Functional GI disorders 2016

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David Sun Lecture 2016 Functional disease of the GI tract: Is there a light at the end of the tunnel?

Talley, MD, MBBS, PhD, MMedSci, FACG University of Newcastle, Australia; Mayo Clinic, Rochester Functional GI disorders

miss them (they make great Board questions) A common FGID often misdiagnosed as GERD or PPI resistant GERD and new

1 David Sun Lecture 2016 Functional disease of the GI tract: Is there a light at the end of the tunnel? Talley & Ford, NEJM 2015 Nicholas J. Talley, MD, MBBS, PhD, MMedSci, FACG University of Newcastle, Australia; Mayo Clinic, Rochester Functional GI disorders 2016 Rome IV criteria 2016 and how to make a positive clinical diagnosis of FGID in practice 4 curable FGIDs do not miss them (they make great Board questions) A common FGID often misdiagnosed as GERD or PPI resistant GERD and new insights into why IBS not one disease but many, diagnosis key (Board question territory), and new treatment options Functional does NOT always mean no pathology new diseases being identified and hopes for cure rising Page 1 of 26

2 Case #1: Unexplained Vomiting 42 year old Public Relations President Since 2012: recurrent vomiting multiple investigations elsewhere for vomiting all unhelpful Fluid/food comes back up into his mouth Not forced to expel it from his mouth Not responded to anti emetic drugs Repetitive belching and bloating Physical exam unremarkable Routine bloods unremarkable EGD and colonoscopy negative, CT normal, gastric emptying normal Case #1: 42 year old man with unexplained vomiting Most likely diagnosis? A. Irritable bowel syndrome B. Depression C. Functional vomiting D. Aerophagia E. Rumination Page 2 of 26

Case # 1: Answer Rumination the best answer NOT vomiting Belching disorder co morbid No features for IBS (does not cause vomiting) Rumination: A clinical diagnosis Effortless regurgitation

3 Case # 1: Answer Rumination the best answer NOT vomiting Belching disorder co morbid No features for IBS (does not cause vomiting) Rumination: A clinical diagnosis Effortless regurgitation postprandially Food may taste as good as the first mouthful (may be acidic) May spit out or re swallow R (spike) wave: associated with increased intra abdominal pressure and TLESR (40%) Esophageal impedance will document UES Therapy: Reassurance, explanation, and behavioral therapy LES O Brien et al. Gastroenterology 1995;108:1024-9; Chial et al. Pediatrics 2003;111: Page 3 of 26

4 Teaching Diaphragmatic Breathing for Rumination Syndrome Instruct patient to take inspiratory and expiratory breaths with the abdominal muscles, keeping the chest motionless This behavior is incompatible with abdominal wall contraction, which is a precipitating behavior for regurgitation in rumination syndrome Biofeedback: Abdomino thoracic muscle activity after a challenge meal recorded by EMG patients in the biofeedback group shown the signal and instructed to control muscle activity superior to placebo in RCT (74% reduction in rumination vs. 1%) Chitkara, Talley et al. Am J Gastroenterol. 2006;101: Barba et al. Am J Gastroenterol (in press) Case #2: Chronic vomiting 32 year old man with chronic vomiting Recurrent episodes of vomiting for 11 years each lasts 3 days Nausea, retching, generalized abdominal pain and anorexia Onset usually in morning, not related to food intake No significant prodrome; completely asymptomatic inbetween Only relieving factor sitting in a hot water tub Physical exam and routine testing negative Page 4 of 26

5 Case #2: 32 year old man with chronic vomiting (he is vomiting!) What is the most likely diagnosis? A. Gastroparesis B. Gastroesophageal reflux disease C. Brain stem lesion D. Cyclic vomiting syndrome E. Drug induced vomiting 32 year old man with chronic vomiting What is the most likely diagnosis? Only relieving factor during the acute episodes was sitting in a hot water bath tub: is this relevant? He bathed compulsively... Page 5 of 26

Triad of Chronic Cannabis Use, Cyclic Vomiting Syndrome, and Compulsive Bathing Cannabinoid Hyperemesis Syndrome Compulsive bathing or washing behavior during acute phase in 9 of 10 patients

6 Triad of Chronic Cannabis Use, Cyclic Vomiting Syndrome, and Compulsive Bathing Cannabinoid Hyperemesis Syndrome Compulsive bathing or washing behavior during acute phase in 9 of 10 patients Persistent vomiting in 3 who did not abstain Return to illness in 3 who re challenged Cessation of cannabis abuse in 7 led to cessation of cyclical vomiting Allen et al. Gut 2004;53: Stanghellini et al. Gastroenterology. 2016;150: Cyclic vomiting in adults Acute episodes; usually no warning; virtually asymptomatic in between Abdominal pain 2/3 Psychiatric diagnoses 1/5 (same as community) May have migraine ( migraine equivalent ) Therapy: tricyclics (partial response 60%, good response <20%), antimigraine drugs Cyclic Vomiting Syndrome Association Stanghellini et al. Gastroenterology 2016;150: Prakash & Clouse Am J Gastroenterol 1999;94: Prakash et al. Am J Gastroenterol 2001;96:684-8 Page 6 of 26

4 curable FGIDs you should recognize Effortless regurgitation think rumination not GERD: diaphragmatic (abdominal) breathing during and post meals Episodic vomiting, well in between, compulsive

7 4 curable FGIDs you should recognize Effortless regurgitation think rumination not GERD: diaphragmatic (abdominal) breathing during and post meals Episodic vomiting, well in between, compulsive bathing: think cyclic vomiting syndrome and stop cannabis (cannabis hyperemesis syndrome) Narcotics, worsening abdominal pain narcotic bowel syndrome: try to stop all narcotics (50% fail long term) Chronic constipation, fails laxatives do a rectal exam and consider dyssynergic defecation: inappropriate contraction of the pelvic floor as measured with anal surface EMG or ARM with adequate propulsive forces during attempted defecationbiofeedback (70% success) Rao et al. Gastroenterology 2016; Drossman et al. Gastroenterology 2016 Woodward et al. Cochrane Database Syst Rev. 2014;3:CD Case #3 39 yr. old male, divorced, physician Early satiety, postprandial fullness and epigastric pain after most meals for 12 months Symptoms began in 2015 after an acute episode of diarrhea and upset stomach in Las Vegas Occasionally he may go symptom free for a few days Denies nausea or vomiting, no weight loss, heartburn 2 3x/month, no dysphagia, normal bowel habit Esomeprazole 40 mg twice daily 3 months no help Physical exam normal; EGD negative; Hp negative Diagnosis: PPI resistant GERD Page 7 of 26

Case #3 YOUR MOST LIKELY DIAGNOSIS? A. Irritable bowel syndrome B.

GERD PPI resistant Additional testing? Therapy?

distress syndrome (PDS) Epigastric pain Epigastric burning Early Satiation

8 Case #3 YOUR MOST LIKELY DIAGNOSIS? A. Irritable bowel syndrome B. Peptic ulcer disease C. Functional dyspepsia D. Get a psychiatrist! E. GERD PPI resistant Additional testing? Therapy? Rome IV Functional Dyspepsia Epigastric pain syndrome (EPS) Postprandial distress syndrome (PDS) Epigastric pain Epigastric burning Early Satiation Postprandial heaviness or fullness Bothersome, at least 1 day a week Bothersome, at least 3 days a week Page 8 of 26

Epidemiology of FD (Rome III) Of 1000 Swedish subjects randomly selected from the general

of FD 122 postprandial distress syndrome (PDS): 78% 17 EPS and PDS overlap: 11% PDS 78% EPS 33%

2009;137:94 100 Overlap of Upper GI Symptoms in USA Symptom prevalence ( 1x/month) n=17,484

9 Epidemiology of FD (Rome III) Of 1000 Swedish subjects randomly selected from the general population: 202 (20%) uninvestigated dyspepsia 157 (16%) FD 52 epigastric pain syndrome (EPS): 33% of FD 122 postprandial distress syndrome (PDS): 78% 17 EPS and PDS overlap: 11% PDS 78% EPS 33% Aro, Talley et al. Gastroenterology. 2009;137: Overlap of Upper GI Symptoms in USA Symptom prevalence ( 1x/month) n=17,484 Heartburn 2nd most common n=3,768 (21.6%) Both n= % 35.5% Early satiety most common n=4,028 (23.0%) Camilleri M, et al. Clin Gastroenterol Hepatol 2005;3: Page 9 of 26

Fact #1: Evidence FD and GERD are part of the same spectrum - FD now

Pleyer, Talley et al. Neurogastroenterol Motil.

Fact # 2: Post infectious FD established New onset of dyspepsia post

13% D 6 months post AGE n=26 47% n=13 23% IBS n=17 30% D 12 months

10 Fact #1: Evidence FD and GERD are part of the same spectrum - FD now often mislabeled GERD Olmsted County, MN, USA GI diagnoses Pleyer, Talley et al. Neurogastroenterol Motil. 2014;26: % of subjects reporting GERD symptoms received a GERD diagnosis, however only 12.5% of subjects reporting FD symptoms received a FD diagnosis GERD FD Fact # 2: Post infectious FD established New onset of dyspepsia post Salmonella enteritis D 3 months post AGE n=39 57% n=21 30% IBS n=9 13% D 6 months post AGE n=26 47% n=13 23% IBS n=17 30% D 12 months post AGE n=18 43% n=15 36% IBS n=9 21% AGE = acute gastroenteritis Post AGE Mearin et al, Gastroenterology 2005; 129: 98 Page 10 of 26

Do not confuse with gastroparesis (think gastroparesis if vomiting, weight loss, or diabetes with complications) Only established

11 FD fact #3: Gastric emptying forget it! Gastric emptying slow in 20% (rarely fast, usually normal) Slow emptying NO link to any FD symptom! Do not confuse with gastroparesis (think gastroparesis if vomiting, weight loss, or diabetes with complications) Only established value of knowing gastric emptying is slow no response to a tricyclic (too recent for your Boards) US Functional Dyspepsia Treatment Trial 20% slow gastric emptying GE can guide therapy Talley et al. Gastroenterology 2015; 149: Page 11 of 26

FD fact #4: Chronic infection and FD (H.

Gastroenterology 2005; 129:1756 80 NNT = 17 (95% CI 11

eosinophilia H. pylori and FD eradication therapy vs.

Duodenal eosinophils Biomarker in FD degranulation and

S100 nerve fibres S100 Eosinophil Carbol degranulation

12 FD fact #4: Chronic infection and FD (H. pylori) Talley, Vakil & Moayyedi. Gastroenterology 2005; 129: NNT = 17 (95% CI 11 33) EPS may be most responsive No increased duodenal eosinophilia H. pylori and FD eradication therapy vs. placebo or PPI and 1 year remission FD fact #5: Duodenal eosinophils Biomarker in FD degranulation and nerves Early satiety (PDS) Gastric accommodation Pain S100 nerve fibres S100 Eosinophil Carbol degranulation Chromotrope Walker MM, Talley NJ et al. J Gastroenterol Hepatol. 2014;29(3): Page 12 of 26

observed in 26 FD (51%) vs. 10 controls (21%) (p=0.003) OR = 11.

001 Independent verification Leuven: Duodenal eosinophils in FD

al. Gut. 2014;63(2):262-71 Immune cell infiltration.

and patients with FD (white dots) Intestinal integrity of

13 Clin Gastroenterol Hepatol : MBP degranulation Clusters of eosinophils in D1 observed in 26 FD (51%) vs. 10 controls (21%) (p=0.003) OR = 11.7 (3.9, 34.9) P<0.001 Independent verification Leuven: Duodenal eosinophils in FD Duodenal biopsies n= 15 FD Rome III and 15 controls VanHeel et al. Gut. 2014;63(2): Immune cell infiltration. Duodenal biopsy specimens from healthy volunteers (black dots) and patients with FD (white dots) Intestinal integrity of healthy controls (black dots) and patients with FD (white dots) was evaluated in Using chambers by measuring TEER (A) and passage of FITC-dx4 (B) Page 13 of 26

FD and duodenal submucous ganglion plexus Neuronal functioning impaired in submucous plexus of FD decreased calcium responses to depolarization Glial (S100) and neuronal (HuCD) markers show gliosis,

controls Significant correlation between number of eos/mast cells and calcium transient amplitudes in submucous ganglia FD Cirillo et al.

14 FD and duodenal submucous ganglion plexus Neuronal functioning impaired in submucous plexus of FD decreased calcium responses to depolarization Glial (S100) and neuronal (HuCD) markers show gliosis, altered ganglionic architecture, and neuronal abnormalities Controls Increased eosinophils and mast cells infiltrated the submucous layer of FD vs. controls Significant correlation between number of eos/mast cells and calcium transient amplitudes in submucous ganglia FD Cirillo et al. Am J Gastroenterol 2015;110: FD & Duodenal Eosinophilia Global Perspective Pathologist will call the biopsy normal unless the number of eosinophils per 5 high power fields are counted (just like in celiac disease where the number of IELs must be counted) Friesen CA et al. J Pediatr Gastroenterol Nutr & Clin Pediatr USA Talley NJ et al. Clin Gastroenterol Hepatol Sweden Bafutto M et al DDW Brazil Walker MM et al. Aliment Pharmacol Ther London Futagami S et al. Am J Gastroenterol Post infectious FD. Japan Pignataro SB et al DDW Argentina Bafutto M et al DDW Brazil Walker MM et al J Gastroenterol Hepatol Australia Wang X et al Ann Diagn Pathol China Vanheel, Tack et algut 2015/ Cirillo C et al Am J Gastro Belgium Page 14 of 26

15 TNF- (pg/ml) * Homing small bowel T cells and FD Cytokine release and CD4+α4β7+CCR9+ lymphocytes correlated with symptom intensity pain, cramps, nausea, vomiting HC FD Delayed gastric emptying correlated (r=0.78, p=0.02) with CD4+α4β7+CCR9+ lymphocytes, and IL 1β, TNF α and IL 10 secretion 0 Tobias, Talley, Holtmann et al. Am J Gastro 2011;106: GET (T1/2) CD CCR9+ (%) Birth & early environment in FD Survey of 670 people from a random population sample from Sydney, Australia who responded to a valid survey in 1997 and 2009 Variables FD % (n) Non FD % (n) OR (95%CI), P Value controlling age/gender Caesarean Delivery 6.3 (5) 3.3 (19) 0.76 (0.24,2.38), P=0.64 Prematurity (Yes) 7.0 (5) 7.8 (43) 0.96 (0.36,2.54), P=0.93 Breastfed (Yes) 85.1 (57) 86.5 (463) 1.09 (0.50,2.35), P=0.83 Duration of 5.50 (3.20) 7.86 (4.87) 0.87 (0.76,1.0), P=0.05 Breastfeeding (months) Pet Exposure (Yes) 67.8 (61) 58.7 (393) 1.39 (0.85,2.28), P=0.19 Herbivore Pet (Yes) 34.4 (31) 22.7 (152) 1.83 (1.17,2.99), P=0.02* Herbivores e.g. horses Carnivore Pet (Yes) 65.6 (90) 54.6 (366) Omnivore Pet (Yes) 4.4 (4) 4.8 (32) 1.49 (0.92,2.42), P= (0.31,2.75), P=0.90 Sharing a bedroom (Yes) 79.3 (69) 72.3 (441) 1.45 (0.82,2.57), P=0.20 Koloski et al. Neurogastroenterol Motil 2015; 27: Hygiene Factors (Yes) 92.2 (83) 84.0 (563) 1.90 (0.85,4.26 ), P=0.12 Page 15 of 26

Why do GERD and FD overlap: Abnormal fundic relaxation inducing increased TLESRs Fundic accommodation or receptive relaxation (vago vagal

redistribution of food to antrum: linked to postprandial distress syndrome (PDS) Ly et al.

Neurogastroenterol Motil 2014; 26: 581 8 Systemic symptoms Small bowel homing T cells Cytokines Anxiety Stress response Brain Gut Brain

16 Why do GERD and FD overlap: Abnormal fundic relaxation inducing increased TLESRs Fundic accommodation or receptive relaxation (vago vagal reflex) Normal Meal Increased TLESRs FD: 40% fundic disaccommodation (and 40% duodenal eosinophilia) Impaired fundic accommodation with a redistribution of food to antrum: linked to postprandial distress syndrome (PDS) Ly et al. Clin Gastroenterol Hepatol 2015; 13: Pauwels et al. Neurogastroenterol Motil 2014; 26: Systemic symptoms Small bowel homing T cells Cytokines Anxiety Stress response Brain Gut Brain Gut Increases TLESRs A disease model for functional dyspepsia (PDS) Gut Brain Duodenal eosinophils & mast cells Acid Smoking Food antigen(s) Post infection, parasites Microbiome duodenum altered Distal GI involvement IBS Talley & Ford, N Engl J Med 2015 Page 16 of 26

17 Traditional pharmacologic strategies for FD Therapeutic intervention Efficacy Comment H. pylori eradication 36% vs 30% placebo; NNT 17 Meta-analysis of 17 RCTs PPIs 33% vs 23% placebo; NNT 10 Meta-analysis of 10 RCTs H 2 -receptor antagonists Antidepressants More efficacious than placebo for epigastric pain/postprandial fullness Higher response than PPIs (more heterogeneous data) NIH FDDT trial (Talley) Mirtazepine Meta-analysis of 11 RCTs; NNT 7 TCAs modest efficacy (SSRIs, SNRIs NO efficacy) Antacids No better than placebo 1 RCT only Bismuth salts No better than placebo Meta-analysis of 5 RCTs Sucralfate No better than placebo Meta-analysis of 2 RCTs Talley & Ford, NEJM 2015 Case #4: Constipation, bloating, and abdominal pain 47 yr. woman with symptoms for 6 months Post menopausal 3 years Bloating with slight distention Lower abdominal pain mainly on right Feeling full early after meals Constipation infrequent stools, previously normal Urinary frequency worsening Abdominal exam benign, colonoscopy negative Page 17 of 26

18 The next step in management is? A. No tests this must be IBS B. Colonoscopy C. Pelvic exam D. CT abdomen and pelvis E. Tissue transglutaminase testing Case = Answer D Ovarian cancer 42 yr. woman with recent constipation, bloating and abdominal pain can mimic IBS PV and PR: Solid, irregular, fixed pelvic mass right ovary Ultrasound, CA 125 (>65 units/ml) Epithelial ovarian cancer (EOC) Majority of cases of EOC present at age and are advanced (stage III or IV) Page 18 of 26

Rome IV Definition of IBS (2016) Abdominal pain at least 1 day per week for 3 months associated with altered

and/ or Change in form (appearance) of stool Gastroenterology 2016 Based only on days with abnormal bowel habits

bowel habit abnormalities Type 2 Type 3 Type 4 Type 5 Type 6 % BM hard or lumpy 75 50 25 Bristol types 1 or 2 1

19 Rome IV Definition of IBS (2016) Abdominal pain at least 1 day per week for 3 months associated with altered bowel function (2 or more) Related to (relieved or worsened) by defecation and/ or Change in frequency of stool and/ or Change in form (appearance) of stool Gastroenterology 2016 Based only on days with abnormal bowel habits IBS subtypes: Rome IV At least 4 days of abnormal bowel habits/month Type Off medications used to treat bowel habit abnormalities Type 2 Type 3 Type 4 Type 5 Type 6 % BM hard or lumpy Bristol types 1 or 2 1 and 2 IBS-C IBS-M plus 6 and 7 Type 7 0 IBS-U IBS-D % BM loose or watery Bristol types 6 or 7 Page 19 of 26

IBS D a disease of immune activation Talley & Fodor

Low grade inflammation Immune response GI & non-gi

symptom with a mechanistic explanation Somatic

girth Visceral hypersensitivity Impaired

relax Impaired viscerosomatic reflexes Increased

20 IBS D a disease of immune activation Talley & Fodor Gastroenterology 2011 un Dysbiosis T cell dysfunction Low grade inflammation Immune response GI & non-gi Abdominal Distension is not functional An objective symptom with a mechanistic explanation Somatic perception Distension: objective increase in abdominal girth Visceral hypersensitivity Impaired viscerovisceral reflexes Diaphragmatic failure to relax Impaired viscerosomatic reflexes Increased intraluminal gas Adapted from Azpiroz et al. Gastroenterology 2009;136: Page 20 of 26

The future finding the causes Colonic Spirochaetosis Associated with Colonic Eosinophilia and Irritable Bowel Syndrome (IBS D) Eosinophils significantly increased in colon biopsies in those with CS

21 The future finding the causes Colonic Spirochaetosis Associated with Colonic Eosinophilia and Irritable Bowel Syndrome (IBS D) Eosinophils significantly increased in colon biopsies in those with CS Increased subepithelial eosinophil clusters in CS in 50% of CS cases vs. 3% controls in sigmoid and rectal sites For IBS as defined by Rome III, 37% with full questionnaire data had non constipation IBS Over a three fold increased risk of IBS in those with CS compared to controls with no IBS (OR 3.59, CI , p= 0.01) Walker, Talley et al. Hum Pathol. 2015;46(2):277-83; Goodsall, Walker, Talley et al. Gut in press The future finding the causes 2% of IBS linked to a sodium channelopathy mutation Molecular and functional evidence that perturbations in SCN5A confer susceptibility to the development of IBS (more often IBS C) Incubation of cells that expressed this variant with mexiletine restored their sodium current Administration of mexiletine to 1 carrier (IBS-C) normalized their bowel habits Beyder, Talley, Farrugia et al. Gastroenterology. 2014;146: Page 21 of 26

22 Fact #1 IBS: you can and should make a positive diagnosis at your first consultation Diagnosis of IBS (Rome IV): Positive symptom criteria, no alarm features Minimal investigations (unless alarm features) CBC, CRP or calprotectin ttg (if D/M, fail therapy and/or celiac pretest probability >1% in your practice) Optional stool O&P, TSH Colonoscopy screen (50+, 45+ if African American), or alarm features, family history colon cancer, bad diarrhea (fails therapy) If you are in, biopsy to exclude microscopic colitis (diarrhea) Breath tests (lactose, fructose)? Postprandial C4 or FGF to exclude bile acid malabsorption (BAM)? Fact #2 IBS: a negative colonoscopy does not provide reassurance You often know before you put the scope in they have IBS Less colon cancer and polyps in those with IBS! Colonoscopy does NOT reassure!!! Colonoscopy and reassurance n = 458 (18 49 years) P=NS 30 Colonoscopy yield of polyps in IBS P < SF 36 PCS Adenoma % Recent colonscopy Distant colonoscopy No colonoscopy 0 IBS (n=466) Controls (n = 457) IBS case vs. control Spiegel et al. GE 2005; 62: Cheyet al. AJG 2010; 105: Page 22 of 26

Diagnosis of IBS criteria limited Positive and negative LRs of diagnostic methods for IBS # # of Positive LRs Negative LRs Diagnostic method studies participants 95% CI 95% CI Manning 5 2428 3.04 (1.

23 Diagnosis of IBS criteria limited Positive and negative LRs of diagnostic methods for IBS # # of Positive LRs Negative LRs Diagnostic method studies participants 95% CI 95% CI Manning (1.88) 0.33 (0.18, 0.60) Rome I (3.00, 3.53) 0.14 (0.01, 1.52) Rome II (2.92, 3.48) 0.14 ( ) Rome III (2.97, 3.79) 0.39 (0.34, 0.46) 10-biomarker panel (1.48, 6.23) 0.52 (0.43, 0.64) 34-biomarker panel (1.67, 3.11) 0.30 (0.21, 0.42) Fecal VOMs (8.27, 58.50) 0.21 (0.10, 0.42) Psychological markers (1.98, 4.40) 0.35 (0.26, 0.46) Biomarkers and Psychological markers (2.89, 25.80) 0.18 (0.12, 0.25) Kruis statistical model (3.85, 12.23) 0.26 (0.17, 0.41) Sood et al. APT 2015; 42: Biomarkers may be the future Anti CdtB and Anti Vinculin Validation study of serum biomarker in IBS-D patients (N=2,375) Comparison groups Crohn s disease (n=73) Ulcerative colitis (n=69) Celiac disease (n=121) Healthy subjects (n=43) Anti-CdtB and anti-vinculin titers significantly higher in IBS-D compared with other groups (P<0.001) Accuracy for Diagnosing IBS-D vs. IBD (specific not sensitive) Optical Density Specificity % Sensitivity % CdtB (cutoff 2.80) Vinculin (cutoff 1.68) Food poisoning Bacterial toxin Autoimmunity E. Coli C. jejuni Shigella CdtB, cytolethal distending toxin. Salmonella Pimentel M, et al. PLoS ONE. 2015;10(5):e Cytolethal Distending toxin (CDT B) Anti-vinculin Page 23 of 26

Efficacy of traditional therapy in IBS (none alter the natural history) Treatment quality NNT Evidence Specialized diets?

Am J Gastroenterol 2014; 109: Suppl 1 Diet and IBS FODMAPs = Fermentable Oligosaccharides, Disaccharides, Monosaccharides, and Polyols Lactose intolerance 1 FODMAPs 2,3

amounts), rye (large amounts), onions, leeks, zucchini Apricots, peaches, artificial sweeteners, artificially sweetened gums Lentils, cabbage, brussels sprouts, asparagus,

24 Efficacy of traditional therapy in IBS (none alter the natural history) Treatment quality NNT Evidence Specialized diets? Very low Fiber 10 Moderate Psyllium 7 Moderate Probiotics? Very low Antispasmodics 5 Low Peppermint oil 3 Moderate Alosetron 8 Moderate Antidepressants 4 High Ford et al. Am J Gastroenterol 2014; 109: Suppl 1 Diet and IBS FODMAPs = Fermentable Oligosaccharides, Disaccharides, Monosaccharides, and Polyols Lactose intolerance 1 FODMAPs 2,3 Excess Fructose Honey, apples, pears, peaches, mangos, fruit juice, dried fruit Food intolerances 1 Soluble fiber intake 1 Fructans Sorbitol Raffinose Wheat (large amounts), rye (large amounts), onions, leeks, zucchini Apricots, peaches, artificial sweeteners, artificially sweetened gums Lentils, cabbage, brussels sprouts, asparagus, green beans, legumes 1. Somers SC, Lembo A. Gastroenterol Clin North Am. 2003;32: Shepherd SJ, et al. Clin Gastroenterol Hepatol. 2008;6: Shepherd SJ, Gibson PR. J Am Diet Assoc. 2006;106: Page 24 of 26

25 Low FODMAP vs. Traditional Diet Multicenter, parallel, single blind N = 75; Rome III criteria; 4 weeks Low FODMAP IBS diet (regular meal times, reduced fat & caffeine, lower insoluble fiber, reduced cruciferous vegetables) Food diary and BSFS measured IBS symptom severity scale (IBS SSS) Responder = 50 point drop in IBS SSS Bohn et al, Gastroenterology 2015; 149: evaluable Pts (mean age = 43; 84% women) IBS-SSS decreased in both groups compared to baseline Women and older patients more likely to respond IBS-C less likely to respond Newer and alternative options Treatment Comment (FDA approved*) Linaclotide High quality (IBS C) (NNT 6)* Lubiprostone Moderate quality (IBS C) (NNT 12.5)* Eluxadoline High quality (IBS D) (pancreatitis <1%)* Rifaximin High quality (IBS D)* SCN5A Bile salt binders Ondansetron Histamine 1 blocker IBS D, low quality evidence IBS D, no pain benefit, 1 trial 1 trial (ebastin) Melatonin STW 5 Pain, low quality evidence Iberogast, low quality evidence Ford et al. Am J Gastroenterol 2014; 109: Suppl 1 Page 25 of 26

Take home points Take a history rumination (effortless regurgitation not vomiting ), cyclic vomiting (episodic vomiting), cannabinoid hyperemesis (hot baths), constipation resistant to laxatives (do

Ask about early satiety Consider gastric emptying testing if severe dyspepsia with vomiting, or if considering a tricyclic otherwise no!

26 Take home points Take a history rumination (effortless regurgitation not vomiting ), cyclic vomiting (episodic vomiting), cannabinoid hyperemesis (hot baths), constipation resistant to laxatives (do a rectal pelvic floor must be ruled out) Is it PPI resistant GERD or actually FD? Ask about early satiety Consider gastric emptying testing if severe dyspepsia with vomiting, or if considering a tricyclic otherwise no! If you think it s IBS it probably is at the first consultation colonosopy does NOT replace making a positive diagnosis and reassurance IBS D or is it celiac disease, or microscopic colitis (don t miss them)? New onset IBS C in a postmenopausal female (be alarmed) do not miss ovarian cancer (rare) FD and IBS not all functional low grade inflammation, dysbiosis, and genes relevant the emerging science is opening up new treatment options (cure?) Duodenal eos in FD H. pylori in FD Colonic spirochaetes in IBS Thank you Questions? Page 26 of 26

Functional Dyspepsia

Functional Dyspepsia American College of Gastroenterology Boston Massachusetts, June 2015 Brian E. Lacy, PhD, MD, FACG Professor of Medicine Geisel School of Medicine at Dartmouth Chief, Section of Gastroenterology