Contemporary Management of Functional Dyspepsia

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Contemporary Management of Functional Dyspepsia

• This educational program, approved by the
  Canadian Association of Gastroenterology, is
  sponsoredby an unrestricted educational grant
  from

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Learning Objectives

• Review the definition and presentations of
  dyspepsia
• Understand dyspepsia and its differential
  diagnosis
• Rationalize testing for dyspepsia
• Choose an optimal therapeutic approach for
  dyspepsia

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Definitions and Epidemiology of Dyspepsia
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Dyspepsia - Definition

• A group of symptoms which alert clinicians to
  consider disease of the upper gastrointestinal
  tract

(British Society of Gastroenterology, 1996)
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Epidemiology of Dyspepsia
DIGEST, 1996 The Domestic/International
Gastrointestinal Disease Study. Canadian
Highlights

• Randomly selected 1036 adults across Canada
• Examined
• 1. Severity of dyspepsia symptoms 2. Quality of
  life

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Overall Prevalence of Dyspepsia in Canada
30
30
29
27
25
British Columbia
Prairie Provinces
Ontario
Quebec
Atlantic Provinces
(DIGEST, 1996)
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Dyspepsia in Canada Sample Breakdown
Total Sample
No dyspepsia71
Dyspepsia29
Acute dyspepsia6.5
Chronic dyspepsia22.5
Less than 1 Month
(DIGEST, 1996)
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Social Impact of Dyspepsia
70
60
50
40
30
20
10
0
Not At All
Slightly
Moderately
Quite A Lot
Extremely
Extent to which dyspepsia has interfered with
normal social activities
(DIGEST, 1996)
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Quality-of-Life
Subjects with no dyspepsia Subjects with
chronic dyspepsia
Score (PsychologicalGeneral Well Being Index)
Anxiety Positive Depressed Self General Vitality
Well Being Mood Control Health
Domain
(DIGEST, 1996)
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Functional Dyspepsia - Definition

• Chronic or recurrent upper GI symptoms not
  explained by biochemical or structural
  abnormalities (does not imply that there is no
  physiological basis)
• Appropriate evaluation using standard diagnostic
  tests reveals no abnormalities
• Also known as nonulcer dyspepsia, essential
  dyspepsia, idiopathic dyspepsia

(Talley N. Scand J Gastro 19911827)
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Dyspepsia
Functional Dyspepsia
Non-GICauses of Symptoms (cardiac
disease,muscular pain, etc.)
Structural Dyspepsia (GERD, PUD,
pancreaticdisease, gallstones, etc.)
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Symptoms of Functional Dyspepsia
Ulcer-like Dominant Dysmotility-like Dominant
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Major Causes of Dyspepsia
Williams 1988 Stanghellini 1996 Heikkinen 1996
(n1386) (n1057) (n766)
of Patients withDiagnosis
Gastric Cancer Peptic Ulcer Esophagitis/ Functiona
l
GERD Dyspepsia
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Pathophysiology of Functional Dyspepsia
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What are the possible causes of functional
dyspepsia?

• Altered enteric visceral perception
  (hyperalgesia)
• Altered enteric motor function
• Altered CNS function
• Helicobacter pylori

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Pathogenesis Pathophysiology of Dyspepsia

• Behavioural factors
• Gastritis
• H. pylori infection

• Increasedvisceralperception

• Alteredmotility

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Mechanisms Underlying Increased Sensory Perception
Reduced descending inhibition

• Increasedsensory input

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Mechanisms Underlying Altered Motility in
Dyspepsia

• Stress
• BehaviouralFactors

Local Factors GastritisH. pylori infection
Abnormal Motility

• Decreased antral motility
• Impaired fundal relaxation

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Putative Pathogenesis of Dyspepsia
Stress
ANS Imbalance
Increased Sensitivity
Increased Afferent Activity
Low Grade Inflammation HP Infection
Impaired Motor Activity Accommodation
Altered Motor Sensory Function
DYSPEPSIA
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Altered Enteric Visceral Perception(Hyperalgesia)
in Functional Dyspepsia
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Proposed Mechanisms of Hyperalgesia
Role of Inflammation
Mucosa Lamina propria Neuromuscular layer
Irritation or Infection
Acute Inflammation
Immune Activation
Altered Neuromuscular Function
Resolution
Normal
Persistent Altered Neuromuscular Function
In some (Genetic)
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Proposed Mechanisms of Hyperalgesia
Is there evidence of inflammation in functional
dyspepsia?

• Endoscopic evidence of gastritis in some patients
• Increased mast cells in the lamina propria in
  some patients
• Some patients have infection with Helicobacter
  pylori

Hypothesis Low-grade inflammation can cause
altered motor function, and altered sensitivity
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Proposed Mechanisms of Hyperalgesia
Normal Pathways
Pain Perception
Cortex
Descending inhibitory fibres
Spinal Cord - ANS. Input 2nd order
neurons Dorsal horn nucleus Dorsal root
ganglion Sensory nerve endings in gut
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Proposed Mechanisms of Hyperalgesia
Peripheral Hyperalgesia
Amplification
Hyperplasia of D.H.N.
Amplification
Hyperplasia of D.R.G.
Irritation orLow GradeInflammation
Recruitment of silent sensory fibres -
Amplification
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Proposed Mechanisms of Hyperalgesia
Central Hyperalgesia
Pain
Loss of Descending Inhibition
Peripheral Signals
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Proposed Mechanisms of Hyperalgesia
Drug Effects on the CNS-Enteric Nervous System
Pain Perception
Cortex
PharmacologicalOptions ? opiates,
tricyclics5HT3 antagonists
Spinal Cord Descending inhibitory fibres -
ANS. Input 2nd order neurons Dorsal horn
nucleus Dorsal root ganglion Sensorynerve
endings in gut
Clonidine ? opiates5HT3 antagonists
Substance PCGRP antagonists
NSAIDs ? opiates5HT3 antagonists
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Visceral Hyperalgesia in Functional Dyspepsia

• Patients with functional dyspepsia have normal
  somatic pain perception
• Visceral sensation is diffusely altered in
  functional dyspepsia, based on balloon distension
  studies in stomach, esophagus, and rectum

(Trimble K. Dig Dis Sci 1995401607)
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Visceral Hyperalgesia in Functional Dyspepsia
Controls (n10) Patients with functional
dyspepsia (n10)
p lt 0.005
p 0.001
Volume of Gastric Distension (mLs)
(Bradette M. Dig Dis Sci 19913652)
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Altered Enteric Motor Function in Functional
Dyspepsia
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Upper GI Motility in Functional Dyspepsia

• Impaired reflex fundal relaxation
• Impaired gastric compliance/receptive relaxation
  to food ingestion
• Weak postprandial antral contractions
• Delayed gastric emptying
• Small bowel motor dysfunction

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Upper GI Motility in Functional Dyspepsia
Abnormal Fundic Relaxation in Response to Meal
in Functional Dyspepsia
Normal
Fundic accommodation or receptive relaxation
Meal
Impaired fundic accommodation with a
redistribution of food to antrum
Functionaldyspepsia
(Gilja O. Dig Dis Sci 199641689)
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Impaired Accommodation in Functional Dyspepsia
P lt 0.05
Differences in area measurements in a sagittal
section of proximal stomach, between patients
with functional dyspepsia and healthy controls.
SEM bars are shown.
(Gilja O. Dig Dis Sci 199641689)
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Weak Postprandial Antral Contractions in
Functional Dyspepsia
Normal
Functional Dyspepsia

• Postprandial antral hypomotility is common
• Can also be seen in PUD or gastritis

(Camilleri M. Dig Dis Sci 1986311169. Kerlin
P. Gut 19893054)
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Delayed Gastric Emptying in Functional Dyspepsia

• Studies have found delayed gastric emptying for
  solids, in 30 to 82 of patients with functional
  dyspepsia

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Small Bowel Motor Dysfunction in Functional
Dyspepsia

• In patients with more severe symptoms
• Hyperactive or uncoordinated duodenal
  contractions
• Absent or abnormal migrating myoelectrical
  complexes

(Kerlin P. Gut 19893054)
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Altered CNS Function in Functional Dyspepsia
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CNS Factors
Psychological factors to be considered inthe
pathogenesis of functional dyspepsia

• Anxiety
• Depression
• Sexual abuse
• Sleep deprivation
• Stressful events

The role of psychological factors in functional
dyspepsia is not as clearly established as it is
in IBS
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Functional Dyspepsia and Irritable Bowel Syndrome
44
29
of Patients with Functional Dyspepsia who also
have IBS
Ulcer-like Dysmotility-like Dyspepsia Dyspepsia
(Jones R. Gut 199031401)
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Helicobacter pylori in Functional Dyspepsia
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Is H. pylori a Factor in Functional Dyspepsia?

• Controversial
• Some evidence- biological plausibility-
  prevalence (45 to 70 in dyspeptics, 13 to
  60 in controls)- eradication studies

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H. pylori Eradication Studies in Functional
Dyspepsia
No Benefit from Length of Benefit from Length
of H. pylori Follow-up H. pylori Follow-up Eradi
cation (yr) Eradication (yr)

• Veldhuyzen van Zanten, 1995 0.5 Lazzaroni,
  1996 0.5
• Elta, 1996 3 Trespi, 1994 0.5
• Schutze, 1996 1 McCarthy, 1995 1
• Sheu, 1996 1

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Canadian Economic AnalysisH. pylori Eradication
in Undiagnosed Dyspepsia

• Based on an American analysis
• Examined management of Hp-seropositive patients
• Scope first strategy 401Treat Hp first 345

(Adapted from Offman J. Ann Int Med 1997126280)
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Testing for H. pylori
Test Sensitivity Specificity Cost Comments

• C13 or C14 90 to 100 96 to 100 Limited -
  requiresurease breath hospital
  nucleartest medicine department
• Serology 91 to 98 75 to 80 Widely
  available through commercial labs and
  Public Health
• Capillary 85 to 90 75 to
  80 Office test, must beblood
  serology purchased by doctor administered
• Endoscopic 99 99 Requires
  specialistbiopsy Invasive

(Cutler A. Gastro 1995109136.Megraud F. Scand
J Gastro 199621557)
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H. pylori Eradication Regimens(All given for one
week)

• Treatments of Choice

Regimen PPI Antibiotics
PPI - AC BID Amoxicillin 1 g bid Clarithromycin
500 mg bid PPI - MC BID Metronidazole 500 mg bid
Clarithromycin 250 mg bid
Alternate
PPI - BMT BID Bismuth 2 tabs qid Metronidazole
250 mg qid Tetracycline 500 mg qid
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Management of Dyspepsia
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Suggested Approach for Management of Dyspepsia
Dyspepsia
Initial interview and examination
Functional dyspepsia
Structural disease or alarm symptoms
Dysmotility-like symptoms dominant
Ulcer-like symptoms dominant
Education/lifestyle modification
Education/lifestyle modification
Test Hp

-
Eradicate
Trial of acid suppression
Trial of prokinetic medication
Success
Fail
Fail
Fail
Success
Success
Investigate/refer
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Interview and Examination Objectives

• Initiate a symptom-based diagnosis
• Address patients concerns and expectations
• Explore psychosocial issues, patterns of illness
  behaviour
• Educate

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Interview and Examination - Symptoms and Signs
Suggest Suggest Ulcer-like Suggest
Dysmotility-like Suggest GERD
Dyspepsia Dyspepsia Structural Disease

• Heartburn Burning pain Nausea Weight loss
• Regurgitation Bloating Dysphagia
• Reflux

Relief of painwith food
Vomiting Bleeding Palpable mass
Early satiety Pain worsewith food
Localized epigastricpain Nocturnal/fasting pain
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Suspected Functional Dyspepsia - Who to
Investigate?

• Over 50 years of age, with new onset of symptoms
• Failed therapy
• Cancer fear
• Symptoms that are severe as perceived by patient
  or physician

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Choice of Investigation for Ulcer-like Dyspepsia
Endoscopy UGI Series

• More expensive Less expensive
• Issues of access/waiting Easy access, usually
  shortlists can be a problem waiting time
• Allows for biopsy If cancer is found,
  endoscopy(cancer, Hp) will be needed
• Allows diagnosis of Often misses mucosal
  lesionsmucosal lesions (erosions)
• Preferred investigation for Alternative,
  especially if dyspepsia access is a concern

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Investigation of Dysmotility-like Dyspepsia

• Investigations are frequently normal
• Reserved for patients with severe symptoms,
  vomiting dominant, unresponsive to therapy
• Solid-phase gastric emptying test may be useful

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Management of Functional Dyspepsia
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Management of Functional Dyspepsia
Functional Dyspepsia
General treatment and specific management based
on dominant symptom complex
Ulcer-like
Dysmotility-like
Follow-up within 3 to 6 weeks
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Management of Ulcer-like Functional Dyspepsia
Ulcer-like Symptoms Dominant
Education/lifestyle modification
Test Hp

-
Eradicate Hp
Trial of acid suppression
Reassess
Success
Failure
Investigate
Trial of prokinetic
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Lifestyle Modification for Patients with
Functional Dyspepsia

• Small frequent meals
• Stop smoking
• Reduce alcohol
• Reduce caffeine
• Avoid irritating foodstuffs
• Maintain an ideal weight
• Review medications

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Acid Suppression Therapy for Ulcer-like
Functional Dyspepsia

• H2-receptor antagonist for 4 weeks
• OR
• Proton pump inhibitor for 2 weeks

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Management of Dysmotility-like Functional
Dyspepsia
Dysmotility-like Symptoms Dominant
Educate/lifestyle modification
Trial of prokinetic medication
Success
Failure
Investigate
Continue withcyclic therapy
Test H. pylori
Gastroscopy or UGI

-
Eradicate
Consider H2antagonists, tricyclics
Success
Failure
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Rationale for the Use of Prokinetic Agents in
Dysmotility-like Functional Dyspepsia

• Accelerate gastric emptying
• Increase antral contractions
• Decrease duration of proximal gastric distention
• Antinausea

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Placebo-controlled Trials of Prokinetic Agents
in Functional Dyspepsia

• Of 11 trials with domperidone, 10 showed
  domperidone better than placebo
• Of 19 trials with cisapride, 15 showed cisapride
  better than placebo

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Placebo-controlled Trials of H2 Blockers in
Dyspepsia

• Only 4 of 12 trials showed benefit vs. placebo
• Overall, 59 response rate for H2 blockers, 48
  for placebo

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Suggested Approach for Management of Dyspepsia
Dyspepsia
Initial interview and examination
Structural disease or alarm symptoms
Functional dyspepsia
Dysmotility-like symptoms dominant
Ulcer-like symptoms dominant
Education/lifestyle modification
Education/lifestyle modification
Test Hp

-
Eradicate
Trial of acid suppression
Trial of prokinetic medication
Success
Fail
Fail
Fail
Success
Success
Investigate/refer
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Summary

• Dyspepsia is common
• On clinical grounds, functional dyspepsia can be
  separated into ulcer-like and dysmotility-like

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Summary (contd)

• Patients with ulcer-like functional dyspepsia
  should be tested for Helicobacter pylori, and
  treated accordingly
• For patients with dysmotility-like functional
  dyspepsia, prokinetic drugs are effective

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Case Presentation

• 34 y.o. security guard
• 5 years of intermittent epigastric discomfort
• Bloating, postprandial nausea
• Smokes, drinks 3 beers/day,4 coffees/day

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• Ranitidine prescribed one year ago
• - Initially beneficial, not now
• Family history of peptic ulcer
• Examination is normal

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• Can a diagnosis be made,based on history and
  examination?

67

• You suspect functional dyspepsia
• The patient requests investigation (worried about
  cancer or infection)

68

• What investigations would you do?
• What management suggestions would you make?
• Would you suggest any medication?