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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