IBS

1. Irritable Bowel Syndrome Dr.Chakravarthy,P.S PG in Gatroenterology AMC/KGH

2. Definition Irritable bowel syndrome (IBS) is a functional bowel disorder in which abdominal pain or discomfort is associated with defecation or a change in bowel habit. Bloating , distension, and disordered defecation are commonly associated features . WGO Practice Guidelines 2009

3. Global P revalence

4. E pidemiology Mainly occurs between the ages of 15 and 65 F irst presentation to physician - 30–50 yrs Prevalence is greater in women (except in India) P revalence in children is similar to that in adults

5. IBS demographics Studies in non-Western countries L ack of female predominance Greater frequency of upper abdominal pain Lower impact of defecatory symptoms on a patient’s daily life Stool frequency - greater in the India as a whole(99 % )

6. IBS demographics Clinical overlap between functional dyspepsia and IBS - very common in China In Latin America- constipation predominance is more frequent than diarrhea predominance

7. Pathophysiology

8. Pathophysiology ALTERED COLONIC AND SMALL BOWEL MOTILITY : High-amplitude propagated contractions (HAPCs) Enhanced gastrocolic response Rectal hypersensitivity Diarrhoea

9. Pathophysiology Increased segmental ( nonpropulsive ) contractions Decreased HAPCs Reduced rectal sensation Constipation

10. ? Precipitating factors of increased colonic & small bowel motility - distension, fatty meal, cholecystokinin , - stress, anger, deoxycholic acid - Autonomic dysfunction - administration of corticotropin releasing hormone (CRH)

11. No consensus on the exact patterns of motor derangement that induce constipation or diarrhea. Motor abnormalities observed in IBS ??? Secondary than primary

12. VISCERAL HYPERSENSITIVITY : Balloon distension of rectum (1970) Found in 60% patients IBS pts more aware of intestinal gas/contractions Abnormal sensitization within the dorsal horn of the spinal cord or higher up in the central nervous system.

13. Neurotransmitters - serotonin, neurokinins , calcitonin gene-related peptide Capsaicin ( redpepper ) receptor on nerve fibers increased in the rectosigmoid colon in IBS - mediate visceral pain N-methyl-d- aspartate (NMDA) receptor modulates central (spinal cord) neuronal excitability

14. Significant increase in serine proteases in the stools of patients with IBS-D Serine proteases  ?? damage tight junctions  increase intestinal permeability Inflammation is responsible for the sensitization

15. ABNORMAL GAS PROPULSION AND EXPULSION Retention of gas following gas infusion into the small intestine is greater in patients with IBS Intestinal gas infusion - more discomfort than controls ??? Involuntary suppression of abd.wall muscle contraction during gas infusion  more distension ??? SIBO contribute to bloating…..uncertain

16. LOCAL INFLAMMATION Increased mast cells and activated T- lymphocytes above normal in the mucosa in patients with IBS Lymphocytic infiltration of the myenteric plexus with neuron degeneration - in severe IBS Recovery from a proved episode of bacterial enteritis in 7-30% patients ( illness lasting > 3wks or caused by toxigenic organisms) A central role of mast cells ???  abd.pain

17. Mediators  5-hydroxytryptamine(5-HT) (?? Central role in inflammation) prostaglandins, bradykinins , adenosine, nerve growth factors

18. ROLE OF FOOD Wheat, dairy products, citrus fruits, potatoes, onions, and chocolate 50% patients showed symptomatic improvement on elimination of pptating diets – uncontrolled trial ?? Subtle forms of gluten intolerance in IBS-D patients ( symptomatic improvement in 70% IBS-D patients with positive HLA-DQ2 status with gluten restricted diet)

19. Fructose & sorbitol malabsorption contributes to IBS ?? ( no difference from controls on double blinded trial)

20. ABNORMAL COLONIC FLORA AND SMALL INTESTINAL BACTERIAL OVERGROWTH Increased colonic fermentation, production of excess gas  symptoms  ?? Role of probiotics High prevalance of SIBO in IBS (based on H2 breath tests & clinical response to non- absorbable antobiotics )

21. CENTRAL DYSREGULATION Alterations in the brain response to visceral stimuli in IBS ( functional MRI & PET) Greater activation of the mid- cingular cortex following delivered or anticipated rectal distention (explains why anxiety or stress can enhance perception of visceral pain, whereas relaxation or distraction decreases pain in IBS)

22. PSYCHOLOGICAL FACTORS Depression, anxiety, and somatization are the most common coexistants in IBS (40% to 94% of patients) H/O sexual, physical, or emotional abuse - more often ( abuse  ?? Alters brain response to visceral pain) Childhood stress – gastric suction– 3times more risk Anxiety secondary to intestinal inflammation (?TNF- alfa )

23. GENETIC FACTORS Familial clustering Greater concordance in monozygotic twins Potential genes : a) lower expression of IL-10 gene b) sodium channel mutation (SCN5) c) serotonin type III receptor gene – functional varient

24. Clinical features Symptoms Bloating Abnormal stool form (hard and/or loose) Abnormal stool frequency (less than three times per week or over three times per day) Straining at defecation Urgency Feeling of incomplete evacuation The passage of mucus per rectum

25. Behavioral features Symptoms present for > 6 months Stress aggravates symptoms Frequent consultations for nongastrointestinal symptoms History of previous medically unexplained symptoms Aggravation after meals Associated anxiety and/or depression

26. Non-colonic symptoms Dyspepsia— in 42–87% patients Nausea Heartburn

27. Non-GI symptoms Lethargy Backache and other muscle and joint pains Headache Urinary symptoms: — Nocturia — Frequency and urgency of micturition — Incomplete bladder emptying Dyspareunia , in women Insomnia Low tolerance to medication

28. Alarming features History Blood in the stool Family H/O colon cancer, IBD, celiac disease Fever Onset after age 50 years Nocturnal symptoms (awakening the patient from sleep) Chronic diarrhea Progressive dysphagia Recurrent vomiting Severe chronic constipation Short history of symptoms Travel history to locations endemic for parasitic diseases Weight loss

29. Alarming features Physical Examination Abdominal mass Arthritis (active) Dermatitis herpetiformis or pyoderma gangrenosum Occult or overt blood on rectal examination Signs of anemia Signs of intestinal obstruction Signs of intestinal malabsorption Signs of thyroid dysfunction

30. Diagnosis Based on history & clinical examination Matching patient’s profile to clinical criteria

31. Diagnostic algorithm( WGO practice guidelines,2009)

32. IBS diagnostic cascade Level 1 History, physical examination, exclusion of alarm symptoms, consideration of psychological factors Blood counts, ESR or C-reactive protein, stool studies (white blood cells, ova, parasites, occult blood) Thyroid function, tissue transglutaminase (TTG) antibody Colonoscopy and biopsy Fecal inflammation marker (e.g., calprotectin ) WGO practice guidelines 2009

33. IBS diagnostic cascade Level 2 Level 1 with sigmoidoscopy Level 3 Level 1 with stool studies WGO practice guidelines 2009

34. Differential Diagnosis Celiac sprue / gluten enteropathy Lactose intolerance Inflammatory bowel disease Colorectal carcinoma Acute diarrhea ( protozoal / bacterial) Small-intestinal bacterial overgrowth (SIBO) Diverticulitis Pelvic inflammatory disease /Endometriosis

35. Severity of disease Rome foundation working team report,2011,Am J GE,July,2011

36. Management EDUCATION AND SUPPORT DIET MEDICATION – laxatives,antispasmodics,antidiarrheals , serotonin receptor drugs,antideprssants , antibiotics,probiotics

37. Antispasmodics Anticholinergics – dicyclomine,propanthelene,hyoscyamine Non- anticholinergics - imetropium,pinaverium Peppermint oil- 0.2ml TID 30 min before food Laxatives Osmotic laxatives may aggravate bloating & pain Stimulant laxatives – safer Lubiprostone – 24 micgm BID WGO practice guidelines 2009

38. Antispasmodics ( Ali Phar Ther,Aug.2004,1253-1269)

39. Laxatives (Ali Phar Ther,Aug.2004,1253-1269)

40. Antidiarrheals Loperamide – effective when used prophylactically 2-16mg/d Cholestyramine Bismuth subsalicylate Serotonin-Receptor Drugs Alosetron ( 5-HT3 antagonist) efficacious in severe IBS-D Starting dose – 0.5 to 1 mg/d Can be escalated upto 1mg BID in absence of side effects Adverse effects – ischemic colitis (0.1% pts), constipation (33%) WGO practice guidelines 2009

41. Alosetron (Ali Phar Ther,Aug.2004,1253-1269)

42. Antidepressants and Anxiolytics Tricyclic antidepressants(TCAs ) - might improve global well-being more than symptoms Start at a low dose (e.g., 10 to 25 mg of desipramine or nortriptyline ) and increase the dose by 10 to 25 mg weekly, aiming for a dose of 75 mg initially Most beneficial in IBS-D Selective serotonin reuptake inhibitors (SSRIs) Fewer side effects More beneficial in IBS-C WGO practice guidelines 2009

43. Anti depressants (Ali Phar Ther,Aug.2004,1253-1269)

44. Antibiotics Nonabsorbable antibiotics – rifaximin (400mg TID for 10days) Treating a recurrence - not recommended Probiotics Bifidobacterium lactis DN-173 010 Bifidobacterium infantis 35624

45. Other Drugs Gabapentin,Pregabalin Leuprolide (GRH analogue) Colchicine , Misoprostol - ?? Role in refractory constipation Domperidone and erythromycin – prokinetic role Octreotide

46. Nonpharmacological methods Aim to reduce avoidance behavior Regular mealtimes, the intake of sufficient fluids, and sufficient physical activity Cognitive/behavioral therapy Behavioral techniques - Relaxation techniques/ Contingency management Hypnosis

47. Lubiprostone ( Aliment Pharmacol Ther Nov.2008,vol.29, 329–341)

48. Management STEP SEVERITY LEVEL OF CARE MANAGEMENT 1 Mild Primary Diagnosis,explanation,reassurance , follow-up 2 Moderate Secondary Reinforce step 1 3 Severe Tertiary Avoid over- testing,add TCA/SSRI, alosetron for severe diarrhea;treat anxiety/ depression;refer to pain clinic

49. Choice of treatment Predominant symptom First step Second step Bloating Adjust, Treat constipation Probiotic,antibiotic,TCA,SSRIs Constipation Fibre supple./ Poly ethylene glycol Lubiprostone Diarrhea Loperamaide Alosetron Abdominal pain Antispasmodic,peppermint oil TCAs,SSRIs , Psychotherapy

50. What’s new ??? IBS-C 5-HT4 receptor agonists- Tegaserod (withdrawn d/t cardiac events) Prucalopride,Naronapride,Velusetrag (no cardiac risk & more efficacy in early studies) Guanylate cyclase C agonists L inaclotide - Chey et al (2012)- 46% pts improved approved for use in the USA by the FDA in August 2012 for adults

51. Adsorbents AST 120, a carbon-based adsorbent (absorption of histamine , serotonin, bacterial products and bile acids ) 32% pts improved in priliminary studies 5‑HT3 receptor antagonist – Ramosetron ( RC trial – 343 patients, no significant benefit)

52. Futuristic therapies Nat. Rev. Gastroenterol. Hepatol. 10, 13–23 ( 2013)

53. Futuristic therapies Nat . Rev. Gastroenterol. Hepatol. 10, 13–23 (2013)

54. Futuristic therapies Nat. Rev. Gastroenterol. Hepatol. 10, 13–23 (2013)

55. Prognosis Relapses are common 9-10% develop organic disease a median of 15 years after diagnosis Poor prognosis excessive psychological distress anxiety, long duration of complaints

56. Take Home Message No more a vague symptom complex Pathophysiology ??? History & examination is of prime importance Always R/O organic disease before diagnosis Treatment – predominantly symptomatic Behavioral therapy is important Newer drugs in pipeline

57. THANK YOU

58. References Sleisenger’s text book of GI diseases,9 th edition WGO practice guidelines,2009 Cochrane database Alimentary phar & therapeutics,reviews 2004-06 Nat. Rev. Gastroenterol. Hepatol. 10, 13–23 (2013)