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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. - PowerPoint PPT Presentation
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RomeRome III based III based IBS and female IBS and female
Full-Young Chang
GI Division
Feb. 7Feb. 7, 200, 20077
at at the Dept of GYN the Dept of GYN
Dr. G (GI & GYN)? 1971Dr. 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 IBS cardinal symptoms description: pain, pain,
derangement of ….digestion, and flatulencederangement 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.
Lecture contents
FGIDFGID disease disease model model
Visceral pain pathophysiologyVisceral pain pathophysiology
Rome III classificationRome III classification
IBSIBS knowledge knowledge Represented Represented IBSIBS reports in Taiwan reports in Taiwan
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.
FGID conceptual modelEarly lifeo Geneticso Environment
Early lifeo Geneticso Environment Psychosocial factors
o Life stresso Psychologic stateo Copingo Social support
Psychosocial factorso Life stresso Psychologic stateo Copingo Social support
Physiologyo Motilityo Sensationo Inflammationo Altered flora
Physiologyo Motilityo Sensationo Inflammationo Altered flora FGID
o Symptomso Behaviors
FGIDo Symptomso Behaviors
Outcomeo Medicationo MD visitso Daily functiono QoL
Outcomeo Medicationo MD visitso Daily functiono QoL
Gut ENSBrain CNS
Drossman DA. Gastroenterology 2006;130:1377-90.
Brain and gut
Effector systems1. Muscle2. Secretory glands3. Blood vessels
ENS: Integratedsynaptic circuits
Wood JD. Schuster Atlas of GI Motility. 2nd ed, 2002:19-42.
Sensory neurons
Afferent nerve transmission
Classic afferent pain pathwayClassic 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.
Classic afferent pain pathway (2)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.
Sensory centralSensory central transmission transmission
Brain imaging in rectal stimulation (fMR)Normal visceral sensation: 1. 1. GenderGender difference, difference, ACC & PFC in ACC & PFC in femalesfemales 2. Common2. Common FGID FGID in in females?females?
Grundy D, et al. Gastroenterology 2006;130:1391-1411.
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.
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;130:1552-6.
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.
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.
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.
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.
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: ImprovementImprovement with defecation 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.
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.
Bristol stool form scaleFigure 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.
Two-dimensional display of IBS subtypes
Longstreth GF, et al. Gastroenterology 2006;130:1480-91.
IBS-C IBS-M
IBS-U IBS-D
% loose or watery stools
25%
25% 75% 100%50%
% h
ard
or
lum
py s
tools
100%
75%
50%
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.
IBS pathophysiology and treatment
Extra-colonic symptoms in IBS More physician visits: X 3 Undergoing more abdominal/GYN surgeries
More chronic pelvic pain GU/GYN dysfunctionsGU/GYN dysfunctions
Dysmenorrhea, dyspareunia, impotence, urinary Dysmenorrhea, dyspareunia, impotence, urinary frequency, nocturia, incomplete bladder emptyingfrequency, 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.
QoL burden in IBS
IBS social cost, USA (1998)
Alarm symptoms in IBS diagnosisAlarm 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.
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.
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.
Enteric nervous system (ENS)Enteric nervous system (ENS)
5-HT and peristaltic reflex
SS ENK
VIP/PACAP/NOCGRP
DescendingRelaxation
Muscle
5 HT5 HT
Ach/ SP/NKA
Muscle
AscendingContraction
EC
Yamada T: Textbook of Gastroenterology 3rd ed, 1999:100
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.
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.
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.
Alternative therapy for IBS
Hussain Z, et al. APT 2006:23:465-71.
IBS in females
VS
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
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;102:1962-7.
Gender factor on IBS symptoms, Taiwan 2005
Lu CL, et al. Aliment Pharmacol Ther 2005; 2005;21:1497-505.
BM type Male, n=266 Female, n=181
P value
<3/wk 5.6% 14.9% 0.001
>3/day 31.6% 17.7% 0.001
Hard, lump 8.6% 18.8% 0.002
Loose, mush 44.4% 29.8% 0.002
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
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;96:2671-6.
Alosetron Effect: Female vs. Male(S3BA2001 study)
0
10
20
30
40
50
60
70
80
1 2 3Month
% re
spon
ders
Mangel AW, et al. APT 1999; 13(suppl) 27:77-82
** *
0
10
20
30
40
50
60
70
80
1 2 3Month
% re
spon
ders
■ Placebo ■ Alosetron (1 mg bid)
P=0.002
Female Male
P=0.073P=0.009
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.
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.
Modulating factors
1. Affective state2. Stress: physiologic & 3. Behavioral4. Gender role5. Gondal hormones /menses
Ouyang A, et al. Am J Gastroenterol 2006;101:S602-9.
Gondal hormones/menses
Gondal hormonesMensesInfection & sequelaeInflammation
Brain-gutaxis
Clinicalexpression
Pain severityCoping behaviorsAffective state
ANS parameters
Bowel habitsMotilityResponse to medication
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.
IBS prevalences of ethnic Chinese
Region, published Number Type Criteria Prevalence M/F
Beijing, 88’ 233 Selected - 22.8% NA
Singapore, 00’ 233 Community - 3.2% NA
Beijing, 00’ 2486 Community Manning
Rome
8.7%
1.09%
1/1.15
NA
Hong Kong, 02’ 1000 Community Rome II 6.6% 1/1.3
Hong Kong, 02’ 1298 Community Rome II 3.8% 1/1.06
Hong Kong, 02’ 1649 Community Rome I 4.1% 1/1.72
Malaysia, 02’ 179 Selected Rome I 16.2% NA
Taiwan, 03’ 2018 Selected Rome I
Rome II
17.5%
22.1%
NA
1/0.64
Malaysia, 04’ 314 Community Rome II 17.5% NA
Singapore, 04’ 196 Community Manning
Rome I
Rome II
11.1%
10.5%
8.7%
1/1.3
1/1.3
1/1.2
South China, 04’ 4178 Community Manning
Rome II
11.5%
5.7%
1/1.34
1/1.25
Chang FY, et al. J Gastroenterol Hepatol 2007; in press.
IBS is an independent factor in predicting negative-appendectomy
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 <0.001
PMNC (<75%) 3.05 1.69 – 5.51 <0.001
Adjusted Odds Ratio95%
Confidence interval
p value
No use of CT scan 2.32 1.27 – 4.26 <0.01
430 patients with emergent appendectomy68 (15.8%): negative exploration, 2003-05
Lu CL, et al. Gut 2007; in press.
Abnormal MMPI score in IBS, Taiwan 1998
Lee CT, et al. Dig Dis Sci.1998; 43:1794-9.
Small bowel transit in IBS subtypes, Taiwan 1998
Lu CL, et al. Clin Sci 1998: 95:165–9.
Smectitie in treating pain disorder of D-IBS
5
10
15
20
25
0Placebo
Dioctahedral smectite
Day 0 Day 28 Day 56Pa
in /
dis
co
mfo
rt s
co
re (
VA
S,
0-1
00
)
* **
# #
#
#
Chang FY, et al. J Gastroenterol Hepatol 2006 (accept).
Nurses’ knowledge in caring IBS patients, Taiwan 2001
120 RN in a tertiary acute care facility, 46-item questionnaire, filled voluntarily Categories: demography, IBS informatio
n 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.
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 sympt
oms Gender effect on IBS manifestations
but no recommended different treatments
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