2471 Inflammatory Bowel Disease CHAPTER 326

Stress

Genetic susceptibility

Microbial flora

Enteropathogens

Antibiotics

Diet, hygiene NSAIDs, smoking

Diet, hygiene

Environmental factors

Immune dysregulation IEC

XBP1

NOD2

ATG16L1

TLR4

XBP1

DLG5

ECM1

ITLN1

SLC22A5

DMBT1

PTGER4

IL23R, IL12B, JAK2, STAT3, CCR6,

NOD2, TLR4, CARD9, IRF5,

ATG16L1, IRGM, LRRK2

TNFSF15, TNFRSF6B

TNFAIP3, PTPN2/22

NLRP3, IL18RAP

ICOSL, ARPC2, STAT3, IL10

FIGURE 326-1 Pathogenesis of inflammatory bowel disease (IBD). In IBD, the tridirectional relationship between the commensal flora (microbiota), intestinal epithelial

cells (IECs), and mucosal immune system is dysregulated, leading to chronic inflammation. Each of these three factors is affected by genetic and environmental factors

that determine risk for the disease. NSAIDs, nonsteroidal anti-inflammatory drugs. (Republished with permission Annual Review of Immunology from Inflammatory Bowel

Disease, A Kaser et al: 28:573, 2010. Permission conveyed through Copyright Clearance Center, Inc.)

Monogenic

Familial

(10%)

Sporadic

Oligogenic Polygenic

Environment

Undiagnosed

infections?

Early onset

Genetics

FIGURE 326-2 A model for the syndromic nature of inflammatory bowel disease

(IBD). Genetic and environmental factors variably influence the development and

phenotypic manifestations of IBD. At the one extreme, IBD is exemplified as a simple

Mendelian disorder as observed in early-onset IBD due to single-gene defects such

as IL10, IL10RA, and IL10RB; and at the other extreme, it may be exemplified by as yet

to be described emerging infectious diseases. (Reproduced with permission from A

Kaser et al: Genes and environment: how will our concepts on the pathophysiology

of IBD develop in the future?, Dig Dis 28:395, 2010.)

FoxP3 transcription factor and suppress inflammation). Maintenance

of homeostasis also involves oversight from local parenchymal cells

including nerve, endothelial, and stromal cells, as well as the commensal microbiota that provide essential remedial factors necessary for

health and serve as a target of the immune response. During the course

of infections or other environmental stimuli in the normal host, full

activation of the lymphoid tissues in the intestines occurs but is rapidly

superseded by dampening of the immune response and tissue repair. In

IBD, such processes may not be regulated normally.

GENETIC CONSIDERATIONS

The genetic underpinning of IBD is known from its concordance

in identical twins, its occurrence in the context of several genetic

syndromes, and the development of severe, refractory IBD in early

life in association with single-gene defects that affect the immune system (Table 326-2). More than 60 different gene defects have been identified in patients with VEOIBD by whole exome sequencing (WES), in

whom the majority of monogenic mutations have been discovered.

These include mutations in genes encoding, for example, interleukin

(IL) 10, the IL-10 receptor (IL-10R), cytotoxic T-lymphocyte-associated

protein-4 (CTLA4), neutrophil cytosolic factor 2 protein (NCF2),

X-linked inhibitor of apoptosis protein (XIAP), lipopolysaccharide

responsive and beige-like anchor protein (LRBA), and tetratricopeptide

repeat domain 7A protein (TTC7), among many other genes that are

involved in host-commensal interactions. A monogenic etiology may

also be possible in a small subset of adult patients with IBD. In addition, IBD has a familial origin in at least 10% of afflicted individuals,

consistent with an inherited basis for this disease (Fig. 326-2). However, the majority of cases of pediatric (non-VEOIBD) and adult IBD

are multigenic (or polygenic) in origin, suggesting a syndromic nature

of this disease that gives rise to multiple clinical subgroups beyond the

simple classification as UC and CD. The polygenic nature of the disease

has been elucidated through a variety of genetic approaches, including

candidate gene studies, linkage analysis, and genome-wide association

studies (GWAS) that focus on the identification of disease-associated

single nucleotide polymorphisms (SNPs) within the human genome

and WES and whole genome sequencing to elucidate the specific mutations potentially involved. GWAS have identified ~240 genetic loci;

two-thirds of these loci are associated with both disease phenotypes,

2472 PART 10 Disorders of the Gastrointestinal System

with the remainder being specific for either CD or UC (Table 326-3).

These genetic similarities account for the overlapping immunopathogenesis and consequently epidemiologic observations of both diseases

in the same families and similarities in response to therapies. Because

the specific causal variants for each identified gene or locus are mostly

unknown as most risk loci are contained within regulatory (noncoding) regions of the associated genes, it is not clear whether the similarities in the genetic risk factors associated with CD and UC are shared

at a structural or functional level. The risk conferred by each identified

gene or locus is unequal and generally small, such that only ~20% of

the disease risk is considered to be explained by the current genetic

information. Further, many of the genetic risk factors identified are

also observed to be associated with risk for other immune-mediated

diseases, suggesting that related immunogenetic pathways are involved

in the pathogenesis of multiple different disorders, accounting for the

common responsiveness to similar types of biologic therapies (e.g.,

anti–tumor necrosis factor [TNF] therapies) and possibly the simultaneous occurrence of these disorders. The diseases and the genetic risk

factors that are shared with IBD include, for example, rheumatoid

arthritis (TNFAIP3), psoriasis (IL23R, IL12B), ankylosing spondylitis

(IL23R), type 1 diabetes mellitus (IL10, PTPN2), asthma (ORMDL3),

and systemic lupus erythematosus (TNFAIP3, IL10), among others.

The genetic factors that are recognized to mediate risk for IBD

have highlighted the importance of shared mechanisms of disease that

variably affect CD and/or UC (Table 326-3). These include the following: those genes that are associated with fundamental cell biologic

processes such as the unfolded protein response due to endoplasmic

reticulum stress, autophagy, and metabolism that regulate the ability

of cells to manage the physiologic needs of the intestinal environment;

those associated with innate immunity associated with nonlymphoid

cells that function in responses to and control of microbes; those

associated with the regulation of adaptive immunity that control the

balance between inflammatory and anti-inflammatory cellular pathways associated with lymphocytes; and, finally, those that are involved

in the development and resolution of inflammation associated with

TABLE 326-2 Primary Genetic Disorders Associated with IBD

NAME GENETIC ASSOCIATION PHENOTYPE

Turner’s syndrome Loss of part or all of X

chromosome

Associated with UC and

colonic CD

Hermansky-Pudlak

syndrome

Autosomal recessive

chromosome 10q23

Granulomatous colitis,

oculocutaneous albinism,

platelet dysfunction,

pulmonary fibrosis

Wiskott-Aldrich

syndrome (WAS)

X-linked recessive

disorder, loss of WAS

protein function

Colitis,

immunodeficiency,

severely dysfunctional

platelets, and

thrombocytopenia

Glycogen storage

disease type B1

Autosomal recessive

disorder of SLC37A4

resulting in deficiency of

the glucose-6-phosphate

translocase

Granulomatous colitis,

presents in infancy with

hypoglycemia, growth

failure, hepatomegaly,

and neutropenia

Immune dysregulation

polyendocrinopathy,

enteropathy X-linked

(IPEX)

Loss of FoxP3

transcription factor and T

regulatory cell function

UC-like autoimmune

enteropathy, with

endocrinopathy (neonatal

type 1 diabetes or

thyroiditis), dermatitis

Early-onset IBD Deficient IL-10 and IL-10

receptor function

Severe, refractory IBD in

early life

Abbreviations: CD, Crohn’s disease; IBD, inflammatory bowel disease; IL, interleukin;

UC, ulcerative colitis.

TABLE 326-3 Some Genetic Loci Associated with Crohn’s Disease and/or Ulcerative Colitis

CHROMOSOME PUTATIVE GENE GENE NAME PROTEIN FUNCTION CD UC

Unfolded Protein Response, Autophagy and Metabolism

2q37 ATG16L1 ATG16 autophagy related 16-like 1 Autophagy +

5q31 SLC22A5 Solute carrier family 22, member 5 β-Carnitine transporter +

5q33 IRGM Immunity-related GTPase family, M Autophagy +

7p21 AGR2 Anterior gradient 2 Unfolded protein response + +

12q12 LRRK2 Leucine-rich repeat kinase 2 Autophagy +

13q14 C13orf1 FAMIN/LACC1 Immunometabolic regulator +

17q21 ORMDL3 Orosomucoid related member 1-like 3 Unfolded protein response and lipid synthesis + +

22q12 XBP1 X-box binding protein 1 Unfolded protein response + +

Innate Immunity

1q23 ITLN1 Intelectin 1 Bacterial binding +

16q12 NOD2 Nucleotide-binding oligomerization

domain containing 2

Bacterial sensing and autophagy activation +

Adaptive Immunity

1p31 IL23R Interleukin 23 receptor TH17 cell stimulation + +

1q32 IL10 Interleukin 10 Treg-associated cytokine +

5q33 IL12B Interleukin 12B IL-12 p40 chain of IL-12/IL-23 + +

18p11 PTPN2 Protein tyrosine phosphatase,

nonreceptor type 2

T-cell regulation +

Inflammation and Healing

3p21 MST1 Macrophage stimulating 1 Macrophage activation + +

5p13 PTGER4 Prostaglandin E receptor 4 PGE2

 receptor + +

6q23 TNFAIP3 Tumor necrosis factor, alpha-induced

protein 3 (A20)

Toll-like receptor regulation +

6q27 CCR6 Chemokine (C-C motif) receptor 6 Dendritic cell migration +

9p24 JAK2 Janus kinase 2 IL-6R and IL-23R signaling + +

17q21 STAT3 Signal transducer and activator of

transcription 3

IL-6R, IL-23R, and IL-10R signaling + +

Abbreviations: CD, Crohn’s disease; GTPase, guanosine triphosphatase; IL, interleukin; PGE2

, prostaglandin E2

; Treg, T regulatory cell; UC, ulcerative colitis.

Source: Adapted from A Kaser et al: Ann Rev Immunol 28:573, 2010; Graham DB and Xavier RJ: Nature 578:527, 2020.

2473 Inflammatory Bowel Disease CHAPTER 326

healing that control leukocyte recruitment and inflammatory mediator production. Each of these genetic susceptibilities contributes in

an incremental manner to IBD risk, variably affects the activities of

virtually all subtypes of immune and nonimmune cells within the

intestines, and encodes mutations (polymorphisms) that promote or

protect from IBD. Some of these loci are associated with specific subtypes of disease such as the association between NOD2 polymorphisms

and fibrostenosing CD or ATG16L1 and fistulizing disease, especially

within the ileum. However, the clinical utility of these genetic risk

factors for the diagnosis or determination of prognosis and therapeutic

responses remains to be defined.

■ COMMENSAL MICROBIOTA AND IBD

The endogenous commensal microbiota within the intestines plays a

central role in the pathogenesis of IBD. Humans are born with sterile

guts and acquire their commensal microbiota initially from the mother

during egress through the birth canal and subsequently from environmental sources. A stable configuration of up to 1000 species of bacteria

that achieves a biomass of ~1012 colony-forming units per gram of feces

is achieved by 3 years of age, which likely persists into adult life, with

each individual human possessing a unique combination of species.

In addition, the intestines contain other microbial life forms including

fungi, archaea, viruses, and protists. The microbiota is thus considered

as a critical and sustaining component of the human organism. The

establishment and maintenance of the intestinal microbiota composition and function are under the control of host (e.g., immune and

epithelial responses), environmental (e.g., diet and antibiotics), and

likely genetic (e.g., NOD2) factors (Fig. 326-1). In turn, the microbiota,

through its structural components and metabolic activity, has major

influences on the epithelial and immune function of the host, which,

through epigenetic effects, may have durable consequences. During

early life when the commensal microbiota is being established, these

microbial effects on the host may be particularly important in determining later life risk for IBD. Specific components of the microbiota

can promote or protect from disease. The commensal microbiota in

patients with both UC and CD is demonstrably different from that of

nonafflicted individuals, a state of dysbiosis suggesting the presence

of microorganisms that drive disease (e.g., Proteobacteria such as

enteroinvasive and adherent Escherichia coli) and to which the immune

response is directed and/or the loss of microorganisms that hinder

inflammation (e.g., Firmicutes such as Faecalibacterium prausnitzii).

Many of the changes in the commensal microbiota occur as a consequence of the inflammation and are thus potential secondary drivers

of disease. In addition, agents that alter the intestinal microbiota such

as metronidazole, ciprofloxacin, and elemental diets, may improve CD.

CD may also respond to fecal diversion, demonstrating the ability of

luminal contents to exacerbate disease.

■ DEFECTIVE IMMUNE REGULATION IN IBD

The mucosal immune system does not normally elicit an inflammatory

immune response to luminal contents due to oral (mucosal) tolerance.

Administration of soluble antigens orally, rather than subcutaneously or

intramuscularly, leads to antigen-specific control of the response and the

host’s ability to tolerate the antigen. Multiple mechanisms are involved

in the induction of oral tolerance and include deletion or anergy (nonresponsiveness) of antigen-reactive T cells or induction of CD4+ T cells

that suppress gut inflammation (e.g., T regulatory cells expressing the

FoxP3 transcription factor) and that secrete anti-inflammatory cytokines such as IL-10, IL-35, and transforming growth factor β (TGF-β).

Oral tolerance may be responsible for the lack of immune responsiveness to dietary antigens and the commensal microbiota in the intestinal

lumen. In IBD, this suppression of inflammation is altered, leading to

uncontrolled inflammation. The mechanisms of this regulated immune

suppression are incompletely known.

Gene knockout (–/–) or transgenic (Tg) mouse models of IBD,

including those that are directed at genes associated with risk for the

human disease, have revealed that deleting specific cytokines (e.g.,

IL-2, IL-10, TGF-β) or their receptors, deleting molecules associated

with T-cell antigen recognition (e.g., T-cell antigen receptors), or

interfering with IEC barrier function and the regulation of responses

to commensal bacteria (e.g., XBP1, mucus glycoproteins, or nuclear

factor-κB [NF-κB]) leads to spontaneous colitis or enteritis. In the

majority of circumstances, intestinal inflammation in these animal

models requires the presence of the commensal microbiota. However,

in some cases, activation of certain elements of the intestinal immune

system may be exacerbated by the absence of bacteria, resulting in

severe colitis and emphasizing the presence of protective properties

of the commensal microbiota. Thus, a variety of specific alterations in

either the microbiota or host can lead to uncontrolled immune activation and inflammation directed at the intestines in mice. How these

relate to human IBD remains to be defined, but they are consistent

with inappropriate responses of the genetically susceptible host to the

commensal microbiota.

■ THE INFLAMMATORY CASCADE IN IBD

In both UC and CD, inflammation likely emerges from the genetic

predisposition of the host in the context of yet-to-be-defined environmental factors. Once initiated in IBD by abnormal innate immune

sensing of bacteria by parenchymal cells (e.g., IECs) and hematopoietic cells (e.g., dendritic cells), the immune inflammatory response

is perpetuated by T-cell activation when coupled together with inadequate regulatory pathways. A sequential cascade of inflammatory

mediators extends the response, making each step a potential target

for therapy. Inflammatory cytokines from innate immune cells such as

IL-1, IL-6, IL-12, IL-23, and TNF have diverse effects on tissues. They

promote fibrogenesis, collagen production, activation of tissue metalloproteinases, and the production of other inflammatory mediators;

they also activate the coagulation cascade in local blood vessels (e.g.,

increased production of von Willebrand factor). These cytokines are

normally produced in response to infection but are usually turned off

or inhibited by cytokines such as IL-10 and TGF-β at the appropriate

time to limit tissue damage. In IBD their activity is not regulated,

resulting in an imbalance between the proinflammatory and antiinflammatory mediators. Some cytokines activate other inflammatory

cells (macrophages and B cells), and others act indirectly to recruit

other lymphocytes, inflammatory leukocytes, and mononuclear cells

from the bloodstream into the gut through interactions between

homing receptors on leukocytes (e.g., α4β7 integrin) and addressins

on vascular endothelium (e.g., MadCAM1). CD4+ T helper (TH) cells

that promote inflammation are of three major types, all of which may

be associated with colitis in animal models and perhaps humans: TH1

cells (secrete interferon [IFN] γ), TH2 cells (secrete IL-4, IL-5, IL-13),

and TH17 cells (secrete IL-17, IL-21, IL-22). TH17 cells may also provide

protective functions. Innate immune-like cells (ILCs) that lack T-cell

receptors are also present in intestines, polarize to the same functional

fates, and may similarly participate in IBD. TH1 cells induce transmural

granulomatous inflammation that resembles CD; TH2 cells and related

natural killer T cells that secrete IL-4, IL-5, and IL-13 induce superficial mucosal inflammation resembling UC in animal models; and

TH17 cells may be responsible for neutrophilic recruitment. However,

neutralization of the cytokines produced by these cells, such as IFN-γ

or IL-17, has yet to show efficacy in therapeutic trials. Each of these

T-cell subsets cross-regulates each other. The TH1 cytokine pathway is

initiated by IL-12, a key cytokine in the pathogenesis of experimental

models of mucosal inflammation. IL-4 and IL-23, together with IL-6

and TGF-β, induce TH2 and TH17 cells, respectively, and IL-23 inhibits

the suppressive function of regulatory T cells. Activated macrophages

secrete TNF and IL-6.

These characteristics of the immune response in IBD explain the

beneficial therapeutic effects of antibodies to block proinflammatory

cytokines or the signaling by their receptors (e.g., anti-TNF, anti-IL-12,

anti-IL-23, anti-IL-6, or Janus kinase [JAK] inhibitors) or molecules

associated with leukocyte recruitment (e.g., anti-α4β7). They also

highlight the potential usefulness of cytokines that inhibit inflammation and promote regulatory T cells or promote intestinal barrier

function (e.g., IL-10) in the treatment of IBD. Therapies such as the

5-aminosalicylic acid (5-ASA) compounds and glucocorticoids are also

2474 PART 10 Disorders of the Gastrointestinal System

potent inhibitors of these inflammatory mediators through inhibition

of transcription factors such as NF-κB that regulate their expression.

PATHOLOGY

■ ULCERATIVE COLITIS: MACROSCOPIC FEATURES

UC is a mucosal disease that usually involves the rectum and extends

proximally to involve all or part of the colon. About 40–50% of patients

have disease limited to the rectum and rectosigmoid, 30–40% have disease extending beyond the sigmoid but not involving the whole colon,

and 20% have a pancolitis. Proximal spread occurs in continuity without areas of uninvolved mucosa. When the whole colon is involved,

the inflammation extends 2–3 cm into the terminal ileum in 10–20%

of patients. The endoscopic changes of backwash ileitis are superficial

and mild and are of little clinical significance. Although variations in

macroscopic activity may suggest skip areas, biopsies from normalappearing mucosa are usually abnormal. Thus, it is important to obtain

multiple biopsies from apparently uninvolved mucosa, whether proximal or distal, during endoscopy. One caveat is that effective medical

therapy can change the appearance of the mucosa such that either skip

areas or the entire colon can be microscopically normal.

With mild inflammation, the mucosa is erythematous and has a

fine granular surface that resembles sandpaper. In more severe disease,

the mucosa is hemorrhagic, edematous, and ulcerated (Fig. 326-3). In

long-standing disease, inflammatory polyps (pseudopolyps) may be

present as a result of epithelial regeneration. The mucosa may appear

normal in remission, but in patients with many years of disease, it

appears atrophic and featureless, and the entire colon becomes narrowed and shortened. Patients with fulminant disease can develop a

toxic colitis or megacolon where the bowel wall becomes thin and the

mucosa is severely ulcerated; this may lead to perforation.

■ ULCERATIVE COLITIS: MICROSCOPIC FEATURES

Histologic findings correlate well with the endoscopic appearance and

clinical course of UC. The process is limited to the mucosa and superficial submucosa, with deeper layers unaffected except in fulminant

disease. In UC, two major histologic features suggest chronicity and

help distinguish it from infectious or acute self-limited colitis. First,

the crypt architecture of the colon is distorted; crypts may be bifid and

reduced in number, often with a gap between the crypt bases and the

muscularis mucosae. Second, some patients have basal plasma cells

and multiple basal lymphoid aggregates. Mucosal vascular congestion,

with edema and focal hemorrhage, and an inflammatory cell infiltrate

of neutrophils, lymphocytes, plasma cells, and macrophages may be

present. The neutrophils invade the epithelium, usually in the crypts,

giving rise to cryptitis and, ultimately, to crypt abscesses (Fig. 326-4).

Ileal changes in patients with backwash ileitis include villous atrophy

and crypt regeneration with increased inflammation, increased neutrophil and mononuclear inflammation in the lamina propria, and

patchy cryptitis and crypt abscesses.

■ CROHN’S DISEASE: MACROSCOPIC FEATURES

CD can affect any part of the gastrointestinal (GI) tract from the mouth

to the anus. Some 30–40% of patients have small-bowel disease alone,

40–55% have disease involving both the small and large intestines, and

15–25% have colitis alone. In the 75% of patients with small-intestinal

disease, the terminal ileum is involved in 90%. Unlike UC, which

almost always involves the rectum, the rectum is often spared in CD.

CD is often segmental with skip areas throughout the diseased intestine (Fig. 326-5). Perianal disease, manifesting as perirectal fistulas,

fissures, abscesses, and anal stenosis, is present in one-third of patients

with CD, particularly those with colonic involvement. Rarely, CD may

also involve the liver and the pancreas.

Unlike UC, CD is a transmural process. Endoscopically, aphthous or

small superficial ulcerations characterize mild disease; in more active

disease, stellate ulcerations fuse longitudinally and transversely to

FIGURE 326-3 Ulcerative colitis. Diffuse (nonsegmental) mucosal disease,

with broad areas of ulceration. The bowel wall is not thickened, and there is no

cobblestoning. (Courtesy of Dr. R. Odze, Division of Gastrointestinal Pathology,

Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts;

with permission.)

FIGURE 326-4 Medium-power view of colonic mucosa in ulcerative colitis

showing diffuse mixed inflammation, basal lymphoplasmacytosis, crypt atrophy and

irregularity, and superficial erosion. These features are typical of chronic active

ulcerative colitis. (Courtesy of Dr. R. Odze, Division of Gastrointestinal Pathology,

Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts;

with permission.)

FIGURE 326-5 Crohn’s disease of the colon showing thickening of the wall, with

stenosis, linear serpiginous ulcers, and cobblestoning of the mucosa. (Courtesy of

Dr. R Odze, Division of Gastrointestinal Pathology, Department of Pathology, Brigham

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

2475 Inflammatory Bowel Disease CHAPTER 326

demarcate islands of mucosa that frequently are histologically normal.

This “cobblestone” appearance is characteristic of CD, both endoscopically and by barium radiography. As in UC, pseudopolyps can form

in CD.

Active CD is characterized by focal inflammation and formation

of fistula tracts, which resolve by fibrosis and stricturing of the bowel.

The bowel wall thickens and becomes narrowed and fibrotic, leading

to chronic, recurrent bowel obstructions. Projections of thickened

mesentery known as “creeping fat” encase the bowel, and serosal and

mesenteric inflammation promotes adhesions and fistula formation.

■ CROHN’S DISEASE: MICROSCOPIC FEATURES

The earliest lesions are aphthoid ulcerations and focal crypt abscesses

with loose aggregations of macrophages, which form noncaseating

granulomas in all layers of the bowel wall (Fig. 326-6). Granulomas are

a characteristic feature of CD and are less commonly found on mucosal

biopsies than on surgical resection specimens. Other histologic features of CD include submucosal or subserosal lymphoid aggregates,

particularly away from areas of ulceration, gross and microscopic skip

areas, and transmural inflammation that is accompanied by fissures

that penetrate deeply into the bowel wall and sometimes form fistulous

tracts or local abscesses.

CLINICAL PRESENTATION

■ ULCERATIVE COLITIS

Signs and Symptoms The major symptoms of UC are diarrhea,

rectal bleeding, tenesmus, passage of mucus, and crampy abdominal

pain. The severity of symptoms correlates with the extent of disease.

Although UC can present acutely, symptoms usually have been present

for weeks to months.

Patients with proctitis usually pass fresh blood or blood-stained

mucus, either mixed with stool or streaked onto the surface of a normal

or hard stool. They also have tenesmus, or urgency with a feeling of

incomplete evacuation, but rarely have abdominal pain. With proctitis

or proctosigmoiditis, proximal transit slows, which may account for

the constipation commonly seen in patients with distal disease.

When the disease extends beyond the rectum, blood is usually

mixed with stool or grossly bloody diarrhea may be noted. Colonic

motility is altered by inflammation with rapid transit through the

inflamed intestine. When the disease is severe, patients pass a liquid

stool containing blood, pus, and fecal matter. Diarrhea is often nocturnal and/or postprandial. Although severe pain is not a prominent

symptom, some patients with active disease may experience lower

abdominal discomfort or mild central abdominal cramping. Severe

cramping and abdominal pain can occur with severe attacks of the disease. Other symptoms in moderate to severe disease include anorexia,

nausea, vomiting, fever, and weight loss.

Physical signs of proctitis include a tender anal canal and blood

on rectal examination. With more extensive disease, patients have

tenderness to palpation directly over the colon. Patients with a toxic

colitis have severe pain and bleeding, and those with megacolon have

hepatic tympany. Both may have signs of peritonitis if a perforation has

occurred. The classification of disease activity is shown in Table 326-4.

Laboratory, Endoscopic, and Radiographic Features Active

disease can be associated with a rise in acute-phase reactants (C-reactive

protein [CRP]), platelet count, and erythrocyte sedimentation rate

(ESR) and a decrease in hemoglobin. Fecal lactoferrin, a glycoprotein

present in activated neutrophils, is a highly sensitive and specific

marker for detecting intestinal inflammation. Fecal calprotectin is

present in neutrophils and monocytes, and levels correlate well with

histologic inflammation, predict relapses, and detect pouchitis. Both

fecal lactoferrin and calprotectin are becoming an integral part of IBD

management and are used frequently to rule out active inflammation

versus symptoms of irritable bowel or bacterial overgrowth. In severely

ill patients, the serum albumin level will fall rather quickly. Leukocytosis may be present but is not a specific indicator of disease activity.

Proctitis or proctosigmoiditis rarely causes a rise in CRP. Diagnosis

relies on the patient’s history, clinical symptoms, negative stool and/or

tissue examination for bacteria, C. difficile toxin, ova and parasites, and

viruses depending on epidemiologic considerations and clinical presentation; sigmoidoscopic appearance (see Fig. 322-4A); and histology

of rectal or colonic biopsy specimens.

Sigmoidoscopy is used to assess disease activity and is usually performed before treatment. If the patient is not having an acute flare,

colonoscopy is used to assess disease extent and activity (Fig. 326-7).

Endoscopically mild disease is characterized by erythema, decreased

vascular pattern, and mild friability. Moderate disease is characterized

by marked erythema, absent vascular pattern, friability, and erosions,

and severe disease is characterized by spontaneous bleeding and ulcerations. Histologic features change more slowly than clinical features but

can also be used to grade disease activity.

Complications Only 15% of patients with UC present initially

with severe disease. Massive hemorrhage occurs in 1% of patients, and

treatment for the disease usually stops the bleeding. Toxic megacolon is

defined as a transverse or right colon with a diameter of >6 cm, with

loss of haustration in patients with severe attacks of UC. It occurs rarely

FIGURE 326-6 Medium-power view of Crohn’s colitis showing mixed acute and

chronic inflammation, crypt atrophy, and multiple small epithelioid granulomas

in the mucosa. (Courtesy of Dr. R Odze, Division of Gastrointestinal Pathology,

Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts;

with permission.)

TABLE 326-4 Montreal Classification of Extent and Severity of

Ulcerative Colitis (UC)

EXTENT ANATOMY

E1: Ulcerative proctitis Involvement limited to the rectum

E2: Left-sided UC (distal UC) Involvement limited to the colorectum distal to

the splenic flexure

E3: Extensive UC (pancolitis) Involvement extends proximal to the splenic

flexure

SEVERITY DEFINITION

S0: Clinical remission Absence of symptoms

S1: Mild disease activity ≤4 stools/d (with or without blood), absence of

systemic illness, normal inflammatory

markers (ESR)

S2: Moderate disease

activity

≥4 stools/d but minimal signs of systemic toxicity

S3: Severe disease activity ≥6 bloody stools/d, pulse ≥90 beats/min,

temperature ≥37.5°C, hemoglobin <10.5 g/100 mL,

and ESR ≥30 mm/h

Abbreviation: ESR, erythrocyte sedimentation rate.

Source: C Gasche et al: A simple classification of Crohn’s disease: Report of

the Working Party for the World Congresses of Gastroenterology, Vienna 1998.

Inflamm Bowel Dis 6:8, 2000; and J Satsangi et al: The Montreal classification of

inflammatory bowel disease: Controversies, consensus, and implications.

Gut 55:749, 2006.

2476 PART 10 Disorders of the Gastrointestinal System

and can be triggered by electrolyte abnormalities and narcotics. About

50% of acute dilations will resolve with conservative management

alone, but urgent colectomy is required for those who do not improve.

Perforation is the most dangerous of the local complications, and the

physical signs of peritonitis may not be obvious, especially if the patient

is receiving glucocorticoids. Although perforation is rare, the mortality

rate for perforation complicating a toxic megacolon is ~15%. In addition, patients can develop a toxic colitis and such severe ulcerations

that the bowel may perforate without first dilating.

Strictures occur in 5–10% of patients and are always a concern in

UC because of the possibility of underlying neoplasia. Although benign

strictures can form from the inflammation and fibrosis of UC, strictures that are impassable with the colonoscope should be presumed

malignant until proven otherwise. A stricture that prevents passage of

the colonoscope is an indication for surgery. UC patients occasionally

develop anal fissures, perianal abscesses, or hemorrhoids, but the

occurrence of extensive perianal lesions should suggest CD.

■ CROHN’S DISEASE

Signs and Symptoms Although CD usually presents as acute or

chronic bowel inflammation, the inflammatory process evolves toward

one of two patterns of disease: a fibrostenotic obstructing pattern or

a penetrating fistulous pattern, each with different treatments and

prognoses. The site of disease influences the clinical manifestations

(Table 326-5).

ILEOCOLITIS Because the most common site of inflammation is the

terminal ileum, the usual presentation of ileocolitis is a chronic history of recurrent episodes of right lower quadrant pain and diarrhea.

Sometimes the initial presentation mimics acute appendicitis with

pronounced right lower quadrant pain, a palpable mass, fever, and

leukocytosis. Pain is usually colicky; it precedes and is relieved by defecation. A low-grade fever is usually noted. High-spiking fever suggests

intraabdominal abscess formation. Weight loss is common—typically

10–20% of body weight—and develops as a consequence of diarrhea,

anorexia, and fear of eating.

An inflammatory mass may be palpated in the right lower quadrant

of the abdomen. The mass is composed of inflamed bowel, induration

of the mesentery, and enlarged abdominal lymph nodes. The “string

sign” on radiographic studies results from a severely narrowed loop

of bowel, which makes the lumen resemble a frayed cotton string. It is

caused by incomplete filling of the lumen as the result of edema, irritability, and spasms associated with inflammation and ulcerations. The

sign may be seen in both nonstenotic and stenotic phases of the disease.

Bowel obstruction may take several forms. In the early stages of

disease, bowel wall edema and spasm produce intermittent obstructive manifestations and increasing symptoms of postprandial pain.

Over several years, persistent inflammation gradually progresses to

fibrostenotic narrowing and stricture. Diarrhea will decrease and be

replaced by chronic bowel obstruction. Acute episodes of obstruction

occur as well, precipitated by bowel inflammation and spasm or sometimes by impaction of undigested food or medication. These episodes

usually resolve with intravenous fluids and gastric decompression.

Severe inflammation of the ileocecal region may lead to localized

wall thinning, with microperforation and fistula formation to the

adjacent bowel, the skin, or the urinary bladder, or to an abscess cavity

in the mesentery. Enterovesical fistulas typically present as dysuria

or recurrent bladder infections or, less commonly, as pneumaturia or

fecaluria. Enterocutaneous fistulas follow tissue planes of least resistance, usually draining through abdominal surgical scars. Enterovaginal fistulas are rare and present as dyspareunia or as a feculent or

foul-smelling, often painful vaginal discharge. They are unlikely to

develop without a prior hysterectomy.

JEJUNOILEITIS Extensive inflammatory disease is associated with a

loss of digestive and absorptive surface, resulting in malabsorption and

steatorrhea. Nutritional deficiencies can also result from poor intake

and enteric losses of protein and other nutrients. Intestinal malabsorption can cause anemia, hypoalbuminemia, hypocalcemia, hypomagnesemia, coagulopathy, and hyperoxaluria with nephrolithiasis in

patients with an intact colon. Many patients need to take intravenous

iron since oral iron is poorly tolerated and often ineffective. Vertebral fractures are caused by a combination of vitamin D deficiency,

hypocalcemia, and prolonged glucocorticoid use. Pellagra from niacin

deficiency can occur in extensive small-bowel disease, and malabsorption of vitamin B12 can lead to megaloblastic anemia and neurologic

symptoms. Other important nutrients to measure and replete if low are

folate and vitamins A, E, and K. Levels of minerals such as zinc, selenium, copper, and magnesium are often low in patients with extensive

small-bowel inflammation or resections, and these should be repleted

as well. Most patients should take daily multivitamin, calcium, and

vitamin D supplements.

Diarrhea is characteristic of active disease; its causes include (1) bacterial overgrowth in obstructive stasis or fistulization, (2) bile acid malabsorption due to a diseased or resected terminal ileum, (3) intestinal

inflammation with decreased water absorption and increased secretion

of electrolytes and (4) enteroenteric fistula(e).

COLITIS AND PERIANAL DISEASE Patients with colitis present with

low-grade fevers, malaise, diarrhea, crampy abdominal pain, and

sometimes hematochezia. Gross bleeding is not as common as in UC

and appears in about one-half of patients with exclusively colonic disease. Only 1–2% exhibit massive bleeding. Pain is caused by passage of

fecal material through narrowed and inflamed segments of the large

bowel. Decreased rectal compliance is another cause for diarrhea in

Crohn’s colitis patients.

FIGURE 326-7 Colonoscopy with acute ulcerative colitis: severe colon

inflammation with erythema, friability, and exudates. (Courtesy of Dr. M. Hamilton,

Gastroenterology Division, Department of Medicine, Brigham and Women’s

Hospital, Boston, Massachusetts; with permission.)

TABLE 326-5 Vienna and Montreal Classifications of Crohn’s Disease

VIENNA MONTREAL

Age at diagnosis A1: <40 years

A2: >40 years

A1: <16 years

A2: Between 17 and 40 years

A3: >40 years

Location L1: Ileal

L2: Colonic

L3: Ileocolonic

L4: Upper

L1: Ileal

L2: Colonic

L3: Ileocolonic

L4: Isolated upper diseasea

Behavior B1: Nonstricturing,

nonpenetrating

B2: Stricturing

B3: Penetrating

B1: Nonstricturing,

nonpenetrating

B2: Stricturing

B3: Penetrating

p: Perianal disease modifierb

a

L4 is a modifier and can be added to L1–L3 when there is concomitant foregut

disease.

b

p is added to B1–B3 when there is concomitant perianal disease.