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Irritable Bowel Syndrome HeeJae Hyun 2011.6.20 CASE 28-year-old woman 7-month history – Recurrent, crampy pain in LLQ – Bloating with abdominal distention – Frequent, loose stools Similar but milder symptoms since childhood Long times in the bathroom – Because she is worried about uncontrollable discomfort and fecal soiling CASE Feel anxious and fatigue She is frustrated that her previous physician did not seem to take her distress seriously. Physical examination is unremarkable except for tenderness over the LLQ How should her case be evaluated and treated? Irritable Bowel Syndrome Character – Chronically recurring abdominal pain or discomfort – Altered bowel habits – In the absence of any organic cause Functional disorder – By symptom-based diagnostic criteria One of several functional gastrointestinal disorders In the absence of any organic cause Irritable Bowel Syndrome One of the most common syndromes Worldwide prevalence : 10 to 15% – Only about 15% of affected people actually seek medical help Prevalence – Woman 7-24% > Man 5-19% in USA , UK – But, Woman 6.0%, Man 7.1% in Korea Irritable Bowel Syndrome Health care costs – Twice that of an asymptomatic person – More appendectomies, cholecystectomies and hysterectomies in those with IBS – The direct medical costs of IBS are US 8 billion in the US each year – Impairment of QOL: worse than in patients with DM or CRF Gralneck etal (2000) Gastroent 119:654 – Time off work: 3 times more often than that for an asymptomatic – Restriction of activities: by 145 days per year Creed etal (2001) Ann Int Med 134:860 Diagnostic criteria 1978년 32명의 IBS환자, 33명의 기질환자 15개의 복부증상 중 IBS환자에서 보다 많은 나타나는 6개의 증상 제한점: 증상의 지속기간, 빈도에 대한 규정 없음, 몇 가지 이상의 증상? 574명 대상의 4개의 연구 – 3가지 증상 이상있을 때 Sensitivity 78%, Specificity 72% Diagnostic criteria 1988년 multinational working team committee가 로마에서 열려 FGID 진단기준 만들었기에 붙여진 이름 22년간 3차례 개정 Rome I Sensitivity 67-83%, Specificity 33-85% Rome II Sensitivity 31-65%, Specificity 30-100% Rome III Functional Gastrointestinal Disorders (FGID) A. Functional esophageal disorders – A1. Functional heartburn – A2. Functional chest pain of presumed esophageal origin – A3. Functional dysphagia – A4. Globus – – – – – B. Functional gastroduodenal disorders – B1. Functional dyspepsia B1a. Postprandial distress syndrome B1b. Epigastric pain syndrome – B2. Belching disorders B2a. Aerophagia B2b. Unspecified excessive belching – B3. Nausea and vomiting disorders B3a. Chronic idiopathic nausea B3b. Functional vomiting B3c. Cyclic vomiting syndrome – B4. Rumination syndrome in adults C. Functional bowel disorders D. Functional abdominal pain syndrome E. Functional gallbladder and Sphincter of Oddi (SO) disorders – – – C1. Irritable bowel syndrome C2. Functional bloating C3. Functional constipation C4. Functional diarrhea C5. Unspecified functional bowel disorder E1. Functional gallbladder disorder E2. Functional biliary SO disorder E3. Functional pancreatic SO disorder F. Functional anorectal disorders – – – F1. Functional fecal incontinence F2. Functional anorectal pain F2a. Chronic proctalgia – – F2a1. Levator ani syndrome F2a2. Unspecified functional anorectal pain F2b. Proctalgia fugax F3. Functional defecation disorders F3a. Dyssynergic defecation F3b. Inadequate defecatory propulsion Drossman D, Corazziari E, Spiller R, Talley N, Thompson W, Whitehead W, eds. Rome III. The Functional Gastrointestinal Disorders. 3rd ed. McLean, VA 2006 Rome III Functional Gastrointestinal Disorders (FGID) G. Functional disorders: neonates and toddlers – G1. Infant regurgitation – G2. Infant rumination syndrome – G3. Cyclic vomiting syndrome – G4. Infant colic – G5. Functional diarrhea – G6. Infant dyschezia – G7. Functional constipation H. Functional disorders: children and adolescents – H1. Vomiting and aerophagia H1a. Adolescent rumination syndrome H1b. Cyclic vomiting syndrome H1c. Aerophagia – H2. Abdominal pain-related functional gastrointestinal disorders H2a. Functional dyspepsia H2b. Irritable bowel syndrome H2c. Abdominal migraine H2d. Childhood functional abdominal pain – H2d1. Childhood functional abdominal pain syndrome – H3. Constipation and incontinence H3a. Functional constipation H3b. Nonretentive fecal incontinence LIFE Genetics Environment Social Context Outcome •Medications • MD visits •Daily function •Quality of life Drossman, DA; Gastro 2006 Diagnostic criteria Rome III (2006) – Recurrent abdominal pain or discomfort three days per month in the last three months associated with two or more of : – Improvement with defecation – Onset associated with a change in frequency of stool – Onset associated with a change in form of stool CLINICAL MANIFESTATIONS Chronic abdominal pain – Crampy sensation with variable intensity, periodic exacerbations – Location, character: widely variable – Factor: emotional stress, eating, defecation... CLINICAL MANIFESTATIONS Altered bowel habits – Diarrhea Frequent loose stools Generally during waking hours – Morning or after meals Lower abdominal cramps, urgency Not associated – Large volume diarrhea, bloody stools, nocturnal diarrhea, greasy stools – Constipation Last from days to months Sense of incomplete evacuation CLINICAL MANIFESTATIONS Other GI Sx – Gastroesophageal reflux, dysphagia, early satiety, intermittent dyspepsia, nausea, non-cardiac chest pain – Abdominal bloating – Increased gas production Flatulence, belching Extraintestinal Sx – Impaired sexual function, dysmenorrhea, dyspareunia, increased urinary frequency, urgency, fibromyalgia Sx Overlapping Upper GI Symptoms in Patients with IBS Symptoms Number of symptoms IBS with constipation (n =76) IBS with diarrhea (n =64) 6.67 4.62 Lower abdominal pain (%) 40.8 24.4 Upper abdominal pain (%) 36.8 24.4 Bloating (%) 75.0 40.9 Indigestion (%) 48.7 36.4 Nausea (%) 46.1 47.7 Early satiety (%) 42.7 25.0 Heartburn (%) 32.9 40.9 Talley et al. Am J Gastroenterol 2003;98:2454–9 4 SUBTYPEs of IBS IBS with constipation (IBS-C) – Hard or lumpy stools > 25% – Loose or watery stools < 25% IBS with diarrhea (IBS-D) – Loose or watery stools >25% – Hard or lumpy stools <25% Mixed IBS (IBS-M) – Hard or lumpy stools > 25% – Loose or watery stools > 25% Unsubtyped IBS – Insufficient abnormality of stool consistency DIAGNOSTIC APPROACH It is important to exclude other causes “Alarm” or atypical symptoms – – – – Rectal bleeding Nocturnal or progressive abdominal pain Weight loss Lab. Abnormalities Anemia, elevated inflammatory markers, electrolyte disturbances – Family history of colon cancer, IBD, Nontropical sprue – Onset of first symptom after 50yr of age – Major change in symptoms Routine lab : normal in IBS DIAGNOSTIC APPROACH DIAGNOSTIC APPROACH Diarrhea predominant IBS – Stool culture Little role in patients with chronic diarrhea Giardia in patient’s clinical history – Celiac disease screening Serum IgA antibody to tissue transglutaminase In a meta-analysis of 14 studies – 4%, Four times than controls without IBS – 24hr stool collection If osmotic or secretory diarrhea or malabsorption is suspected – Colonoscopy or flexible sigmoidoscopy and biopsy DIAGNOSTIC APPROACH Constipation predominant IBS – Radiography Detect retained stool – Flexible sigmoidoscopy and colonoscopy If a structural lesion is suspected Older than 50 because of the increased risk of colon cancer Usefulness of Warning Signs Onset of first symptom after 50yr of age – Odds ratio (OR) : 2.65 (95% confidence interval 1.4-5.0) Gut 2004;53:666-672 Rectal bleeding – Sensitivity 64% (95% CI=55-73%), Specificity 52% (95% CI=42-63%) Am J Gastroenterol 2002;97:S7-S26 Anemia – Sensitivity 19% (95% CI=5.5-33%), Specificity 90% (95% CI=87-92%) 과민성 장증후군의 진단: 체계적인 문헌고찰 Korean J Gastroenterol 2010;55:308-315 Usefulness of Warning Signs Weight loss – Sensitivity 22% (95% CI=14-31%), Specificity 89% (95% CI=8195%) Am J Gastroenterol 2002;97:S7-S26 Family history of colon cancer, IBD, Nontropical sprue – Association of colon cancer risk Gastroenterology 2003;124:544-560 N Eng med 2002;347:417-429 Nocturnal abdominal pain – Not association of organ disease Gut 2004;53:666-672 과민성 장증후군의 진단: 체계적인 문헌고찰 Korean J Gastroenterol 2010;55:308-315 Usefulness of Warning Signs Accuracy of warning sign – Not as satisfactory as expected – Rectal bleeding, nocturnal symptom – Anemia, weight loss IBS Sx (0) + Anemia, Weight loss, Family Hx (X) = IBS (?) PATHOPHYSIOLOGY of IBS uncertain PATHOPHYSIOLOGY of IBS Gastrointestinal motility Visceral hypersensitivity Intestinal inflammation Postinfectious Alteration in fecal microflora Bacterial overgrowth Food sensitivity Genetics Psychosocial dysfunction PATHOPHYSIOLOGY of IBS Gastrointestinal motility – No predominant pattern of motor activity – In some patients Frequency and irregularity of luminal contractions Prolonged transit time Exaggerated motor response to – Cholecystokinin and meal ingestion – Pharmacologic stimulation of gut motility Reduce gas retention Improve symptom PATHOPHYSIOLOGY of IBS Gastrointestinal motility – Pre-prandial colonic tone and motility is increased in IBS patients Vassallo, MJ; Mayo Clinic Proc 1992 – Functional GI disease patients like IBS have greater motility response to stressors- both physiologic and psychologic when compared to normal Drossman, DA; Gastro 2002 PATHOPHYSIOLOGY of IBS Visceral hypersensitivity (increased sensation in response to stimuli) – Nerves in the bowels are overactive in people with IBS Normal amounts of gas or movement are perceived as excessive and painful – Several studies Selective hypersensitization of visceral afferent verves in the gut, triggered by bowel distention or bloating Repetitive rectal balloon inflations lead to a progressive increase in pain that occurs longer and with greater intensity than controls Munakata K; Gastro 1997 – ? By local GI nervous system By central modulation from the brain By some combination By specific GI mediators (serotonin, kinins) PATHOPHYSIOLOGY of IBS Intestinal inflammation – Mucosal immune system activation – Lymphocytes, mast cells – Proinflammatory cytokines – 50% IBS patients have increased activated mucosal inflammatory cells Chadwick, VS; Gastro 2002 – 33% pts with IBS can correlate symptoms to an enteric infection – 25% of pts with an acute enteric infection go on to develop IBS like or dyspeptic symptoms Gwee, KA; Gut 1999 – Meta-analysis of post-infectious IBS Halvorson, HA; Am J Gastro 2006 PATHOPHYSIOLOGY of IBS Postinfectious – – – – Malabsorption Increase in enteroendocrine cells/lymphocytes Antibiotic use Review of 18 studies IBS incidence 10%, increased sixfold after an acute GI infection Risk factor: young age, prolonged fever, anxiety, depression PATHOPHYSIOLOGY of IBS Alteration in fecal microflora – Fecal microflora in individuals with IBS differ from healthy controls – Eradication of small intestinal bacterial overgrowth reduces symptoms of IBS Anderson, ML; Am J Gastro 2000 – Normalization of lactulose breath testing correlates with symptomatic improvement in IBS Pimentel, M; Am J Gastro 2003 PATHOPHYSIOLOGY of IBS Bacterial overgrowth – In some studies Abnormal breath hydrogen levels in IBS Improvement in symptoms after erdication of the overgrowth Food sensitivity – Food allergy : food specific antibodies – Carbohydrate malabsorption – Gluten sensitivity PATHOPHYSIOLOGY of IBS Genetics – Several twin studies – Associations between specific genes and IBS PATHOPHYSIOLOGY of IBS Psychosocial factors – Psychosocial factors may influence the expression of IBS symptoms – Anxiety, depression, phobias, somatization in IBS Pts. – History of physical, verbal, or sexual abuse – Psychological stress exacerbates GI symptoms in everyone- but to a greater degree in patients with IBS – 50% of patients with IBS seen at referral centers meet the criteria for a psychological disorder – Chronic illness such as IBS has psychosocial consequences Drossman, DA; Gastro 2006 PATHOPHYSIOLOGY of IBS Brain Gut Interaction – Brain and gut are hardwired bidirectionally – Anxiety is associated with increased anterior cingulate cortex activity during rectal pain in IBS Morgan, V; Gastro 2001 – IBS and history of abuse have synergistic effects on cingulate activation in response to rectal distention Ringel Y; Gastro 2003 TREATMENT of IBS RELIEF Relationship Education Diet Fiber Medication Probiotics Psychosocial Alternative- Gut directed hypnotherapy, acupuncture, herbal medicine, peppermint oil, melatonin, extract of artichoke TREATMENT of IBS Therapeutic physician-patient relationship – Most important component Patients with a strong positive therapeutic relationship with their physician have fewer IBS related office visits Owens, W; Annals IM 1995 262 pts with IBS – – – – Group 1 control Group 2 sham acupuncture and little provider interaction Group 3 sham acupuncture and high provider interaction Level of improvement Group 3 >>Group 2 >> Group 1 Kaptchuk M; BMJ 2008 TREATMENT of IBS Patient education – Review elements of the pathophysiology May I explain your problem? – Clearly convey “You have IBS” – This is a chronic disease and benign nature – There is help with management but no known cure – This disease will not shorten your life span or lead to any other complicating illness TREATMENT of IBS Dietary modification – Lactose Lactose intolerance – The similarity in Sx of IBS – Undiagnosed – Exclusion of gas-producing foods Increase flatulense – Beans, onions, celery, carrots, raisins, bananas, apricots, prunes, brussel sprouts, wheat, prtzels, bagels – Visceral hyperalgesia in IBS • Exaggerated discomfort – Food allergy – Gluten sensitivity – Carbohydrate malabsorption : unclear, trial TREATMENT of IBS Fiber – An increase in the intake of fiber – But not all authorities agree British guideline: up to 12 g per day , particularly insolube fiber such as bran – Mechanisms Enhancement of water holding properties of the stool Formation of gells to provid lubrication Binding fo agents such as bild – Systematic review: no convincing evidence Am J Gastro 2009 TREATMENT of IBS Fiber – Synthetic fiber such as polycarbophil, methylcellulose More soluble Less bloating But, not determined – A trial of fiber is reasonable In all patients with IBS Especially constipation predominant IBS TREATMENT of IBS Psychosocial therapies – Behavioral treatments, Hypnosis, Biofeedback, Psychotherapy 2009 meta-analysis – Psychological therapy were significantly more effective than control therapy for at least a 50 % reduction in symptoms Am J Gastroenterol 2009; 104 suppl 1:S1 Cognitive behavioral therapy is more effective than patient education and desipramine and placebo Drossman DA; Gastro 2003 Cognitive behavioral therapy improves symptoms but no better than standard care or relaxation therapy. Boyce, PM; American J of Gastro 2003 TREATMENT of IBS Medications – Only an adjunct to treatment in IBS – Drug chosen varies depending on the patient’s major symptoms – Chronic use of drugs : Minimized or avoided Lifelong nature of this disorder Lack of convincing therapeutic benefit – Difficulty in demonstrating efficacy Heterogeneous population diagnosed with IBS The lack of disease markers High placebo response rates MEDICATIONS Antispasmodic agents – Directly affect intestinal smooth muscle relaxation Mebeverine, pinaverine – Via anticholinergic or antimuscarinic propeties Dicyclomine, hyoscyamine – Meta-analysis of 23 controlled trials of smooth muscle relaxants More effective than placebo 41 % improvement in pain with placebo 53% improvement in pain with antispasmodic Aliment Pharm Ther 2001 – ACG 2009 review showed little evidence for efficacy MEDICATIONS Antidepressants – Analgesic properties – Beneficial in patients with neuropathic pain – TCA Via anticholinergic properties Slow intestinal transit time : diarrhea-predominant IBS Low doses than required for treatment of depression – Delayed onset of action, three to four weeks of therapy MEDICATIONS Antidepressants – TRICYCLICS Pain benefit Desipramine/ nortriptyline have fewer side effects Start low 10-20mg qhs and increase to 50-75 Efficacy of desipramine in moderate to severe IBS over placebo: 73% response vs 50% Drossman, D; Am J Gastro 2009 MEDICATIONS Antidepressants – Less published experience (SSRI, SNRI) A meta-analysis concluded that overall treatment effects were similar to TCA Gut 2009;58:367 SSRI – Use for anxiolysis – Not much pain benefit Paroxetine (Paxil) better than placebo Tabas G; Am J Gastro 2004 Fluoxetine (Prozac) better than placebo in IBS-C Vahedi H; Alim Pharm Ther 2005 Citalopram (Celexa) efficacious in nondepressed IBS Tack J; Gut 2006 Psychotherapy and Paroxetine cost effective when compared to routine care for severe IBS Creed, F; Gastro 2003 MEDICATIONS Antidiarrheal agents – Loperamide More effective than placebo for treatment of IBS-C Not for treatment of global IBS symptoms or abdominal pain Preferred to a regular scheduled dosing Not be used in patients with constipation MEDICATIONS Benzodiazepines – Anxiolytic agents Of limited usefulness in IBS – Risk of drug interactions, habituation, rebound withdrawal Useful for short term reduction of acte situational anxiety MEDICATIONS Serotonin modulators – Serotonin A monoamine neurotransmitter Found in cardiovascular tissue, the peripheral nervous system, blood cells, and the CNS 95 % resides in the GI tract The function of serotonin is exerted upon its interaction with specific receptors. 7 distinct families of 5HTreceptors; 5HT1, 5HT2, 5HT3, 5HT4, 5HT5, 5HT6, and 5HT7 – Serotonin plays a major role in modulating intestinal movement and perception of pain. Helps to soften stools by releasing water. Am J Gastroenterol 2000; 95(10): 2698 MEDICATIONS Serotonin modulators – 5HT3 antagonists Slow intestinal transit Decrease intestinal secretions Decrease the water content of stool Diminish colonic pain – 5HT4 agonists Accelerate gastric emptying Accelerate small and large bowel transit Increase stool water content MEDICATIONS 5HT3 antagonists – Alosetron, cilansetron, ondansetron, granisetron – Meta-anlysis A benefit in global improvement in IBS Relief of abdominal pain and discomfort Clin Gastroenterol Hepatol 2008;6:545 – Alosetron (Lotronex) Effective in female patients with IBS-C FDA approved 2000 Withdrawn 2000 Ischaemic colitis (1:1000) A few deaths attributed to it Reintroduced 2002 Reduced dose Severe restrictions (counselling, consent) MEDICATIONS 5HT4 agonists – Rationale for use in IBS-D – Tegaserod (Zelnorm) Removed from the market in March 2007 because of cardiovascular side-effects MEDICATIONS Lubiprostone – Locally acting chloride channel activator Enhances choride-rich intestinal fluid secretion For Tx of chronic idiopathic constipation Later for Tx of IBS-C in women 18 yrs and older – Multicenter placebo-controlled trials 1154 (92% women) with IBS-C Ramdom lubiprostone or placebo for 12 weeks Response 18 vs 10% Adverse events : similar to placebo Aliment Pharmacol Ther 2009;29:329 MEDICATIONS Antibiotics – Rifaximin 400 mg tid for 10 days better than placebo in IBS- 36% vs 21% Pimentel, M; Ann Int Med 2006 – Rifaximin 550mg tid for 14 days decreased IBS symptoms including bloating and pain. Effects lasted for 10 week study period -41% vs 31% NEJM 2011;364;22 – Modest benefit and relatively short-term F/U – Not suggest the routine use of antibiotics – But if failed to respond to all other therapies, reasonable to consider two-week trial of rifaximin IBS: Symptomatic Therapy Smooth muscle relaxants 5-HT agonists/antagonists TCAs, SSRIs Smooth muscle relaxants 5-HT agonists/antagonists Antiflatulents Abdominal pain/ discomfort CONSTIPATION Fibres Osmotic agents 5-HT4 agonists Prokinetics Bloating Altered bowel function DIARRHEA Loperamide Cholestyramine 5-HT3 antagonists None of these medications effectively treat the multiple symptoms of IBS. May exacerbate individual symptoms e.g., fiber and bloating; antispasmodics and constipation MEDICATIONS Alternative therapies – – – – Their role remains uncertain Herbs Probiotics Acupuncture Enzyme 치료 권고 등급 약제의 조합: ‘과민성 장증후군은 여러 가지 병태생리가 관여되어 다양 한 증상 양상을 보이는 이질적인 질환군이며 각각의 증상 에 대한 약제를 조합하는 것이 치료에 효과적이다’ Grade 1B, 권고수준: 강함, 증거수준: 중등 도 진경제: ‘진경제는 과민성 장증후군 환자에서 복통 및 복부 불편감 의 치료에 효과적이다’ Grade 1B, 권고수준: 강함, 증거수준: 중등 도 선택적 염소통로활성제: ‘선택적 염소통로활성제는 변비형 과민성 장증후군 환자의 치료에 효과적이다’ Grade 1B, 권고수준: 강함, 증거수준: 중등 도 항우울제: ‘삼환계 항우울제와 선택적 세로토닌 재흡수 억제제는 일 부 과민성 장증후군 환자의 치료에 도움을 준다’ Grade 2A, 권고수준: 약함, 증거수준: 높음 세로토닌 3형 수용체 길항제: ‘세로토닌 3형 수용체 길항제는 설사형 과민성 장증후군의 치료에 도움을 준다’ Grade 2A, 권고수준: 약함, 증거수준: 높음 세로토닌 4형 수용체 작용제: ‘세로토닌 4형 수용체 작용제는 변비형 과민성 장증후군 환자의 치료에 도움을 준다’ Grade 2A, 권고 수준: 약함, 증거수준: 높음 과민성 장증후군 치료에 관한 임상진료지침 Korean J Gastroenterol 2011;57(2):82-99 치료 권고 등급 부피형성 하제: ‘부피형성 하제는 과민성 장증후군의 일부 증상의 치료에 도움을 준다’ Grade 2B, 권고수준: 약함, 증거수준: 중등 도 지사제: ‘지사제는 과민성 장증후군에서 배변 형태를 호전시키고 배변 횟수를 줄이는데 도움을 준다’ Grade 2B, 권고수준: 약함, 증거수준: 중등 도 비흡수성 경구용 항생제: ‘비흡수성 경구용 항생제의 단기간 사용은 일부 과민성 장 증후군 환자의 치료에 도움을 준다’ Grade 2B, 권고수준: 약함, 증거수준: 중등 도 정신과적 치료(인지행동치료 등): ‘인지-행동 요법, 역동정신요법, 최면요법은 일부 과민성 장증후군 환자의 치료에 도움을 준다’ Grade 2B, 권고수준: 약함, 증거수준: 중등 도 삼투성 하제: ‘변비형 과민성 장즈후군 환자에서 삼투성 하제는 배변 횟 수를 증가시키는데 도움을 줄 수 있다’ Grade 2C, 권고수준: 약함, 증거수준: 낮음 프로바이오틱스: ‘프로바이오틱스는 일부 과민성 장증후군 환자의 치료에 도움을 줄 수 있다’ Grade 2C, 권고수준: 약함, 증거수준: 낮음 과민성 장증후군 치료에 관한 임상진료지침 Korean J Gastroenterol 2011;57(2):82-99 Augmentation Therapy for Refractory Abdominal Pain Use more than one treatment to enhance benefit Remember lower doses to minimize side effects Examples: – Add buspirone to SSRI – Add SNRI to tricyclic – Add mood stabilizer lamotrigine (lamictal) to antidepressant Drossman, DA; Am J Gastro 2009
