Definition

Crohn's disease (CD) is a disorder of unknown aetiology characterised by transmural inflammation of the
GI tract. CD may involve any or all parts of the entire GI tract from mouth to perianal area, although it is
usually seen in the terminal ileal and perianal locations. Unlike ulcerative colitis (UC), CD is characterised
by skip lesions (where normal bowel mucosa is found between diseased areas). The transmural
inflammation often leads to fibrosis causing intestinal obstruction. The inflammation can also result in
sinus tracts that burrow through and penetrate the serosa, thereafter giving rise to perforations and
fistulae.

Epidemiology

The incidence of CD in the US is 6 to 7 per 100,000 people. It is estimated that there are around 500,000
to 1 million people affected with inflammatory bowel disease in the US. [2] [8]

A European Commission-funded study of 20 European centres showed that the overall incidence per
100,000 at ages 15 to 64 years (standardised for age and sex) of CD was 5.6. Rates of CD in northern
centres were 80% higher than those in the south (rate ratio [RR] = 1.8). For CD the highest reported
incidence was in Maastricht (the Netherlands; 9.2) and Amiens (north-west France; 9.2). The lowest
incidence of CD was in Ioannina (north-west Greece; 0.9). [9]

The highest incidence of CD is in northern climates and in developed countries, and the lowest in
southern climates and less developed areas. The incidence and prevalence seem to be lower in Asia,
Japan, and South America. A rise in the incidence of CD has been consistently observed over the last 60
years. [10] The incidence is now approximately equivalent to that of ulcerative colitis (UC) in North
America and Europe. [1] [11]

The peak age of onset is between 15 and 40 years, and there is a smaller second peak between 60 and
80 years. CD is equally prevalent among men and women. It is more common in white people and
Ashkenazi Jews. Some studies have shown a higher prevalence among smokers.

Aetiology

The aetiology of CD remains unclear, with various studies suggesting a role for genetic and
environmental factors.

1. Genetic factors [13]

Genome-wide association (GWA) studies have identified over 71 different genetic susceptibility
loci, with the strongest associations being between CARD15 (caspase recruitment domain family,
member 15), which encodes the NOD2 (nucleotide-binding oligomerisation domain containing
2) pathogen recognition protein, and other loci, such as the IBD5 locus, the autophagy gene
ATG16L1 (ATG16 autophagy 16-like 1), and the interleukin-23 receptor. [14] [15]
 However, current research suggests that vital genetic clues have been missed, with all the genes
identified to date accounting for <20% of the total heritable risk for CD. This is supported by the
fact that the disease-associated loci appear to have a low penetrance and a relatively high
frequency in the general population. [16]

2. Environmental factors

Include: smoking, oral contraceptive pill, diet high in refined sugar, nutritional deficiencies
(especially zinc), and infectious agents (measles virus, and a possible association
with Mycobacterium avium paratuberculosis). [17] [18]

Some studies have indicated a possible role of NSAIDs in the development of CD. [19] [20]

Correlation between acute gastroenteritis and subsequent risk of CD has also been suggested.

Pathophysiology

Current theories about the pathophysiology of CD indicate a role for infectious, immunological,
environmental, dietary, and psychosocial factors in a genetically and immunologically susceptible person.
[13] [17] [18] [21] [22] [23]

The initial lesion starts as an inflammatory infiltrate around intestinal crypts that subsequently develops
into ulceration of the superficial mucosa. The inflammation progresses to involve deeper layers and
forms non-caseating granulomas. These granulomas involve all layers of the intestinal wall and the
mesentery and regional lymph nodes. The finding of these granulomas is highly suggestive of CD, yet
their absence does not exclude the diagnosis. [24] [25]

Early endoscopic findings include hyperaemia and oedema of the inflamed mucosa. This progresses to
discrete deep superficial ulcers located transversely and longitudinally, creating a cobblestone
appearance.View imageView image These lesions are separated by healthy areas known as skip lesions.
[4]

Acute transmural inflammation results in bowel obstruction due to mucosal oedema associated with
spasm. Chronic transmural inflammation thickens the bowel wall and leads to scarring, luminal
narrowing, and stricture formation. This may lead to fistulisation, sinus tract formation, perforation,
and/or abscess formation. Chronic inflammation also damages the intestinal mucosa, resulting in
deficient absorptive ability. This can lead to malnutrition, dehydration, and vitamin and nutrient
deficiencies. Involvement of the terminal ileum interferes with bile acid absorption, which leads to
steatorrhoea, fat-soluble vitamin deficiency, and gallstone formation. Excessive fat in the stool binds to
calcium, thereby increasing oxalate absorption and predisposing to oxalate kidney stone formation. [1]
[4] [22] [26] [27] [28]

In addition to manifestations related to the GI tract, CD may involve multiple extra-intestinal organs and
systems including skin, joints, mouth, eyes, liver, and bile ducts. Some of these disorders have
autoimmune mechanisms.
Classification

Vienna classification of CD [3]

Classifies patients with CD into 24 subgroups. Mostly used for research purposes.

1. Age at diagnosis - when first definitively established by radiology, endoscopy, pathology, or

surgery.

o A1 <40 years of age.

o A2 40 years of age or more.

2. Location - maximum extent of disease involvement at any time before the first resection.
Minimum involvement for a location is aphthous lesion or ulceration. Both small- and large-
bowel examination is required for classification.

o L1 - terminal ileum - limited to terminal ileum, with or without spill-over into the
caecum.

o L2 - colon - any colonic location between the caecum and rectum, with no small bowel
or upper GI involvement.

o L3 - ileocolonic - disease of ileum and any location between the ascending colon and
rectum.

o L4 - upper GI - any disease proximal to the terminal ileum (excluding mouth), regardless
of additional involvement of the terminal ileum or colon.

3. Behaviour

o B1 - non-stricturing, non-penetrating.

o B2 - stricturing - constant luminal narrowing demonstrated by radiological, endoscopic,

or surgical-pathological methods, with pre-stenotic dilation or obstructive
signs/symptoms, without the presence of penetrating disease, at any time in the course
of the disease.

o B3 - penetrating - occurrence of intra-abdominal or perianal fistulae, inflammatory

masses, and/or abscesses at any time in the course of the disease. Perianal ulcers are
included. Postoperative intra-abdominal complications and skin tags are excluded.

Secondary prevention

Smoking cessation is the only lifestyle modification shown to have an effect on the prevention of
recurrence in CD. [C Evidence]

Although there is no consensus on guidelines for colorectal cancer screening in patients with CD, it is
widely accepted to perform surveillance colonoscopy every 1 to 2 years, starting at 8 years after
establishing the diagnosis of pancolitis and 15 years in the case of left-sided colitis.
History & examination

Key diagnostic factors

presence of risk factors (common)

Key risk factors include white ethnicity, FHx of CD, and age 15 to 40 years or 60 to 80 years.

abdominal pain (common)

May be cramp or constant pain.

Right lower quadrant and peri-umbilical regions are common locations if ileitis present. May be
partially relieved by defecation.

Crohn's colitis produces diffuse abdominal pain, which may be accompanied by mucus, blood,
and pus in the stool.

prolonged diarrhoea (common)

Non-bloody or bloody intermittent diarrhoea are common complaints in CD.

Nocturnal diarrhoea may occur.

perianal lesions (common)

Up to 20% to 30% of patients with CD may have perianal lesions including skin tags, fistulae,
abscesses, scarring, or sinuses.

Other diagnostic factorshide all

bowel obstruction (common)

Caused by acute inflammatory oedema and spasm of the bowel or chronic scarring and stricture.

Manifests as bloating, distension, cramping abdominal pains, loud borborygmi, vomiting,

constipation, and obstipation.

blood in stools (common)

Guaiac-positive stools are common in CD.

Gross bleeding is more common in Crohn's colitis.

fever (common)

Induced by the inflammation of CD or a complication such as perforation, abscess, or fistula.

fatigue (common)

Caused by malnutrition, weight loss, and inflammation.

abdominal tenderness (common)

 Abdominal tenderness is a common manifestation of CD. It may be secondary to inflammation,
localised collections, strictures causing small bowel or more rarely colonic obstruction, or
proximal constipation. Terminal ileal inflammation may present with localised right lower
quadrant pain and tenderness.

weight loss (uncommon)

Failure to thrive is common in children and may be a very early manifestation of the disease. This
is a result of intentional avoidance of food to relieve pain in the obstructing segments of
inflamed bowel.

Malabsorption is a later cause of poor nutritional status.

oral lesions (uncommon)

Patients with CD may have oral involvement with recurrent aphthous ulcers and pain in the
mouth and gums.

abdominal mass (uncommon)

Terminal ileal inflammation may present as a tender mass in the right lower quadrant.

Proximal constipation may also be palpable as irregular stool mass on abdominal examination.

extra-intestinal manifestations (e.g., erythema nodosum or pyoderma gangrenosum) (uncommon)

Extra-intestinal manifestations occur in 20% to 40% of patients with CD.[45]

Manifestations may include symptoms and signs of arthropathy, cutaneous lesions (e.g.,
erythema nodosum, View image pyoderma gangrenosum), and ocular symptoms and signs (e.g.,
of uveitis orepiscleritis).

Risk factors

Strong

white ancestry

CD is more common in white than in black or Asian people. Ashkenazi Jews have a 2- to 4-fold
increased risk of CD. [1] [2]

age 15-40 or 60-80 years

Most patients develop symptoms of CD before the age of 40 years. Bimodal age distribution for
onset: first peak between 15 and 40 years and second between 60 and 80 years. [2]

FHx of CD

Around 10% to 25% of affected patients have a first-degree relative with CD. [13] [17]

Weak
cigarette smoking

Smokers are more than twice as likely to develop the disease as non-smokers. [12] [29] This is in
contrast to ulcerative colitis, in which smoking reduces the risk of developing the disease by up
to 40%. [30] [31]

diet high in refined sugar

Linked with increased incidence in some studies. [1] [17]

oral contraceptive pill

Women taking oral contraceptive pill were 1.7 times more likely to develop CD than those not
taking it. [21]

not breastfed

Children with CD were 3 to 4 times less likely to have been breastfed. [32]

NSAIDS

Have been shown to increase risk of CD in some studies.

Diagnostic investigations

1st investigations to order

Test

FBC

Anaemia can be due to chronic inflammation, chronic blood loss, iron malabsorption, and/or malabsorption of vitamin
folic acid.

Leukocytosis is associated with acute or chronic inflammation, abscess, or corticosteroid treatment.

Thrombocytosis is a useful marker of active inflammation.

iron studies (serum iron, serum ferritin, total iron binding capacity [TIBC], transferrin saturation)

Iron deficiency may be associated with GI bleeding or malabsorption of iron.

serum vitamin B12

Deficiency may be secondary to malabsorption.

Deficiency most common in ileocaecal CD and post-ileocaecal resection.

serum folate
Deficiency may be secondary to malabsorption.

comprehensive metabolic panel (CMP)

These findings are associated with chronic or severe disease. In addition, hypomagnesaemia and hypophosphataemia
caused by diarrhoea and hypoprothrombinaemia may reflect vitamin K deficiency.

C-reactive protein (CRP) and ESR

Inflammatory markers correlate closely with the activity of CD. [46]

stool testing

Testing for Clostridium difficile toxin is indicated especially if history of recent antibiotic use.

Yersinia enterocolitica serology

Important to exclude Y enterocolitica, a bowel pathogen that causes an acute ileitis.

plain abdominal films

Suggestive of the diagnosis of CD and useful to assess severity.

CT abdomen

Helps in localisation of the disease and diagnosing fistulae, abscesses, and other extra-mural complications. [33] [34]
imageView image

MRI abdomen/pelvis

Superior to CT scanning in demonstrating pelvic lesions.

Used when CT with intravenous contrast is contraindicated.

Also has an emerging role in staging disease activity. [47]

Differential diagnosis

Condition Differentiating s

Ulcerative colitis (UC) UC prese

abdomin

Does no
disease.

Infectious colitis History o

Pseudomembranous History o
colitis
Caution
conditio
flare-up

Ischaemic colitis Physical

correlate

Most pa
diseases
hypoten

Radiation colitis History o

Symptom
chronic

Yersinia enterocolitica Y entero

picture r

Amoebiasis Amoebia

Recent t

Cytomegalovirus colitis Immuno

Condition Differentiating signs/symptoms Differentiating investigation

have received solid organ transplant, patients on long- Classic histological fi

term immunosuppressants, or patients with HIV pleomorphic nuclei
infection / AIDS.

Colorectal cancer Increased risk associated with increasing age and a CT scan may show p
positive FHx.
Colonoscopy provid

Diverticular disease Commonly presents with left-sided abdominal pain in CT scan shows evide
patients aged 50 years and older.

Acute appendicitis Younger patients. CT scan showing infl

Pain may start in the peri-umbilical area, with

subsequent localisation to the right lower quadrant.

Ectopic pregnancy All acute presentations with abdominal pain in women Urine and or serum
of childbearing age should be considered to be due to
Pelvic ultrasound m
an ectopic pregnancy until proven otherwise.
If rupture is suspect
May be a history of amenorrhoea, known positive
and surgery is requi
pregnancy test, vaginal bleeding.

Pelvic inflammatory Vaginal discharge, dyspareunia, and pelvic pain. Pelvic ultrasonograp
disease evaluation is neede

Endometriosis Patients usually have cyclical symptoms starting with Laparoscopy demon
the menses.

Irritable bowel Chronic change in stool frequency, form, or appearance. Screening blood tes
syndrome Commonly associated with abdominal bloating and
Biopsy does not sho
passing mucus per rectum.
Faecal calprotectin m
Spasmodic abdominal pain is often relived by
distinguish a higher
defecation.
evaluation. [41]
CD should be suspected if symptoms are progressive or
include bloody or nocturnal diarrhoea.