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Inflammatory Bowel Disease 103
Host immune response
• IBD results from a defective mucosal immune system producing an
abnormal response to luminal antigens such as bacteria which enter the
intestine via a leaky epithelium.
• In the genetically predisposed individual, there is an exaggerated
immune response with effector T cells (T helper (Th)1, Th2 and Th17)
predominating over regulatory T cells.
• Pro-inflammatory cytokines (interleukin (IL)-12, interferon (IFN)-γ, IL-5,
IL-17) released by these activated T cells stimulate macrophages to
produce tumour necrosis factor (TNF)-α, IL-1 and IL-6.
• There is also activation of other cells (neutrophils, mast cells and
eosinophils) that together lead to increased production of a wide variety
of inflammatory mediators, all of which can lead to cell damage.
Pathology
CD and UC have some overlapping clinical and pathological features but also
key differences at macroscopic and microscopic levels (Table 3.8).
Clinical features
Crohn’s disease
Symptoms depend on the region(s) of involved bowel, with the commonest
site being the ileocaecal region in 40% of patients. Small bowel disease
Table 3.8 Differences between Crohn’s disease and ulcerative
colitis
Crohn’s disease Ulcerative colitis
Macroscopic
Microscopic
Affects any part of
gastrointestinal tract
Oral and perianal disease
Discontinuous involvement
(‘skip lesions’)
Deep ulcers and fissures
in mucosa: ‘cobblestone
appearance’
Transmural inflammation
Granulomas present in 50%
Affects only the colon
Begins in rectum and extends
proximally in varying degrees
Continuous involvement
Red mucosa, bleeds easily
Ulcers and pseudopolyps
(regenerating mucosa) in
severe disease
Mucosal inflammation
No granulomata
Goblet cell depletion
Crypt abscesses
104 Gastroenterology and nutrition
causes abdominal pain, usually with weight loss. Less commonly, terminal
ileal disease presents as an acute abdomen with right iliac fossa pain mimicking appendicitis. Colonic disease presents with diarrhoea, bleeding and
pain related to defecation. In perianal disease there are anal tags, fissures,
fistulae and abscess formation.
Ulcerative colitis
Diarrhoea is the predominant symptom, often containing blood and mucus.
The clinical course may be one of persistent diarrhoea, relapses and remissions or severe fulminant colitis (Table 3.9). Patients with IBD may also have
one or more extraintestinal manifestations (Table 3.10).
Table 3.9 Ulcerative colitis severity index
Mild Severe
Bloody diarrhoea
Fever
Tachycardia
Erythrocyte sedimentation rate
Anaemia
Serum albumin
Severe colitis requires bloody diarrhoea plus any one of the systemic features. Moderate
colitis lies between these two definitions.
<4 per day
Absent
Absent
<20 mm/h
Absent
Normal
>6 per day
>37.5°C
>90/min
>30 mm/h
Hb <100 g/L
<30 g/L
Table 3.10 Extragastrointestinal manifestations of inflammatory
bowel disease
Eyes Uveitis, episcleritis, conjunctivitis
Joints Arthralgia*, small joint arthritis, monoarticular arthritis
Skin Erythema nodosum, pyoderma gangrenosum (necro-
Hepatobiliary Fatty liver*, sclerosing cholangitis, chronic hepatitis,
Renal calculi Oxalate stones in patients with small bowel disease
Venous thrombosis
All uncommon, occur in less than 10% of patients other than those marked*.
(knees and ankles), ankylosing spondylitis, inflammatory back pain
tizing ulceration of the skin, commonly on lower legs)
cirrhosis, gallstones*
or after resection
Inflammatory Bowel Disease 105
Investigations
The purpose of investigations is to establish the diagnosis of IBD with differentiation between CD and UC, to define the extent and severity of bowel
involvement, identify any extraintestinal manifestations and exclude other
diseases that may present similarly.
Blood tests Anaemia is common and may be normochromic, normocytic
anaemia of chronic disease or due to deficiency of iron, vitamin B12 or folate.
The platelet count, erythrocyte sedimentation rate (ESR) and C-reactive
protein (CRP) are often raised in acute CD, and the serum albumin is low in
severe disease. Liver biochemistry may be abnormal, related to associated
liver disease.
Stool tests Stool cultures, including C. difficile toxin assay, should always
be performed if diarrhoea is present. Microscopy for parasites is essential in
patients with a relevant travel history. Faecal calprotectin and lactoferrin are
raised in active intestinal disease. Faecal calprotectin is useful for disease
monitoring in IBD.
Radiology and imaging
Plain abdominal X-ray should be performed in all patients admitted
to hospital with acute severe colitis. It helps to assess extent of colonic
involvement and identifies toxic dilatation of the colon.
Ultrasonography is helpful in delineating abdominal and pelvic abscesses
and will show thickened bowel in involved areas. Abdominal CT scanning is
also used in patients with suspected abscesses.
Rigid or flexible sigmoidoscopy will establish the diagnosis of UC and
CD (if the rectum and/or sigmoid colon is involved). A rectal biopsy is taken
for histological examination to determine the nature of the inflammation.
Colonoscopy allows the exact extent and severity of colonic and terminal
ileal inflammation to be determined and biopsies to be taken.
Small bowel imaging is performed to determine the extent of small
bowel involvement with CD. Specific imaging type depends on local expertise
and includes small bowel barium follow-through or MR enteroclysis with oral
contrast. Affected bowel shows an asymmetrical alteration in the mucosal
pattern, with deep ulceration and areas of narrowing (‘string sign’) commonly
confined to the ileum. Skip lesions may be seen. Video capsule endoscopy is
increasingly used to detect small bowel disease and is more sensitive than a
barium follow-through. It is contraindicated in stricturing disease.
Perianal CD is usually assessed by MRI and sometimes by endoanal
ultrasound.
Radiolabelled white cell scanning is a safe, non-invasive investigation.
It helps to identify small bowel and colonic disease but lacks specificity.
Differential diagnosis
CD must be differentiated from other causes of chronic diarrhoea, malabsorption and malnutrition. In children it is a cause of short stature. Other
106 Gastroenterology and nutrition
causes of terminal ileitis are tuberculosis and Yersinia enterocolitica infection
(causing an acute illness). IBD affecting the colon must be differentiated from
other causes of colitis: infection, ischaemia, radiation and microscopic colitis.
Management
Medical
The aim of treatment is to induce and maintain a remission. Patients with
CD who smoke should be advised to stop with help offered to achieve this.
Therapy for IBD is a rapidly evolving field. In general the treatments used
have many anti-inflammatory and immunosuppressive properties combined
with an antibacterial action in some cases (e.g. metronidazole).
Induction of remission Treatment of CD depends on the site and
severity of disease and also if the disease is stricturing or fistulating:
• Oral 5-aminosalicylic acid (5-ASA) is less efficacious than in UC and is
used in mild disease only. It is generally well tolerated. Rare potentially
serious side effects are bloody diarrhoea (resembling acute colitis),
Stevens–Johnson syndrome, acute pancreatitis and renal impairment.
• Steroids: Oral prednisolone (40 mg/day) is used to induce remission in
moderate/severe disease. It is reduced gradually according to severity
and patient response. Mild to moderate disease should be treated with
budesonide, which has reduced systemic availability and is associated
with a lower frequency and intensity of steroidal side effects.
• Liquid enteral nutrition with an elemental (liquid preparation of amino
acids, glucose and fatty acids) or polymeric diet induces a remission
in active CD. The exact mode of action is not known. These diets are
unpalatable and may have to be given via a nasogastric tube.
Patients with symptoms that do not respond to conventional therapy
should be re-assessed to exclude an alternative diagnosis such as a stricture
or penetrating abscess. In patients with disease limited to the terminal ileum,
surgical resection may be appropriate.
Maintenance of remission The goal of maintenance therapy is to
prevent disease progression, as well as to reduce the need for corticosteroids,
which are associated with a high burden of side effects. Therapies that
induce mucosal healing result in better outcomes. All maintenance therapies
require careful monitoring to ensure optimal disease control and prevent side
effects. If there is ongoing evidence of disease activity, adherence should be
confirmed and dose optimization or therapy escalation undertaken.
• The thiopurine drugs, azathioprine or its metabolite 6-mercaptopurine,
are used to maintain a remission and are given to patients who require
two or more corticosteroid courses per year. Major side effects are bone
marrow suppression (neutropenia, thrombocytopenia and anaemia), acute
pancreatitis and allergic reactions. The enzyme thiopurine methyltransferase
(TPMT) is essential in metabolism of thiopurines and activity should be
measured on a blood sample before treatment is given. Approximately
Inflammatory Bowel Disease 107
1 in 300 patients have absent TPMT activity and will not metabolize the
drug. These patients are at high risk for pancytopenia and treatment is
contraindicated. About 10% of patients have reduced TMPT activity and a
lower drug dose is indicated (a half to one-third of normal dosing).
• Metronidazole is useful in severe perianal CD as a result of both its
antibacterial and immunosuppressive action.
• Methotrexate (intramuscular) is used in a minority of patients with
active CD that is resistant to conventional treatment with steroids. It is
also used to maintain a remission in those refractory or intolerant to
azathioprine/6-mercaptopurine.
• Anti-TNF antibodies (infliximab, adalimumab, certolizumab) are used
to induce a remission in patients resistant to corticosteroids/
immunosuppressives. Scheduled treatment at 8-weekly intervals is
thengiven to maintain a remission.
• Novel biological therapies (e.g. vedolizumab, ustekinumab, risankizumab)
are reserved for moderately to severely active Crohn’s disease who are
intolerant to an anti-TNF or in whom it is contraindicated, or in those
patients who have had an inadequate response or lost response to an
anti-TNF agent.
Treatment of UC depends on severity (see Table 3.9) and distribution of
disease (Table 3.11). The management of acute, severe UC is summarized in
Emergency Box 3.2.
Table 3.11 Summary of treatments used in ulcerative colitis
Disease
severity
Mild/moderate
Severe
Severe with
systemic
features
Maintain
remission
5-ASA, 5-Aminosalicylic acid; left-sided disease, up to splenic flexure; proctitis, rectal
inflammation.
Medication Indications
Oral 5-ASA
Rectal 5-ASA/
First line for left-sided/extensive
For proctitis or proctosigmoiditis
steroids
Oral prednisolone
Second line, if inadequate response
to 5-ASA
Oral prednisolone
Hydrocortisone
See Emergency Box 3.2
Ciclosporin
Infliximab
5-ASA
Most patients require maintenance
treatment
Azathioprine/6mercaptopurine
For patients who relapse frequently
despite ASA or are ASA-intolerant
108 Gastroenterology and nutrition
Emergency Box 3.2 Management of acute severe colitis
Admit to hospital
• Joint inpatient management between gastroenterologist and colorectal surgeon
Investigations
• FBC, CRP, liver biochemistry, serum albumin and electrolytes
• Blood cultures (Gram-negative sepsis occurs)
• Plain abdominal X-ray looking for colonic dilatation (transverse colon
diameter >5 cm), and mucosal islands
• Stool cultures (× 3) and C. difficile toxin to exclude coincidental infection
(do not delay steroids while awaiting result)
Treatment
• Stop drugs that may precipitate colonic dilatation (anticholinergics,
antidiarrhoeals, non-steroidal anti-inflammatory drugs, opioids)
• i.v. hydrocortisone 100 mg 6-hourly
• Correct electrolyte and fluid imbalance
• Low molecular weight heparin to reduce the risk of venous thrombosis
• Consider i.v. ciclosporin (2 mg/kg over 24 hours) or infliximab if no
response after 4 days of i.v. hydrocortisone. Colectomy may be necessary.
Monitor
• Stool chart: frequency, type and presence of blood
• Vital signs at least four times daily
• Daily bloods and abdominal X-ray if admitting film abnormal
Surgery
In CD and UC, surgery is indicated for:
• Failure of medical therapy with acute or chronic symptoms producing ill
health
• Complications (Table 3.12)
• Failure to grow in children despite medical treatment.
Resections are kept to a minimum in CD as recurrence is almost
inevitable in the remaining bowel. In some patients with small bowel disease,
strictures can be widened (stricturoplasty) without resection.
The surgical options in UC are:
• Colectomy with ileoanal anastomosis: the terminal ileum is used to
form a reservoir (a ‘pouch’), and the patient is continent with a few
bowel motions per day. The pouch may become inflamed (‘pouchitis’),
leading to bloody diarrhoea which is treated initially with metronidazole.
Probiotics (live microorganisms that modify composition of enteric
bacteria) are sometimes used to prevent and treat pouchitis.
• Panproctocolectomy with ileostomy: the whole colon and rectum are
removed and the ileum brought out on to the abdominal wall as a stoma.
Inflammatory Bowel Disease 109
Table 3.12 Complications of inflammatory bowel disease
Toxic dilatation of the colon + perforation
Stricture formation*
Abscess formation (Crohn’s disease)
Fistulae and fissures (Crohn’s disease)*
Colon cancer
*Surgical intervention only necessary if symptomatic and not responding to medical
treatment.
Cancer in inflammatory bowel disease
Extensive UC and Crohn’s colitis of more than 10 years’ duration is associated with an increased risk of colorectal cancer (CRC, cumulative risk 12%
after 25 years). Patients with colitis should undergo colonoscopy at 10
years from diagnosis and an assessment of cancer risk is made. High-risk
patients (extensive colitis with moderate/severe activity, primary sclerosing cholangitis or family history of CRC in first-degree relative <50 years)
are offered a further colonoscopy and multiple colonic biopsies (to look for
dysplasia) 1 year later. Lower-risk patients undergo colonoscopy 3–5 years
later. Colectomy is recommended if high-grade dysplasia is discovered and
increased surveillance (6–12 monthly) with low-grade dysplasia.
Prognosis
Both diseases are characterized by relapses and remissions. Almost all
patients with CD have a significant relapse over a 20-year period. The
prognosis of UC is variable. Only 10% of patients with proctitis develop more
extensive disease, but with severe fulminant disease there is a risk of colonic
perforation and death.
Microscopic colitis
The colonic mucosa looks normal at endoscopy but histological examination of mucosal biopsies shows lamina propria inflammation and increased
intraepithelial lymphocytes in lymphocytic colitis and thickening of the
subepithelial collagen layer in collagenous colitis. Presentation is most commonly with chronic, watery diarrhoea in a middle-aged or elderly person.
Microscopic colitis can be drug induced (e.g. NSAIDs) and occurs with
increased frequency in coeliac disease. Treatment is symptomatic initially
with antidiarrhoeal drugs such as loperamide. Budesonide is the first-line
therapy for both induction and maintenance of response in patients not controlled with symptomatic treatment. Aminosalicylates, bismuth subsalicylate,
colestyramine and systemic steroids are used in resistant cases. Microscopic
colitis does not progress to overt inflammatory bowel disease.
110 Gastroenterology and nutrition
THE COLON AND RECTUM
The main role of the colon is absorption of water and electrolytes and propulsion of contents from the caecum to the anorectal region. About 9 L of water
containing electrolytes enters the gastrointestinal tract each day; the majority
from gastrointestinal secretions (stomach, pancreas, bile, intestinal secretion)
and only a small amount from the diet. Most is absorbed in the small intestine
and only about 1500 mL passes through the ileocaecal valve into the colon, of
which about 1350 mL is normally absorbed.
Constipation
This is a common problem in the general population, particularly in the
elderly (associated with immobility and poor diet), and in young women
(associated with slow colonic transit or post-partum pelvic floor abnormalities). Specific definitions are infrequent passage of stools (<3/week),
straining, passage of hard stools, incomplete evacuation and sensation of
anorectal blockage. There is a long list of possible causes (Table 3.13), but in
Table 3.13 Causes of constipation
General
Pregnancy, inadequate fibre intake, immobility
Metabolic/endocrine
Diabetes mellitus, hypothyroidism, hypercalcaemia, porphyria
Functional
Irritable bowel syndrome, idiopathic slow transit
Drugs
Opiates, antimuscarinics, calcium channel blockers, e.g. verapamil
Antidepressants, e.g. tricyclics, iron
Neurological
Spinal cord lesions, Parkinson’s disease
Psychological
Depression, anorexia nervosa, depressed urge to defecate
Gastrointestinal disease
Intestinal obstruction (e.g. by colon cancer) and pseudo-obstruction
Painful anal conditions, Hirschsprung’s disease
Defecatory disorders
Rectal prolapse, pelvic floor dyssynergia
Megarectum, large rectocele
The Colon and Rectum 111
many patients it is their perception that there is an abnormality and requires
no more than dietary advice and reassurance. In many patients it is part of
the irritable bowel syndrome.
Investigation
Initial evaluation is with a history and physical examination, including a
rectal examination during which the patient is asked to strain. A patient with
a defecatory disorder has paradoxical contraction rather than the normal
relaxation of the puborectalis and external anal sphincter during straining,
which may prevent defecation.
Routine blood tests, radiography and endoscopy are not usually indicated
in the evaluation of patients with constipation without alarm symptoms; the
latter includes rectal bleeding, anaemia or recent onset of constipation in the
middle aged or elderly (>50 years), particularly if associated with a sense of
incomplete evacuation.
A few patients with no obvious underlying cause (idiopathic constipation)
may require studies of colonic transit (measured using radiopaque markers
taken orally) and anorectal physiology to determine if they have normal
colonic transit, slow transit or a defecatory disorder.
Management
Any underlying cause should be corrected. Patients with normal and slow
transit constipation are treated with a high-fibre diet together with plenty
of liquids. Long-term laxatives are only used in severe and unresponsive
cases. A wide variety of laxatives are available but many patients are not
satisfied with their treatments. Prucalopride is a high-affinity 5HT4 agonist
which increases colonic transit and is an effective therapy for refractory
constipation. Linaclotide, a minimally absorbed peptide agonist of guanylate
cyclase-C receptor, increases gastrointestinal fluid secretion. Lubiprostone
is an orally active agonist for type-2 chloride channels and therefore also
increases GI fluid secretion. Patients with defecatory disorders may require
referral to a specialist centre.
Faecal incontinence
This is recurrent uncontrolled passage of flatus and/or stool. Continence
depends on a number of factors including mental function, stool volume
and consistency, structural and functional integrity of the anal sphincters,
puborectalis muscle, pudendal nerve function, rectal distensibility and anorectal sensation. Faecal impaction is a common cause of faecal incontinence
in the elderly (overflow diarrhoea). Anal sphincter tears or trauma to the
pudendal nerve can occur after childbirth or anal surgery (e.g. for haemorrhoids). Impaired rectal sensation occurs with diabetes mellitus, multiple
sclerosis, dementia and spinal cord injuries. A detailed history and examination with digital rectal examination will help diagnose and exclude most
112 Gastroenterology and nutrition
common causes. Specific investigations include sigmoidoscopy to exclude
mucosal disease, imaging of the anal sphincters (by anal endosonography, or
MRI), anorectal manometry (to assess anal sphincter pressures), and sensory
testing by rectal balloon distension to assess rectal sensation and compliance. Treatment depends on the cause.
Diverticular disease
Pouches of mucosa extrude through the colonic muscular wall via weakened
areas near blood vessels to form diverticula. The term diverticulosis means
the presence of diverticula. Diverticulitis implies inflammation, which occurs
when faeces obstruct the neck of the diverticulum. Diverticula are common,
affecting 50% of the population over 50 years of age.
Aetiology
The precise cause of diverticular disease is unknown, although it appears
to be related to the low-fibre diet eaten in Western populations; insufficient
dietary fibre leads to increased intracolonic pressure, which causes herniation of the mucosa at sites of weakness.
Clinical features
It is asymptomatic in 95% and usually discovered incidentally when a barium
enema or colonoscopy is performed for other reasons. Symptoms are the result
of luminal narrowing (causing pain and constipation), bleeding which may be
massive, or diverticulitis. The latter present with left iliac fossa pain, fever and
nausea and may result in perforation (leading to abscess formation or peritonitis), fistula formation into the bladder or vagina, or intestinal obstruction. Acute
diverticulitis is diagnosed by CT scan or in some cases by ultrasound.
Management
Acute attacks are treated with antibiotics. Surgery is indicated rarely for
complications and for frequent attacks of diverticulitis.
Miscellaneous conditions
Megacolon
This term describes a number of congenital and acquired conditions in which
the colon is dilated. The most common cause is chronic constipation; in
some parts of the world Chagas’ disease is a common cause. Treatment of
megacolon is usually with laxatives. In all young patients with megacolon,
Hirschsprung’s disease should be excluded. In this condition, which presents in
the first years of life, an aganglionic segment of the rectum (megarectum) gives
rise to constipation and subacute obstruction. Occasionally, Hirschsprung’s disease affecting only a short segment of the rectum can be missed in childhood.
Treatment of Hirschsprung’s disease requires surgical resection.