Rome III based IBS and female

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


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


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


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


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


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


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


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


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


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


Modulating factors

1. Affective state2. Stress: physiologic & 3. Behavioral4. Gender role5. Gondal hormones /menses


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

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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

Documents

Rome III based IBS and female