Ulcerative colitisGwo-Tzer Ho

Charles Lees

Jack Satsangi

AbstractUlcerative colitis (UC) andCrohns disease (CD) represent the twomajor 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,

nesis;

studies. In adults at presentation, about 55% have proctitis, 30%

t risk

of UC.2 The consumption of red and processed meat, alcohol and

here

UC and CD share some genetic susceptibility factors (host immune

Senior Lecturer at the Institute of Genetics and Molecular Medicine,

INFLAMMATORY BOWEL DISEASEUniversity 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.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

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 Honoraryulcerative colitis

Epidemiology

In the UK, the incidence of ulcerative colitis (UC) is approxi-

mately 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 theseKeywords inflammatory bowel disease; management; pathogeclinical features, and management of ulcerative colitis are reviewed.MEDICINE 39:4 224response for examples); and disparate environmental/luminal

factors drive the different clinical presentations of UC and CD.

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 inflam-

mation in contrast to CD. In UC, a shift in the healthy micro-

biota 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 dysregu-

lated epithelial homeostasis and increased susceptibility to

injury, with subsequent impairment of barrier function.leukin-23 signalling pathway d IL2-3R, JAK2, STAT3, and

This highlights the complex nature of disease mechanism wlow dietary fibre is also associated with an increased likelihood of

relapse.

Genetics

Genomewide association (GWA) studies have providedmany new

insights into the pathogenesis of UC. Although UC has lower

heritability (ls, sibling recurrence risk 10e15) than Crohnsdisease (ls 20e35), more than 30 UC susceptibility loci havebeen identified in six GWA studies (up-to-date information avail-

able 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 histocom-

patibility 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 inter-

p40.polyunsaturated fatty acid (n-6 PUFA)present in redmeat, co

oils andmargarines,was associatedwith an increased incidenfactors 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 aremore 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 Europeandescent showed that high intakeof linoleic acid, ann-6

oking 2011 Elsevier Ltd. All rights reserved.

ding

may

Summary of ulcerative colitis

Epidemiology Onset typically third or fourth decade

Equal sex distribution (1:1)

Environmental

factors

Smoking and appendicectomy protect

against UC. High intake of n-6 PUFA, linoleic

acid associated with an increased incident

risk of UC

Genetics 30 susceptibility genes/loci identified from

GWA studies. Shared susceptibility genes in

the IL-23 signalling pathway with CD.

Immunology Atypical TH2 response with predominant IL-5

and -13 responses. Increased epithelial IL-33

production.

Clinical features 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

Macroscopic Continuous superficial inflammation from

rectum extending proximally to a variable

distance

Histology Superficial confluent neutrophilic infiltration

with loss of crypt architecture, cryptitis, basal

plasmacytosis, goblet cell depletion and

crypt abscess

Medical therapy 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)

Surgical indications 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

Surgical options 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

Malignancy 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

INFLAMMATORY BOWEL DISEASEpredominate 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

Diagnosis

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 character-

istically confluent. The earliest signs tend to be subtle loss of

vascular patterns with hyperaemia and oedema of the mucosa.

Withmore active inflammation, themucosa becomes granularwith

presence ofmucopus and contact bleeding. In advanced cases, deep

ulceration may present, which may mimic severe CD. In the diag-

nosis 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.

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).

Assessment of disease severity

The risk of colectomy in UC is also strongly influenced by the

severity of disease at initial presentation. The Truelove andWitts

criteria provide themost 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 UCwill develop a severe attack of colitis requiring in-

patient medical management and high-dose intravenous(rectosigmoid involvement), the symptoms of rectal irritationIL-10 and IL-23R are particularly intriguing. Complete, loss-

of-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.

Clinical features

The major symptoms of UC include diarrhoea with urgency, rectal

bleeding and colicky abdominal pain. In patientswith distal diseaseatypical TH2 response, mediated by natural killer T cells (

that secrete IL-13.5 Two major susceptibility genes, encoAn 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

NKT)MEDICINE 39:4 225 2011 Elsevier Ltd. All rights reserved.

corti-

ing

INFLAMMATORY BOWEL DISEASEcorticosteroid therapy; 30e40% of these will fail to respond

adequately and require colectomy. The in-patient mortality asso-

ciated with such attacks has fallen from 31 to 61% to the present

level of 1e2% following the introduction of high-dose corticoste-

roid 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 andmortality. 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

disease unclassified e IBDU) features (e.g. perianal abscesses;

backwash ileitis)

Bacterial dysentery Shigellosis; salmonellosis;

Campylobacter infection

Amoebic dysentery Watery bloody diarrhoea,

recent travel to endemic area

Cytomegalovirus (CMV) Immunocompromised patients

(e.g. HIV/AIDS)

Clostridium difficile Co-exists with UC in w5e10%

of refractory cases

Ischaemic colitis Watershed areas (e.g. deep

ulceration at distal transverse

colon and splenic flexure):

present with bloody diarrhoea

Table 2(inflammatory bowel with colitis, often with overlappDifferential diagnosis of ulcerative colitis

Differential diagnosis Features

Crohns colitis

Indeterminant colitis Present in w10% of patientsHistology

The histological appearances of UC are characterized by the

presence of a predominantly acute inflammatory process associ-

ated 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 deple-

tion and crypt abscesses are prominent. Basal plasma cells and

multiple basal lymphoid infiltrate are indicative of chronicity.

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 mildemo-

derate, 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,

d-line

MEDICINE 39:4 226medical therapy needs careful risk/benefit consideration. Clinical

trials comparing ciclosporin and infliximab are in progress.

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 three-

fold (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 demon-

strating 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-MPclinical setting is associated with major adverse events, m

serious infections, which may be fatal. Thus, the use of seconcosteroidswill either require surgery or be corticosteroid dependent

after 1 year of the initiation of therapy.10,11

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 corti-

costeroids 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 remis-

sion in 60e80% of patients with severe active UC.14,15 Although

most adverse effects areminor andmanagedwithmild adjustments

in dose, severe opportunistic infections, most notably Pneumo-

cystis 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 demon-

strated efficacy of infliximab in active UC.16 Whilst the primary

endpoints of disease response at week 8 were achieved, cortico-

steroid-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 andpositioning of infliximab, as with ciclosporin, is to use this as

a bridge to longer-term immunosuppressivemaintenance treatment

such as azathioprine. As with ciclosporin, infliximab therapy in this

ainlypatients will relapse in the medium term. Based on two ince

cohort studies, approximately 50% of patients treated withwhen 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.

Inpatientswithmore extensive or severedisease, orwith 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 corticoste-

roids needs to be borne in mind as a substantial proportion of

ption 2011 Elsevier Ltd. All rights reserved.

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 2e3months after the initiation of

therapy. Patients who take azathioprine/6-MP should avoid allo-

purinol (a xanthineoxidase inhibitor) as it inhibits thebreakdownof

azathioprine/6-MP and increases the risk of myelosuppression.

Figure 1

INFLAMMATORY BOWEL DISEASESurgery

The indications for surgery are usually categorized into emer-

gency and elective operations. In the former, the absolute indi-

cations 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 thisFigure 2 Colonic dilatation in acute severe ulcerative colitis.

MEDICINE 39:4 227setting 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.20Ileo-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.

Truelove and Witts criteria for severe ulcerative colitis

C Bloody diarrhoea >6/24 h

C Tachycardia (resting pulse >90/min)

C Fever (temperature >37.8C at presentation)C Anaemia (haemoglobin 30 mm/h)

Table 3

2011 Elsevier Ltd. All rights reserved.

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

ulcerative colitis and Crohns disease: record linkage studies. BMJ

2007; 335: 1033.

9 Nicholls RJ, Clark DN, Kelso L, et al. Nationwide linkage analysis in

Scotland implicates age as the critical overall determinant of

mortality in ulcerative colitis. Aliment Pharmacol Ther 2010; 31:

INFLAMMATORY BOWEL DISEASEcolleagues 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 sulfasala-

zine, 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

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Ulcerative colitisEpidemiologyPathogenesisEnvironmentGeneticsMicrobiota, epithelial barrier function and mucosal response

Clinical featuresDiagnosisAssessment of disease extentAssessment of disease severity

HistologyTreatmentInduction of remissionMedical therapies in acute severe UCMaintenance of remission

SurgeryMalignancy riskReferences