1258 1258

SECTION X Abdomen

hypokalemia, can be a cause of ileus and should be corrected.

Plain abdominal films are usually not helpful to distinguish an
ileus from obstruction. CT may be useful in this regard, and
in particular, enteroclysis studies may be helpful in determining
whether an obstruction exists and, if so, the level of the obstruction.
6 More than 90% of early postoperative obstructions
are partial and will resolve spontaneously, given ample time.
Conservative management in the form of bowel rest, fluid resuscitation,
electrolyte replacement, and parenteral nutrition, if
necessary, is routinely successful. However, the development of
complete obstruction or signs of strangulation mandates reoperative
intervention. Postoperative bowel obstruction after laparoscopic
surgery is more commonly associated with a definitive
obstruction point, such as a port site, hernia, or an internal hernia,
and should prompt a high index of suspicion for the need
for operative intervention.

Ileus

An ileus is defined as intestinal distention and the slowing or absence

of passage of luminal contents without a demonstrable mechanical
obstruction. An ileus can result from a number of causes,
including those that are drug induced, or from metabolic, neurogenic,
and infectious factors (Box 50.3).

Pharmacologic agents that can produce an ileus include anticholinergic

drugs, autonomic blockers, antihistamines, and
various psychotropic agents, such as haloperidol and tricyclic
antidepressants. One of the more common causes of drug-induced
ileus in the operative patient is the use of opiates, such
as morphine or meperidine. Metabolic causes of ileus are common
and include hypokalemia, hyponatremia, and hypomagnesemia.
Other metabolic causes include uremia, diabetic coma,
and hypoparathyroidism. Neurogenic causes of an ileus include
postoperative ileus, which occurs after abdominal operations.
Spinal injury, retroperitoneal irritation, and orthopedic procedures
on the spine or pelvis can result in an ileus. Finally, infections
can result in an ileus; common infectious causes include
pneumonia, peritonitis, and generalized sepsis from a nonabdominal
source.

Patients often present in a manner similar to those with a mechanical

small bowel obstruction. Abdominal distention, usually
without the colicky abdominal pain, is the typical and most notable
finding. Nausea and vomiting may occur but may also be
absent. Patients with an ileus may continue to pass flatus and diarrhea,
which may help distinguish these patients from those with a
mechanical small bowel obstruction.

BOX 50.3 Causes of ileus.

􀀀􀁳�
After laparotomy
􀀀􀁳�
Metabolic and electrolyte derangements (e.g., hypokalemia, hyponatremia,
hypomagnesemia, uremia, diabetic coma)
􀀀􀁳�
Drugs (e.g., opiates, psychotropic agents, anticholinergic agents)
􀀀􀁳�
Intraabdominal inflammation
􀀀􀁳�
Retroperitoneal hemorrhage or inflammation
􀀀􀁳�
Intestinal ischemia
􀀀􀁳�
Systemic sepsis

Adapted from Turnage RH, Bergen PC. Intestinal obstruction

and ileus. In Feldman M, Scharschmidt FG, Sleisenger MH, eds.

Sleisenger and Fordtran’s Gastrointestinal and Liver Disease:

Pathophysiology, Diagnosis, Management. Philadelphia: WB Saunders;
1998:1799–1810.

Radiologic studies may help distinguish ileus from small

bowel obstruction. Plain abdominal radiographs may reveal distended
small bowel as well as large bowel loops. In cases that are
difficult to differentiate from obstruction, barium studies may
be beneficial.

The treatment of an ileus is entirely supportive, with nasogastric

decompression and IV fluids. The most effective treatment
to correct the underlying condition may be aggressive treatment
of the sepsis, correction of any metabolic or electrolyte abnormalities,
and discontinuation of medications that may produce
an ileus. Pharmacologic agents have been used but for the most
part have been ineffective. Drugs that block sympathetic input
(e.g., guanethidine) or stimulate parasympathetic activity (e.g.,
bethanechol, neostigmine) have been tried. Hormonal manipulation,
using cholecystokinin or motilin, has been evaluated, but
the results have been inconsistent. Erythromycin has been ineffective,
and cisapride, although apparently beneficial in stimulating
gastric motility, does not appear to alter intestinal ileus. Chewing
gum has been suggested as an easy and inexpensive method to
stimulate the cephalic phase of digestion (e.g., vagal cholinergic
stimulation and the release of gastrointestinal hormones) and
therefore a potential adjunct to prevent and to treat ileus. A more
recent randomized trial demonstrated that chewing gum provides
no benefit regarding return of bowel function or length of stay and
even suggested that postoperative ileus may be further exacerbated
by the use of sugared gum.

INFLAMMATORY AND INFECTIOUS DISEASES

Crohn Disease

Crohn disease is a chronic, transmural inflammatory disease of

the gastrointestinal tract for which the definitive cause is unknown,
although a combination of genetic and environmental
factors has been implicated. Crohn disease can involve any
part of the alimentary tract from the mouth to the anus but
most commonly affects the small intestine and colon. The most
common clinical manifestations are abdominal pain, diarrhea,
and weight loss. Crohn disease can be complicated by intestinal
obstruction or localized perforation with fistula formation.
Medical and surgical treatments are palliative; however, operative
therapy can provide effective symptomatic relief for patients
with complications from Crohn disease and produces a reasonable
long-term benefit.

History

The first documented case of Crohn disease was described by Morgagni

in 1761. In 1913, the Scottish surgeon Dalziel described
nine cases of intestinal inflammatory disease. However, it is the
landmark paper by Crohn and colleagues in 1932 that provided,
in eloquent detail, the pathologic and clinical findings of this inflammatory
disease in young adults.10 This classic paper crystallized
the description of this inflammatory condition. Although
many different (and sometimes misleading) terms have been used
to describe this disease process, Crohn disease has been universally
accepted as its name.

Incidence and Epidemiology

Crohn disease is the most common primary surgical disease of

the small bowel. The annual incidence of Crohn disease, which
is rising in the United States, is 3 to 20 cases per 100,000 individuals.
11 The total direct and indirect costs for Crohn disease in
the United States have been estimated at more than $800 million
CHAPTER 50 Small Intestine

1259
when factoring both inpatient stays and outpatient visits. Crohn
disease primarily attacks young adults in the second and third decades
of life. However, a bimodal distribution is apparent, with a
second smaller peak occurring in the sixth decade of life. Crohn
disease is more common in urban dwellers, and although earlier
reports suggested a somewhat higher female predominance, the
two genders are affected equally. The risk for development of
Crohn disease is about twice as high in smokers as in nonsmokers.
Several studies indicate an increased incidence of Crohn disease
in women using oral contraceptives; however, more recent studies
have shown no differences. Worldwide, Crohn disease is relatively
uncommon in African Americans; however, in the United States,
the rates of Crohn disease in African Americans is similar to that
seen in Caucasians. Certain ethnic groups, particularly Ashkenazi
Jews, have a two- to four fold higher incidence of Crohn disease
than age- and gender-matched control subjects. Individuals born
during the spring months (e.g., April to June) are more likely to
develop Crohn disease; there also appears to be a north-south gradient
worldwide, and populations in higher latitudes have higher
incidence rates than populations in lower latitudes. Of note, within
one generation, migrants moving from a low-risk region to a
high-risk region develop Crohn disease at similar rates to those in
the high-risk region. There is a strong familial association, with
the risk for development of Crohn disease increased about 30-fold
in siblings and 14- to 15-fold for all first-degree relatives. Other
analyses that support a genetic role for Crohn disease have shown
a concordance rate of only 4% in dizygotic twins but a 20% to
50% rate in monozygotic twins. More recent studies evaluating
twins with and without Crohn disease have used advanced genomic
and proteomic techniques to show that intestinal micro-
flora and epigenetic changes induced by environmental factors
play an important role in disease development and progression in
genetically susceptible individuals.12

Etiology

The cause(s) of Crohn disease remain unknown. A number of

potential causes have been proposed, with the most likely possibilities
being infectious, immunologic, and genetic. Other possibilities
that have met with various levels of enthusiasm include
environmental and dietary factors, smoking, and psychosocial factors.
Although these factors may contribute to the overall disease
process, it is unlikely that they represent the primary etiology for
Crohn disease.

Infectious agents. Although a number of infectious agents have

been proposed as potential causes of Crohn disease, the two that
have received the most attention are mycobacterial infections,
particularly Mycobacterium paratuberculosis and enteroadherent E.
coli. The existence of atypical mycobacteria as a cause for Crohn
disease was proposed by Dalziel in 1913. Subsequent studies using
polymerase chain reaction (PCR) techniques have confirmed
the presence of mycobacteria in intestinal samples of patients with
Crohn disease. Transplantation of tissue from patients with Crohn
disease has resulted in ileitis, but antimicrobial therapy directed
against mycobacteria has not been effective in ameliorating the
established disease process. Strains of enteroadherent E. coli are
in higher abundance in patients with Crohn disease compared
with the general population based on PCR analysis. More recent
studies have used fluorescent in situ hybridization to demonstrate
increased numbers of E. coli in the lamina propria of patients with
active Crohn disease compared with those with inactive disease.
Furthermore, an increased number of E. coli has been associated
with a shorter time before relapse of the disease.

Immunologic factors. Humoral and cell-mediated immune reactions

directed against intestinal cells in Crohn disease suggest
an autoimmune phenomenon. Attention has focused on the role
of cytokines, such as interleukin (IL)-1, IL-2, IL-8, and TNF-α,
as contributing factors in the intestinal inflammatory response.
The role of the immune response remains controversial in Crohn
disease and may represent an effect of the disease process rather
than an actual cause.

Genetic factors. Genetic factors play an important role in the

pathogenesis of Crohn disease because the single strongest risk
factor for development of disease is having a first-degree relative
with Crohn disease. Several genome-wide association sequencing
studies have been performed and have identified more than
200 alleles associated with Crohn disease (Table 50.5). The genes
with the strongest and most frequently replicated associations
with Crohn disease are NOD2, MHC, and MST1 3p21. Putative
inflammatory bowel disease loci have been identified on chromosomes
16q, 5q, 19p, 7q, and 3p. The most important gene
in Crohn disease development is NOD2. The NOD2 gene is associated
with a decreased expression of antimicrobial peptides
by Paneth cells. Heterozygosity of one NOD2 variant confers
a 2- to 4-fold increase in risk of Crohn disease, while homozygosity
confers a 17- to 40-fold increase in risk. In addition,
NOD2 has been identified as a genetic predictor of ileal disease,
ileal stenosis, fistula, and Crohn-related surgery.12 Another gene,
CARD15, leads to impaired activation of the transcription factor
nuclear factor kappa B (NF-κB) and also specifically codes for
a protein expressed in monocytes, macrophages, dendritic cells,
epithelial cells, and Paneth cells. CARD15 is also helpful in distinguishing
Crohn disease from ulcerative colitis as it is more
strongly associated with Crohn disease, especially in patients of
northern European descent. The FHIT gene located on 3p14.2
has been identified as a tumor suppressor gene and is suggested
to play a role in the pathogenesis of Crohn disease as well as in
the development and progression of Crohn disease–related cancers.
A complex cellular and molecular crosstalk occurs between
the genes NOD2/CARD15 and the autophagy gene ATG16L1,
which is associated with a synergistic increase in earlier onset
and disease severity. Genetic profiling may be helpful in selecting
patients who will benefit from intensified treatment with immunomodulators
and anti-TNF therapy, thus decreasing medical
nonresponse.

More recent genome-wide association sequencing studies

in monozygotic twins have shown no reproducible differences
within twin pairs in comparing whole genome sequences and
tissue-specific variants in the intestinal mucosa directly affected
by the inflammation of Crohn disease. These findings suggest
that it is unlikely that somatic mutations have a substantial
impact on the development of the disease, and simple Mendelian
inheritance cannot account for the pattern of occurrence.
Therefore, it is likely that multiple causes (e.g., environmental
factors) contribute to the cause and pathogenesis of this disease.

Environmental factors. Low-risk countries in Asia that have

adopted a more Western lifestyle have noted a significant rise in
the incidence of Crohn disease. Smoking is the single largest environment
factor, with a two fold increase in risk of Crohn disease.
Single nucleotide polymorphisms associated with smoking
increase the risk of Crohn disease in smokers, identifying a genetic
disposition for an environmental risk factor.13 In addition, other
factors that increase the risk of Crohn disease include medications
(oral contraceptives, aspirin, nonsteroidal antiinflammatory drugs
1260 1260
SECTION X Abdomen

TABLE 50.5 Genetic polymorphisms

related to Crohn disease.
Genes and the Diagnosis of Crohn Disease

Genes related to innate pattern

NOD2/CARD15, OCTN, TLR

recognition receptors

Genes related to epithelial barrier IBD5, DLG5

homeostasis

Genes related to molecular mimicry ATG16L1, IRGM, LRRK2

and autophagy

Genes related to lymphocyte IL23R, STAT3

differentiation

Genes related to secondary immune MHC, HLA

response and apoptosis

Genes and the Prognosis of Crohn Disease

Genes related to age at Crohn disease TNFRSF6B, CXCL9, IL23R, NOD2,

onset ATG16L1, CNR1, IL10, MDR1, DLG5,
IRGM

Genes Related to Crohn Disease Behavior

Stenotic/structuring behavior NOD2, TLR4, IL12B, CX3CR1, IL10, IL6

Penetrating/fistulizing behavior NOD2, IRGM, TNF, HLADRB1, CDKAL1
Inflammatory behavior HLA
Granulomatous disease TLR4/CARD15

Genes Related to Crohn Disease Location

Upper gastrointestinal NOD2, MIF

Ileal IL10, CRP, NOD2, ZNF365, STAT3
Ileocolonic ATG16L1, TCF4 (TCF7L2)
Colonic HLA, TLR4, TLR1, TLR2, TLR6

Other Genes Related to Crohn Disease

Genes related to Crohn disease activity HSP702, NOD2, PAI1, CNR1

Genes related to surgery NOD2, HLAG
Genes related to dysplasia and cancer FHIT
Genes related to extraintestinal CARD15, FcRL3, HLADRB103, HLAB27,

manifestations HLA-B44, HLA-B35, TNFa-308A,

TNF-1031C, STAT3
Pharmacogenetics in Crohn CARD15, NAT, TPMT, MDR1, MIF,
Disease DLG5, TNF, LTA
multi-institutional study proposed a three-category model
to better characterize inflammatory bowel disease into ileal
Crohn disease, colonic Crohn disease, and ulcerative colitis.
These categories provide risk stratification for surgical complications
and genetic risk score based on location.15 Ileal involvement
has been shown with mutations of IL10, CRP, NOD2,
ZNF365, and STAT3; ileocolonic involvement has been shown
with mutations of ATG16L1, TCF4, and TCF7L2; and colonic
involvement has been associated with mutations of HLA,
TLR4, TLR1, TLR2, and TLR6. The involvement of the large
and small intestine has been noted in about 55% of patients.
Thirty percent of patients present with small bowel disease
alone, and in 15%, the disease appears limited to the large intestine.
The disease process is discontinuous and segmental. In
patients with colonic disease, rectal sparing is characteristic of
Crohn disease and helps distinguish it from ulcerative colitis.
Perirectal and perianal involvement occurs in about one third
of patients with Crohn disease, particularly those with colonic
involvement. Crohn disease can also involve the mouth,
esophagus, stomach, duodenum, and appendix. Involvement
of these sites can accompany disease in the small or large intestine,
but in only rare cases have these locations been the only
apparent sites of involvement.

Gross pathologic features. At exploration, thickened gray-

pink or dull purple-red loops of bowel are noted, with areas
of thick gray-white exudate or fibrosis of the serosa. Areas of
diseased bowel separated by areas of grossly appearing normal
bowel, called skip areas, are commonly encountered. A striking
finding of Crohn disease is the presence of extensive fat wrapping
caused by the circumferential growth of the mesenteric fat
around the bowel wall, also known as creeping fat (Fig. 50.16).
As the disease progresses, the bowel wall becomes increasingly
thickened, firm, rubbery, and almost incompressible (Fig.
50.17). The uninvolved proximal bowel may be dilated secondary
to obstruction of the diseased segment. Involved segments
often are adherent to adjacent intestinal loops or other viscera,
with internal fistulas common in these areas. The mesentery
of the involved segment is usually thickened, with enlarged
lymph nodes often noted.

On opening of the bowel, the earliest gross pathologic lesion

is a superficial aphthous ulcer noted in the mucosa. With increasing
disease progression, the ulceration becomes pronounced, and
complete transmural inflammation results. The ulcers are characteristically
linear and may coalesce to produce transverse sinuses

Adapted from Tsianos EV, Katsanos KH, Tsianos VE. Role of genetics in
the diagnosis and prognosis of Crohn’s disease. World J Gastroenterol.
2012;18:105–118.

[NSAIDs]), decreased dietary fiber, and increase fat intake. In addition,

dysbiosis with a decrease in intraluminal Bacteroides and
Firmicutes and an increase in Gammaproteobacteria and Actinobacteria
are associated with higher risk. Specifically, an increase of mucosal—
adherent—invasive E. coli survive within macrophages and
induce higher TNF-α production.14 There are numerous studies
evaluating the therapeutic benefits of microbiota manipulation.
Pathology

The most common sites of Crohn disease are the small intestine
and colon. The location of disease involvement is biologically
defined by the genetic variation. As such, a large

FIG. 50.16 Crohn disease with evidence of creeping fat. Laparoscopic

evaluation of extensive fat wrapping caused by the circumferential
growth of the mesenteric fat around the bowel wall. (Courtesy Dr. John
Draus, University of Kentucky Medical Center, Lexington, KY.)
CHAPTER 50 Small Intestine

1261
A B
FIG. 50.17 Gross pathologic features of Crohn disease. (A) Serosal
surface demonstrates extensive fat wrapping and inflammation. (B) Resected
specimen demonstrates marked fibrosis of the intestinal wall,
stricture, and segmental mucosal inflammation. (Courtesy Dr. Mary R.
Schwartz, Baylor College of Medicine, Houston, TX.)

with islands of normal mucosa in between, thus giving the characteristic

cobblestone appearance.

Microscopic features. Mucosal and submucosal edema may

be noted microscopically before any gross changes. A chronic
inflammatory infiltrate appears in the mucosa and submucosa
and extends transmurally. This inflammatory reaction is characterized
by extensive edema, hyperemia, lymphangiectasia,
intense infiltration of mononuclear cells, and lymphoid hyperplasia.
Characteristic histologic lesions of Crohn disease are
noncaseating granulomas with Langerhans giant cells. Granulomas
appear later in the course and are found in the wall of the
bowel or in regional lymph nodes in 60% to 70% of patients
(Fig. 50.18).

Clinical Manifestations

Crohn disease can occur at any age, but the typical patient is a
young adult in the second or third decade of life. The onset of
disease is often insidious, with a slow and protracted course. Characteristically,
there are symptomatic periods of abdominal pain
and diarrhea interspersed with asymptomatic periods of varying
lengths. With time, the symptomatic periods gradually become
more frequent, more severe, and longer lasting. The most common
symptom of Crohn disease is chronic diarrhea, followed by
intermittent and colicky abdominal pain, most commonly noted
in the lower abdomen. The pain, however, may be more severe
and localized in the right lower quadrant and may mimic the signs
and symptoms of acute appendicitis.16 In contrast to ulcerative
colitis, patients with Crohn disease typically have fewer bowel
movements, and the stools rarely contain mucus, pus, or blood.
Systemic nonspecific symptoms include a low-grade fever present
in about one third of the patients, weight loss, loss of strength,
and malaise.

Clinically, Crohn disease is often classified on the basis of age

at onset, behavior, and site of origin. The Montreal Classification
(Table 50.6) divides all patients into distinct categories based on

symptom onset (before or after the age of 40 years), disease behavior

(nonstricturing/nonpenetrating, stricturing, or penetrating),
and disease site (terminal ileum, colon, ileocolonic, upper
gastrointestinal tract). This classification was developed to provide
a reproducible staging of the disease, to help predict remission
and relapse, and to direct therapy. The main intestinal complications
of Crohn disease include obstruction and perforation. Obstruction
can occur as a manifestation of an acute exacerbation of
active disease or as the result of chronic fibrosing lesions, which
eventually narrow the lumen of the bowel, producing partial or
near-complete obstruction. Free perforations into the peritoneal
cavity leading to a generalized peritonitis can occur in patients
with Crohn disease, but this presentation is rare. More commonly,
fistulas occur between the sites of perforation and adjacent organs,
such as loops of small and large intestine, urinary bladder, vagina,
stomach, and sometimes the skin, usually at the site of a previous
laparotomy. Localized abscesses can occur near the sites of
perforation. Patients with Crohn colitis may develop toxic mega-
colon and present with a marked colonic dilation, abdominal
tenderness, fever, and leukocytosis. Bleeding is typically indolent
and chronic, but massive gastrointestinal bleeding can occasionally
occur, particularly in duodenal Crohn disease associated with
chronic ulcer formation.

Long-standing Crohn disease predisposes to cancer of the

small intestine and colon. These carcinomas typically arise at sites
of chronic disease and more commonly occur in the ileum as a
result of the chronic inflammation of the mucosa. Most are not
detected until in advanced stages, and the prognosis is poor. Although
the relative risk for small bowel cancer in Crohn disease is
approximately 100-fold, the absolute risk is still small. Of greater
concern is the development of colorectal cancer in patients with
colonic involvement and a long duration of disease. Dysplasia is
the putative precursor lesion for Crohn disease–associated cancer.
Patients with long-standing Crohn disease should have an
equally aggressive colonoscopic surveillance regimen as patients
with extensive ulcerative colitis.17 Small bowel adenocarcinoma
associated with Crohn disease has an aggressive behavior and a
strong probability of extracellular mucin. In surgical specimens
from patients with Crohn disease, mucinous-appearing anal
fistulas and ileal areas of adhesion/retraction should always be
closely examined by a pathologist to evaluate for dysplasia or
malignancy.

Extraintestinal cancer, such as squamous cell carcinoma of the

vulva and anal canal and Hodgkin and non-Hodgkin lymphomas,
may be more frequent in patients with Crohn disease, especially
those treated with immunomodulators.

Perianal disease (fissure, fistula, stricture, or abscess) is common

and occurs in 25% of patients with Crohn disease limited to
the small intestine, 41% of patients with ileocolitis, and 48% of
patients with colonic involvement alone. Perianal disease may be
the sole presenting feature in 5% of patients and may precede the
onset of intestinal disease by months or even years. Crohn disease
should be suspected in any patient with multiple, chronic perianal
fistulas.

Extraintestinal manifestations of Crohn disease may be present

in 30% of patients. The most common symptoms are skin
lesions (Fig. 50.19), which include erythema nodosum and pyoderma
gangrenosum, arthritis and arthralgias, uveitis and iritis,
hepatitis, pericholangitis, and aphthous stomatitis. In addition,
amyloidosis, pancreatitis, and nephrotic syndrome may occur in
these patients. These symptoms may precede, accompany, or appear
independently of the underlying bowel disease.
1262 1262
SECTION X Abdomen

A
C
B
FIG. 50.18 Microscopic features of Crohn disease. (A) Transmural inflammation. (B)
Fissure ulcer (arrows).
(C) Noncaseating granuloma located in the muscular layer of the small bowel
(arrow). (Courtesy Dr. Mary R.
Schwartz, Baylor College of Medicine, Houston, TX.)
Diagnosis

A diagnosis of Crohn disease should be considered in patients

with chronic recurring episodes of abdominal pain, diarrhea,
and weight loss. However, there is not a single diagnostic test for
Crohn disease; a multimodal approach of laboratory testing, endoscopy,
radiology, and pathology is required.

Laboratory. Serologic markers may useful in the diagnosis of

Crohn disease. In particular, perinuclear antineutrophil cytoplasmic
antibody (and its target proteins bactericidal/permeability
increasing protein [BPI], lactoferrin, cathepsin G and elastase),
anti–Saccharomyces cerevisiae antibody (ASCA), outer membrane
porin of flagellin (anti-CBir1), and outer membrane porin of

E. coli (OmpC-IgG) can predict the development of inflammatory

bowel disease even in patients thought to be at low risk for
development of disease.18 ASCA is also useful in differentiating
Crohn disease from ulcerative colitis as well as playing a role in
determining patients who will require surgery in the future.

Noninvasive inflammatory markers, historically C-reactive

protein and erythrocyte sedimentation rate, were used to aid in the
initial diagnosis, to rule out exacerbations, to monitor response
to systemic therapy, and to predict relapse; however, these markers
were generally nonspecific and have largely been abandoned.
Stool lactoferrin, an iron-binding protein in the secretory granules
of neutrophils, and fecal calprotectin, a protein with antimicrobial
properties released by squamous cells in response to inflammation,
are inflammatory markers specific to the intestine that
have shown promising results for the detection and surveillance of
Crohn disease. A prospective study showed that both calprotectin
CHAPTER 50 Small Intestine

1263
TABLE 50.6 Montreal classification of
Crohn disease.
Age at diagnosis (years) A1: ≤16
A2: 17–40
A3: >40
Behavior B1: Nonstricturing/nonpenetrating
B2: Stricturing
B3: Penetrating
P: Perianal disease modifier (can add to B1-3)
Location L1: Ileal
L2: Colonic
L3: Ileocolonic
L4: Isolated upper gastrointestinal tract (can add
to L1-3)

Adapted from Spekhorst LM, Visschedijk MC, Alberts R, et al.

Performance of the Montreal classification for inflammatory bowel
diseases. World J Gastroenterol. 2014;20:15374–15381.

and lactoferrin levels correlate well with CT enterography (CTE)

images of small bowel inflammation (mucosal irregularity, hyper-
density, stenosis, prestenotic dilation and mesenteric hypervascularity
[i.e., comb sign]). Fecal calprotectin levels greater than 140
ng/mL, predicted small bowel inflammation with a sensitivity of
69% and a specificity of 82%. Similarly, fecal lactoferrin (>6 ng/
mL) predicted small bowel inflammation with a sensitivity of 69%
and a specificity of 79%. Fecal calprotectin is associated with elevated
C-reactive protein and erythrocyte sedimentation rate levels,
whereas fecal lactoferrin is only associated with elevated C-reactive
protein levels. Together, these findings identify fecal calprotectin
and lactoferrin as helpful screening tools for detecting early small
bowel Crohn disease.19

Radiology. CTE or magnetic resonance enterography (MRE) are

often used as the initial assessment of Crohn disease to complement

FIG. 50.19 Crohn disease patient with erythema nodosum. The most
common extraintestinal presentations of Crohn disease are skin lesions,
which include erythema nodosum and pyoderma gangrenosum.

direct ileocolonoscopy. Imaging studies can provide information

regarding severity of inflammation, length, and focality and identify
complications (e.g., obstruction or fistula). In addition, these
studies support surgical planning and the evaluation of response to
medical therapy.20 Previously, barium enema was commonly used
to identify features of Crohn disease. For example, long lengths of
narrowed terminal ileum (Kantor string sign) may be present with
long-standing disease (Fig. 50.20). Segmental and irregular patterns
of bowel involvement may be noted. Fistulas between adjacent bowel
loops and organs may be apparent (Fig. 50.21).

CTE may be useful in demonstrating the marked transmural

thickening; it can also greatly aid in diagnosing extramural complications
of Crohn disease, especially in the acute setting (Fig.
50.22). Both MRE and CTE are equally accurate in assessing disease
activity and bowel damage; however, MRE may be superior to
CTE in detecting intestinal strictures and ileal wall enhancement.20
Recent studies suggest limiting the use of CTE in patients with
long-standing Crohn disease because of its significant radiation
exposure and need for numerous studies during the course of the
disease. MRE is a useful adjunct to determine intestinal strictures
as well as fistulas and sinus tracks; however, the relatively high cost,
prolonged examination time, and limited availability may preclude
many patients from receiving this procedure. Ultrasonography has
limited value in the evaluation of patients with Crohn disease and
has an especially lower accuracy for detecting the disease proximal
to the terminal ileum. One study determined that this modality
failed to identify disease proximal to the terminal ileum in up to
67% of patients; however, ultrasound may be helpful in the assessment
of undiagnosed right lower quadrant pain.

FIG. 50.20 Small bowel obstruction secondary to Crohn disease. Small

bowel series in a patient with Crohn disease demonstrates a narrowed
distal ileum (arrows) secondary to chronic inflammation and fibrosis.
(Courtesy Dr. Melvyn H. Schreiber, The University of Texas Medical
Branch, Galveston, TX.)
1264 1264
SECTION X Abdomen

FIG. 50.21 Intraabdominal fistulas in Crohn disease. Multiple short fistulous

tracts communicating between the distal loops of ileum and the
proximal colon in a patient with Crohn disease (arrows). (Courtesy Dr.
Melvyn H. Schreiber, The University of Texas Medical Branch, Galveston,
TX. Adapted from Evers BM, Townsend CM Jr, Thompson JC. Small
intestine. In: Schwartz SI, ed. Principles of Surgery. 7th ed. New York:
McGraw-Hill; 1999:1233.)

R L
FIG. 50.22 Mechanical small bowel obstruction secondary to chronic
structuring disease. Computed tomography enterography of a patient
with Crohn disease demonstrates marked thickening of the bowel (arrows)
with a high-grade partial small bowel obstruction and dilated proximal
intestine. (Courtesy Dr. Melvyn H. Schreiber, The University of Texas
Medical Branch, Galveston, TX. Adapted from Evers BM, Townsend CM
Jr, Thompson JC. Small intestine. In: Schwartz SI, ed. Principles of Surgery.
7th ed. New York: McGraw-Hill; 1999:1233.)

Endoscopy. Ileocolonoscopy with biopsies of the terminal

ileum are the gold standard for the diagnosis of Crohn disease.
When the colon is involved, sigmoidoscopy or colonoscopy
may reveal characteristic aphthous ulcers with granularity and a
normal-appearing surrounding mucosa. Intubation of the ileocecal
valve during colonoscopy allows examination and biopsy
of the terminal ileum but fails to evaluate other segments of the

small intestine. With more progressive and severe disease, the

ulcerations involve progressively more of the bowel lumen, and
it may be difficult to distinguish Crohn disease from ulcerative
colitis. However, the presence of discrete ulcers and cobblestoning
as well as the discontinuous segments of involved bowel
favors a diagnosis of Crohn disease. Endoscopic advances that
allow better evaluation of the small intestine include single-
balloon enteroscopy, double-balloon enteroscopy, and spiral
enteroscopy; the most well-established technique is double-
balloon enteroscopy, which allows increased enteral intubation
(240–360 cm) compared with push enteroscopy (90–150 cm)
or ileocolonoscopy (50–80 cm). Limitations include specialized
examiner skills and equipment, prolonged procedure times, and
a 1% risk of complications (e.g., pancreatitis, perforation, or
bleeding). After the diagnosis is confirmed, the Crohn Disease
Endoscopic Index of Severity (CDEIS) or the Simple Endoscopic
Score for Crohn Disease (SES-CD) is used to define extent
of disease and severity.

Recently, capsule endoscopy was approved by the U.S. Food

and Drug Administration (FDA) in 2001 and is helpful in the
diagnosis of superficial mucosal abnormalities. The most commonly
used criterion for an abnormal finding is the presence of
three or more ulcers in the absence of NSAID use. The use of
this modality is limited because of concern for capsule retention,
defined as the presence of the capsule in the gastrointestinal tract
for more than 2 weeks, which is of greater concern to patients
with Crohn disease due to a significantly higher risk of retention
(13%) compared with the general population (1%–2.5%).
However, capsule endoscopy has been found to be superior to
any other modality in the identification of intestinal ulceration.
Severity is measured utilizing the Capsule Endoscopy Crohn
Disease Activity Index (CECDAI or Niv score).21 Further studies
are needed to provide a more comprehensive evaluation of
Crohn disease in the entire intestinal tract since new generations
of capsule endoscopy devices will also provide visualization of
colonic mucosa.

Histology

Differential diagnosis. The differential diagnosis of Crohn disease

includes specific and nonspecific causes of intestinal inflammation.
Bacterial inflammation (such as that caused by Salmonella
and Shigella), intestinal tuberculosis, and protozoan infections
(such as amebiasis) may manifest as an ileitis. In the immunocompromised
host, rare infections, particularly mycobacterial and
cytomegalovirus (CMV) infections, have become more common
and may cause ileitis. Acute distal ileitis may be a manifestation of
early Crohn disease, but it also may be unrelated, such as when it
is caused by a bacteriologic agent (e.g., Campylobacter, Yersinia).
Patients usually present in a similar fashion to those presenting
with acute appendicitis, with a sudden onset of right lower quadrant
pain, nausea, vomiting, and fever. These entities normally resolve
spontaneously, and when they are noted during surgery, no
biopsy or resection should be performed.

In most cases, Crohn disease of the colon can be readily distinguished

from ulcerative colitis; however, in 5% to 10% of
patients, the delineation between Crohn disease and ulcerative
colitis may be difficult if not impossible to make (Table 50.7).
Ulcerative colitis almost always involves the rectum most severely,
with lessening inflammation from the rectum to the ileocolic area.
In contrast, Crohn disease may be worse on the right side of the
colon than on the left side, and sometimes the rectum is spared.
Ulcerative colitis also demonstrates continuous involvement from
CHAPTER 50 Small Intestine

1265
TABLE 50.7 Diagnosis of Crohn colitis versus ulcerative colitis.
PARAMETER CROHN COLITIS ULCERATIVE COLITIS
Symptoms and Signs
Diarrhea Common Common
Rectal bleeding Less common Almost always
Abdominal pain (cramps) Moderate to severe Mild to moderate
Palpable mass At times No (unless large cancer)
Anal complaints Frequent (>50%) Infrequent (<20%)
Radiologic Findings
Ileal disease Common Rare (backwash ileitis)
Nodularity, fuzziness No Yes
Distribution Skip lesions Rectum extending proximally and continuously
Ulcers Linear, cobblestone, fissures Collar-button
Toxic dilation Rare Uncommon
Proctoscopic Findings
Anal fissure, fistula, abscess Common Rare
Rectal sparing Common (50%) Rare (5%)
Granular mucosa No Yes
Ulceration Linear, deep, scattered Superficial, universal

Adapted from Waugh N, Cummins E, Royle P, et al. Faecal calprotectin testing for
differentiating amongst inflammatory and non-inflammatory
bowel diseases: systematic review and economic evaluation. Southampton, UK: NIHR
Journals Library; 2013 Nov. (Health Technology
Assessment, No. 17.55. Appendix 1, Comparison of ulcerative colitis, Crohn’s
disease, irritable bowel syndrome and coeliac disease.

rectum to proximal segments, whereas Crohn disease is segmental.

Although ulcerative colitis involves the mucosa of the large
intestine, it does not extend deep into the wall of the bowel as
does Crohn disease. Bleeding is a more common symptom in
ulcerative colitis. Perianal involvement and rectovaginal fistulas
are unusual in ulcerative colitis but are more common in Crohn
disease. Other endoscopic features of Crohn disease are skip lesions,
asymmetric involvement of bowel, and the cobblestone appearance
that results from ulcerations interspersed with islands of
edematous mucosa.

Management

Medical therapy. There is no cure for Crohn disease. Therefore,

medical therapies are directed toward inducing and maintaining
steroid-free remission as well as preventing acute exacerbations or
complications of the disease. However, it is important to note that
endoscopic healing has emerged as the therapeutic goal due to
poor association of inflammation with symptoms.14 Surgery is advocated
for neoplastic and preneoplastic lesions, obstructing stenoses,
suppurative complications, or medically intractable disease.
Narcotic analgesia should be avoided except during the perioperative
period because of the potential for tolerance and abuse in the
setting of chronic disease. Drugs that have demonstrated efficacy
in the induction or maintenance of remission in Crohn disease
include aminosalicylates, such as sulfasalazine and mesalamine;
corticosteroids; TNF antagonists, such as infliximab, adalimumab,
and certolizumab; immunosuppressive agents, such as azathioprine
(AZT), 6-mercaptopurine (6-MP), methotrexate (MTX),
and tacrolimus (FK-506); antiadhesion molecules such as vedolizumab,
etrolizumab, and natalizumab; the interleukin inhibitor
ustekinumab; and antibiotics. The recent increase in the use of
immunomodulators and biologic agents has significantly reduced
surgery rates. The primary target of medical treatment is the reduction
of the Crohn Disease Activity Index (CDAI), which uses
eight major clinical factors to evaluate disease severity (Box 50.4).

BOX 50.4 Crohn disease activity index

(CDAI).
Number of liquid or soft stools (each day for 7 days)
Abdominal pain, sum of 7 daily ratings (0 = none, 1 = mild, 2 = moderate, 3 =
severe)
General well-being, sum of 7 daily ratings (0 = generally well, 1 = slightly
under par, 2 = poor, 3 = very poor, 4 = terrible)
Number of listed complications (arthritis or arthralgia, iritis, uveitis, erythema
nodosum or pyoderma gangrenosum, aphthous stomatitis, anal fissure, fistula
or abscess, fever greater than 37.8°C [100°F]).
Use of diphenoxylate or loperamide for diarrhea (0 = no, 1 = year)
Abdominal mass (0 = no, 2 = questionable, 5 = definite)
Hematocrit (males >47%, or females >42%)
Body weight (1 - weight/standard weight) × 100 (add or subtract according
to sign)

Adapted from Sandborn WJ, Feagan BG, Hanauer SB, et al. A

review of activity indices and efficacy endpoints for clinical trials of
medical therapy in adults with Crohn’s disease. Gastroenterology.
2002;122:512–530.

Clinical remission is achieved when CDAI is below 150, and clinical

response to therapy occurs with a drop of 100 points.22 A score
between 150 and 220 is considered mild to moderate disease and
can be followed by outpatient visits; a score between 220 and 450
is considered moderate to severe disease and occurs after failure
to first line therapy; a score greater than 450 is considered severe
fulminant disease with failed medical therapy and complications
of obstruction, peritonitis, and abscess. Other innovative therapies
such as MadCAM-1 ([mucosal addressin cell adhesion molecule

1] inhibitor), tofacitinib (JAK3 pathway inhibitor), mongersen

(SMAD7 inhibitor), and ozanimod (S1P1 inhibitor) are all currently
under phase II/III clinical trials.
1266 1266
SECTION X Abdomen

Aminosalicylates. Sulfasalazine (azulfidine) is an aminosalicylate

with 5-aminosalicylic acid as the active moiety. Although a
clear benefit has been noted in patients with colonic involvement,
the effectiveness of sulfasalazine alone in the treatment of small
bowel Crohn disease is controversial, and its use in maintenance
therapy has fallen out of favor. Mesalamine, which is also an aminosalicylate,
provides a slow release of 5-aminosalicylic acid with
passage through the small bowel and colon. Clinical trials have
demonstrated efficacy of mesalamine at a dosage of 4 g/day without
an increase in side effects. However, 1% of patients will develop
interstitial nephritis and renal function evaluation is needed
periodically. If remission is achieved with mesalamine induction,
then the medicine should be continued for maintenance.11 Studies
are currently being conducted to evaluate the efficacy of higher
dosages of mesalamine to determine its continued utility as an
appropriate first-line therapy.

Corticosteroids. Steroids are fast acting and effective at

inducing remission but are not ideal as maintenance therapy.
Budesonide, a corticosteroid, has a high first-pass hepatic metabolism,
which allows targeted delivery to the intestine while
mitigating the systemic effects of steroid therapy. Controlled ileal
release budesonide (9 mg/day) is effective when active disease
is confined to the ileum or right colon and has been shown to
be more effective than either placebo or mesalamine.23 Given
a relatively good response and its relative safety, budesonide is
recommended as the preferred primary treatment to mesalamine
for patients with mild to moderately active Crohn disease with
localized ileal disease.

An alternative corticosteroid, prednisone, can be beneficial

in moderate to severe Crohn disease. Prednisone is not ideal for
maintenance therapy as more than 50% of patients, particularly
smokers, treated with corticosteroids become “steroid dependent,”
and chronic treatment is associated with osteoporosis and
increased rates of Crohn disease relapse.11 Patients with moderate
to severe disease should be treated with high-dose (40–60 mg
daily) prednisone until resolution of symptoms and resumption of
weight gain. Parenteral corticosteroids are indicated for patients
with severe disease once the presence of an abscess has been excluded.
Steroids should be tapered once the patient experiences
clinical improvement. Currently, there are no standards for corticosteroid
taper, but doses are generally tapered by 5 to 10 mg/
week until 20 mg, and then by 2.5 to 5 mg weekly until cessation.
Dual-energy x-ray absorptiometry scan, calcium and vitamin D
supplementation, and consideration of bisphosphonate therapy
are warranted once corticosteroid therapy is initiated to identify
baseline bone density and to prevent steroid-induced loss of bone
mineral density.

Antibiotics. Certain antibiotics were found to be effective

as a primary therapy for Crohn disease. Promising results were
initially reported for metronidazole, but later studies determined
that it was no more effective than placebo for inducing remission.
Other antibiotics that have been used with varying success include
ciprofloxacin, rifaximin, clofazimine, ethambutol, isoniazid, and
rifabutin. Antibiotic therapy has a clear role in the septic complications
associated with Crohn disease and is beneficial in perianal
disease.11 The mechanism of action of antibiotics in Crohn disease
is unclear, and side effects of these antibiotics preclude their longterm
use. Therefore, antibiotics may play an adjunctive role in the
treatment of Crohn disease and, in selected patients, may be useful
in treating perianal disease, enterocutaneous fistulas, or active
colonic disease but should not be used in maintenance therapy or
to induce remission.

Immunosuppressive agents. The immunosuppressive agents

AZT, 6-MP, and MTX are effective in maintenance therapy and
for the treatment of moderate to severe Crohn disease. AZT and
6-MP are effective for maintaining steroid-induced remission, and
weekly IV MTX is effective for both induction and maintenance
therapy.11 Because of the slow onset of action of immunosuppressive
agents and to prevent flares, steroids are needed for induction
and continued until the transition to immunosuppressive agents is
complete. Despite their potential toxicity, these drugs have proved
to be relatively safe in patients with Crohn disease; the most common
side effects are pancreatitis, hepatitis, fever, and rash. The
more disconcerting complications of immunosuppressants include
chronic liver disease, bone marrow suppression, and the potential
for malignant transformation. No prospective controlled trial has
evaluated dose escalation or initiation of therapy using these drugs.
Genetic polymorphisms for thiopurine methyltransferase (TPMT),
which is the primary enzyme that metabolizes AZT and 6-MP, have
been identified and suggested for use to regulate therapy according
to the measurement of their metabolites (6-thioguanine nucleotides).
Patients with decreased TPMT activity have a significantly
increased risk of fatal bone marrow suppression. Previous studies
reported severe myelosuppression in patients who are wild-type or
heterozygous carriers for TPMT variant alleles; these findings suggest
that TPMT genotype testing may be a safe screening tool to determine
which patients may have a genetic predisposition to adverse
outcomes. MTX also has side effects of hepatotoxicity and can cause
myelosuppression and should not be used in pregnant women.

Other immunosuppressive agents that have been used with

some efficacy include cyclosporine and FK-506. FK-506 inhibits
the production of IL-2 by helper T cells and was found to be effective
for fistula improvement, but not fistula remission, in patients
with perianal Crohn disease. Both of these agents have been used
in patients with severe disease who do not respond to IV steroids.
Low-dose cyclosporine was not found to be efficacious; however,
in uncontrolled studies, FK-506 demonstrated some benefit in patients
with steroid-refractory disease.

Anti-TNF therapy. The introduction of anti-TNF therapy for

Crohn disease was considered a breakthrough in medical management.
The first anti-TNF agent introduced was infliximab, a
chimeric monoclonal antibody to TNF-α. Infliximab is efficacious
and safe as a monotherapy in the treatment of moderate to severe
Crohn disease and effective both an induction and maintenance
agent. Multiple studies demonstrated that treatment with
infliximab results in perineal fistula closure in approximately two-
thirds of patients. Although it is highly effective in certain Crohn
disease patients with penetrating and extraintestinal disease, not
every patient responds to infliximab. Other FDA-approved TNF
antagonists include adalimumab (humanized IgG1 monoclonal
antibody), which is an effective maintenance agent that can be
self-administered, and certolizumab (humanized antibody fragment),
which is ideal in pregnant and nursing women as it is
linked to a polyethylene glycol moiety and does not cross the placenta
and is not excreted in breast milk. Safety profiles for these
three anti-TNF medications are similar. There is an increased risk
for tuberculosis reactivation, invasive fungal and other opportunistic
infections, demyelinating central nervous system lesions,
activation of latent multiple sclerosis, exacerbation of congestive
heart failure, and concerns for increased risk of melanoma. Patients
who develop a flare while on anti-TNF agents require measurement
of serum drug concentrations and antidrug antibodies
(antibodies binding to competitive and noncompetitive sites to
inhibit drug function). Measured levels would indicate the need
CHAPTER 50 Small Intestine

1267
to increase dosage (if low drug concentration and low antibodies),
switch to another anti-TNF agent (high antidrug antibodies), or
switch to another drug class (normal drug concentration). Due to
the potential for immunogenicity of monoclonal antibodies, the
combination of an anti-TNF agent and an immunosuppressive
provides optimal drug levels and low antidrug antibodies.11

Novel therapies. Other therapeutic agents for Crohn disease

include leukocyte trafficking inhibitors, interleukin inhibitors,
and antibodies to antiadhesion molecule. These agents are often
used if the patient has failed or is unable to tolerate anti-TNF
therapy. Natalizumab, a recombinant humanized monoclonal
antibody against α4 integrin, showed effectiveness in the induction
and maintenance of remission in patients with active Crohn
disease. It was removed from the market after several patients developed
progressive multifocal leukoencephalopathy but was later
reinstated for refractory Crohn disease and approved for use in
2008. Similarly, vedolizumab is a humanized monoclonal antibody
that specifically binds to α4β7 integrin and blocks its interaction
with MadCAM-1; this action inhibits the translocation of
memory T lymphocytes into inflamed gastrointestinal parenchymal
tissues. Vedolizumab can be used for induction of remission,
but it has a very slow onset of action. Because MadCAM-1 is preferentially
expressed on blood vessels in the gastrointestinal tract,
vedolizumab is more gut specific and therefore a more targeted
form of immunosuppression. Also, vedolizumab prevents the
gastrointestinal mucosal or transmural inflammation without the
nonspecific neurologic side effects seen in less selective α4 integrin
inhibitors, such as natalizumab. Vedolizumab was approved for
use in 2014 in those with a poor response to anti-TNF or immunosuppressants.
14 Ustekinumab is a humanized IgG1 monoclonal
antibody that inhibits IL-12/23 through targeting of a shared p40
subunit. In two large trials, it was shown to be effective in severe
Crohn disease that is refractory to anti-TNF therapies with
similar efficacy. Ustekinumab was approved for use in 2016.11
Compounds are also being evaluated that block certain signaling
pathways (e.g., NF-κB, mitogen-activated protein kinases, and
peroxisome proliferator-activated receptor-γ) in limited studies.
Some compounds have shown clinical improvement, but results
have varied, and these agents are still under development.

Nutritional therapy. Nutritional therapy in patients with Crohn

disease has been used with varying success. The use of chemically
defined elemental diets has been shown in some studies to reduce
disease activity, particularly in patients with disease localized to
the small bowel, and they can reduce corticosteroid-induced
toxicities. Liquid polymeric diets may be as effective as elemental
feedings and are more acceptable to patients. With few exceptions,
standard elemental diets have not been effective to prevent relapse
of Crohn disease. Total parenteral nutrition (TPN) was also useful
in patients with active Crohn disease; however, complication rates
exceed those for enteral nutrition. Although the primary role of
nutritional therapy is questionable in patients with inflammatory
bowel disease, there is definitely a secondary role for nutritional
supplementation to replenish depleted nutrient stores, allowing
intestinal protein synthesis and healing, and to prepare patients
for surgery.

Smoking cessation. Although the implication of tobacco abuse

as a causative factor in the development of Crohn disease has
been difficult to prove, smoking clearly affects the disease course.
Smoking is associated with the late bimodal onset of disease and
has been shown to increase the incidence of relapse and failure
of maintenance therapy. It also appears to be associated with the
severity of disease in a linear dose-response relationship. Tobacco

exposure is an independent predictor of the need for maintenance

treatment, specifically biologic therapy. Therefore, smoking cessation
therapy is an important component of medical therapy.

Surgical treatment. Although medical management is indicated

during acute exacerbations of disease, most patients with
chronic Crohn disease will require surgery at some time during
the course of their illness. The goals are to preserve bowel length
while minimizing postoperative complications and disease recurrence.
Approximately 70% of patients will require surgical resection
within 15 years after diagnosis. Indications for surgery include
failure of medical treatment, bowel obstruction, fistula or
abscess formation, steroid dependence, dysplasia or malignancy.
Most patients can be treated with elective surgery, especially with
the improvement of medical management in the past decade.
However, patients with intestinal perforation, peritonitis, excessive
bleeding, or toxic megacolon require urgent surgery.24 Children
with Crohn disease and resulting systemic symptoms, such as
growth retardation, may benefit from resection. The extraintestinal
complications of Crohn disease, although not primary indications
for operation, often subside after resection of the involved
bowel; exceptions are that problems may continue with ankylosing
spondylitis and hepatic complications.

The aim of surgery for Crohn disease has shifted from a radical
operation to one that achieves inflammation-free margins with
minimal surgery, intended to remove just grossly inflamed tissue
or to increase the luminal diameter of the bowel (i.e., dilation or
strictureplasty). Even if adjacent areas of bowel are clearly diseased,
they should be ignored. Fistulizing disease rarely requires operative
intervention unless the fistula involves the bladder, vagina or skin.
A bowel resection with fistulotomy may be needed. Early in the history
of surgical therapy for Crohn disease, surgeons tended to perform
wider resections with the hope of cure or significant remission.
However, recurring wide resections resulted in neither cure nor a
greater incidence of remissions and led to short bowel syndrome, a
devastating surgical complication. Frozen sections to determine microscopic
disease are unreliable and should be performed only when
malignant disease is suspected. It must be emphasized that operative
treatment of a complication must be limited to that segment of
bowel involved with the complication, and no attempt should be
made to resect more bowel, even though grossly evident disease may
be apparent. However, often after removal of a diseased segment,
endoscopic recurrence can occur up to 70% to 90% within 1 year
after surgery in patients with Crohn disease.24

Laparoscopic surgery for patients with Crohn disease has been

determined to be safe and feasible in appropriately selected patients,
for example, those with localized abscesses, simple intra-
abdominal fistulas, perianastomotic recurrent disease, and disease
limited to the distal ileum. A large comparative study evaluating
laparoscopic colectomy for Crohn colitis determined that the laparoscopic
group had a significantly shorter median operative time,
earlier return of bowel function, and shorter hospital stay.25 Multiple
randomized clinical trials verified that laparoscopic surgery
is associated with a more rapid recovery of bowel function and
shorter hospital stay; importantly, the rate of disease recurrence
is similar when compared with open procedures. Randomized
controlled trials with long-term follow-up have demonstrated that
patients undergoing laparoscopic ileocolonic resection for Crohn
disease had improved body image and satisfaction with cosmesis
of surgery and less incidence of incisional hernia compared
with the open surgery group. The potential for earlier recovery
after laparoscopic resection has stimulated interest in extending
the role of surgical resection to induce remission; the LIR!C trial
1268 1268
SECTION X Abdomen

is a randomized multicenter trial that found laparoscopic resection

of uncomplicated ileocecal disease (terminal ileum <40 cm)
that failed steroid treatment could be an alternative to anti-TNF
therapy.26

Another difficult surgical decision important in Crohn disease

involves performing a primary anastomosis versus initial ostomy formation
with delayed reconstruction. Patients with Crohn disease are
often malnourished, and receive intensive immunosuppressive therapy,
or present with an element of intraabdominal sepsis. In general,
standard surgical principles should direct this decision. Patients with
adequate nutrition and minimal intraabdominal sepsis can safely
undergo primary anastomosis at the initial operation, whereas malnourished
and septic patients are best served by diversion, if possible.
Although caution should be exercised in performing an anastomosis
in the setting of high-dose immunosuppression, large series have
confirmed that surgery is safe for patients with Crohn disease while
they are receiving perioperative infliximab or immunosuppressive
therapy. Regarding the anastomotic technique, several studies suggest
that creating a wider anastomosis with a stapled functional endto-
end anastomosis may decrease fecal stasis and subsequent bacterial
overgrowth, which are implicated in anastomotic recurrence in
Crohn disease. However, a randomized controlled trial comparing
side-to-side anastomosis versus end-to-end anastomosis determined
that there was no difference in overall complication rates, anastomotic
leak rates, or rates of symptomatic recurrence, with only a slight increase
in endoscopic recurrence seen in the end-to-end anastomosis
group (43% vs. 38%). Additionally, a new antimesenteric functional
end-to-end hand-sewn anastomosis (known as Kono-S anastomosis)
was created to minimize anastomotic restenosis in Crohn disease.
This technique was demonstrated to have a significantly lower rate of
stenosis and recurrence compared to conventional end to end anastomosis.
Although further randomized control trials are needed, these
findings demonstrate a promising novel surgical approach that may
decrease the need for additional biologic therapy.27

Specific Problems

Acute ileitis (nonstricturing, nonpenetrating). Patients can

present with acute abdominal pain localized to the right lower
quadrant, signs and symptoms consistent with a diagnosis of
acute appendicitis. At exploration, the appendix is found to be
normal, but the terminal ileum is edematous and beefy red with a
thickened mesentery and enlarged lymph nodes. This condition,
known as acute ileitis, is a self-limited disease. Acute ileitis may
be a manifestation of early Crohn disease but is most often unrelated.
Bacteriologic agents such as Campylobacter and Yersinia may
cause acute ileitis. Intestinal resection should not be performed.
Although past management of the appendix was controversial, it
is clear now that, in the absence of acute inflammatory involvement
of the appendix or the cecum, appendectomy should be performed.
This eliminates the appendix as a source of abdominal
pain in the future.

Stricturing disease. Intestinal obstruction is the most common

indication for surgical therapy in patients with Crohn disease.
Obstruction in these patients is often partial, and nonoperative
management is initially indicated. The success of nonoperative
management can often be predicted on the basis of the chronicity
of symptoms at the affected site. In patients for whom it is difficult
to determine whether the site of obstruction is caused by
an acute exacerbation or a chronically strictured segment, stool
lactoferrin and calprotectin levels may help identify acute inflammation,
whereas certain genetic markers (e.g., NOD2, TLR4, CX3CR1)
may predict potential success of medical therapy. In case of

FIG. 50.23 Ileocecal resection secondary to Crohn disease. Resection

of the ileum, ileocecal valve, cecum, and ascending colon for Crohn dis-
ease of the ileum. Intestinal continuity is restored by end-to-end anasto-
mosis.

a chronic strictured segment, medical therapy is rarely effective.

Operative intervention is required for patients with complete obstruction
and partial obstruction whose condition does not resolve
with nonoperative management. The treatment of choice for intestinal
obstruction in patients with Crohn disease is segmental
resection of the involved segment with primary reanastomosis.
This may involve segmental resection and primary anastomosis
of a short segment of ileum or an ileocecectomy if both the ileum
and cecum are involved (Fig. 50.23).

In selected patients with obstruction caused by strictures (single

or multiple), one option is to perform a strictureplasty that effectively
widens the lumen but avoids intestinal resection. Strictureplasty
is performed by making a longitudinal incision through the
narrowed area of the intestine, followed by closure in a transverse
fashion in a manner similar to that for a Heineke-Mikulicz pyloroplasty
(Fig. 50.24A). For longer diseased segments (>10 cm), the
strictureplasty can be performed similar to a Finney pyloroplasty
(Fig. 50.24B) or a side-to-side isoperistaltic strictureplasty.24 Strictureplasty
is best used in those patients with multiple short areas
of narrowing present over long segments of intestine, in those who
have already had several previous resections of the small intestine,
and in those with chronic fibrous obstruction. This procedure preserves
intestine and is associated with complication and recurrence
rates comparable to those of resection and reanastomosis. Given
the concerns for development of carcinoma at chronically strictured
segments, full-thickness biopsy with frozen section of the
stricture site has been advocated at the time of surgery to rule out
malignant disease before strictureplasty is performed (Box 50.5).

In the past, bypass procedures were commonly used. There are

two types of bypass operations: exclusion bypass and simple (continuity)
bypass. For certain types of ileocecal disease associated
with an abscess or phlegmon densely adherent to the retroperitoneum,
the proximal transected end of the ileum is anastomosed
to the transverse colon in an end-to-side fashion with or without
construction of a mucous fistula using the distal transected end of
the ileum (exclusion bypass), or an ileotransverse colonic anastomosis
is made in a side-to-side fashion (continuity bypass). Currently,
bypass with exclusion is used only in patients with severe
gastroduodenal Crohn disease not amenable to strictureplasty, older
poor-risk patients, patients who have had several prior resections
and cannot afford to lose any more bowel, and those in whom
CHAPTER 50 Small Intestine

1269
FIG. 50.24 Types of strictureplasty. (A) Technique of short strictureplasty in the
manner of a Heineke-Mikulicz
pyloroplasty. (B) For longer diseased segments, strictureplasty may be performed in
a manner similar to Finney
pyloroplasty. (Adapted from Alexander-Williams J, Haynes IG. Up-to-date management
of small-bowel Crohn’s
disease. In: Mannick JA, ed. Advances in Surgery. St. Louis: Mosby; 1987:245–264.)

BOX 50.5 Contraindications to

strictureplasty.
􀁳�
Excessive tension due to rigid and thickened bowel segments
􀁳�
Perforation of the intestine
􀁳�
Fistula or abscess formation at the intended strictureplasty site
􀁳�
Hemorrhagic strictures
􀁳�
Multiple strictures within a short segment
􀁳�
Malnutrition or hypoalbuminemia (<2.0 g/dL)
􀁳�
Suspicion of cancer at the intended strictureplasty site

Adapted from Yamamoto T, Watanabe T. Surgery for luminal Crohn’s

disease. World J Gastroenterol. 2014;20:78–90.

resection would necessitate entering an abscess or endangering a

normal structure.

Penetrating disease. Fistula and abscess in patients with Crohn

disease are relatively common and usually involve adjacent small
bowel, colon, or other surrounding viscera (e.g., bladder). The presence
of a radiographically demonstrable enteroenteral fistula with
no signs of sepsis or other complications is not in itself an indication
for surgery. Furthermore, penetrating disease is particularly sensitive
to anticytokine therapy, and a conservative, surgical approach to

Crohn disease–related fistula is most appropriate.24 Enterocutaneous

fistulas may develop but are rarely spontaneous and are more
likely to follow resection or drainage of intraabdominal abscesses.
These fistulas may close spontaneously, and treatment should entail
outflow reduction, preventing infection, maximizing nutrition and
optimal skin care. If conservative management fails, excision of the
fistula tract and primary anastomosis is preferred. Note that preoperative
optimization is necessary, as Crohn patients with penetrating
disease tend to have longer operative times, higher reoperation rates,
increased length of stay, and postoperative complications. If the fistula
forms between two or more adjacent loops of diseased bowel,
the involved segments should be excised. Alternatively, if the fistula
involves an adjacent normal organ, such as the bladder or colon,
only the segment of the diseased small bowel and fistulous tract
should be resected, and the defect in the normal organ should simply
be closed. Most patients with ileosigmoid fistulas do not necessarily
require resection of the sigmoid because the disease is usually
confined to the small bowel. However, if the segment of sigmoid is
also found to have Crohn disease, it should be resected along with
the segment of diseased small bowel.

Perforation. Penetrating disease in the form of free perforation

into the peritoneal cavity is uncommon in patients with
Crohn disease. Typically, penetration is manifested with a localized
abscess densely adherent to the diseased segment of bowel.
1270 1270
SECTION X Abdomen

Patients who have an abscess smaller than 3 cm and have not

been on biologics or have an associated fistula can be treated
with antibiotics alone.14 Abscesses that do not meet these criteria
should undergo percutaneous drainage. In fact, early treatment
of an abscess is key regardless of percutaneous or surgical drainage,
in terms of time to resolution. In cases of free perforation,
the segment of involved bowel should be resected, and in the
presence of minimal contamination, a primary anastomosis can
be performed. If generalized peritonitis is present, a safer option
may be to create an ostomy until the intraabdominal sepsis is
controlled and then have the patient return for restoration of
intestinal continuity after a period of 4 to 6 weeks. Abscesses can
be treated with percutaneous drainage and antibiotics; however,
fistula or uncontrolled sepsis may develop, requiring resection
with or without primary anastomosis.

Gastrointestinal bleeding. Although anemia from chronic

blood loss is common in patients with Crohn disease, life-threatening
gastrointestinal hemorrhage is rare. The incidence of hemorrhage
is more common in patients with Crohn disease involving
the colon rather than the small bowel. As with the other complications,
the segment involved should be resected and intestinal continuity
restored. Arteriography may be useful to localize the bleeding
before surgery. In cases of bleeding associated with duodenal
disease, endoscopic intervention is usually successful. However, in
cases of failure, duodenotomy with oversewing of the bleeding ulcerative
area is indicated.

Urologic complications. Genitourinary complications occur in

up to one third of patients with Crohn disease. The most common
urologic complication is ureteral obstruction, which is usually
secondary to ileocolic disease with retroperitoneal inflammatory
compression. Surgical treatment of the primary intestinal disease
is adequate in most patients. In a few cases of long-standing inflammatory
disease, periureteric fibrosis may be present and require
ureterolysis with or without ureteral stenting.

Cancer. Patients with long-standing Crohn disease of the small

bowel and, in particular, the colon have an increased incidence of
cancer. The management of these patients is the same as that for
any patient—resection of the cancer with appropriate margins,
lymphadenectomy, and perioperative chemotherapy/radiation.
Patients with cancer associated with Crohn disease commonly
have a worse prognosis than those who do not have Crohn disease,
largely because the diagnosis in these patients is often delayed. In
addition, a strictureplasty should not be performed if malignant
disease is suspected.

Colorectal disease. The same principle applies to patients with

Crohn disease limited to the colon as to those with disease to the
small bowel; that is, surgical resection should be limited to the
main segment involved. Indications for surgery include a lack of
response to medical management and complications of Crohn
colitis, which include obstruction, hemorrhage, perforation, and
toxic megacolon. Depending on the diseased segments, procedures
commonly include segmental colectomy with colocolonic anastomosis,
total abdominal colectomy with ileorectal anastomosis,
total proctocolectomy with ileoanal anastomosis, and in patients
with extensive perianal and rectal disease, abdominoperineal resection
with end ileostomy. Strictureplasty has limited usefulness
in colonic Crohn disease, and concerns of malignant transformation
at an area of colonic obstruction should limit its application.

A particularly troubling problem after abdominoperineal resection

in patients with Crohn disease is delayed healing of the
perineal wound. More than half of perineal wounds are open 6
months after surgery in patients with Crohn disease. Persistent

nonhealing wounds require excision with secondary closure. Large

cavities or sinuses may be filled by using well-vascularized pedicles
of muscle (e.g., gracilis, semimembranosus, rectus abdominis) or
omentum or by using an inferior gluteal myocutaneous graft.

Although controversial, continence-preserving operations, such

as ileal pouch–anal anastomosis or continent ileostomies (Kock
pouch), may be considered in very carefully selected patients with
Crohn disease isolated to the colon who undergo thorough counseling
about the increased risk of anastomotic failure and wound
complication. However, these procedures should never be considered
in patients with evidence of terminal ileal or perianal disease
as these patients have a significantly increased rate of recurrence
of Crohn disease in the pouch, fistulas to the anastomosis, and
peripouch abscesses.

Perianal disease. Diseases involving the perianal region include

fissures and fistulas and are common in patients with Crohn disease,
particularly those with colonic involvement. The treatment
of perianal disease should be nonoperative unless an abscess or
complex fistula develops, and even in these cases, surgery should
be approached cautiously and limited to addressing the specific
problem with minimal tissue loss. Nonsuppurative, chronic fistulization
or perianal fissuring is treated with antibiotics, immunosuppressive
agents (e.g., AZT or 6-MP), and infliximab, which is
the most widely supported therapy as it has shown the best results
in fistula closure.11 Several uncontrolled studies have shown some
benefit with cyclosporine or FK-506 treatment.

Wide excision of abscesses or fistulas is not indicated, but more

conservative interventions, including the liberal placement of
drainage catheters and noncutting setons, are preferable. Definitive
fistulotomy is indicated for most patients with superficial, low
trans-sphincteric, and low intersphincteric fistulas, although one
must recognize that some degree of anal stenosis may occur as
a result of chronic inflammation. High transsphincteric, suprasphincteric,
and extrasphincteric fistulas are usually treated with
noncutting setons. Fissures are usually lateral, relatively painless,
large, and indolent and often respond to conservative management.
Abscesses should be drained, but large excisions of tissue
should not be performed. Advancement flap closure of perineal
fistulas may be required in certain cases. Selective construction
of diverting stomas has good results in combination with optimal
medical therapy to induce remission of inflammation. Proctectomy
is infrequent but required in a subset of patients who have
persistent and unremitting disease despite conservative medical
and surgical therapy.

Duodenal disease. Crohn disease of the duodenum occurs

in less than 5% of patients with Crohn disease and occurs most
commonly in the duodenal bulb.14 Operative intervention is uncommon.
The primary indication for surgery in these patients is
duodenal obstruction that does not respond to medical therapy,
with endoscopic balloon dilation and surgery being the mainstays
of treatment. Gastrojejunostomy to bypass the disease rather than
duodenal resection is the procedure of choice. Strictureplasties
have been performed with success in selected patients and may
avoid the marginal ulceration and diarrhea associated with gastrojejunostomy.

Prognosis

Crohn disease is a chronic inflammatory disorder that is not medically

or surgically curable; therefore, therapeutic approaches are required
to induce and to maintain symptomatic control, to improve
quality of life, and to minimize long-term complications. It is estimated
that approximately 71% of patients will require surgery
CHAPTER 50 Small Intestine

1271
within 10 years of diagnosis, and 50% require a second procedure
within 20 years.28 Symptomatic recurrence varies from 40% to
80%, and endoscopic recurrence is much higher, with up to 90%
of patients having visible lesions within 5 years. The only clearly
modifiable risk factor is smoking cessation. Surgery is generally
indicated when the patient fails to respond to medical therapy or
develops complications, and multiple studies have shown that patients
report significant improvement in quality of life scores after
surgical intervention. Although postsurgical recurrence is high,
algorithms using careful endoscopic surveillance combined with
maintenance immunomodulators, anti-TNF antibodies, anti-integrin
therapy, and even investigational traditional Chinese medicine
all play a role in the prevention of postoperative recurrence of
Crohn disease (Fig. 50.25). Although there is currently no cure for
this disease, advances in medical and surgical therapies have clearly
increased quality of life and disease-free progression.

Standardized mortality rates in patients with Crohn disease

show an increase in those whose disease began before the age of
20 years and in those who have had disease for longer than 13
years. Long-term survival studies suggest that patients with Crohn
disease have a death rate approximately two to three times higher
than that of the general population, which is most commonly related
to chronic wound complications and sepsis. Gastrointestinal
cancer remains the leading cause of disease-related deaths in patients
with Crohn disease; other causes of disease-related deaths
include sepsis, thromboembolic complications, and electrolyte
disorders.

Typhoid Enteritis

Typhoid fever remains a significant problem in developing countries,

most commonly in areas with contaminated water supplies
and inadequate waste disposal. Roughly 21.6 million people
worldwide develop typhoid fever with an estimated 200,000
deaths per year. Children and young adults are most often affected.
Improvements in sanitation have decreased the incidence
of typhoid fever in industrialized countries. Most cases of typhoid
fever in the United States arise in international travelers; however,

unrecognized and untreated typhoid fever is a life-threatening illness

with significant long-term morbidity.

Typhoid enteritis is an acute systemic infection caused primarily

by Salmonella typhi. The pathologic events of typhoid fever are
initiated in the intestinal tract after oral ingestion of the typhoid
bacillus. These organisms penetrate the small bowel mucosa, making
their way rapidly to the lymphatics, and then spreading systemically.
Hyperplasia of the reticuloendothelial system, including
lymph nodes, liver, and spleen, is characteristic of typhoid fever.
Peyer patches in the small bowel become hyperplastic and may
subsequently ulcerate, complicated by hemorrhage or perforation.

The diagnosis of typhoid fever is confirmed by isolating the

organism from blood (positive in 90% of the patients during the
first week of the illness), bone marrow, and stool cultures. In addition,
the finding of high titers of agglutinins against O and H
antigens (Widal test) was used historically but is nonspecific and
is no longer an acceptable clinical method. Assays for the diagnosis
of S. typhi using PCR analysis are unpredictable. Combining
blood and urine cultures achieved a sensitivity of 83% and
reported specificity of 100%. Indirect hemagglutination, indirect
fluorescent Vi antibody, and indirect enzyme-linked immunosorbent
assay for IgM and IgG antibodies to S. typhi polysaccharide
are promising, but the success rates of these assays vary greatly in
the literature.

Typhoid fever and uncomplicated typhoid enteritis are treated

by antibiotic administration. If a patient presents with clinical
symptoms and has been in an endemic area, broad-spectrum
empirical antibiotics should be started immediately. Treatment
should not be delayed for confirmatory tests because prompt treatment
drastically reduces the risk of complications and fatalities.
Antibiotic therapy should be narrowed once more information
is available. Chloramphenicol was initially the mainstay of treatment
in the 1950s, but widespread antibiotic resistance occurred.
Currently, the most widely used agents are fluoroquinolones and
third-generation cephalosporins.

Complications requiring potential surgical intervention include

hemorrhage and perforation. The incidence of hemorrhage

Predicted risk of
clinical recurrence
“Low”
“High”
Anti-TNF or
AZT/6MP
Anti-TNF or
AZT/6MP
Surveillance
endoscopy
Modify or
intensify medical
therapy
Endoscopic
surveillance and
continue therapy
Endoscopic
recurrence
No
recurrence
Endoscopic
surveillance
Metronidazole
for 3 months
Surveillance
endoscopy
Endoscopic
recurrence
No
recurrence
FIG. 50.25 Postoperative surveillance algorithm for Crohn disease. (Adapted from
Vaughn BP, Moss AC. Pre-
vention of post-operative recurrence of Crohn’s disease. World J Gastroenterol.
2014;20:1147–1154; and Reg-
ueiro M, Feagan BG, Zou B, et al. Infliximab reduces endoscopic, but not clinical,
recurrence of Crohn’s disease
after ileocolonic resection. Gastroenterology. 2016;150:1568–1578). AZT,
Azathioprine; 6MP, 6-mercaptopu-
rine; TNF, tumor necrosing factor.
1272 1272
SECTION X Abdomen

was reported to be as high as 20% in one series, but with the

availability of antibiotics, this figure has decreased. When hemorrhage
occurs, transfusion is indicated and usually suffices.
Rarely, laparotomy must be performed for uncontrollable, life-
threatening hemorrhage. Intestinal perforation through an ulcerated
Peyer patch occurs in approximately 2% of cases. Typically,
it is a single perforation in the terminal ileum, and simple
closure of the perforation is the treatment of choice. Multiple
perforations, which occur in about 25% of patients, may require
resection with primary anastomosis or exteriorization of the intestinal
loop.

Enteritis in the Immunocompromised Host

The acquired immunodeficiency syndrome (AIDS) epidemic, as

well as the widespread use of immunosuppressive agents after organ
transplantation, has resulted in a number of rare and exotic
pathogens infecting the gastrointestinal tract. Almost all patients
with AIDS have gastrointestinal symptoms during their illness,
the most common of which is diarrhea. A surgeon may be asked to
evaluate the immunocompromised patient with abdominal pain,
acute abdomen, or gastrointestinal bleeding; a number of protozoal,
bacterial, viral, and fungal organisms may be responsible.

Protozoa

Protozoa (e.g., Cryptosporidium, Isospora, and Microsporidium) are

the most frequent class of pathogens causing diarrhea in patients
with AIDS. The small bowel is the most common site of infection.
Diagnosis may be established by acid-fast staining of the stool or
duodenal secretions, and the introduction of specific antigen tests
for stool examination has improved diagnostic capabilities. Immunochromatography
cards for the rapid detection of protozoal
proteins from a small sample of stool are available from several
different commercial sources and are more sensitive and specific
(>90%) than traditional microscopic examinations. Symptoms are
most commonly related to diarrhea, which may be at times intractable.
Current treatment regimens have not been entirely effective,
but drugs such as prophylactic cotrimoxazole and a highly active
antiretroviral therapy appear to elicit a response to human immunodeficiency
virus (HIV)–related diarrheal illnesses.29

Bacteria

Infections by enteric bacteria are more frequent and more virulent

in individuals infected with HIV than in healthy hosts. Salmonella,
Shigella, and Campylobacter are associated with higher rates of
bacteremia and antibiotic resistance in the immunocompromised
patient. The diagnosis of Shigella or Salmonella infection may be
established by stool cultures. The diagnosis of Campylobacter infection
is not as easily established because stool cultures are often negative,
but PCR techniques evaluating stool and serum have shown
promising diagnostic results in patients with negative cultures.
These enteric infections are manifested clinically with high fever,
abdominal pain, and diarrhea that may be bloody. Abdominal pain
may mimic an acute abdomen. Bacteremia and serious infections
should be treated by IV administration of imipenem antibiotics;
ciprofloxacin is an attractive choice if the organisms are multiply
resistant; the pregnant patient may be safely treated with erythromycin.
The incidence of Campylobacter infection among patients
with AIDS who were treated with rifabutin prophylaxis was reported
to be decreased compared with untreated controls.

Diarrhea caused by Clostridium difficile is more common in

patients with AIDS because of the increased antibiotic use in this
population compared with healthy hosts. Diagnosis is by standard

assays of stool for C. difficile enterotoxin. Treatment with metronidazole

or vancomycin is usually effective.

Mycobacteria

Mycobacterial infection is a frequent cause of intestinal disease

in immunocompromised hosts. This can be secondary to Mycobacterium
tuberculosis or Mycobacterium avium complex (MAC),
which is an atypical mycobacterium related to the type that causes
cervical adenitis (scrofula). The usual route of infection is by swallowed
organisms that directly penetrate the intestinal mucosa. The
luminal gastrointestinal tract is affected by MAC infection, with
massive thickening of the proximal small intestine often noted
(Fig. 50.26). Clinically, patients with MAC present with diarrhea,
fever, anorexia, and progressive wasting.

The most frequent site of intestinal involvement of M. tuberculosis

is the distal ileum and cecum, with approximately 90%
of patients demonstrating disease at this site. The gross appearance
can be ulcerative, hypertrophic, or ulcerohypertrophic. The
bowel wall appears thickened, and an inflammatory mass often
surrounds the ileocecal region. Acute inflammation is apparent,
as are strictures and even fistula formation. The serosal surface is
normally covered with multiple tubercles, and mesenteric lymph
nodes are frequently enlarged and thickened; on sectioning, caseous
necrosis is noted. The mucosa is hyperemic, edematous, and,
in some cases, ulcerated. On histologic evaluation, the distinguishing
lesion is a granuloma, with caseating granulomas found
most commonly in the lymph nodes. Most patients complain of
chronic abdominal pain that may be nonspecific, weight loss, fever,
and diarrhea.

The diagnosis of mycobacterial infection is made by identification

of the organism in tissue by direct visualization with an

FIG. 50.26 Contrasted radiograph of thickened intestinal folds secondary

to bacterial infection. A patient with acquired immunodeficiency syndrome
shows thickened intestinal folds consistent with enteritis secondary
to atypical mycobacterium. (Courtesy Dr. Melvyn H. Schreiber, The
University of Texas Medical Branch, Galveston, TX.)
CHAPTER 50 Small Intestine

1273
acid-fast stain, culture of the excised tissue, or PCR assay. Radiographic
examinations usually reveal a thickened mucosa with distorted
mucosal folds and ulcerations. CT may be useful and shows
a thickening of the ileocecal valve and cecum.

The treatment of M. tuberculosis is similar in the immunocompromised

or nonimmunocompromised host. The organism is usually
responsive to multidrug antimicrobial therapy. The therapy
for MAC infection is evolving; drugs that have been successfully
used invivo and invitro include amikacin, ciprofloxacin, cycloserine,
and ethionamide. Clarithromycin has also been successfully
used in combination with other agents. Surgical intervention may
be required for intestinal tuberculosis, particularly M. tuberculosis.
Obstruction and fistula formation are the leading indications
for surgery; however, with current treatment, most fistulas now
respond to medical management. Surgery may be necessary for
ulcerative complications when free perforation, perforation with
abscess, or massive hemorrhage occurs. The treatment is usually
resection with anastomosis.

Viruses

CMV is the most common viral cause of diarrhea in immunocompromised

patients. Clinical manifestations include intermittent
diarrhea accompanied by fever, weight loss, and abdominal
pain. The manifestations of enteric CMV infection result from
mucosal ischemic ulcerations, which account for the high rate of
perforations noted with CMV. As a result of the diffuse ulcerating
involvement of the intestine, patients may present with abdominal
pain, peritonitis, or hematochezia. Diagnosis of CMV is
made by demonstrating viral inclusions. The most characteristic
form is an intranuclear inclusion, which is often surrounded by a
halo, producing a so-called owl’s eye appearance. There may also
be cytoplasmic inclusions (Fig. 50.27). Cultures for CMV are usually
positive when inclusion bodies are present, but these cultures
are less sensitive and specific than histopathologic identification.
Once CMV infection is diagnosed, treatment is usually effective
with ganciclovir. An alternative to ganciclovir is foscarnet, a pyrophosphate
analogue that inhibits viral replication. Infections
with other less common viruses, including adenovirus, rotavirus,
and novel enteric viruses such as astrovirus and picornavirus, have
been reported.

FIG. 50.27 Intestinal cytomegalovirus infection inclusions. Microscopic

section of small bowel in a patient with acquired immunodeficiency syn-
drome who has cytomegalovirus enteritis. Multiple large cells with in-
tranuclear and intracytoplasmic inclusions typical of cytomegalovirus are
demonstrated (arrows). (Courtesy Dr. Mary R. Schwartz, Baylor College
of Medicine, Houston, TX.)

Fungi

Fungal infections of the intestinal tract have been recognized in

patients with AIDS. Gastrointestinal histoplasmosis occurs in the
setting of systemic infection, often in association with pulmonary
and hepatic disease. Diagnosis is made by fungal smear and culture
of infected tissue or blood. The infection is most commonly
treated by the administration of amphotericin B. Coccidioidomycosis
of the intestinal tract is rare and, like histoplasmosis, occurs
in the context of systemic infection.

NEOPLASMS

General Considerations

Despite composing 75% of the length and 90% of the surface

area of the gastrointestinal tract, the small bowel develops relatively
few primary neoplasms and less than 2% of gastrointestinal
malignant neoplasms. However, the incidence of small bowel
cancer has increased an average of approximately 2% each year
during the past 10 years. In 2018, an estimated 10,470 adults in
the United States will be diagnosed with small bowel cancer, and
approximately 1450 individuals will die of this disease. The 5-year
survival for localized small bowel cancer is approximately 85%.
Unfortunately, only 32% of patients are diagnosed with local
disease; therefore, patients with regional and distant disease have
5-year survival rates of approximately 75% and 42%, respectively.
This trend may be a reflection of the increase in incidence of small
bowel carcinoids in the past decade.

The mean age at presentation is 62 years in the setting of benign

tumors and approximately 57 years for malignant tumors.
Similar to other cancers, there appears to be a geographic distribution,
with the highest cancer rates found among the Maori of
New Zealand and ethnic Hawaiians. The incidence of small bowel
cancer is particularly low in India, Romania, and other parts of
Eastern Europe. The incidence of small bowel neoplasia varies
considerably, with benign lesions identified more often at autopsy.
In contrast, malignant neoplasms account for 75% of symptomatic
lesions that lead to surgery. This reflects the fact that most
benign neoplasms are asymptomatic and often identified as an
incidental finding. Stromal tumors and adenomas are the most
frequent of the benign tumors and appear to be more common in
the distal small bowel but may be somewhat misleading because
of the relatively short length of the duodenum. Adenocarcinoma
is the most common malignant neoplasm, accounting for 30% to
50% of malignant neoplasms of the small intestine; neuroendocrine
tumors (NETs) account for 25% to 30% of small intestine
malignant neoplasms. Adenocarcinomas are more prevalent in
the proximal small bowel, whereas the other malignant lesions are
more common in the distal small bowel.

The risk factors and associated conditions related to small

bowel neoplasms have been described. These include patients
with familial adenomatous polyposis (FAP), hereditary nonpolyposis
colorectal cancer, Peutz-Jeghers syndrome, Crohn disease,
gluten-sensitive enteropathy (i.e., celiac sprue), prior peptic ulcer
disease, cystic fibrosis, and biliary diversion (i.e., previous cholecystectomy).
Controversial factors that may contribute to small
bowel neoplasms include smoking, heavy alcohol consumption
(>80 g/day of ethanol), and consumption of red meat or salt-
cured foods.
Although the molecular genetics of small bowel neoplasms have
not been entirely characterized, similar to colorectal cancers, mutations
of the KRAS gene are commonly identified. Allelic losses, particularly
involving tumor suppressor genes at chromosome locations