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Advances in the Epidemiology of Functional GI Disorders. Dr Smita Halder Mount Sinai Hospital Toronto DDH Symposium March 20 th 2009. Outline. FGID general overview New advances. What is a Functional GI Disorder?. Common, unexplained disorders Irritable Bowel Syndrome

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Advances in the Epidemiology of Functional GI Disorders


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advances in the epidemiology of functional gi disorders

Advances in the Epidemiology of Functional GI Disorders

Dr Smita Halder

Mount Sinai Hospital

Toronto

DDH Symposium

March 20th 2009

outline
Outline
  • FGID general overview
  • New advances
what is a functional gi disorder
What is a Functional GI Disorder?
  • Common, unexplained disorders
    • Irritable Bowel Syndrome
    • Functional Dyspepsia
  • Chronic abdominal symptoms in the absence of biochemical or structural explanation
  • Abdominal pain, bloating, nausea, erratic bowel habit, early satiety
how prevalent in uk
How prevalent in UK?
  • IBD rates at age 30:
    • 38 (per 10,000) for Crohn’s disease,
    • 30 (per 10,000) for Ulcerative Colitis
  • IBS rates:
    • 826 (per 10,000)
  • ~ 25 times more common

Ehlin et al, Gut 2003

natural history
Natural History

Difficult to assess due to:

  • Lack of prospective population databases
  • Indistinct nature of the phenotype
  • Short duration of follow up in previous studies
symptom transitions
Symptom Transitions
  • In general:
    • one third had resolution of symptoms
    • one third had symptom stability
    • one third transitioned to a new group

Halder et al, Gastro 2007

slide10

consulters

population

FGIDs – how big a problem?

50% of GI clinic workload

2%

7%

25%

Majority of symptoms last >1 year

burden of illness 1
Burden of illness (1)
  • Quality of life is significantly  in IBS sufferers

Halder et al, 2004

  • IBS sufferers
    • Make more physician visits than non-IBS
    • Visit for non-GI complaints with more frequency

Longstreth et al, 2003

burden of illness 2
Burden of illness (2)
  • Annual expenditure for IBS, direct and indirect costs:
    • $30 billion in the US; £45.6 million in the UK
    • £1000 spent / year / affected patient in the UK
  • Expenditure for FD: £1 billion per year
    • Cost to the NHS (prescriptions / diagnostic OGDs): £500 million per year

Moayyedi et al, 2002

rome iii process
Rome III Process
  • International classification system
  • Evolved from Manning criteria, 1978
  • Symptom clusters- anatomical regions
  • Rome III published 2006
  • Aids standardisation in clinical studies
  • Rarely used in non-research settings

Robinson et al, Gut 2001

rome iii criteria
IBS

Recurrent abdominal pain or discomfort at least 3 days per month in the last 3 months that has two or more of the following features:

Improved with defæcation

Onset associated with a change in frequency

Onset associated with a change in form

Functional Dyspepsia

One or more of:

Bothersome postprandial fullness

Early satiation

Epigastric pain

Epigastric burning

AND

No evidence of organic disease (including at upper endoscopy) that is likely to explain the symptoms

Rome III Criteria
rome iii criteria17
IBS

Recurrent abdominal pain or discomfort at least 3 days per month in the last 3 months that has two or more of the following features:

Improved with defæcation

Onset associated with a change in frequency

Onset associated with a change in form

Functional Dyspepsia

One or more of:

Bothersome postprandial fullness

Early satiation

Epigastric pain

Epigastric burning

AND

No evidence of organic disease (including at upper endoscopy) that is likely to explain the symptoms

Rome III Criteria
pathophysiology
Pathophysiology
  • Brain-Gut Axis
    • ENS / CNS interaction
  • Visceral hypersensitivity
  • Dysmotility of GI tract
  • Biopsychosocial model
slide19

Psychosocial Factors

  • Life stress
  • Psychological state
  • Coping
  • Social support

Outcome

QoL

Daily function

Health care use

Medications

Work absenteeism

IBS

Symptoms

Early life

Genetic

Environment

Physiology

Illness

Behaviour

CNS

PNS

Brain-Gut

Axis

Intestinal Function

Drossman, 2001

phd study

PhD Study

Functional Gastrointestinal Symptoms:

Risk factors for Consultation and Persistence

hypothesis
Hypothesis

Psychosocial profile

Consultation

Clinical

factors

Persistence

Infection

overall study design

Baseline

Follow-up

FGID

No

FGID

FGID

?

Onset

Time

Measure Risk Factors

Measure Outcome

Overall Study Design
results
Results
  • Descriptive statistics
  • Consultation factors
  • Persistence factors
recruitment for gi study

610 consulted GP with GI symptoms (12%)

66.6 % F

473 eligible

368 participated

105 refused

68.5% F

Recruitment for GI study
results29
Results
  • Descriptive statistics
  • Consultation factors
  • Persistence factors
slide30

4.00

4.00

3.50

3.50

3.00

3.00

2.65

2.50

2.50

Hazard Ratio*

*Adjusted for age & gender

2.00

2.00

1.50

1.50

1.46

1.28

1.00

Highest level

Sleep disturbance

Highest level

Illness behaviour

Females

Hazard Ratios for Consulting: Multivariate Analysis

results31
Results
  • Descriptive statistics
  • Consultation factors
  • Persistence factors
slide32

10

10

5

5

4.59

Odds Ratio*

3.08

3

3

2.45

*Adjusted for age & gender

1

1

GHQ at time

of symptoms

Symptoms for

>3 months

Symptom duration

>2 hours

0.1

Odds Ratios for Persistence: Multivariate Analysis

slide33

Odds Ratios for Persistence: Multivariate Analysis

10

10

5

5

Odds Ratio*

3

3

*Adjusted for age & gender

2.29

1

1

0.23

0.23

0.1

0.1

Adverse impact

on daily life

Change in diet

Gastroenteritis

recent advances
Recent advances
  • Genetics
  • Brain imaging
genetics of fgid
Genetics of FGID
  • Unlikely to be single genetic factor
  • Probably a complex interaction between
    • genetic profile
    • environmental influences
    • phenotype

all increase susceptibility to sx onset

familial clustering
Familial clustering
  • UK study:
    • 100 IBS patients: 33% reported FHx IBS
    • 100 matched controls: 2% reported FHx IBS

Whorwell et al, Gut 1986

  • Mayo study:
    • OR 2.3 [1.3-3.9] of having 1stº relative with abdo pain/ bowel probs and reporting IBS/FD

Locke et al, 2000

twin studies
Twin Studies
  • IBS twice as frequent in MZ twins cf DZ

Morris-Yates et al, 1998; Levy et al 2001

  • Inherited pathophysiological mechanisms

or learned response?

  • Children of IBS parents visit hospital more often than children of non-IBS parents

Levy et al, Am J Gastro 2000

  • Intergenerational transmission of illness behaviour
individual genes 1
Individual genes (1)

Serotonin transporter gene:

  • Functional polymorphism in SLC6A4 linked with diarrhoea in women with IBS
  • LL genotype associated with response to alosetron (5HT3 rec antagonist)
  • S allele associated with response to tegaserod

Camilleri et al, Lancet 2000

individual genes 2
Individual genes (2)

Cytokines:

  • Interleukin-10 (anti-inflammatory)
    • High-producer genotype more prevalent in controls than IBS

Gonsalkorale et al, Gut 2003

  • TNF (pro-inflammatory)
    • High-producer genotype more prevalent in IBS than controls

van der Veek et al, Am J Gastro 2005

candidate genes for ibs
Candidate Genes for IBS

Receptors:

Alpha-2A-adrenergic rec (ADRA2A)

Alpha-2C-adrenergic rec (ADRA2C)

5-HT2A receptor (5-HT2A)

Neurotransmitter transporters:

Serotonin transporter (SLC6A4)

Norepinephrine transporter (NET)

Neurotransmitter metabolism:

Fatty acid amide hydrolase (FAAH)

Inflammatory markers:

Interleukin-10 (IL-10)

Transforming growth factor-β1

(TGF-β1)

Tumor necrosis factor-alpha

(TNF-α)

Intracellular cell signaling:

G protein β3 subunit (GNβ3)

Ion channels:

Sodium channel (SCN5A)

functional dyspepsia
Functional Dyspepsia
  • Homozygous GN β3 825CC carrier status significantly associated with upper-abdominal sx

Holtmann et al, Gastro 2004

gn 3 c825t in lower fgid
GN β3 C825T in lower FGID
  • Olmsted County Study, Mayo Clinic
  • 82 IBS-C; 94 IBS-D; 38 IBS-Alternating; 19 Abdo Pain
  • 152 Controls
  • GN β3 C825T genotype distributions similar btwn cases/ controls
  • No associations found in lower FGIDs overall

Andresen et al, Gastro 2006

limitations to genetic studies
Limitations to genetic studies
  • Bias inherent in the study design
  • Poor statistical analysis
  • Small sample size
  • Over interpretation of data
functional brain imaging
Functional Brain Imaging
  • Aids in investigating
    • Brain-Gut interactions
    • CNS role in visceral pain perception
  • Positron Emission Tomography (PET)
  • Functional Magnetic Resonance Imaging (fMRI)
  • Magnetoencephalography (MEG)
slide47
Advantages

Excellent spatial resolution

Can study receptor sites

Disadvantages

Poor temporal resolution

Radiation

Expensive

PET

Radioisotope injected

- cerebral blood flow measured

slide48

ACC

Control

ACC

IBS

Silverman, Gastro 1997

slide49

Control

IBS

Silverman, Gastro 1997

slide51
Advantages

Non-invasive

Non-cumulative

Good spatial resolution

Disadvantages

Not real time

Response to pain not easily mapped

fMRI

Neuronal activity leads to changes in

blood flow, volume and oxygenation of Hb

slide53

Activation by rectal pain during stress

ACC:caudal anterior cingulate; PFC: right prefrontal cortex; pACC: perigenual anterior cingulate

Morgan et al, Gut 2005

slide55
MEG

Cortical neuromagnetic activity detected

Does not depend on metabolic changes

Advantages

  • Non-invasive
  • Good spatial resolution
  • Excellent temporal resolution (ms)

Disadvantages

  • Expensive
  • Not widely available
slide57
IBS
  • Abnormal pattern of ACC activation during pain perception
  • Amitriptyline reduces pain-related activation in pACC during stress
limitations to fgid research
Limitations to FGID Research
  • Difficult phenotype
  • Study settings: referral clinics
    • ? External validity
  • Study designs: cross-sectional
    • ? Causal factors or concurrent factors
  • Bias:
    • Recall
    • Misclassification of cases
  • Usually focus on one risk domain: psychological / infection / genetics