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1 2013 대한임상건강증진학회추계합동학술대회 역류성식도염의진단및치료 박영규 분당제생병원가정의학과 Contents Introduction Overview of GERD GERD 임상진료지침개정안 2012 치료중심 Long-term use of PPI Barrett s esophagus Gastroesophageal reflux Backflow of stomach contents in to esophagus Physiologic in nature Gastroesophageal reflux disease (GERD) symptoms or complications resulting from the reflux of gastric contents into the esophagus or beyond, into the oral cavity (including larynx) or lung GERD: GERD Sx with erosions on endoscopy NERD: GERD Sx without erosions Guidelines for the Diagnosis and Management of Gatroesophageal Reflux Disease Am J Gastroenterol 2013; 108: Epidemiology Pathophysiology Anti-Reflux Barrier Esophageal Contact Time Gastric contents 대한소화기학회지 2010;55(4 Suppl) 166

역류성식도염의진단및치료 / 박영규 Associated conditions Age: intensity of Sx after age of 50yrs (frequency of Sx: no change) Sex M: more erosive esophagitis, Barret s,

4A): S99 103 Medications that can cause GERD or esophagitis Classification of GERD Decrease LES Pressure Adrenergic agonists, including inhalers Adrenergic

Injury Alendronate Aspirin Iron salts Nonsteroidal anti inflammatory drugs Potassium chloride tablets Quinidine Tetracycline Spectrum of GERD 생리적역류 기능성가슴쓰림

2 역류성식도염의진단및치료 / 박영규 Associated conditions Age: intensity of Sx after age of 50yrs (frequency of Sx: no change) Sex M: more erosive esophagitis, Barret s, esophageal adenoca F: more NERD Risk factors Alcohol use Obesity(BMI) Pregnancy Smoking de Caestecker, BMJ 2001; 323:736 9 Johanson, Am J Med 2000; 108(Suppl 4A): S Medications that can cause GERD or esophagitis Classification of GERD Decrease LES Pressure Adrenergic agonists, including inhalers Adrenergic antagonists Anticholinergics Calcium channel blockers Diazepam Estrogens Narcotics Progesterone Theophylline Tricyclic antidepressants Cause Direct Mucosal Injury Alendronate Aspirin Iron salts Nonsteroidal anti inflammatory drugs Potassium chloride tablets Quinidine Tetracycline Spectrum of GERD 생리적역류 기능성가슴쓰림 증상만있는경우 (NERD, 비미란성 ) 전형적증상 식도외질환동반군 역류성식도염 (GERD, 미란성 ) 전형적증상 식도외질환동반군 합병증을동반한식도염 바렛식도, 식도선암 식도협착 Classic Sx Heartburn Regurgitation Clinical features(1) : esophageal symptoms 167

2013 대한임상건강증진학회추계합동학술대회 Clinical features(1) Clinical features(2) : extra-esophageal symptoms Reflux Sx: at least

Asthma Chronic sinusitis Dental erosions Aphthous ulcers Halitosis Pharyngitis Laryngitis Laryngospasm Postnasal

bronchitis Bronchiectasis Noncardiac chest pain Sleep apnea "Alarm" signs for further evaluation of GERD Diagnosis

Advanced age Endoscopy Updated Guidelines 2012 for Gastroesophageal Reflux Disease Korean J Gastroenterol Vol. 60 No.

3 2013 대한임상건강증진학회추계합동학술대회 Clinical features(1) Clinical features(2) : extra-esophageal symptoms Reflux Sx: at least twice a week Heartburn Acid regurgitation Chest pain Globus sensation Hoarseness Cough Epigastric pain Otitis media Asthma Chronic sinusitis Dental erosions Aphthous ulcers Halitosis Pharyngitis Laryngitis Laryngospasm Postnasal drip Frequent throat clearing Globus Tracheobronchitis Chronic cough Aspiration pneumonia Pulmonary fibrosis Chronic bronchitis Bronchiectasis Noncardiac chest pain Sleep apnea "Alarm" signs for further evaluation of GERD Diagnosis Dysphagia Odynophagia Weight loss Gastrointestinal (GI) bleeding Family history of upper GI tract cancer Anemia Advanced age Endoscopy Updated Guidelines 2012 for Gastroesophageal Reflux Disease Korean J Gastroenterol Vol. 60 No. 4, October 2012 Updated Guidelines 2012 for Gastroesophageal Reflux Disease Korean J Gastroenterol Vol. 60 No. 4, October

역류성식도염의진단및치료 / 박영규 Diagnosis(1): Sx and empirical Tx A presumptive diagnosis of GERD can be established in the setting of typical symptoms of heartburn and regurgitation.

(Strong recommendation) Empiric PPI therapy (a PPI trial) is a reasonable approach to confirm GERD when it is suspected in patients with typical symptoms sensitivity of 78 % and specificity of 54 %

Endoscopy is recommended in the presence of alarm symptoms and for screening of patients at high risk for complications risk factors for Barrett s esophagus: age over 50, chronic GERD symptoms (for

4 역류성식도염의진단및치료 / 박영규 Diagnosis(1): Sx and empirical Tx A presumptive diagnosis of GERD can be established in the setting of typical symptoms of heartburn and regurgitation. Empiric medical therapy with a PPI is recommended in this setting. (Strong recommendation) Empiric PPI therapy (a PPI trial) is a reasonable approach to confirm GERD when it is suspected in patients with typical symptoms sensitivity of 78 % and specificity of 54 % Diagnosis(2): Endoscopy Upper endoscopy is not required in the presence of typical GERD symptoms. Endoscopy is recommended in the presence of alarm symptoms and for screening of patients at high risk for complications risk factors for Barrett s esophagus: age over 50, chronic GERD symptoms (for >5~10yrs), obesity, male sex Repeat endoscopy is not indicated in patients without Barrett s esophagus in the absence of new symptoms Guidelines for the Diagnosis and Management of Gatroesophageal Reflux Disease Am J Gastroenterol 2013; 108: Consider early for noncardiac chest pain or patients unresponsive to PPI Diagnosis(3): LA classification 역류성식도염의 LA 분류 Grade N M A B C D Description Normal mucosa Minimal change (erythema/turbidity) Non-confluent mucosal break <5 mm Non-confluent mucosal break >5 mm Confluent breaks < 75% circumferential Confluent breaks > 75% circumferential I. Minor changes I. Localized/diffuse/patchy erythema II. Indistinctness or blurring III. Friability IV. Increased vascularity V. Edema/accentuation II. Mucosal breaks(discrete areas of erythema ± exudate) III. Ulcers(mucosal breaks 2mm + overlying exudate) IV. Stricture V. Metaplasia What is the diagnostic utility of endoscopic scoring systems in children? Turk J Gastroenterol 2013; 24 (1): LA minimal change 169

5 2013 대한임상건강증진학회추계합동학술대회 LA - A LA - B LA - C LA-D 170

역류성식도염의진단및치료 / 박영규 Management of GERD - 최신임상진료지침중심으로 - Treatment Treatment (1): lifestyle

! Healing of esophagitis Prevention of complication Prevention of recurrence Treatment options

prokinetic agent GABA-R agonist cytoprotective agent 지침 13.

( 근거및권고등급 : 1A) NERD: 미란성역류질환보다 PPI 의증상호전효과가낮다 현재사용가능한양성자펌프억제제의종류에따라증상호전에미치는영향의차이는크지않다 지침 14.

6 역류성식도염의진단및치료 / 박영규 Management of GERD - 최신임상진료지침중심으로 - Treatment Treatment (1): lifestyle modification Treatment Goals Relief of symptom: most important!! Healing of esophagitis Prevention of complication Prevention of recurrence Treatment options Treatment (2): Pharmacologic Tx Proton Pump Inhibitor H2-receptor Antagonist Antacid Etc: prokinetic agent GABA-R agonist cytoprotective agent 지침 13. 양성자펌프억제제는미란성및비미란성위식도역류질환치료에가장효과적인약물이다. ( 근거및권고등급 : 1A) NERD: 미란성역류질환보다 PPI 의증상호전효과가낮다 현재사용가능한양성자펌프억제제의종류에따라증상호전에미치는영향의차이는크지않다 지침 14. 히스타민수용체길항제는간헐적인위식도역류증상의조절에유용하다. ( 근거및권고등급 : 2A) 간헐적인가슴쓰림증상, 특히식사후유발되는위식도역류증상을조절하는데필요시요법으로권장가능 : 약제효과는복용후 30 분 ~12hrs 히스타민수용체길항제를사용하여증상의호전이없는경우, 용량을증량하는것은추가적인효과가없다 약제관용 (drug tolerance): 히스타민수용체길항제는지속적으로약물을투여하는경우약효가감소 2 주이상지속적사용금기 171

7 2013 대한임상건강증진학회추계합동학술대회 지침 16. 위식도역류질환의초치료는 1일 1회양성자펌프억제제표준용량을최소 4-8주간투여하는것이효과적이다. ( 근거및권고등급 : 1A) 양성자펌프억제제표준용량 : omeprazole 20 mg, lansoprazole 30 mg, pantoprazole 40 mg, rabeprazole 20 mg, esomeprazole 40 mg 심한식도염 : 8주이상의표준용량 PPI 치료가필요 NERD의초치료 : 최소 4주이상의지속적인표준용량 PPI 치료 지침 17. 양성자펌프억제제표준용량하루한번의초치료에반응이없는경우에는표준용량두배 ( 아침, 저녁식전의 1 일 2 회투여 ) 의양성자펌프억제제가도움을줄수있다. ( 근거및권고등급 : 2B) 지침 18. 위식도역류질환의증상이양성자펌프억제제로조절되지않는일부환자에서히스타민수용체길항제병용치료가도움을준다. ( 근거및권고등급 : 2B) 야간위산돌파 (nocturnal gastric acid breakthrough) 는밤동안위내산도가 ph<4 로한시간이상지속되는것 하루두번 PPI 투여로도야간역류증상억제가불충분할경우단기간혹은간헐적인 H2-R antagonist HS 추가투여가도움이될수있다 지침 15. 제산제는간헐적으로발생하는위식도역류증상의조절에유용하다. ( 근거및권고등급 : 2C) alginates 등을포함한제산제는경도혹은간헐적산역류증상의조절에안전하고효과적으로사용될수있다 지침 19. 양성자펌프억제제초치료후에재발방지를위하여장기간양성자펌프억제제유지요법이권장된다. ( 근거및권고등급 : 1A) 재발의억제를위해 PPI 의유지요법은비용효과적이며우월하다 PPI 유지요법 : 장기간 PPI 사용에따른부작용의감소를위하여재발을억제할수있는최소용량까지감량하는것을추천 재발관련요인 : 열공탈장, 식도기능이상, 식도청소기능의저하등이동반된경우, PPI or 위산분비억제제의투여중단후발생하는반발성위산과분비 PPI 유지요법 지침 20. 일부환자에서양성자펌프억제제의장기간유지요법의방법으로필요시투여법이사용될수있다. ( 근거및권고등급 : 1A) 필요시투여법 : PPI 를복용하는환자가스스로자신의증상에따라투약간격을조절하는방법 경증의 GERD, NERD 환자에서유지요법으로가능 cf) 미란성역류질환 : 매일투여법선호 지침 21. 위장운동촉진제는위산분비억제제 (PPI) 와병합치료로위식도역류질환환자의증상을개선하는데도움을줄수있다. (2C) 지침 22. 항우울제및항불안제의병합은난치성위식도역류질환의일부환자에서도움을줄수있다. (2B) 지침 25. 기타위식도역류질환에서사용가능성있는치료 1) 하부식도조임근작용제 : GABA-R 수용체항진제 baclofen 은일과성하부식도조임근이완을억제하는기전으로위식도역류질환치료에 PPI 와병합요법으로사용할수있다 2) 점막보호제 : Sucralfate, Rebamipide PPI 와병합요법으로고려가능하나임상적근거불충분 Refractory GERD 불응성위식도역류질환 하루 2 배용량의 PPI 치료에도증상의호전이부족한경우 하루 1 회표준용량의 PPI 치료에도충분한증상호전이없을때 국내의료보험기준을고려한다면표준용량 PPI 를 8 주이상사용해도증상의호전이없을때 원인 : 환자의투약순응도부족 투약확인및복약지도 식도운동장애동반 고용량 PPI / 수술전확인필요 야간산도증가 (night acid breakthrough) HS PPI or H2-B PPI 약제의약물역동학적대사에따른차이 dex-lansoprazole: 낮은체내제거율, 식사무관하게 1 일 1 회 약산성역류등역류가 PPI 로조절되지않은경우, 호산구식도염등의다른식도염 172

역류성식도염의진단및치료 / 박영규 Treatment (3): Surgical Tx laparoscopic fundoplication 적응증 장기간 PPI 유지치료가필요한환자에서장기간약물치료피하기위해 PPI 투여로증상이충분히조절되지않는환자의일부에서시도 효과 Good: 위식도역류가증명되고 PPI 에반응좋았던경우 Poor: 위식도역류뚜렷하지않고, medical

epithelium 이 GE junction 에서 3cm 이상일때 Short-segment Barrett s esophagus(ssbs) : 3cm 미만일때 Complication Barrett s esophagus Definition A change in the distal esophageal epithelium of any length that can

8 역류성식도염의진단및치료 / 박영규 Treatment (3): Surgical Tx laparoscopic fundoplication 적응증 장기간 PPI 유지치료가필요한환자에서장기간약물치료피하기위해 PPI 투여로증상이충분히조절되지않는환자의일부에서시도 효과 Good: 위식도역류가증명되고 PPI 에반응좋았던경우 Poor: 위식도역류뚜렷하지않고, medical Tx 에반응적었던경우 바렛식도 한계 Long term f/u 부족, 국내수술경험부족 Complication Barrett s esophagus Definition 식도하부의정상편평상피점막이화생성원주상피로치환된것 (Columnar metaplasia of the esophagus) Tranditional(long-segment) : columnar epithelium 이 GE junction 에서 3cm 이상일때 Short-segment Barrett s esophagus(ssbs) : 3cm 미만일때 Complication Barrett s esophagus Definition A change in the distal esophageal epithelium of any length that can be recognized as columnar type mucosa at endoscopy and is confirmed to have intestinal metaplasia by biopsy of the tubular esophagus Adequate biopsy for diagnosis of IM : 8 specimen British society exclude the need for IM from the diagnosis (Updated guideline 2008 BE Am J Gastroenterol 2008) Complication Barrett s esophagus 임상적의의 역류성식도염환자의 10% 백인의경우 0.5%/1 년 선암으로진행 50 X increased incidence of cancer as compared to the general population Barrett s Esophagus 내시경 : EGJ 보다상방으로이동한 SCJ 조직검사 : goblet cell 을포함한 columnar metaplasia SCJ GEJ 173

2013 대한임상건강증진학회추계합동학술대회 Barrett s Esophagus Length of Barrett s Esophagus Prague Criteria SCJ SCJ Goblet cell C2M5 GEJ SCJ metaplasia Normal CLE BE Gastoenterology 2006;131:1392 1399 Biopsy of

9%) M/55, Acid regurgitation X X X X 4) 1cm 간격 4 방향 (15.2%) 5) 2cm 간격 4 방향 (15.

9 2013 대한임상건강증진학회추계합동학술대회 Barrett s Esophagus Length of Barrett s Esophagus Prague Criteria SCJ SCJ Goblet cell C2M5 GEJ SCJ metaplasia Normal CLE BE Gastoenterology 2006;131: Biopsy of Barrett s Esophagus Seattle protocol Gastric fold의 proximal margin에서시작 4-quadrant biopsy 2 cm 간격 HGD에서는 1 cm 간격 4 cm 길이의바렛식도라면 12개조직검사 국내의현실 1) 안한다 (17.4%) 2) 1-2개 (28.3%) 3) 3-4개 (23.9%) M/55, Acid regurgitation X X X X 4) 1cm 간격 4 방향 (15.2%) 5) 2cm 간격 4 방향 (15.2%) X X Complication Barrett s esophagus Treatment (without dysplasia) PPI 장기간투여시이형성및식도암의발생이낮았다는보고 NSAIDs/aspirin COX-2 억제제투여한경우선암의발생을줄일수있음 Aspirin 복용환자에서선암발생위험을 43% 줄여줌 Others 비타민 A, C, E 등과같은항산화제 Statin 야채나과일등 Complication Barrett s esophagus Treatment (with dysplasia) EMR 병변의크기가작고국소적인경우시도 크기가큰경우한번에절제불가능 ESD 큰병변을일괄절제가능 고도의이형성을동반한바렛식도나조기바렛식도암의치료에사용 174

10 역류성식도염의진단및치료 / 박영규 Barrett s Cancer 175

11 2013 대한임상건강증진학회추계합동학술대회 장기간 PPI 사용의부작용 흡수장애 : Vit B12, Iron, Mg, Ca 저하 Long term use of PPI 골다공증, 골절 위의위축성변화진행 or 증식성병변 : fundic gland polyp, gastric Ca 위장관계감염증가 : C. difficile, Salmonella, Campylobacter 폐렴증가 약물상호작용 : Clopidogrel ( 항혈전제 ) 의약효저하 1. 흡수장애 Subclinical Vit B12 deficiency 원인 장기간저산증 : 단백질에포함된 Vit B12 의분리과정이저해 소장내세균과증식 : Vit B12 의흡수저하 임상적의의 Vit B12 부족으로인한빈혈, 신경병증은거의없다 Hypomagnesemia Sx: rare but severe ( 근육경련, 감각저하, 전신쇠약감, 정신혼란 ~) PPI 투여를중단하면 1-2 주내에회복, oral Mg replacement 위험인자 : 고령, 이뇨제복용자, digoxin 복용자, 당뇨병, 심혈관계질환, 장절제술 Hx 장기간 PPI 투여시 Mg level 확인필요!! 2. 골다공증및골절 장기간 PPI 사용이골대사에미치는영향 가설 칼슘흡수의억제 PPI 에의해파골세포 (osteoclast) 의프로톤펌프의억제 Vit B12 의부족으로조골세포 (osteoblast) 의활성도에영향 PPI 에의한고가스트린혈증이부갑상선과형성을유발 PTH 를증가시켜골밀도를감소 임상적의의 장기간 PPI 사용시고관절골절위험성증가할수있음 단기연구상 Ca 흡수저하에는영향없음 젊고건강한일반인에서의골절위험성증가는아직명확한결론없음 고위험군 ( 고령이나, 스테로이드투여, 만성음주 / 흡연, 골다공증의고위험군 ) 에서는최소용량의 PPI 사용 & 수용성 Ca 제제, Vit D 등을함께투여, 필요시 BMD check 3. 위의위축성 or 증식성변화 Fundic gland polyps m/c gastric polyps, at most benign lesions Increased risk of fundic gland polyps (OR 2.2)with long-term use (1yr) of PPIs compared with short-term use (OR 1.0) Dysplastic changes in fundic gland polyps developing during PPI therapy are rare Hypergastrinemia Decreased acid production colonization of H. pylori in the body of stomach corpus predominant gastritis impairs acid secretion despite the increase in gastrin PPI therapy affects the pattern and severity of H. pylori gastritis and accelerates the process of corpus gland loss At present, there is no evidence to suggest that this increases the risk of gastric cancer Limited data from from both Japan and Europe: persistent corpus predominant gastritis and atrophy are major risk factors for the development of gastric cancer 4. 감염증가 Acid suppressive agents Loss of normal stomach acidity: associated with colonization of the normally sterile upper GI tract Affect leukocyte function Enteric infections Clostridium difficile Infection 지속적인저산증에의해 C.difficile 가발육형태로보다쉽게위장관내에서증식 Other infections: Salmonella, Campylobacter Pneumonia Subsequent studies confirmed the association of acid suppression with pneumonia, especially in critically ill patients Limitations: retrospective & small sized study 임상적의의는아직부족하며대규모장기간연구가필요함 176

Guidelines 2012 for Gastroesophageal Reflux Disease ( 위식도역류질환임상진료지침개정안 2012) (Korean J Gastroenterol Vol. 60 No.

12 역류성식도염의진단및치료 / 박영규 Clopidogrel 5. 약물상호작용 Am J Gastroenterol 2010; 105: References Guidelines for the Diagnosis and Management of Gatroesophageal Reflux Disease (Am J Gastroenterol 2013; 108: ) Updated Guidelines 2012 for Gastroesophageal Reflux Disease ( 위식도역류질환임상진료지침개정안 2012) (Korean J Gastroenterol Vol. 60 No. 4, October 2012) 전공의와개원의를위한소화기내시경아틀라스 ( 대한소화기내시경학회 ) 위식도역류질환에서양성자펌프억제제의장기처방 ( 대한내과학회지 : 제 84 권제 2 호 2013) Long-term Safety Concerns with Proton Pump Inhibitors (The American Journal of Medicine, Vol 122, No 10, Oct. 2009) Cardiovascular and Gastrointestinal Outcomes in Clopidogrel Users on Proton Pump Inhibitors: Results of a Large Dutch Cohort Study (Am J Gastroenterol 2010; 105: ) 177

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<B0E6C8F1B4EBB3BBB0FAC0D3BBF3B0ADC1C E687770> 개원의와함께하는임상강좌 2011 역류성식도질환제대로이해하기 Division of Gastroenterology, Department of Internal Medicine, Kyung Hee University College of Medicine, Seoul, Korea Jae-Young Jang, M.D., PhD. 개원의와함께하는임상강좌 2011 109 최신치료