Prevalence of IBS Irritable Bowel Syndrome: Diagnosis Past, … - PDF of Slides.pdf · 2018. 11....
Transcript of Prevalence of IBS Irritable Bowel Syndrome: Diagnosis Past, … - PDF of Slides.pdf · 2018. 11....
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Irritable Bowel Syndrome:Past, Present, and Future
G. Nicholas Verne, M.D.Professor and Division Director
Division of Gastroenterology, Hepatology, NutritionDepartment of Internal Medicine
Ohio State University Columbus, OH
Drossman et al., Dig Dis Sci, 1993
Prevalence of IBS in the US
Ages in Years
0
2
4
6
8
10
12
14
15-34 35-44 >45
%
Male
Female
IBS
Primary CarePractice
GastroenterologyPractice
All Other PC Diagnoses
88%
12%
IBS
28%Other GI15%
IBD14%
Peptic20%
Liver10%
Other Functional
13%
Mitchell & Drossman, Gastroenterology, 1987
Prevalence of IBS Diagnosis
Quality-of-life impact of IBS vs other conditions
Subscale score (100=good; 0=bad)
PhysicalFunctioning
Role Physical
BodilyPain
Role Emotional
Mental Health
Social Functioning
General Health
Vitality0
102030405060708090
100
IBSUS General Population
MigraineAsthma female (15-34)
GERD
Frank et al, Clin Ther 2002
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Medical Costs Associated With IBS
• IBS results in an estimated $8 billion in direct medical costs annually
• IBS sufferers incur 74% more direct healthcare costs than non-IBS sufferers
• IBS patients have more physician visits for both GI and non-GI complaints
Talley et al., Gastroenterology, 1995
IBS: SymptomsChronically recurring symptoms
Abdominal painAltered bowel function
Incomplete evacuationUrgencyBloating
Diarrheapredominant
Constipationpredominant
Alternator
Stool Character-Description
Prevalence by IBS subgroups
Talley et al, 1995
Survey respondents (%)
IBS-constipation
5.2
6.7
3.5
IBS-diarrhea
5.5 5.3 5.6
0
8 OverallFemalesMales
3022 residents surveyed in Minnesota
536 respondents
IBS-alternating
5.2 5.64.7
3
Longstreth, Gastroenterology, 2006
Rome I-II Criteria Rome III Criteria1. At least 3 months of continuous
or recurrent symptoms of abdominal pain or discomfort that is:
Relieved by defecation and/orAssociated with a change in frequency of stool; and/orAssociated with a change in consistency of stool
2. 2 or more of the following at least 25% of the time:
Altered stool frequencyAltered stool formAltered stool passage (straining, urgency, feeling of incomplete evacuation)Passage of mucous; and/orBloating or feeling of abdominal distension
1. At least 12 weeks, which need not be consecutive, in the past 12 months of abdominal discomfort or pain that has 2 of 3 features:
Relieved by defecation; and/orOnset associated with a change in frequency of stool; and/orOnset associated with a change in form (appearance) of stool
IBS-PathophysiologyStress affects
GI function
Motility
MealsPain / motility
Myoelectrical Marker
Brain-Gut Interactions
Visceral/SomaticHypersensitivity
Mechanisms
Pain sensitivity
3 cpmmotility
Clusteredcontractions
CNS / ENSAutonomic reactivity
Visceralhypersensitivity
19701950 1960 1980 1990 2000
Post-infectiousIBS
Inflammation
Viscera
Visceral Hypersensitivity in IBS
Ascending pain pathwayBrain stem
Spinal cord
Dorsal root ganglion
Pain
Verne & Price, 2002
Visceral Pain Thresholds
Whitehead et al., Dig Dis Sci, 1980
20 60 100 140 180
% R
epor
ting
Pain
Rectosigmoid balloon volume (mL)
0
20
40
60
IBS
Normal
Pain produced by rectosigmoid balloon distension
4
Distender Series ®/Barostat
Barostat Catheter/Balloon
Visceral Stimulation Protocol
Verne & Price, 2002
Somatic Hypersensitivityin IBS Patients
• IBS patients also exhibit a number of extra-intestinal symptoms such as migraine headaches, back and muscle pain
• Consistent with central hyperalgesic mechanism(s)
• Recent studies have suggested that somatic hyperalgesia may also occur in IBS patients
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Hot Water Immersion
Mechanical Visual Analogue Scale
Price et al., Pain, 1994
Thermal Hyperalgesiain IBS
*
*
*P<0.001
Verne et al., Pain 2001.
ViscerosomaticConvergence
Colon AnterolateralTract axon
Foot
Verne et al., Gut, 2006
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Visceral Hypersensitivity:Pathophysiology• Triggers: chemical, environmental, physical,
stress, inflammatory• Postulated mechanisms:
hyperexcitability/activation of neurotransmitters (sub P, CGRP)modulation of nociceptive transmission (NMDA)recruitment of silent nociceptorsloss of inhibitory modulation to dorsal horn neuronsneuroplasticity leading to chronic visceral hypersensitivity
Mayer & Raybould, Gastroenterology, 1990;Mayer & Gebhart, Gastroenterology, 1994
Sensitization Following Peripheral Injury
Dorsal root ganglion
Mechanosensitiveafferent
Sensitized spinal circuits
Peripheral Injury
Some Possible Mediators of Motility and Visceral Sensitivity
• Visceral sensitivity:- serotonin- tachykinins- calcitonin gene-related
peptide - neurokinin A- enkephalins
Kim and Camilleri, Am J Gastroenterol 2000Grider et al., Gastroenterology 1998
• Motility:- serotonin- acetylcholine- nitric oxide- substance P- vasoactive intestinal
peptide - cholecystokinin
Plasma 5-HT levelsin IBS
123456
Controls (n=6)
Meal
0 1.0 2.0 3.0 4.00
200
400
600
800
1000
1200
1400
Time (h after meal)
7891011
IBS patients (n=5)
0 1.0 2.0 3.0 4.00
200
400
600
800
1000
1200
1400
Time (h after meal)
Meal
9
8
10
11
7
5-HT (nmol/l) 5-HT (nmol/l)
Bearcroft et al., Gut, 1998
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Serotonin and EC cells in Altered GI Motility
Decreased number of EC cellsin constipation
Increased number of EC cellsin post-infectious IBS
Increased circulating 5-HT Diarrhea
Constipation
Bearcroft et al., Gut 1998 Spiller et al, Gut 2000
Integration EffectInput
SightSoundSmell
Somatosensory
ViscerosensoryMotility
SecretionBlood Flow
CognitionAffect
IBS - Pathophysiology
Diagnostic Tests for IBSIf patient has typical features of IBS:• Labs:
CBC, electrolytes, LFTs, TSH• Stool studies:
Occult blood, leukocytes, O & P, Giardialamblia antigen
• Endoscopy:Sigmoidoscopy ± air-contrast barium enema or colonoscopy if ≥ 50 yrs
“Red Flags”
• Anemia
• Fever
• Persistent diarrhea
• Rectal bleeding
• Severe constipation
• Weight loss
Additional diagnostic screening needed for atypical presentations such as:
• Nocturnal symptoms of pain and abnormal bowel function
• Family history of GI cancer, inflammatory bowel disease, or celiac disease
• New onset of symptoms in patients 50+ years of age
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• 19 yo wf with hx “refractory IBS”• 12 year hx constipation, abdominal pain,
and marked abdominal distension• Previous workup including endoscopy:
negative • 3 weeks noted between spontaneous
bowel movements• On exam, marked distension of abdomen
is noted with decreased bowel sounds• KUB obtained:
Case Presentation
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Current Management of IBS• Establish a positive diagnosis• Reassure patient that there is no
serious organic disease or alarming symptoms
• No “gold standard” treatment• Existing therapies:
marginal efficacyside effectstarget only 1 symptom
Psychological Treatments for IBS
• Some patients with IBS may also benefit from:Referral to a psychologist or psychiatristHypnotherapyBiofeedbackPsychodynamic therapyStress management/relaxationCognitive behavioral programs
Drossman DA et al. The Functional GI Disorders, 2000.
Available Treatments for IBS
AntispasmodicsAntiflatulentsAnticholinergic/
AntispasmodicsTCAs/SSRIs
LoperamideCholestyraminePsylliumMethylcellulose
Calcium polycarbophilLactulose70% sorbitolPEG solution
Pain Bloating
AlteredBowel
Motility
Therapy of Functional Gut Pain: A Unique Problem
• Current treatment modalities are based on unproven pathophysiological concepts
• Placebo response rates vary from 20-88 %
• Few therapies have ever been conclusively been shown to be superior to placebo in well designed studies
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Placebo Response Rate in IBS
31 controlled treatment trials 1966-98, n= 2469
• Overall range 17-84%• Median 52 %• Mean 55.6 %• Range 17-40 % : 10 studies, n = 472• Range 41-60 %: 8 studies, n = 557• Range 61-84 %: 13 studies, n = 1440
Tricyclic Antidepressants and SSRIs
• Used for pain
• Reserved for patients with severe or refractory symptoms
Are effective for neuropathic pain
Have central analgesic/anticholinergic effects
Drossman & Thompson, Ann Intern Med., 1992
Low Dose TCAs: Possible Mechanisms of Analgesic Action• Reuptake inhibition of NE and 5HT
• Receptor antagonism of H1, 5HT-2, D2, muscarinic sites
• NMDA receptor antagonist
• Induction of glucocorticoid receptor expression
• Direct effect on peripheral afferent nerves
Physiological Distribution of 5-HT
CNS – 5%
• enterochromaffin cells• neuronal
GI tract – 95%
Gershon, Aliment Pharmacol Ther.,1999
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Serotonin (5-HT) Receptors in the Gut• Currently 14 5-HT receptor or recognition
sites identified: • 5-HT1A, 5-HT1P, 5-HT1C, 5-HT2, 5-HT3, 5-
HT4 found in gut• 5-HT1: Inhibition of neurotransmitter
release and increased smooth muscle contraction
• 5-HT2: Contraction of gut smooth muscle
EC Cells
5-HT3
Nodose Ganglionto Brain
5-HT from EC cells activates 5-HT3 & 5-HT4receptors on extrinsic afferents
DistentionStimulation
5-HT
5-HT4CGR
P
5-HT3Aδ
Mast Cells
Pharmacologic Action
5-HT3 Antagonists
5-HT4 Agonists
Accelerates UGI Transit + +
Increased colonic motor activity
- +
Slows colonic transit + -
Anti-emetic properties + ?
Analgesic + ?
Anxiolytic + ?
Serotonin (5-HT) Receptors in the Gut
Serotonin Agents5-HT3 Receptor Antagonists
Alosetron (Lotronex®)Odansetron (Zofran®)Cilansetron
5-HT4 Receptor AgonistsCisapride (Propulsid®)Prucalopride (Resolor®)Tegaserod (Zelnorm®)
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Alosetron (Lotronex®) in IBS
Selective 5-HT3 receptor antagonist
Enhances jejunal water/salt absorption
Increases colonic compliance
Slows colonic transit
FDA approved for women with diarrhea-predominant IBS
Alosetron (Lotronex®) Pain Relief in IBS
**p<0.001 *p<0.05
0102030
40506070
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
placebo alosetron %
With
Rel
ief
Week
*** * ** ** ** ** **
↑
↑
Treatment Follow-up
**
Camilleri et al., Lancet, 2000
Alosetron (Lotronex®): Contraindications
• Chronic or severe constipation
• History of intestinal obstruction, adhesions, perforation, or toxic megacolon
• Diverticulitis
• History of Crohn’s disease or ulcerative colitis
• Ischemic colitis
Serotonin (5-HT) andMotor Activity
Adopted from Grider et al, Gastroenterology 1998; 115: 370
Enterochromaffin cells release 5-HT
5-HT
Oradmotor neurons(contraction)Ach / SP
5-HT4Receptors
CaudadMotor neurons(relaxation)VIP / NO
Interneuronsin the
myentericplexus
SensoryneuronCGRP
Proximal Distal
Movement of gut content
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Tegaserod (Zelnorm®)• Selective 5HT4 receptor agonist• Increases release of CGRP and Sub P• Accelerates colonic transit• Inhibition of afferent nerve activity • Previously approved for women with
constipation-predominant IBS• Previously approved for men and women
with chronic constipation
New Directions in IBS Treatment
• 5-HT3 receptor antagonists• 5-HT4 receptor agonists• Opioid-like agents (Mu, kappa receptor)• Enkephalin/endorphin analogs• NMDA receptor antagonists• Substance P (NK-1) and CGRP antagonists• Amitiza: Secretion at Chloride channel
Motility DisordersCarlo Di Lorenzo, MD
Professor of Clinical PediatricsNationwide Children’s Hospital
Objectives• To describe normal and abnormal
upper and lower GI tract motility• To discuss methodology to study
gastrointestinal motility• To discuss treatment for motility
disorders
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Pathophysiology of FGID
AchalasiaHirschsprung’s
She has received:• Esophageal manometry• Antroduodenal
manometry• Colonic manometry • Anorectal manometry
Manometry studies tell us:• If we are dealing with a
motility problem (vs emotional, sensory,parental hypervigilance, etc)
• What works and what does not
• Why it does not work (?)• How to make it work better
(directs rx)• Whether it will it ever work
(prognosis)• What organs to transplant
Enteric Nervous System (ENS) Comprises the Myenteric and Submucosal Plexus
Longitudinal muscleCircular muscle
Mucosa
Myenteric plexus
Submucosal plexus
Myenteric ganglion
Submucosal ganglion
Interganglionic fiber tract
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Enteric Nervous System:The “Brain-In-The-Gut” Concept
Brain-like functions of ENS•Program library•Feedbackcontrol•Reflexes•Informationprocessing
“Brain-in-the Gut”
ENS
Interneurons•Reflexes•Program
library• Information
processingSensory neurons
Motor neurons
•Muscle•Secretory
epithelium•Blood
vessels•Motility patterns•Secretory patterns•Circulatory
patterns
Gut Behavior
Enteric nervous system
Sensory, Motor, and Interneuronsare Synaptically Interconnected to Form the Microcircuits of the ENS
ENS Contains a Limited Library of Programs for Specific Patterns of Intestinal Motor Behavior
Postprandial program
(Mixing pattern)
Aboral powerPropulsion
program
Physiologicileus
(Contraction absent)
Small and large intestine
Small and large intestine
Small intestine
Small intestine
Large intestine
Small intestine
Haustralprogram(Segmental
contractions)
Interdigestive program
(MMC pattern)
Emetic program
(Oral power propulsion)
ProgrammedDefense
Central nervous system
Interneurons•Reflexes
•Program library
• Information processing
•Feedback control
Sensory neurons
•Muscle
•Secretory epithelium
•Blood vessels
•Motility patterns
•Secretory patterns
•Circulatory patterns
Gut Behavior
Bidirectional Communication Betweenthe ENS and the CNS
Motor neurons
Enteric nervous system
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Powerful influence of emotions and CNS on gut mucosal and motor functionExamples: finals, big game, getting married,
Efficacy of reassurance, behavioral modifications and relaxation techniques
“The problem is in your head”
Bodily changes during experimental “headache”
Tightening the ”head device”
Engorgement ofthe bowel
Contractile state of the bowel
Time
1
32
123
Pulse80
120
0 30
Colonic changes accompanying baseless fear in a healthy subject
Discovery of “carcinoma of rectum”
Hoax explained
Engorgement ofthe bowel
Contractile state of the bowel
Time
1
3
2
1
2
3
Almy TP et al. Gastroenterology. 1950;15:95-103
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Motility:Methods &
Measurements
Established Parameters & Techniques
• Intraluminal pressure:• Manometry (stationary, ambulatory)
Phasic contractions : rhythmic phasic, HAPC, propulsive / nonpropulsive
• Barostat (single, dual)Tonic contractionsTonic reflexes
•Myoelectric activity:• Electromyography
Slow wave, spike bursts
• Wall motion:
• Ultrasonography, SPECT, MRI
• Organ volumes, contractile activity, gastric accommodationManometry:
• The “SmartPill”
• Other biomechanical properties:
• High frequency intraluminal ultrasound, impedance planimetry
• Wall tension, wall stress, wall strain
Emerging Parameters & Techniques
Motor Patterns in the GutFasting Fed
Defecation ENS + CNS
Periodic motor activity with 3 sequential phases
(MMC)
no motor activity
sporadic activity
regular activity
ENS modulated by CNS
Fundic relaxationVagovagal reflex
Sustained but irregular and non-periodic activity until all nutrient has left the stomach
ENS modulated by vagal receptors
Sporadic, mixing activity; absent in sleepENS modulated by CNS
Defecation ENS + CNS
Increase in high amplitude propagated contractions, phasic contractions & tone
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The Stomach is Divided into Three Anatomic and Two Functional Motor Regions
Anatomic regions
Body(corpus)
Functional motor regions
Fundus
Antrum
PylorusLower
esophageal sphincter
Gastric reservoir
Tonic contractions
Antral pumpPhasic contractions
Functional motor and anatomic regions do not correspond
Onset and Rate of Gastric Emptying Varies with the Composition of the Meal
% Meal remaining in
stomach
Lag phase Emptying phase
19Time after meal (min)
Solid meal
Liquid meal
100
75
50
25
0
200 6040 10080
Semi-solid meal
Barostat = Constant Pressure
PressuremmHg
Volumeml
non-compliant balloon
contraction relaxation
Swallowing Evokes Reflex Gastric Relaxation and Increased Volume
Gastric stretch receptors
Vagal allerents
BrainMedulla
Vagal ellerents
Enteric nervous system
Interneuronalcircuits
Inhibitory motor neurons
Muscle relaxation
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Adaptive Relaxation in the Gastric Reservoir isLost After Vagotomy
Barostat volume (ml)
Post vagotomyIntragastric
pressure(cm H2O)
Normal
DiscomfortFullness
25
20
15
10
5
01000 300200 500400 700600
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Functional DyspepsiaGastric
dysrhythymias
Impaired proximal stomach accommodation
Delayed gastric emptying
Altered antroduodenal
contractions
Antral dilatation
Abnormal intragastric distribution and reflexes
Dyspepsia Pathophysiologic defect determines the symptom
SymptomImpaired accommodation
Delayed gastric emptying
Hyperalgesia
Mechanism Early satiety and weightloss
Nausea, vomiting, and postprandial fullness
Pain, belching, weight loss
Motility:Small Intestine
20
25
The Migrating Motor Complex (MMC) is the Small Intestinal Motility Pattern of the Interdigestive State
Pressure recording ports on catheter
MMC activity
front
20151050Time (min)
Feeding Shifts Neural Programming from the Interdigestive Motility Pattern (MMC) to the Digestive
Pattern (Segmentation)
Interdigestive
4321 Time (hours)
Meal Digestive
Ileum
Segmenting motility
Segmenting motility
Segmenting motility
Segmenting motility
Segmenting motility
Phase I
Phase III
Phase II
CNS Modulation
Asleep StressedAwake0
2
4
6
8
MMC’sper
8 hr.
IBS
Normal
Why is Motility Abnormal?
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Acquired Intestinal Aganglionosis and Circulating Autoantibodies withour
Neoplasia or Other Neural Involvement
Eosinophilic Ganglionitis
Schappi MG, et al. Gut 2003; 52: 752-5
Control
IBS
IBS
Activated mast cells in IBS
N
Degranulating
Close proximity (<5 µm) between mast cells and nerves correlates with abdominal pain in IBS
Barbara et al. Gastroenterology 2004;126:693-702
Constipation
Delayed colonic transit:segmental, generalized
Reduced/absent HAPCs;Absence of normal predefecatorypropagating sequences
Altered small bowel motility
? Delayed gastric emptying
Attenuated colonic response to meals and waking
Pelvic floor dyssynergia
Impaired low amplitudecontractile activity
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Anorectal Manometry
•Assesses the internal and external anal sphincters, rectal sensations and expulsion patterns
•A pressure-sensitive catheter is inserted into the anorectum to measure resting and squeeze pressures of the anal canal
Balloon Distension in the Rectum Evokes Relaxation of the Internal Anal Sphincter and Contraction of the
External Anal Sphincter
Internal anal sphincter
External anal sphincter
Pressure recording
Distend rectum
Rectal pressure
Anal canal pressure
Abnormal
Increase
Biofeedback Training Defecation Disorders
Biofeedback Training Defecation Disorders
Rectal pressure
Anal canal pressure
Normal
Decrease
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Components of the Continence Apparatus
Puborectalis
Symphysispubis
Superficial external anal sphincter (EAS)
Internal anal sphincter
Coccyx
The Ano-Rectal Angle is Determined by the Contractile State of the Puborectalis Muscle
Defecography•Detects structural
abnormalities of the rectum
• Thickened barium is instilled into the rectum
•Radiographic films are taken during defecation
Colonic Transit Study
• Measures rate at which fecal residue moves through colon
• The patient swallows a capsule filled with radiopaque markers
• Serial abdominal radiographs are taken 120 hours later
• Hinton technique
24
R L
Colonic Transit Study (Metcalf Technique)
• Ingest 24 radiopaque markers on 3 successive days
• No laxatives, enemas, or medicines that affect bowel function
• Days 4&7: abdominal plain film
• Colonic transit = markers (on day 4 and 7), normal <70 markers 101
Types of ProkineticsDopamine-2 5-HT4 5-HT3 Motilin Cholinesterase QTantagonist agonist antagonist Receptor Inhibitor prolon-
agonist gation
Metoclopramide + +
Domperidone + +
Cisapride + + + + +
Erythromycin, + + + +ABT-229
Itopride + + + +
Tegaserod + +
FDA-Approved Treatment Options for Constipation
Physicians’ Desk Reference 2005. Montvale, NJ. Thomson PDR; 2005
Osmotic agents Lactulose Indicated for the treatmentof constipation
Polyethylene Indicated for the short-termglycol (PEG) treatment of occasional
constipation
5-HT4- Tegaserod* Indicated for:Receptor Men and women < 65 years oldAgonist with chronic idiopathic
constipationWomen with irritable bowelsyndrome with constipation*(Suspended 3/30/07, IND 21/07/07)
Chloride Lubiprostone Indicated for:Channel Chronic idiopathic constipationactivator in adults
Pathophysiology of FGID