Irritable bowel syndrome

1. Irritable Bowel Syndrome Dr Junaid Saleem

2. Conflict of Interest Statement • Sponsored by Abbott for this lecture • No other conflicts of interest 2

3. Short Version • Irritable Bowel Syndrome – Definition? – Aetiology? – Pathology? – Clinical Features – Diagnosis? – Treatment? – Prognosis +/- 3

4. Introduction • First described in 1771. • 50% of patients present <35 years old. • 70% of sufferers are symptom free after 5 years. • GPs will diagnose one new case per week. • GPs will see 4-5 patients a week with IBS. • Point prevalence of 40-50 patients per 2000 patients. 4

5. What Is IBS? • A syndrome. • One man’s constipation is another man’s normality. • Cause unknown. • 20% seem to start after an episode of gastroenteritis. 5

6. Psychosocial factors •IBS aetiology is multi-factorial •Emotions significantly affect colonic response in IBS – Stressful stimuli disrupt upper GI motility in several ways, including mean • oesophageal peristaltic amplitude, • rate of gastric emptying, • small bowel transit, and • increased upper oesophageal sphincter pressure Aetiology

7. Psychosocial factors •The response to stress is mediated by corticotrophin releasing factor (CRF) secreted by the enteric neurons, enteroendocrine cells and immune cells – CRF binds to CRF receptors present on smooth muscle cells and increase the number of discrete cluster contractions – Psychosocial factors exacerbate the symptoms of IBS but a definite link has not been established Aetiology

8. Pathophysiology

9. • Exact pathophysiology remains uncertain • Dysregulation within the brain gut axis, • interactions between genetics, • psychosocial factors, • post-inflammatory changes and • motor and sensory dysfunction are all likely to influence the development of IBS Pathophysiology Spiller R, Aziz Q, Creed F, et al. Guidelines on the irritable bowel syndrome: mechanisms and practical management. Gut 2007;56:1770-1798. Mawe GM, Coates MD, Moses PL. Intestinal serotonin signalling in irritable bowel syndrome. Aliment Pharmacol Ther 2006;23:1067-1076.

10. • Exact pathophysiology remains uncertain • Visceral hypersensitivity – enhanced pain sensitivity of the gut – may play an important role in the development of chronic pain and discomfort in IBS1 • Heightened sensitivity of the peripheral nervous system is caused by immune and inflammatory mediators acting at the site of tissue injury and inflammation Pathophysiology Spiller R, Aziz Q, Creed F, et al. Guidelines on the irritable bowel syndrome: mechanisms and practical management. Gut 2007;56:1770-1798. Mawe GM, Coates MD, Moses PL. Intestinal serotonin signalling in irritable bowel syndrome. Aliment Pharmacol Ther 2006;23:1067-1076.

11. • Exact pathophysiology remains uncertain • Serotonin (5-HT) – present extensively in the GI tract – is the most important neurotransmitter in the pathogenesis of IBS, • peripheral sensitisation causes an area of hypersensitivity to develop in the surrounding uninjured tissue – this phenomenon is called central sensitisation Pathophysiology Spiller R, Aziz Q, Creed F, et al. Guidelines on the irritable bowel syndrome: mechanisms and practical management. Gut 2007;56:1770-1798. Mawe GM, Coates MD, Moses PL. Intestinal serotonin signalling in irritable bowel syndrome. Aliment Pharmacol Ther 2006;23:1067-1076.

12. Disturbances in GI motility •A proportion of IBS patients, specifically those reporting constipation or dyspeptic symptoms, exhibit delayed gastric emptying, especially of solids, this correlates with absence of post-prandial increase in electrogastrography (EGG) amplitude Pathophysiology Hammerle CW, Surawicz CM. Updates on treatment of irritable bowel syndrome. World J Gastroenterol 2008;14(17):2639-2649.

13. Disturbances in GI motility •Disturbances in small bowel motor activity occur, including • frequency and duration of discrete cluster contractions, • increased frequency of migrating motor complex (MMC), • more retrograde duodenal and jejunal contractions • exaggerated motor response to meal ingestion Pathophysiology Hammerle CW, Surawicz CM. Updates on treatment of irritable bowel syndrome. World J Gastroenterol 2008;14(17):2639-2649.

14. Disturbances in GI motility •Corticotrophin releasing hormone, e.g. secreted in response to stress, increases the number of discrete cluster contractions. •More commonly observed in IBS patients with diarrhoea than in those with constipation Pathophysiology Hammerle CW, Surawicz CM. Updates on treatment of irritable bowel syndrome. World J Gastroenterol 2008;14(17):2639-2649.

15. Visceral hypersensitivity •Visceral pain and discomfort cause considerable morbidity in IBS1 •Visceral hypersensitivity seen in two-thirds of patients with IBS and plays an important role in abdominal pain and discomfort1 •Animal and human studies suggest that visceral hypersensitivity is caused by a combination of factors involving heightened sensitivity of peripheral and central nervous system1 Pathophysiology Spiller R, Aziz Q, Creed F, et al. Guidelines on the irritable bowel syndrome: mechanisms and practical management. Gut 2007;56:1770-1798

16. Subjectsreportingpain(%) Whitehead et al. Dig Dis Sci 1980 Distending volume (mL) Healthy controls 20 60 100 140 180 IBS RECTAL HYPERSENSITIVITY IN IBS

17. 0 10 20 30 40 50 IBS (n=86) Healthy volunteers (n=25) Pressure(mmHg) Barostat rectal distension Discomfort/Pain Bouin et al. Gastroenterology 2002 Rectal barostat at 40 mmHg, to identify IBS patients from HV and non-IBS pts sensitivity = 96%, specificity = 72%; PPV = 85% , NPV = 90%. RECTAL HYPERSENSITIVITY IN IBS

18. 0 20 40 60 80 100 IBS (n=126) Healthy volunteers (n=30) Subjectswithhypersensitivity Barostat rectal distension Discomfort/Pain Ludidi et al. Neurogastro Motil 2012 Optimal cutoff for visceral hypersensitivity at pressure 26 mmHg with a VAS ≥20 mm RECTAL HYPERSENSITIVITY IN IBS 64% 7%

19. Diagnostic Criteria • Manning’s Criteria. • Rome II Diagnostic criteria. 19

20. Manning Kruis Rome Rome I Rome II Rome III 1978 1984 1989 1990 1999 2006 IBS diagnostic criteria

21. Manning’s Criteria. • Three or more features should have been present for at least 6 months: – Pain relieved by defecation. – Pain onset associated with more frequent stools. – Looser stools with pain onset. – Abdominal distension. – Mucus in the stool. – A feeling of incomplete evacuation after defecation. 21

22. Rome Publications Gastroenterolo gy International Journal 1989 1990 1994 1999 2000 2006 1st IBS criteria 1992-1995 5 Rome I publications 2003 Rome Foundation Gastroenterolo gy Supplement + Rome III Book Degnon Assoc. 1683 1st FGID classificatio n Rome I Book Little Brown Rome II Gut Supplement Rome II Book Degnon Assoc.

23. Rome II Diagnostic criteria for IBS At least 12 weeks, which need not be consecutive, in the preceding 12 months of abdominal discomfort or pain that has two of three features: • Relieved with defecation; and/or • Onset associated with a change in frequency of stool; and/or • Onset associated with a change in form (appearance) of stool. Thompson et al Gut 1999;45 Suppl 2:II43-II47

24. Rome II Diagnostic Criteria. • Supportive symptoms. – Constipation predominant: one or more of: • Bowel movement less than 3 times a week. • Hard or lumpy stools. • Straining during a bowel movement. – Diarrhoea predominant: one or more of: • More than 3 bowel movements per day. • Loose [mushy] or watery stools. • Urgency. 24

25. Rome II Diagnostic Criteria. –General: • Feeling of incomplete evacuation. • Passing mucus per rectum. • Abdominal fullness, bloating or swelling. 25

26. Rome III Committees – Issues and Limitations • Criteria Not Fully Evidence Based  Limited data for most functional GI disorders  Original criteria by consensus  Changes based on new evidence  New changes need validation •The Field is Expanding and Growing  Information not “set in stone”  Knowledge can quickly become outdated  Classifications will change – e.g., “Organification” •Need for Quality Control  Disclosure of relationships with Pharmaceuticals  Confidentiality statements  International Resource Committee  Embargo on information until final editing stages 1778

27. Rome III Diagnostic Criteria for IBS* • Recurrent abdominal pain or discomfort ≥ 3 days per month in the last three months associated with two or more of the following • Improvement with defecation; and/or • Onset associated with a change in frequency of stool; and/or • Onset associated with a change in form (appearance) of stool * Criteria fulfilled for the last 3 months with symptom onset ≥ 6 months prior to diagnosis

28. Rome III Criteria* – Irritable Bowel Syndrome Improveme nt with defecation Recurrent abdominal pain or discomfort at least 3 days/month In the last 3 months associated with 2 or more : Onset associated with a change in frequency of stool Onset associated with a change in form (appearance) of stool and and Longstreth GF, Gastroenterology 2006 1782

29. • Introduction of a frequency threshold of ≥3 days/ month over 3 months for symptoms • Reduction of the duration of symptoms before one can make firm diagnosis from 12 to 6 months • Refining of subtypes Main Changes in IBS Criteria

30. Subclassifying IBS Why bother? • Important for choosing therapies which alter bowel habit • Subtypes likely to have different pathophysiology • Transit • Stool consistency • Rectal sensitivity?

31. Previous Features Used to subclassify IBS Patients • Diarrhea-predominant 1 or more of 2, 4, or 6 and none of 1, 3, or 5 (or 2 of 2, 4 or 6 and 1 of 1 or 5 but not 3) • Constipation-predominant 1 or more of 1, 3, or 5 and none of 2, 4, or 6 (or 2 of 1, 3 or 5 and 1 of 2, 4 or 6) 1. Fewer than three bowel movements a week 2. More than three bowel movements a day 3. Hard or lumpy stools 4. Loose (mushy) or watery stools 5. Straining during a bowel movement 6. Urgency (having to rush to have a bowel movement)

32. Problems With Old System • Complex to apply and caused confusion in both patients and clinicians! • Multidimensional but different dimensions don’t correlate well • Failed to deal adequately with patients with both hard and loose stools

33. IBS Patients with Features of Both Constipation and Diarrhea are Common Reference N IBS-D IBS-C IBS-M Mearin 2003 209 10 24 37 Tillisch 2005 1102 32 17 32 Drossman 2005 317 36 34 31

34. Rome III subtyping is based on Stool Consistency alone • Assessed from stool form

35. Defining Stool Consistency Bristol Stool Form Scale Hard Normal Loose

36. Why Stool Consistency as Main Determinant of Subtype? • Correlates best with colonic transit

37. Why Stool Consistency as Main Determinant of Subtype? • Correlates best with colonic transit • Correlates best with what patients and community samples think of as “diarrhoea” • Principle determinant of incontinence • Other features occur in IBS with both loose & hard stools • Stool frequency <3/weeks or >3/day • Urgency, Sense of incomplete evacuation

38. Association of bowel symptoms with stool consistency Tillisch et al Am J Gastroenterol. 2005; 100:896-904

39. Proposed New Subtyping Based on Stool Consistency Alone • IBS with constipation - IBS-C • IBS with diarrhoea - IBS-D • IBS mixed type - IBS-M • IBS unsubtyped - IBS-U • IBS-mixed : patients with both hard & loose stools over periods of hours or days

40. 0 25 50 75 100 % Hard or lumpy stools 0 25 50 75 100 % Loose or watery stools IBS-U IBS-C IBS- M IBS-D Rome III – Subtypes of IBS 1709

41. Alternating IBS • Patients who change subtype over periods of weeks and months

42. Quantifying Stool Form Date Pain Pain Severity Urgency Y/N Bloating Y/N 1 2 3 4 5 6 7 8 Pain: grade 0-10 0= absent 5=moderate 10 very severe Stool form 1= separate hard lumps, like nuts 6 = fluffy pieces with ragged edges 2= sausage shaped but lumpy 7 = watery, no solid pieces 3= like a sausage or snake, but with cracks on its surface 4= like a sausage or snake, smooth and soft 5= soft blobs with clear cut edges

43. Changes to IBS classification Rome III Summary • No change to basic criteria • Length of time needed to define chronicity reduced to 6 months • Threshold ≥3 days / month introduced for frequency of pain / discomfort • Subtyping simplified (stool consistency) • Stability of subtypes and link to other features like visceral sensitivity and response to treatment remain to be determined

44. Manning Kruis Rome Rome I Rome II Rome III 1978 1984 1989 1990 1999 2006 IBS diagnostic criteria Rome IV 2016 INTERNAL USE ONLY. DO NOT COPY. DO NOT DISTRIBUTE EXTERNALLY.

45. Associated Symptoms • In people with IBS in hospital OPD. – 25% have depression. – 25% have anxiety. • Patients with IBS symptoms who do not consult doctors [population surveys] have identical psychological health to general population. • In one study 70% of women IBS sufferers have dyspareunia. 45

46. Associated Symptoms • Stressful life events are associated. • Compared with controls people with IBS are less well educated and have poorer general health. • Women:Men = 3:1. 46

47. Reasons to Refer • Age > 45 years at onset. • Family history of bowel cancer. • Failure of primary care management. • Uncertainty of diagnosis. • Abnormality on examination or investigation. 47

48. Urgent Referral • Constant abdominal pain. • Constant diarrhoea. • Constant distension. • Rectal bleeding. • Weight loss or malaise. 48

49. Differential Diagnosis • Inflammatory bowel disease. • Cancer. • Diverticulosis. • Endometriosis. • A positive diagnosis, based on Manning’s criteria may provoke less anxiety than extensive tests. 49

50. Examination • Results should be normal or non-specific. • Abdomen and rectal examination. • FBC, CRP. • No consensus as to whether FOBs or sigmoidoscopy is needed. 50

51. Treatment • Patients’ concerns. • Explanation. • Treatment approaches. 51

52. Patients’ Concerns. • Usually very concerned about a serious cause for their symptoms – Cancer phobias • Take time to explore the patients agenda. • Remember that investigations may heighten anxiety. 52

53. Explanation. 53 • Must offer a plausible reason for symptoms. • Even if cause is unknown, patients require some explanation. • Drawing a parallel with baby colic may help. • Stress is currently a socially acceptable explanation for many symptoms in life.

54. Treatment Approaches. 54 • Placebo effect of up to 70% in all IBS treatments. • Treatment should depend on symptom sub-type. • Often considerable overlap between sub-groups.

55. Psychotherapy • Antidepressants – Poor evidence for efficacy – Better evidence for tricyclics • May have some effect other than antidepressant effect – Very little evidence for SSRIs • Relaxation therapies may be useful adjunct. • CBT (Cognitive Behavioral Therapy) 55

56. 5HT related drugs • 5HT Receptor Antagonists – Allosetron • 5HT Rerceptor Agonists – Tegarasod 56

57. Constipation Predominant. • Increased fibre. • Osmotic laxatives helpful, Ispaghula husk is one. • Stimulant laxatives make symptoms worse. • Lactulose may aggravate distension and flatulence. 57

58. Pain Predominant. • Antispasmodics will help 66%. • Mebeverine is probably first choice. • Hyoscine 10mg qid can be added. • Bloating may be helped by peppermint oil. • Nausea may require metoclopramide. 58

59. IRRITABLE BOWEL SYNDROME Spasmolytic agents Alverine Cimetropium Dicyclomine Hyoscine Mebeverine Otilonium Pinaverium Pirenzipine Prifinium Propinox Rociverine Trimebutine

60. others • Antibiotics – Rifaximin • Pre-biotics • Pro-biotics Sept 2001 Bruce Davies 60

61. Diet • Dietary manipulation may help. • Food intolerance is common • Food allergy is rare. 61

62. Spiller and Thompson 2010 World Gastroenterology Organisation Global Guideline 2009 IBS-C, irritable bowel syndrome with constipation; IBS-D, irritable bowel syndrome with diarrhoea; SSRI, selective serotonin reuptake inhibitor IRRITABLE BOWEL SYNDROME Rome/WGO management cascade Patient with chronic or recurrentabdominal pain/discomfort associated with disordered bowel habit no History and clinical examination Alarm features? yes Investigations as indicated Consider limited screening tests Any abnormality identified? yes IRRITABLE BOWEL SYNDROME (IBS) Initial therapy: treat primary symptom: spasmolytic yes Symptom relief? no Assess symptom pattern Long-term management IRRITABLE BOWEL SYNDROME WITH DIARRHOEA (IBS- D) IRRITABLE BOWEL SYNDROME WITH CONSTIPATION (IBS-C) IRRITABLE BOWEL SYNDROME WITH PAIN Alosetron, rifaximin, ….? Lubiprostone, linaclottide, ….. Tricytlic, SSRI, …..

63. Referral • About 15% of patients seen by GPs with IBS are referred. • Gastroenterology – Mainly upper GI symptoms. • General Surgical – Lower GI symptoms. • 63

64. Psychological Thoughts • Should a mental health assessment always be done? • Should all therapy be directed at psychological causes? • Is IBS a physical or a somatisation disorder? 64

65. Thank you • Questions? Sept 2001 Bruce Davies 65