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

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

6. 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）

7. IBS, an example of FGID
IBS cardinal symptoms description: pain, derangement of ….digestion, and flatulence
Powell R. Med Trans Royal Coll Phys 1818;6:
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:
Separated IBS from functional diarrhea, began with an enteric infection
Chaudhary NA, et al. Q J Med 1962;31;
Thompson WG. Gastroenterology 2006;130:

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

9. 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:

10. 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:

11. 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.

12. Afferent nerve transmission

13. 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.

14. 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.

15. Sensory central transmission

16. 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:

17. 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:

18. History of the Rome diagnostic criteria
1978: the Manning criteria for IBS
1984: the Kruis criteria for IBS
1989: the Rome guidelines for IBS
1990: the Rome classification system for FGIDs (Rome-1)
1992: the Rome criteria for IBS and the FGIDs (1994)
1999: the Rome II criteria for IBS and the FGIDs
2006: the Rome III criteria
Thompson WG. Gastroenterology 2006;130:

19. Rome III Rome board Preliminary discussion for Rome IV
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:

20. 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:

21. 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:

22. 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:

23. 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:

24. 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:

25. Bristol stool form scale
Figure
Type
Description 1
Separate hard lump like nuts (difficult to pass) 2
Sausage shaped but lumpy 3
Like a sausage but with cracks on it surface 4
Like a sausage or snake, smooth and soft 5
Soft blobs with clear-cut edges (passed easily) 6
Fluffy pieces with raged edges, a mushy stool 7
Watery, no solid pieces, entirely liquid
Heaton KW, Fast Facts of IBS 1999;27.

26. 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:

27. 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.

28. IBS pathophysiology and treatment

29. 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:

30. QoL burden in IBS

31. IBS social cost, USA (1998)

32. 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:

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

34. 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:

35. Enteric nervous system (ENS)

36. 5-HT and peristaltic reflexSS
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

37. 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:

38. ZAP trial for C-IBS, tegaserod vs. placebo, Asia-Pacific 2003
We also are also involved in the large scale double blind randomized trial of tegaserod in asis pacific region. As you can seen here, tegaserod , a 5-HT4 agonist can improve the overall satisfactory symptom relief over placebo with therapeutic gain around 19%.
Tegaserod 6 mg twice daily (n=259) or placebo (n=261) for 12 week
Kellow J, et al. Gut 2003;52:671-6.

39. 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.

40. Alternative therapy for IBS
Hussain Z, et al. APT 2006:23:

41. VS
IBS in females

42. 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: )
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

43. IBS symptom number according to Manning criteria
Sx no 1 2 3 4 5 6
Male
27%
10.7% 5%
2.3%
1.3%
0.9%
Female
46.8%
24%
13.1% 6%
2.9%
1.4%
Heaton KW, et al. Gastroenterology 1992;102:

44. Gender factor on IBS symptoms, Taiwan 2005
BM type
Male, n=266
Female, n=181
P value
<3/wk
5.6%
14.9%
0.001
>3/day
31.6%
17.7%
Hard, lump
8.6%
18.8%
0.002
Loose, mush
44.4%
29.8%
Social impact
GI consultation
56%
54.1% NS
Absenteeism
20.7%
32.6%
0.006
Total days/yr
0.7±3.1
2.3±6.4
0.01
Sleep disturbance
35.3%
50.3%
0.002
Lu CL, et al. Aliment Pharmacol Ther 2005; 2005;21:

45. Gender influence on IBS-D
Change
Female, n=15
Males, n=15
P value
% colon filling at 6 hr
-8.7±6.5
13±8.8 NS
Colon geometric center at 24 hr
-1.45±0.25
-0.32±0.27
0.005
Colon GC at 48 hr
-0.84±0.27
-0.23±0.14
0.054
Ascending colon empty, T 1/2
7.5±2.8
3±1.8
0.19
Viramontes BE, Am J Gastroenterol 2001;96:

46. Alosetron Effect: Female vs. Male (S3BA2001 study)*
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

47. 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.

48. 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.

49. Brain-gut Modulating factors Clinical axis 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.

50. 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
We conducted a study to investigate the epidemiology of IBS in Taiwan. This is already published in APT. Two thousand and eighteen subjects receiving physical check up were enrolled. Then we found the prevalence of IBS in this Taiwanese population is 22.1 % on Rome II criteria and 17.5 % on Rome I criteria.
Lu CL, et al. Aliment Pharmacol Ther 2003;18:

51. IBS prevalences of ethnic Chinese
Region, published
Number
Type
Criteria
Prevalence
M/F
Beijing, 88’
233
Selected -
22.8% NA
Singapore, 00’
Community
3.2%
Beijing, 00’
2486
Manning
Rome
8.7%
1.09%
1/1.15
Hong Kong, 02’
1000
Rome II
6.6%
1/1.3
1298
3.8%
1/1.06
1649
Rome I
4.1%
1/1.72
Malaysia, 02’
179
16.2%
Taiwan, 03’
2018
17.5%
22.1%
1/0.64
Malaysia, 04’
314
Singapore, 04’
196
11.1%
10.5%
1/1.2
South China, 04’
4178
11.5%
5.7%
1/1.34
1/1.25
Chang FY, et al. J Gastroenterol Hepatol 2007; in press.

52. IBS is an independent factor in predicting negative-appendectomy
430 patients with emergent appendectomy
68 (15.8%): negative exploration,
Rome-II IBS
2.17
1.14 – 4.24
0.02
Degree of Anxiety
1.12
1.02 – 1.49
0.04
Absence of migrating pain
3.43
1.90 – 5.95
<0.001
Absence of muscle guarding
3.72
2.07 – 6.70
PMNC (<75%)
3.05
1.69 – 5.51
Adjusted Odds Ratio
95% Confidence interval
p value
No use of CT scan
2.32
1.27 – 4.26
<0.01
Lu CL, et al. Gut 2007; in press.

53. Abnormal MMPI score in IBS, Taiwan 1998
In addition, we also used Minnissota multiphasic personality inventory (MMPI) to investigate the personality characteristics in IBS patients. When compared with the controls, we found the IBS patients do have some abnormal clinical scales indeprssion, hsyteria and paranoia. These results suggested the psychological roles in the IBS pathogenesis.
Lee CT, et al. Dig Dis Sci.1998; 43:

54. Small bowel transit in IBS subtypes, Taiwan 1998
In Taiwan, we have also try to investigate the role of the small bowel motility in controls and IBS patients. We found that the constipation–predominant IBS had longer oral cecal transit time, while the diarrhea type IBS had shorter oral cecal transit time. This results suggested small bowel dysmotility also exiss in IBS patient and may contribute to the clinical symptoms in IBS-subtype.
Lu CL, et al. Clin Sci 1998: 95:165–9.

55. Smectitie in treating pain disorder of D-IBS
Chang FY, et al. J Gastroenterol Hepatol 2006 (accept).

56. Nurses’ knowledge in caring IBS patients, Taiwan 2001
120 RN in a tertiary acute care facility, 46-item questionnaire, filled voluntarily
Categories: demography, IBS information source, nurses’ IBS knowledge, perception, beliefs, learning requirement
92.5%: agree or strongly agree having limited IBS knowledge
53.3%: cannot explain IBS well to patients
10.8%: able to recognize IBS symptoms
Little specific IBS knowledge of Taiwan nurses
Chen H, et al. Nur Health Sci 2001; 3:173-7.

57. Conclusions
FGID has been a problem of living, it means biopsychosocial disorder
Current Rome III clearly addresses IBS and its subtypes
IBS treatments based on main symptoms
Gender effect on IBS manifestations but no recommended different treatments