Advances in the Epidemiology of Functional GI Disorders

1. Advances in the Epidemiology of Functional GI Disorders Dr Smita Halder Mount Sinai Hospital Toronto DDH Symposium March 20th 2009

2. Outline • FGID general overview • New advances

3. What is a Functional GI Disorder? • Common, unexplained disorders • Irritable Bowel Syndrome • Functional Dyspepsia • Chronic abdominal symptoms in the absence of biochemical or structural explanation • Abdominal pain, bloating, nausea, erratic bowel habit, early satiety

4. How prevalent in UK? • IBD rates at age 30: • 38 (per 10,000) for Crohn’s disease, • 30 (per 10,000) for Ulcerative Colitis • IBS rates: • 826 (per 10,000) • ~ 25 times more common Ehlin et al, Gut 2003

5. Adapted from Talley, 1999 Prevalence of IBS (%) IBS prevalence worldwide?

6. Prevalence of IBS by age and gender in Olmsted County, MN Talley, 1999

7. Natural History Difficult to assess due to: • Lack of prospective population databases • Indistinct nature of the phenotype • Short duration of follow up in previous studies

8. Prevalence per 100 of FGID subgroups at two time points Halder et al, Gastro 2007

9. Symptom Transitions • In general: • one third had resolution of symptoms • one third had symptom stability • one third transitioned to a new group Halder et al, Gastro 2007

10. consulters population FGIDs – how big a problem? 50% of GI clinic workload 2% 7% 25% Majority of symptoms last >1 year

11. Burden of illness (1) • Quality of life is significantly  in IBS sufferers Halder et al, 2004 • IBS sufferers • Make more physician visits than non-IBS • Visit for non-GI complaints with more frequency Longstreth et al, 2003

12. Burden of illness (2) • Annual expenditure for IBS, direct and indirect costs: • $30 billion in the US; £45.6 million in the UK • £1000 spent / year / affected patient in the UK • Expenditure for FD: £1 billion per year • Cost to the NHS (prescriptions / diagnostic OGDs): £500 million per year Moayyedi et al, 2002

13. Rome III Process • International classification system • Evolved from Manning criteria, 1978 • Symptom clusters- anatomical regions • Rome III published 2006 • Aids standardisation in clinical studies • Rarely used in non-research settings Robinson et al, Gut 2001

16. IBS Recurrent abdominal pain or discomfort at least 3 days per month in the last 3 months that has two or more of the following features: Improved with defæcation Onset associated with a change in frequency Onset associated with a change in form Functional Dyspepsia One or more of: Bothersome postprandial fullness Early satiation Epigastric pain Epigastric burning AND No evidence of organic disease (including at upper endoscopy) that is likely to explain the symptoms Rome III Criteria

17. IBS Recurrent abdominal pain or discomfort at least 3 days per month in the last 3 months that has two or more of the following features: Improved with defæcation Onset associated with a change in frequency Onset associated with a change in form Functional Dyspepsia One or more of: Bothersome postprandial fullness Early satiation Epigastric pain Epigastric burning AND No evidence of organic disease (including at upper endoscopy) that is likely to explain the symptoms Rome III Criteria

18. Pathophysiology • Brain-Gut Axis • ENS / CNS interaction • Visceral hypersensitivity • Dysmotility of GI tract • Biopsychosocial model

19. Psychosocial Factors • Life stress • Psychological state • Coping • Social support Outcome QoL Daily function Health care use Medications Work absenteeism IBS Symptoms Early life Genetic Environment Physiology Illness Behaviour CNS PNS Brain-Gut Axis Intestinal Function Drossman, 2001

20. Potential Stressors

21. Potential Stressors

22. Potential Stressors

23. PhD Study Functional Gastrointestinal Symptoms: Risk factors for Consultation and Persistence

24. Hypothesis Psychosocial profile Consultation Clinical factors Persistence Infection

25. Baseline Follow-up FGID No FGID FGID ? Onset Time Measure Risk Factors Measure Outcome Overall Study Design

26. Results • Descriptive statistics • Consultation factors • Persistence factors

27. 610 consulted GP with GI symptoms (12%) 66.6 % F 473 eligible 368 participated 105 refused 68.5% F Recruitment for GI study

28. Distribution of symptoms %

29. Results • Descriptive statistics • Consultation factors • Persistence factors

30. 4.00 4.00 3.50 3.50 3.00 3.00 2.65 2.50 2.50 Hazard Ratio* *Adjusted for age & gender 2.00 2.00 1.50 1.50 1.46 1.28 1.00 Highest level Sleep disturbance Highest level Illness behaviour Females Hazard Ratios for Consulting: Multivariate Analysis

31. Results • Descriptive statistics • Consultation factors • Persistence factors

32. 10 10 5 5 4.59 Odds Ratio* 3.08 3 3 2.45 *Adjusted for age & gender 1 1 GHQ at time of symptoms Symptoms for >3 months Symptom duration >2 hours 0.1 Odds Ratios for Persistence: Multivariate Analysis

33. Odds Ratios for Persistence: Multivariate Analysis 10 10 5 5 Odds Ratio* 3 3 *Adjusted for age & gender 2.29 1 1 0.23 0.23 0.1 0.1 Adverse impact on daily life Change in diet Gastroenteritis

34. Recent advances • Genetics • Brain imaging

35. Genetics of FGID • Unlikely to be single genetic factor • Probably a complex interaction between • genetic profile • environmental influences • phenotype all increase susceptibility to sx onset

36. Familial clustering • UK study: • 100 IBS patients: 33% reported FHx IBS • 100 matched controls: 2% reported FHx IBS Whorwell et al, Gut 1986 • Mayo study: • OR 2.3 [1.3-3.9] of having 1stº relative with abdo pain/ bowel probs and reporting IBS/FD Locke et al, 2000

37. Twin Studies • IBS twice as frequent in MZ twins cf DZ Morris-Yates et al, 1998; Levy et al 2001 • Inherited pathophysiological mechanisms or learned response? • Children of IBS parents visit hospital more often than children of non-IBS parents Levy et al, Am J Gastro 2000 • Intergenerational transmission of illness behaviour

38. Individual genes (1) Serotonin transporter gene: • Functional polymorphism in SLC6A4 linked with diarrhoea in women with IBS • LL genotype associated with response to alosetron (5HT3 rec antagonist) • S allele associated with response to tegaserod Camilleri et al, Lancet 2000

39. Individual genes (2) Cytokines: • Interleukin-10 (anti-inflammatory) • High-producer genotype more prevalent in controls than IBS Gonsalkorale et al, Gut 2003 • TNF (pro-inflammatory) • High-producer genotype more prevalent in IBS than controls van der Veek et al, Am J Gastro 2005

40. Candidate Genes for IBS Receptors: Alpha-2A-adrenergic rec (ADRA2A) Alpha-2C-adrenergic rec (ADRA2C) 5-HT2A receptor (5-HT2A) Neurotransmitter transporters: Serotonin transporter (SLC6A4) Norepinephrine transporter (NET) Neurotransmitter metabolism: Fatty acid amide hydrolase (FAAH) Inflammatory markers: Interleukin-10 (IL-10) Transforming growth factor-β1 (TGF-β1) Tumor necrosis factor-alpha (TNF-α) Intracellular cell signaling: G protein β3 subunit (GNβ3) Ion channels: Sodium channel (SCN5A)

41. Functional Dyspepsia • Homozygous GN β3 825CC carrier status significantly associated with upper-abdominal sx Holtmann et al, Gastro 2004

42. GN β3 C825T in lower FGID • Olmsted County Study, Mayo Clinic • 82 IBS-C; 94 IBS-D; 38 IBS-Alternating; 19 Abdo Pain • 152 Controls • GN β3 C825T genotype distributions similar btwn cases/ controls • No associations found in lower FGIDs overall Andresen et al, Gastro 2006

43. Limitations to genetic studies • Bias inherent in the study design • Poor statistical analysis • Small sample size • Over interpretation of data

44. Advances in research tools

45. Functional Brain Imaging • Aids in investigating • Brain-Gut interactions • CNS role in visceral pain perception • Positron Emission Tomography (PET) • Functional Magnetic Resonance Imaging (fMRI) • Magnetoencephalography (MEG)

46. PET scanner

47. Advantages Excellent spatial resolution Can study receptor sites Disadvantages Poor temporal resolution Radiation Expensive PET Radioisotope injected - cerebral blood flow measured

48. ACC Control ACC IBS Silverman, Gastro 1997

49. Control IBS Silverman, Gastro 1997

50. fMRI