INFLAMMATORY BOWEL DISEASE

Ulcerative colitis

factors triggering a breakdown in the regulatory constraints on

mucosal immune responses to enteric bacteria in genetically
susceptible individuals. The relatively weaker concordance in
monozygotic twin pairs with UC (6e14%) compared with CD
(44e50%) suggests that environmental factors are more important
than genetic factors in the pathogenesis of UC.1 Cigarette smoking,
appendicectomy and diet are well-characterized environmental
factors. The protective effect of smoking on UC is in stark contrast
to the detrimental effect seen in Crohns disease (CD); this is the
most consistent environmental factor within inflammatory bowel
disease (IBD). Thirteen published studies have consistently
demonstrated a protective effect of appendicectomy against the
development of UC. Recent dietary data from 200,000 individuals
of European descent showed that high intake of linoleic acid, an n-6
polyunsaturated fatty acid (n-6 PUFA) present in red meat, cooking
oils and margarines, was associated with an increased incident risk
of UC.2 The consumption of red and processed meat, alcohol and
low dietary fibre is also associated with an increased likelihood of
relapse.

Gwo-Tzer Ho
Charles Lees
Jack Satsangi

Abstract
Ulcerative colitis (UC) and Crohns disease (CD) represent the two major forms
of inflammatory bowel disease (IBD). UC is a chronic idiopathic inflammatory
condition affecting the colon and rectum. Maintenance of a healthy gut
requires a complex interplay between components of the innate immune
system and environmental factors, notably the microflora. This relationship
is dysregulated in UC. Current concepts of the epidemiology, pathogenesis,
clinical features, and management of ulcerative colitis are reviewed.

Keywords inflammatory bowel disease; management; pathogenesis;

ulcerative colitis

Genetics
Genomewide association (GWA) studies have provided many new
insights into the pathogenesis of UC. Although UC has lower
heritability (ls, sibling recurrence risk 10e15) than Crohns
disease (ls 20e35), more than 30 UC susceptibility loci have
been identified in six GWA studies (up-to-date information available via: www.ibdgenetics.org/). These studies broadly implicate
genes that are involved in the maintenance of epithelial integrity
(HNF-a, CDH-1 encoding e-cadherin, LAMB-1, ECM-1, PTPN2),
innate immune function (PLA2G2E, CARD9), immune regulatory
function (HLA-region, IL-10, BTNL2, IFNg-IL25, NKX2-3), and
cellular homeostasis in response to endoplasmic reticulum (ER)
stress (ORMDL3) in UC. Associations within the major histocompatibility complex class II region near HLA-DRA (a-chain) are the
most significant and consistent observation. Of interest, there is an
overlap with CD susceptibility genes, most notably in the interleukin-23 signalling pathway d IL2-3R, JAK2, STAT3, and p40.
This highlights the complex nature of disease mechanism where
UC and CD share some genetic susceptibility factors (host immune
response for examples); and disparate environmental/luminal
factors drive the different clinical presentations of UC and CD.

Epidemiology
In the UK, the incidence of ulcerative colitis (UC) is approximately 10/100,000 with a point prevalence of 200/100,000. UC
can present at any age, but typically does so in the third to fourth
decade (later than Crohns disease (CD)). Men and women are
equally affected. The incidence rates for UC have in recent years
remained constant in areas such as Northern Europe and North
America. In areas with previously low incidence, such as
Southern Europe and Asia, the incidence appears to be
increasing, although differences in case ascertainment and study
design introduce a degree of difficulty in comparing these
studies. In adults at presentation, about 55% have proctitis, 30%
left-sided colitis, and 15% extensive colitis or total colitis.

Pathogenesis
Environment
Both human and animal studies suggest that the intestinal
inflammation in UC is likely to be a consequence of environmental

Microbiota, epithelial barrier function and mucosal response

The microbial influences in UC primarily focus on their metabolic
effects on epithelial homeostasis and function. The colon
harbours 1011,12 predominantly anaerobic bacteria. The colonic
epithelium derives 70% of its energy from short-chain fatty acids
(SCFAs), principally butyrate, which are products of anaerobic
bacterial fermentation. Faecal diversion in UC worsens inflammation in contrast to CD. In UC, a shift in the healthy microbiota such as Bifidobacterium and Bacteriodes with a concurrent
reduction in SCFAs has been described,3 along with an increase
of sulphate-reducing bacteria (SRB) of the genus Desulfovibrio.
SRB convert sulphate to sulphide, which inhibits butyrate
oxidation and is directly toxic to colonic epithelial cells. Thus, in
one hypothesis, epithelial-nutrient deficiency leads to dysregulated epithelial homeostasis and increased susceptibility to
injury, with subsequent impairment of barrier function.

Gwo-Tzer Ho PhD MRCP is a Medical Research Council (MRC) Clinician

Scientist and Honorary Consultant Gastroenterologist at the Institute of
Genetics and Molecular Medicine, University of Edinburgh, Western
General Hospital, Edinburgh, UK. Competing interests: none declared.
Charles Lees PhD MRCP is a Consultant Gastroenterologist and Honorary
Senior Lecturer at the Institute of Genetics and Molecular Medicine,
University of Edinburgh, Western General Hospital, Edinburgh, UK.
Competing interests: none declared.
Jack Satsangi DPhil FRCP is Professor of Gastroenterology at the
Gastrointestinal Unit, Institute of Genetics and Molecular Medicine,
University of Edinburgh, Western General Hospital, Edinburgh, UK.
Competing interests: none declared.

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INFLAMMATORY BOWEL DISEASE

An aberrant immune response in UC (as in CD) is present. The

primary factors that initiate and perpetuate such a rigorous
inflammatory response are not yet clear. UC is traditionally
considered to have a TH2 profile, but IL-4 and IL-5 cytokine
concentrations, which are normally elevated, have been variable
in UC tissues.4 It has been proposed that UC demonstrates an
atypical TH2 response, mediated by natural killer T cells (NKT)
that secrete IL-13.5 Two major susceptibility genes, encoding
IL-10 and IL-23R are particularly intriguing. Complete, lossof-function mutations in the IL-10 receptor result in a Crohns
disease phenotype. IL-23 drives Th-17 cell differentiation and
IL-17 production, typically a feature of CD. The functional roles
of these genes in UC are currently under evaluation.

Summary of ulcerative colitis

Epidemiology
Environmental
factors

Genetics

Immunology

Clinical features
The major symptoms of UC include diarrhoea with urgency, rectal
bleeding and colicky abdominal pain. In patients with distal disease
(rectosigmoid involvement), the symptoms of rectal irritation may
predominate e namely tenesmus (the sensation of incomplete
emptying), small-volume diarrhoea, proximal constipation and
rectal bleeding. In contrast, in extensive colitis (beyond the splenic
flexure), profuse bloody diarrhoea, abdominal cramping and, in
severe cases, systemic features such as weight loss, fever and
tachycardia are more prominent. Symptoms tend to present
insidiously but may also present acutely, mimicking an infective
aetiology. In children, extensive colitis is typical at diagnosis.6

Macroscopic

Diagnosis

Medical therapy

Clinical features

Histology

The diagnosis of UC is principally based on clinical, endoscopic and

histological grounds. UC invariably affects the rectum and extends
proximally to a variable distance. The inflammation is characteristically confluent. The earliest signs tend to be subtle loss of
vascular patterns with hyperaemia and oedema of the mucosa.
With more active inflammation, the mucosa becomes granular with
presence of mucopus and contact bleeding. In advanced cases, deep
ulceration may present, which may mimic severe CD. In the diagnosis of UC, the two critical features influential in the subsequent
management are disease extent and disease severity. A summary of
the differential diagnosis of UC is shown in Tables 1 and 2.

Surgical indications

Assessment of disease extent

Patients with extensive disease have an increased likelihood of
medically refractory and severe disease. A review of selected
referral centre-based and population-based cohorts have shown
that the actuarial risk of colectomy is influenced by disease
extent. The risk of colectomy among patients with only limited
proctitis ranged from 2 to 9% while patients with extensive
colitis had 5-year colectomy rates of 30e44%. Disease extent is
not static and proximal extension can occur in patients with
previously distal disease (Figures 1 and 2).

Surgical options

Assessment of disease severity

The risk of colectomy in UC is also strongly influenced by the
severity of disease at initial presentation. The Truelove and Witts
criteria provide the most widely used definition for severe disease,
encompassing descriptions of profuse bloody diarrhoea and the
clinical features of systemic upset (Table 3). Historically, 15% of
patients with UC will develop a severe attack of colitis requiring inpatient medical management and high-dose intravenous

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Malignancy

Onset typically third or fourth decade

Equal sex distribution (1:1)
Smoking and appendicectomy protect
against UC. High intake of n-6 PUFA, linoleic
acid associated with an increased incident
risk of UC
30 susceptibility genes/loci identified from
GWA studies. Shared susceptibility genes in
the IL-23 signalling pathway with CD.
Atypical TH2 response with predominant IL-5
and -13 responses. Increased epithelial IL-33
production.
Limited disease e rectal bleeding, tenesmus,
proximal constipation. Extensive disease e
profuse bloody diarrhoea, abdominal
cramps. Severe disease e systemic features
such as fever and tachycardia
Continuous superficial inflammation from
rectum extending proximally to a variable
distance
Superficial confluent neutrophilic infiltration
with loss of crypt architecture, cryptitis, basal
plasmacytosis, goblet cell depletion and
crypt abscess
Induction of remission
C
5-aminosalicylates (topical or oral)
C
Corticosteroids (topical or oral)
C
Ciclosporin (acute severe UC)
C
Infliximab
Maintenance of remission
C
5-aminosalicylates
C
Azathioprine/6-mercaptopurine
C
Methotrexate (evidence less strong)
Emergency colectomy
C
Perforation
C
Massive haemorrhage
C
Toxic dilatation
C
Failed medical therapy (commonest)
Elective colectomy
C
Chronic continuous disease
C
Corticosteroid dependency
C
Malignancy/dysplasia
C
Total colectomy with end ileostomy
C
Proctocolectomy with the formation of
ileo-anal pouch (IPAA)
C
Proctocolectomy with ileo-rectal
anastomosis
C
Proctocolectomy with the formation of
a continent ileostomy or Kochs pouch
Risk increases with disease duration in
extensive and severe disease (1% increase
likelihood every year after 10 years) and in
primary sclerosing cholangitis (PSC)

Table 1

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INFLAMMATORY BOWEL DISEASE

when it should be administered as a suppository. In left-sided

disease, topical 5-ASA or corticosteroid foam or retention enemas
should be used. 5-ASA is more effective than corticosteroid, and
therefore should be used as first line.
In patients with more extensive or severe disease, or with disease
unresponsive to oral 5-ASA, oral or parenteral corticosteroids are
required to induce remission. Although effective in the short term
(in up to 70% of the cases), the adverse effect profile of corticosteroids needs to be borne in mind as a substantial proportion of
patients will relapse in the medium term. Based on two inception
cohort studies, approximately 50% of patients treated with corticosteroids will either require surgery or be corticosteroid dependent
after 1 year of the initiation of therapy.10,11

Differential diagnosis of ulcerative colitis

Differential diagnosis
Crohns colitis
Indeterminant colitis
(inflammatory bowel
disease unclassified e IBDU)
Bacterial dysentery
Amoebic dysentery
Cytomegalovirus (CMV)
Clostridium difficile
Ischaemic colitis

Features
Present in w10% of patients
with colitis, often with overlapping
features (e.g. perianal abscesses;
backwash ileitis)
Shigellosis; salmonellosis;
Campylobacter infection
Watery bloody diarrhoea,
recent travel to endemic area
Immunocompromised patients
(e.g. HIV/AIDS)
Co-exists with UC in w5e10%
of refractory cases
Watershed areas (e.g. deep
ulceration at distal transverse
colon and splenic flexure):
present with bloody diarrhoea

Medical therapies in acute severe UC

High-dose intravenous corticosteroids remain the first-line
medical therapy in acute severe UC. In patients who respond, this
is typically converted to oral prednisolone after 5e7 days.
Prognostic models, such as the Edinburgh Colitis Risk Score12
and Paediatric UC Activity Index,13 can identify subsets of
adults and children who are at risk of not responding to corticosteroids and who will benefit from early second-line medical
therapies, such as ciclosporin, infliximab or early colectomy.
Ciclosporin acts mainly by inhibiting T lymphocyte function,
which is essential for the propagation of inflammation. Controlled
trial data have shown that intravenous ciclosporin induces remission in 60e80% of patients with severe active UC.14,15 Although
most adverse effects are minor and managed with mild adjustments
in dose, severe opportunistic infections, most notably Pneumocystis jirovecii pneumonia, and nephrotoxicity have been reported.
Infliximab, a chimeric monoclonal antibody directed against
tumour necrosis factor-alpha (TNF-a), has been used for the
treatment of CD for over 10 years. The ACT-1/2 study demonstrated efficacy of infliximab in active UC.16 Whilst the primary
endpoints of disease response at week 8 were achieved, corticosteroid-free remission at 1 year was observed in only 21%.
Jarnerot et al. demonstrated that a single infusion of infliximab 5
mg/kg was effective rescue therapy in hospitalized patients with
acute severe UC failing to respond to first-line intensive medical
therapy ( p 0.017, odds ratio 4.7).17 The current strategy and
positioning of infliximab, as with ciclosporin, is to use this as
a bridge to longer-term immunosuppressive maintenance treatment
such as azathioprine. As with ciclosporin, infliximab therapy in this
clinical setting is associated with major adverse events, mainly
serious infections, which may be fatal. Thus, the use of second-line
medical therapy needs careful risk/benefit consideration. Clinical
trials comparing ciclosporin and infliximab are in progress.

Table 2

corticosteroid therapy; 30e40% of these will fail to respond

adequately and require colectomy. The in-patient mortality associated with such attacks has fallen from 31 to 61% to the present
level of 1e2% following the introduction of high-dose corticosteroid therapy, better joint medicalesurgical management, and the
acceptance of a policy of early surgery in patients not responding to
medical therapy.7 Severe UC remains an entity with considerable
morbidity and mortality. In UK, reported 3-year mortality rates are
approximately 12% following the presentation of severe UC;8 the
increase in mortality is greatest in the elderly population (>65
years old) and those with significant co-morbidities.9

Histology
The histological appearances of UC are characterized by the
presence of a predominantly acute inflammatory process associated with the destruction of mucosal cells, particularly epithelial
cells. Loss of crypts (atrophy) and destruction of crypt architecture
are present at all stages of disease. Crypt inflammation (cryptitis) is
a feature of UC that can also be found in CD and infective colitis.
Histologically, two features are critical in the diagnosis of UC e
chronicity and disease distribution. In the latter, the rectum is
invariably involved with confluent inflammation limited to the
mucosa or superficial submucosa (except in severe fulminant
disease). In active UC, neutrophilic infiltration, goblet cell depletion and crypt abscesses are prominent. Basal plasma cells and
multiple basal lymphoid infiltrate are indicative of chronicity.

Maintenance of remission
The cornerstone of maintenance of remission is based on 5-ASA
therapy. This reduces the likelihood of relapse over a year by threefold (from a likelihood of relapse of 70e80% without therapy to
10e30% per year on 5-ASA maintenance therapy). Azathioprine
and 6-mercaptopurine (6-MP) are immunosuppressants demonstrating clinical benefit evident in two-thirds of the patients.
Azathioprine or 6-MP is used in patients who are refractory to, or
dependent on, corticosteroids or have poor control with frequent
relapses. In this group, azathioprine is superior to 5-ASA alone.18
One limitation is that adverse drug reactions to azathioprine/6-MP

Treatment
Induction of remission
Medical management is based on the induction and maintenance
of remission. 5-aminosalicylic acid (5-ASA; sulphasalazine and
mesalazine) is considered first-line therapy for active mildemoderate, left-sided or extensive UC. Combinations of oral and rectal
(enema) formulations of 5-ASA lead to faster and higher remission
rates. Rectal 5-ASA is often sufficient on its own in active proctitis,

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INFLAMMATORY BOWEL DISEASE

Figure 1

occur in 15e28% of patients and often necessitate withdrawal of

therapy. The most serious adverse effect is profound bone marrow
suppression in patients (1 in 300 individuals) who are deficient in
thiopurine methyl transferase (TPMT), the enzyme involved in the
metabolism of azathioprine/6-MP. The optimal therapeutic effect
for azathioprine/6-MPis observed 2e3 months after the initiation of
therapy. Patients who take azathioprine/6-MP should avoid allopurinol (a xanthine oxidase inhibitor) as it inhibits the breakdown of
azathioprine/6-MP and increases the risk of myelosuppression.

setting is associated with increased morbidity, operative

complications and mortality. The elective indications for surgery
are usually considered in patients with chronic continuous
symptoms, corticosteroid dependency, partial response to
medical therapy and the presence of malignancy/dysplasia.
Generally, four surgical approaches are considered:
 total colectomy with end ileostomy
 proctocolectomy with the formation of ileo-anal pouch (ileal
poucheanal anastomosis; IPAA)
 proctocolectomy with ileo-rectal anastamosis
 proctocolectomy with the formation of a continent ileostomy
or Kocks pouch.
There is general agreement that the operation of choice in the
emergency situation is sub-total colectomy with ileostomy and
the preservation of the rectum e with removal of the rectum at
a later time. Total proctocolectomy with construction of an IPAA
has become the standard of care for patients with UC who require
removal of the colorectum. This involves abdominal colectomy
and construction of an ileal pouch that is anastomosed to
the anus. In younger patients, the option of IPAA is more
attractive as it avoids the need for a stoma.
The most common and widely reported complication is
inflammation of the ileal pouch. Such pouchitis presents with
watery, frequent diarrhoea or rectal bleeding, accompanied by
urgency, incontinence, abdominal cramping, malaise, and fever.
The cumulative probability of pouchitis, determined on the basis
of symptoms, endoscopy, and histopathology in 468 IPAA
patients was 20% at 1 year, 32% at 5 years, and 40% at
10 years.19 The incidence of pouch failure is reported to be 10% at
10 years, with severe pouchitis accounting for 10% of failures.20
Ileo-rectal anastomosis may be considered in young female
patients in order to avoid proctectomy and pelvic dissection e
given that the latter are associated with impaired fertility.

Surgery
The indications for surgery are usually categorized into emergency and elective operations. In the former, the absolute indications for surgery are perforation and massive haemorrhage,
with commoner indications being failed medical therapy and
toxic megacolon. The timing of emergency surgery in the case of
failed medical therapy or toxic megacolon is dependent on
careful joint medicalesurgical decision. Delayed surgery in this

Truelove and Witts criteria for severe ulcerative colitis

C
C
C
C
C

Table 3

Figure 2 Colonic dilatation in acute severe ulcerative colitis.

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Bloody diarrhoea >6/24 h

Tachycardia (resting pulse >90/min)
Fever (temperature >37.8 C at presentation)
Anaemia (haemoglobin <10.5 g/dl)
Elevated inflammatory markers (ESR >30 mm/h)

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INFLAMMATORY BOWEL DISEASE

Malignancy risk
Patients with UC have a higher risk of colorectal cancer than the
general population.21 Disease extent and duration are the two
critical factors underlying this association, although recent data
suggest that disease severity may also be influential. Ekbom and
colleagues reported standardized incidence ratios for colorectal
cancer risk of 1.7 for patients with proctitis, 2.8 for patients with
disease extending beyond the rectum but no further than the
hepatic flexure, and 14.8 for patients with disease extending
beyond the hepatic flexure.22 A family history of colorectal
cancer and the presence of primary sclerosing cholangitis and
backwash ileitis are also independently associated with increased
cancer risk. Continuation of maintenance 5-ASA and sulfasalazine, cigarette smoking, and possibly folic acid and vitamin E
supplementation are protective factors.23 In a study by Eaden
et al., a relative reduction of 75% in the risk of cancer was
demonstrated in those patients regularly taking 5-ASA, even at
low doses (1.2 g daily).24 The current guidelines recommend
that patients who have had extensive UC for more than 8 years or
left-sided disease for 15 years should be considered for
surveillance.
A

10

11

12

13

14

15
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