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Rome III based IBS and female

Rome III based IBS and female. Full-Young Chang GI Division Feb. 7 , 200 7 at the Dept of GYN. Dr. G (GI & GYN)? 1971. Hospital of the University of Pennsylvania (HUP) 美國費城賓州大學附屬醫院（1989年7月至1990年7月）. IBS, an example of FGID.

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Rome III based IBS and female

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  1. Rome III based IBS and female Full-Young Chang GI Division Feb. 7, 2007 at the Dept of GYN

  2. Dr. G (GI & GYN)? 1971

  3. Hospital of the University of Pennsylvania (HUP) 美國費城賓州大學附屬醫院（1989年7月至1990年7月）

  4. IBS, an example of FGID • IBS cardinal symptoms description: pain, derangement of ….digestion, and flatulence • Powell R. Med Trans Royal Coll Phys 1818;6:106-17. • The bowels are at one time constipated and at another lax in the same person-----how the disease has two such different symptoms I do not propose to explain • Cumming W. London Med Gazette 1849;NS9:969-73. • Separated IBS from functional diarrhea, began with an enteric infection • Chaudhary NA, et al. Q J Med 1962;31;307-22. Thompson WG. Gastroenterology 2006;130:1552-6.

  5. Lecture contents • FGID disease model • Visceral pain pathophysiology • Rome III classification • IBS knowledge • Represented IBS reports in Taiwan

  6. FGID, 2006 • Nonstructural symptoms • Enigmatic, less amenable to explain or effective treatment • Problems of living: physiological, intrapsychiatric, and sociocultural impacts on daily life activities • There is no evidence of an inflammatory, anatomic, metabolic or neoplastic process that explains the patient’s symptoms • From single biological etiology to integrated biopsychosocial model of illness/disease • Mind amenable to scientific study, playing role in illness • Link of mind & body  dysregulation  illness • AGA 704 member survey of FGID • No known structural: 81% • Stress disorder: 57% practitioners, 34% academicians/ trainees • Motility disorders: 43% practitioners, 26% academicians/ trainees • Physicians deny FGID existence or unneeded studies Drossman DA. Gastroenterology 2006;130:1377-90.

  7. FGID conceptual model • Early life • Genetics • Environment • Psychosocial factors • Life stress • Psychologic state • Coping • Social support • Outcome • Medication • MD visits • Daily function • QoL Brain CNS Gut ENS • Physiology • Motility • Sensation • Inflammation • Altered flora • FGID • Symptoms • Behaviors Drossman DA. Gastroenterology 2006;130:1377-90.

  8. Brain and gut Effector systems Muscle Secretory glands Blood vessels Sensory neurons ENS: Integrated synaptic circuits Wood JD. Schuster Atlas of GI Motility. 2nd ed, 2002:19-42.

  9. Afferent nerve transmission

  10. Classic afferent pain pathway • First order: viscera to spinal cord • Pass through autonomic nerve plexus (nerve web to major artery supply) • Run within regional splanchnic nerves • Vagal afferents: mainly autonomic functions, but also with pain conduction • Sympathetic chain (thoraco-lumbar) • Enter spinal cord white ramus, synapsed in dorsal horn (laminae I, II, V) • 1st order neuron body: dorsal root ganglia • Second order: spinal cord to brain stem • Third order: brain stem to higher levels of cortex Michael D, et al. Schuster Atlas of GI Motility. 2nd ed, 2002:43-55.

  11. Classic afferent pain pathway (2) • Second order: spinal cord to brain stem • Postsynaptic neurons: superficial laminae of dorsal horn  cross to contralateral side  cephalad within ventrolateral quadrant of spinal cord (tracts)  synapse within thalamic and reticular formation nuclei of pons and medulla • Spinothalamic tract • Spinoreticular tract • Third order: brain stem to higher levels of cortex • Widely distributed in brain • Spinothalamic tract: somatosensory cortex for pain perception, quality and localization • Spinoreticular tract: limbic system, frontal cortex, motivation-affective pain perception (unpleasant) Michael D, et al. Schuster Atlas of GI Motility. 2nd ed, 2002:43-55.

  12. Sensory central transmission

  13. Brain imaging in rectal stimulation (fMR) • Normal visceral sensation: • 1. Gender difference,  ACC & PFC in females • 2. Common FGID in females? Grundy D, et al. Gastroenterology 2006;130:1391-1411.

  14. Psychological factors • Strong emotion, stress:  motility •  motor response to stressors, partially correlated with symptoms • Modulators of experience, behavior, clinical outcomes • Not necessary to diagnose FGID • Evidence • Stress  GI symptoms • Modifying experience, behaviors & seeking care of illness • FGID with psychosocial consequences on general well-being, daily function status, sense, future functioning at work or at home Drossman DA. Gastroenterology 2006;130:1377-90.

  15. History of the Rome diagnostic criteria Thompson WG. Gastroenterology 2006;130:1552-6.

  16. Rome III • Rome board • 2002, London: 7-member coordinating committee • Validation, promotion of evidence • Gender, society, patient, social issues • Encouraging “developing world” participation • China, Brazil, Chile, Venezuela, Hungary, Romania • 87 participants from 18 countries in 14 committees, • Nov/Dec 2004: culminated meeting in Rome • Prepared drafts, published and reported: May 2006 • Preliminary discussion for Rome IV Thompson WG. Gastroenterology 2006;130:1552-6.

  17. Rome III classification of FGIDs • 28 adults, 17 pediatric • Symptom-based, motor/sensory/CNS relationship • Symptoms may be overlapped • 6 domains in adults • Esophageal, gastroduodenal, bowel, functional abdominal pain syndrome (FAPS), biliary, anorectal • Bowel: IBS, FD, FC, functional bloating • Pediatric; age category • Neonate/toddler, child/adolescent Drossman DA. Gastroenterology 2006;130:1377-90.

  18. FGID (bowel & pain) • Functional bowel disorders • C1: IBS • C2: Functional bloating • C3: Functional constipation • C4: Functional diarrhea • C5: Unspecified functional bowel disorder • D: Functional abdominal pain syndrome Drossman DA. Gastroenterology 2006;130:1377-90.

  19. Irritable bowel syndrome (IBS) • IBS is a functional bowel disorder in which abdominal pain or discomfort is associated with defecation or a change in bowel habit, and with features of disordered defecation • 10-20% adults in world, female predominant • Come and go over time, overlap with other FGID • Poor QoL, high heath care costs Longstreth GF, et al. Gastroenterology 2006;130:1480-91.

  20. Diagnostic criteria for IBS, C1 • Recurrent abdominal pain or discomfort at least 3 days per month in the last 3 months associated with 2 or more of the following: • Improvement with defecation • Onset associated with a change in frequency of stool • Onset associated with a change in form (appearance) of stool • Criteria fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis • Discomfort: uncomfortable sensation not described as pain Longstreth GF, et al. Gastroenterology 2006;130:1480-91.

  21. Sub-typing IBS by predominant stool pattern • Subtype (absent use of antidiarrheals or laxatives) • IBS-C (IBS with constipation): hard or lumpy stools >25% and loose (mushy) or watery stools <25% of BMs • IBS-D (IBS with diarrhea): loose (mushy) or watery stools >25% and hard or lumpy stool <25% of BMs • IBS-M (mixed IBS): hard or lump stools >25% and loose (mushy) or watery stools > 25% of BMs • IBS-U (unsubtyped IBS): insufficient abnormality of stool consistency to meet criteria for IBS-C, D, or M • Stool form:Bristol scale Longstreth GF, et al. Gastroenterology 2006;130:1480-91.

  22. Bristol stool form scale Heaton KW, Fast Facts of IBS 1999;27.

  23. Two-dimensional display of IBS subtypes 100% 75% 50% IBS-C IBS-M % hard or lumpy stools 25% IBS-U IBS-D 25% 50% 75% 100% % loose or watery stools Longstreth GF, et al. Gastroenterology 2006;130:1480-91.

  24. IBS clinical manifestations • Abdominal pain • Generalized or lower abdomen • Relieved by defecation, strongly associated with stress • Others • Bloating, distension, mucus, urgency, incomplete defecation • Changed frequency and consistency of BM • No unique etiology to explain clinical disorders • Motor, sensory disorders • Local inflammation • Central, peripheral mechanisms • Psychological • No universally effective therapy • Symptom based therapy: subgroups of IBS Bueno L. Curr Opin Pharmacol 2005;5:583-8.

  25. IBS pathophysiology and treatment

  26. Extra-colonic symptoms in IBS • More physician visits: X 3 • Undergoing more abdominal/GYN surgeries • More chronic pelvic pain • GU/GYN dysfunctions • Dysmenorrhea, dyspareunia, impotence, urinary frequency, nocturia, incomplete bladder emptying • Fibromylagia: 2/3 reported rheuma sx • Associated with IBS severity • 63% chronic fatigue with IBS • Others: headaches, back pain, HCVD? PU? Skin rash, insomnia, palpitation, loss of concentration, unpleasant taste Hasler WL, et al. Yamada T, Textbook of Gastroenterol 4th ed, 2003: 1817-42.

  27. QoL burden in IBS

  28. IBS social cost, USA (1998)

  29. Alarm symptoms in IBS diagnosis • Age of onset over 50 yrs • Progressive or very severe non-fluctuating symptoms • Nocturnal symptoms waking from sleep • Persisted diarrhea, recurrent vomiting • Rectal bleeding, anemia • Unexplained BW loss • Family history of colon cancer • Fever • Abnormal physical examinations Talley NJ, et al. Lancet 2002;360:555-564.

  30. Natural history of IBS • A safe diagnosis • Chronic disorder with extremely variable • Fluctuated symptoms • Stable prevalence in community over 12-20 months • Repeated investigations: reinforce illness behavior • Considering alarming factors • No  to other organic disorders Camilleri M. Management of the IBS. Gastroenterology 2001;120:652-68.

  31. IBS treatment • Positive clinical diagnosis • Exclude other organic disorders • Reassurance, explanation, advice precipitating factors • Targeting on major symptoms • Follow up in treatment response • Good doctor-patient relationship  visits • Subgroup based treatment on bowel habit • Unsatisfactory in medicine • Poorly understood • High placebo effect: 30%~80% in short-term trials and  with time • Targeting new receptors Talley NJ. Lancet 2001;358:2061-8.

  32. Enteric nervous system (ENS)

  33. 5-HT and peristaltic reflex SS ENK CGRP VIP/PACAP/NO Ach/ SP/NKA Muscle Muscle Ascending Contraction Descending Relaxation 5 HT EC Yamada T: Textbook of Gastroenterology 3rd ed, 1999:100

  34. Tegaserod treatment • Partial 5-HT4 agonist (also blocking 5-HT2B) • Approved, female C-IBS (2004 review) •  overall symptoms, BM •  no BM days • No effect: abdomen pain/discomfort • Potential indications:  GE, stomach compliance • UGI: dyspepsia, gastroparesis • Intestinal pseudo-obstruction? Galligan JJ, et al. Neurogastroenterol Motil 2005;17:643-653.

  35. ZAP trial for C-IBS, tegaserod vs. placebo, Asia-Pacific 2003 Tegaserod 6 mg twice daily (n=259) or placebo (n=261) for 12 week Kellow J, et al. Gut 2003;52:671-6.

  36. Alternative therapies • Replaced colon flora: in controlled trial, efficacy, safety? • Local action of antibiotics: effect in some, need rigorous test • Probiotics:  flatulence in IBS • Peppermint oil: no convincing data • Chinese herb drug: significant in a trial • Mixture, true action? Need other trials to confirm • Acupuncture: uncertain benefit Talley NJ. Am J Gastroenterol 2003;98:750-8.

  37. Alternative therapy for IBS Hussain Z, et al. APT 2006:23:465-71.

  38. IBS in females VS

  39. IBS characters in Asian large scale studies • IBS in Japan (Kumano H. Am J Gastroenterol 2004;99:370-6) • 4000 (M:50%) subjects, national wide random questionnaire • Rome II: 6.1% • M/F: 4.5%/7.8%, p<0.001 • Highly associated morbidity, agoraphobia • Female: higher morbidity • No different in consulters or non-consulters • IBS in Southern China (Xiong LS, et al. Aliment Pharmacol Ther 2004;19:1217-1224) • 4178 (M: 45.6%), face to face interview, random cluster sampling Guangzhou • Manning: 11.5%; Rome II: 5.7% • Female predominance: Manning (1:1.34), Rome II (1: 1.25) • Risk factors: NSAID using, food allergy, psychological distress, life event stress, dysentery, negative copying style,  health related QoL

  40. IBS symptom number according to Manning criteria Heaton KW, et al. Gastroenterology 1992;102:1962-7.

  41. Gender factor on IBS symptoms, Taiwan 2005 Lu CL, et al. Aliment Pharmacol Ther 2005; 2005;21:1497-505.

  42. Gender influence on IBS-D Viramontes BE, Am J Gastroenterol 2001;96:2671-6.

  43. Alosetron Effect: Female vs. Male(S3BA2001 study) Female Male * P=0.009 P=0.073 P=0.002 ** ■ Placebo ■ Alosetron (1 mg bid) Mangel AW, et al. APT 1999; 13(suppl) 27:77-82

  44. Sex hormones or gender impacts on brain-gut axis • Animals • Low threshold for visceromotor response in rat proestrus vs estrus phase •  potency of opiates to  visceromotor response in male rats • Modulation of response in afferent neurons of male GP • Drugs: estrogen/progesteron on P-450 system • CYP3A4: women clearing drugs quickly • Humans • Slow GE in women • Women experience greater pain to most stimuli • Different areas of brain activation: males vs females • Different polymorphism of 5-HT transporter promoter: males vs females Ouyang A, et al. Am J Gastroenterol 2006;101:S602-9.

  45. Clinical differences of IBS: males vs females • Motility: no confirmed data • Autonomic system:  sympathetic/ vagal activity to colorectal distension in men • Afferent sensory pathways:  threshold to rectal distension in women IBS • Female: easily developing PI-IBS • Psychological status:  depression, anxiety, somatization in women • Drug response:  efficacy of 5-HT3 antagonists, 5-HT4 agonists Ouyang A, et al. Am J Gastroenterol 2006;101:S602-9.

  46. Modulating factors Brain-gut axis Clinical expression Affective state Stress: physiologic & Behavioral Gender role Gondal hormones /menses Pain severity Coping behaviors Affective state ANS parameters Gondal hormones /menses Gondal hormones Menses Infection & sequelae Inflammation Bowel habits Motility Response to medication Ouyang A, et al. Am J Gastroenterol 2006;101:S602-9.

  47. IBS in Taiwan, 2003 • 2,018 (M:60.2%), paid physical check up, self-administered questionnaire • Prevalence: • Rome II: 22.1% • Rome I: 17.5%(=0.73) • No gender difference but younger, decreasing with age • IBS subjects • Absenteeism, physician visits (GI, non-GI) • More chance with cholecystectomy • not with appendectomy / hysterectomy • Sleep disturbance Lu CL, et al. Aliment Pharmacol Ther 2003;18:1159-69.

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