Irritable Bowel Syndrome

John McLaughlin Clinical Lecturer/Consultant

Gastroenterologist Hope Hospital, Salford.

IBS

• What is (are?) IBS?

• Symptoms and diagnosis

• Aetiology

• Therapy and management

What is IBS?

• IBS is NOT a disease• IBS is NOT a singular pathological entity• IBS cannot have a single aetiology

– but

• IBS is a useful term, coined to group patients with similar, medically unexplained symptoms

• IBS is difficult to manage, particularly pharmacologically

IBS: features

• IBS patients have symptoms characterised by– Unexplained abdominal pain– Disturbed bowel habit– Bloating

• No ‘red flags’: bleeding, weight loss, abdominal masses, malnutrition etc

• Clinical diagnosis here VERY SAFE <40-50 yrs• By definition, conventional investigations are

normal: colonoscopy, histology, blood tests, radiology

Current Diagnostic Criteria: Rome II 1999

• At least 12 weeks or more (in last year) of abdominal pain or discomfort with 2 out of 3 of the following:– Relieved by defaecation

– Associated with change in stool frequency • >3/day or <3/week

– Associated with change in stool form

• Also supported by passage of mucus, bloating, straining, urgency, sense of incomplete evacuation

Problems with Rome II

• PATIENT A• Abdominal pain• Urgent loose stool 3-4

times each morning• Sense of incomplete

evacuation

• PATIENT B• Abdominal pain• Strains to pass pellety

stool every 3-4 days• Bloating++

Can these very different patients really have the same disorder or common pathophysiology?

‘Diarrhoea-predominant’IBS

– But when stools collected mean stool weight= 150g/day in ‘severe diarrhoea’ group

– Diarrhoea is strictly >300g/day

– More accurate to define as increased defaecatory frequency

• NO! Seek and you shall find:– Functional Dyspepsia– Chronic Fatigue– Unexplained muscle pain (Fibromyalgia)– Temporomandibular dysfunction– Bladder symptoms– Gynaecological symptoms– Headaches– Backache– (All these body areas are normal too when investigated)

Are symptoms confined to the bowel in IBS patients?

IBS symptoms are common

• 3-30% prevalence in unselected subjects

• 5% of all visits to GPs

• 25% of all visits to gastroenterologists

• Estimated 1% annual incidence

• No mortality from the disorder itself

• cf mortality from drugs, investigations, surgical procedures

IBS symptoms are common

• 3-30% prevalence in unselected subjects

• 5% of all visits to GPs

• 25% of all visits to gastroenterologists

• Estimated 1% annual incidence

• No mortality from the disorder itself

• cf mortality from drugs, investigations, procedures

Alosetron: 5-HT3 antagonist (GSK)• Approved February 9, 2000, and voluntarily withdrawn from the

market November 28, 2000.  -Women with diarrhoea-predominant IBS.

• By November 10, 2000, FDA had reviewed 70 cases of serious post-marketing adverse events– 49 cases of ischaemic colitis – 21 cases of severe constipation. – Of the 70 cases, 34 resulted in hospitalization without surgery, 10

resulted in surgical procedures, and three resulted in death. • In some cases alosetron produced constipation serious enough to

require surgery. • ?1:350-700 risk of ischaemic colitis.• Put back on the market June 7, 2002 with stricter criteria,

patient-doctor agreement

Aetiology of FGDAetiology of FGID

? Gut

Hypersensitivity

? Gut

Hypersensitivity

? Abnormal

processing

? Abnormal

processing

Spinal CordSpinal Cord

? Hypervigilance? Hypervigilance

((

))

Central

Sensitisation?motility disorder

Altered Motility?- probably not • Evidence is inconsistent: maybe just epiphenomena of

invasive study methods• Stress induces colonic contractility in IBS and control

subjects• ‘Diarrhoea’-predominant

– Prominent motility response to feeding– Some reports of accelerated transit and fast propagation of

colonic contractions

• Constipation-predominant– Some reports of reduced propagation of colonic contractions

Where is the Problem ?

?

?Hypersensitive

Gut ?

Hypervigilant

CNS?

Functional gut disorders

• ‘VISCERAL HYPERSENSITIVITY’– Low thresholds to gut pain (eg inflating balloons

in rectum, pain with lower volumes in ballon)– Perhaps reflects previous injury?

• Inflammation, infection, nerve fibre injury (TAH)

– akin to secondary hyperalgesia eg after burns– However, problem may still lie in central

connections: why the associated disorders if due to gut injury??

Post-infectious IBS

• Post Campylobacter best reported (Spiller)• Persistent neuroimmune dysfunction • Persistent subtle inflammation

– eg mast cell infiltration; increased permeability

• Enteroendocrine cell hyperplasia– eg rectal 5-HT cells in rectum– Increased circulating 5-HT reported in females

• ……‘IBS’ common in ‘IBD’

Where is the Problem ?

?

?Hypersensitive

Gut ?

Hypervigilant

CNS?

Hypervigilance

• Can alter sensory thresholds by focussing attention on any body area

• If in pain, convinced something’s wrong, subject will focus attention there

• Vicious circle of increasing symptoms could arise

• Anxiety/depression heightens this further

Prevalence of psychological problems

• Community IBS: no excess• GP • Hospital

• Cause of symptoms or driver to seek medical care?

• Psychological factors may worsen outcome– eg physical or sexual abuse reportedly

Relative risk of postinfectious IBS- both biological and psychological!

• Adverse life events in the previous year: x 2• Female sex: x 3.4• Hypochondriasis: x 2• All 3 factors: x 7• Bacterial factors : 1 in 10 of Campylobacter infected

individuals developed post-infective IBS compared with just 1 out of 100 with Salmonella

‘Biopsychosocial model’

• Likely that components from each of these dimensions contribute to aetiology of IBS

• …. and other functional gut disorders

Therapeutic approach to IBS• Need a better understanding of precise causes in

mechanistically defined patient subgroups, not just ROME compliant trials– Peripheral/central origins

• Symptom-based approach: non-drug– Behavioural, psychological, hypnotherapy– Diet, exclusion

• Symptom-based approach: drugs– NB 20-70% placebo responses– Placebo benefits last 12 months or more

Therapeutic approach to IBS

• Positive diagnosis, rather than just failure to find something else

• Reassurance, minimal investigation

• Explanation

• ‘problem with the wiring rather than the plumbing’

Evidence for Therapy in IBS

• Fibre– Relieves constipation but worsens bloating

• Loperamide: empirically helpful

• Antispasmodics/anticholinergics– No good evidence

– But may safely provide the placebo benefit

Evidence for Therapy in IBS

• Tricyclic antidepressants– Superior to placebo in meta-analysis

• SSRIs– No definite benefit from trials

• 5-HT3 antagonist (alosetron)– 12-17% benefit in female D-IBS

• 5-HT4 agonist (tegasorod)– 5-15% benefit in female C-IBS

• These need trials vs simple Rx not just placebo!

Evolving Therapy in IBS• Novel agents in development

– Antihypersensitivity• Peripheral opioid antagonists• Substance P, NMDA

– Central pathways• Corticotrophin releasing hormone antagonists

– Motility• CCK antagonists

– Inflammation• Steroids unhelpful in PI-IBS

– Probiotics….

Summary and prospects

• IBS will remain a major cause of morbidity until its constituent causes are better understood

• As it has a social and experiential component, pharmacotherapy will largely be adjunctive at best

• Naïve studies with agents affecting visceral sensitivity are the best hope at present