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Integrated Approach to Irritable Bowel Syndrome

Integrated Approach to Irritable Bowel Syndrome. Douglas A. Drossman, M.D. Co-Director UNC Center for Functional GI & Motility Disorders Chapel Hill, NC, USA. www.RomeCriteria.org. IBS - Definition.

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Integrated Approach to Irritable Bowel Syndrome

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  1. Integrated Approach to Irritable Bowel Syndrome Douglas A. Drossman, M.D. Co-Director UNC Center for Functional GI & Motility DisordersChapel Hill, NC, USA

  2. www.RomeCriteria.org

  3. IBS - Definition • . . . a group of functional bowel disorders in which discomfort or pain is associated with defecation or a change in bowel habit, and with features of disordered defecation. • Possible Subgroups Include: • Motor Dysfunction • Visceral Hypersensitivity • Post-Infectious – Immune Dysfunction • Central Pain Dysregulation Rome II Book, 2000

  4. AGA Burden of Illness Study (2000) 20,000 16,000 Prevalence (thousands) Adjusted annual costs (millions) 12,000 8,000 4,000 0 GERD IBS Peptic ulcer Diverticular disease IBD CRC Sandler RL, Gastrenterology 2002; 122:1500

  5. IBS - Physiologic Research Stress affects GI function Pain sensitivity Clustered contractions CNS / ENS Autonomic reactivity Meals Pain / motility 3 cpm motility Visceral hypersensitivity Post-infectious IBS 1950 1960 1970 1980 1990 2000 Mechanisms Brain-Gut Interactions Motility Myoelectrical Marker Inflammation Visceral Hypersensitivity

  6. IBS - Physiology 2000 1500 1000 Meal Sigmoid Motility Index IBS 500 Normal 0 0 130 100 50 Minutes Rogers J, Gut 1989; 30:634

  7. IBS Pathophysiology Diarrhea Constipation Segmental (non-propulsive) contractions HAPCs (propulsive) Postprandial rectal tone Rectal hypersensitivity Gastrocolic response Camilleri, Gastroenterology 2001; 120:652

  8. Alternator Proportion of IBS-D, IBS-M, IBS-C by Diary Cards 317 253 185 175 174 163 100 IBS-D 80 60 IBS-M % 40 IBS-C 20 0 Baseline 12 wks. 3 mo. 6 mo. 9 mo. 12 mo. Drossman et al., Gastroenterology 2005, 128:580

  9. Alternator Time to Change Classifications Curves, IBS-C, IBS-D, IBS-M 1.00 .75 Survival distribution function .50 IBS-C IBS-D .25 IBS-M 0 0 12 wks. 3 mo. 6 mo. 9 mo. 12 mo. Drossman et al., Gastroenterology 2005, 128:580

  10. IBS - Physiology 60 IBS 40 % Reporting Pain 20 Normal 0 20 60 100 140 180 Rectosigmoid balloon volume (ml) Whitehead et al., Gastroenterology 1990;98:1187

  11. IBS - Hypersensitivity End Organ Sensitivity CNS Modulation • Mucosal inflammation • Mechanical distension • Cingular cortex • Brainstem Visceral Hypersensitivity Hyperalgesia Allodynia Spinal Hyperexcitability Sensitization • Post-infectious IBS • NO activation • C-FOS activation • Neuroplasticity

  12. IBS Influences on Visceral Sensitization • Abnormal inputs • Repetitive bowel stimulation • Acute inflammation • Infection • ? other • Neurological trauma • Operations • Invasive procedures Drossman DA et. al., Gastroenterology 2002, Dec;123(6):2108-31.

  13. IBS – Physiology 45 Baseline 40 Post sigmoid stimulation 35 Rectal Pain Threshold (mm Hg) 30 25 20 0 Controls IBS Munakata J, Gastroenterology 1997; 112:55

  14. IBS - Sensory Sensitization Mechanosensitive afferent Sensitized spinal circuits Dorsal root ganglion Repeated stimulation

  15. IBS - Sensitization Hyperalgesia Pain sensation Insult Allodynia Normal Innocuous Noxious Stimulus Intensity

  16. IBS Physiology - Colonic Immune Cells Control n=28 NSMC n=31 Non-specific microscopic colitis Rome I - IBS IBSNI n=38 IBS - non-inflamed LC n=8 Lymphocytic colitis *** 2000 p<0.05 * p<0.001 *** *** *** 1500 Cells / sq. mm lamina propria *** *** * 1000 500 0 CD3 CD8 Mast Cells Chadwick, et. al., Gastroenterology 2002; 122:1778

  17. p<0.05 * p<0.01 ** p<0.001 *** IBS Physiology - Colonic Immune Cells Control n=28 NSMC n=31 Non-specific microscopic colitis Rome I - IBS IBSNI n=38 IBS - non-inflamed LC n=8 Lymphocytic colitis 3 50 50 * numerous aggregates *** *** 40 40 *** *** 2 moderate 30 30 % per 100 epithelial cells Cells / sq. mm lamina propria 20 20 few 1 ** * 10 10 absent 0 0 0 CD25 NK1 IELs Chadwick, et. al., Gastroenterology 2002; 122:1778

  18. IBS - Physiology Mast Cells Degranulation Close to Neurons 20 Number of degranulated mast cells 10 0 0 5 10 15 20 Number of mast cells <5mm from nerves Barbara G., et al., Gastroenterology 2004; 126:693

  19. IBS - Physiology Relation of Mast Cells Close to Neurons with Abdominal Pain 4 4 3 3 Abdominal pain severity score Abdominal pain frequency score 2 2 1 1 0 0 0 5 10 15 20 0 5 10 15 20 Number of mast cells <5mm from nerves Barbara G., et al., Gastroenterology 2004; 126:693

  20. IBS Physiology Serotonin (5HT) in the Gut • 95% GI tract (EC cells, mast cells); 5% CNS • Mediates GI function in ENS / CNS • Motility • Sensation / perception • Secretion • Mechanical / chemical stimuli 5HT • 5HT increased after a meal (IBS > controls) EC cells Mast cells

  21. IBS - Physiology Post-Prandial 5-HT Concentration 80 Meal 70 IBS-C IBS-D Control 60 50 40 5-HT concentration (nmol/L) 30 20 10 0 -120 -60 0 30 60 90 120 150 180 210 240 Time relative to meal (minutes) Atkinson W, et al., Gastroenterology 2006; in press

  22. IBS Physiology Serotonin (5-HT) in the Human Gut 5-HT1 5-HT3 5-HT4 Gastric accommodation Transit Colonic tone Sensation Secretion ?

  23. IBS - Physiology - Serotonin Receptors 5-HT4 Inhibitory motor neuron Excitatory motor neuron 5-HT1A 5-HT3 ACh NO, VIP 5-HT1D Contraction Relaxation

  24. IBS - Physiology VIP / NO Neurons ACh / SP Motor Neurons CGRP CGRP 5-HT4 Receptor Grider et. al., Gastroenterology 1998; 115:370

  25. Serotonin Signaling • Enterochromaffin (EC) cells secrete serotonin • Serotonin binds to receptors on nerves to modulate motility, secretion and sensation • SERT (serotonin reuptake transporter) mediates the uptake of serotonin into epithelial cells to inactivate it Adapted from Gerson MD, Rev Gasterol Dis 2003; 3:S25

  26. IBS - Pathopathology Number of EC Cells in IBS and UC 50 40 30 Number EC Cells per mm muscularis mucosa 20 p<0.05 * 10 0 Control Mild Severe IBS-D IBS-C UC Coates, et al. Gastroenterology 2004, 126:1657

  27. IBS - Pathopathology Basal and Stimulated 5HT Release Basal 5HT Release Stimulated 5HT Release 5 5 4 4 3 3 Pmol / mg wet weight Pmol / mg wet weight 2 2 2 1 0 0 Control UC IBS-D IBS-C Control UC IBS-D IBS-C Coates, et al. Gastroenterology 2004, 126:1657

  28. IBS - Pathopathology SERT Activity in IBS and UC SERT mRNA SERT- IR Intensity .05 100 p<0.001 * p<0.05 * .04 75 .03 Mean pixel intensity (0-256 scale) fg / pg b-actin mRNA 50 .02 * * 25 * * .01 * * 0 0 Control UC IBS-D IBS-C Control UC IBS-D IBS-C Coates, et al. Gastroenterology 2004, 126:1657

  29. Effect of 2 Hour Intestinal Gas Infusion in IBS and Health 1400 Gas evacuated ml Health IBS 0 0 120 Infusion time (minutes) Serra et. al, Gut 2001; 48:14

  30. IBS - Physiology Intestinal Gas and Perception 6 IBS Health Perception score 3 0 -400 0 600 1,600 Gas retained (mL) Serra et al, Gut 2001;48:14

  31. IBS - Physiology Sensory Thresholds (IBS with Bloating) Without distension n=16 With distension n=21 40 Normal range for healthy volunteers * * 30 * =p<0.02 Pressure (mmHg) 20 10 0 first sensation stool sensation discomfort Lea R, Reilly B, Gastroenterology 2004; 126:A-53

  32. IBS - Pathophysiology Integration Effect Input Cognition Affect Sight Sound Smell Somatosensory Motility Secretion Blood Flow Inflammation Viscerosensory Mayer EA. Gastroenterol. 1990; 99:1688

  33. HPA Axis Behavior, appetite, mood CRH ACTH ACTH IL-1, 2, 6 TNF PGE2 PAF Neuroendocrine Immune _ Glucocorticoids

  34. Exaggerated Colonic Response to CRH in IBS IBS (n = 10) Normal (n = 10) *p<0.05 Motility index (mmHg min/min) * * 500 * * 0 -60 -30 0 30 60 90 120 Time (min.) CRH 2mg/Kg i.v. Fukudo et al., Gut 1998; 42:845

  35. CRH Antagonist Inhibition of Exaggerated Motility in IBS 700 IBS(n = 9) Normal(n = 10) • *p<0.05 vs. normal • **p<0.05 vs. 1st E. stim. • ***p<0.05 vs. 2nd baseline 600 500 Motility index (mmHg %) * 400 ** 300 * 200 *** 100 0 Electrical stimulation Baseline Recovery Electrical stimulation Baseline Recovery a-helical CRH Sagami Y et al., Gut 2004; 53:958

  36. 9 6 3 0 CRH Antagonist Inhibits Intensity of Abdominal Pain in IBS IBS(n = 10) Normal(n = 10) *p<0.05, 2-way ANOVA **p<0.05 vs. 1st ES (IBS) Pain or ordinate scale (0=none, 10=maximum) Dist. B S D P 30 R B S D P 30 R Dist. Dist. ** Electrical stimulation Electrical stimulation Sagami Y et al., Gut 2004; 53:958

  37. CRH Antagonist Inhibits Visceral Stimulation-induced Anxiety in IBS 5 IBS(n = 10) Normal(n = 10) Mean ± SE 4 *p<0.05, 2-way ANOVA **p<0.05 vs. P1 (IBS) 3 Pain or ordinate scale (0=none, 10=maximum) 2 ** 1 0 Dist. B S D P 30 R B S D P 30 R Dist. Dist. Electrical stimulation Electrical stimulation a-helical CRH Sagami Y et al., Gut 2004; 53:958

  38. IBS - Ascending Visceral Pain Pathway Primary somatosensory cortex MCC pACC Thalamus Insula Reticulothalamic Spinothalamic Spinoreticular Spinomesencephalic Dorsal reticular nucleus Colon

  39. Virtual Electrode Averaged MEG Data ~90ms Red trace – painful Black trace – not painful Sensory cortex (pain sensation) Temporal sequence of activation ~120ms 250ms Cingulate cortex (pain affect) Hobson A, et al. Gastroenterology 2005; 128:610

  40. Descending Visceral Pain Pathway ACC Thalamus PAG Locus coeruleus Caudal raphe nucleus Amygdala Noradrenergic Rostral ventral medulla Serotonergic Opioidergic Colon

  41. “. . . physical pain and the more psychological pain of rejection are processed by the same areas of the brain.”

  42. IBS - Cingulate Cortex - Functional Associations Anterior Cingulate Cortex (ACC) Anterior Midcingulate Cortex 32' Midcingulate MCC 24c' 24c' 24b' Anterior MCC 24a' aMCC, dACC, ACC-CD Posterior Perigenual ACC pACC rACC Retrosplenial Infragenual Unpleasantness / fear Visuospatial Affective Autonomic Motivational /somatic Memory Drossman DA, Gut 2005; 54:569

  43. Control IBS IBS - Post Rectal Stimulation Activation (PET) in Normals and IBS Anticipation of Distension 45 mm Hg of Distension Mid Cingulate Cortex Mid Cingulate Cortex Medial Prefrontal Cortex Dorsal Pons/PAG Dorsal Pons/PAG Naliboff, et. al., Psychos Med 2001; 63:365

  44. Severe IBS / Psychological Distress Clinical Recovery (8 months later) +10 +2 +14 +24 Z=+44 +38 8 BA 40 MCC SI also +38 BA 22 BA 6/44 Ant. ins. 6 4 2 Drossman et al. Gastroenterol 2003;124:754-761

  45. Synergistic Effect of IBS and Abuse on Cingulate Cortex Activation - 50 mmHg Distention IBS / Abuse > IBS IBS / Abuse > Abuse 5 P<0.05 4 3 2 1 n = 5 n = 5 n = 5 0 IBS Abuse IBS/Abuse Pain Report Ringel, Drossman, Gastroenterology 2003 (abstract)

  46. IBS - Post Infectious Psychologic distress Younger age Factors Predicting GI Symptoms Females Duration of diarrhea Duration of abdominal pain Neal R, BMJ, 1997; 314:779 Gwee et al, Gut 1999; 44:400

  47. IBS - Epidemiology Prevalence of Dyspepsia and IBS Post-Infection Dyspepsia IBS 20 20 16 16 12 12 % 8 8 Control 4 4 Control 0 0 3 months 6 months 12 months Pre infection 3 months 6 months 12 months Pre infection Post-infection Post-infection Mearin, et al,. Gastroenterology 2005; 129:98

  48. IBS – Epidemiology Overlap of Dyspepsia and IBS Post-Infection Dyspepsia IBS 57% 43% 47% n=21 n=15 n=39 n=18 n=9 n=26 n=13 30% 38% n=17 13% n=9 23% 30% 21% 3 months post-infection 6 months post-infection 12 months post-infection Mearin, et al,. Gastroenterology 2005; 129:98

  49. IBS - Post-infection Gut Dysfunction 94 Acute Gastroenteritis Psych testing Rectal biopsy + Psych + Psych - 3 months 22 IBS+Rome I 72 No GI symptoms 18 Controls Abnormal physiology Rectal inflammation + + + - - - Gwee et. al., Gut 1999; 44:400

  50. PI - IBS Bowel Symptoms: 4 Months Post-infection 100 PI-IBS (n=28) PT-Controls (recovered, n=28) 80 Healthy Controls (n=34) 60 % 40 20 0 Loose Urgency >3 BM/wk Straining Hard stools Bloating Dunlop et al, Gastroenterology 2003;125:1651

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