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1 대한내과학회지 : 제 89 권제 2 호 특집 (Special Review) - 헬리코박터파일로리감염의최신지견 헬리코박터파일로리감염의진단과치료 : 국내및국외의진료지침 서울대학교의과대학내과학교실, 간연구소 최지민 김상균 Diagnosis and Treatment of Helicobacter Pylori Infection: Korean and Overseas Guidelines Ji Min Choi and Sang Gyun Kim Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea The Korean College of Helicobacter and Upper Gastrointestinal Research proposed revised guidelines for the diagnosis and treatment of Helicobacter pylori infection in These new guidelines were developed using an adaptation process, and addressed the revised recommendations especially in the changes of indication and treatment of H. pylori infection in Korea. They included 19 statements: 11 on the indications for tests and treatment, four for the diagnosis, and four for the treatment. A critical difference between the new and previous guidelines was that the proposed treatment regimen was more detailed, in consideration of the increasing resistance to antibiotics in Korea. Although clarithromycin-containing triple therapy was proposed as the first-line treatment option, per the previous guidelines, a bismuth-based quadruple regimen was also proposed as an effective alternative. In the case of treatment failure following bismuth quadruple therapy, second-line treatment should be based on two or more antibiotics that had not been used previously. Several overseas guidelines from America, Europe, Canada, Japan, and the Asia-Pacific region have been published concerning H. pylori infection; they indicate regional differences in epidemiology, antibiotic susceptibility, and national health insurance systems. This review compares the guidelines for H. pylori infection among these regions. (Korean J Med 2015;89: ) Keywords: Helicobacter pylori; Guideline; Diagnosis; Therapeutics 서론 1998년대한상부위장관 헬리코박터학회의전신인대한 Helicobacter pylori (H. pylori) 연구회에서 한국인에서의 H. pylori 감염의진단및치료 라는제목으로진료지침을발 표하였던이래로, H. pylori 에관한연구결과가축적되면서 H. pylori 감염이위암을포함한상부위장관질환의중요한원인으로주목받아왔다 [1]. 이에힘입어국내에서도건강보험으로인정되는제균치료의적응증이확대되었고, 이에따라 H. pylori 제균치료가점차증가하였다 [2]. 이러한배경 Correspondence to Sang Gyun Kim, M.D., Ph.D. Division of Gastroenterology, Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul , Korea Tel: , Fax: , harley1333@hanmail.net * This work was supported by a grant from Liver Research Institute, Seoul National University College of Medicine. Copyright c 2015 The Korean Association of Internal Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

2 - The Korean Journal of Medicine: Vol. 89, No. 2, Table 1. Level of evidence and grade of recommendation Items Level of evidence Definitions A. High-quality evidence Further research is unlikely to change our confidence in the estimate of effect. Consistent evidence from RCTs without important limitations or exceptionally strong evidence from observational studies. B. Moderate-quality evidence C. Low-quality evidence Strength of recommendation Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Evidence from RCTs with important limitations (inconsistent results, methodologic flaws, indirect or imprecise), or very strong evidence from observational studies. Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Evidence for at least one critical outcome from observational studies, case series, or from RCTs with serious flaws, or indirect evidence, or expert s consensus. 1. Strong recommendation Recommendation can apply to most patients in most circumstances. 2. Weak recommendation The best action may differ depending on circumstances or patient or society values. Other alternatives may be equally reasonable. RCT, randomized controlled trial. 아래 2009년대한 Helicobacter 및상부위장관연구학회가주축이되어 H. pylori 감염의진단및치료에대한진료지침을개정하여보급하였으나, 이진료지침은근거평가방법이체계적이지못하였고, 국내전문가의견을도출하는방법에서객관성이떨어졌으며, 다학제참여가부족하였다는한계점이있었다. 최근의연구성과에따르면, 국내에서 H. pylori 제균을위해양성자펌프억제제를포함한삼제요법이주로사용된 2005년이후 40대미만을중심으로 H. pylori 감염률은감소하는양상이며, 재감염률또한상대적으로높지않다 [2-4]. 이러한변화된역학적특성및위암과의높은연관성을고려하였을때기존의 H. pylori 감염의진단및치료의적응증, 치료방법에대한재고가필요하며, 이에 2013년대한상부위장관 헬리코박터학회의주도로개정된진료지침이발표되었다 [5-11]. 새로운진료지침은수용개발 (adaptation) 방법을통해개정되었으며, 1995년부터 2012년 7월사이에발표된근거중심의진료지침중국문또는영문으로작성된지침등의조건을통해수용개발의대상을선정하였다 [12]. 각지역의진료지침은해당국가및지역에서의 H. pylori 의역학, 항생제내성률및국가건강보험체계등에따라세부내용에차이를보이는데, 이들중총 6개의진료지침 년국내헬리코박터진료지침, 2007년 American College of Gastroenterology 진료지침, 2012년 Maastricht IV/Florence 진료지침, 2009년아시아- 태평양진료지침, 2009년일본진료지침, 2004년캐나다진료지침 - 을바탕으로국내여건에맞게개정안을마련하였다 [13-18]. 이에 H. pylori 제균치료의적응대상에대한지 침 11개, 진단에대한지침 4개, 치료에대한지침 4개로총 19개의권고안을채택하였고, 권고안마다근거수준및권고등급을같이제시하였다 (Table 1) [19,20]. 새로개정된진료지침에서는과거제균에대한근거가부족한것으로판단되었던위축성위염및장상피화생환자에서도제균치료의필요성이언급되었으며, 점차증가하는국내의항생제내성률을감안하여제균치료방법에도변화가있었다. Clarithromycin 내성이의심되는경우일차제균치료로서기존의삼제요법대신이전진료지침에서는이차치료제로사용이권고되었던 bismuth 포함사제요법을첫치료로고려할수있게하였고, bismuth 포함사제요법에실패한경우기존에사용되지않은항생제 2개이상을포함하여구성하도록권고하였다. 본고에서는개정된 H. pylori 감염의진단및치료에대한국내진료지침의세부내용및대표적인국외의 6개의진료지침을비교, 분석해보고자한다. H. pylori 감염의국내임상진료지침권고안 H. pylori 제균치료의적응증 1. H. pylori 에감염된소화성궤양환자에서제균치료가필요하다 ( 근거수준및권고등급 : Grade 1A). 2. 점막연관림프조직림프종 (mucosa-associated lymphoid tissue lymphoma) 에서 H. pylori 제균치료가필요하다 ( 근거수준및권고등급 : Grade 1A). 3. H. pylori 에감염된조기위암환자는내시경절제술후제균치료가필요하다 ( 근거수준및권고등급 : Grade 1A)

3 - Ji Min Choi, et al. Guidelines of Helicobacter pylori infection - 소화성궤양, 점막연관림프조직림프종및내시경으로절제된조기위암은국내권고안에서제균치료를강력히추천하는세가지질환이다. H. pylori 제균치료는위 십이지장궤양치료에도움을주며재발방지및출혈등의합병증감소에효과가있다 [21-23]. 또한위에서발생하는점막연관림프조직림프종의 60-90% 는 H. pylori 감염과연관이있는것으로알려져있으며, 이러한환자에서 H. pylori 제균치료는 60-80% 에이르기까지내시경적, 조직학적호전을유도한다 [24,25]. 한편, 조기위암에서내시경절제술이후 H. pylori 제균치료를시행하면이시성병변 (metachronous gastric cancer) 의발생이감소한다는여러문헌보고가있으나, 일부에서는상반된결과를보이고있어이에대해서는추가적인연구가필요하다 [26-28]. 4. 위축성위염 / 장상피화생환자의일부에서 H. pylori 제균치료가위암예방에도움이된다 ( 근거수준및권고등급 : Grade 2C). 5. 위암의가족력이있는경우 H. pylori 에감염된가족에서제균치료가위암예방에도움이될수있다 ( 근거수준및권고등급 : Grade 2B). 국내권고안에서는위암예방을목표로한위축성위염및장상피화생환자에서의제균치료는권고등급이낮다. 특히장상피화생을대상으로한연구들은제균치료후에도조직학적호전을보이지못한경우가대부분으로, 장상피화생은위암발생과정중 point of no return 을지난것으로간주된다 [15,17,29-32]. 그러나내시경으로위축성위염환자에서동반된초기장상피화생의유무를구별하기쉽지않기때문에이전연구들에선택편향 (selection bias) 이개입되었을가능성이있으며, 위축성위염환자에서의긍정적인연구결과를고려할때제균치료를통해위축성위염과장상피화생환자에서일부염증을호전시키고위암발생을감소시킬수있을것으로기대한다. 위암환자의직계가족은정상대조군에비해 2-3배더높은위암발생률을나타내며, 직계가족력과 H. pylori 감염이동시에있는경우에는상승효과가있어대조군에비해 5-8 배더높은위암발생률을보고하였다 [33-35]. 그러나현재까지제균치료후에위암발생이감소하였다는연구결과는없으며, 국내권고안에서도위암환자의직계가족에대한제균치료는권고등급이낮다. 향후연구가필요한부분이다. 6. 소화불량증에서는 H. pylori 검사후제균치료보다내시경검사를권장한다 ( 근거수준및권고등급 : Grade 1C). 7. 일부기능성소화불량증에서 H. pylori 제균치료가장기적증상개선에도움이된다 ( 근거수준및권고등급 : Grade 2A). 8. H. pylori 제균치료는위식도역류질환의발생및임상경과에영향을미치지않는다 ( 근거수준및권고등급 : Grade 2B). 서구에서는나이가젊고경고증상이없는소화불량증에대해 H. pylori 감염여부를확인하여양성이면비교적안전하면서도의료비용을감소시킬수있는제균치료를먼저하는방법 (test-and-treat strategy) 을권장하고있다 [36-40]. 그러나우리나라는위암의유병률이높고발병연령이낮으며, 내시경비용이상대적으로적어소화불량증환자에서기질적질환의가능성을배제하기위한내시경검사를먼저권장한다 [41-43]. 또한기능성소화불량증환자에서 H. pylori 제균치료를통한증상개선의유무는연구마다다른결과를보고하였고, 모든기능성소화불량증환자에게제균치료를하는것은항생제내성등의문제가발생할수있어비용효과에대한분석결과를기반으로치료의효과와위험성을고려하여야한다 [44-49]. 한편, H. pylori 에의한전정부및체부위염에서는위산분비기능이감소될수있는데, 이런환자의제균치료는위산분비를증가시켜위식도역류질환이악화될수있는가능성이있다 [50,51]. 그러나인구기반관찰연구에서는위식도역류질환의유병률과 H. pylori 감염이역의상관성을보였으나, 제균치료후에위식도역류질환의임상양상을평가한연구에서는의미있는결과를보이지못하였다 [52-55]. 9. 소화성궤양의병력이있는환자에서장기간저용량아스피린을투여하는경우소화성궤양재발방지를위하여 H. pylori 제균치료가필요하다 ( 근거수준및권고등급 : Grade 2C). 10. 장기간비스테로이드소염제를투여하는환자에서 H. pylori 제균치료만으로는소화성궤양발생의위험을감소시키지못한다 ( 근거수준및권고등급 : Grade 1A). 11. 만성특발성혈소판감소성자반증환자에서 H. pylori 제균치료를권장한다 ( 근거수준및권고등급 : Grade 1A). 아스피린은소화성궤양의위험인자로, 특히 H. pylori 감염이동반된경우궤양발생의위험성이증가한다 [56,57]. 소화성궤양의병력이있는 H. pylori 양성환자에서제균치료가성공한경우에는장기간아스피린을투여하더라도소화성궤양재발에의한출혈위험은매우낮게보고되어소화성궤양및합병증의병력이있는경우에는제균치료를권장한다 [58]. 비스테로이드소염제의경우, 장기간투여시

4 - 대한내과학회지 : 제 89 권제 2 호통권제 660 호 H. pylori 제균치료가궤양발생의위험을줄일수있다는연구결과와함께그렇지않다는결과의연구들이함께존재한다 [59-63]. 특히이전에소화성궤양의병력이있었던경우에는장기간의비스테로이드소염제사용이그원인일가능성이높으므로제균치료단독으로는궤양의재발을예방하는데부족하며, 양성자펌프억제제를함께투여하는것이궤양의재발을막을수있다 [59]. 만성특발성혈소판감소증환자의일부에서 H. pylori Cag A 단백과혈소판항원이교차분자유사성을보이는데, 이로인한면역반응결과혈소판감소증이유발될수있다 [64]. 국외의여러연구에서 H. pylori 제균치료에따른임상적인효과를보이고있어권고안에서만성특발성혈소판감소증환자의제균치료를강력히권고하고있으나, 아직까지국내의연구결과는없어이에대한추시가필요하다. H. pylori 감염의진단 12. H. pylori 진단의비침습적검사방법으로요소호기검사, 대변항원검사와혈청검사등이있으며, 요소호기검사와대변항원검사의경우검사직전 2 주간항생제혹은양성자펌프억제제를중단하여야한다 ( 근거수준및권고등급 : Grade 1B). H. pylori 진단의비침습적검사방법에는요소호기검사, 대변항원검사및혈청검사등이있으며, 내시경을이용하지않으므로환자의불편이감소되고비용이적게드는장점이있다. 요소호기검사는 95% 이상의높은민감도와특이도를보이며시행이용이하여널리사용된다 [65]. 그러나항생제나양성자펌프억제제를사용중이거나, 중단한직후에는 30% 이상의위음성을보일수있어최소한검사시행 2주전에이를중단하도록추천한다 [66-68]. 대변항원검사는다클론항체및단클론항체를이용한방법이이용되고있으며, 단클론항체법의민감도와특이도가각각 94% 및 97% 로보고되어다클론항체법에비해높았다 [69-71]. 대변항원검사역시양성자펌프억제제나항생제사용후에일부에서위음성이관찰되는단점이있다 [72]. 혈청검사는비침습적이고가격이비교적저렴하며쉽고빠르게검사할수있다는장점이있으나, 제균치료후에항체가사라지거나역가가의미있게감소하기위해서는 1년이상의기간이소요되기때문에제균치료의성공여부를바로판정하기에는부적당하여제균치료의추적관찰방법보다는감염의선별검사로이용된다 [73]. 양성자펌프억제 제나항생제를복용한환자나출혈성궤양환자등다른검사에서위음성의결과를보일가능성이높은경우에는혈청검사가도움이될수있다 [74]. 13. H. pylori 의침습적진단방법으로급속요소분해효소검사또는조직검사를추천한다 ( 근거수준및권고등급 : Grade 1B). 14. H. pylori 진단의침습적검사를위해서는전정부및체부에서각각조직을채취하는것이바람직하나, 한곳에서만시행하는경우위축성위염및장상피화생이없거나적은부위에서조직을채취하는것을권장한다 ( 근거수준및권고등급 : Grade 1B). 내시경을통한 H. pylori 진단방법에는급속요소분해효소검사 (rapid urease test), 조직검사및배양검사등이사용되고있다. 침습적검사또한검사직전 2주간항생제혹은양성자펌프억제제를중단하지않는경우진단이부정확할수있다 [68]. 급속요소분해효소검사는위생검조직을요소기질에넣어 H. pylori 가분비하는요소분해효소에의해생성된암모니아에의해 ph가상승하는것을색조변화로알아보는간편하고정확한검사로서, 민감도 85-98%, 특이도 % 로보고되고있다 [75]. 조직검사는 H. pylori 진단외에도점막의염증, 위축그리고장상피화생등과같은추가정보를얻을수있는장점이있다. H&E 염색외에 Giemsa 등의특수염색법을병행하면특이도를 % 까지높일수있어, Giemsa 혹은 Warthin- Starry은염색법등의특수염색법을병용하는것을추천한다 [76,77]. H. pylori 제균치료에실패한경우에는균배양을통해항생제내성검사를시행함으로써이차혹은삼차제균요법을선정할수있다. 그러나검사방법이복잡하고오래걸리므로배양검사를 H. pylori 감염의일차진단목적으로이용하기는어렵다. 이러한위생검조직을이용한진단방법들은균이위점막에균일하게분포하고있지않은경우가있어생검위치및개수에따라위음성의가능성이있다 [78]. 특히, 위축성위염및장상피화생은 H. pylori 의생존에호의적인환경이아니므로균이발견되지않을수있다 [79]. 따라서전정부에서 2 표본이상, 체부에서 2 표본이상조직을채취하는것이바람직하며, 한곳에서만생검을시행하는경우에는위축성위염및장상피화생이없거나적은부위에서조직을채취하는것을권장한다 [79,80]

5 - 최지민외 1 인. 헬리코박터파일로리국내외진료지침 제균확인검사는제균치료종료 4 주 ( 양성자펌프억제제는 2 주 ) 후시행한다. 비침습적검사로는요소호기검사또는대변항원검사를, 침습적검사로는전정부와체부에서조직검사혹은급속요소분해효소검사를추천한다 ( 근거수준및권고등급 : Grade 1B). 제균치료종료직후에는위음성의가능성이있으므로적어도 4주 ( 양성자펌프억제제는 2주 ) 후에제균확인검사를시행하는것을추천하며, 비침습적인제균확인검사로요소호기검사를추천한다 [14-17,65,81,82]. 대변항원검사역시국내소아에서제균후의민감도와특이도가 89% 및 92% 로서유용한검사이지만임상적편리성이떨어지므로, 성인에서는요소호기검사를주로이용한다 [83]. 기저질환의추적관찰을위해내시경검사가필요한경우조직검사혹은급속요소분해효소검사를통해 H. pylori 제균성공여부를확인할수있다. 제균치료후에는박멸여부에상관없이 H. pylori 집락의감소와불균등분포로인해전정부와체부에서각각 2 표본이상조직을채취하는것을추천한다 [84]. H. pylori 감염의치료 16. 일차제균치료는삼제요법으로서양성자펌프억제제표준용량, amoxicillin 1 g, clarithromycin 500 mg 을하루 2 회 7-14 일간투여한다 ( 근거수준및권고등급 : Grade 1A). 17. Clarithromycin 내성이의심되는경우일차제균치료로서 bismuth 를기본으로한사제요법인양성자펌프억제제표준용량하루 2 회, metronidazole 500 mg 하루 3 회, bismuth 120 mg 하루 4 회, tetracycline 500 mg 하루 4 회로 7-14 일간투여한다 ( 근거수준및권고등급 : Grade 1A). 일차적인 H. pylori 제균요법으로적합하기위해서는최소한 80% 이상의제균율을보여야한다 [85]. 현재까지일차치료로권고되고있는것은양성자펌프억제제, clarithromycin 및 amoxicillin을포함한삼제요법이다 [13,86]. 제균기간에있어서는최근의제균율저하를극복하기위해 14일로투여기간을늘려삼제요법을시행한일부연구에서는제균율이향상되었으나, 다른연구에서는 7일군과차이가없는등상반된결과가보고되어아직결론이나지않았다 [87-89]. 한편, 최근 10년동안 clarithromycin 내성률이점차증가하고있어제균율저하의주원인이되고있다 [90]. 국내에서도지역에따라제균율의차이를보이는만큼기존의삼제요법의제균율이저하된지역의경우 clarithromycin 내성률이높을가능성이있으므로, 이러한지역에서는기존의삼제요법 과제균율에서큰차이를보이지않는 bismuth 포함사제요법을일차치료로고려해볼수있다 [14-16,18]. 18. 일차제균치료로서삼제요법에실패한경우이차치료로 bismuth 를기본으로한사제요법을시행한다 ( 근거수준및권고등급 : Grade 1A). 19. 일차제균치료로서 bismuth 를기본으로한사제요법에실패한경우의이차제균치료는일차치료에사용하지않은항생제 2 개이상을포함하여구성한다 ( 근거수준및권고등급 : Grade 1C). Bismuth 를기본으로한사제요법은양성자펌프억제제표준용량 1일 2회, metronidazole 500 mg 1일 3회, bismuth 120 mg 1일 4회, tetracycline 500 mg 1일 4회로 7-14일동안투여함을원칙으로한다. 이러한사제요법은현재까지발표된여러국내외진료지침에서이차치료법으로서의효과를인정받고있는전통적인치료법이다 [13-16,91,92]. 다만, 치료기간에따른제균율의차이에대해서는여러연구에서엇갈린보고를하고있어추가연구가필요하다. 제균치료실패시에는, 이전치료약제에대한내성발현가능성을고려하여가급적이면이전치료에사용하지않았던약제들로이차치료약제를구성하는것이원칙이다 [14-17]. 이를바탕으로일차제균치료로서 bismuth를기본으로한사제요법에실패한경우순차치료, 동시치료등을이차치료로고려할수있다. 그러나이와같은요법은현재까지주로일차치료의대안으로연구가이루어져있으며, 삼차치료로서의효과는규명되지않은상태이다. 순차치료 순차치료는양성자펌프억제제와 amoxicillin으로 5일간치료하고, 이후 5일간양성자펌프억제제와 clarithromycin, nitroimidazole (metronidazole 또는 tinidazole) 을사용하는것으로구성되어있다. 순차치료의이론적근거는초기 amoxicillin 을병합한이제요법이위강내세균밀도를낮추어이후투여되는 clarithromycin 포함삼제요법의효과를증가시킬수있으며, 또한 amoxicillin이세균의세포벽을약화시키고유출채널의발달을저해하여, 이후투여되는 clarithromycin 내성을예방할수있다는것이다 [93,94]. 동시치료 Bismuth 비포함사제요법이라고도불리는동시치료는 clarithromycin 포함삼제요법과동시에 nitromidazole을투여하는것이다. 국내의연구에의하면 5일간의동시치료는 clarithromycin 포함삼제요법과제균율에통계적차이가없었으며, 순차치료와동시치료를비교한연구에서는두치료법간

6 - The Korean Journal of Medicine: Vol. 89, No. 2, 에제균율차이는없었다 [95,96]. 국외임상진료지침권고안의비교분석세계각국가및지역마다 H. pylori 감염및이로인한질환의유병률은다양하며, 최근증가하는항생제내성또한지역별로다양한정도로보고되어, 각국가의특성을고려한진단및치료지침이제정되어왔다. 2013년국내임상진료지침개정안마련의토대가된 6개지역의대표적인진료지침들의구체적인차이는다음과같으며, 이중일본의진료 지침은 2013년새로개정된진료지침을대상으로분석하였다 [11,14-16,18,97,98]. H. pylori 제균치료의적응증각진료지침에서제시하는 H. pylori 제균치료의적응증은표 2와같다. 제균치료가인정되는세부항목은진료지침마다차이가있으며, Maastricht IV/Florence 진료지침에서가장많은적응증을제시하고있다 [15]. 소화성궤양및점막연관림프조직림프종환자에서는 6개의대표적인진료지침에서모두제균치료를강력히권고하고있으나, 국내진료 Table 2. Strongly-recommended indications of Helicobacter pylori eradication in various guidelines American College of Gastroenterology (2007) Maastricht IV/Florence Consensus (2012) Second Asia-Pacific Consensus (2009) Japanese Society of Helicobacter Research (2013) Canadian Helicobacter Study Group (2004) Korean College of Helicobacter and Upper Gastrointestinal Research (2013) Peptic ulcer Peptic ulcer Peptic ulcer Peptic ulcer Peptic ulcer Peptic ulcer Gastric MALT lymphoma After endoscopic resection of EGC Gastric MALT lymphoma After endoscopic or surgical resection of EGC Gastric MALT lymphoma Uninvestigated Uninvestigated dyspepsia b Uninvestigated dyspepsia a dyspepsia c Gastric MALT lymphoma After endoscopic resection of EGC Gastric MALT lymphoma Uninvestigated dyspepsia c Functional dyspepsia Non-ulcer dyspepsia Before starting NSAID Before starting NSAID Aspirin user with a history of peptic ulcer Iron-deficiency anemia ITP ITP ITP First-degree relatives of family members with GC Risk of gastritis d H. pylori-related gastritis Chronic gastric acid inhibition for 1 year Strong environmental risk factors for GC e H. pylori-positive patients with a fear of GC Communities with high incidence of GC Patients wishes Gastric MALT lymphoma After endoscopic resection of EGC MALT, mucosa-associated lymphoid tissue; EGC, early gastric cancer; NSAID, nonsteroidal antiinflammatory drug; ITP, idiopathic thrombocytopenic purpura; GC, gastric cancer; H. pylori, Helicobacter pylori. a Patients with uninvestigated dyspepsia who are under the age of 55 year and have no alarm features. b In populations where the H. pylori prevalence is high ( 20%). c Patients with uninvestigated dyspepsia who have no alarm features. d Severe pan-gastritis, corpus-predominant gastritis, severe atrophy. e Heavy smoking, high exposure to dust, coal, quartz, cement and/or work in quarries

7 - Ji Min Choi, et al. Guidelines of Helicobacter pylori infection - 지침에서제균치료가강력히추천되는내시경으로절제된조기위암환자의경우, 아시아-태평양및캐나다진료지침에서는권고등급이낮다 [11,14-16,18,97,98]. 소화불량증을호소하는환자에대한우선치료로 H. pylori 제균치료를권할지여부에대해서는서구와한국및일본등의위암유병률이높은국가의진료지침사이에차이를보인다. 국내에서는위암의발병연령이낮고, 유병률이높으며내시경비용이상대적으로적어소화불량증환자에서제균치료보다내시경검사를먼저권하나, 서구에서는경고증상이없고나이가젊은소화불량증에대해서는 H. pylori 감염여부를먼저확인하여양성이면제균치료를먼저권장한다 [11,14-16,18]. 새로개정된일본의진료지침에서가장두드러진차이점은국가건강보험에서모든 H. pylori 감염환자의제균치료를보험범위내로인정해주면서, H. pylori 연관성위염 이라는광범위한질환을제균치료의적응증으로인정한점이다 [97,98]. H. pylori 감염의진단각진료지침에서 H. pylori 감염의초기진단및제균치료후추적관찰에권장하는검사방법은다음과같다 (Table 3). H. pylori 감염의초기진단시국내진료지침에서는비침습적방법및배양검사를제외한침습적방법중하나를시행하도록권하고있으며, 미국진료지침에서는최근양성자펌프억제제의광범위한사용으로급속요소분해효소검사의임 상적인유용성이감소하였음을고려하여급속요소분해효소검사단독보다는다른침습적검사또는비침습적검사와병행할것을추천한다 [11,14]. 한편, 일본진료지침에서는검사의위음성을배제하기위해서침습적인검사보다는비침습적검사두가지이상을동시에시행하는것을권고하며, 유럽, 아시아-태평양및캐나다진료지침에서는초기진단시혈청검사를추천하지않는것에비해일본에서는이를가장신뢰도가높은검사로인정한다 [15,16,18,97,98]. 또한, 국내진료지침에서는침습적인검사방법인배양검사가검사방법이복잡하고오래걸려초기진단의수단으로는권장하지않고있으나, 유럽및일본의진료지침에서는이를초기진단의한방법으로인정하고있다 [11,15,97,98]. 제균치료여부를알기위한검사에서도각국의진료지침사이에차이점을보이는데, 국내, 미국, 유럽및아시아-태평양가이드라인에서는공통적으로요소호기검사또는대변항원검사등의비침습적검사나, 전정부와체부에서의조직검사혹은급속요소분해효소검사등의침습적검사를추천하며일본에서는추가적으로혈청검사및배양검사또한유용한검사로인정한다 [11,14-16,97,98]. 특히혈청검사의경우, 제균치료후항체가사라지거나역가가의미있게감소하려면 6-12개월정도의기간이소요되어일본을제외한다른진료지침에서는제균치료의추적관찰방법으로추천하지않고있음에반해일본에서는제균 6개월후에항체역가가치료전의 50% 미만으로떨어지면성공적인제균치료로판 Table 3. Recommended diagnostic testing for Helicobacter pylori in various guidelines American College of Gastroenterology (2007) Maastricht IV/Florence Consensus (2012) Second Asia-Pacific Consensus (2009) Japanese Society of Helicobacter Research (2013) Canadian Helicobacter Study Group (2004) Korean College of Helicobacter and Upper Gastrointestinal Research (2013) UBT, urea breath test; SAT, stool antigen test; RUT, rapid urease test. Initial diagnosis Follow-up after eradication Non-invasive Invasive Non-invasive Invasive UBT SAT Serology RUT Histology Culture UBT SAT Serology RUT Histology Culture Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο

8 - 대한내과학회지 : 제 89 권제 2 호통권제 660 호 Table 4. Treatment of Helicobacter pylori infection in various guidelines American College of Gastroenterology (2007) Maastricht IV/Florence Consensus (2012) a Second Asia-Pacific Consensus (2009) Japanese Society of Helicobacter Research (2013) Canadian Helicobacter Study Group (2004) Korean College of Helicobacter and Upper Gastrointestinal Research (2013) First-line CLR-containing triple therapy for days Bismuth-based quadruple therapy for days Sequential therapy Low CLR resistance area: CLR-containing triple or bismuth-based quadruple therapy High CLR resistance area: Bismuth-based quadruple or non-bismuth quadruple (either sequential or concomitant) CLR-containing triple therapy for 7 days Bismuth-based quadruple therapy for 7-14 days CLR-containing triple therapy for 7 days b CLR-containing triple therapy for 7 days Bismuth-based quadruple therapy for days CLR-containing triple therapy for 7-14 days Bismuth-based quadruple therapy for 7-14 days Second-line Bismuth-based quadruple therapy for 7-14 days Levofloxacin-based triple therapy for 10 days Low CLR resistance area: Bismuth-based quadruple or levofloxacin-based triple therapy High CLR resistance area: Levofloxacin-based triple therapy Standard triple therapy that has not been previously used Bismuth-based quadruple therapy for 7-14 days Levofloxacin-based triple therapy for 10 days Rifabutin-based triple therapy Metronidazole-containing triple therapy for 7 days Bismuth-based quadruple therapy for days Bismuth-based quadruple therapy for 7-14 days Regimen including other 2 or more antibiotics CLR, clarithromycin. a A threshold of 15-20% was recommended to separate the regions of low and high clarithromycin resistance. b In Japan, CLR-containing therapy regimen consists of lower dose of antibiotics than other countries; Japan: Proton pump inhibitor (PPI), amoxicillin 750 mg, and CLR 200 mg (or 400 mg) twice daily; Other countries: PPI, amoxicillin 1,000 mg, and CLR 500 mg twice daily. 단한다 [97,98]. 한편, 캐나다의진료지침에서는다른진료지침과는달리대변항원검사는초기진단및제균후의검사에서도유용성을인정받지못하였다 [18]. H. pylori 감염의치료 Clarithromycin 포함삼제요법은 6개의대표적인진료지침모두에서일차제균치료로인정되고있으며일본을제외한다른진료지침에서는 bismuth를기본으로한사제요법역시대체가능한일차제균치료요법으로제시하고있다 [11, 14-16,18,97,98] (Table 4). 유럽의진료지침에서는일차제균치료약제를선택함에있어해당지역의 clarithromycin 내성률을고려하도록하였고, 국내진료지침의경우 clarithromycin 내성이의심될때일차제균치료로 clarithromycin 포함삼제요법을생략하고바로 bismuth를기본으로한사제요법을투여하도록권고한다 [11,15]. 투약용량및기간에대해서도진료지침마다차이를보이는데, 특히일본의경우다른진료지침에비해항생제의투약용량이적고, 투약기간도 7일로짧다 [97,98]. 또한아시아-태평양및캐나다의진료지침에서 는 clarithromycin 포함삼제요법에서 metronidazole이대체가능한약제로인정되었으나, 일본에서는 metronidazole을일차제균치료에사용하는것을제한하고있으며, 국내에서는 fluoroquinolon에대한높은내성률로인해 H. pylori 제균치료제로의사용이제한적이다 [11,16,18,97,98]. 일차제균치료에실패하였을때는진료지침별로차이가있지만 bismuth를기본으로한사제요법또는 levofloxacin 포함삼제요법등을사용해볼수있으며, 국내진료지침에서는순차치료, 동시치료및 rifabutin 포함삼제요법도이차제균치료법으로제시되고있다 [11]. 일본에서는 bismuth를기본으로한사제요법은권장되지않는반면, 상대적으로낮은 metronidazole 내성률을고려하여 metronidazole 포함삼제요법을이차제균치료제로권장한다 [97,98]. 결론 2009년 H. pylori 진단및치료에대한개정된국내진료지침이도출된지 4년만에새로운개정안이발표되었다. 이번

9 - 최지민외 1 인. 헬리코박터파일로리국내외진료지침 - 진료지침에서는위암의전구병변으로인정되고있는위축성위염및장상피화생에서도제균치료의필요성이일부언급되었고, 제균치료의방법으로증가하는 clarithromycin 의내성률을고려하여 bismuth 포함사제요법을대체가능한일차치료요법으로제시하였다. 또한, 제균치료실패시선택할수있는대안으로순차치료, 동시치료등의요법을추가하였다. 최근증가하는항생제내성률을고려하였을때, 이차치료에도불구하고제균이되지않은경우국외의진료지침에서는 CYP2C19 다형성및항생제내성검사등을통한맞춤형치료를시도하고있으며, 국내에서도이에대한적극적인연구가필요할것으로생각된다 [15,16]. 중심단어 : 헬리코박터파일로리 ; 진료지침 ; 진단 ; 치료 REFERENCES 1. Korean H. Diagnosis and treatment of Helicobacter pylori infection in Korea. Korean J Gastroenterol 1998;32: Yim JY, Kim N, Choi SH, et al. Seroprevalence of Helicobacter pylori in South Korea. Helicobacter 2007;12: Niv Y. H pylori recurrence after successful eradication. World J Gastroenterol 2008;14: Kim MS, Kim N, Kim SE, et al. Long-term follow-up Helicobacter pylori reinfection rate and its associated factors in Korea. Helicobacter 2013;18: Shin A, Kim J, Park S. Gastric cancer epidemiology in Korea. J Gastric Cancer 2011;11: Chang WK, Kim HY, Kim DJ, et al. Association between Helicobacter pylori infection and the risk of gastric cancer in the Korean population: prospective case-controlled study. J Gastroenterol 2001;36: Cho SJ, Choi IJ, Kim CG, et al. Helicobacter pylori Seropositivity Is Associated with Gastric Cancer Regardless of Tumor Subtype in Korea. Gut Liver 2010;4: Lee SA, Kang D, Shim KN, Choe JW, Hong WS, Choi H. Effect of diet and Helicobacter pylori infection to the risk of early gastric cancer. J Epidemiol 2003;13: Shin A, Shin HR, Kang D, Park SK, Kim CS, Yoo KY. A nested case-control study of the association of Helicobacter pylori infection with gastric adenocarcinoma in Korea. Br J Cancer 2005;92: Kim N, Park RY, Cho SI, et al. Helicobacter pylori infection and development of gastric cancer in Korea: long-term follow-up. J Clin Gastroenterol 2008;42: Kim SG, Jung HK, Lee HL, et al. Guidelines for the diagnosis and treatment of Helicobacter pylori infection in Korea, 2013 revised edition. Korean J Gastroenterol 2013;62: Fervers B, Remy-Stockinger M, Graham ID, et al. Guideline adaptation: an appealing alternative to de novo guideline development. Ann Intern Med 2008;148: ; author reply Kim N, Kim JJ, Choe YH, Kim HS, Kim JI, Chung IS; Korean College of Helicobacter and Upper Gastrointestinal Research; Korean Association of Gastroenterology. Diagnosis and treatment guidelines for Helicobacter pylori infection in Korea. Korean J Gastroenterol 2009;54: Chey WD, Wong BC; Practice Parameters Committee of the American College of Gastroenterology. American College of Gastroenterology guideline on the management of Helicobacter pylori infection. Am J Gastroenterol 2007;102: Malfertheiner P, Megraud F, O'Morain CA, et al. Management of Helicobacter pylori infection--the Maastricht IV/ Florence Consensus Report. Gut 2012;61: Fock KM, Katelaris P, Sugano K, et al. Second Asia-Pacific Consensus Guidelines for Helicobacter pylori infection. J Gastroenterol Hepatol 2009;24: Asaka M, Kato M, Takahashi S, et al. Guidelines for the management of Helicobacter pylori infection in Japan: 2009 revised edition. Helicobacter 2010;15: Hunt R, Fallone C, Veldhuyzan van Zanten S, et al. Canadian Helicobacter Study Group Consensus Conference: Update on the management of Helicobacter pylori--an evidence-based evaluation of six topics relevant to clinical outcomes in patients evaluated for H pylori infection. Can J Gastroenterol 2004;18: Guyatt GH, Cook DJ, Jaeschke R, Pauker SG, Schünemann HJ. Grades of recommendation for antithrombotic agents: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008;133 (6 Suppl):123S-131S. 20. Schünemann HJ, Oxman AD, Brozek J, et al. Grading quality of evidence and strength of recommendations for diagnostic tests and strategies. BMJ 2008;336: Leodolter A, Kulig M, Brasch H, Meyer-Sabellek W, Willich SN, Malfertheiner P. A meta-analysis comparing eradication, healing and relapse rates in patients with Helicobacter pylori-associated gastric or duodenal ulcer. Aliment Pharmacol Ther 2001;15: Sharma VK, Sahai AV, Corder FA, Howden CW. Helicobacter pylori eradication is superior to ulcer healing with or without maintenance therapy to prevent further ulcer haemorrhage. Aliment Pharmacol Ther 2001;15: Miwa H, Sakaki N, Sugano K, et al. Recurrent peptic ulcers in patients following successful Helicobacter pylori eradication: a multicenter study of 4940 patients. Helicobacter 2004;9:

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