Functional Disorders of the Lower GI tract: A Forty Year Clinical Perspective

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Peura, MD, FACP, MACG, AGAF Emeritus Professor of Medicine

Charlottesville, VA Mary 31-year-old Teacher and New Mother

difficult bowel movements per week Straining with defecation

incomplete evacuation Severe abdominal cramping with

enemas, suppositories, stimulant laxatives, 1 hour dedicated

Missing days from teaching due to symptoms Reluctant to go on

1 Functional Disorders of the Lower GI tract: A Forty Year Clinical Perspective David A. Peura, MD, FACP, MACG, AGAF Emeritus Professor of Medicine University of Virginia Health Sciences Center Charlottesville, VA Mary 31-year-old Teacher and New Mother She has a 10-year history of the following symptoms: 4-5 difficult bowel movements per week Straining with defecation Stools are hard and lumpy (type 1 or 2) Sensation of incomplete evacuation Severe abdominal cramping with defecation Treatments Increased fiber intake Bulking agents, enemas, suppositories, stimulant laxatives, 1 hour dedicated bathroom time each morning Effects of symptoms on Q-O-L: Missing days from teaching due to symptoms Reluctant to go on vacation Avoids certain foods she enjoys Feelings of frustration, irritable, occasionally tearful Symptoms impact Q-O-L of her husband and son 1

(continued): Grammie 65-year-old Retired Teacher Moves with Her Husband to Live with their Son and Family Continued but worsening symptoms: 4-5 difficult bowel movements per week Now worse Straining

Florida house Symptoms interfering with her painting hobby Feelings of frustration, and hopelessness Symptoms now impacting her extended family Treatments Increased fiber intake -fanatical Bulking

2 (continued): Grammie 65-year-old Retired Teacher Moves with Her Husband to Live with their Son and Family Continued but worsening symptoms: 4-5 difficult bowel movements per week Now worse Straining with defecation developed rectocele Stools never normal- hard and lumpy Incomplete evacuation and severe cramping with defecation Effects of symptoms on Q-O-L: Reluctant to travel son bought parents Florida house Symptoms interfering with her painting hobby Feelings of frustration, and hopelessness Symptoms now impacting her extended family Treatments Increased fiber intake -fanatical Bulking agents, enemas, suppositories, stimulant laxatives, compulsive medication schedule Dedicated bathroom time each morning (continued) Grandfather 85-year-old Diagnosed with Non-resectable Lung Cancer Large cancer seen on chest X-ray done for chronic coughing On advice of son elected to take no treatment Home hospice and palliative care Terminal pain control with high doses of opiates Severe constipation developed Major impact on the quality of his remaining life Emotionally impacted his family The rest of the story Grammie died 4 years later The family now all grown and successful Son became the 100 th president of the AGA My experiences have allowed me to empathize and communicate more effectively with my patients 2

3 My Forty Year Clinical Journey with Functional Lower GI Disorders 1970s Stress induced /psychological/psychosomatic disorder Abnormal myoelectric activity, abnormal motility Bran, fiber, antispasmodics, laxatives 1980s Hyperalgesia, altered sensation, food sensitivity Behavioral therapy, TCAs, anxiolytics, food elimination, anti-diarrheals 1990s Brain gut interaction, ENS and 5HT receptors 1 st Rome criteria Symptom based diagnosis of FGID, study design Alosetron (5HT3 antagonist), tegaserod (5HT4 partial agonist) 2000s Microbiome host interaction, role of inflammation and tight junctions, visceral hypersenstivity, mast cell activation, serotonin and 5-HT genetic polymorphisms Serum testing for biomarkers Chloride channel activators, antibiotics, probiotics, FODMAP, 5-ASA, oral Ig Functional Lower GI Disorders Symptoms attributable to the mid or lower GI tract Significant overlapping of symptoms May have multiple etiologies Symptom-based classification No structural findings or biochemical markers Chronic disorders Presence of symptoms at least 3 days per month, during last 3 months Onset of symptoms at least 6 months prior to diagnosis IBS = irritable bowel syndrome Constipation IBS Bloating Diarrhea Unspecified Longstreth GF, et al. Gastroenterology. 2006;130:

4 Key Differentiating Factors Among the Functional Lower GI Disorders Disorder Functional constipation Irritable bowel syndrome Functional bloating Functional diarrhea Unspecified FBD Key Differentiating Factors Persistently difficult, infrequent, or incomplete defecation; does not meet IBS criteria Abdominal pain/discomfort associated with change in bowel habits Recurrent sensation of abdominal distention; not part of another FBD Continuous or recurrent syndrome characterized by the passage of loose or watery stools; no abdominal pain Bowel symptoms do not meet criteria for previously defined categories FBD = functional bowel disorder Longstreth GF, et al. Gastroenterology. 2006;130: Functional Lower GI Disorders: Prevalence Disorder Prevalence Gender Prevalence Functional constipation 27% 1 Women (2:1) 2 IBS 10%-20% 1 Women (2:1) 3 Functional bloating (FB) 10%-30% 1 Women (2:1) 4 Functional diarrhea (FD) 4.8% 1 None 1 Unspecified FBD None reported 1 None 1 Women tend to report symptoms and seek medical intervention more often 5 1 Longstreth GF, et al. Gastroenterology. 2006;130: Choung RS, et al. Aliment Pharmacol Ther. 2007;26: Brandt LJ, et al. Am J Gastroenterol. 2002;97(11 suppl):s7-s26. 4 Zar S, et al. Aliment Pharmacol Ther. 2002;16: Locke GR III, et al. Gastroenterology. 2000;119:

Current Understanding of Functional Lower GI Disorders- 3 Components 1. Altered peripheral regulation of gut function (including altered peripheral sensory and secretory mechanisms) 2.

5 Current Understanding of Functional Lower GI Disorders- 3 Components 1. Altered peripheral regulation of gut function (including altered peripheral sensory and secretory mechanisms) 2. Altered brain gut signaling (including visceral hypersensitivity) 3. Psychological distress. Hungin A Neurogastroenterol Motil. 2015; 27:750. Integrating the Three Hypotheses of Functional Lower GI Disorders Hungin A Neurogastroenterol Motil. 2015; 27:750. 5

Postinfectious IBS Approximately 10% of IBS cases are caused by gastroenteritis 1 Gulf War Syndrome Causative organisms 1 : Campylobacter, Shigella, Salmonella, Viral Duration of initial infection is

Most affected individuals can expect to have chronic episodic symptoms like in IBS without infectious onset revalence of IBS (%) Pr *Exposed group experienced recent acute gastroenteritis outbreak;

6 Postinfectious IBS Approximately 10% of IBS cases are caused by gastroenteritis 1 Gulf War Syndrome Causative organisms 1 : Campylobacter, Shigella, Salmonella, Viral Duration of initial infection is the strongest risk factor for the development of PI-IBS 1 : Symptom duration > 3 weeks increases risk 11-fold to develop PI-IBS Consider PI-IBS in previously asymptomatic individuals 1 Prognosis 1 : Most affected individuals can expect to have chronic episodic symptoms like in IBS without infectious onset revalence of IBS (%) Pr *Exposed group experienced recent acute gastroenteritis outbreak; control group was randomly selected with no recent outbreak Prevalence of IBS Postinfection 2 : (Salmonella enteritis acute gastroenteritis) 0 Pre infection 3 months Control group (n = 1201) Exposed* group (n = 677) IBS Control 6 months Postinfection 12 months 1 DuPont AW. Curr Gastroenterol Rep. 2007;9: Mearin F, et al. Gastroenterology. 2005;129: IBS and Small Intestinal Bacterial Overgrowth Criterion: H 2 rise by > 20 ppm by 180 min (LHBT) n = 111 n = 15 n = 39 n = 20 n = 138 n = 22 n = 46 n = 20 Evidence for SIBO is conflicting Antibiotics improve symptoms in some patients but this is usually temporary Colonic rather than SB microbes may be more important in the pathogenesis of symptoms SIBO = small intestinal bacterial overgrowth Spiegel B Clin Gastro and Hepatol 2011;9:461 6

Biomarkers for IBS-D (IBSchek ) Serum from 2681 subjects from 180 centers participating in TARGET-3 study 2

7% Host cell adhesion protein- vinculin- specificity 83.8%%: sensitivity 32.6% Pimentel MPLOS ONE DOI:10.

0126438 May 13, 2015 Alterations in Immunity Mast Cells Increased circulating levels of TNF- α 1 and IL-6 2

Increased activation of mast cells may be most important also a target for therapy Control IBS 1 Bashshati

7 Biomarkers for IBS-D (IBSchek ) Serum from 2681 subjects from 180 centers participating in TARGET-3 study 2 Markers of altered gut flora Cytolethal distending toxin B (CdtB) -specificity 91.6%: sensitivity 43.7% Host cell adhesion protein- vinculin- specificity 83.8%%: sensitivity 32.6% Pimentel MPLOS ONE DOI: /journal.pone May 13, 2015 Alterations in Immunity Mast Cells Increased circulating levels of TNF- α 1 and IL-6 2 Activated intestinal immune response (T cells and macrophages) 3 Increased numbers of mast cells in colon 4 Increased activation of mast cells may be most important also a target for therapy Control IBS 1 Bashshati M. Neurogastrenterol and Motil 2014;26: Dinan TG, et al. Gastroenterology ;130: Piche T, et al. Gut. 2008;57; Barbara G, et al. Gastroenterology. 2004;126:

8 Diagnosing IBS: Symptom Based Criteria (not a diagnosis of exclusion) American College of Gastroenterology IBS Task Force: Abdominal pain or discomfort that occurs in association with altered bowel habits over a period of at least 3 months 1 Rome III Diagnostic Criteria for IBS: Recurrent abdominal pain or discomfort at least 3 days per month in the last 3 months associated with 2 or more of the following* 2 : Improvement with defecation Onset associated with change in stool frequency Onset associated with change in stool form * Criteria fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis 1 Brandt LJ, et al. Am J Gastroenterol. 2009;104(suppl 1):S8-S35. 2 Longstreth GF, et al. Gastroenterology. 2006;130: The Bristol Stool Form Scale Slow Gut Transit Rapid Gut Transit Type 1 Type 2 Type 3 Type 4 Type 5 Type 6 Type 7 Separate hard lumps Sausage-like but lumpy Sausage-like but with cracks in the surface Smooth and soft Soft blobs with clear-cut edges Fluffy pieces with ragged edges, a mushy stool Watery, no solid pieces Lewis SJ and Heaton KW. Scand J Gastroenterol. 1997;32:

9 IBS Subtypes Are Based on the Nature of the Predominant Stool Form Subtype IBS-C IBS With Diarrhea (IBS-D) IBS-Mixed (IBS-M) Unsubtyped IBS (IBS-U) Stool Form 25% hard/lumpy and < 25% watery/loose 25% watery/loose and < 25% hard/lumpy 25% hard/lumpy and 25% watery/loose Insufficient abnormality of stool consistency to meet IBS-C, IBS-D, or IBS-M criteria Stools Percen ntage of Hard or Lumpy IBS-C* IBS-U IBS-M IBS-D Percentage of Loose or Watery Stools *Bristol Stool Form Scale 1-2 Bristol Stool Form Scale 6-7 Adapted from Longstreth GF, et al. Gastroenterology, 2006;130: Diagnostic Testing for IBS: ACG Recommendations Recommended for Routine Use Serology for celiac sprue (IBS-D or IBS-M) Not Recommended for Routine Use Complete blood count (CBC) Serum chemistries Thyroid function studies Stool for ova and parasites Abdominal imaging/colonoscopy Consider lactose hydrogen breath testing in patients who may have lactose maldigestion. Brandt LJ, et al. Am J Gastroenterol. 2009;104(suppl 1):S8-S35. 9

10 Potential Mechanisms of Functional Lower GI Disorders Developed Into Diagnostic Tests Sood,R Nat. Rev. Gastroenterol. Hepatol. 2014; 11: 683 Management of Functional Lower GI Disorders: An Evidenced or Eminenced Based Approach? 10

11 Patient-Health Care Provider: Vicious Cycle Anxiety Hypervigilance Patient Experience Pain Disability Expects cure Urgent visits, requests tests Patient Cognitions Dissatisfaction Pessimism Maladaptive coping Lack of control Health care provider Organic etiology focus Drained biased attitudes Referrals, tests, drugs, surgery, iatrogenic harm, high costs Components of Effective Care of Functional Lower GI Disorders The cornerstone of effective care is a good health care provider patient relationship 1 Nonjudgmental, patient-centered interview may reveal: Stress-related symptoms or comorbid psychologic symptoms Issues that may potentially contribute to illness severity and impaired daily functioning and health-related outcome Patient s understanding of the illness Concern about cancer Worsening pain Patient education Educational information is associated with reduced office visits 2 Advice about diet, exercise, stress, and medications improved IBS symptoms in > 80% of patients after 6 months 3 Assist with self-management strategies; advice for trigger avoidance 1 Involvement of the patient in treatment decisions Establish realistic goals! 1 Videlock EJ and Chang L. Gastroenterol Clin North Am. 2007;36: Owens DM, et al. Ann Intern Med. 1995;122: Colwell LJ, et al. Am J Gastroenterol. 1998;93:

Effective Patient Communication is Key to Successful Management of Functional Lower GI Disorders Hungin A Neurogastroenterol Motil. 2015; 27:750.

products, fructose Poorly absorbed carbohydrates (beans, legumes) Insoluble fiber: bran, cruciferous vegetables (cabbage, broccoli) Fats 60%-70% of sufferers think their symptoms are 3 related to

12 Effective Patient Communication is Key to Successful Management of Functional Lower GI Disorders Hungin A Neurogastroenterol Motil. 2015; 27:750. Treatment of Lower GI Disorders: Dietary Modifications Specific foods may trigger lower GI symptoms 1,2 : Dairy products (lactose) Carbonated beverages, caffeine Artificial sweeteners, sugar-free products, fructose Poorly absorbed carbohydrates (beans, legumes) Insoluble fiber: bran, cruciferous vegetables (cabbage, broccoli) Fats 60%-70% of sufferers think their symptoms are 3 related to food sensitivity 3 ACG: insufficient evidence that food allergy testing or exclusion diets are efficacious in functional lower GI disorders 3 1 Wilson JF. Ann Intern Med. 2007;147:ITC7-1-ITC Foxx-Orenstein AE and Clarida JC. J Am Osteopath Assoc. 2001;101(12 suppl pt 2):S12-S16. 3 Brandt LJ, et al. Am J Gastroenterol. 2009;104(suppl 1):S8-S35. 12

High FODMAP Foods by Type of FODMAP Psychological Therapies May Reduce Lower GI Symptoms 32 Twenty 6- to 12-week randomized controlled trials compared psychological l therapies to sham therapy or

13 High FODMAP Foods by Type of FODMAP Psychological Therapies May Reduce Lower GI Symptoms 32 Twenty 6- to 12-week randomized controlled trials compared psychological l therapies to sham therapy or usual management in 1278 IBS patients 1 ACG IBS Task Force recommended cognitive behavioral therapy, dynamic psychotherapy, py hypnotherapy, py and multicomponent therapy 2 Relative Risk (RR) of global IBS symptom persistence 1 95% confidence interval (CI) Greene 1994 Payne 1995 Vollmer 1998 Boyce 2003 Drossman 2003 Tkachuk 2003 Kennedy 2005 Cognitive behavioral therapy Hypnotherapy Multi-component psychological therapy Dynamic psychotherapy Galovski 1998 Simren 2004 Blanchard 1992 Neff 1987 Blanchard 1992 Heitkemper 2004 Guthrie 1991 Creed Ford AC, et al. Gut. 2009;58: Brandt LJ, et al. Am J Gastroenterol. 2009;104(suppl 1):S8-S Favors treatment Favors control 13

14 Factors That Influence Composition of Gut Microbiota Bennet S Gut Liver 2015;9:318 Possible Host-microbiota Interactions in Patients with Functional GI Disorders Bennet S Gut Liver 2015;9:318 14

Serum-derived Bovine Immunoglobulin (SBI [EnteraGam ]) in IBS-D Statistically significant results have listed p-values and average change ( ) For 5 g group, reduction in

2013; 6:49 Probiotics in Functional Lower GI Disorders 1) Physical barrier 2) Altered epithelial surface glycosylation pattern 3) Increased mucin production 4) Secretion

Basolateral side ACG IBS Task Force as well as recent Cochrane review suggested that combinations of probiotics demonstrated efficacy in IBS Increasingly used in patients

15 Serum-derived Bovine Immunoglobulin (SBI [EnteraGam ]) in IBS-D Statistically significant results have listed p-values and average change ( ) For 5 g group, reduction in incomplete evacuation was also significantly reduced (not shown above) Wilson D, Clin Med Insights Gastroenterology. 2013; 6:49 Probiotics in Functional Lower GI Disorders 1) Physical barrier 2) Altered epithelial surface glycosylation pattern 3) Increased mucin production 4) Secretion of antimicrobial peptides 5) Modulation of the immune system Probiotic bacteria Pathogenic bacteria Antimicrobial peptides 2 1 Luminal side Nucleus Epithelial cell Basolateral side ACG IBS Task Force as well as recent Cochrane review suggested that combinations of probiotics demonstrated efficacy in IBS Increasingly used in patients in whom conventional therapy has failed 3 Borowiec AM and Fedorak RN. Curr Gastroenterol Rep. 2007;9: Brandt L Am J Gastroenterol, 2009;104 (Suppl 1) pp. S1 Ford A Am J Gastroenterol. 2014;109: TNF-α, IFN-γ, IL-8 IL

16 Receptors and Channels Involved in Visceral Pain Arcela de Carvalho Rochaa H, Ann Gastroenterol 2014; 27: 200 Effect of Antidepressants in IBS Ford A Am J Gastroenterol 2014;109:

Pharmacologic Options Commonly Used to Treat IBS by Subtype IBS-C 1-3 Bulking agents, laxatives, lubiprostone, Linaclotide IBS-D 1,2,4,5 IBS-M 1-3 Antidiarrheals, antibiotics (rifaximin), bile acid

selective serotonin reuptake inhibitors (SSRIs) 2 * Infrequent but serious GI adverse events have resulted in hospitalization, and, rarely, blood transfusion, surgery, and death 6 1 Wilson JF.

Neurogastroenterol Motil. 2005;17:311-316. 5 Castiglione F, et al. Ital J Gastroenterol. 1991;23(suppl 1):53-55. 6 Physicians Desk Reference. 61st ed. Montvale, NJ: Thomson PDR; 2007.

17 Pharmacologic Options Commonly Used to Treat IBS by Subtype IBS-C 1-3 Bulking agents, laxatives, lubiprostone, Linaclotide IBS-D 1,2,4,5 IBS-M 1-3 Antidiarrheals, antibiotics (rifaximin), bile acid sequestrants (cholestyramine), tincture of opium, alosetron *,ondansetron Symptomatic treatment of constipation and diarrhea For abdominal pain: antispasmodics, tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs) 2 * Infrequent but serious GI adverse events have resulted in hospitalization, and, rarely, blood transfusion, surgery, and death 6 1 Wilson JF. Ann Intern Med. 2007;147:ITC7-1-ITC Videlock EJ and Chang L. Gastroenterol Clin North Am. 2007;36: Chey WD and Cash BD. Curr Gastroenterol Rep. 2006;8: Camilleri M. Neurogastroenterol Motil. 2005;17: Castiglione F, et al. Ital J Gastroenterol. 1991;23(suppl 1): Physicians Desk Reference. 61st ed. Montvale, NJ: Thomson PDR; Eluxadoline (VIBERZI ) for IBS-D Approved May 2015 mixed mu (μ) opioid receptor agonist / delta (δ) opioid receptor antagonist Pancreatitis (0.2%) and SOD (0.4%) ETOH and CCY risk factors Nausea and constipation in ~ 8% 17

Peppermint Oil (IBgard ) for IBS Hot Topics in Functional Lower GI Disorders The Next Few Years Role of celiac disease and non celiac gluten sensitivity

Mucosal - mast cell numbers and location, cytokines Intestinal permeability urine excretion of mannitol and lactulose Manipulation of microbiota Probiotics,

18 Peppermint Oil (IBgard ) for IBS Hot Topics in Functional Lower GI Disorders The Next Few Years Role of celiac disease and non celiac gluten sensitivity Biomarkers for diagnosis Fecal - calprotecten,, fecal bile acids, granins, proteases, VOMs Serum - CRP, gene expression microarray and biologic marker panel Mucosal - mast cell numbers and location, cytokines Intestinal permeability urine excretion of mannitol and lactulose Manipulation of microbiota Probiotics, prebiotics, symbiotics and antibiotics Serum-derived bovine immunoglobulin New pharmacologic agents targeting ti ghrelin, opiate, neurokinin i and H 1 receptors Diet FODMAP 18

Diagnosis and Management of Irritable Bowel Syndrome (IBS) For the Primary Care Provider

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