Today we are presenting
a lecture on Crohn's disease.
The learning objectives of today
is to first understand
the epidemiology
and pathophysiology
of Crohn's disease,
and to develop the ability
to recognize the manifestations
of Crohn's disease clinically,
learn about how to diagnose
Crohn's, be able to identify
the histological features
for Crohn's.
At the end of the presentation,
the student should have
a general idea
of the different methods
to classify the disease
and its severity, and at
the same time,
understand
the possible complications
of the disease.
The student should have
a brief understanding
of the possible treatment
options available.
Epidemiology.
Within Europe and North America,
there seems to be a north
to south gradient
in the frequency of Inflammatory
Bowel Disease, or IBD.
The highest incidence
is
observed in temperate climates
and more industrialized
parts of the world,
such as Western Europe and North
America.
In most
Western European countries,
the incidence has stabilized,
averaging 7 per 100,000 persons,
while the incidence
in Asian countries
seem to be significantly lower.
The age of onset is bimodally
distributed with the first peak
being at 15 to 30 years old,
while the second peak is usually
women at around 60 to 70 years
old.
The frequencies of IBD
is similar in both genders.
Frequency, however,
in the pediatric population
is reversed, where there's
a higher incidence in boys.
Pathophysiology of Crohn's
disease.
Crohn's disease
is a lifelong disease observed
primarily in the developed
countries.
It arises
from a complex interaction
between genetic and disturbances
of physiologic environment
and pathways,
as well as
environmental factors.
In the genetics of Crohn's
disease, a mutation in the NOD2
or CARD15 gene,
which is produced by the Paneth
cells
in the base
of the intestinal crypts,
causes
a defective sensing
intracellular bacteria resulting
in reduced production
of defensins.
A mutation in the ATG16L1
autophagy gene also causes
a decrease in exocytosis
of secretory
granules in Paneth cells,
thereby decreasing
crypt concentrations
of defensins,
lysozymes, phospholipase A2.
A major component
in the pathophysiology
of Crohn's disease
consists of host's
immune response dysregulation.
Mucosal defense mechanisms
include mucus-coated epithelium
with tight junctions, IgA
secretion, and defensins.
There is
a dysregulated proinflammatory
response and overly aggressive
acquired T cell immune response
to commensal gut bacteria
that develop in genetically
susceptible hosts.
Defense mechanisms depressed,
leading
to uncontrolled microbial
proliferation and K kappa B
dependent genes stimulated
to produce proinflammatory
cytokines, such as TNF-alpha,
interleukin 1 and 6,
chemokine, and interleukin-8.
Cytokine and chemokine
production attract T cell
infiltration, mainly T helper
1 cells amplifying
inflammatory response.
Environmental factors are known
to have an effect on Crohn's
disease.
These include smoking, which has
been shown to double this risk
of Crohn's.
Crohn's may also improve when
changed to a liquid diet.
And fatty foods exacerbate
Crohn's.
Bacterial infections by E. coli,
mycobacterium paratuberculosis,
and measles virus.
And drugs, such as oral
contraceptive pills, NSAIDs, has
been shown to affect Crohn's.
The clinical presentation
of Crohn's disease.
The symptoms of Crohn's disease
are
heterogeneous and non-specific,
but more commonly includes
diarrhea for more than six
weeks.
Weight loss and abdominal pain
is also seen in about 60% to 70%
of the population suffering from
Crohn's.
While blood or mucus
in the stools
can be seen in up to 40% to 50%
of the patients.
Abnormalities of the
musculoskeletal system are
the most common manifestations
of Crohn's.
Because Crohn's is such
a heterogeneous disease,
it's a major challenge
in the field
of clinical investigation
to determine and classify
the disease
into distinct subsets
of patients.
Therefore, in 2005,
a new revision of the Vienna
Classification Scheme
in Montreal was proposed
to allow for a more accurate
disease characterization.
The Montreal classification used
parameters such as age
at diagnosis, location,
and behavior to characterize
the disease so
that the appropriate treatment
can be optimized.
It's important for practicing
clinicians in clinical decision
making,
such as when to start
immunomodulators.
Differential diagnosis
for Crohn's disease.
There are conditions that can
mimic Crohn's colitis.
And they can be divided
into infective and non-infective
differentials.
I'd like to also point out
that tuberculosis infection
would be one
of the top differentials
in Singapore.
In tuberculosis infection
of the colon, granulomas can
also be present.
And it can be
difficult to differentiate
between the two.
The diagnosis of Crohn's
disease.
Because Crohn's disease
comprises of a variety
of complex phenotypes
in terms of age, disease
location, and behavior,
therefore, a combination
of evaluation methods is used.
The diagnosis of Crohn's can be
broadly classified
into macroscopically
or microscopically.
Macroscopic investigations
include clinical endoscopic and
radiological investigations.
Under clinical evaluation,
one should take a full history,
including asking about onset
of symptoms, recent travel, food
intolerances, medication,
including antibiotics and NSAID,
and history of appendectomy.
Also ask about proven risk
factors such as smoking, family
history,
and recent infectious
gastroenteritis, and also
nocturnal symptoms,
other extraintestinal
manifestations involving
the mouth, skin, eye, or joints.
Episodes of perianal abscess
or anal fissure
is appropriate as well.
A general physical examination
should be performed
and also looking out
for abdominal tenderness
or distention, palpable masses.
Perineal or oral inspection,
and rectal digital examination
should be performed.
Measurement of body weight
and calculation of body mass
index are recommended.
Endoscopic features, looking out
for discontinuous involvement
or skip lesions, anal lesions,
cobblestoning, and strictures.
Multiple biopsies, at least two,
from five sites
around the colon,
including rectum and ileum,
should be obtained
for proper diagnosis.
Radiological investigations,
such as CT or MRI,
are
of similar diagnostic accuracy
for small intestine inflammatory
lesions.
MR and CT
enterography or enteroclysis
is an imaging technique
with the highest
diagnostic accuracy
for the detection
of intestinal involvement
and penetrating lesions
in Crohn's used to establish
disease extension and activity
based on wall thickness
and increased IV contrast
enhancement.
Other imaging techniques include
abdominal ultrasound,
leukocyte scintigraphy,
small bowel capsule endoscopy,
and double-balloon enteroscopy.
Biochemical investigations,
looking out for anemia,
thrombocytosis,
and hypoalbuminemia.
There might also
be electrolyte abnormalities.
One should also do liver
function tests, looking out
for raised alkaline phosphatase
and gamma glutamyl transferase
levels.
Raised CRP of protein
or erythrocite sedimentation
rate are some of the common
changes in the blood work
of patients with Crohn's.
Histological features
for diagnosis of Crohn's.
Microscopically, the features
include transmural inflammation
with multiple lymphoid
aggregates, chronic inflammation
areas with increased lamina
propria plasma cells
and lymphocytes,
submucosal thickening,
neuromuscular hyperplasia
of the submucosa,
crypt irregularity
with crypt loss, abscess,
architectural distortion.
Skip lesions comprising
of focal patch erosions
or ulcers, vertical fissures,
and fistulas.
Sarcoid granuloma, including
in lymph nodes
that are non-necrotizing
well-circumscribed groups
of epithelioid histocytes,
with or without accompanying
giant cells of the Langerhan
type, and fissures.
Complications of Crohn's
disease.
Since Crohn's is
a systemic disease
and can cause
many different kinds
of complications
with varying severities,
not everyone with Crohn's
disease will experience
these complications.
However, early recognition
and prompt treatment is key.
The intestinal complications
tend to occur when
the intestinal inflammation is
severe, widespread, chronic,
and transmural.
They are anal and perianal
complications.
Undernutrition, short bowel
syndrome, increased risk
of colorectal carcinoma,
intra-abdominal abscess.
Extraintestinal complications
are illustrated
in the following picture.
And they can be divided
into either occurring
during the active phase, whereby
you have complications
such as erythema nodosum,
pyoderma gangrenosum,
episcleritis and uveitis,
and arthropathy.
Or unrelated
to inflammatory bowel disease
activities, such as sclerosing
cholangitis, ankylosing
spondylitis, and osteoporosis.
In order to describe
the different classification
of disease severity
for research purposes,
an arbitrary numerical figure
known as the Crohn's Disease
Activity Index, or CDAI,
is used.
Different treatments are
recommended at different grades
of severity.
In the treatment of Crohn's
disease,
there are many modalities
of treatments available.
However, the management plan
should take into account
the activity site and behavior
of the disease, which should
always been discussed
with the patient.
The appropriate choice
of medication is often a balance
between the drug potency
and potential side effects,
previous response to treatment
for refractory disease,
and also the presence
of extraintestinal manifestation
or complications.
Different drug preparations
can be released
at different sites
and can have local focus
activity.
Therefore, the treatment
administered to the patient
is always best tailored
to the individual patient's
severity and pattern of disease.
The details
of different medications
for different severity
and involvement
is out of the scope
of this presentation.
One can see that it is
the multi-disciplinary approach,
involving dietary changes,
nutritional and pharmaceutical
therapies.
It's also important to note that
surgery does play an important
part in the treatment
of Crohn's.
However, surgery is often
the treatment of last resort
as it carries implicit risk
and entails higher risk
of septic complications.
In summary, Crohn's is
a lifelong disease.
But early intervention
and intensive therapy
appears to improve healing
and sustain remission
of the disease.
It is therefore
important to clinically
recognize
the nonspecific symptoms
of Crohn's and utilize
the appropriate investigative
modalities to secure
a diagnosis.
It is also important
that the disease is
appropriately classified
in terms of behavior
and severity,
allowing optimal therapy to be
administered.
Management of Crohn's requires
a multi-disciplinary approach
involving medical, therapy,
surgical and non-pharmacological
interventions,
as well as social support.
It's therefore critical
that the management of Crohn's
is individually tailored
and closely discussed
with the patient.
Here are some key references.
