IBS Slides 2014 080307 · 2018. 4. 3. · “Please consider how your felt in the past week in...
Transcript of IBS Slides 2014 080307 · 2018. 4. 3. · “Please consider how your felt in the past week in...
8/4/2014
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Irritable Bowel Syndrome:
What’s the Latest?
Tim Burke, DO
Pacific Digestive Associates
Clackamas, OR
Rome III Criteria for IBS
Recurrent abdominal pain or discomfort at least 3 days/month in the last 3 months associated with ≥ 2
of the following:
Recurrent abdominal pain or discomfort at least 3 days/month in the last 3 months associated with ≥ 2
of the following:
Improvement with defecationImprovement
with defecation
Onset associated with a change in
frequency of stool
Onset associated with a change in
frequency of stool
Onset associated with change in form of stool
Onset associated with change in form of stool
Criteria fulfilled for the last 3 months with symptom onset at
least 6 months prior to diagnosis
Longstreth GF, et al. Gastroenterology 2006; 130: 1480-1491
IBS: What’s the Latest?
• IBS subtypes: patients aren’t stagnant
• Distinguishing IBS-C from CC
• Utility of testing
• Methane
• Antibiotics
• Probiotics
• Celiac disease
• Diet
• Osmotic agents
• Secretagogues
In Clinical Practice Patients Move from
Group to Group
IBS-MIBS-M
CCCCIBS-CIBS-C
IBS-C: IBS with constipation
CC: Chronic Constipation
IBS-M: mixed or alternating
symptoms of constipation and
diarrhea
Simren M, et al. Scand J Gastroenterol 2001; 36(5):545-52
Tillisch K, et al. Am J Gastroenterol 2005; 100(4):896-904
Simren M, et al. Eur J Gastroenterol Hepatol 2003; 15(2):165-72
Simren M, et al. Gastroenterology 2005; 128(3):580-9
Simren M, et al. Am J Gastroenterol 2010; 105:2228-2234
Distinguishing IBS-C from CC
• No firm rationale to distinguish IBS-C from CC
by the Rome committee
• Treatments are often similar
– Tegaserod (no longer available in N.A.)
– Lubiprostone
– 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
CC IBS-C
- PAIN/DISCOMFORT & GAS/BLOATING +
Brandt LJ, et al. Am J Gastroenterol 2005; 100(suppl 1): S5
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Utility of Testing:
Yield of Colonoscopy in IBSHistologic Findings in IBS Patients and Controls;
Populations Not Matched for Age and Gender
Lesion IBS Patients
n=466
(%)
Controls
n=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) NS
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
Celiac Disease 3.6 0.7
Celiac disease: antibodies2 7.3 4.8
Celiac disease: confirmed2 0.41 0.44
1. American College of Gastroenterology Task Force on Irritable Bowel Syndrome, et al. Am J Gastroenterol
2009; 104(suppl 1): S1-S35.
2. Cash BD, et al. Gastroenterology 2011; 141:1187-1193
Methane & Constipation
• About 1/3rd of the population
produces CH4
• 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
Prevalence of CH4 in slow transit
ConstipationAUC of methane on breath test
Attaluri, et al. Am J Gastro, 2010;105, 1407.
Methane Gas Infusion Slows Transit
69% mean slowing of transit
Pimentel, et al. AJPGI. 290;1089,2006.
Rifaximin: Most Extensively Studied
Antibiotic for IBS
• Gut-directed antibiotic
• Not systemically absorbed
• Doses studied for IBS: 400 mg BID to 550 mg
TID
• Generally well tolerated
• Adverse effects include: headache, abdominal
pain, and upper respiratory tract infection
*This agent is not currently FDA approved for IBS
Ford AC, et al. Clin Gastroenterol Hepatol 2009;7:1279-1286. Pimentel M, et al. N Engl J Med 2011; 364:22-32
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Rifaximin Trials: Global Relief of IBS
Without Constipation
• 2 Phase 3 randomized
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
symptoms (p<0.001)
T-I, TARGET 1 trial; T-II, TARGET 2 trial; Comb, Combination of both trials.
*Rifaximin is not currently FDA-pproved for IBS Pimentel M, et al. N Engl J Med 2011;364:22-32
Probiotics
• What about Probiotics? Could some
methane-producing bacteria respond to
probiotics?
Probiotics for IBS
• Lactobacilli – anaerobic, gram (+) rods– casei
– plantarum
– acidophilus
– reuteri
• Bifidobacteria – anaerobic, gram (+) rods
• VSL #3 (8 separate organisms: 3 Bifidobacteria, 1 Stretococcus, 4 Lactobacilli)
• Enterococcus
• Streptococcus salivarius
• Saccharomyces
Moayyedi P, et al. GUT 2010:59:325-332. Epub 2008 Dec 17
Probiotics: Mechanisms of Action
• Competitive inhibition
• Barrier protection
• Immune effects
• Anti-inflammatory effects
• Production of various substances (enzymes, SCFA, bacteriocidal agents)
• Ability to alter local pH and physiology
• Provides nutrition to colonocytes
Camilleri. J Clin Gastroenterol 2006;40,264.
Bifidobacteria Infantis 35624 for IBS
Global Assessment of Relief
SGA: (Subjects’ Global Assessment) a yes/no response to the following question:
“Please consider how your 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 distention, and altered
bowel habit. Compared with the way you felt before beginning the medication, have you had
adequate relief of your IBS symptoms?”
Whorwell PJ, et al. Am J Gastroenterol 2006;101:1581-1590
B Infantis B Infantis B Infantis Placebo
1 x 1010 1 x 108 1 x 106
Wheat & IBS
• Gluten-related disorders
– Celiac disease
– Dermatitis herpetiformis
– Gluten Ataxia
– Non-celiac gluten sensitivity
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Gluten
• A storage protein in wheat, barley, and 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 = 0.41%2
• KEY POINT: The vast majority of IBS patients do not have celiac disease
1Green. Lancet 362; 383:2003; 2Cash et al. Gastroenterology 141;1187:2011
IBS & Diet
• Low carbohydrate
• Low fructose/fructan
• Low gluten
• Low FODMAP
– (Fermentable Oligosaccharides, Disaccharides,
Monosaccarides, and Polyol)
Low Carbohydrate Diet
• Prospective, randomized, controlled study
• 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 study
• All 13 met the responder definition
• 10 experienced adequate relief for all 4 weeks
Austin et al, Clin Gastro & Hepatol 7;706:2009
Low Carbohydrate Diet
• Secondary Endpoints also improved
– Decrease in stool frequency
– Improvement in stool consistency
– Decreased abdominal pain
– Improvement in quality-of-life
IBS & Low Fructose/Fructan Diet
• 26 IBS patients with fructose malabsorption(Rome II; + breath test; mean age = 38)
• Prior response to low fructose/low fructandiet
• 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;106:508.
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IBS & Low Gluten Diet
Biesiekierski et al, Am J Gastro, 2011; 106:508.
IBS and Gluten-free Diet
• 45 Pts with ISB-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
What Are FODMAPs?
Fermentable Oligo-, Di-, Monosaccharides And Polyols
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.
Excess Fructose
Honey, apples, pears,
peaches, mangos, fruit
juice, dried fruit
Fructans
Wheat (large amounts), rye
(large amounts), onions,
leeks, zucchini
Sorbitol
Apricots, peaches, artificial
sweeteners, artificially
sweetened gums
Raffinose
Lentils, cabbage, brussel
sprouts, asparagus, green
beans, legumes
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, mangarin oranges
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 FODMAPs
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, 24, 487.
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Improvements in IBS Symptom Scores:
Low FODMAP vs. Control Diet
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%)
Osmotic Agents: PEG for IBS-C
• 27 adolescents: PEG
improved number of
BMs (p < 0.05) but not
pain in IBS-C patients
SMs, bowel movements; PEG, polyethylene glycol
Khoshoo V, et al. Aliment Pharmacol Ther 2006;23:191-196
Osmotic Agents: PEG for IBS-C
• Prospective, multi-center, R, DB, PC
• 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/day
• Results: At week 4, 4.4 SBM/week vs. 3.1 SBM/week (PEG vs. placebo; p < .0001)
Chapman. Am J Gastroenterol 2013;108,1508
PEG 3350 for IBS-CEfficacy of Linaclotide in Patients with
IBS-C
ANCOVA, analysis of convariance; RW, randomized withdrawl *p < 0.0001 for linaclotide patients vs. placebo patients (ANCOVA)
¥p < 0.001 for linaclotide/linaclotide patients vs. linaclotide/placebo
patients (ANCOVA)
Treatment Period* RW Period¥
Treatment Period RW Treatment Sequence
Rao S, et al. Am J Gastroenterol 2012;107:1714-1724.
n = 800
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Linaclotide Phase 3 IBS-C Trial:
Adbominal Pain Over 26 Weeks
ITT population, observed cases, LS-mean presented: p-values basted on ANCOVA at each
week. Bars represent 95% CI
n = 804ITT, intention to treat; LS, least squares
Chey WD, et al. Am J Gastroenterol 2012;107:1702-1712.
p = 0.0007 for week 1
P < 0.0001 for weeks 2-26
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
few years