Propels in the Epidemiology of Functional GI Disorders

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Progresses in the Epidemiology of Functional GI Disorders Dr Smita Halder Mount Sinai Hospital Toronto DDH Symposium March 20 th 2009

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Outline FGID general diagram New advances

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What is a Functional GI Disorder? Basic, unexplained clutters Irritable Bowel Syndrome Functional Dyspepsia Chronic stomach indications without biochemical or basic clarification Abdominal torment, bloating, sickness, inconsistent gut propensity, early satiety

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How predominant in UK? IBD rates at age 30: 38 (per 10,000) for Crohn's ailment, 30 (per 10,000) for Ulcerative Colitis IBS rates: 826 (per 10,000) ~ 25 times more basic Ehlin et al, Gut 2003

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Adapted from Talley, 1999 Prevalence of IBS (%) IBS predominance around the world?

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Prevalence of IBS by age and sexual orientation in Olmsted County, MN Talley, 1999

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Natural History Difficult to survey because of: Lack of forthcoming populace databases Indistinct nature of the phenotype Short term of follow up in past studies

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Prevalence per 100 of FGID subgroups at two time focuses Halder et al, Gastro 2007

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Symptom Transitions by and large: 33% had determination of side effects 33% had manifestation dependability 33% transitioned to another gathering Halder et al, Gastro 2007

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consulters populace FGIDs – how enormous an issue? half of GI center workload 2% 7% 25% Majority of manifestations last >1 year

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Burden of ailment (1) Quality of life is fundamentally  in IBS sufferers Halder et al, 2004 IBS sufferers Make more doctor visits than non-IBS Visit for non-GI grumblings with more recurrence Longstreth et al, 2003

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Burden of sickness (2) Annual use for IBS, immediate and roundabout expenses: $30 billion in the US; £45.6 million in the UK £1000 spent/year/influenced persistent in the UK Expenditure for FD: £1 billion every year Cost to the NHS (remedies/indicative OGDs): £500 million every year Moayyedi et al, 2002

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Rome III Process International arrangement framework Evolved from Manning criteria, 1978 Symptom groups anatomical areas Rome III distributed 2006 Aids institutionalization in clinical concentrates Rarely utilized as a part of non-research settings Robinson et al, Gut 2001

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IBS Recurrent stomach agony or distress no less than 3 days for every month in the most recent 3 months that has at least two of the accompanying elements: Improved with defæcation Onset connected with an adjustment in recurrence Onset connected with an adjustment in shape Functional Dyspepsia at least one of: Bothersome postprandial totality Early satiation Epigastric torment Epigastric copying AND No proof of natural malady (counting at upper endoscopy) that is probably going to clarify the side effects Rome III Criteria

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IBS Recurrent stomach torment or uneasiness no less than 3 days for each month in the most recent 3 months that has at least two of the accompanying components: Improved with defæcation Onset connected with an adjustment in recurrence Onset connected with an adjustment in frame Functional Dyspepsia at least one of: Bothersome postprandial completion Early satiation Epigastric torment Epigastric smoldering AND No confirmation of natural ailment (counting at upper endoscopy) that is probably going to clarify the side effects Rome III Criteria

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Pathophysiology Brain-Gut Axis ENS/CNS collaboration Visceral touchiness Dysmotility of GI tract Biopsychosocial demonstrate

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Psychosocial Factors Life stretch Psychological state Coping Social bolster Outcome QoL Daily capacity Health mind utilize Medications Work non-attendance IBS Symptoms Early life Genetic Environment Physiology Illness Behavior CNS PNS Brain-Gut Axis Intestinal Function Drossman, 2001

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Potential Stressors

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Potential Stressors

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Potential Stressors

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PhD Study Functional Gastrointestinal Symptoms: Risk elements for Consultation and Persistence

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Hypothesis Psychosocial profile Consultation Clinical elements Persistence Infection

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Baseline Follow-up FGID No FGID ? Onset Time Measure Risk Factors Measure Outcome Overall Study Design

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Results Descriptive insights Consultation elements Persistence components

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610 counseled GP with GI manifestations (12%) 66.6 % F 473 qualified 368 took an interest 105 declined 68.5% F Recruitment for GI ponder

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Distribution of side effects %

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Results Descriptive insights Consultation elements Persistence elements

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4.00 3.50 3.00 2.65 2.50 Hazard Ratio* *Adjusted for age & sexual orientation 2.00 1.50 1.46 1.28 1.00 Highest level Sleep aggravation Highest level Illness conduct Females Hazard Ratios for Consulting: Multivariate Analysis

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Results Descriptive insights Consultation variables Persistence elements

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10 5 4.59 Odds Ratio* 3.08 3 2.45 *Adjusted for age & sex 1 GHQ at time of indications Symptoms for >3 months Symptom term >2 hours 0.1 Odds Ratios for Persistence: Multivariate Analysis

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Odds Ratios for Persistence: Multivariate Analysis 10 5 Odds Ratio* 3 *Adjusted for age & sex 2.29 1 0.23 0.1 Adverse effect on day by day life Change in eating routine Gastroenteritis

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Recent advances Genetics Brain imaging

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Genetics of FGID Unlikely to be single hereditary element Probably an unpredictable communication between hereditary profile natural impacts phenotype all expansion powerlessness to sx onset

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Familial bunching UK concentrate on: 100 IBS patients: 33% reported FHx IBS 100 coordinated controls: 2% reported FHx IBS Whorwell et al, Gut 1986 Mayo study: OR 2.3 [1.3-3.9] of having 1 st º relative with abdo torment/inside probs and reporting IBS/FD Locke et al, 2000

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Twin Studies IBS twice as incessant in MZ twins cf DZ Morris-Yates et al, 1998; Levy et al 2001 Inherited pathophysiological systems or learned reaction? Offspring of IBS guardians visit healing facility more regularly than offspring of non-IBS guardians Levy et al, Am J Gastro 2000 Intergenerational transmission of sickness conduct

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Individual qualities (1) Serotonin transporter quality: Functional polymorphism in SLC6A4 connected with looseness of the bowels in ladies with IBS LL genotype connected with reaction to alosetron (5HT 3 rec adversary) S allele connected with reaction to tegaserod Camilleri et al, Lancet 2000

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Individual qualities (2) Cytokines: Interleukin-10 (mitigating) High-maker genotype more pervasive in controls than IBS Gonsalkorale et al, Gut 2003 TNF (star fiery) High-maker genotype more common in IBS than controls van der Veek et al, Am J Gastro 2005

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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 digestion system: Fatty corrosive amide hydrolase ( FAAH ) Inflammatory markers: Interleukin-10 ( IL-10 ) Transforming development consider β 1 ( TGF-β1 ) Tumor putrefaction calculate alpha ( TNF-α ) Intracellular cell flagging: G protein β 3 subunit ( GNβ3 ) Ion channels: Sodium channel ( SCN5A )

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Functional Dyspepsia Homozygous GN β 3 825CC bearer status essentially connected with upper-stomach sx Holtmann et al, Gastro 2004

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GN β 3 C825T in lower FGID Olmsted County Study, Mayo Clinic 82 IBS-C; 94 IBS-D; 38 IBS-Alternating; 19 Abdo Pain 152 Controls GN β 3 C825T genotype dispersions comparable btwn cases/controls No affiliations found in lower FGIDs general Andresen et al, Gastro 2006

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Limitations to hereditary studies Bias inborn in the study plan Poor factual examination Small specimen estimate Over elucidation of information

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Advances in research instruments

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Functional Brain Imaging Aids in exploring Brain-Gut associations CNS part in instinctive torment observation Positron Emission Tomography (PET) Functional Magnetic Resonance Imaging (fMRI) Magnetoencephalography (MEG)

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PET scanner

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Advantages Excellent spatial determination Can contemplate receptor locales Disadvantages Poor transient determination Radiation Expensive PET Radioisotope infused - cerebral blood stream measured

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ACC Control ACC IBS Silverman, Gastro 1997

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Control IBS Silverman, Gastro 1997

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Advantages Non-obtrusive Non-combined Good spatial determination Disadvantages Not continuous Response to torment not effortlessly mapped fMRI Neuronal action prompts to changes in blood stream, volume and oxygenation of Hb

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Activation by rectal torment amid stretch ACC: caudal front cingulate; PFC: right prefrontal cortex; pACC : perigenual foremost cingulate Morgan et al, Gut 2005

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MEG Cortical neuromagnetic movement recognized Does not rely on upon metabolic changes Advantages Non-intrusive Good spatial determination Excellent worldly determination (ms) Disadvantages Expensive Not broadly accessible

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IBS Abnormal example of ACC initiation amid agony discernment Amitriptyline diminishes torment related actuation in pACC amid push

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Limitations to FGID Research Difficult phenotype Study settings: referral centers ? Outer legitimacy Study outlines: cross-sectional ? Causal variables or simultaneous components Bias: Recall Misclassification of cases Usually concentrate on one hazard area: mental/contamination/hereditary qualities

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Thank you

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