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).