The authors review recent advances in the pathophysiology, treatment, and imaging of Crohn's disease and suggest imaging strategies and findings that will help radiologists in properly identifying this disease. This article has been accredited for 1 hour of Category A CME Credit.
The last decade has seen many advances in the pathophysiology,
treatment, and imaging of Crohn's disease. This article will review
these recent advances and suggest imaging strategies and findings
that will help radiologists assist internists, surgeons, and
gastroenterologists caring for patients with Crohn's disease.
Pathophysiology of Crohn's disease
Crohn's disease is thought to result from genetic susceptibility
as well as a complex interaction between enteric flora and the gut.
These factors lead to an altered immune response that causes
mucosal and transmural inflammation of the bowel.
In the late 1990s, several groups from the United States and
abroad discovered nucleotide polymorphisms within a gene on
chromosome 16, conferring Crohn's disease susceptibility in
affected sibling pairs.
This gene, called Nod-2 (or CARD-15), is an intracellular protein
in lymphocytes. Homozygosity for mutation in the Nod-2 gene leads
to susceptibility for Crohn's disease that is 20 to 40 times
normal. The Nod-2 gene plays a role in binding bacterial
endotoxins, and potentially in apoptosis (programmed cell death).
The Nod-2 gene also initiates a cascade that produces tumor
necrosis factor-alpha (TNF-*), the potent inflammatory cytokine
that is markedly elevated in Crohn's disease. Mutations in the
Nod-2 gene result in decreased binding of bacterial antitoxins.
Other foci of genetic susceptibility for Crohn's disease exist, but
their role is unclear.
Enteric flora also play an important role in the development of
Clinical response to antibiotics, and diminished bowel inflammation
subsequent to fecal diversion, demonstrate the pro-inflammatory
role enteric flora can play. Patients with Crohn's disease have
increased mucosal permeability to bacteria, resulting in increased
interaction between bacteria and the mucosa. Some investigational
therapies entering human clinical trials are aimed at changing the
composition of enteric flora, employing probiotics (including
) to decrease inflammation.
New therapies for Crohn's disease
There is a panoply of new therapies for Crohn's disease. Their
targets range from the gut lumen and the modulation of enteric
flora (eg, probiotics and antibiotics), to global downregulation of
inflammatory response (eg, purine synthesis inhibitors such as
azathioprine, 6-mercaptopurine) to a full range of targeted
Infliximab is a chimeric antibody composed of a human constant
portion and a murine variable portion, which binds to human TNF-*.
Clinical trials have shown infliximab to be effective in treating
moderate, severe, fistulizing, and refractory Crohn's disease. One
early study found that 81% of patients with moderate or severe
Crohn's disease responded to therapy, with nearly half of the
patients entering remission 4 weeks after a single infusion of the
Multiple doses of infliximab are usually necessary for treatment of
fistulizing disease, with more than half of fistulas demonstrating
Multiple dosing is sometimes required to maintain remission.
The alpha-4 integrins are a class of leukocyte adhesion
molecules that are thought to help mediate the migration of
inflammatory cells from the capillaries of the gut into the lamina
In early clinical trials, natalizumab, an anti-alpha-4 integrin
antibody, has shown promise as a treatment for Crohn's disease.
Challenges for the gastroenterologist
The principle challenge for the gastroenterologist in patients
with Crohn's disease is to determine if symptoms are due to active
disease that is medically or surgically treatable. There has
consequently arisen a large array of activity indices for Crohn's
disease that seek to correlate biological inflammation with
symptoms, fistulous disease, and endoscopic severity.
Histologic assessments of Crohn's disease do not correlate well
with other estimates of disease activity, and clinical activity
indices rely upon subjectivity of both the patient and the
Challenges for the radiologist
Identifying only the presence or absence of Crohn's disease is
no longer adequate. Given the major advances in pathophysiologic
understanding of Crohn's and the development of targeted biologic
therapeutic agents, it is incumbent upon radiologists to identify
active inflammation, as well as disease complications that alter
the selection of medical and/or surgical therapies. Accurately
characterizing the cause of bowel stenosis and the nature of any
extraenteric complications will help clinicians make appropriate
therapeutic choices as they treat patients with Crohn's
The improved spatial and temporal resolution of computed
tomography (CT) and magnetic resonance (MR) scanners now allow the
detection of some mucosal disease. Mucosal disease is identified by
mucosal hyperenhancement and thickening, while transmural disease
is characterized by bowel-wall thickening, mural stratification,
transmural ulcers, and hyperemic vasa recta (the "comb sign"). As
radiologists, we need to translate our visual paradigm of active
disease at fluoroscopy to the cross-sectional modalities (Figure
Mucosal hyperenhancement is best identified when using a
negative contrast agent in the bowel lumen and intravenous (IV)
contrast. Mucosal enhancement can be confidently identified when
the bowel lumen is distended and the mucosa is hyperenhancing
compared with adjacent normal-appearing small bowel. With
transmural inflammation, mural stratification will often accompany
hyperenhancement (Figure 3). Mural stratification, also called the
target sign, refers to hyperenhancement of the mucosa and
muscularis propria with decreased attenuation of the submucosa,
representing either submucosal edema or fat (Figure 4). Mural
stratification indicates that transmural fibrosis has not yet
When the low attenuation of the mucosa resembles edema and is
accompanied by hyperemia in the vasa recta and mucosal
hyperenhancement, one can be confident active inflammation is
We have found the hyperemic vasa recta, or "comb sign," to be a
helpful finding in patients with active disease (Figure 5).
Lee et al
recently found that hyperemic vasa recta correlated positively with
the symptom severity, aggressive treatment, and length of hospital
stay. Barium findings correlating with the hyperemic vasa recta
included mesenteric border linear ulcers, perpendicular
ulcerations, and long segments of Crohn's disease.
Bowel-wall thickening is the least specific sign of Crohn's
disease. When we encounter sporadic bowel-wall thickening, we
exclude vascular compromise before considering Crohn's disease.
When accompanied by other signs more specific for Crohn's disease,
inflammatory bowel disease can be suggested.
Paraenteric findings of Crohn's disease included fibrofatty
proliferation, mild adenopathy, fistula, phlegmon, and abscess. In
a large surgical series, fibrofatty proliferation was highly
specific for Crohn's disease of the small bowel.
Fibrofatty proliferation, like linear ulcers, occurs along the
mesenteric border (Figure 6). Fibrofatty proliferation may not
simply represent a benign reaction to adjacent inflammation, but
may promote intestinal inflammation, as TNF-* is also produced in
the perienteric fat.
Fibrofatty proliferation associated with the rectum and sigmoid,
unlike the mesenteric border distribution of fatty proliferation in
the small bowel, may appear circumferential.
Cross-sectional imaging has long been used to identify phlegmon
and abscess as complications of Crohn's disease. We find that with
the speed and smaller slice thicknesses available with
multidetector CT, we see more interloop abscesses as well as their
connection with the bowel lumen. Small abscesses will likely
respond to antibiotics and anti-inflammatory therapy.
While radiologists are comfortable with identifying fistulas as
tracts containing barium and positive enteric contrast, we need to
be more comfortable identifying fistulas using negative oral
contrast agents and IV contrast. In this setting, fistulas appear
as linear, hyperenhancing extraenteric tracts connecting bowel to
bowel, or bowel to other structures. When performing CT of the
abdomen and pelvis in Crohn's patients, it is imperative to scan
through the perineum to identify fistulous perianal disease (Figure
Perianal anatomy is best demonstrated on MR imaging. The
internal anal sphincter is contiguous with the inner circular
muscle of the rectum and demonstrates slightly hyperintense T2
signal compared with the external sphincter. It also demonstrates
intense enhancement after gadolinium (Figure 8). The external
sphincter, puborectalis, and levator ani muscles demonstrate
uniformly low signal and enhance minimally with gadolinium.
Fistulas are described by their Parks classification
(which describes the relationship of a fistula to the sphincters
and puborectalis), external openings on the skin, and internal
openings in the anorectum (Figure 9). Small, simple fistulas below
the level of the puborectalis (ie, superficial, intersphincteric,
and transsphincteric fistulas) can often be treated successfully
with antibiotics, 6-mercaptopurine (or azathioprine) and
infliximab, without surgical treatment.
They may also be treated with a fistulotomy if the sphincters are
not involved. When patients have proctocolitis, or fistulas extend
more superiorly (posing a greater risk to sphincter integrity), a
noncutting seton is typically employed, in addition to medical
therapy. A noncutting seton is a suture that passes through the
fistula and the anal canal, allowing the fistula to drain,
preventing premature fistula closure and abscess formation.
Abscesses are usually treated with incision and drainage when they
are superficial, or a catheter drainage when deeper.
Proctocolectomy is usually reserved for severe recurrent disease.
Many fistulas cause horseshoe tracts or abscesses about the anal
rectum (Figure 10).
We typically image perianal fistulas with a noninvasive protocol
employing a phased-array torso coil, fast spin-echo imaging with
fat saturation in three planes, with a slice thickness of 5 mm and
a skip of 0 mm.
These images are used for fistula detection. A corresponding set of
axial fast spin-echo images without fat saturation is used to
classify the fistula according to its relationship to the
puborectalis and anal sphincters. Finally, we obtain
two-dimensional (2D) spoiled gradient-recalled (SPGR) images after
gadolinium in axial and coronal planes. When employing this
noninvasive protocol, the performance of MR is similar to
endoscopic ultrasound (EUS) or examination under anesthesia.
One advantage of MR over EUS is that it often demonstrates systemic
complications (Figure 11).
Many complications of Crohn's disease are unsuspected at the
time of imaging. Crohn's patients are at increased risk for colon
and small-bowel cancers as well as lymphoma.
They are also prone to the development of several hepatobiliary
complications including cholelithiasis, hepatic abscess, and
primary sclerosing cholangitis (PSC). Approximately 1% of Crohn's
patients will develop PSC, and approximately 10% of the patients
with PSC have Crohn's.
Crohn's patients are also prone to pancreatitis and
nephrolithiasis. Toxic megacolon is one complication that can be
difficult to diagnose at cross-sectional imaging. Findings include
colonic dilation, loss of the normal haustral markings, and
pericolonic inflammatory stranding. These findings should prompt
plain-film correlation, if necessary. Sacroiliitis is another
important complication to recognize, as it can predate the
development of enteric disease.
CT and MR enterography
MR and CT enterography are high-resolution, cross-sectional
studies of the small bowel performed after small-bowel enema.
Small-bowel enema can be achieved either through the placement of a
nasojejunal tube and the infusion of methylcellulose, or by having
the patient ingest a large volume of oral contrast over a specified
period of time.
A negative oral contrast agent should be employed, in conjunction
with IV contrast material, so that mucosal hyperenhancement and
mural stratification can be easily recognized.
We recently performed a feasibility study of CT enterography,
with some of the patients receiving a 1800 mL methylcellulose
infusion via nasojejunal tube and the remainder receiving four 450
mL aliquots of water at 75, 50, 25, and 10 minutes prior to CT
Both groups of patients received IV glucagon immediately prior to a
contrast-enhanced CT scan. Luminal distention was similar between
the two groups of patients.
Additionally, the accuracy of both techniques was between 80% and
90% for detecting active Crohn's disease in the neoterminal ileum,
compared with ileoscopy, which served as the gold standard.
Small-bowel follow-through in these patients had an accuracy of
74%. CT enterography identified more fistulas and more abscesses
than small-bowel follow-through, and was equally sensitive in
identifying partial small-bowel obstruction. The volume challenge
of enterography improves the sensitivity of MR or CT for partial
obstruction as well as active inflammation. In addition,
cross-sectional imaging provides direct visualization of loops deep
in the pelvis, which are often difficult to evaluate
Findings at CT and MR enterography are as previously described
with MR and CT, except they are more conspicuous. Additionally, the
jejunal and ileal fold patterns are demonstrated in the distended
small bowel (Figure 12). Jejunal loops can sometimes falsely appear
thickened due to a combination of prominent valvulae conniventes
and peristalsis. When a question arises, a delayed scan through the
region of interest usually resolves any concerns.
We now offer CT enterography as a routine clinical test. Scanner
room time is the same as a standard CT of the abdomen and pelvis,
but patients arrive 90 minutes early to begin oral hydration. We
believe that CT enterography works well in Crohn's patients because
there is a degree of intrinsic obstruction due to bowel
inflammation, and we observe, anecdotally, that the small bowel is
not as well distended in some normal patients without any
underlying bowel obstruction or inflammation. Multiple
investigators are examining the use of additives, osmotic agents,
and/or nonabsorbable fluids as oral agents for MR and CT
We believe these new oral agents will greatly aid the assessment of
Crohn's disease and other small-bowel pathologies in the future
Crohn's disease develops as a result of genetic susceptibility
and gut-flora interactions. These factors lead to an exaggerated
inflammatory response by the host immune system. Targeted
biological therapies, such as infliximab, are now used to treat
many patients who would previously have gone to surgery. The role
of the radiologist is to identify medically treatable disease, as
well as complications that will require surgical intervention. The
optimization of radiologic studies tailored to the clinical
question (eg, cross-sectional enterography for imaging of the small
bowel, and MR with phased-array coil for the imaging of perianal
disease), allows radiologists to detect active disease and its
complications with a high degree of accuracy. Understanding the
pathophysiology of Crohn's and modern treatments will help
radiologists assist clinicians in treating these patients, who
often present with protean and nonspecific symptoms.