Irritable Bowel Syndrome

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Irritable Bowel Syndrome

• John McLaughlin
• Clinical Lecturer/Consultant Gastroenterologist
• Hope Hospital, Salford.

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IBS

• What is (are?) IBS?
• Symptoms and diagnosis
• Aetiology
• Therapy and management

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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

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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 lt40-50 yrs
• By definition, conventional investigations are
  normal colonoscopy, histology, blood tests,
  radiology

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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
• gt3/day or lt3/week
• Associated with change in stool form
• Also supported by passage of mucus, bloating,
  straining, urgency, sense of incomplete evacuation

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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?
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Diarrhoea-predominantIBS

• But when stools collected mean stool weight
  150g/day in severe diarrhoea group
• Diarrhoea is strictly gt300g/day
• More accurate to define as increased defaecatory
  frequency

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Are symptoms confined to the bowel in IBS
patients?

• 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)

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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

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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

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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. 
• ?1350-700 risk of ischaemic colitis.
• Put back on the market June 7, 2002 with stricter
  criteria, patient-doctor agreement

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?motility disorder
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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

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Where is the Problem ?
Hypersensitive Gut ?
?
?
Hypervigilant CNS?
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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??

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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

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Where is the Problem ?
Hypersensitive Gut ?
?
?
Hypervigilant CNS?
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Hypervigilance

• Can alter sensory thresholds by focussing
  attention on any body area
• If in pain, convinced somethings wrong, subject
  will focus attention there
• Vicious circle of increasing symptoms could arise
• Anxiety/depression heightens this further

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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

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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

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Biopsychosocial model

• Likely that components from each of these
  dimensions contribute to aetiology of IBS
• . and other functional gut disorders

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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

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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

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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

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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!

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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.

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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

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