대한내과학회지 : 제 86 권제 6 호 2014 http://dx.doi.org/10.3904/kjm.2014.86.6.655 특집 (Special Review) - 소화성궤양에대한최신지견 Helicobacter pylori 연관소화성궤양 한림대학교의과대학강동성심병원소화기내과 서승인 김학양 Helicobacter pylori-related Peptic Ulcer Disease Seung In Seo and Hak Yang Kim Division of Gastroenterology, Department of Internal Medicine, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea Although the worldwide prevalence of Helicobacter pylori (H. pylori) infection has decreased, peptic ulcer disease (PUD) remains prevalent due to increased usage of non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin. In recent years, the prevalence of H. pylori infection in PUD cases and the distribution of PUD have changed in Korea. The incidence of idiopathic H. pylori-negative ulcers has increased, and research is needed to determine the cause of these idiopathic ulcers. The eradication of H. pylori infection decreases PUD recurrence, and plays a crucial role in the treatment of PUD. The H. pylori test-and-treat strategy is beneficial for patients starting NSAIDs and long-term aspirin users with a history of bleeding ulcers. Although the H. pylori eradication rate is declining steadily due to antibiotic resistance, especially to clarithromycin, current guidelines still recommend standard triple therapy, including a proton pump inhibitor, amoxicillin, and clarithromycin, as a first-line therapy. Recently, various treatment regimens, including sequential or concomitant therapies, have been developed in an attempt to overcome the low eradication rate observed with standard triple therapy. The aim of this article is to review recent trends in H. pylori-related PUD, focusing on epidemiology and treatment strategies. (Korean J Med 2014;86:655-663) Keywords: Helicobacter pylori peptic ulcer; Epidemiology; Treatment 서론 Helicobacter pylori (H. pylori) 는세계인구의 50% 이상에서감염을보이는가장흔한감염균으로만성위염과위궤양, 십이지장궤양, 위암및변연부 B세포림프종등을일으키는것으로알려져있다 [1]. H. pylori 제균치료는소화성궤양의 재발방지와출혈등의합병증발생을감소시키는것으로입증되어있으며이에각국의지침에서는모든소화성궤양환자에서 H. pylori 의제균치료를권고하고있다 [2-7]. 국내에서는대한상부위장관 헬리코박터학회에서 1998년에처음으로진단및치료가이드라인을제정한후 2009년에두번째가이드라인, 2013년에는세번째가이드라인이발표되었다. Correspondence to Hak Yang Kim, M.D. Division of Gastroenterology, Department of Internal Medicine, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, 150 Seongan-ro, Gangdong-gu, Seoul 134-701, Korea Tel: +82-2-2224-2113, Fax: +82-2-2224-2647, E-mail: bacter@hallym.or.kr Copyright c 2014 The Korean Association of Internal Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution - 655 - Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
- The Korean Journal of Medicine: Vol. 86, No. 6, 2014 - Figure 1. Trends of seroprevalence of H. pylori infection in asymptomatic subjects without a history of H. pylori eradication in 1998, 2005, and 2011 [11]. 현재까지전세계적으로표준치료로여겨지고있는것은 proton pump inhibitor (PPI), amoxicillin 과 clarithromycin을기본으로하는삼제요법이다. 그러나 H. pylori 에대한항생제내성의증가로국내뿐만아니라전세계적으로제균율이낮아지고있으며이로인해최근 H. pylori 의치료에대한연구가활발히이루어졌다. 본고에서는 H. pylori 연관소화성궤양에관한모든분야를다루기에는제한이있어최근발표된가이드라인을바탕으로역학과치료에대하여중점적으로정리해보고자한다. 본 론 H. pylori 연관소화성궤양의역학 H. pylori 감염은 Nonsteroidal anti-inflammatory drugs (NSAIDs) 와함께소화성궤양의주요한원인으로알려져있다. 소화성궤양의유병률은전세계적으로 0.1-4.7% 로연간발생률은 0.19-0.3% 정도로보고된다 [8]. 국외대다수의연구에서소화성궤양의발생률과유병률의감소를보고하였는데이는 H. pylori 연관소화성궤양의감소로인한결과로추정된다 [9]. H. pylori 감염의빈도는선진국일수록낮고개발도상국에서높으며성별, 연령, 지역적분포및종족간에차이를보인다. 최근 22개국가에서시행한 37개의연구를분석한메타분석에따르면전세계적으로 H. pylori 의감염률은전반적인사회경제적요인과위생상태의개선에따라감소하는결과를 보였으며 [10], 국내에서역시무증상성인에서 H. pylori 의혈청학적유병률은 1998년 66.9% 에서 2005년 59.6%, 2011년 54.4% 로유의하게감소하는추세를보였다 (Fig. 1) [11]. H. pylori 균은십이지장궤양의약 73-100%, 위궤양환자의약 65-100% 에서검출되며 [12-14], 다수의연구에서십이지장궤양에서 H. pylori 감염의유병률이더높은것으로알려져있다 [15,16]. 그러나국내에서시행한다기관전향적연구에의하면 1994년과 2004년을비교하였을때 10년전에비하여위궤양에서의 H. pylori 감염의유병률은 66.1% 에서 73.1% 로증가하였으며, 십이지장궤양에서는반대로 79.3% 에서 68.1% 로감소하여소화성궤양에서 H. pylori 감염의분포에변화가있음을보여주었다 [17]. 또한이연구에서 1994년과비교하여 2004년에위궤양의유병률이 44.3% 에서 47.8% 로증가하고십이지장궤양의경우 44.9% 에서 38.9% 로감소하는결과를보여주었는데그원인은위궤양환자에서평균연령이높아 aspirin과 NSAIDs를복용한경우가많았기때문으로설명하였다. 국내 17개병원에서시행한역학연구에따르면소화성궤양의유병률은 1995년에 18%, 2005년에 20.2% 로증가하는양상을보여서구에서의보고와달리 H. pylori 제균치료의발전에도불구하고여전히높은유병률을나타냈다. 특히위궤양의비율이 9.6% 에서 12% 로증가하고이중에서도 NSAIDs 와같은약물에의한위궤양은 17.6% 에서 28% 로점차증가하는경향을보여인구의고령화에따라소화성궤양의원인이변화하고있음을시사하였다 [18]. 또한 H. pylori 나 NSAIDs 와관련이없는소위특발성궤양 (idiopathic ulcer) 의유병률이전세계적으로 4-40% 로증가하는경향을보였으며국내연구에서도 22% 정도로높게나타나이에대한추가적인연구가필요한상태이다 [17,19]. 소화성궤양으로인한출혈은상부위장관출혈의가장흔한원인으로전체의약 30-50% 를차지하고있으며소화성궤양출혈에서 H. pylori 감염의유병률은 72% 정도로보고되고있다 [20]. 강력한위산분비억제제와내시경지혈술의발전, H. pylori 제균치료로소화성궤양출혈의발생률과사망률의감소가예상되었으나인구의고령화와 aspirin, NSAIDs 사용의증가로인해실제소화성궤양출혈의빈도는감소하지않았으며 [21], 여전히 5.8% 정도의사망률을나타낸다 [22,23]. 출혈을동반한궤양에서 H. pylori 감염의진단정확도가감소할수있고진단의위음성은특발성궤양의비율증가와 - 656 -
- Seung In Seo, et al. Helicobacter pylori-related peptic ulcer disease - 연관이될수있다. 따라서특발성궤양으로오진하지않기위해서는출혈궤양에서적어도두가지이상의다른검사법을사용하여 H. pylori 감염을정확히진단하는것이중요하며이를토대로한소화성궤양의원인에대한역학연구가필요하다고생각된다. H. pylori 와 Aspirin, NSAIDs 실제임상에서는인구고령화에따라퇴행성질환과심혈관계질환의유병률이증가하면서이들질환군에서 H. pylori 감염은높고 NSAIDs, aspirin 의사용이동반되는경우가흔하다. NSAIDs는다양한기전을통해위장관손상을주게되는데 NSAIDs 장기사용자의 2-5% 에서소화성궤양의합병증으로입원치료를받으며 [24], aspirin의장기복용은매년위장관출혈의위험성을 0.04% 정도증가시키는것으로알려져있다 [25]. Aspirin 이소화성궤양출혈의위험인자인것은잘알려져있으며특히과거소화성궤양및출혈의병력, 고령, 신부전, 항응고제나스테로이드제제를함께투여한경우와 H. pylori 감염이동반된경우에궤양출혈발생의위험이증가한다 [26]. 이러한위험인자들중교정가능한것이 H. pylori 감염을확인하고치료하는것이기때문에이에대한많은연구가이루어졌다. Aspirin 을장기복용하는환자에서 H. pylori 의제균치료와 PPI 장기투여를비교한연구결과양군에서궤양예방효과에있어차이를보이지않았고 [27], 최근홍콩에서시행된 10년간의전향적코호트연구에의하면 aspirin 사용자에서 H. pylori 의성공적인제균치료시행후궤양재출혈의발생률이낮으므로제균치료가잘되었다면지속적인 PPI의복용이요구되지않으며단지항응고제나다른종류의 NSAIDs 를병용할경우선택적으로제균치료이후 PPI 사용이필요할수있다고제시하였다 [26]. 따라서 Maastricht IV/Florence 가이드라인과국내가이드라인에서는소화성궤양의병력이있는환자에서장기간저용량 aspirin 을투여하는경우소화성궤양재발방지를위하여 H. pylori 제균치료를시행하도록권고하고있으며과거소화성궤양병력이나다른위험요인이없는경우에서 H. pylori 의제균치료의필요성에대해서는아직권장되지않는다 [6,7]. H. pylori 와 NSAIDs는모두소화성궤양의독립적인위험인자이며두인자가동시에작용시궤양출혈에상승작용을하는것으로알려져있다. 처음 NSAIDs를투여시약물투 여전 H. pylori 의제균치료는소화성궤양과그합병증발생을줄이는것으로알려져있어권장되며소화성궤양병력이있는경우필수적으로권장된다 [7]. 그러나장기간 NSAIDs 를투여하는환자에서 H. pylori 감염이궤양발생에미치는영향과효용성에대한연구는부족하며제균치료가궤양발생의위험을줄일수있다는연구들과영향이없거나오히려궤양치유를지연시킨다는여러상반되는연구결과를보인다 [28-30]. 이중외국의한메타분석에의하면 H. pylori 제균치료보다는 PPI의사용이궤양을방지하는데효과적이었다고결론지어 [30] 장기간 NSAIDs 사용자에서제균치료만으로는소화성궤양발생의위험을감소시키지못함을시사하였다. H. pylori 연관소화성궤양의치료 H. pylori 제균치료는소화성궤양치료의근간이되며합병증이없는십이지장궤양에서제균치료후지속적인 PPI의사용은권장되지않으며합병증이있는십이지장궤양과위궤양에서는궤양이치유될때까지제균치료후지속적인 PPI 의사용이필요하다고알려져있다 [7]. 적합한 H. pylori 제균치료법은 per protocol analysis (PP 분석 ) 에서 90% 이상, intention-to-treat analysis (ITT 분석 ) 에서 80% 이상의제균율을보여야하는데전세계적으로제균율이감소함에따라최근의가이드라인에서도몇가지변화가있었다. 일차치료최근수년간전세계적으로 clarithromycin을포함하는삼제요법의제균율이감소하고있음에도불구하고 [31-34], 여전히국내와국외가이드라인에따르면 PPI 표준용량, amoxicillin 1.0 g, clarithromycin 500 mg을 1일 2회 1-2주간투여하는것을표준일차치료로권고하고있다 [6,7]. 제균율감소에영향을미치는인자로는항생제내성률이외에도복용순응도, 기저질환, 흡연, 항생제사용과거력등이있으며일차치료의제균율을향상시키기위한여러가지대안이제시되었다. 먼저치료기간에따른삼제요법의제균율을분석한결과에서 7일에서 14일로의기간연장이의미있는제균율상승을보여주지못했다는국내연구들이있었으나 [35, 36], 국외 4개의메타분석에의하면치료기간의연장이약 5% 정도제균율을높일수있다고결론지어일차치료시이를고려해볼수있겠다 [7]. - 657 -
- 대한내과학회지 : 제 86 권제 6 호통권제 646 호 2014 - Table 1. Helicobacter pylori treatment algorithm according to clarithromycin resistance Regions with low prevalence of clarithromycin resistance Regions with high prevalence of clarithromycin resistance First line PPI-clarithromycin-amoxicillin/metronidazole or Bismuth Quadruple Bismuth Quadruple If not available: non-bismuth Quadruple (either sequential or concomitant) Second line Bismuth Quadruple or PPI-levofloxacin/amoxicillin PPI-levofloxacin/amoxicillin Third line Based on susceptibility testing only Treatment regimen should be selected according to areas of low and high clarithromycin resistance. Low prevalence of clarithromycin resistance if < 20%, high prevalence if > 20%. Adapted from Figure 1 of the article by Malfertheiner et al. Gut 2012;61:646-664 [7]. PPI의종류에따른제균율에대한분석을보면, rabeprazole 과 esomeprazole이다른 PPI에비하여위산분비억제능력이강하다는실험적연구결과들이있었으나 [37] 대다수의메타분석에서 PPI의종류에따라제균율에차이가없었다 [38,39]. 이에상반되는결과로최근국내대구, 경북지역의 13년다기관연구에서는 esomeprazole과 rabeprazole 투여군에서제균율이높게나타났으나후향적연구이고누락된자료가많아제한점이있으며 [40], 외국의최근메타분석에서도 esomeprazole, rabeprazole 투여군에서약간의향상된제균율을보였으나임상적으로의미있는차이를보이지는못하였다 [41]. 국내에서 clarithromycin 은과거에는내성이거의관찰되지않았으나최근 10년동안내성률이점차증가하여제균율저하의주요원인이되고있으며국내한단일기관연구에의하면 2003-2005년 16.7% 에서 2007-2009년 38.5% 로급격한내성률의증가를보고하였다 [42]. 이에 2012년 Maastricht IV/ Florence 가이드라인에서는 clarithromycin 내성률 20% 을기준으로제균치료전략을달리하는것으로개정되었다 (Table 1) [7]. 2013년개정된국내가이드라인에서역시 clarithromycin 내성이의심되는경우 bismuth를기본으로한사제요법 (PPI 표준용량 1일 2회, metronidazole 500 mg 1일 3회, bismuth 120 mg 1일 4회, tetracycline 500 mg 1일 4회 ) 을일차치료로고려해볼수있다고권고하였다 [6]. 최근중합효소연쇄반응 (polymerase chain reaction) 을이용해서 H. pylori 의 clarithromycin 내성을조직검사를통해비교적간단하게알아낼수있는검사법이상품화되어일부진료현장에서사용되고있다 [43]. 이검사의민감도와특이도는 80-85% 정도로최근국내한연구에의하면제균치료전 clarithromycin 내성에따라맞춤형치료 (tailored therapy) 를하였을경우제균율이 PP 분석에서 91.2% 로표준삼제요법 75.9% 에비해통계적으로유의하게높게나타나 [44] 향후맞춤형치료가표준일차치료의새로 운대안으로고려될수있을것으로생각된다. 이차치료일차치료로삼제요법에실패한경우이차제균치료로 bismuth를기본으로한사제요법을 7일에서 14일간투여함을원칙으로한다. 이러한사제요법은국내외여러진료지침에서이차치료법으로서의효과를인정받고있는전통적인치료법으로, 최근국내무작위배정연구에서대체로 80% 이상의제균율을보고하였으며치료기간에따른제균율에대해서는엇갈린보고를하고있어향후연구가필요하다 [45-47]. 일차치료로 bismuth를기본으로한사제요법에실패한경우이차제균치료는일차치료에사용하지않은항생제 2개이상을포함하여구성하는것을원칙으로한다. 최근활발한연구가진행되고있는순차치료 (sequential therapy) 와동시치료 (concomitant therapy) 는주로일차치료에대한연구이나일차치료로 clarithromycin과 nitroimidazole을사용하여제균에실패할경우이차치료약제선택에어려움이예상되므로국내가이드라인에서는이차치료로이를권고하고있다. 순차치료는 PPI와 amoxicillin으로 5일간치료하고, 이후 5일간 PPI와 clarithromycin, nitroimidazole (metronidazole 또는 tinidazole) 을사용하는것으로구성되어있다. 순차치료의이론적근거는초기 amoxicillin을사용하는이제요법으로위내의 H. pylori 수를감소시켜이후투여하는삼제요법의효과를높이고, amoxicillin이세포벽을약화시키고 clarithromycin 의유출채널 (efflux channel) 의발달을저해함으로써 clarithromycin 내성발현을줄인다는이론이다 [48,49]. 순차치료와관련된국내여러연구에서순차치료가 ITT 분석에서제균율 77.8-85.9% 로 clarithromycin 포함삼제요법의제균율 62.2-75% 에비해효과적이었다 [50-55]. 그러나국내에서는 clarithromycin - 658 -
- 서승인외 1 인. Helicobacter pylori 연관소화성궤양 - 과 metronidazole 에동시내성을보이는비율이상대적으로높아순차치료의제균율이외국에비해낮으므로 [51,56,57] 기존의표준삼제요법을대신하는치료로는아직까지부족할수있을것이라판단되며기간및용량의변화등추가적연구가필요할것으로생각된다. 동시치료는 bismuth를사용하지않는사제요법으로순차치료에사용되는세가지항생제, amoxicillin, clarithromycin, metronidazole 또는 tinidazole을 PPI와함께동시에투여하는방법이다. 2000년이후발표된 3개의국외메타분석에서동시치료의제균율은 ITT 분석에서 90% 정도로표준삼제요법에비해우수한결과를보였으나 [58-60] 최근시행된국내의연구에서동시치료의제균율은외국보다는낮아 ITT 분석에서 80.7% 로표준삼제요법의제균율 72.6% 에비해높았으나통계적차이는없었다 [61]. 동시치료는환자의순응도를높여순차치료에비하여제균율을높일것으로예상되었으나동시치료와순차치료를비교한국내연구결과에서제균율은 ITT 분석에서각각 80.8% 와 75.6% (p = 0.42) 로두치료법간에통계적인제균율차이는없었고 [62], 최근발표된스페인의다기관전향적연구에서도 ITT 분석에서각각 87% 와 81% (p = 0.15) 로동시치료에서통계적인제균율의향상은보여주지못하였다 [63]. 삼차치료두번의제균치료에실패하였을경우삼차치료에대해서는아직표준화된치료법이없는실정이다. Maastricht IV/ Florence 가이드라인에서는항생제감수성결과를토대로약제선택을할것을권고하고있으며아시아- 태평양가이드라인에서는 CYP2C19 다형성을고려하여약제선택을하도록권고하고있으나 [7,64] 실제진료현장에서이를이용하기가쉽지않다. 삼차구제요법으로사용가능한약물로 quinolone 계열을고려해볼수있는데 levofloxacin을주로일차치료또는순차치료에 clarithromycin을대체하여사용한연구들이있었고 [65] 국내에서는 53.3-74% 정도로외국에비해낮은제균율을보여주었으며 [66] 이는국내에서 quinolone계항생제사용증가에따른내성률증가때문으로생각된다. 새로운 quinolone 인 sitafloxacin 이 H. pylori 의 quinolone 내성에중요한역할을하는 gyra 돌연변이에대해강력한효과를나타내어가장낮은 MIC (minimum inhibitory concentration) 를나타낸다는 실험연구를바탕으로 [67] 최근에발표된일본의연구에서는표준치료와이차치료에실패한경우에서 sitafloxacin을토대로한삼제요법치료시 PP분석에서 90% 이상의제균율을나타내는결과를보여주어이에대한연구가더필요하겠다 [68]. 이외에비정형결핵치료에사용되는 rifabutin을삼차치료에사용해볼수있으나골수억제등의부작용과국내소규모후향적연구에서 71.4% 정도의낮은제균율을나타낸점을고려하였을때 [69], 여러번의제균치료에실패한경우에한하여제한적으로사용해볼수있을것이다. 기타치료유산균제제의사용이 H. pylori 제균치료에보조적으로유용하게사용될수있음이여러연구를통해입증되었다. 국내연구에서 Saccharomyces boulardii를일주일간일차치료와함께 4주간투약하였을때의미있는제균율의향상을보였으며 [70] 국외여러메타분석에서도 S. boulardii, Lactobacillus가제균율을의미있게증가시키고부작용, 특히설사를감소시키는결과를보여 [71,72] 향후유산균제제의보조치료역시일차치료에서고려해볼수있겠다. 또한 simvastatin을삼제요법에추가로투여하여제균율의향상을보여준연구결과도있었다 [73]. 이렇듯제균율감소를극복하기위한많은연구들이이루어졌고항생제내성에따른제균실패를줄이기위한항생제원칙에대한다음과같은제안도있었는데, 1) 해당지역사회에서 PP분석에서 90% 이상의제균율을보이지않을경우 PPI를기본으로하는삼제요법을사용하지말것, 2) clarithromycin, metronidazole 저용량이효과가없다면고용량 500 mg을사용할것, 3) 7일요법으로효과가없다면 14일로기간을연장할것, 4) 과거 clarithromycin을사용했거나흔히처방되는지역에서는 clarithromycin 포함삼제요법을사용하지말것, 5) quinolone 계열의약제를이전에사용한적이있는경우사용하지말것, 6) 일차치료실패후 clarithromycin 과 quinolone 을사용하지말아야한다는것으로 [74] 항생제내성이높은국내현실을감안하여고려해볼만한권고로생각된다. 맺는말 H. pylori 감염과관련된소화성궤양은전반적으로감소하 - 659 -
- The Korean Journal of Medicine: Vol. 86, No. 6, 2014 - 고있으나 NSAIDs, aspirin 사용과고령인구의증가로전체소화성궤양의유병률은여전히높은상태이다. H. pylori 감염률의전반적인감소와함께 H. pylori 음성특발성궤양의비율이과거에비해증가하여 H. pylori 감염의정확한진단과약물복용력의자세한문진이더욱중요하게되었으며이를바탕으로하는대규모역학연구가필요한실정이다. H. pylori 제균치료는소화성궤양의재발과합병증방지를위해필수적이다. H. pylori 제균치료가활발히이루어지면서항생제내성의증가로지난 10년간제균율은전반적으로감소하는결과를보여주었고이에따른다양한치료가시도되었다. 여전히표준일차치료에는변함이없으나 clarithromycin 내성이의심되는경우 bismuth 기본사제요법을권고하며순차치료, 동시치료를일차치료의대안으로한연구결과에서제균율의향상을나타내어이에대한연구가지속되어야하겠다. 국내의 clarithromycin 내성이증가하는현실을감안하여 clarithromycin 내성을확인하여치료하는맞춤형치료에대해서도대규모전향적연구가필요하다. 현재대한상부위장관 헬리코박터학회주관으로 H. pylori 제균율에대한전국적인다기관연구가시행되었으며향후이결과를바탕으로하는국내가이드라인개정이필요하다고생각한다. 중심단어 : 헬리코박터파일로리 ; 소화성궤양 ; 역학 ; 치료 REFERENCES 1. McColl KE. Clinical practice: helicobacter pylori infection. N Engl J Med 2010;362:1597-1604. 2. Ford AC, Delaney BC, Forman D, Moayyedi P. Eradication therapy for peptic ulcer disease in Helicobacter pylori positive patients. Cochrane Database Syst Rev 2006;(2): CD003840. 3. Hentschel E, Brandstätter G, Dragosics B, et al. Effect of ranitidine and amoxicillin plus metronidazole on the eradication of Helicobacter pylori and the recurrence of duodenal ulcer. N Engl J Med 1993;328:308-312. 4. 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 pyloriassociated gastric or duodenal ulcer. Aliment Pharmacol Ther 2001;15:1949-1958. 5. 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;9:9-16. 6. 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; 62:3-26. 7. Malfertheiner P, Megraud F, O'Morain CA, et al. Management of Helicobacter pylori infection: the Maastricht IV/ Florence Consensus Report. Gut 2012;61:646-664. 8. Sung JJ, Kuipers EJ, El-Serag HB. Systematic review: the global incidence and prevalence of peptic ulcer disease. Aliment Pharmacol Ther 2009;29:938-946. 9. Wang AY, Peura DA. The prevalence and incidence of Helicobacter pylori-associated peptic ulcer disease and upper gastrointestinal bleeding throughout the world. Gastrointest Endosc Clin N Am 2011;21:613-635. 10. Peleteiro B, Bastos A, Ferro A, Lunet N. Prevalence of Helicobacter pylori infection worldwide: a systematic review of studies with national coverage. Dig Dis Sci 2014 Feb 22 [Epub]. DOI:10.1007/s10620-014-3063-0. 11. Lim SH, Kwon JW, Kim N, et al. Prevalence and risk factors of Helicobacter pylori infection in Korea: nationwide multicenter study over 13 years. BMC Gastroenterol 2013; 13:104. 12. Borody TJ, George LL, Brandl S, et al. Helicobacter pylori-negative duodenal ulcer. Am J Gastroenterol 1991; 86:1154-1157. 13. Ciociola AA, McSorley DJ, Turner K, Sykes D, Palmer JB. Helicobacter pylori infection rates in duodenal ulcer patients in the United States may be lower than previously estimated. Am J Gastroenterol 1999;94:1834-1840. 14. Jang MK, Kim HY, Cho BD, et al. Prospective Study for the prevalence of Helicobacter pylori infection in patients with gastric ulcer and duodenal ulcer among Korean population. Korean J Med 1997;52:457-465. 15. Kuipers EJ, Thijs JC, Festen HP. The prevalence of Helicobacter pylori in peptic ulcer disease. Aliment Pharmacol Ther 1995;9(Suppl 2):59-69. 16. Tsuji H, Kohli Y, Fukumitsu S, et al. Helicobacter pylorinegative gastric and duodenal ulcers. J Gastroenterol 1999; 34:455-460. 17. Jang HJ, Choi MH, Shin WG, et al. Has peptic ulcer disease changed during the past ten years in Korea? a prospective multi-center study. Dig Dis Sci 2008;53:1527-1531. 18. Kim JI, Kim SG, Kim N, et al. Changing prevalence of upper gastrointestinal disease in 28 893 Koreans from 1995 to 2005. Eur J Gastroenterol Hepatol 2009;21:787-793. 19. Chow DK, Sung JJ. Is the prevalence of idiopathic ulcers really on the increase? Nat Clin Pract Gastroenterol Hepatol 2007;4:176-177. - 660 -
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