1
Functional Dyspepsia
Nicholas J. Talley MD, PhD
University of Newcastle Callaghan
NSW, Australia
2
• Structural and functional disease
– Peptic ulcer disease
– Gastroesophageal reflux (often diagnosed even if
no esophagitis, heartburn rare and/or PPI fails)
– Malignancy (gastric, esophageal, liver)
– Drugs (all NSAIDs)
– Pancreatic disease (chronic pancreatitis);
not gallstones
– Gastroparesis (vomiting, weight loss, very rare!)
• Functional dyspepsia (60%)
– No structural or biochemical explanation found
Major Causes of
Endoscopy-negative Dyspepsia
Talley, Gastroenterology 1998; 114: 582
Talley, Gastroenterology 2003; 125: 1219
3
• Positive celiac serology
higher in dyspepsia (7.9%)
vs. controls (3.9%), but not
significant
(OR 1.89; 95% CI 0.90-3.99)
• Prevalence of biopsy-proven
celiac following positive
serology higher (3.2% in
cases vs. 1.3% in controls),
but not significant
(OR 2.85; 95% CI 0.60-13.38)
Celiac Disease and Dyspepsia?
Am Fam Physician. 2007 15;76:1795-1802 Ford et al. Aliment Pharmacol Ther. 2009;30:28-36
4
Epigastric pain syndrome (EPS):
Postprandial distress syndrome (PDS): meal-related FD
Postprandial heaviness or
fullness
Early
Satiation
Epigastric
burning
Epigastric
pain
Rome III Functional Dyspepsia
5
Epidemiology of FD (Rome III)
Of 1000 Swedish subjects:
• 202 (20%)
uninvestigated dyspepsia
• 157 (16%) FD
• 52 Epigastric Pain
Syndrome (EPS): 33% of FD
• 122 postprandial distress
syndrome (PDS): 78%
• 17 EPS and PDS overlap: 11%
Of 1033 Italian subjects:
• 156 (15%)
uninvestigated dyspepsia
• 114 (11%) FD
• 55 Epigastric Pain
Syndrome (EPS): 48% of FD
• 77 postprandial distress
syndrome (PDS): 68%
• 18 EPS and PDS overlap: 16%
Aro, Talley et al. Gastroenterology. 2009;137:94-100
Zagari et al. Gastroenterology. 2010;138: 1302-11
6
Epigastric Pain Syndrome (EPS)
Aro, Talley et al. Gastroenterology. 2009;137:94-100
• No association with anxiety or depression
Postprandial distress syndrome (PDS)
• Major anxiety (5.1 vs. 3.2; OR=4.35, 95% CI: 1.81-10.46)
• Use of NSAIDs (OR=2.75, 95% CI: 1.38-5.50)
• Low education level (OR=1.73, 95% CI: 1.04-2.87)
7
• Prospective
Australian
population data
• Controls
(n=626)
followed for
12 years
(1997-2009)
Pre-morbid Anxiety Increases Risk of
Functional Dyspepsia
Koloski, Jones & Talley DDW 2010
30.00
25.00
20.00
15.00
10.00
5.00
0.00
IBS
IBS
+
FD
FD
+
Ch
es
t p
ain
He
art
bu
rn
Ae
rop
ha
gia
Od
ds r
ati
o (
an
xie
ty)
FGID
Analysis
Unadjusted
Adjusted
Mean Odds Ratio
Mean Odds Ratio
8
• Olmsted County, MN
• Nested case-control study, dyspepsia (n = 52)
and healthy controls (n = 40)
• Independent risk factors for dyspepsia adjusted
for age, sex, BMI and PPI:
1. Positive family history (OR = 4.7, 95% CI = 1.5-14.9)
2. Sleep difficulty (OR = 8.2, 95% CI = 2.2-31.5)
3. High somatic score (OR = 5.6, 95% CI = 1.5-20.7)
Risk Factors for FD
Gathaiya, Talley et al. Neurogastroenterol Motil. 2009 ;21: 922-e69.
9
• Traditionally, FD is a diagnosis of exclusion -
peptic ulcer, GERD, malignancy (rare!)
• In FD, meal related symptoms are
characteristic
• Diagnostic meal testing to positively
identify FD?
Functional Dyspepsia:
Is a Positive Diagnosis Possible?
Talley NJ. Gut 2008;57:1487-9
10
Symptoms of Functional Dyspepsia are
Induced by a Standard Meal
Bisschops et al. Gut. 2008;57:1495-503
Bloating
Belching
Nausea
Pain
Burning
Fullness
0
0.5
1
1.5
2
2.5
0 15 30 45 60 75 90 105 120 135 150 165 180 195 210 225 240
Time after the meal (min)
Sym
pto
m s
co
re
MEAL-RELATED
0 0 15 30 45 60 75 90 105 120 135 150 165 180 195 210 225 240
Time after the meal (min) S
ym
pto
m s
co
re
0.5
1
1.5
2
2.5 MEAL-UNRELATED
Test meal 60 g white bread, egg, 300 ml water consumed within
10 min (250 kcal: 14 g protein, 26 g carbohydrate, 10 g fat)
11
• Nutrient drink test
• Water load test
• Meal challenge
Non-invasive Assessment of Fundic Dysaccommodation
and Visceral Sensation (drink & puke test)
Talley et al. Aliment Pharmacol Ther. 2008;27:1122-31.
Promote selection of patients with true post- prandial
symptoms (=FD) for targeted therapy?
12
Functional Dyspepsia
Traditional Pathophysiology
Tack et al, J Clin Gastroenterol 2005; 39: S211
Impaired
accommodation 1/3
Delayed gastric
emptying 1/3
Hypersensitivity
to gastric
distention
1/3
Functional dyspepsia with
early satiety and weight loss?
Functional dyspepsia but
symptom associations
controversial (nausea, vomiting
and postprandial fullness)
Functional dyspepsia with
pain, belching and
weight loss?
13
Gastric Emptying is Abnormal in Population Based
(Non-health Care Seeking) Dyspeptic Subjects
Haag, Talley, Holtmann Gut. 2004;53:1445-51
*P values vs asymptomatic controls
P<.025*
Ga
str
ic e
mp
tyin
g t
ime
(t ½
[min
])
350
300
250
200
150
100
50
0 Asymptomatic
Controls
Blood donors
with symptoms
IQ
range
Functional
dyspepsia patients
P<.001*
14
Gastric Volume Changes
in Health and Disease
Tack et al. Gastroenterology 1998; 115:1346-52
Meal
Normal
Fundic accommodation or receptive relaxation
15
Functional Dyspepsia Abnormal Fundic Relaxation in Response to Meal
Tack et al. Gastroenterology 1998; 115:1346-52
Dyspepsia:
40%
Meal
Normal
Impaired fundic accommodation with a redistribution of food to antrum
Fundic accommodation or receptive relaxation
16
Accommodation Reflex
- -
-
NO
Nicotinic receptor
5-HT receptor
CNS
Vagal
afferent GI tract
Sumatriptan
5HT4 agonists
Iberogast
Inhibitory
motor
neuron
+ +
Interneuron Vagal
efferent
Possible pathways for which experimental data exists
Tack J et al. Verh K Acad Geneeskd Belg. 2000;62:183-207.
17
Visceral Hypersensitivity (barostat)
Mertz et al, Gut 1998; 42: 814
Tack et al, Gastroenterology 2001; 121: 526
Boeckxstaens et al, Am J Gastroenterol 2002; 97: 40
Strain gauge
Pressure
selector
Ct P 0
20
40
60
80
100
Control Organic
dyspepsia
Functional
dyspepsia
Prevalence (% of patients)
Normal sensitivity
Hypersensitivity
18
• FD patients failed to activate pACC, to deactivate dorsal pons during distension, and to deactivate amygdala during sham by PET
• Arousal-anxiety-driven failure of pain modulation? • Gastric sensitivity and abuse history independently
influence gastric sensation as well as brain activity in FD
Regional Cerebral Blood Flow Abnormal at Rest and
During Anticipated Gastric Balloon Distention in FD
Van Oudenhove et al. Am J Gastroenterol. 2010; 105: 113-24
Van Oudenhove et al. Gastroenterology. 2010 in press
O F O F
R
L
19
Infection and Functional Dyspepsia:
H. pylori Gastritis
Talley et al. Gastroenterology 2005; 129:1756-80.
20
H. pylori a Cause of FD?
NNT = 17
(95% CI 11 - 33)
Talley, Vakil & Moayyedi. Gastroenterology. 2005; 129:1756-80
Eradication therapy beats placebo but is this a non-specific antibiotic effect
(no trials in Hp negative cases)?
Blum 98
McColl 98
Koelz 03
Talley(Orchid) 99
Talley(USA) 99
Miwa 00
Malfertheiner 03
Varannes 01
Froehlich 01
Koskenpato 01
Gisbert 04
Hsu 01
Van Zanten 03
Overall (95% CI)
0.92 (0.81,1.03)
0.85 (0.77,0.93)
0.95 (0.81,1.11)
0.97 (0.85,1.11)
1.07 (0.86,1.34)
0.91 (0.70,1.18)
0.95 (0.85,1.06)
0.83 (0.68,1.00)
0.86 (0.60,1.24)
0.91 (0.78,1.07)
0.76 (0.40,1.46)
0.93 (0.66,1.33)
0.94 (0.65,1.35)
0.91 (0.87,0.96)
13.4
23.0
8.0
12.0
4.2
2.9
17.6
5.6
1.5
8.1
0.5
1.6
1.5
Study Risk ratio
(95% CI) % Weight
Favors eradication Favors placebo
21
New onset of Dyspepsia Post
Salmonella Gastroenteritis
Mearin et al, Gastroenterology 2005; 129: 98
3 months
post-AGE n=39
57%
n=21
30%
n=9
13% IBS
D
6 months
post-AGE n=26
47%
n=13
23%
n=17
30% IBS
D
12 months
post-AGE n=18
43%
n=15
36%
n=9
21% IBS
D
20
16
12
8
4
0
3.8
2.5
17.7
2.0
12.6
4.2
13.4
2.6
Cases
Controls
Dyspepsia
Post-AGE
20
16
12
8
4
0
2.9
2.3
9.2
1.7
10.2
2.1
10.0
0.7
Cases
Controls
IBS
Pre-AGE 3 months 6 months 12 months
AGE = acute gastroenteritis
22
• Cohort study Walkerton, Ontario, Canada
2002-2003 – follow -up 2008
• Of 2597 subjects eligible, 1088 (42%)
provided data for analysis: 706 (65%)
acute gastroenteritis
• Risk for dyspepsia at 8 years in exposed by
Rome II 2.30 (95% CI 1.63-3.26)
Bacterial Dysentery and FD
Ford et al. Gastroenterology 2010;138:1727-36
• Prevalence of dyspepsia higher in
females; smokers; premorbid IBS;
anxiety or depression; >7 days
diarrhea or cramps during acute illness
23
Post-infectious FD & IBS
Spiller. Gastroenterology 2010;138:1660-3
• Rotavirus infection
leads to transient
delayed gastric
emptying
• Giardia intestinalis
produces mainly post
infectious FD
• Salmonella spp. and
Campylobacter jejuni
cause terminal ileitis
and colitis, associated
equally with both
postinfectious FD and
postinfective IBS
Adverse
life events
Personality Hypochondriasis
Neuroticism Depression Smoking Gender
Reported
symptoms
Rotavirus
transient gastroparesis
Giardia
PI-FD and PI-IBS
Salmonella
PI-FD and PI-IBS
C. jojuni
FD and PI-IBS
Shigella
PI-IBS
Local injury
Inflammation
Rectal bleeding
Prolonged diarrhea Altered enteric nerves
Altered enteroentocrine signaling
24
Presumed Post-infectious FD
Tack et al. Gastroenterology 2002; 122: 1738
Unspecified
Presumed post-infections
*
* P < 0.05
80
70
60
50
40
30
20
10
0
H. Pylori infection Delayed emptying Hypersensitivity
to distention
Impaired
accomodation
Pre
vale
nce (
% o
f p
ati
en
ts)
19 18
25
31 35
41
30
69
25
Homing Small Bowel T Cells and FD
Tobias et al. AJG 2011
• Cytokine release and
CD4+α4β7+CCR9+
lymphocytes correlated
with symptom intensity
pain, cramps,
nausea, vomiting
• Delayed gastric
emptying correlated
(r=0.78, p=0.02) with
CD4+α4β7+CCR9+
lymphocytes, and
IL-1β, TNF-α and
IL-10 secretion
14
12
10
8
6
4
2
0
50 100 150 200 250 300
CD
4+α
4β
7+
CC
R9
+(%
)
GET(T1/2)
26
MBP -degranulation
Clusters of eosinophils in D1
observed in 26 FD (51%)
vs. 10 controls (21%) (p=0.003)
Clin Gastroenterol Hepatol. 2007 5:1175-83
Nonulcer Dyspepsia and Duodenal Eosinophilia: An Adult
Endoscopic Population-Based Case-Control Study
NICHOLAS J. TALLEY, MARJORIE M. WALKER, PERTTI ARO, JUKKA RONKAINEN, TOM STORSKRUBB,
LAURA A. HINDLEY, W. SCOTT HARMSEN, ALAN R. ZINSMEISTER, and LARS AGREUS
27
Duodenal Eosinophilia (UK)
Walker, Talley et al. Aliment Pharmacol Ther. 2010
• 155 patients (mean age 55 years,
59% females) with normal
duodenal biopsies
randomly selected
• Controls: mean duodenal
eosinophil count 15/5HPFs;
prevalence of duodenal
eosinophilia 22.5%
• Postprandial distress syndrome
(PDS) mean eosinophil counts
(20.2/5HPF, p<0.04) and
prevalence of duodenal
eosinophilia (47%, p<0.04) higher
• Duodenal eosinophilia associated
with allergy (OR 5.04, 95% CI
2.12-11.95, p<0.001) but not IBS
or medications
50
45
40
35
30
25
20
15
10
5
0 GERD PDS Vomit FAP Control
Eosinophil counts/5HPFs
28
Eosinophilia in FD
• What is the pathogenesis?
• Hypersensitivity?
– Acid, allergen, pathogen
• Utility of treating duodenal eosinophilia in FD?
Smooth muscle cell
Lipid mediators
Leukotrienes (LT)
PAF Cytokines
IL-2, IL-3, IL-4,
IL-5, IL-6, IL-8,
IL-10, IL-12, IL-13,
IL-16, IL-18,
TGF-a1b, TNF
Cytotoxic secretory products
EPO, MBP, ECP, EDN
IL-4
Antigen
presentation
NGF
VIP
Substance P
MBP
MBP
Nerve
Mast cell Lymphocyte
29
G-Protein (GNß3) Polymorphisms
Holtmann, Talley et al. Gastroenterology 2004
a
b b g
CT
a
b g
CC
a
g b
TT
Amplified signal
transduction
responses
Diminished signal
transduction
responses
FD %: 7.1 32.1 60.7
Controls %: 3.6 55.5 41.1 CC: OR = 2.2
95% CI 1.1-4.3
30
Candidate Genotypes Associated with
Functional Dyspepsia
Van Lelyfeld et al. Neurogastroenterol Motil. 2008;20:767-73
(Oshima et al. BMC Med Genet. 2010;11:13 – confirmed TT association)
• FD (n = 112)
• Healthy controls
(n = 336)
• FD higher prevalence
of T allele GNB3
C825T vs. controls
(OR = 1.60, 95% CI:
1.03-2.49, P = 0.038)
HTR3A C178T
SERT-P L/S
GNβ3 C825T
0.5 1.0 1.5 2.0 3.0
OR 95% CI
OR = 1.60*
OR = 0.95
OR = 1.26
31
Functional Dyspepsia:
Rome III Subgroup Pathogenesis?
• Postprandial distress
syndrome (PDS):
Meal-related FD
– Impaired accommodation
– Delayed emptying
– Duodenal
hypersensitivity/inflammation.
• Epigastric pain
syndrome (EPS):
Meal-unrelated FD
– H. pylori infection
– Immune activation
– Visceral sensitivity
– Brain pain pathways
Functional dyspepsia
32
Response to Acid Suppression
Moayyedi, Talley et al. Gastroenterology. 2004; 127: 1329
Patient sub-group Risk ratio
(95% C.I.)
Reflux group
Epigastric pain group
Dysmotility group
0.76 (0.66-0.88)
0.85 (0.79-0.92)
1.02 (0.92-1.13)
0.65 1 1.55 Risk ratio
Favors PPI therapy Favors placebo
33
PPI Withdrawal Induces Dyspepsia
Niklasson et al. Am J Gastroenterol. 2010
4 Screen failures
58 Screened
participants
54 Eligible
participants
50 Randomly
allocated
25 Allocated to
pantoprazole
25 Allocated to
placebo
2 Drop out
25 In analysis 23 In analysis
4 Excluded
H. pylori positive
Start of therapy Cessation of
therapy
Me
an
sym
pto
m s
co
re
9
8
7
6
5
4
3
2
1
0
W1 w2 w3 w4 w5 w6 w7 w8 w9 w10 w11
*
*
34
Bismuth and Sucralfate in FD
Moayyedi et al. Aliment Pharmacol Ther 2003: 17: 1215-1227.
Kang et al 0.82 (0.52-1.30) 22.6
Kazi et al 0.41 (0.21-0.82) 19.2
Lambert et al 0.79 (0.43-1.44) 20.5
Loffeld et al 1.19 (0.52-2.69) 17.4
Valra et al 0.21 (0.11-0.39) 20.2
Overall (95% CI) 0.58 (0.32-1.04)
Study Risk ratio (95% CI)
Weight (%)
1 0.11 8.89
Risk ratio
Favors bismuth salts Favors placebo
Bismuth
Sucralfate: RRR = 29%;
95% CI -40%, 62%)
NOT statistically significant
35
Fundus Relaxing Drugs:
A Therapeutic Target in FD
• Serotonin 5HT4 agonists: cisapride
• Serotonin 1 agonists: sumatriptan (5HT1p), buspirone (5HT1a)
• Selective serotonin reuptake inhibitors (some!)
• STW 5
Health
Impaired accommodation
36
Functional Dyspepsia:
RCT of Herbal Drug STW 5
Von Arnim et al. Am J Gastroenterol. 2007;102:1268-75
• Angelicae radix
(Garden angelica)
• Cardui mariae fructus
(Milk thistle fruits)
• Carvi fructus
(Caraway fruits)
• Chelidonii herba
• Iberis amara*
(Bitter candy tuft)
• Liquiritiae radix
(Liquorice root)
• Matricariae flos
(Chamomile flowers)
• Melissae folium
(Balm leaves)
• Menthae piperitae
folium (Peppermint leaves)
GIS
Su
m S
co
re (
M+
SD
) [S
co
re p
oin
ts]
0
2
4
6
8
10
12
Day -7
* *
Day 0 Day 14 Day 28 Day 56
STW 5
Placebo
* = P < 0.05
37
STW 5 in Healthy Men Relaxes
the Gastric Fundus
Pilichiewicz et al. Am J Gastroenterol. 2007;102:1276-83
• STW5
increased
proximal
gastric volume
(max volume;
control 104 ±
12 mL, STW5
174 ± 23 mL,
P < 0.05)
Intrabag volume, as mean of 10-minute segments,
after oral administration of 1.1 mL control solution
or Iberogast, with 50 mL water
Intr
a-b
ag
vo
lum
e (
mL
)
Minutes
Controls
Iberogasat®
0
20
40
60
80
100
120
140
160
-10 0 20 40 60 80 100 120
38
Functional Dyspepsia & Tricyclics:
a Summary of the Worlds Literature
Mertz et al. Am J Gastroenterol. 1998; 93: 160-5
Amitryptiline and visceral hypersensitivity Placebo
Amitryptiline
100
150
200
250
300
350
400
450
Intr
a-b
allo
on
vo
lum
e (
ml)
0
50
Fullness Discomfort Pain
0
1
2
3
4
5
6
7
Placebo Amitryptiline
Ab
do
min
al p
ain
ra
tin
g
*
n = 7
39
• Randomized, double-blind, placebo-controlled n=160
• Persistent dyspeptic symptoms, negative EGD
• 8 weeks venlafaxine XR (2 wks 75 mg once daily,
4 wks 150 mg once daily, and 2 wks 75 mg once daily)
• 56% and 73% of participants completed treatment with
venlafaxine or placebo
Venlafaxine Not Efficacious
Clin Gastroenterol Hepatol. 2008;6:746-52
Venlafaxine
Placebo
100
80
60
40
20
0 8 20
%
Weeks
% symptom free days
40
Functional Dyspepsia Treatment Trial
(FDTT): NIH UO1 (Talley)
• Mayo Clinic (Florida, Arizona, Rochester)
• 6 sites around the USA; McMaster (Moayyedi)
• We would welcome referrals
a
b g
CC/TT
Amitryptiline vs. Escitalopram vs. Placebo 12 weeks (6 mo. follow-up)
Anxiety
http://clinicaltrials.gov/ct2/show/NCT00248651
41
Traditional Pharmacologic Treatment
Strategies for Functional Dyspepsia
Saad & Chey, Aliment Pharmacol Ther 2006; 24: 475
Therapeutic
intervention Efficacy Notes
H. pylori eradication 36% vs 30% placebo; NNT 18 Meta-analysis of 13
RCTs
PPIs 33% vs 23% placebo; NNT 9 Meta-analysis of 8 RCTs
H2-receptor antagonists
More effective than placebo for
epigastric pain + postprandial
fullness only
Meta-anlaysis of 11 RCTs
Antidepressants
– TCAs
???
NIH FDDT trial
Single RCT demonstrating
efficacy by PP analysis only
Antacids No better than placebo 1 RCT only
Bismuth salts No better than placebo Meta-analysis of 5 RCTs
Sucralfate No better than placebo Meta-analysis of 2 RCTs
42
• FD often misdiagnosed as gastroesophageal
reflux disease or gastroparesis
• Rome III criteria for FD (EPS, PDS):
increasingly accepted
• FD remains a diagnosis of exclusion
• Almost all meal related – a diagnostic test?
• H. pylori an uncommon cause
• Acid suppression 1st line (usually fails)
• Gastroduodenal dysfunction common
• Duodenal eosinophilia: a novel target?
• Role of antidepressants?
Functional Dyspepsia