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Rome III based IBS and female

This article discusses the Rome III classification of irritable bowel syndrome (IBS) and its association with female patients. It explores the cardinal symptoms of IBS, the pathophysiology of visceral pain, and the impact of psychological factors on the disease. The article also highlights the need for an integrated biopsychosocial model of illness and the potential role of mind-body dysregulation in IBS.

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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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