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Diagnostic Approach to IBSDiagnostic Approach to IBSBrooks Cash, MD
National Naval Medical Center
The Functional Bowel Disorders (FBDs)The Functional Bowel Disorders (The Functional Bowel Disorders (FBDsFBDs))
Longstreth GF et al. Gastroenterology. 2006;130:1480-1491.
Recognition ChallengesRecognition ChallengesRecognition Challenges
• Irritable bowel syndrome (IBS) remains undiagnosed, even among patients being seen for other medical conditions– 25% eventually diagnosed with IBS seen
for GI complaints at least 5 times before diagnosis1
– Many never seek care or diagnosis• Self-treat (OTC agents, CAM) or simply accept• Approximately 1 out of 4 people with IBS
diagnosed
1. Hungin AP, et al. Aliment Pharmacol Ther. 2005;21:1365-1375.2. Lacy BE, et al. Scand J Gastroenterol. 2006;41:892-902.
Pathophysiology of Functional GI DisordersPathophysiology Pathophysiology of Functional GI Disordersof Functional GI Disorders
CNS: Stress, CNS: Stress, psychosocial factorspsychosocial factors
MotilityMotility SensitivitySensitivity
? Bacteria / inflammation? Bacteria / inflammation
The Brain Gut Axis and the Control of GI Function
The Brain Gut Axis and the Control The Brain Gut Axis and the Control of GI Functionof GI Function
Posserud et al, World J Gastroenterol 2006; 12: 2830–8.Rao, Gastroenterol Clin North Am 2007; 36: 687–711.
Cong et al, Gastroenterology 2007; 133: 445–53.
What are the symptoms of IBS?
What are the symptoms of IBS?
Irritable Bowel Syndrome: Diagnostic Criteriaa (Rome Committee)
Irritable Bowel Syndrome: Diagnostic Irritable Bowel Syndrome: Diagnostic CriteriaCriteriaaa (Rome Committee)
• Improvement with defecation
•Onset associated with a change in the frequency of stool
•Onset associated with a change in the form of stool
aCriteria fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis.
Recurrent abdominal pain or discomfort at least 3 days/month associated with 2 or more
of the following:
Longstreth GF et al. i. 2006; 130:1480.
Irritable Bowel Syndrome: Diagnostic Criteriaa (ACG Task Force)
Irritable Bowel Syndrome: Diagnostic Irritable Bowel Syndrome: Diagnostic CriteriaCriteriaaa (ACG Task Force)(ACG Task Force)
•All criteria lack reference standard test
•No symptom-based criteria have perfect accuracy
•Rome criteria have been inadequately evaluated
Abdominal pain or discomfort that occurs in association with altered bowel habits over a
period of at least 3 months
Brandt LJ et al. Am J Gastroenterol. 2009;104(suppl 1):S8-S35.
What are the diagnostic What are the diagnostic criteria and subtypes?criteria and subtypes?
IBS Subtypes: Stool Form Is the Differentiating Factor
IBS Subtypes: Stool Form Is the IBS Subtypes: Stool Form Is the Differentiating FactorDifferentiating Factor
% BMhard or lumpy
% BMhard or lumpy
% BM loose or watery% BM loose or watery
00
2525
5050
7575
100100
00 2525 5050 7575 100100
IBS-UIBS-U
IBS-CIBS-C IBS-MIBS-M
IBS-DIBS-D
25% of BM is the threshold for classification
25% of BM is the threshold for classification
Bristol types 1 and 2
Bristol types 1 and 2
Bristol types 1 and 6
Bristol types 1 and 6
Bristol type 6Bristol type 6
What other conditions can What other conditions can mimic IBS?mimic IBS?
Differential Diagnosis for IBSDifferential Diagnosis for IBSDifferential Diagnosis for IBS
• Chronic constipation
• Celiac disease
• IBD
• Microscopic colitis
• Infectious colitis
• Colon cancer
• Small intestinal bacterial overgrowth
• Functional dyspepsia
• Gallstones
• Gynecologic conditions
– endometriosis
– ovarian cancer
– other chronic pelvic pain conditions
• Musculoskeletal pain
• Renal colic
Wilson, Ann Intern Med 2007; 147: ITC7–16.
Overlapping IBS SymptomsOverlapping IBS SymptomsOverlapping IBS Symptoms
Frissora & Koch, Curr Gastroenterol Rep 2005; 7: 264–271.Matheis et al, World J Gastroenterol 2007; 13: 3446–3455.
Condition Overlapping IBS symptomChronic constipation Straining, hard and lumpy stools
Celiac disease Abdominal pain, bloating, diarrhea, constipation, flatulence, depression
IBD Diarrhea, abdominal pain
Endometriosis Abdominal pain
Chronic pelvic pain Pelvic pain with defecation or altered bowel habit with chronic pelvic pain
Depression, anxiety, history of abuse
Chronic functional abdominal pain
Constant or frequent abdominal pain, anxiety, depression
• Abdominal pain – 29% state this is the predominant symptom1
• Misinformation– 15% believe IBS will turn into cancer2
– 30% believe IBS increases risk of IBD3
– 17% believe IBS will lead to malnutrition4
• Lack of information– etiology thought due to anxiety (80.5%) or depression
(63.2%)2
– only 2/3 of patients recognize that IBS does not shortena patient’s life expectancy3
What Brings Patients to Your Office?What Brings Patients to Your Office?What Brings Patients to Your Office?
1Lembo et al, Am J Gastroenterol 1999; 94: 1320–1326. 2Lacy et al, Am J Gastroenterol 2005; 100: S324.
3Noddin et al, Am J Gastroenterol 2005; 100: S323.4Lee et al, Am J Gastroenterol 2005; 100: S336.
Bridging the Physician-Patient Disconnect
Bridging the PhysicianBridging the Physician--Patient Patient DisconnectDisconnect
Halpert et al, Am J Gastroenterol 2007; 102: 1972–1982. Chang et al, Gastroenterology 2006; 130: 1435–1446.
Lacy et al, Aliment Pharmacol Ther 2007; 25: 1329–1341.
Listen to complaintsListen to complaintsAcknowledge concernsAcknowledge concernsLegitimize symptomsLegitimize symptomsProvide convincing explanation Provide convincing explanation
about nature of symptomsabout nature of symptoms
Proactively inquire about beliefs; Proactively inquire about beliefs; address misconceptionsaddress misconceptions
Eliciting thoughts / feelings is Eliciting thoughts / feelings is palliative to anxiety palliative to anxiety
Providing reassurance to patients Providing reassurance to patients leads to a better responseleads to a better response
Ask about stress / distressAsk about stress / distressPatients volunteer this information Patients volunteer this information
infrequently infrequently An open approach to inquiring An open approach to inquiring
about stressabout stress--related factors is related factors is validatingvalidating
Educate patients on IBSEducate patients on IBSPatients interested in causes of Patients interested in causes of
IBS, role of diet in IBS, coping IBS, role of diet in IBS, coping strategies, medicationsstrategies, medications
Can reduce healthcare costs and Can reduce healthcare costs and primary care consultationsprimary care consultations
History and Physical Examination for Lower GI Symptoms
History and Physical Examination History and Physical Examination for Lower GI Symptomsfor Lower GI Symptoms
• Presenting symptoms
• Establish history timeline
• Presence of alarm signals
• Family history: IBS, organic GI disorders
• Review diet and current medications
• Presenting symptoms
• Establish history timeline
• Presence of alarm signals
• Family history: IBS, organic GI disorders
• Review diet and current medications
HistoryHistory• Signs of systemic and
local diseases that might cause constipation or diarrhea
• Assess the anorectumand pelvic floor muscles
• Other relevant abnormalities
• Signs of systemic and local diseases that might cause constipation or diarrhea
• Assess the anorectumand pelvic floor muscles
• Other relevant abnormalities
ExaminationExamination
What tests are helpful in What tests are helpful in discriminating IBS from discriminating IBS from
other conditions?other conditions?
Utility of Tests in Diagnosing IBSUtility of Tests in Diagnosing IBSUtility of Tests in Diagnosing IBS
1Cash et al, Gastroenterology 2007; 132(suppl. 2): W1182 & 986.2Cash et al, Gastroenterology 2006; 130(4. suppl. 2): A111.
3Bratten et al, Am J Gastroenterol 2008; 103: 958–963.
Organic diseaseIBS patients
(n=366)(%)
Control / population(n=276)
(%)Colitis / IBD 1.1 0.7
Colorectal cancer 0.4 4–6a
Celiac disease 1.1 0.7
Thyroid dysfunction 5.5 6a
Lactose malabsorption2 22.3 26.6/25
aPrevalence in the US population.
IBS Experts Use Fewer Tests Than Nonexperts
IBS Experts Use Fewer Tests IBS Experts Use Fewer Tests Than Than NonexpertsNonexperts
Spiegel et al, Gastroenterology 2006; 130(suppl. 2): S1134.
PCPs, nurse practitioners and
gastroenterologists(n=281)
IBS experts(n=45) P
IBS is diagnosis of exclusion? (% yes) 72 8 <0.0001
IBS-CDiagnostic tests (n)Cost of testing ($)
2.2550
1.4288
0.060.03
IBS-DDiagnostic tests (n)Cost of testing ($)
4.1658
2297
<0.01<0.01
Investigation in Patients With No Alarm Features (Rome)
Investigation in Patients With No Alarm Features (Rome)
• Flexible sigmoidoscopy• Colonoscopy• Rectal biopsy• Barium enema• Abdominal ultrasound• Routine laboratory
investigations• Fecal occult blood test
• Flexible sigmoidoscopy• Colonoscopy• Rectal biopsy• Barium enema• Abdominal ultrasound• Routine laboratory
investigations• Fecal occult blood test
Insufficient evidence to recommend routine testinga
Insufficient evidence to recommend routine testinga
aResults based on a literature review.aResults based on a literature review.
Should be consideredaShould be considereda
Routine use of colonoscopy for CRC screening is recommended for all patients ≥50 years oldRoutine use of colonoscopy for CRC screening is recommended for all patients ≥50 years old
Serological tests for celiac diseaseSerological tests for celiac disease
Longstreth GF et al. Gastroenterology. 2006; 130:1480Longstreth GF et al. Gastroenterology. 2006; 130:1480
Investigation in Patients With No Investigation in Patients With No Alarm Features Alarm Features (ACG) (ACG)
• Flexible sigmoidoscopy• Barium enema• Abdominal ultrasound• Routine laboratory
investigations• Fecal occult blood test
• Flexible sigmoidoscopy• Barium enema• Abdominal ultrasound• Routine laboratory
investigations• Fecal occult blood test
Insufficient evidence to recommend routine testing
Insufficient evidence to recommend routine testing
Brandt LJ et al. Am J Gastroenterol. 2009;104(suppl 1):S3.Brandt LJ et al. Am J Gastroenterol. 2009;104(suppl 1):S3.
Routine with IBS-Mand IBS-D
Routine with IBS-Mand IBS-D
Routine use of colonoscopy for CRC screening is recommended for all patients ≥50 years old or those with alarm featuresRoutine use of colonoscopy for CRC screening is recommended for all patients ≥50 years old or those with alarm features
Serological tests for celiac disease Colonoscopy with random biopsiesSerological tests for celiac disease Colonoscopy with random biopsies IBS-DIBS-D
Breath testing for lactose intoleranceBreath testing for lactose intolerance When no response to diet & still suspiciousWhen no response to diet & still suspicious
What are the red flags and What are the red flags and how useful are they?how useful are they?
Alarm Features for Organic DisordersAlarm Features for Organic Disorders(Rome Committee)(Rome Committee)
• Age ≥50 years old
• Blood in stools
• Nocturnal symptoms
• Weight loss(unintentional)
• Change in symptoms
• Recent antibiotics
• Family history of organic GI disease
If alarm features are present, investigate and treat
appropriately
If alarm features are present, investigate and treat
appropriately
Alarm Features (ACG Task Force)Alarm Features
(ACG Task Force)
• Anemia
• Weight loss(unintentional)
• Family history of organic GI disease
• CRC
• IBD
• Celiac disease
• Anemia
• Weight loss(unintentional)
• Family history of organic GI disease
• CRC
• IBD
• Celiac disease
If symptom-based criteria are met and alarm features are
absent, the clinician should be reassured that the diagnosis of
IBS is correct
If symptom-based criteria are met and alarm features are
absent, the clinician should be reassured that the diagnosis of
IBS is correct
Utility of Red Flag Symptom Exclusions in Diagnosis of IBS
Utility of Red Flag Symptom Exclusions Utility of Red Flag Symptom Exclusions in Diagnosis of IBSin Diagnosis of IBS
Whitehead et al. Aliment Pharmacol Ther. 2006;24:137-146.
Excluding any patient with a red flag improved agreement between Rome II criteria and clinical diagnosis by 5% but left 84% of patients diagnosed with IBS by their physicians without a diagnosisThe fact that 84% of patients with functional GI symptoms endorse ≥1 red flag symptoms significantly reduces utility of these symptoms as screening questions
D26D26
Multiple Contributing Factors for IBS
Multiple Contributing Factors for IBS
IBS Symptom Complex
IBS Symptom Complex
Visceral hypersensitivity
Visceral hypersensitivity
Post-infectiousPost-infectious
InflammationInflammation
Brain - gut dysfunctionBrain - gut
dysfunction
Abnormal central processing
Abnormal central processing
Genetic predisposition
Genetic predispositionPsychological
abuse historyPsychologicalabuse history
Environmental factors
Environmental factors
Food sensitivity
Food sensitivity
GI dysmotility
GI dysmotility
Factors Activating Mucosal Immune System
Factors Activating Mucosal Immune System
= antigen / bacteriaPP= Peyer’s patchesMLN= mesenteric lymph node
Evidence of Mucosal Inflammation in IBS
Evidence of Mucosal Inflammation in IBS
Mast Cells in Descending Colon IBS vs Controls
Mast Cells in Descending Colon IBS vs Controls
Controls (n=22) IBS (n=44)
Barbara et al, Gastroenterology. 2004; 126:693.
Mast cells area % mucosa 3.32 ± 10.8% 9.2 ± 2.5%
5-HT immunoreactivity
Enterochromaffin (EC) Cell Hyperplasiain Post-infective IBS
Enterochromaffin (EC) Cell Hyperplasiain Post-infective IBS
Dunlop et al, Clin Gastroenterol Hepatol 2005; 3:349.
Plasma 5-HT Following a 520 kcal Test Mealin Patients With IBS and Healthy Controls
Plasma 5-HT Following a 520 kcal Test Mealin Patients With IBS and Healthy Controls
600–700 pathways60,000–70,000 markers
Identified pathways affected in IBS
2000–3000 markersIdentified markers common across multiple pathways
Selection of Biomarkers to Distinguish IBS From Non-IBS
Selection of Biomarkers to Distinguish IBS From Non-IBS
250 markersSelected potentialserum-based IBS markers
16 markersSelected IBS-specific markers
Identified biomarkers measurable with commercially available
assays
140 markers
Tested assay values in cohorts of IBS and non-IBS samples
Final 10 Biomarkers Selected for PROMETHEUS®
IBS Diagnostic Final 10 Biomarkers Selected for PROMETHEUS®
IBS Diagnostic
Interleukin 1b (IL-1b)a
Anti-neutrophil cytoplasmic antibody (ANCA) Growth-related oncogene a (GROa)
Brain-derived neurotrophic factor (BDNF)Anti-Saccharomyces cerevisiae antibody IgA (ASCA IgA)
Anti-human tissue transglutaminase (tTG)TNF-like weak inducer of apoptosis (TWEAK)
Antibody against CBir1 (anti-CBir1)b
Tissue inhibitor of metalloproteinase-1 (TIMP-1)Neutrophil gelatinase-associated lipocalin (NGAL)
Natural History of IBSNatural History of IBS
Patients with IBS diagnosis (%)
Alternative diagnosis 2–5Worsened IBS symptoms 2–18Symptom-free 12–38Unchanged IBS symptoms 30–50
Patients with IBS diagnosis (%)
Alternative diagnosis 2–5Worsened IBS symptoms 2–18Symptom-free 12–38Unchanged IBS symptoms 30–50
• IBS is a stable diagnosis
• <5% IBS patients are diagnosed with an alternative organic GI disorder; repeated diagnostic evaluation is not warranted
• IBS is a stable diagnosis
• <5% IBS patients are diagnosed with an alternative organic GI disorder; repeated diagnostic evaluation is not warranted
• 6 months to 6 years after original IBS diagnosis• 6 months to 6 years after original IBS diagnosis
Total n=1099; 14 studies includedTotal n=1099; 14 studies included
El-Serag HB et al. Aliment Pharmacol Ther. 2004;19:861.El-Serag HB et al. Aliment Pharmacol Ther. 2004;19:861.
D35D35
Pragmatic Issues in IBSPragmatic Issues in IBS
• Patient expectations
• Effect on clinical outcomes
• Reassurance value / Impact on symptoms
• Legal implications of delayed diagnosis of organic GI disease
• Patient expectations
• Effect on clinical outcomes
• Reassurance value / Impact on symptoms
• Legal implications of delayed diagnosis of organic GI disease
BenefitsBenefitsCostCost
• IBS patients often remain undiagnosed, even after medical attention
– Differential diagnosis of IBS comprises other conditions, eg, IBD, which have several overlapping symptoms with IBS
• In IBS patients without alarm features, the prevalence of organic disease is similar to the general population and exclusionary tests have a low pre-test probability of being positive
– Caveat: Routine celiac disease screening in IBS-D and IBS-M and consider random colonic biopsies to exclude microscopic colitis in IBS-D1
• Patients with alarm features must be investigated and treated appropriately but the relevance of alarm features remains unknown
Diagnosis of IBS: SummaryDiagnosis of IBS: SummaryDiagnosis of IBS: Summary
Brandt et al, Am J Gastroenterol 2009; 104 (suppl1).