Contemporary Management of Functional Dyspepsia


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Contemporary Management of Functional Dyspepsia

  1. 1. Contemporary Management of Functional Dyspepsia This educational program, approved by the Canadian Association of Gastroenterology, is sponsored by an unrestricted educational grant from JANSSEN-ORTHO Inc.
  2. 2. Learning Objectives <ul><li>Review the definition and presentations of dyspepsia </li></ul><ul><li>Understand dyspepsia and its differential diagnosis </li></ul><ul><li>Rationalize testing for dyspepsia </li></ul><ul><li>Choose an optimal therapeutic approach for dyspepsia </li></ul>
  3. 3. Definitions and Epidemiology of Dyspepsia
  4. 4. Dyspepsia - Definition <ul><li>A group of symptoms which alert clinicians to consider disease of the upper gastrointestinal tract </li></ul>(British Society of Gastroenterology, 1996)
  5. 5. Epidemiology of Dyspepsia <ul><li>Randomly selected 1036 adults across Canada </li></ul><ul><li>Examined </li></ul><ul><li>1. Severity of dyspepsia symptoms 2. Quality of life </li></ul>DIGEST, 1996: The Domestic/International Gastrointestinal Disease Study. Canadian Highlights
  6. 6. Overall Prevalence of Dyspepsia in Canada (DIGEST, 1996) British Columbia Prairie Provinces Ontario Quebec Atlantic Provinces 25% 30% 29% 27% 30%
  7. 7. Dyspepsia in Canada: Sample Breakdown * Less than 1 Month (DIGEST, 1996) Total Sample No dyspepsia 71% Dyspepsia 29% Acute* dyspepsia 6.5% Chronic dyspepsia 22.5%
  8. 8. Social Impact of Dyspepsia 0 10 20 30 40 50 60 70 Not At All Slightly Moderately Quite A Lot Extremely Extent to which dyspepsia has interfered with normal social activities (DIGEST, 1996)
  9. 9. Quality-of-Life Score (Psychological General Well Being Index) Anxiety Positive Depressed Self General Vitality Well Being Mood Control Health Domain (DIGEST, 1996) Subjects with no dyspepsia Subjects with chronic dyspepsia
  10. 10. Functional Dyspepsia - Definition <ul><li>Chronic or recurrent upper GI symptoms not explained by biochemical or structural abnormalities (does not imply that there is no physiological basis) </li></ul><ul><li>Appropriate evaluation using standard diagnostic tests reveals no abnormalities </li></ul><ul><li>Also known as nonulcer dyspepsia, essential dyspepsia, idiopathic dyspepsia </li></ul>(Talley N. Scand J Gastro 1991;182:7)
  11. 11. Dyspepsia Functional Dyspepsia Non-GI Causes of Symptoms (cardiac disease, muscular pain, etc.) Structural Dyspepsia (GERD, PUD, pancreatic disease, gallstones, etc.)
  12. 12. Symptoms of Functional Dyspepsia Ulcer-like Dominant Dysmotility-like Dominant Nocturnal pain Localized epigastric burning Better with food Heartburn Retrosternal burning Nausea Bloating Early satiety Worse with food
  13. 13. Major Causes of Dyspepsia Williams 1988 Stanghellini 1996 Heikkinen 1996 (n=1386) (n=1057) (n=766) % of Patients with Diagnosis Gastric Cancer Peptic Ulcer Esophagitis/ Functional GERD Dyspepsia
  14. 14. Pathophysiology of Functional Dyspepsia
  15. 15. What are the possible causes of functional dyspepsia? <ul><li>Altered enteric visceral perception (hyperalgesia) </li></ul><ul><li>Altered enteric motor function </li></ul><ul><li>Altered CNS function </li></ul><ul><li>Helicobacter pylori </li></ul>
  16. 16. Pathogenesis & Pathophysiology of Dyspepsia <ul><li>Increased visceral perception </li></ul><ul><li>Altered motility </li></ul><ul><li>Behavioural factors </li></ul><ul><li>Gastritis </li></ul><ul><li>H. pylori infection </li></ul>
  17. 17. Mechanisms Underlying Increased Sensory Perception <ul><li>Increased sensory input </li></ul>Reduced descending inhibition
  18. 18. Mechanisms Underlying Altered Motility in Dyspepsia <ul><li>Stress </li></ul><ul><li>Behavioural Factors </li></ul><ul><li>Decreased antral motility </li></ul><ul><li>Impaired fundal relaxation </li></ul>Abnormal Motility Local Factors: Gastritis H. pylori infection
  19. 19. Putative Pathogenesis of Dyspepsia Stress Increased Sensitivity Increased Afferent Activity ANS Imbalance Impaired Motor Activity Accommodation Altered Motor & Sensory Function DYSPEPSIA Low Grade Inflammation ± HP Infection Sensory Inhibition Sensitivity . . .
  20. 20. Altered Enteric Visceral Perception (Hyperalgesia) in Functional Dyspepsia
  21. 21. Proposed Mechanisms of Hyperalgesia Role of Inflammation Mucosa Lamina propria Neuromuscular layer Acute Inflammation Immune Activation “ Normal” Altered Neuromuscular Function Resolution Persistent Altered Neuromuscular Function In some (Genetic) Irritation or Infection
  22. 22. Proposed Mechanisms of Hyperalgesia <ul><li>Endoscopic evidence of gastritis in some patients </li></ul><ul><li>Increased mast cells in the lamina propria in some patients </li></ul><ul><li>Some patients have infection with Helicobacter pylori </li></ul>Is there evidence of inflammation in functional dyspepsia? Hypothesis: Low-grade inflammation can cause altered motor function, and altered sensitivity
  23. 23. Proposed Mechanisms of Hyperalgesia Normal Pathways Spinal Cord - ANS. Input 2nd order neurons Dorsal horn nucleus Dorsal root ganglion Sensory nerve endings in gut Pain Perception Cortex Descending inhibitory fibres
  24. 24. Peripheral Hyperalgesia Hyperplasia of D.R.G. Hyperplasia of D.H.N. Irritation or Low Grade Inflammation Recruitment of “silent” sensory fibres - Amplification Amplification Amplification Proposed Mechanisms of Hyperalgesia Traffic
  25. 25. Central Hyperalgesia Pain Peripheral Signals Loss of Descending Inhibition Proposed Mechanisms of Hyperalgesia
  26. 26. Spinal Cord Descending inhibitory fibres - ANS. Input 2nd order neurons Dorsal horn nucleus Dorsal root ganglion Sensory nerve endings in gut Pain Perception Cortex Drug Effects on the CNS-Enteric Nervous System Pharmacological Options  opiates, tricyclics 5HT 3 antagonists Clonidine  opiates 5HT 3 antagonists Substance P CGRP antagonists NSAIDs  opiates 5HT 3 antagonists Proposed Mechanisms of Hyperalgesia
  27. 27. Visceral Hyperalgesia in Functional Dyspepsia <ul><li>Patients with functional dyspepsia have normal somatic pain perception </li></ul><ul><li>Visceral sensation is diffusely altered in functional dyspepsia, based on balloon distension studies in stomach, esophagus, and rectum </li></ul>(Trimble K. Dig Dis Sci 1995;40:1607)
  28. 28. Visceral Hyperalgesia in Functional Dyspepsia Volume of Gastric Distension (mLs) (Bradette M. Dig Dis Sci 1991;36:52) p < 0.005 p = 0.001 Controls (n=10) Patients with functional dyspepsia (n=10)
  29. 29. Altered Enteric Motor Function in Functional Dyspepsia
  30. 30. Upper GI Motility in Functional Dyspepsia <ul><li>Impaired reflex fundal relaxation </li></ul><ul><li>Impaired gastric compliance/receptive relaxation to food ingestion </li></ul><ul><li>Weak postprandial antral contractions </li></ul><ul><li>Delayed gastric emptying </li></ul><ul><li>Small bowel motor dysfunction </li></ul>
  31. 31. Upper GI Motility in Functional Dyspepsia Abnormal Fundic Relaxation in Response to Meal in Functional Dyspepsia Normal Impaired fundic accommodation with a redistribution of food to antrum Fundic accommodation or receptive relaxation Meal Functional dyspepsia (Gilja O. Dig Dis Sci 1996;41:689)
  32. 32. Impaired Accommodation in Functional Dyspepsia Differences in area measurements in a sagittal section of proximal stomach, between patients with functional dyspepsia and healthy controls. SEM bars are shown. (Gilja O. Dig Dis Sci 1996;41:689) P < 0.05
  33. 33. Weak Postprandial Antral Contractions in Functional Dyspepsia <ul><li>Postprandial antral hypomotility is common </li></ul><ul><li>Can also be seen in PUD or gastritis </li></ul>(Camilleri M. Dig Dis Sci 1986;31:1169. Kerlin P. Gut 1989;30:54) Normal Functional Dyspepsia
  34. 34. Delayed Gastric Emptying in Functional Dyspepsia <ul><li>Studies have found delayed gastric emptying for solids, in 30% to 82% of patients with functional dyspepsia </li></ul>
  35. 35. Small Bowel Motor Dysfunction in Functional Dyspepsia <ul><li>In patients with more severe symptoms </li></ul><ul><li>Hyperactive or uncoordinated duodenal contractions </li></ul><ul><li>Absent or abnormal migrating myoelectrical complexes </li></ul>(Kerlin P. Gut 1989;30:54)
  36. 36. Altered CNS Function in Functional Dyspepsia
  37. 37. CNS Factors <ul><li>Anxiety </li></ul><ul><li>Depression </li></ul><ul><li>Sexual abuse </li></ul><ul><li>Sleep deprivation </li></ul><ul><li>Stressful events </li></ul>The role of psychological factors in functional dyspepsia is not as clearly established as it is in IBS Psychological factors to be considered in the pathogenesis of functional dyspepsia:
  38. 38. Functional Dyspepsia and Irritable Bowel Syndrome % of Patients with Functional Dyspepsia who also have IBS (Jones R. Gut 1990;31:401) Ulcer-like Dysmotility-like Dyspepsia Dyspepsia 29% 44%
  39. 39. Helicobacter pylori in Functional Dyspepsia
  40. 40. Is H. pylori a Factor in Functional Dyspepsia? <ul><li>Controversial </li></ul><ul><li>Some evidence - biological plausibility - prevalence (45% to 70% in dyspeptics, 13% to 60% in controls) - eradication studies </li></ul>
  41. 41. H. pylori Eradication Studies in Functional Dyspepsia <ul><li>Veldhuyzen van Zanten, 1995 0.5 Lazzaroni, 1996 0.5 </li></ul><ul><li>Elta, 1996 3 Trespi, 1994 0.5 </li></ul><ul><li>Schutze, 1996 1 McCarthy, 1995 1 </li></ul><ul><li>Sheu, 1996 1 </li></ul>No Benefit from Length of Benefit from Length of H. pylori Follow-up H. pylori Follow-up Eradication (yr) Eradication (yr)
  42. 42. Canadian Economic Analysis H. pylori Eradication in Undiagnosed Dyspepsia <ul><li>Based on an American analysis </li></ul><ul><li>Examined management of Hp -seropositive patients </li></ul><ul><li>Scope first strategy: $401 Treat Hp first: $345 </li></ul>(Adapted from Offman J. Ann Int Med 1997;126:280)
  43. 43. Testing for H. pylori <ul><li>C13 or C14 90% to 100% 96% to 100% ++ Limited - requires urease breath hospital nuclear test medicine department </li></ul><ul><li>Serology 91% to 98% 75% to 80% + Widely available through commercial labs and Public Health </li></ul><ul><li>Capillary 85% to 90% 75% to 80% + Office test, must be blood serology purchased by doctor administered </li></ul><ul><li>Endoscopic 99% 99% ++++ Requires specialist biopsy Invasive </li></ul>Test Sensitivity Specificity Cost Comments (Cutler A. Gastro 1995;109:136. Megraud F. Scand J Gastro 1996;215:57)
  44. 44. H. pylori Eradication Regimens (All given for one week) <ul><li>Treatments of Choice </li></ul>PPI - AC BID Amoxicillin 1 g bid Clarithromycin 500 mg bid PPI - MC BID Metronidazole 500 mg bid Clarithromycin 250 mg bid Regimen PPI Antibiotics Alternate PPI - BMT BID Bismuth 2 tabs qid Metronidazole 250 mg qid Tetracycline 500 mg qid
  45. 45. Management of Dyspepsia
  46. 46. Suggested Approach for Management of Dyspepsia Dyspepsia Ulcer-like symptoms dominant Initial interview and examination Education/lifestyle modification Functional dyspepsia Structural disease or alarm symptoms Dysmotility-like symptoms dominant Education/lifestyle modification Test Hp + - Eradicate Success Fail Trial of acid suppression Trial of prokinetic medication Investigate/refer Fail Fail Success Success
  47. 47. Interview and Examination Objectives <ul><li>Initiate a symptom-based diagnosis </li></ul><ul><li>Address patient’s concerns and expectations </li></ul><ul><li>Explore psychosocial issues, patterns of illness behaviour </li></ul><ul><li>Educate </li></ul>
  48. 48. <ul><li>Heartburn Burning pain Nausea Weight loss </li></ul><ul><li>Regurgitation Bloating Dysphagia </li></ul><ul><li>Reflux </li></ul>Interview and Examination - Symptoms and Signs Suggest Suggest Ulcer-like Suggest Dysmotility-like Suggest GERD Dyspepsia Dyspepsia Structural Disease Relief of pain with food Early satiety Pain worse with food Vomiting Bleeding Palpable mass Localized epigastric pain Nocturnal/ fasting pain
  49. 49. Suspected Functional Dyspepsia - Who to Investigate? <ul><li>Over 50 years of age, with new onset of symptoms </li></ul><ul><li>Failed therapy </li></ul><ul><li>Cancer fear </li></ul><ul><li>Symptoms that are severe as perceived by patient or physician </li></ul>
  50. 50. Choice of Investigation for Ulcer-like Dyspepsia <ul><li>More expensive Less expensive </li></ul><ul><li>Issues of access/waiting Easy access, usually short lists can be a problem waiting time </li></ul><ul><li>Allows for biopsy If cancer is found, endoscopy (cancer, Hp ) will be needed </li></ul><ul><li>Allows diagnosis of Often misses mucosal lesions mucosal lesions (erosions) </li></ul><ul><li>Preferred investigation for Alternative, especially if dyspepsia access is a concern </li></ul>Endoscopy UGI Series
  51. 51. Investigation of Dysmotility-like Dyspepsia <ul><li>Investigations are frequently normal </li></ul><ul><li>Reserved for patients with severe symptoms, vomiting dominant, unresponsive to therapy </li></ul><ul><li>Solid-phase gastric emptying test may be useful </li></ul>
  52. 52. Management of Functional Dyspepsia
  53. 53. Management of Functional Dyspepsia Functional Dyspepsia General treatment and specific management based on dominant symptom complex Follow-up within 3 to 6 weeks Ulcer-like Dysmotility-like
  54. 54. Management of Ulcer-like Functional Dyspepsia Ulcer-like Symptoms Dominant Education/lifestyle modification Test Hp + - Eradicate Hp Success Failure Trial of acid suppression Investigate Trial of prokinetic Reassess
  55. 55. Lifestyle Modification for Patients with Functional Dyspepsia <ul><li>Small frequent meals </li></ul><ul><li>Stop smoking </li></ul><ul><li>Reduce alcohol </li></ul><ul><li>Reduce caffeine </li></ul><ul><li>Avoid irritating foodstuffs </li></ul><ul><li>Maintain an ideal weight </li></ul><ul><li>Review medications </li></ul>
  56. 56. Acid Suppression Therapy for Ulcer-like Functional Dyspepsia <ul><li>H 2 -receptor antagonist for 4 weeks </li></ul><ul><li> OR </li></ul><ul><li>Proton pump inhibitor for 2 weeks </li></ul>
  57. 57. Management of Dysmotility-like Functional Dyspepsia Dysmotility-like Symptoms Dominant Educate/lifestyle modification Test H. pylori + - Continue with cyclic therapy Success Failure Investigate Trial of prokinetic medication Eradicate Gastroscopy or UGI Success Failure Consider H 2 antagonists, tricyclics
  58. 58. Rationale for the Use of Prokinetic Agents in Dysmotility-like Functional Dyspepsia <ul><li>Accelerate gastric emptying </li></ul><ul><li>Increase antral contractions </li></ul><ul><li>Decrease duration of proximal gastric distention </li></ul><ul><li>Antinausea </li></ul>
  59. 59. Placebo-controlled Trials of Prokinetic Agents in Functional Dyspepsia <ul><li>Of 11 trials with domperidone, 10 showed domperidone better than placebo </li></ul><ul><li>Of 19 trials with cisapride, 15 showed cisapride better than placebo </li></ul>
  60. 60. Placebo-controlled Trials of H 2 Blockers in Dyspepsia <ul><li>Only 4 of 12 trials showed benefit vs. placebo </li></ul><ul><li>Overall, 59% response rate for H 2 blockers, 48% for placebo </li></ul>
  61. 61. Suggested Approach for Management of Dyspepsia Dyspepsia Ulcer-like symptoms dominant Initial interview and examination Education/lifestyle modification Functional dyspepsia Structural disease or alarm symptoms Dysmotility-like symptoms dominant Education/lifestyle modification Test Hp + - Eradicate Success Fail Trial of acid suppression Trial of prokinetic medication Investigate/refer Fail Fail Success Success
  62. 62. Summary <ul><li>Dyspepsia is common </li></ul><ul><li>On clinical grounds, functional dyspepsia can be separated into ulcer-like and dysmotility-like </li></ul>
  63. 63. Summary (cont’d) <ul><li>Patients with ulcer-like functional dyspepsia should be tested for Helicobacter pylori , and treated accordingly </li></ul><ul><li>For patients with dysmotility-like functional dyspepsia, prokinetic drugs are effective </li></ul>
  64. 64. Case Presentation <ul><li>34 y.o. security guard </li></ul><ul><li>5 years of intermittent epigastric discomfort </li></ul><ul><li>Bloating, postprandial nausea </li></ul><ul><li>Smokes, drinks 3 beers/day, 4 coffees/day </li></ul>
  65. 65. <ul><li>Ranitidine prescribed one year ago </li></ul><ul><ul><li>- Initially beneficial, not now </li></ul></ul><ul><li>Family history of peptic ulcer </li></ul><ul><li>Examination is normal </li></ul>
  66. 66. <ul><li>Can a diagnosis be made, based on history and examination? </li></ul>
  67. 67. <ul><li>You suspect functional dyspepsia </li></ul><ul><li>The patient requests investigation (worried about cancer or infection) </li></ul>
  68. 68. <ul><li>What investigations would you do? </li></ul><ul><li>What management suggestions would you make? </li></ul><ul><li>Would you suggest any medication? </li></ul>