Iitbl B lS dIrritable Bowel Syndrome: What’s the...
Transcript of Iitbl B lS dIrritable Bowel Syndrome: What’s the...
Brian E. Lacy, MD, PhD, FACG
I it bl B l S dIrritable Bowel Syndrome: What’s the Latest?American College of Gastroenterology
Las Vegas, January 2014B i E L Ph D M D FACGBrian E. Lacy, Ph.D., M.D., FACG
Professor of Medicine Geisel School of Medicine at Dartmouth
Chief, Section of Gastroenterology & HepatologyDartmouth-Hitchcock Medical Center
Lebanon, NH
Rome III Criteria for IBS
Recurrent abdominal pain or discomfort
Onset associated with a change in frequency of
Onset associated with a change inImprovement with
d f i
pat least 3 days/month in the last 3 months
associated with ≥ 2 of the following:
Longstreth GF, et al. Gastroenterology 2006;130:1480-1491
Criteria fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis
a change in frequency ofstool
change inform of stooldefecation
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Brian E. Lacy, MD, PhD, FACG
IBS: What’s the Latest?• IBS subtypes: patients aren’t stagnant• Distinguishing IBS-C from CCDistinguishing IBS C from CC• Utility of testing• Methane• Antibiotics• Probiotics• Celiac disease
Di• Diet• Osmotic agents• Secretagogues
In Clinical Practice Patients Move from Group to Group
IBS-C: IBS with constipation
CCIBS-C
IBS-M
p
CC: Chronic constipation
IBS-M: mixed or alternating symptoms of constipation and diarrhea)
Simren M, et al. Scand J Gastroenterol 2001;36(5):545–52Tillisch K, et al. Am J Gastroenterol 2005;100(4):896–904Mearin F, et al. Eur J Gastroenterol Hepatol 2003;15(2):165–72 Drossman DA, et al. Gastroenterology 2005;128(3):580–9Wong RK, et al. Am J Gastroenterol 2010;105:2228-2234
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Brian E. Lacy, MD, PhD, FACG
Distinguishing IBS-C from CC
• No firm rationale to distinguish IBS-C from CC b th R ittby the Rome committee
• Treatments are often similar– Tegaserod (no longer available in N.A.)– Lubiprostone– Prucalopride (available in the EU)Prucalopride (available in the EU)– Linaclotide
Distinguishing IBS-C From CC
• Symptom-based criteria for CC and IBS overlap– Abdominal pain/discomfort and gas/bloating creates
a spectrum between CC and IBS
PAIN/DISCOMFORT & GAS/BLOATING- +
IBS-C
Brandt LJ, et al. Am J Gastroenterol 2005;100(suppl 1):S5 .
CC
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Brian E. Lacy, MD, PhD, FACG
Histologic Findings in IBS Patients and Controls;Populations Not Matched for Age or Gender
Utility of Testing: Yield of Colonoscopy in IBS
Populations Not Matched for Age or Gender
LesionIBS Patients
n=466 (%)
Controlsn=451
(%)P Value
Adenomas 36 (7.7) 118 (26.1) <0.0001
Hyperplastic polyps 39 (8.4) 52 (11.5) NS
Colorectal adenocarcinoma 0 (0.0) 1 (0.2) NSCo o ecta ade oca c o a 0 (0 0) (0 ) S
IBD 2 (0.4) 0 (0.0) NS
Microscopic colitis 7 (1.5) N/A N/A
Microscopic colitis was more common in a subset of patients with IBS-D who were ≥45 years (2.3%).
IBD, inflammatory bowel disease; IBS-D, irritable bowel syndrome diarrhea-predominant; N/A, not applicable; NS, not significant.
Chey WD, et al. Am J Gastroenterol 2010;105:859-865.
Pretest Probability of Organic Disease1
Organic DiseaseIBS Patients
(%)Control/Population
(%)
Colitis/IBD 0.51-0.98 0.3-1.2
Colorectal cancer 0-0.51 0-6 (varies with age)
Lactose malabsorption 38 26
Thyroid dysfunction 4.2 5-9
1. American College of Gastroenterology Task Force on Irritable Bowel Syndrome, et al. Am J Gastroenteroll 2009;104(suppl 1):S1-S35. 2. Cash BD, et al. Gastroenterology 2011;141:1187-
1193.
y y
Celiac disease 3.6 0.7
Celiac disease: antibodies2 7.3 4.8
Celiac disease: confirmed2 0.41 0.44
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Brian E. Lacy, MD, PhD, FACG
Methane & Constipation
• About 1/3rd of population produces CHCH4
• Predominant organism is Methanobrevibacter smithii
• Thought to be present in 60% of humans in left colon
• 107-1010 per g dry weight
Methane and Constipation
80 2 0P<0 05
Prevalence of CH4 in slow transitConstipation
AUC of methane on breath test
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wit
h M
eth
ane
>3p
pm
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than
e A
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(p
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P<0.05P<0.05
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Control NormalTransit
SlowTransit
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50
Control NormalTransit
SlowTransit
Met
Attaluri, et al. Am J Gastro, 2010Attaluri, et al. Am J Gastro, 2010..
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Brian E. Lacy, MD, PhD, FACG
Methane Gas Infusion Slows Transit
80
20
40
60%
Ma
rke
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ec
ov
ery n=5, p<0.0001
69% mean slowing
0Room Air Methane
Pimentel, et al. Am J Physiol 2006.
69% mean slowing of transit
Rifaximin: Most Extensively Studied Antibiotic for IBS
G t di t d tibi ti• Gut-directed antibiotic• Not systemically absorbed• Doses studied for IBS: 400 mg BID to 550 mg TID • Generally well tolerated
Ad ff i l d h d h bd i l• Adverse effects include: headache, abdominal pain, and upper respiratory tract infection
Ford AC, et al. Clin Gastroenterol Hepatol 2009;7:1279-1286. Pimentel M, et al. N Engl J Med 2011;364:22-32.
*This agent is not currently FDA approved for IBS.
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Brian E. Lacy, MD, PhD, FACG
Rifaximin Trials: Global Relief of IBS Without Constipation
• 2 Phase 3 randomized controlled trials; N=1260 40
45
controlled trials; N 1260 patients
• Rifaximin 550 mg TID x 2 weeks; patients followed additional 10 weeks
• 40.7% vs. 31.7% with adequate relief of global
15
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25
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35
40
RifaximinPlacebo
adequate relief of global symptoms (P<0.001)
0
5
10
T-I T-II CombT-I, TARGET 1 trial; T-II, TARGET 2 trial; Comb, Combination of both trials.*Rifaximin is not currently FDA-approved for IBS.
Pimentel M, et al. N Engl J Med 2011;364:22-32.
Probiotics
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Brian E. Lacy, MD, PhD, FACG
Probiotics for IBS• Lactobacilli – anaerobic, gram (+) rods
– casei– plantarum – acidophilus– reuteri
• Bifidobacteria – anaerobic, gram (+) rods• VSL #3 (8 separate organisms: 3 Bifidobacteria, 1
Streptococcus, 4 Lactobacilli)• Enterococcus• Streptococcus salivarius• Saccharomyces
Moayyedi P, et al. Gut 2010:59:325-332. Epub 2008 Dec 17.
Probiotics: Mechanisms of Action
• Competitive inhibitionB i t ti• Barrier protection
• Immune effects• Anti-inflammatory effects• Production of various substances (enzymes,
SCFA, bacteriocidal agents), g )• Ability to alter local pH and physiology• Provides nutrition to colonocytes
Camilleri M. J Clin Gastroenterol 2006;40:264-269.
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Brian E. Lacy, MD, PhD, FACG
Bifidobacteria Infantis 35624 for IBS Global Assessment of Relief
8070ee
k P=0.01187060504030
Answ
erin
g “Y
es” a
t We
4 (%
)
20
Whorwell PJ, et al. Am J Gastroenterol 2006;101:1581-1590.
SGA: (Subjects’ Global Assessment) a yes/no response to the following question:
“Please consider how you felt in the past week in regard to your IBS, in particular your general well being, and symptoms of abdominal discomfort or pain, bloating or distension, and altered bowel habit. Compared with the way you felt before beginning the medication, have you had adequate relief of your IBS symptoms?”
PlaceboB Infantis1 x 106
B Infantis1 x 108
B Infantis1 x 1010
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Wheat & IBS
• Gluten-related disorders– Celiac disease– Dermatitis herpetiformis– Gluten ataxia– Non-celiac gluten sensitivity
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Brian E. Lacy, MD, PhD, FACG
Gluten
• A storage protein in wheat, barley, rye• Genetically susceptible individuals (HLA-DQ2 and
HLA-DQ8) develop an immune response• Worldwide prevalence of celiac disease in IBS
patients = 4%1
• US prevalence of celiac disease in IBS patients = p p0.41%2
• KEY POINT: The vast majority of IBS patients don’t have celiac disease.
1Green Lancet 2003; 2Cash et al, Gastroenterology 2011
IBS & Diet• Low carbohydrate• Low fructose/fructanLow fructose/fructan• Low gluten• Low FODMAP
(Fermentable Oligosaccharides, Disaccharides, Monosaccharides, and Polyol)
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Brian E. Lacy, MD, PhD, FACG
Low Carbohydrate Diet
• Prospective, randomized, controlled study17 d t IBS D ti t• 17 moderate-severe IBS-D patients
• 4-week very low carbohydrate diet (VLCD)– 51% fat; 45% protein; 4% carbohydrate
• Endpoint: adequate relief for > 2 weeks• 13 completed the study13 completed the study• All 13 met the responder definition• 10 experienced adequate relief for all 4 weeks
Austin et al, Clin Gastro & Hepatol 2009
Low Carbohydrate Diet
• Secondary Endpoints also improved– Decrease in stool frequency– Improvement in stool consistency– Decreased abdominal pain– Improvement in quality-of-life
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Brian E. Lacy, MD, PhD, FACG
IBS & Low Fructose/Fructan Diet•26 IBS patients with fructose malabsorption (Rome II; + breath test; mean age = 38) •Prior response to low fructose/low fructan diet•Randomly re-challenged with offending foods•70% of those receiving fructose, 77% receiving fructans, and 79% receiving a mixture noted return/worsening of symptoms compared to glucose (14%; p < 0.002)
Sheperd et al, Clin Gastroenterol Hepatol 2008;6:765-771
IBS & Low Gluten
• R, DB, PC, re-challenge study• 34 IBS patients (Rome III); celiac excluded• Prior improvement in Sx on gluten-free diet• 16 gm of non-fermentable gluten/day vs. 16
grams of gluten• Primary endpoint: adequate symptom relief• Gluten-group had less improvement in Sx than
those on gluten-free (68% vs. 40%; p = .001)
Biesiekierski et al, Am J Gastro 2011
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Brian E. Lacy, MD, PhD, FACG
IBS & Low Gluten Diet
Biesiekierski et al, Am J Gastro 2011
IBS and Gluten-free Diet
• 45 Pts with IBS-D (43 women); 4-weeks• Gluten-free diet (23) vs. Gluten-diet (22)• Genotype analysis performed• Stool frequency, intestinal transit and
intestinal permeability measured• Results: Gluten diet was associated with
increased SB permeability, especially in HLA-DQ2/8 positive patients
Vazquez-Roque et al, Gastroenterology 2013;144:903-911
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Brian E. Lacy, MD, PhD, FACG
What Are FODMAPs?
Honey, apples, pears, peaches mangos fruit juice
Excess
Fermentable Oligo-, Di-, Monosaccharides And Polyols
Sorbitol
peaches, mangos, fruit juice, dried fruit
Apricots, peaches, artificial sweeteners artificially
Wheat (large amounts), rye (large amounts), onions, leeks, zucchini
Fructose
Fructans
Shepherd SJ, et al. J Am Diet Assoc. 2006;106:1631-1639. Shepherd SJ, et al. Clin Gastroenterol Hepatol 2008;6:765-771. Gibson PR, et al. J Gastroenterol Hepatol 2010;25:252-
258.
Lentils, cabbage, Brussels sprouts, asparagus, green beans, legumes
Raffinose
sweeteners, artificially sweetened gums
IBS & Low FODMAP Diet: Or, what is there left to eat?
• Lean proteins• Gluten-free breads, rolls, pasta• Rice, corn, oat products• Quinoa• Safe fruits and vegetables:
– Snow peas, bok choy, mandarin oranges
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Brian E. Lacy, MD, PhD, FACG
IBS & Low FODMAP Diet: Some Problems Exist
• What is the cut-off for FODMAP content?• Resources differ on low FODMAP diets• Total meal FODMAPs should be counted, not
individual FODMAP
IBS: Prospective study to Evaluate Low FODMAP diet
• 82 consecutive IBS patients (NICE criteria)• Detailed symptom and dietary evaluation• 9 month evaluation – performed in UK• Individual symptoms and global IBS symptoms
measured• 39 in the standard diet group• 42 in the low FODMAP diet group
Staudacher et al, J Hum Nutr Diet, 2011
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Brian E. Lacy, MD, PhD, FACG
90100
d %Standard Diet
** † †
Improvements in IBS Symptom Scores: Low FODMAP vs Control Diet
2030405060708090
Patie
nts W
ith Im
prov
edSy
mpt
om R
espo
nse,
% Low FODMAP Diet** † †
††
010
Staudacher HM, et al. J Hum Nutr Diet 2011;24:487-495.
*P≤0.001† P<0.05
IBS Symptom Improvement: Low FODMAP Diet vs. Standard Diet
• Bloating (82% vs. 49%)• Abdominal pain (85% vs. 61%)• Flatulence (87% vs. 50%)• Nausea (67% vs. 29%)• Diarrhea (83% vs. 62%; ns)( ; )• Composite symptom score (86% vs. 49%)
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Brian E. Lacy, MD, PhD, FACG
Osmotic Agents: PEG for IBS-C
7
8
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Pretreatment
• 27 adolescents: PEG improved number ofBMs (P<0.05) but not pain in IBS-C patients
1. Khoshoo V, et al. Aliment Pharmacol Ther 2006;23:191-196.
0
1
2
# BMs Pain Level
Posttreatment
BMs, bowel movements; PEG, polyethylene glycol.
Osmotic Agents: PEG for IBS-C
• Prospective, multi-center, R, DB, PCR III it i• Rome III criteria
• 139 patients (mean age = 41; 83% women)• 28 day study; 13.8 gm/ sachet;• 1-3 sachets/day vs. placebo• Primary endpoint: mean # of SBM/dayPrimary endpoint: mean # of SBM/day• Results: At week 4, 4.4 SBM/week vs. 3.1
SBM/week (PEG vs. placebo; p < .0001)
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PEG 3350 for IBS-C
Efficacy of Linaclotide in Patients With IBS-C
3Treatment Period* RW Period†
z
Mea
n Ch
ange
Fro
mBa
selin
e +/
-SEM
2
1
0BL 1 2 3 4 5 6 7 8 9 10 11 1212 13 14 15 16
z
N=800
Weeks
BL 1 2 3 4 5 6 7 8 9 10 11 12
Treatment PeriodPlaceboLinaclotide 290 µg
Rao S, et al. Am J Gastroenterol 2012;107:1714-1724.
*P<0.0001 for linaclotide patients vs placebo patients (ANCOVA).†P<0.001 for linaclotide/linaclotide patients vs linaclotide/placebo patients (ANCOVA).
ANCOVA, analysis of covariance; RW, randomized withdrawal.
12 13 14 15 16
RW Treatment SequencePlacebo/linaclotide 290 µgLinaclotide 290 µg/linaclotide 290 µgLinaclotide 290 µg/placebo
Weeks
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Brian E. Lacy, MD, PhD, FACG
Linaclotide Phase 3 IBS-C Trial:Abdominal Pain Over 26 Weeks
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0 Linaclotide 290 µg PlaceboCh
ange
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orst
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Pai
n, %
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Chey WD, et al. Am J Gastroenterol 2012;107:1702-1712.
ITT population, observed cases, LS-mean presented: P-values based on ANCOVA at each week. Bars represent 95% CI.
P=0.0007 for week 1P<0.0001 for weeks 2-26
-60
Trial Week
BL 2 4 6 8 10 12 14 16 18 20 22 24 26
N=804ITT, intention to treat; LS, least squares.
Summary
• IBS is a constantly evolving field• Rome IV 2015 – expect changes in the
definition• Our understanding of IBS physiology continues
to expand• Expect new treatment options within the next• Expect new treatment options within the next
few years
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