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Community Health Education Seminar

Diarrhea After Eating The Argument for Intermittent Maldigestion Condition and not just “Irritable Bowel Syndrome-Diarrhea” March 22, 2011 M. E. Money, M.D., FACP Clinical Associate Professor Department of Medicine University of Maryland School of Medicine Office 354 Mill Street

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Community Health Education Seminar

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  1. Diarrhea After Eating The Argument for Intermittent Maldigestion Condition and not just “Irritable Bowel Syndrome-Diarrhea” March 22, 2011 M. E. Money, M.D., FACP Clinical Associate Professor Department of Medicine University of Maryland School of Medicine Office 354 Mill Street Hagerstown, MD 301-797-0210 Community Health Education Seminar

  2. Brief Overview IRRITABLE BOWEL SYNDROME M. E. Money. M.D.

  3. IBS is a functional bowel disorder in which abdominal pain or discomfort is associated with defecation or a change in bowel habit. Bloating, distension, and disordered defecation are commonly associated features. Irritable bowel syndrome: a global perspective. World Gastroenterology Organizational Global Guideline. April 20, 2009 Definition of IBS M. E. Money. M.D.

  4. Diagnostic Criteria (Rome III) • Onset of symptoms at least 6 months before diagnosis • Recurrent abdominal pain or discomfort for >3 days per month during the past 3 months • At least two of the following features: • Improvement with defecation • Association with a change in frequency of stool • Association with a change in stool form NB: What precedes the symptoms is not included. WGO Practice Guidelines Irritable bowel syndrome 2009 M. E. Money. M.D.

  5. Sub Types of IBS IBS-Diarrhea 33% IBS-Constipation 32% IBS-diarrhea and constipation 35% Executive Summary: IBS in Women: The Unmet Needs. Society for Women’s Health Research. 2003 M. E. Money. M.D.

  6. Mainstream concepts about IBS • Exact cause of irritable bowel syndrome not known. • Multiple factors thought to contribute to etiology. • To date an 'IBS gene' has not been identified. • The concept of IBS as a diagnosis of exclusion is “not acceptable any more”. • The treatment of IBS is targeted at symptom relief. • Cognitive behavioral therapy is very beneficial. M. E. Money. M.D.

  7. Precipitating Factors Acute and chronic stress (life events) History of abuse Infection and inflammation Bacterial flora and small bowel bacterial overgrowth Intestinal gas and motility Predisposing, and precipitating factors for irritable bowel syndrome Predisposing factors • Genetic predisposition • Early life experiences • Intergenerational transmission of illness behavior • Gender M. E. Money. M.D.

  8. Perpetuating factors for irritable bowel syndrome • Maladaptive coping • Poor social support • Psychological co-morbidity • Somatization disorder • Depression • Anxiety • Panic Disorder Gastrointestinal Disorders: Irritable Bowel Syndrome. Journal of Clinical Outcomes Volume 1 (4). 2007 M. E. Money. M.D.

  9. Irritable bowel syndrome impact • Estimated: 15 Million people in the U.S. • Prevalence 10-20% of adults • $2 Billion in direct annual costs • $20 Billion in indirect annual costs • Estimated only 1/3 patients seek medical attention for condition. Laudanum, U. Irritable Bowel Syndrome. Advanced Studies in Medicine. Vol. 4, No. 3. March 2004. Pages 128-134. Executive Summary: IBS in Women: The Unmet Needs. Society for Women’s Health Research.2003. M. E. Money. M.D.

  10. Antispasmodics Lactase supplementation Antibiotics Serotonin modulators Antidiarrheals drugs (Lomotil, etc) Deodorized tincture of opium Mainstream treatment options for IBS-Diarrhea • Antidepressants • Anticholinergics (Bentyl, Levsin, etc) • Bulking agents (metamucil, etc) • Chinese Herbal therapies • Cholestyramine M. E. Money. M.D.

  11. Treatment options conclusion in Prescire International 2009 “There is currently no way of radically modifying the natural course of recurrent irritable bowel syndrome” • Patients frequently complain of occasional bowel movement disorders, associated with abdominal pain or discomfort, but they are rarely due to an underlying organ involvement. Even when patients have recurrent symptoms, serious disorders are no more frequent in these patients than in the general population, unless other manifestations, anemia, or an inflammatory syndrome is also present; Irritable bowel syndrome: a mild disorder; purely symptomatic treatment. Prescrire.Int. 18(100), 75-79. 2009 M. E. Money. M.D.

  12. Accuracy of symptom-based criteria for diagnosis of IBS in primary care1 Reviewed 25 primary diagnostic studies. 2 research questions: Performance of symptom-based criteria in excluding organic GI disease. Performance of signs and symptoms in identifying IBS Conclusion: “organic disease cannot be accurately excluded by symptom-based IBS criteria alone.” 1Jellema, P. et al. Systematic review: accuracy of symptom-based criteria for diagnosis of irritable bowel syndrome in primary care. Alimentary Pharmacology & Therapeutics. 7-3-09. DOI: 10.1111/j.1365-2036 M. E. Money, MD

  13. In September 2001, one of my patients came in “demanding” that I prescribe something to help with her diarrhea that would occur after she ate out in restaurants with her family By that time, I had given pancreatic enzymes to 2 patients in my practice for after meal diarrhea due to surgery on the pancreas with good results and decided to give it to her as a “clinical experiment.” She returned 4 weeks later, reporting that “1 pill before the meal worked just fine”, 4 made her constipated. By Christmas, I had prescribed it to another 10 individuals and all but one had complete symptom relief. How did this research get started? M. E. Money, M.D

  14. By Christmas, I had also researched the current recommendations for IBS-D and had discovered pancreatic enzymes were not mentioned. I had also checked with 2 specialists to assure there was no harm in using enzymes, and decided to do my own study comparing pancreatic enzymes to placebos. The study was approved by the Washington County Review Board in January 2002 and the first patients were enrolled in February. It concluded in 2003. 49 patients enrolled, 10 dropped out, and 25/39 who did participate “picked” the enzymes as the effective agent. How did this research get started? M. E. Money. M.D

  15. DOUBLE BLIND, PLACEBO CONTROLLED TRIAL USING PANCREATIC ENZYMES Effectiveness of PAncreatic EnZyme in Reduction of IrritAble Bowel Syndrome (IBS) Symptoms “PAZAS” Hypothesis • Symptoms of post prandial IBS-D are due to maldigestion and/or malabsorption of certain foods, thus causing the abdominal symptoms including diarrhea for some patients. Approved by WCH IRB 2/01, completed 11/03 M. E. Money. M.D.

  16. PAZAS Inclusion Criteria Meet the Rome II Criteria • Be at least 18 and willing to give written informed consent, • Have onset of symptoms before the age of 50 • Have symptoms occurring postprandial greater than 90% of the time within 3 hours of the trigger food/meal. Ideally should be able to identify some of the foods/spices/ or types of meals that precipitate the symptoms. (i.e. restaurant dining, Italian, Chinese, specific foods, lactose based*). • *Participants must have at least one other food/spice that causes symptoms in addition to Lactose based foods. • Be willing to comply with all of the study protocol. • Have had a normal Colonoscopy or barium enema within the same time period of current symptoms. • Have had IBS postprandial symptoms for greater than 5 years. M. E. Money. M.D.

  17. Methodology Study stages: 1. Patients consumed 6 trigger meals recording symptoms (baseline) 2. Consumed same meals with blinded capsule. 3. Wash out period 2 weeks. 4. Consumed same meals with second blinded capsule. 5. Picked either drug 1 or 2 to use for another 25-50 meals. 6. Unblinded to patient only after patient completed study; unblinded to staff at study conclusion. M. E. Money. M.D.

  18. Symptoms evaluated and scoring SYMPTOMPOINTS POSSIBLE Cramping 0-10 Bloating. 0-10 Borborygami (gurgling, noises, churning) 0-10 Nausea 0-10 Intensity of the urge to have a bowel movement 0-10 Other symptoms (sweating, chills, weakness) 0-10 Global pain intensity 0-10 Number of Bowel Movements after eating the meal (1 point for each BM) Pilot study: a randomised, double blind, placebo controlled trial of pancrealipase for the treatment of postprandial irritable bowel syndrome-diarrhoea. Money, ME; Walkowiak,J; Virgilio,C.; Talley, NJ;Frontline Gastroenterology.2011;2:48–56. M. E. Money. M.D.

  19. Summary of results Total number of patients enrolled in study: 49 Number of patients who dropped out: 10 Number of patients who selected Enzymes as the “effective agent” after trying both capsules: 25 Number of patients who selected placebo as the “effective agent”: 10 In an intention to treat analysis, overall, 30/49 (61%) would have chosen enzymes (p=0.078) Pilot study: a randomised, double blind, placebo controlled trial of pancrealipase for the treatment of postprandial irritable bowel syndrome-diarrhoea. Money, ME; Walkowiak,J; Virgilio,C.; Talley, NJ;Frontline Gastroenterology.2011;2:48–56. M. E. Money. M.D.

  20. Subset Analysis of Enzyme Patients Preliminary Results I M. E. Money. M.D.

  21. Subset Analysis of Enzyme Patients Preliminary Results II M. E. Money. M.D.

  22. Subset Analysis of Enzyme Patients Preliminary Results III M. E. Money. M.D.

  23. Quality of Life (QOL) survey Patients were asked to score how each of 34 questions applied to their quality of life before and at conclusion of study. 0-Not at all, 1-slightly, 2-moderately, 3-quite a bit, 4-a great deal, extremely. Used with the permission of  Dr. D. L. Patrick, University of Washington. M. E. Money. M.D.

  24. Examples of QOL questions • I feel helpless because of my bowel problems. • I feel like I’m losing control of my life because of my bowel problems. • I feel depressed about my bowel problem. • I feel isolated from others because of my bowel problems. • Long trips are difficult for me because of my bowel problems. • My bowel problems are affecting my closest relationships. M. E. Money. M.D.

  25. QOL statistical analysisStudy enzyme subgroup Statistical T-test Procedure “p” values comparing QOL scores at baseline and end of study Helpless p <.0001 Losing control of life <.0001 Depressed .0002 Worry <.0001 Avoid stressful situations .0065 Affecting closest relationships .0062 M. E. Money. M.D.

  26. Effectiveness of pancreatic enzymes A retrospective review was recently completed of all of the patients in my practice who had the diagnosis of IBS and had been treated by me from 2001-2010 to evaluate the effectiveness of the enzymes. 278 patients had received a diagnosis of spastic colon or IBS • 134 excluded since they had been treated by another practitioner • 144 seen by me, and 104 had been offered PEZ • 86/104 patients returned for follow-up, and 82.5% (71) reported positive improvement M. E. Money. M.D.

  27. Examples of Food Triggers Among 49 “users” M. E. Money. M.D. UMD GI Grand Rounds

  28. Example of new patient • 43 yr female seen by me as a new patient 7/24/09 • History: Complains of intermittent increased loose stools after meals for 11 yrs, sometimes at night if eats late. She wonders if she has IBS. Symptoms may last for weeks once it gets started, otherwise only when eats out in restaurants. Worse with spicy foods, onions, garlicky Italian meals and tomatoes. • Exam entirely normal. 64” tall, 161# • Chronic medical problems other than above: Asthma • Current meds: Zyrtec, Advair Diskus, Ventolin inhaler • Mother has similar digestion problem. • Patient had never had a colonoscopy. 28 M. E. Money. M.D.

  29. New patient continued • Patient referred to gastroenterologist who wrote: “Patient states she has cramping, watery diarrhea alternating with constipation, up to 10x/day, mild in nature…..symptoms are suggestive of IBS.” • Investigation by gastroenterologist: • Colonoscopy negative • X-rays for the stomach and small intestine were normal • Blood tests for Celiac disease was normal • Biopsy of colon negative for pathology • Treatment: Patient encouraged to try probiotics by gastroenterologist. M. E. Money. M.D.

  30. New patient continued Additional testing ordered by me: • Stool for fat: SMALL amount (8/19/09) • Fecal elastase-1: 487 (normal >200) (test for pancreatic insufficiency) • Patient seen 9/4 in office. Probiotics tried by patient but did not prevent post restaurant dining diarrhea. I therefore gave the patient some samples of prescription pancreatic enzymes to try before restaurant meal or “triggers”. They worked with the first meal! • Current treatment: Pancreatic Enzymes before “trigger” meals eliminates both the abdominal pain and diarrhea. M. E. Money. M.D.

  31. Why do the enzymes work? For the last 8 years, I have pursued trying to figure out why the pancreatic enzymes work. This presentation will focus on my current hypothesis and why making the diagnosis of “irritable bowel syndrome-diarrhea” may limit further research into this condition. M. E. Money. M.D.

  32. Pancreatic Enzymes • Composition: Amylase, Lipases, Proteases, Co-lipases, other enzymes • Known Action • Initiates digestion of carbohydrates, lipids and proteins in the stomach • Amylase potentiates the action disaccharidases by 10-20x. (Quezada-Calvillo, R. et al. Contribution of Mucosal Maltase-Glucoamylase Activities to Mouse Small Intestinal Starch α-Glucogenesis. Journal of Nutrition. 137:1725-1733, 2007 M. E. Money. M.D. UMD GI Grand Rounds

  33. Sub types of IBS IBS-Diarrhea 33% IBS-Constipation 32% IBS-diarrhea and constipation 35% Executive Summary: IBS in Women: The Unmet Needs. Society for Women’s Health Research. 2003 M. E. Money. M.D.

  34. Incidence of diarrhea occurring after eating 50% of patients suffering with the diarrhea or mixed form of IBS related symptoms to eating. However, the current definition of IBS does not encourage nor require the physician to inquire about any precipitating factor such as the condition occurring ONLY after eating. M. E. Money. M.D.

  35. Differential diagnosis for IBS • Celiac Sprue/gluten enteropathy • Lactose intolerance (inherited or 2nd to mucosal damage) • Inflammatory bowel disease • Colorectal carcinoma • Lymphocytic and collagenous colitis • Acute diarrhea due to protozoa or bacteria • Small-intestinal bacterial overgrowth (SIBO) • Diverticulitis • Endometriosis • Pelvic inflammatory disease • Ovarian cancer • WGO Practice Guideline IBS 2009 M. E. Money. M.D.

  36. What is missing from this differential diagnosis? 1. Bile acid malabsorption diarrhea 2. Pancreatic insufficiency 3. Carbohydrate Malabsorption • Alpha glucosidases (disaccharidases) deficiencies (maladigestion of starches) • Congenital sucrase-isomaltase deficiency • Fructase deficiency • ? Possible disaccharidase inhibition M. E. Money. M.D.

  37. Bile acid malabsorption • Bile acid malabsorption can occur in patients with or without an intact gall bladder • Bile acid malabsorption(BAM) may affect up to 30-50% of patients with chronic diarrhea • Can be treated with bile acid binding agents: Welchol, Cholestyramine, Questran • Diagnosis by measurement of serum 7alphaC4 (not available for routine testing) M. E. Money. M.D

  38. Diarrhea predominant IBS (IBS-D): fact or fiction • Dr. Saad Habba, gastroenterologist in NY, analyzed all patients seen by him over the last 8 yrs for “IBS-D”. • 575 patients seen, only 303 patients completed all of the studies. Of these 303 patients, 204 (68%) responded to bile acid binding agents with resolution of diarrhea. Diarrhea Predominant Irritable Bowel Syndrome-Diarrhea: Fact or Fiction. Habba,S., Medical Hypotheses 76(2011) 97-99. M. E. Money. M.D

  39. Pancreatic insufficiency Pancreatic insufficiency was found in 6.1% (19/314) patients who had been diagnosed as having IBS-D by the Rome Criteria. This was determined by the measurement of the fecal elastase-1 concentration in the stool. Patients were then treated with pancreatic enzyme supplements with a statistical improvement in stool frequency, consistency, and abdominal pain. Some Patient With Irritable Bowel Syndrome May Have Exocrine Pancreatic Insufficiency. Leeds, J et al, Clinical Gastroenterology and Hepatology 2010; 8:433-438. M. E. Money. M.D

  40. Carbohydrate malabsorption “Carbohydrate malabsorption and intolerance is suggested by the patient’s clinical history. The relation of symptoms to feeding and the occurrence of remission while fasting are crucial to the history. In older children and adults the symptoms can resemble those of dyspepsia or irritable bowel syndrome (IBS)…The diagnosis of functional bowel disease usually is made without evaluation of carbohydrate digestion… symptoms from IBS and carbohydrate intolerance can be confused easily”. Disaccharide Digestion: Clinical and Molecular Aspects. Robayo-Torres, C. et al; Clinical Gastroenterology and Hepatology. 2006;4:276-287 M. E. Money. M.D.

  41. 1° Lactose malabsorption • Frequency: Isolated deficiency in 16-24% of patients with IBS and in 12% of patients with functional bowel complaints. (Autosomal recessive, C>T 13910, Intron 13 or MCMG 6 gene.) • Is usually combined with fructose, sorbitol, glucoamylase, sucrase, and maltase deficiency among patients with functional GI complaints. • Disaccharide Digestion: Clinical and Molecular Aspects. Robayo-Torres, C. et al; Clinical Gastroenterology and Hepatology. 2006;4:276-287 M. E. Money. M.D.

  42. Disaccharide Maldigestion Due to alpha-glucosidase(s) deficiency Symptoms after the ingestion of carbohydrates (lettuce, beans, corn, etc) Abdominal pain Cramps Urgent diarrhea Time of onset: variable depending upon quantity and sensitivity of patient Carbohydrate malabsorption syndromes 1° Lactose Maldigestion • Due to Lactase deficiency, (a beta-glucosidase) • Symptoms after the ingestion of milk products: • Abdominal pain • Cramps • Urgent diarrhea • Time of onset: variable depending upon quantity and sensitivity of patient M. E. Money. M.D.

  43. Initial hydrolysis of starches begin with the action of amylase from the saliva. 95% of starches are not broken down until they reach the small intestine where pancreatic amylase breaks the starch into smaller units: maltose, maltotriose, and limits dextran size. Digestion of starches M. E. Money. M.D.

  44. Further hydrolysis of carbohydrates after amylase involves the brush border disaccharidases also known as “alpha-glucosidases:” Maltase Isomaltase Sucrase Trehalase Gluco-amylase Digestion of disaccharides:alpha-glucosidases M. E. Money. M.D.

  45. Alpha-glucosidase inhibition Drugs: Acarbose ( a diabetic medication to reduce absorption of carbohydrates by preventing absorption). Side effect: >30% patients experience diarrhea Spices and foods: >1000 known to affect a-glucosidases Examples: Clove extract Quercetin (found in onions, 5x more potent than acarbose) Some spices >1000x more potent than acarbose (verbal report Dr. Buford Nichols) Bacterial Overgrowth M. E. Money. M.D.

  46. Sucrase-isomaltase deficiency in adults and varied symptoms Sucrose-Isomaltose Malabsorption in an Adult Woman (Sonntag, W. M. et al, 1964, Gastroenterology 47:18.) 20 Greenlandic Eskimos found to have sucrose malabsorption 8 adults, only 1 with symptoms (McNair, et al. 1972, Sucrose malabsorption in Greenland, Br. Med J. 2:19.) Ringrose (1980): 13 adult patients with bx proven SI def. 5 had persistant or intermittent symptoms since childhood 2 symptoms in childhood, disappeared again until 20; 40. 3 symptoms first appeared in first or second decade. (1980, Dig. Dis. Sci. 25:384) Gudmand-Hayer (1985) Studied 31 children, and 12 adults hospitalized in Greenland. Of the 12 adults, 8 had a “long-lasting history of chronic diarrhea and abdominal complaints”. M. E. Money. M.D.

  47. Sucrase-isomaltase and glucoamylase deficiency in children 1-2% of children with severe diarrhea from birth are found to have an inherited sucrase-isomaltase disaccarhidase deficiency Recent research by Dr. Buford Nichols (Baylor College, Houston, Texas) in collaboration with Dr. Susan Baker ( Woman and Children Hospital of Buffalo, NY ) have found 26% of children with digestion symptoms have difficulty digesting starch due to a deficiency of glucoamylase. M. E. Money. M.D.

  48. More support for maldigestion as possible cause of diarrhea A very low-carbohydrate diet improves symptoms and quality of life in IBS-D patients. 2009 Prospective Study 17 enrolled with moderate to severe IBS-D Initially had 2 weeks of standard diet, then 4 weeks of very low (20gm carbohydrate/day). 13 completed the study. 10 (77%) reported adequate relief for all 4 weeks on the low carb diet; stool number decreased, QOL improved, and decrease in pain. Clin Gastroenterol Hepatol. Austin, GL; Dalton, CB; et.al. 2009 June; 7(6) 706-708.el.doi:10.10167/j.cgh.2009.02.023 M. E. Money. M.D.

  49. More support for maldigestion as possible cause of diarrhea In Indonesia, biopsies taken from the small intestine were examined for concentration of Lactase, Sucrase, and Maltase from 13 patients with chronic diarrhea, and compared to biopsies from 34 patients with “dyspepsia”. Results: All of enzyme concentrations from the patients with chronic diarrhea were statistically lower than those with dypepsia. Examination of small bowel enzymes in chronic diarrhea. J Gastroenterol Hepatol. Simadibrata, m., et al.18(1): 53-6. M. E. Money. M.D.

  50. Working hypothesis Diarrhea occurring after meals may actually be a subclinical form of inherited or acquired maldigestion, possibly related to a bile acid malabsorption or a mild deficiency, relative ineffectiveness or suppression of one or more enzymes: amylase, lipase, the disaccharidases, or others. M. E. Money. M.D.

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