkers, but the

test is costly, and reliable results are based on the pretest probability

of the patient having IBD. PROSPECT is a validated web-based tool

to display individual CD outcomes and considers multiple variables

including disease location (large or small bowel, perianal), serologies

(ASCA, CBir1, ANCA), and genetics (NOD2 frameshift mutation).

Clinical factors described at diagnosis are more helpful than

serologies at predicting the natural history of IBD. Except in special

circumstances (such as before consideration of an ileal pouch-anal

anastomosis [IPAA] in a patient with indeterminate colitis), serologic

markers have only minimal clinical utility.

FIGURE 326-9 A coronal magnetic resonance image was obtained using a half

Fourier single-shot T2-weighted acquisition with fat saturation in a 27-year-old

pregnant (23 weeks’ gestation) woman. The patient had Crohn’s disease and was

maintained on mercaptopurine and prednisone. She presented with abdominal

pain, distension, vomiting, and small-bowel obstruction. The image reveals a 7-

to 10-cm long stricture at the terminal ileum (white arrows) causing obstruction

and significant dilatation of the proximal small bowel (white asterisk). A fetus

is seen in the uterus (dashed white arrows). (Courtesy of Drs. J. F. B. Chick and

P. B. Shyn, Abdominal Imaging and Intervention, Department of Radiology, Brigham

and Women’s Hospital, Harvard Medical School, Boston, Massachusetts; with

permission.)

FIGURE 326-10 A coronal balanced, steady-state, free precession, T2-weighted

image with fat saturation was obtained in a 32-year-old man with Crohn’s disease

and prior episodes of bowel obstruction, fistulas, and abscesses. He was being

treated with mercaptopurine and presented with abdominal distention and diarrhea.

The image demonstrates a new gastrocolic fistula (solid white arrows). Multifocal

involvement of the small bowel and terminal ileum is also present (dashed white

arrows). (Courtesy of Drs. J. F. B. Chick and P. B. Shyn, Abdominal Imaging and

Intervention, Department of Radiology, Brigham and Women’s Hospital, Harvard

Medical School, Boston, Massachusetts; with permission.)

FIGURE 326-11 Axial T2-weighted fat-saturated image obtained in a 39-year-old

male with Crohn’s disease shows a defect in the internal sphincter at the 6 o’clock

position of the mid anal canal (open white arrow) communicating with a 1.1-cm

intersphincteric collection (black arrow). Wide defect in the external sphincter at the

7 o’clock position (solid white arrow) leads to a moderate-sized perianal abscess in

the ischioanal fossa (asterisk). (Courtesy of Drs. J.S. Quon and P.B. Shyn, Abdominal

Imaging and Intervention, Department of Radiology, Brigham and Women’s Hospital,

Harvard Medical School, Boston, Massachusetts; with permission.)

2479 Inflammatory Bowel Disease CHAPTER 326

DIFFERENTIAL DIAGNOSIS OF UC AND CD

Once a diagnosis of IBD is made, distinguishing between UC and CD

is impossible initially in up to 15% of cases. These are termed indeterminate colitis. Fortunately, in most cases, the true nature of the underlying colitis becomes evident later in the course of the patient’s disease.

Approximately 5% (range 1–20%) of colon resection specimens are

difficult to classify as either UC or CD because they exhibit overlapping

histologic features.

■ INFECTIOUS DISEASES

Infections of the small intestines and colon can mimic CD or UC. They

may be bacterial, fungal, viral, or protozoal in origin (Table 326-6).

Campylobacter colitis can mimic the endoscopic appearance of severe

UC and can cause a relapse of established UC. Salmonella can cause

watery or bloody diarrhea, nausea, and vomiting. Shigellosis causes

watery diarrhea, abdominal pain, and fever followed by rectal tenesmus

and by the passage of blood and mucus per rectum. All three are usually self-limited, but 1% of patients infected with Salmonella become

asymptomatic carriers. Yersinia enterocolitica infection occurs mainly

in the terminal ileum and causes mucosal ulceration, neutrophil invasion, and thickening of the ileal wall. Other bacterial infections that

may mimic IBD include C. difficile, which presents with watery diarrhea, tenesmus, nausea, and vomiting; and E. coli, three categories of

which can cause colitis. These are enterohemorrhagic, enteroinvasive,

and enteroadherent E. coli, all of which can cause bloody diarrhea and

abdominal tenderness. Gonorrhea, Chlamydia, and syphilis can also

cause proctitis.

GI involvement with mycobacterial infection occurs primarily

in the immunosuppressed patient but may occur in patients with

normal immunity. Distal ileal and cecal involvement predominates,

and patients present with symptoms of small-bowel obstruction and

a tender abdominal mass. The diagnosis is made most directly by

colonoscopy with biopsy and culture. Although most of the patients

with viral colitis are immunosuppressed, cytomegalovirus (CMV) and

herpes simplex proctitis may occur in immunocompetent individuals.

CMV occurs most commonly in the esophagus, colon, and rectum

but may also involve the small intestine. Symptoms include abdominal pain, bloody diarrhea, fever, and weight loss. With severe disease,

necrosis and perforation can occur. Diagnosis is made by identification

of characteristic intranuclear inclusions in mucosal cells on biopsy.

Herpes simplex infection of the GI tract is limited to the oropharynx,

anorectum, and perianal areas. Symptoms include anorectal pain,

tenesmus, constipation, inguinal adenopathy, difficulty with urinary

voiding, and sacral paresthesias. Diagnosis is made by rectal biopsy

with identification of characteristic cellular inclusions and viral culture. HIV itself can cause diarrhea, nausea, vomiting, and anorexia.

Small-intestinal biopsies show partial villous atrophy; small-bowel

bacterial overgrowth and fat malabsorption may also be noted.

Protozoan parasites include Isospora belli, which can cause a

self-limited infection in healthy hosts but causes a chronic profuse,

watery diarrhea and weight loss in AIDS patients. Entamoeba histolytica or related species infect ~10% of the world’s population; symptoms

include abdominal pain, tenesmus, frequent loose stools containing

blood and mucus, and abdominal tenderness. Colonoscopy reveals

focal punctate ulcers with normal intervening mucosa; diagnosis is

made by biopsy or serum amebic antibodies. Fulminant amebic colitis

is rare but has a mortality rate of >50%.

Other parasitic infections that may mimic IBD include hookworm

(Necator americanus), whipworm (Trichuris trichiura), and Strongyloides stercoralis. In severely immunocompromised patients, Candida

or Aspergillus can be identified in the submucosa. Disseminated histoplasmosis can involve the ileocecal area.

■ NONINFECTIOUS DISEASES

Diverticulitis can be confused with CD clinically and radiographically.

Both diseases cause fever, abdominal pain, tender abdominal mass,

leukocytosis, elevated ESR, partial obstruction, and fistulas. Perianal

disease or ileitis on small-bowel series favors the diagnosis of CD. Significant endoscopic mucosal abnormalities are more likely in CD than

in diverticulitis. Endoscopic or clinical recurrence following segmental

resection favors CD. Diverticular-associated colitis is similar to CD,

but mucosal abnormalities are limited to the sigmoid and descending

colon.

Ischemic colitis is commonly confused with IBD. The ischemic

process can be chronic and diffuse, as in UC, or segmental, as in CD.

Colonic inflammation due to ischemia may resolve quickly or may persist and result in transmural scarring and stricture formation. Ischemic

bowel disease should be considered in the elderly following abdominal

aortic aneurysm repair or when a patient has a hypercoagulable state

or a severe cardiac or peripheral vascular disorder. Patients usually

present with sudden onset of left lower quadrant pain, urgency to

defecate, and the passage of bright red blood per rectum. Endoscopic

examination often demonstrates a normal-appearing rectum and a

sharp transition to an area of inflammation in the descending colon

and splenic flexure.

The effects of radiotherapy on the GI tract can be difficult to distinguish from IBD. Acute symptoms can occur within 1–2 weeks of starting radiotherapy. When the rectum and sigmoid are irradiated, patients

develop bloody, mucoid diarrhea and tenesmus, as in distal UC. With

small-bowel involvement, diarrhea is common. Late symptoms include

malabsorption and weight loss. Stricturing with obstruction and bacterial overgrowth may occur. Fistulas can penetrate the bladder, vagina,

or abdominal wall. Flexible sigmoidoscopy reveals mucosal granularity,

friability, numerous telangiectasias, and occasionally discrete ulcerations. Biopsy can be diagnostic.

Solitary rectal ulcer syndrome is uncommon and can be confused with IBD. It occurs in persons of all ages and may be caused

by impaired evacuation and failure of relaxation of the puborectalis

muscle. Single or multiple ulcerations may arise from anal sphincter

overactivity, higher intrarectal pressures during defecation, and digital

TABLE 326-6 Diseases That Mimic IBD

Infectious Etiologies

Bacterial Mycobacterial Viral

Salmonella Tuberculosis Cytomegalovirus

Shigella Mycobacterium avium Herpes simplex

Toxigenic Parasitic HIV

Escherichia coli Amebiasis Fungal

Campylobacter Isospora Histoplasmosis

Yersinia Trichuris trichiura Candida

Clostridium difficile Hookworm Aspergillus

Gonorrhea Strongyloides

Chlamydia trachomatis

Noninfectious Etiologies

Inflammatory Neoplastic Drugs and Chemicals

Appendicitis Lymphoma NSAIDs

Diverticulitis Metastatic Phosphosoda

Diversion colitis Carcinoma Cathartic colon

 Collagenous/

lymphocytic colitis

Carcinoma of the ileum

Carcinoid

Familial polyposis

Gold

Oral contraceptives

Cocaine

 Immune checkpoint

inhibitor colitis

Mycophenolate mofetil

Ischemic colitis

 Radiation colitis/

enteritis

 Solitary rectal ulcer

syndrome

 Eosinophilic

gastroenteritis

Neutropenic colitis

Behçet’s syndrome

 Graft-versus-host

disease

Abbreviations: IBD, inflammatory bowel disease; NSAIDs, nonsteroidal antiinflammatory drugs.

2480 PART 10 Disorders of the Gastrointestinal System

removal of stool. Patients complain of constipation with straining

and pass blood and mucus per rectum. Other symptoms include

abdominal pain, diarrhea, tenesmus, and perineal pain. Ulceration,

which may be as large as 5 cm in diameter, is usually observed anteriorly or anterolaterally 3–15 cm from the anal verge. Biopsies can be

diagnostic.

Several types of colitis are associated with nonsteroidal

anti-inflammatory drugs (NSAIDs), including de novo colitis, reactivation of IBD, and proctitis caused by use of suppositories. Most patients

with NSAID-related colitis present with diarrhea and abdominal pain,

and complications include stricture, bleeding, obstruction, perforation,

and fistulization. Withdrawal of these agents is crucial, and in cases of

reactivated IBD, standard therapies are indicated.

Colitis secondary to immune checkpoint inhibitors (ICIs), termed

ICI-related colitis, has emerged as these agents have found use in a

wide variety of cancers. Immune checkpoint proteins such as cytotoxic

T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell

death protein 1 (PD-1) are receptors expressed on the surface of effector T cells that interact with their ligands CD80/CD86 (CTLA-4) and

programmed death-ligand 1 (PD-1) on antigen-presenting cells and

normally function as inhibitors of immune responses. ICIs block these

inhibitory pathways and promote the activation and proliferation of the

native adaptive T-cell response against malignant cells as their mechanism of antitumor activity. While very effective at enhancing antitumor

T-cell activity, ICIs also activate global T-cell responses that induce

several autoimmune-related adverse events. Although immune-related

adverse events of ICIs occur in multiple organ systems, the GI tract is

affected in 21–44% of patients. The most common clinical presentation

is self-limited diarrhea that can be associated with frank colitis and

can lead to significant morbidity and mortality if not managed appropriately. Treatment is generally based on symptom severity. Moderate

to severe symptoms usually require glucocorticoids, whereas biologics

such as anti-TNF agents and integrin inhibitors are used in steroidrefractory cases.

■ THE ATYPICAL COLITIDES

Two atypical colitides—collagenous colitis and lymphocytic colitis—

have completely normal endoscopic appearances. Collagenous colitis

has two main histologic components: increased subepithelial collagen deposition and colitis with increased intraepithelial lymphocytes. The female-to-male ratio is 9:1, and most patients present in

the sixth or seventh decade of life. The main symptom is chronic

watery diarrhea. Risk factors include smoking; use of NSAIDs, proton pump inhibitors, or beta blockers; and a history of autoimmune

disease.

Lymphocytic colitis has features similar to collagenous colitis,

including age at onset and clinical presentation, but it has almost equal

incidence in men and women and no subepithelial collagen deposition on pathologic section. However, intraepithelial lymphocytes are

increased. Use of sertraline (but not beta blockers) is an additional

risk factor. The frequency of celiac disease is increased in lymphocytic

colitis and ranges from 9 to 27%. Celiac disease should be excluded

in all patients with lymphocytic colitis, particularly if diarrhea does

not respond to conventional therapy. Treatments for both microscopic

colitides vary depending on symptom severity and include, antidiarrheals (e.g., loperamide and diphenoxylate), bismuth, aminosalicylates,

budesonide, systemic glucocorticoids, and biologics for refractory

disease.

Diversion colitis is an inflammatory process that arises in segments

of the large intestine that are not continuous with the fecal stream. It

usually occurs in patients with ileostomy or colostomy when a mucus

fistula or a Hartmann’s pouch has been created. Clinically, patients

have mucus or bloody discharge from the rectum. Erythema, granularity, friability, and, in more severe cases, ulceration can be seen on

endoscopy. Histopathology shows areas of active inflammation with

foci of cryptitis and crypt abscesses. Crypt architecture is normal,

which differentiates it from UC but not necessarily CD. Short-chain

fatty acid enemas may help in diversion colitis, but the definitive therapy is surgical reanastomosis.

EXTRAINTESTINAL MANIFESTATIONS

Up to one-third of IBD patients have at least one extraintestinal disease

manifestation. Please see Table 326-7 for a summary of IBD EIMs.

■ DERMATOLOGIC

Erythema nodosum (EN) occurs in up to 15% of CD patients and

10% of UC patients. Attacks usually correlate with bowel activity;

skin lesions develop after the onset of bowel symptoms, and patients

frequently have concomitant active peripheral arthritis. The lesions of

EN are hot, red, tender nodules measuring 1–5 cm in diameter and are

found on the anterior surface of the lower legs, ankles, calves, thighs,

and arms. Therapy is directed toward the underlying bowel disease.

Pyoderma gangrenosum (PG) is seen in 1–12% of UC patients and

less commonly in Crohn’s colitis. Although it usually presents after

the diagnosis of IBD, PG may occur years before the onset of bowel

symptoms, run a course independent of the bowel disease, respond

poorly to colectomy, and even develop years after proctocolectomy. It

is usually associated with severe disease. Lesions are commonly found

on the dorsal surface of the feet and legs but may occur on the arms,

chest, stoma, and even the face. PG usually begins as a pustule and

then spreads concentrically to rapidly undermine healthy skin. Lesions

then ulcerate, with violaceous edges surrounded by a margin of erythema. Centrally, they contain necrotic tissue with blood and exudates.

Lesions may be single or multiple and grow as large as 30 cm. They are

sometimes very difficult to treat and often require IV antibiotics, IV

glucocorticoids, dapsone, azathioprine, thalidomide, IV cyclosporine

(CSA), infliximab, or adalimumab.

Other dermatologic manifestations include pyoderma vegetans,

which occurs in intertriginous areas; pyostomatitis vegetans, which

involves the mucous membranes; Sweet syndrome, a neutrophilic

dermatosis; and metastatic CD, a rare disorder defined by cutaneous

granuloma formation. Psoriasis affects 5–10% of patients with IBD

and is unrelated to bowel activity, consistent with the potential shared

immunogenetic basis of these diseases. Perianal skin tags are found in

75–80% of patients with CD, especially those with colon involvement.

Oral mucosal lesions, seen often in CD and rarely in UC, include aphthous stomatitis and “cobblestone” lesions of the buccal mucosa.

■ RHEUMATOLOGIC

Peripheral arthritis develops in 15–20% of IBD patients, is more

common in CD, and worsens with exacerbations of bowel activity. It

is asymmetric, polyarticular, and migratory and most often affects

large joints of the upper and lower extremities. Treatment is directed

at reducing bowel inflammation. In severe UC, colectomy frequently

cures the arthritis.

Ankylosing spondylitis (AS) occurs in ~10% of IBD patients and

is more common in CD than UC. About two-thirds of IBD patients

with AS express the HLA-B27 antigen. The AS activity is not related to

bowel activity and does not remit with glucocorticoids or colectomy.

It most often affects the spine and pelvis, producing symptoms of diffuse low-back pain, buttock pain, and morning stiffness. The course

is continuous and progressive, leading to permanent skeletal damage

and deformity. Anti-TNF therapy reduces spinal inflammation and

improves functional status and quality of life.

Sacroiliitis is symmetric, occurs equally in UC and CD, is often

asymptomatic, does not correlate with bowel activity, and does not

always progress to AS. Other rheumatic manifestations include hypertrophic osteoarthropathy, pelvic/femoral osteomyelitis, and relapsing

polychondritis.

■ OCULAR

The incidence of ocular complications in IBD patients is 1–10%. The

most common are conjunctivitis, anterior uveitis/iritis, and episcleritis.

Uveitis is associated with both UC and Crohn’s colitis, may be found

during periods of remission, and may develop in patients following

bowel resection. Symptoms include ocular pain, photophobia, blurred

vision, and headache. Prompt intervention, sometimes with systemic

glucocorticoids, is required to prevent scarring and visual impairment.

Episcleritis is a benign disorder that presents with symptoms of mild

2481 Inflammatory Bowel Disease CHAPTER 326

TABLE 326-7 Extraintestinal Manifestations

CATEGORY CLINICAL COURSE TREATMENT

Rheumatologic disorders (5–20%)

Peripheral arthritis Asymmetric, migratory

Parallels bowel activity

Reduce bowel inflammation

Sacroiliitis Symmetric: spine and hip joints

Independent of bowel activity

Steroids, injections, methotrexate, anti-TNF

Ankylosing spondylitis Gradual fusion of spine

Independent of bowel activity

Two-thirds have HLA-B27 antigen

Physical therapy, steroids, injections, methotrexate,

anti-TNF, IL-17 inhibitors, tofacitinib

Metabolic bone disorders (up to 40% of patients)

Osteoporosis Risk increased by glucocorticoids, cyclosporine, methotrexate, total parenteral

nutrition, malabsorption, and inflammation

Fracture rates highest in the elderly (age >60)

Screening with DEXA scan, check vitamin D levels,

treat if osteoporosis or osteopenia on long-term

corticosteroids

Osteonecrosis Death of osteocytes and adipocytes and eventual bone collapse; affects hips

more than knees or shoulders; risk factor is steroid use

Pain control, injections, joint replacement

Dermatologic disorders (10–20%)

Erythema nodosum Hot, red, tender, nodules/extremities

Parallels bowel activity

Reduce bowel inflammation

Pyoderma gangrenosum Ulcerating, necrotic lesions on extremities, trunk, face, stoma

Independent of bowel activity

Antibiotics, steroids, cyclosporine, infliximab, dapsone,

azathioprine, intralesional steroids; not debridement or

colectomy

Psoriasis Unrelated to bowel activity Topical steroids, light therapy, methotrexate, infliximab,

adalimumab, ustekinumab

Pyoderma vegetans Intertriginous areas

Parallels bowel activity

Evanescent; resolves without progression

Pyostomatitis vegetans Mucous membranes

Parallels bowel activity

Evanescent; resolves without progression

Metastatic Crohn’s

disease (CD)

CD of the skin

Parallels bowel activity

Reduce bowel inflammation

Sweet syndrome Neutrophilic dermatosis

Parallels bowel activity

Reduce bowel inflammation

Aphthous stomatitis Oral ulcerations

Parallels bowel activity

Reduce bowel inflammation/topical therapy

Ocular disorders (1–11%)

Uveitis Ocular pain, photophobia, blurred vision, headache

Independent of bowel activity

Topical or systemic steroids

Episcleritis Mild ocular burning

Parallels bowel activity

Topical corticosteroids

Hepatobiliary disorders (10–35%)

Fatty liver Secondary to chronic illness, malnutrition, steroid therapy Improve nutrition, reduce steroids

Cholelithiasis Patients with ileitis or ileal resection

Malabsorption of bile acids, depletion of bile salt pool, secretion of lithogenic bile

Reduce bowel inflammation; cholecystectomy in

symptomatic patients

Primary sclerosing

cholangitis (PSC)

Intrahepatic and extrahepatic

Inflammation and fibrosis leading to biliary cirrhosis and hepatic failure

7–10% cholangiocarcinoma

Small-duct PSC involves small-caliber bile ducts and has a better prognosis

ERCP/high-dose ursodiol lowers risk of colonic

neoplasia; cholecystectomy in patients with gallbladder

polyps due to the high incidence of malignancy

Urologic

Nephrolithiasis (10–20%) CD patients following small-bowel resection; calcium oxalate stones most

common

Low-oxalate diet; control of bowel inflammation;

surgical intervention

Less common extraintestinal manifestations

Thromboembolic

disorders

Increased risk of venous and arterial thrombosis; factors responsible include

abnormalities of the platelet-endothelial interaction, hyperhomocysteinemia,

alterations in the coagulation cascade, impaired fibrinolysis, involvement of

tissue factor–bearing microvesicles, disruption of the normal coagulation system

by autoantibodies, and a genetic predisposition

Anticoagulation; control of inflammation

Cardiopulmonary Endocarditis, myocarditis, pleuropericarditis, interstitial lung disease Treatment is varied; stop 5-ASA agents as they can

rarely cause interstitial lung disease

Systemic amyloidosis Secondary (reactive) in long-standing IBD, especially CD Colchicine

Pancreatitis Duodenal fistulas, ampullary CD, gallstones, PSC, drugs (MP, azathioprine,

5-ASAs), autoimmune, primary CD of the pancreas

Treatment is varied; stop offending medication; diagnose

and treat with ERCP and/or cholecystectomy

Abbreviations: 5-ASA, 5-aminosalicylic acid; DEXA, dual-energy x-ray absorptiometry; ERCP, endoscopic retrograde cholangiopancreatography; IBD, inflammatory bowel

disease; IL, interleukin; MP, mercaptopurine; TNF, tumor necrosis factor.

2482 PART 10 Disorders of the Gastrointestinal System

ocular burning. It occurs in 3–4% of IBD patients, more commonly in

Crohn’s colitis, and is treated with topical glucocorticoids.

■ HEPATOBILIARY

Hepatic steatosis is detectable in about one-half of the abnormal liver

biopsies from patients with CD and UC; patients usually present

with hepatomegaly. Fatty liver usually results from a combination of

chronic debilitating illness, malnutrition, and glucocorticoid therapy.

Cholelithiasis occurs in 10–35% of CD patients with ileitis or ileal

resection. Gallstone formation is caused by malabsorption of bile

acids, resulting in depletion of the bile salt pool and the secretion of

lithogenic bile.

Primary sclerosing cholangitis (PSC) is a disorder characterized by

both intrahepatic and extrahepatic bile duct inflammation and fibrosis, frequently leading to biliary cirrhosis and hepatic failure; ~5% of

patients with UC have PSC, but 50–75% of patients with PSC have IBD.

PSC occurs less often in patients with CD. Although it can be recognized after the diagnosis of IBD, PSC can be detected earlier or even

years after proctocolectomy. Consistent with this, the immunogenetic

basis for PSC appears to be overlapping but distinct from UC based on

GWAS, although both IBD and PSC are commonly pANCA positive.

Most patients have no symptoms at the time of diagnosis; when symptoms are present, they consist of fatigue, jaundice, abdominal pain,

fever, anorexia, and malaise. The traditional gold standard diagnostic

test is endoscopic retrograde cholangiopancreatography (ERCP), but

magnetic resonance cholangiopancreatography (MRCP) is sensitive,

specific, and safer. MRCP is reasonable as an initial diagnostic test in

children and adults and can visualize irregularities, multifocal strictures, and dilatations of all levels of the biliary tree. In patients with

PSC, both ERCP and MRCP demonstrate multiple bile duct strictures

alternating with relatively normal segments.

Gallbladder polyps in patients with PSC have a high incidence of

malignancy, and cholecystectomy is recommended, even if a mass

lesion is <1 cm in diameter. Gallbladder surveillance with ultrasound

should be performed annually. Endoscopic stenting may be palliative

for cholestasis secondary to bile duct obstruction. Patients with symptomatic disease develop cirrhosis and liver failure over 5–10 years and

eventually require liver transplantation. PSC patients have a 10–15%

lifetime risk of developing cholangiocarcinoma and then cannot be

transplanted. Patients with IBD and PSC are at increased risk of colon

cancer and should be surveyed yearly by colonoscopy and biopsy.

In addition, cholangiography is normal in a small percentage of

patients who have a variant of PSC known as small duct primary sclerosing cholangitis. This variant (sometimes referred to as “pericholangitis”) is probably a form of PSC involving small-caliber bile ducts. It

has similar biochemical and histologic features to classic PSC. It has a

significantly better prognosis than classic PSC, although it may evolve

into classic PSC. Granulomatous hepatitis and hepatic amyloidosis are

much rarer EIMs of IBD.

■ UROLOGIC

The most frequent genitourinary complications are calculi, ureteral

obstruction, and ileal bladder fistulas. The highest frequency of nephrolithiasis (10–20%) occurs in patients with CD following small-bowel

resection. Calcium oxalate stones develop secondary to hyperoxaluria,

which results from increased absorption of dietary oxalate. Normally,

dietary calcium combines with luminal oxalate to form insoluble calcium oxalate, which is eliminated in the stool. In patients with ileal

dysfunction, however, nonabsorbed fatty acids bind calcium and leave

oxalate unbound. The unbound oxalate is then delivered to the colon,

where it is readily absorbed, especially in the presence of inflammation.

■ METABOLIC BONE DISORDERS

Low bone mass occurs in 14–42% of IBD patients. The risk is increased

by glucocorticoids, CSA, methotrexate (MTX), and total parenteral

nutrition (TPN). Malabsorption and inflammation mediated by IL-1,

IL-6, TNF, and other inflammatory mediators also contribute to low

bone density. An increased incidence of hip, spine, wrist, and rib fractures has been noted: 36% in CD and 45% in UC. The absolute risk of

an osteoporotic fracture is ~1% per person per year. Fracture rates, particularly in the spine and hip, are highest among the elderly (age >60).

One study noted an OR of 1.72 for vertebral fracture and an OR of 1.59

for hip fracture. The disease severity predicted the risk of a fracture.

Only 13% of IBD patients who had a fracture were on any kind of antifracture treatment. Up to 20% of bone mass can be lost per year with

chronic glucocorticoid use. The effect is dose-dependent. Budesonide

may also suppress the pituitary-adrenal axis and thus carries a risk of

causing osteoporosis.

Osteonecrosis is characterized by death of osteocytes and adipocytes

and eventual bone collapse. The pain is aggravated by motion and

swelling of the joints. It affects the hips more often than knees and

shoulders, and in one series, 4.3% of patients developed osteonecrosis

within 6 months of starting glucocorticoids. Diagnosis is made by bone

scan or MRI, and treatment consists of pain control, cord decompression, osteotomy, and joint replacement.

■ THROMBOEMBOLIC DISORDERS

Patients with IBD have an increased risk of both venous and arterial thrombosis even if the disease is not active. Factors responsible

for the hypercoagulable state have included abnormalities of the

platelet-endothelial interaction, hyperhomocysteinemia, alterations in

the coagulation cascade, impaired fibrinolysis, involvement of tissue

factor–bearing microvesicles, disruption of the normal coagulation

system by autoantibodies, and a genetic predisposition. A spectrum of

vasculitides involving small, medium, and large vessels has also been

observed.

■ OTHER DISORDERS

More common cardiopulmonary manifestations include endocarditis,

myocarditis, pleuropericarditis, and interstitial lung disease. A secondary or reactive amyloidosis can occur in patients with long-standing

IBD, especially in patients with CD. Amyloid material is deposited systemically and can cause diarrhea, constipation, and renal failure. The

renal disease can be successfully treated with colchicine. Pancreatitis is

a rare EIM of IBD and results from duodenal fistulas; ampullary CD;

gallstones; PSC; drugs such as mercaptopurine, azathioprine, or, very

rarely, 5-ASA agents; autoimmune pancreatitis; and primary CD of the

pancreas.

TREATMENT

Inflammatory Bowel Disease

5-ASA AGENTS

These agents are effective at inducing and maintaining remission

in UC. Peroxisome proliferator–activated receptor γ (PPAR-γ) may

mediate 5-ASA therapeutic action by decreasing nuclear localization of NF-κB. Sulfa-free aminosalicylate formulations include

alternative azo-bonded carriers, 5-ASA dimers, and delayed-release

and controlled-release preparations. Each has the same efficacy as

sulfasalazine when equimolar concentrations are used.

Sulfasalazine is effective treatment for mild to moderate UC, but

its high rate of side effects limits its use. Although sulfasalazine is

more effective at higher doses, at 6 or 8 g/d, up to 30% of patients

experience allergic reactions or intolerable side effects such as headache, anorexia, nausea, and vomiting that are attributable to the

sulfapyridine moiety. Hypersensitivity reactions, independent of

sulfapyridine levels, include rash, fever, hepatitis, agranulocytosis,

hypersensitivity pneumonitis, pancreatitis, worsening of colitis, and

reversible sperm abnormalities. Sulfasalazine can also impair folate

absorption, and patients should be given folic acid supplements.

Balsalazide contains an azo bond binding mesalamine to the carrier molecule 4-aminobenzoyl-β-alanine; it is effective in the colon.

Delzicol and Asacol HD (high dose) are enteric-coated forms

of mesalamine with the 5-ASA being released at pH >7. They disintegrate with complete breakup of the tablet occurring in many

different parts of the gut ranging from the small intestine to the

splenic flexure; they have increased gastric residence when taken