Transcript 소화기질환에서_중복증후군의_임상적_의미

기능성 소화기질환에서 중복증후군의 임상적 의미
Nayoung Kim
Department of Internal Medicine,
Seoul National University College of Medicine
Seoul National University Bundang Hospital
Definition of FGID : A variable combination of chronic
or1988
recurrent GI symptoms not explained by structural or
biochemical abnormalities. (Rome criteria 1990)
2015
Rome IV
▶Classification of FGID
by region
pathogenesis
↓
by symptom in Rome III
Esophageal
Biliary
Gastroduodenal
Bowel
Anorectal / pelvic floor
▶Rome III Classification of FGIDs
A. Functional esophageal disorders
A1. Functional heartburn
A2. Functional chest pain of presumed esophageal
origin
A3. Functional dysphagia
A4. Globus
C. Functional bowel disorders
C1. Irritable bowel syndrome
C2. Functional bloating
C3. Functional constipation
C4. Functional diarrhea
C5. Unspecified functional bowel disorder
B. Functional gastroduodenal disorders
B1. Functional dyspepsia
B1a. Postprandial distress syndrome
B1b. Epigastric pain syndrome
B2. Belching disorders
B2a. Aerophagia
B2b. Unspecified excessive belching
B3. Nausea and vomiting disorders
B3a. Chronic idiopathic nausea
B3b. Functional vomiting
B3c. Cyclic vomiting syndrome
B4. Rumination syndrome in adults
G. Functional disorders: neonates and toddlers
H. Functional disorders: children and adolescents
•Exclusive criteria
•Good for enroll homogeneous
population in clinical study
D. Functional abdominal pain syndrome (FAPS)
E. Functional gallbladder and Sphincter of Oddi
(SO) disorders
E1. Functional gallbladder disorder
E2. Functional biliary SO disorder
E3. Functional pancreatic SO disorder
F. Functional anorectal disorders
F1. Functional fecal incontinence
F2. Functional anorectal pain
F2a. Chronic proctalgia
F2a1. Levator ani syndrome
F2a2. Unspecified functional anorectal pain
F2b. Proctalgia fugax
F3. Functional defecation disorders
F3a. Dyssynergic defecation
F3b. Inadequate defecatory propulsion
▶Overlap in the symptomatology
Upper and lower GI symptoms commonly overlap!
Functional
Functional
Abdominal
abdominal
bloating
bloating
Functional
Functional
Abdominal
pain
abdominal
pain
Functional
Functional
diarrhea
diarrhea
Functional
Functional
constipation
constipation
IBS
IBS
Contents
• Prevalence of overlap in FGID
• Common pathogenesis
1) Hypersensitivity
2) Dysmotility
3) Inflammation
• Symptomatic feature
• Treatment
CLINICAL ASPECT OF
OVERLAP IN FGID
1) Definition & type
2) Prevalence
3) Impact on quality of life
Overlap syndrome in FGID
 More than one functional gastrointestinal disorder (FGID)
Type of overlap in patients with dyspepsia
1. Overlap with GI diseases
Upper GI diseases
(GERD, NERD, functional heartburn, non-cardiac chest pain &
chronic idiopathic nausea)
Lower GI diseases (IBS)
2. Overlap with non-GI diseases
Functional somatic syndrome
(fibromyalgia, chronic fatigue syndrome, interstitial cystitis/ bladder pain syndrome
& overactive bladder syndrome)
Atrial fibrillation
3. Internal subgroup overlap
PDS and EPS
(Fujiwara et al. 2014 JNM)
▶Overlaps of FGIDs including GERD
• GERD + FD
• GERD + IBS
• FD ＋ IBS
• FD ＋ Belching disorders
• FD ＋ Functional heartburn
• IBS ＋ Belching disorders
• IBS ＋ Functional heartburn
• Functional heartburn ＋ Belching disorders
• FD ＋ IBS ＋ Belching disorders
• FD ＋ IBS ＋ Functional heartburn
• FD ＋ Belching disorders ＋ Functional heartburn
• IBS ＋ Belching disorders ＋ Functional heartburn
• FD ＋ IBS ＋ Belching disorders ＋ Functional heartburn
Many subjects
present with
2 or more
FGIDs
or complain of
symptoms.
Prevalence of FGID overlap
Prevalence
Total
Patients with other FGID
FD
11-29%
32% in patients with IBS
IBS
10-15%
11-37% in patients with FD
•
Prevalence of FD-IBS
overlap is high.
(Suzuki et al. 2011 JNM)
FGID overlapping with IBS
• Overlap FD-IBS is most
common.
(Nakajima et al. 2010 JGH)
▶Overlaps in Korea by Rome III
• 48.9% of FD overlap with IBS
• 56.1% of IBS overlap with FD
JM Park, JNM 2011
Non-Korean meta-analysis
FD
IBS
JM Park, JNM 2011
Ford. CGH 2010
FD has an 8-fold increase of prevalence of IBS
OR 8.00 (5.74-11.16 )
(Ford et al. 2010 CGH)
▶Sub-type of FD
• FD ＋ IBS : most common overlap syndrome
• FD is defined as the presence of symptoms thought to originate
in the gastroduodenal region, in the absence of any organic,
systemic, or metabolic disease that is likely to explain the
symptoms. (Gastroenterology, 2006)
a. Bothersome postprandial fullness
b. Early satiation
c. Epigastric pain
d. Epigastric burning
Postprandial Distress Syndrome
(PDS)
Epigastric Pain Syndrome
(EPS)
Internal
subgroup overlap
JM Park, JNM 2011
▶Sub-type of IBS
1. IBS with
constipation
hard or lumpy stoolsa >25%
2. IBS with diarrhea
loose (mushy) or watery stoolsb >25%
loose (mushy) or watery stoolsb <25% of bowel movements.c
hard or lumpy stoola <25% of bowel movements.c
3. Mixed IBS (IBS-M)
hard or lumpy stoolsa >25%
loose (mushy) or watery stoolsb >25% of bowel movements.c
4. Unsubtyped IBS
insufficient abnormality of stool consistency to meet criteria for
IBS-C, D, or M.c
a
Bristol Stool Form Scale 1–2
b
Bristol Stool Form Scale 6–7
c
In the absence of use of antidiarrheals or
Gastroenterology 2006
laxatives
▶Clinical spectrum of FD-IBS overlap
Overlap
FD symptom
IBS symptom
PDS + IBS-C
PDS + IBS-D
PDS + IBS-M
Constipation
• Bothersome
postprandial
fullness
• Early satiation
PDS + IBS-U
EPS + IBS-C
EPS + IBS-D
• Epigastric pain
EPS + IBS-M
• Epigastric burning
EPS + IBS-U
• Recurrent
abdominal pain
or
discomfort
(>3 days/month)
Diarrhea
• Improvement
with defecation
Constipation
C+D
Various
Diarrhea
C+D
Various
▶Clinical characteristics of overlap syndrome
• Frequent, or more severe symptoms
• Poorer HR-QOL
• Higher somatization score
• Anxiety
• Depression
• Insomnia
Quality of Life
More frequent or more severe symptoms
*
* P < 0.05
*
*
*
Fullness
bloating
Early
satiety
Weight
loss
(Corsetti et al. 2004 Am J Gastroenterol)
Quality of Life
Poorer health-related quality of life (HR-QOL)
FD only
IBS only
FD-IBS
HR-QOL assessed by 8-items
60
*
*
*
*
*
*
*
40
20
0
Physical Role physical Bodily pain
functioning
*
P < 0.005
General
health
perception
Vitality
Social
functioning
Role
emotional
Mental
health
(Kaji et al. 2010 JGH)
Quality of Life
Poorer quality of sleep
IBS (n = 14)
• Overlap showed a
NERD (n = 12)
lower quality of sleep
FD alone (n = 59)
compared to FD alone
Healthy volunteers (n = 41)
(Futagami et al. 2013
J Nippon Med Sch).
FD + NERD + IBS (n = 23)
FD + IBS (n = 27)
FD + NERD (n = 30)
*
P < 0.05
FD alone (n = 59)
Higher PSQI score means that the subject does not sleep wells.
*
Quality of Life
Higher risk of depression
• Depressive mood was significantly related to FD and IBS-FD
overlap but not to IBS alone based on Rome III criteria.
(Lee et al. 2010 Gen Hos Psychiatry)
Beck depression
inventory
*
30
*
20
10
0
Normal
(n = 127)
*
P < 0.05
IBS alone
(n = 82)
FD alone
(n = 28)
IBS-FD
overlap
(n = 42)
SYMPTOM ASSOCIATION
1)
2)
3)
EPS and GERD
IBS-C and PDS
Postprandal fullness, nausea, vomiting…
1) EPS and GERD (NERD)
• Compared to RE, NERD is more frequently
overlapped with FD, especially EPS. (Noh et al.,
2010
JNM)
P < 0.05
FD
*
*
*
*
EPS
PDS
*
*
74.3
80
*
68.9
Percentage
60
(%)
48.6
40
20
10.5
5.2
7.3
5.4
2.2
0
RE
NERD
Normal
4.3
2) PDS and IBS-C
• IBS-C had more frequent abdominal pain, bloating
and early satiety than IBS-D.
(Talley et al., 2003 Am J Gastroenterol)
IBS-C
IBS-D
* P < 0.05
Lower
Lower
left
abdomen
quadrant
P=0.05
3) Postprandial fullness
• Postprandial fullness symptom was a risk factor
for FD-IBS overlap.(Wang et al. 2008 BMC
Gastroenterol)
Risk factors for FD-IBS overlap in FD alone (multivariable analysis)
Potential risk factor
β
OR
P value
95% CI
Postprandial fullness
0.98
2.67
0.005
1.34-5.31
Epigastric burning
0.38
1.47
0.07
0.97-2.21
EPS alone
0.15
1.16
0.66
0.59-2.29
Risk factors for FD-IBS overlap in IBS alone (multivariable analysis)
Potential risk factor
β
OR
P value
95% CI
Male
0.68
1.37
0.11
0.93-2.03
IBS-D
0.64
1.44
0.10
0.93-2.22
IBS-M
0.48
1.62
0.21
0.77-3.40
3) Postprandial fullness, nausea and vomiting
• Postprandial distress syndrome was associated
with nausea, vomiting.(Ford et al. 2011 Gut
Suppl )
Overlap of ROME III FGIDs
Hen-and-egg argument
Different disorders
with a common
pathophysiology?
Different manifestations
in one disease?
Limitation of symptom-based criteria
• Heterogeneity of FGID
• Symptomatology approach
• Relatively low frequency/severity thresholds in diagnostic questionnaires
• linguistic or cultural differences
THE COMMON
PATHOPHYSIOLOGY OF
OVERLAP IN FGID
1) Visceral hypersensitivity
2) Dysmotility
3) Infection
4) Food
5) Psychological factors, stress
FGID Conceptual Model
Early Life
• Genetics
• Environmental
Psychological
Factors
• Life stress
• Psychological state
• Coping
• Social support
Brain
CNS
Gut
ENS
Physiology
• Motility
• Sensation
• Inflammation
• Altered bacterial flora
(Drossman DA et al.
2006 Gastroenterology)
Outcome
FGID
• Symptoms
• Behavior
•Medication
•MD visit
•Daily function
•Quality of life
▶Evolving conceptual model of FGIDs (2013)
Microbiota
Chey et al. AJG 2013
▶Suggested common pathogenesis in FD-IBS overlap
FD
IBS
• Visceral hypersensitivity
• Visceral hypersensitivity
• Altered GI (gastric) motility
• Altered GI (colonic) motility
• Infectious etiology
• Infectious etiology
• Microinflammation?
• Microinflammation
• Intestinal micorbiota, SIBO
• Stressful early life events
• Stressful early life events
• Food
• Food
• Genetics
• Genetics
1) Hypersensitivity
• Visceral hypersensitivity is a common
pathophysiological marker in FD and IBS.
(Talley et al. 2004 APT)
FD patients
Healthy control
*
Sensory score
Reporting pain (%)
IBS patients
P < 0.05 vs. healthy control
*
*
*
*
*
*
Healthy control
1) Hypersensitivity
• FD-IBS overlap showed a lower threshold for first perception and
a greater prevalence of hypersensitivity to gastric distention.
(Corsetti et al. 2004 Am J Gastroenterol)
FD + IBS
FD alone
Distending pressure (mmHg)
Prevalence (% of patients)
*
*
P < 0.05 compared to FD alone
*
*
2. Altered GI motility
• Altered gastric motility in FD ①
Delayed GE
② Impaired accommodation
GE
rate (%/h)
*
*
• IBS-FD, not IBS alone, showed
delayed solid gastric emptying
in both genders
Stanghellini et al. Am J Gastroenterol 2002
Male
Female
• The patient with IBS-FD overlap seems to have both upper and lower
GI dysmotility.
3) Infection
Prevalence
• Salmonella gastroenteritis is a significant risk factor
both IBS and FD.
(Mearin et al. 2005 Gastroenterology)
4) Food
Luminal component
Dietary component
• FOADMAP
-Fructose
-Fructans
-Galactooligosaccharides
-Polyols
-Lactose
• Gluten
• Food allergens
• Lipid
Central
Nervous
System
Gut wall
Autonomic
Nerves
hormones
Commensal microbiota
• Short-chain fatty acids
• Bile acids
• Gases
• Inflammation
• Immune
activation
• Activation of
sensory nerve
endings
• Triggering of
motor and
secretory
responses
Gut
(Normal or Diseased)
Enteric pathogen
Hayes et al. Gastro Hep 2014
원광의대 김용성 교수 slide
▶특정 FD 증상과 연관된 음식군
Symptom
Fullness
Food items
Study
Year
Red meat, bananas, bread, cakes, pasta, sausage,
fried foods, beans, mayonnaise, milk, chocolate,
eggs, sweat and orange
Carvalho
2010
Wheat, fried foods, onions, cakes, red meat beans,
citrus, sweets and chocolate
Filipovil
2011
Carbonated drinks, onions, beans and bananas
Carvalho
2010
Milk, beans, onions, banana and carbonated drinks
Filipovil
2011
Coffee, cheese, onions, pepper, milk, chocolate,
pineapples
Carvalho
2010
Coffee, pepper, chocolate and onions
Filipovil
2011
Bloating
Epigastric pain
Carvalho RV et al. Dig Dis Sci 2010;55:60-65
Filipovic BF et al. Eur J Intern 2011;22:300-304
• Food can cause a FGID symptoms.
• Food items related to FD and IBS, not all, is similar.
원광의대 김용성 교수 slide
▶특정 IBS 증상과 연관된 음식군
Most common food
Abdominal distension
1
2
3
4
5
Pizza (8%)
Cabbage (7%)
Peas/beans
(6%)
Deep-fried
food (5%)
Onion (5%)
Raw
vegetables
(6%)
Red/green
pepper (4%)
Gas problems (25%)
Cabbage (11%)
Onion (11%)
Peas/beans
(9%)
Abdominal pain (23%)
Hot spices
(6%)
Cream (5%)
Onion (5%)
Pizza (5%)
Cabbage (5%)
Gastroesophageal
reflux (4%)
Coffee (14%)
Smoked food
(10%)
Citrus fruits
(10%)
Deep-fried
food (8%)
Hot spices
(7%)
Dyspeptic symptoms
(17%)
Deep-fried
food (7%)
Pizza (6%)
Coffee (6%)
Pastries (5%)
Cream (5%)
Loose stools/urgency
(13%)
Cream (8%)
Alcohol (8%)
Coffee (7%)
Pizza (6%)
Milk (6%)
Hard stools (2%)
Tea (20%)
White bread
(19%)
Milk (6%)
Cheese (6%)
Pizza (6%)
Borborygmus (5%)
Onion (7%)
Cabbage (7%)
Coffee (6%)
Peas/beans
(5%)
Apples (5%)
Allergy like symptoms
(1%)
Chocolate
(11%)
Apples (11%)
Tomatoes
(11%)
Red/green
pepper (11%)
Citrus fruits
(8%)
원광의대 김용성 교수 slide
Simren M et al. Digestion 2001;63:108-115
5) Psychopathological factor
Psychopathological features
GSI, global severity index; SOM, somatization; OBS, obsessive-compulsive;
SENS, interpersonal sensitivity; DEP, depression; ANX, anxiety; HOS, anger-hostility;
PHOB, phobic anxiety; PAR, paranoid ideation; PSYC, psychoticism.
*P < 0.05; ** P < 0.01; ***P < 0.001
(Piacentino et al. 2011BMC Gastroenterology)
6) Genetics
• No apparent association between GNB3 C825T
polymorphism and the susceptibility to FD, IBS or FD-IBS.
(Kim et al. 2012 JNM)
Model
FD vs Controls
IBS vs Controls
Overlap vs Controls
P value
OR (95% CI)
P value
OR (95% CI)
P value
OR (95% CI)
Co-dominant
0.329
1.13 (0.88-1.46)
0.723
0.93 (0.63-1.37)
0.112
1.31 (0.94-1.83)
Dominant
0.718
1.04 (0.84-1.28)
0.671
0.93 (0.67-1.29)
0.160
1.21 (0.93-1.55)
Recessive
0.220
1.13 (0.93-1.38)
0.874
0.97 (0.72-1.33)
0.234
1.19 (0.89-1.61)
5) Genetics
• Genetic polymorphism of SLC6A4 5-HTTLPR & TRPV1
945G>C could be a pathophysiological factor of FD.
(Hwang et al. 2014 JGH)
• SLC6A4 5-HTTLPR & ADRA2A −1291C>G could be a
pathophysiological factor of IBS.
(Choi et al. 2014 JNM)
6) Altered brain activation
• Hypersensitive IBS, not normosensitive IBS showed
greater activation of insula and reduced deactivation in
pregenual anterior cingulate cortex (ACC) during noxious
rectal distensions, compared to control.
(Larsson et al. 2012 Gastroenterology)
Yellow, activation
• Presence of aberrant brain activity of ACC and thalamus in
FD. (Nan et al. 2014 NM )
Evidence for pathophysiological mechanisms
IBS
FD
+++
+++
Upper gastrointestinal dysmotility
+
+++
Lower gastrointestinal dysmotility
+++
+
Brain processing abnormalities
++
+
Genetics
+
+
Psychiatric comorbidities
++
+
Post-infection
++
+
Serotonin signaling abnormalities
+
+
Visceral hypersensitivity
중복증후군의 치료
No definite guideline or consensus for overlap syndrome
약을 먹어도
더부룩해요
약을 먹어도
속이 쓰려요
Miwa H, et al. CGH 2011
▶Common medication for FD/IBS
Psychological
Factors
•Life stress
•Psychologic state
•Coping
•Social support
Brain
CNS
Gut
ENS
Physiology
•Motility
•Sensation
•Inflammation, acid related
•Altered bacterial flora/HP
Psychotropic drugs
Anxiolytics
Prokinetics (5HT4A agonist)
Antispasmodics (5HT3A antagonist, CCB)
Improving accommodation (5HT1A agonist)
Enkephalin Agonist
Laxatives, linaclotide, Lubiprostone
Reducing sensation: TCA, SSRI
Acid reducing agent: H2RB, PPI
Rifaximin
HP eradication
원광의대 김용성 교수 제공
▶Clinical spectrum of FD-IBS overlap
Overlap
FD symptom
IBS symptom
PDS + IBS-C
PDS + IBS-D
PDS + IBS-M
Constipation
• Bothersome
postprandial
fullness
• Early satiation
PDS + IBS-U
EPS + IBS-C
EPS + IBS-D
• Epigastric pain
EPS + IBS-M
• Epigastric burning
EPS + IBS-U
원광의대 김용성 교수 제공
• Recurrent
abdominal pain
or
discomfort
(>3 days/month)
Diarrhea
• Improvement
with defecation
Constipation
C+D
Various
Diarrhea
C+D
Various
▶Effects of Mosapride on GI motility and
sensation
• Improved esophageal motility
• Increased esophageal bolus transit
• Shortened gastric emptying time
GERD
Functional
dyspepsia
• Shortened colonic transit time
• Facilitated defecation in patients with lower GI disorders
Constipation
• Improved visceral sensitivity in animal model
IBS
원광의대 김용성 교수 제공
 프로토콜 요약
제
목
과민성장증후군 변비 아형으로 진단된 환자를 대상으로 Motilitone® 투여시
유효성과 안전성을 평가하는 무작위 배정, 양측눈가림, 위약대조군 연구
시 험 기 관 분당서울대병원 소화기내과 김 나 영
투
여
군 위약군30, 모티리톤 30, 4주 투여 (2주 스크리닝+1주 관찰기+4주간 3회/day 식전)
IBS-C형 환자 대상 모티리톤의 임상적 유효성에 대한 가능성 확보
시 험 목 적 유효성 입증 위해 군당 200예의 대규모 임상 필요  30예의 소규모 임상으로
임상적 유효성에 대한 가능성을 확인하여 허가 임상에 대한 기초 자료 활용
1. 만 20세 이상 75세 이하 건강한 성인 남녀
선 정 기 준 2. Rome III 진단 기준(2006)에 준하는 IBS-C 환자
3. 내시경 또는 대장 조영술 검사 기질적 병변이 없는 자
유효성
평 가 변수
 전반적 증상 평가에 대한 반응자 비율
 복통과 복부 불편감 증상 변화, 변 형태 변화, 일일 배변 횟수 변화, QoL변화
FD기준에 만족하는 환자에서:
소그룹 평가
 전반적 증상 평가 반응자의 비율
 명치가 아프거나 쓰림 변화량; 조기포만감 변화량; 식후 불쾌한 충만감 변화량
 1차 유효성 평가변수 (전반적 증상 평가)
 “지난 1주간의 치료가 당신의 증상을 적절하게 개선시켰습니까?” 에 대해 피험자가 예/아니
오 로 답변 개선된 주가 총 투여기간의 75%이상이면 반응자(responder)로 정의
※ 증상 전체의 개선을 평가하는 것, 자각 증상의 개선이 임상적으로 중요하기 때문에 치료약의 효과에 대한 평가는
피험자가 하는 것을 (Patient-reported outcome, PRO) 권장(FDA Guidance, 2012)
비율 (%)
모티리톤
80
70
60
50
40
30
20
10
0
위약
모티리톤
P-value
위약
53.3
40.0
반응자
반응자
12(40%)
16(53.33%)
0.3006†
†: Pearson's chi-square test
Not published
Tegaserod
60.0
모티리톤
46.7
비반응자
18(60%)
14(46.67%)
위약
Tegaserod
P-value
반응자
Week 1-4
Week 1-12
28.3%
43.0%
48.6%
57.2%
<0.0001
0.002
N
261
259
Gut 2003;52:67
 소그룹 평가 (FD대상)
전반적 증상 평가
비율 (%)
80
P=0.1382
60
69.0
50.0
40
위약
모티리톤
50.0
0.2
-0.4
0
-0.6
반응자
1
조기 만복감
-0.8
위약
모티리톤
Ch2
Ch3
Ch4
2
3
식후 포만감
4
위약
모티리톤
-0.6
-0.4
-0.4
-0.2
-0.2
Not published
Ch1
P-value Change
0.2407 § Change
0.2407 § Change
0.2407 § Change
0.2407 §
비반응자
-0.6
P-value
모티리톤
0.4
-0.2
20
0.0
위약
0.0
31.0
-0.8
복부 통증 쓰림
0.6
Ch1
Ch1
Ch2
Ch2
Ch3
Ch3
Ch4
Change§ Change§ Change§ Change§
0.2823
1
0.1467
2
0.0864
3
0.2614
4
0.0
P-value
Ch1
Ch2
Ch3
Ch4
Ch1
Ch2
Ch3
Change Change Change Change
0.2399 § 0.2399 § 0.2399 § 0.2399 §
1
2
3
4
▶Effect of Prucalopride on lower GI tract
Selective stimulation
of 5-HT4 receptors
on smooth muscle
and intrinsic neurons
Triggering peristaltic
reflex and colonic
mass movement
Prucalopride significantly
accelerates
overall colonic transit
and
proximal colonic emptying
1Briejer
et al., Eur J Pharmacol 2001; 423: 71
et al., Gastroenterology 1998; 115: 370
3Prins et al., Br J Pharmacol 2000; 131: 927
4Bouras et al., Gut 1999; 44: 682
2Grider
원광의대 김용성 교수 제공
▶Optimal target of selective 5HT4 agonist
in Patient with Overlap syndrome
Epigastric fullness, bloating,
early satiety,
nausea, vomiting
Reflux symptoms
Constipation, IBS-C, Not IBD-D
원광의대 김용성 교수 제공
▶Dual Effect of Trimebutine
(Enkephaline agonist)
• Polybutine : Enkephalin의 Agonist
• 각 부위의 enkephalin의 농도에 따라 trimebutine의 결합부위가 달라지므로,촉진
(연동) 또는 억제(경진)의 양면작용  비정상화된 위장관의 운동을 정상화시킴
원광의대 김용성 교수 제공
▶Effect of Trimebutine on FD or IBS
FD patients with dealyed GE : 3주 동안 Polybutine 300 mg/day 투여
 위 배출 정체 시간 감소, 고형음식 위배출 속도 증가, 음식 섭취 100분 시점에
음식 정체량 감소 효과가 확인
Non-ulcer dyspepsia
Controls
Abnormal gastric emptying
Pre-treatment
Post-treatment
VLAG(min)
15.7±8.7
28.7±12.4
15.3±7
TLAG(min)
45.1±16.1
67.2±18.6
40.6±19.5
κ
0.016±0.005
0.009±0.003
0.018±0.031
β
2.22±0.67
2.04±0.66
1.71±0.39
R100(%)
37.5±8.4
63.7±9.5
약
물
작용양식
46.5±7.8
Annals of Nuclear medicine 1999
소화관운동에 미치는 영향
위
소장
대장
Trimebutine
말초성 엔켈팔린 효능제
항진 혹은 억제 (+) (-)
+ + + PHASE III
항진 혹은 억제 (+) (-)
Metoclopramide
아세틸콜린 분비촉진 및
항도파민제(중추성)
+
+
0
항도파민제
+
0
0
++
+ + + PHASE II
+
+++
?
?
Domperidone
Cisapride
Erythromycin I.V.
원광의대 김용성 교수 slide
아세틸콜린 분비 촉진
모탈린 효능제
European Journal of Clinical Pharmacology
Bidirectional brain-visceral interactions
Central pain amplification:
increased activity of
pain facilitation and
reduced pain inhibition
Neuroplasticity
Interoceptive
hypothalamic
pituitary axis
feedback
Prolonged dysregulation
of these interactions
-> ↓ gray matter density
involved in emotional and
pain regulation (fMRI)
Mayer EA, et al. Annu Rev Med. 2011
Psychological and behavioral treatments
Most often used for patients with severe symptoms
Three major classes of antidepressants and psychotropic agent:
1. TCA, Tricyclic antidepressants (amitriptyline, desipramine, nortriptyline)
2. SSRI, selective serotonin reuptake inhibitors (fluoxetine, paroxetine, escitalopram
etc)
3. SNRI, serotonin norepinephrine reuptake inhibitors (duloxetine, etc)
-> initially try TCA or SNRI due to enhanced pain benefit
SSRI if there are dominant symptoms of anxiety
Rationale for their use to treat epigastric pain
Reducing afferent signals from the gut or modulating bowel symptoms
Neuroplasticity: Antidepressants can restore lost neurons through BDNF
(brain-derived neurotrophic factor)
Drossman DA. Am J Gastroenterol 2009;104;2897-902
Treatment options for severe dyspepsia – Augmentation therapy
If single medication treatments are not successful then intensify
the treatments by using combinations of treatments.
Drossman DA. Am J Gastroenterol 2009;104;2897-902
Rationale for augmentation therapy
Synergistic effect by two or more treatments that act on
different receptor sites or areas of brain
to enhance the therapeutic effect
Aliment Pharmacol Ther
2011;33: 514–24
Summary and Conclusion
1. Prevalence of FD+IBS overlap has been reported to be 11.4-27.6%.
2. PDS FD type was frequently overlapped with IBS-C type.
3. Common pathogenesis such as visceral hypersensitivity, abnormal GI
motility, infection, psychological distress play a role in development of
overlap syndrome.
4. The symptom was severe in FD+IBS and quality of life of this overlap
was poorer compared to single disorder.
5. GI motility modulators such as 5HT4 agonist or enkephalin agonist
could be used as 1st line drug for overlap syndrome.
6. Appropriate combination of available drugs should be selected by
symptoms and their pathogenic mechanism including TCA or SSRI.
7. However, there is no consensus for management of overlap syndrome.
Thank you for your attention