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Diagnostic Testing in IBS:
Evidence-Based Updates
Brennan Spiegel, MD, MSHS
Cedars-Sinai Medical Center
Cedars-Sinai Center for Outcomes Research and Education (CS-CORE)
The Brain-Gut Axis
Central nervous
system (CNS)
Higher brain activation in
response to stress
Thinner grey matter density
Altered amygdala reactivity
Brain-gut axis
Enteric nervous
system (ENS)
Mayer E. et al; Gastroenterol 2010;139:48
Mayer E. et al; Gastroenterol 2011;140:1943
Intestinal infections
“Leaky” gut
Low-grade inflammation
Visceral hypersensitivity
Dysmotility
Evolving IBS Disease Model
“Hit”
Susceptible
Host
Underlying dysfunction in:
•
•
•
•
•
Intestinal dysbiosis
Mast cell number and function
Serotonin trafficking
HPA Axis
Cortical pain processing
Stress
Infection
Diet
Allergy
Disease
Expression
Existential Question: What Is IBS?
Malabsorption
Dietary factors
High sorbitol diet
High-fiber diet
FODMAP Diet
Caffeine
Alcohol
Celiac sprue
Carb intolerance
Pancreatic disease
Bile acid malabsorption
Inflammation
Ulcerative colitis
Crohn’s disease
Microscopic colitis
IBS
Psychological
Infection
SIBO
C. diff
Giardiasis
Endocrine
Hyperthyroidism
Diabetes
Carcinoid
Gastrinoma
Anxiety
Somatization
Depression
PTSD
Is IBS an absence of other things?
IBS
Or is it some thing… unto itself?
Proposed Pathophysiological Mechanisms
Involved in IBS
Visceral
hypersensitivity
Altered brain–
gut interactions
Inflammation
IBS
Bacterial-Host
Interactions
Genetic
factors
Psychosocial
factors
Risk for PI-IBS Increases After
Traveler’s Diarrhea
Overall PI-IBS Incidence
(Pooled from 6 studies)
Overall PI-IBS, %
Pooled OR: 3.51
(95% CI: 2.25-5.48)
Healthy subjects
(n=2833)
Scwille-Kiuntke J et al. Aliment Pharmacol Ther. 2015;41:1029-1037.
TD subjects
(n=1597)
Case History
• 42-year-old white man complains of intermittent
abdominal pain and diarrhea for 2 years
• Has 4-8 bowel movements daily
• Stools “loose” and often come on urgently
• LLQ crampy pain that improves with stool passage, and
worse with eating
• No recent travel, unusual food ingestions, antibiotics,
gastroenteritis, or intolerance of dairy products.
Spiegel et al. Amer J Gastroenterol 2010;105:848-58
Case History – Continued
• No nighttime symptoms
• No GI “alarm symptoms”
• No GI “alarm signs”
• Stool guaiac negative
• CBC and chemistries normal
Spiegel et al. Amer J Gastroenterol 2010;105:848-58
Question #1
 Does this patient have IBS?
A) Yes
B) No
C) Unsure – need more data
Does this Patient Have IBS?
Results of U.S. Survey
Believes patient probably
has IBS
Prepared to confidently
affirm diagnosis with
patient
Spiegel et al. Amer J Gastroenterol 2010;105:848-58
Diagnostic Battery is Extensive
IBS “Look-Alikes”
Performing the wrong tests
Bacterial overgrowth
Breath-testing
can leadGiardiasis
to excessive
resource
Stool Ova & Parasites
Hyperthyroidism
Thyroid function
testing
utilization
and worsen
patient
IBD
ESR / CRP / Colonoscopy
outcomes
Lactose intolerance
Breath-testing
Infectious colitis
Microscopic colitis
Celiac sprue
Diagnostic Battery
Stool leukocytes / C&S / C. diff
Colonoscopy / Flexsig
Sprue Serologies
Predictors of Diagnostic Testing in IBS
• In study of 201,322 IBS patients in US claims
database, diagnostic testing predicted by…
– Higher age
– Higher symptom burden
– Female gender
– More specialist visits
Luo et al. DDW 2016; AB 363
How Accurate are the Rome Criteria?
100%
100
98%
65%
50
0
Retrospective
Sensitivity
Retrospective
Specificity
Prospective
Positive Predictive
Value
Vanner S. et al, Am J Gastro 1999
How Accurate are the Rome III Criteria?
96%
100
82%
50%
50
17%
0
Sensitivity
Specificity
PPV
NPV
Ford A. et al, Gastroenterol 2013;145:1262
Diagnostic Battery is Extensive
IBS “Look-Alikes”
Bacterial overgrowth
Giardiasis
Diagnostic Battery
Breath-testing
Stool Ova & Parasites
Hyperthyroidism
Thyroid function testing
IBD
ESR / CRP / Colonoscopy
Lactose intolerance
Infectious colitis
Microscopic colitis
Celiac sprue
Breath-testing
Stool leukocytes / C&S / C. diff
Colonoscopy / Flexsig
Sprue Serologies
How Often is Structural Colon
Evaluation Normal in IBS?
100
98%
99%
100%
100%
% Normal
Exams 50
0
Hamm et al.
AJG 1999
Tolliver et al.
AJG 1994
MacIntosh et al.
AJG 1992
Francis et al.
AJG 1996
So Why Perform Colonoscopy?
• May provide reassurance if normal
• May improve quality of life if normal
• May reduce later resource utilization if normal
Differences in Reassurance
Percent
“Reassured”
83%
87%
Negative colonoscopy may69%not
provide reassurance or improve
quality of life in IBS
100
50
0
No previous
colonoscopy
Distant Normal
Colonoscopy
Recent Normal
Colonoscopy
Spiegel et al, Gastrointest Endo 2005
Colitis in IBS
IBS-D / IBS-M
Healthy Controls
% Patients
10
P<0.01
5
4.9
1.8
1.5%
0
Mucosal
“Erythema” or
Ulcerations
Microscopic Colitis
Chey et al. Amer J Gastroenterol 2010;105:859-64
Diagnostic Battery is Extensive
IBS “Look-Alikes”
Bacterial overgrowth
Giardiasis
Diagnostic Battery
Breath-testing
Stool Ova & Parasites
Hyperthyroidism
Thyroid function testing
IBD
ESR / CRP / Colonoscopy
Lactose intolerance
Infectious colitis
Microscopic colitis
Celiac sprue
Breath-testing
Stool leukocytes / C&S / C. diff
Colonoscopy / Flexsig
Sprue Serologies
Yield of Stool Studies in IBS
• Stool ova & parasite:
– Hamm et al: 0.09% positive (N=1154)
– Tolliver et al: 0.0% positive (N=170)
• Stool leukocytes
– No data, though yield likely very low
• Stool C. diff / stool culture
– No data, though yield likely very very low
Hamm LR, et al. Am J Gastro 1999;94:1279
Tolliver BA, et al. Am J Gastro 1994;89:176
Diagnostic Battery is Extensive
IBS “Look-Alikes”
Bacterial overgrowth
Giardiasis
Diagnostic Battery
Breath-testing
Stool Ova & Parasites
Hyperthyroidism
Thyroid function testing
IBD
ESR / CRP / Colonoscopy
Lactose intolerance
Infectious colitis
Microscopic colitis
Celiac sprue
Breath-testing
Stool leukocytes / C&S / C. diff
Colonoscopy / Flexsig
Sprue Serologies
Yield of ESR / CRP / TSH
• Yield of ESR / CRP
– Sanders et al Lancet 2001
– 1/300 with elevated ESR  diagnosed with IBD
– 2/300 with elevated CRP  diagnosed with IBD
• Yield of TSH
– Hamm et al AJG 1999  3% hyper-, 3% hypo– Tolliver et al AJG 1994  0.6% “abnormal” TSH
– Yield not different from normal population (5-9%)
Sanders DS, et al. Lancet 2001;358:1504
Hamm LR, et al. Am J Gastro 1999;94:1279
Tolliver BA, et al. Am J Gastro 1994;89:176
Diagnostic Battery is Extensive
IBS “Look-Alikes”
Bacterial overgrowth
Giardiasis
Diagnostic Battery
Breath-testing
Stool Ova & Parasites
Hyperthyroidism
Thyroid function testing
IBD
ESR / CRP / Colonoscopy
Lactose intolerance
Infectious colitis
Microscopic colitis
Celiac sprue
Breath-testing
Stool leukocytes / C&S / C. diff
Colonoscopy / Flexsig
Sprue Serologies
IBS
100% Have Symptoms
Consistent with Sprue
Celiac
Sprue
20-75% Have Symptoms
Consistent with IBS
O’Leary C, et al. Am J Gastro 2002;97:1463
Zipser RD, et al. Dig Dis Sci 2003;48:761
Biopsy-Proven Celiac Disease in IBS:
Results of Meta-Analysis
It is cost-effective to screen for
celiac sprue in IBS if pre-test
likelihood exceeds 1%
Spiegel et al. Gastroenterology 2004;126:1721
Ford A, Chey W, Talley N, Malhotra A, Spiegel B, Moayyedi P. Arch Int Med 2009;13:169
Diagnostic Battery is Extensive
IBS “Look-Alikes”
Bacterial overgrowth
Giardiasis
Diagnostic Battery
Breath-testing
Stool Ova & Parasites
Hyperthyroidism
Thyroid function testing
IBD
ESR / CRP / Colonoscopy
Lactose intolerance
Infectious colitis
Microscopic colitis
Celiac sprue
Breath-testing
Stool leukocytes / C&S / C. diff
Colonoscopy / Flexsig
Sprue Serologies
Prevalence of Abnormal* Lactulose Breath
Tests in Rome I IBS
OR=26.2 (95% CI=4.7, 104)
100
84%
50
20%
0
IBS
N=111
*Single peak >20 ppm rise of H2 by 90 min
Controls
N=15
Pimentel et al. Am J Gastro 2003;98:412
IBS vs. Controls: H2 rise > 20 ppm by 180
<0.001
NS
NS
NS
NS
90
Control
80
70
% Positive
IBS
60
50
40
30
20
10
0
N=126
N=204
N=126
N=42
N=192
Positive Lactulose Breath Test:
Odds in IBS vs. Controls
Lupascu 2005
10.89 (3.33, 45.67)
Parodi 2007
14.00 (3.26, 124.54)
Posserud 2007
1.13 (0.14, 52.89)
Bratten 2008
0.45 (0.18, 1.23)
Grover 2008
2.29 (0.86, 7.16)
Rana 2008
12.38 (1.96, 513.13)
Pooled OR (95% CI)
3.45 (0.94, 12.72)
0.1 0.2
0.5
1
2
5
10
100
1000
Ford, Talley, Spiegel, Moayeddi . Clin Gastro Hep 2009
Biomarkers for IBS?
The IBS Microbial Hypothesis At Work
Food
poisoning
E. Coli
C. jejuni
Shigella
Salmonella
Bacterial
toxin
Cytolethal
Distending toxin
(CDT B)
Autoimmunity
Anti-vinculin
Pimentel M et al. PLoS ONE. 2015;10(5):e0126438.
Gut nerve
damage
Bacterial
overgrowth
Reduced ICC
Reduced MMC
Breath testing
Culture
qPCR
Deep sequencing
IBS
Anti-Vinculin / CdtB Antibody
IBS Diagnosis: Take-Away Messages
• If patient fulfills Rome criteria, there is rarely underlying organic
disease (that we can reliably identify)
• Guidelines indicate IBS is a diagnosis of exclusion, but many disagree
• Structural colonic abnormalities are no higher in IBS vs. controls, but
1.5% have microscopic colitis
• ESR and sprue serologies are useful in some patients
• Breath testing is of unclear clinical utility
• Anti-vinculin/Anti-CdtB antibody promising new IBS diagnostic
• Bottom line: we should remain judicious in performing exclusionary
diagnostic testing in IBS; the yield remains generally low
Questions or Comments?
Email: [email protected]
@BrennanSpiegel