대한소화기내시경학회지 2008;37:161-166 Helicobacter pylori 재감염과관련된임상적요인에대한분석 서울대학교의과대학내과학교실, 간연구소, * 분당서울대학교병원내과 김재환ㆍ양효준ㆍ장은선ㆍ조은주ㆍ조현진ㆍ천재영ㆍ최종경ㆍ황성욱ㆍ이상협 * 박영수 * ㆍ황진혁 * ㆍ김진욱 * ㆍ정숙향 * ㆍ김나영 * ㆍ이동호 * ㆍ정현채ㆍ송인성 Clinical Features of Re-infection of Helicobacter pylori after Successful Eradication Jai Hwan Kim, M.D., Hyo Joon Yang, M.D., Eun Sun Jang, M.D., Eun Ju Jo, M.D., Hyun Jin Jo, M.D., Jae Young Chun, M.D., Jong Kyung Choi, M.D., Sung Wook Hwang, M.D., Sang Hyub Lee, M.D.*, Young Soo Park, M.D.*, Jin Hyeok Hwang, M.D.*, Jin Wook Kim, M.D.*, Sook Hyang Jung, M.D.*, Na Young Kim, M.D.*, Dong Ho Lee, M.D.*, Hyun Chae Jung, M.D. and In Sung Song, M.D. Department of Internal Medicine and the Liver Research Institute, Seoul National University College of Medicine, Seoul, *Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea 목적 : H. pylori 의성공적인제균못지않게중요한것은재발한환자의치료이지만어떤환자에게서재발이잘일어나는지는알려진바가많지않다. 이러한 H. pylori 의재발, 특히재감염과관련된임상적인요인을찾는다면제균후환자를추적관찰할때선별적인검사가가능하므로임상적으로유용할수있으며이에본연구는 H. pylori 관련위장관질환이나내시경으로채취한위의조직학적소견등이재감염과관련이있는지살펴보고자하였다. 대상및방법 : 2003 년 5 월부터 2007 년 9 월까지분당서울대병원을방문하여 H. pylori 감염치료후제균판정뒤추적검사를시행한 129 명의환자를대상으로하였다. 제균치료는 PPI 를포함하는삼제또는사제요법으로이루어졌으며진단은조직학적검사나 CLO 검사, UBT 검사로하였다. 결과 : 129 명의환자들에게서제균한달이후추적검사를시행하였고 29 명에게서재발이발견되었으며, 그중 1 년내재발이 17 명, 1 년에서 2 년사이가 8 명, 2 년에서 3 년사이가 4 명, 3 년이후재발한경우는없었다. 29 명중만성위축성위염은 8 명, 소화성궤양 14 명, 위암 5 명, MALT 림프종 2 명이었고, 각위장관질환에따른재발률에는통계적인차이가없었다. 또한만성위염의등급을나타내는 H. pylori 군집밀도나호중구, 단핵구의침윤정도역시재발과는관련이없었다. 결론 : 만성위축성위염과소화성궤양, 위암및 MALT 림프종등위장관질환에따른재감염은질환들사이에통계적으로차이가없었으며, The Updated Sydney System 에따른만성위염의조직학적등급도재감염과는연관이없었다. 한편치료후재발은 1 년이내높은빈도를보이다이후감소하는경향을보였으며이점은 1 년이내재발하는경우재활성화가많이포함되어있다는기존연구들과같은결과였고, 본연구에서연간재감염률은약 6.2% 였다. 색인단어 : 헬리코박터, 재발, 재감염, 위장관질환, 조직학 서 론 접수 :2008 년 1 월 29 일, 승인 :2008 년 7 월 15 일연락처 : 이동호, 경기도성남시분당구구미동 300 번지 (463-802) 분당서울대학교병원내과전화 : 031-787-7029, 팩스 : 031-787-4052 이메일 : dhljohn@yahoo.co.kr H. pylori 감염은만성위축성위염과소화성궤양의중요한위험인자인동시에위암발생을증가시킨다는점에서임상적으로중요하며, 그간여러연구로 H. pylori의병태생리및제균치료에많은발전이있었던 161
162 대한소화기내시경학회지 2008;37:161-166 것에비해 1,2 제균성공후 H. pylori의재발과관련된임상적인요인들에대해서는아직알려진바가적다. 이러한 H. pylori의연간재발률은각나라의사회경제적수준및감염률에따라세계적으로약 0% 에서 73% 까지다양한정도로관찰되며, 3 국내에서보고된연구들에서는일년이내 18.3%, 일년이후연간 9.5% 재발했다는보고 4 와 26.8개월간연평균 6% 에서재발을했다는상대적으로높은재발률의보고 5 가있었으나가장최근발표된연구에서는 3년간연간재발률을 2% 라고보고한바있다. 6 한편이러한제균후재발과관련된임상적요인들에대해서이루어진일부연구에서환자의젊은나이, 7 제균확인을위해시행한 13 C-urea breath test (UBT) 상높은 delta score, 7,8 소화불량의증상정도 9 등이재발과관련이있다고보고되었으나, 그외다른요인들에대해서는아직까지잘알려진바가없다. 이에본연구에서는 H. pylori의재감염과관련된임상적요인을찾기위해 H. pylori 감염과관련이있다고알려진위장관질환들이재감염과상관관계가있는지알아보고자하였다. 또한같은맥락에서 H. pylori의군집밀도나위염의염증정도와위장관질환발생이관련되어있다 10 는점을감안할때제균치료전위조직의 The Updated Sydney System에따른 H. pylori 군집밀도, 호중구침윤, 단핵구침윤의정도가 H. pylori의재감염과상관관계가있는지살펴보고자하였다. 11 1. 연구대상 대상및방법 본연구는 2003년 5월부터 2007년 9월까지분당서울대학교병원에서 H. pylori 제균치료를받은환자들중제균치료후재발여부를확인하기위해추적검사를했던 129명의환자를대상으로하였으며환자들의의무기록을후향적인방법으로분석하였다. 연구에포함된 129명의환자중남자는 71명 (55%), 여자는 58명 (45%) 이었으며평균연령은 58.6±11.1세 ( 최소 26세, 최고 79세 ) 였다. 2. 연구방법 대상환자들의 H. pylori 감염여부는 13 C-UBT (Otsuka Electronics, UBiT-IR 300) 또는 rapid urease test (CLO, Kimberly-Clark, CLOtest Rapid Urease Test) 또는조직학적염색 (Wright Giemsa stain) 으로판단하였고, 제균여부는치료 4주이후세가지검사를하나이상시행하여모두가음성을보였을때로정의하였으며, 재발은제균판정을한뒤 1개월이상지난후재시행한추적검사들 중하나라도양성일경우라고정의하였다. 한편재발한환자들중 12개월이내재발한경우는재감염 (reinfection) 외에재활성화 (recrudescence) 가포함되어있다고여겨지기때문에 12개월이후재발한경우만을재감염이라고정의하였다. 12 환자들은일차치료약제로프로톤펌프억제제 (proton pump inhibitor, PPI) 를포함하는삼제요법 (omeprazole 20 mg bid 또는 lansoprazole 30 mg bid 또는 pantoprazole 40 mg bid, amoxicillin 1,000 mg bid, clarithromycin 500 mg bid) 으로치료받았으며, 일차약제에실패하였을경우이차약제로는 PPI와 bismuth를포함하는하는사제요법 (PPI, bismuth 120 mg qid, metronidazole 500 mg tid, tetracycline 500 mg qid) 또는 moxifloxacin을포함하는삼제요법 (PPI, amoxicillin 1,000 mg bid, moxifloxacin 400 mg qd) 으로치료받았다. 3. 통계분석 통계적분석은 SPSS version 12.0 for windows를사용하였으며재발시기에따른평균나이의비교를위해서는 ANOVA (Analysis of Variance) 를사용하였고, 성별의비교를위해서는 chi-square test를사용하였다. 위장관질환에따른추적기간의비교를위해서는 ANOVA를사용하였고, 질환에따른재감염과의관련성을비교하기위해서는 odds ratio와 Fisher s Exact test를사용하였다. 한편 The Updated Sydney System의각항목에따른재발혹은재감염여부의비교를위해서는 Fisher s Exact test를사용하였으며모든경우에서 p값이 0.05 미만일때를통계적으로유의하다고판정하였다. 결 1. 대상환자군의특성 129명의추적검사를받은환자들중 29명에서재발이발견되었고, 비재발군과 12개월이내재발한환자군, 12개월이후재발한환자군의평균연령은 58.8±11.1세와 60.0±11.5세, 55±10.6세로통계적인차이가없었으며 (p=0.46), 남녀환자는 53/47명과 10/7명, 8/4명으로역시통계적인차이는관찰되지않았다 (p=0.63). 그리고가장짧은기간동안추적검사가이루어진환자는 4개월이었고, 가장긴기간동안추적검사가이루어진환자는 49개월이었으며, 평균 20.83±9.88개월기간동안추적검사가이루어졌다. 한편재발이일어나지않은군과 12 개월이내재발이일어난군, 12개월이후재발이있었던재감염군의추적기간은각각 20.27±10.07, 24.00± 9.60, 26.33±7.77개월이었으며역시통계적인차이는없 과
김재환외 : Helicobacter pylori 재감염관련임상요인 163 었다 (p=0.07) (Table 1, Fig. 1). 2. 재발빈도및누적발생률 재발빈도 ( 발생률 ) 는 1년이내 17명 (13.2%) (6개월이내 7명 (5.4%), 6개월에서 1년사이 10명 (7.8%)), 1년에서 2 년사이가 8명 (6.2%), 2년에서 3년사이가 4명 (3.1%) 이었고 3년이상에서는관찰되지않았다 (Table 2, Fig. 2). 관찰기간동안재발군에서가장짧은기간에재발한환자는 2개월만에재발하였으며가장오랜기간후에재발한환자는 32개월만에재발하였고평균재발시기는 12.62±8.40개월이었다. 3. 위장관질환과재감염과의관계 재발환자중각질환의빈도는만성위축성위염 8명, 소화성궤양 14명, 위암 5명, MALT 림프종 (gastric mucosaassociated lymphoid tissue lymphoma, 점막연관림프종 ) 2 Table 1. Comparison of Demographic Features among Nonrecurrence, Recurrence within 12 Months and Recurrence after 12 Months Group Recurrence Recurrence Non-recurrence within after p-value 12 mo 12 mo No. of patients 100 17 12 Age (years) 58.78±11.07 60±11.50 55±10.63 0.46 Sex (Male/Female) 53/47 10/7 8/4 0.63 Mean follow-up periods (months) 20.27±10.07 24.00±9.60 26.33±7.77 0.07 명이었으며소화성궤양 14명중위궤양은 4명, 십이지장궤양 9명, 위와십이지장궤양모두있는환자는 1명이었고각질환에따른추적기간은통계적으로차이가없었다 (p=0.49)(table 3). 한편만성위축성위염환자군과소화성궤양환자군, 위암환자군에서각위장관질환에따른재발여부및재발시기는통계적으로유의하지않은범위에서의차이만관찰되었으며, 특징적으로 MALT 림프종환자 2명은모두재발하였는데 12개월이전과이후에각각재발을하였다 (Table 4). 이러한결과를바탕으로각위장관질환중재감염과더관련이있는질환이있는지여부를확인하기위해두질환을짝지어재발하지않은환자와재감염된환자를대상으로 odds ratio를구해비교해보았으나유의한통계적의미는찾을수없었다 (Table 5). 특히 MALT 림프종의경우상대적으로재활성화환자및재감염환자의비율은 Table 2. Mean Follow-up Periods of Non-recurrence, Recurrence within 12 Months and Recurrence after 12 Months Group Recurrence Recurrence Non-recurrence within after Total 12 mo 12 mo Until 12 mo 22 3 0 25 From 13 to 24 mo 47 5 4 56 From 25 to 36 mo 31 9 8 48 Total 100 17 12 129 Figure 1. Mean follow-up periods of groups of non-recurrence, recurrence within 12 months and recurrence after 12 months. Among 3 groups, there were no significant differences in follow-up periods. The circles represent mean value, and the bars represent 2 standard deviations (p=0.07). Figure 2. The number of patients and cumulative percentage of H. pylori recurrence according to the recurrence period. Like other previous studies, there was a high recurrent rate within one year and a rapid decline tendency after then.
164 대한소화기내시경학회지 2008;37:161-166 Table 3. Mean Follow-up Periods in Each Gastroduodenal Disease (Months) No. of patients Mean* SD Min Max CAG 55 20.51 9.65 6 44 PU 54 21.19 9.70 8 53 GC 18 23.33 11.82 6 49 MALTOMA 2 29.50 9.19 23 36 Total 129 21.33 9.97 6 53 CAG, chronic atrophic gastritis; PU, peptic ulcer; GC, gastric cancer; MALTOMA, mucosa-associated lymphoid tissue lymphoma; SD, standard deviation; Min, minimum; Max, maximum. *p=0.49 between groups. 높았지만추적이이루어진환자수가 2명으로매우적었기때문에통계적으로는유의한결과를얻을수없었다. 4. 만성위염의활동성과재발과의관계 129명의환자중제균치료전내시경조직검사를시행한환자는 102명으로재발하지않은환자 79명, 12개월이내재발한환자 14명, 12개월이후재발한환자 9 명이었고, The Updated Sydney System에따른 H. pylori 군집밀도나호중구침윤, 단핵구침윤등의만성위염활동성지표를 absent 또는 mild; weak, moderate 또는 marked; strong이라고하여재발혹은재감염과관련이있는지비교해본결과통계적으로유의한상관관계는 Table 4. Frequency and Percentage of H. pylori Recurrence in Each Gastroduodenal Disease Recurrence Recurrence Non-recurrence within after Total 12 mo 12 mo CAG 47 (85.5%) 3 (5.45%) 5 (9.0%) 55 (100%) PU 40 (74.1%) 11 (20.4%) 3 (5.5%) 54 (100%) GC 13 (72.2%) 2 (11.1%) 3 (16.7%) 18 (100%) MALTOMA 0 (0%) 1 (50%) 1 (50%) 2 (100%) Total 100 (77.5%) 17 (13.2%) 12 (9.3%) 129 (100%) CAG, chronic atrophic gastritis; PU, peptic ulcer; GC, gastric cancer; MALTOMA, mucosa-associated lymphoid tissue lymphoma; CAG vs PU, p=0.49; CAG vs GC p=0.24; PU vs GC p=0.45. Table 5. Comparison of Odds Ratio between Matched Two Gastroduodenal Diseases Odds ratio CI p-value CAG vs. PU 1.42 0.32 6.31 0.73 CAG vs. GC 0.46 0.10 2.19 0.38 CAG vs. MALTOMA 0.10 0.04 0.22 0.11 PU vs. GC 0.33 0.06 1.81 0.33 PU vs. MALTOMA 0.07 0.02 0.21 0.09 GC vs. MALTOMA 0.19 0.07 0.52 0.24 CAG, chronic atrophic gastritis; PU, peptic ulcer; GC, gastric cancer; MALTOMA, mucosa-associated lymphoid tissue lymphoma; CI, confidence interval. Table 6. Comparison of H. pylori Colonization Density, Neutrophil Infiltration, Monocyte Infiltration Grade of Pre-eradication Stomach Tissue between Non-recurrence versus Recurrence within 12 Months or after 12 Months Weak Strong Total vs within 12 mo p-value vs after 12 mo Colonization Non-recurrence 22 57 79 0.60 0.57 density Recurrence within 12 mo 4 11 15 Recurrence after 12 mo 3 7 10 Total 29 75 104 Neutrophil Non-recurrence 14 65 79 0.31 0.57 infiltration Recurrence within 12 mo 4 11 15 Recurrence after 12 mo 2 8 10 Total 20 84 104 Monocyte Non-recurrence 5 74 79 0.31 0.52 infiltration Recurrence within 12 mo 2 13 15 Recurrence after 12 mo 1 9 10 Total 8 96 104 Weak, absent or mild; Strong, moderate or severe; vs within 12 mo, non-recurrence versus recurrence within 12 months; vs after 12 mo, non-recurrence versus recurrence after 12 months.
김재환외 : Helicobacter pylori 재감염관련임상요인 165 관찰할수없었다 (Table 6). 고 H. pylori는각지역, 인종및연령마다매우다양한정도로감염되어있으며전세계적으로도약절반가량의인류가감염되었다고보고한연구가있고, 13 우리나라에서도성인의약 59.6% 에서혈청학적양성이라는보고가있을정도로매우유병률이높은감염질환이다. 14 따라서이에대한관리는사회전체의공공보건의료및관련질환의치료를위한비용과의료자원의절감 15 을위해서매우중요한동시에임상적으로는위십이지장궤양의치료및재발을감소시켜질환의자연경과를크게바꿀수있다는점 16 에서소화성궤양의관리에중요하며, 특히위암발생률이매우높은우리나라에서는위암의중요한위험인자중한가지를관리한다는측면에서도그역할은크다고할수있다. 2 이에본연구는 H. pylori의제균치료후재감염과관련된임상적인요인을찾는다면제균후추적관찰에서재감염가능성이높은환자에게보다선별적으로재감염여부를검사하여필요시재치료를통해관련질환들을보다효율적으로관리할수있다는배경에서이루어졌다. 본연구에서재발빈도는제균후 1년까지약 13.2% 정도로매우높았으나 1년이후 2년까지는약 6.2%, 2년이후 3년까지는약 3.1% 로 1년이내재발한군에비해현저히감소한경향을보여시간이지날수록재발률이감소하는양상을보였다. 이와같은 12개월전후재발률차이는다른전향적인연구 17 에서도관찰된결과로, 최근한연구에서는재발한환자의치료전후균주를 PCRbased RFLP (polymerase chain reaction-based restriction fragment length polymorphism) 등으로비교한결과 1년이내재발한경우동일한균주의빈도가높았다 18 라고보고하였다. 따라서본연구에서의제균후 1년이내높은제균률역시재감염외재활성화가포함되었기때문이라고여겨진다. 그러나기존연구들에서 12개월이후재감염률이비교적일정했던것에비해본연구에서는 2년째와 3년째의재감염률에차이가있었으며, 이러한차이를보이는이유는아마도재발하지않은환자들의평균추적기간이 20.27±10.07개월로 24개월미만의추적기간을갖는환자가전체 100명중 69명이나되었기때문으로여겨지며, 따라서본연구결과에따른연간재감염률은약 6.2% 정도라고여겨진다. 그러나이는최근우리나라에서발표된재감염률에대한다른연구들보다높은결과로서이에대한결론을위해서는추후 찰 좀더장기간의추적기간을대상으로하는연구가필요하다고하겠다. 한편 H. pylori 감염이소화성궤양의치료후재발과관련이있다는점이나 H. pylori 감염이만성위염을통한위암의발암인자라는점등으로미루어 H. pylori 관련위장관질환들에서재감염률이차이가있는지알아보고자대표적인 H. pylori 관련위장관질환 4가지-만성위축성위염, 소화성궤양, 위암, MALT 림프종-에대해재발과의상관관계가있는지조사한결과만성위축성위염의경우상대적으로재발하지않은환자군의비중이높았으며, 소화성궤양의경우 1년이내재발한재활성화군의비율이높았고, 위암의경우 1년이후재발한재감염군의비율이높았으나각각의재발시기는통계적으로의미있는차이가없었다. 각질환에따른재발여부및시기와관련되어특히재감염률이질환들사이에차이가있는지살펴보기위해두위장관질환을짝지어 odds ratio를구해비교해본결과각위장관질환들사이에재감염과관련되어통계적으로유의한차이는없었으며, 특징적으로각질환을 MALT 림프종과비교할경우 1미만의현저히낮은 odds ratio를관찰할수있었음에도불구하고본연구에서추적이이루어진 MALT 림프종환자들의빈도가매우낮았기때문에통계적인유의성은찾을수없었다. 한편 H. pylori 의감염밀도가높을수록제균이쉽지않아재활성화가능성이높고, 만성위염의염증이심할수록위장관질환의발생과도연관이깊다는측면에서 The Updated Sydney System에따른위조직의 H. pylori 군집밀도, 호중구침윤, 단핵구침윤정도가재발과관련이있는지비교하였으나역시통계적인차이를찾을수없었으며이로인해위조직의조직학적검사결과역시 H. pylori 재감염또는재발과는상관관계가없다고판단된다. 결론적으로본연구결과로부터 H. pylori 관련위장관질환이나위의조직학적소견은 H. pylori 의재감염을예상할수있는임상적인지표로는부적절하다고여겨지나상대적으로낮은빈도의재감염환자로인해해석에제한이많았으며따라서추후더욱큰환자군을대상으로하는연구가필요하다고하겠다. 또한 H. pylori 의균주에따른감염력의차이등을고려하지못한점이나, 후향적인연구로추적검사방법이나추적검사시기가환자들마다일정하지않았다는점도본연구의한계라고여겨진다. ABSTRACT Background/Aims: Studies on re-infection of Helico-
166 대한소화기내시경학회지 2008;37:161-166 bacter pylori are limited. This study was designed to determine if there are clinical features of H. pylori reinfection related to gastroduodenal diseases or histological findings. Methods: From a population of patients that were treated for H. pylori eradication from May 2003 to September 2007, 129 subjects were enrolled. Regimens were PPI-based triple or quadruple agents and follow-up methods were UBT, CLO or histology. Results: A total of 29 subjects experienced a recurrence (within one year, 17 subjects; between one and two years, eight subjects; more than two years, four subjects). Recurrence periods were 2 to 32 months, and the mean period was 12.62± 8.40 months. Among 29 subjects, eight subjects had chronic atrophic gastritis, 14 subjects had a peptic ulcer, five subjects had stomach cancer and two subjects had a MALT lymphoma; there were no statistical differences of the odds ratio between matched diseases. By use of the Updated Sydney System, neither H. pylori colonization density nor neutrophil infiltration nor monocyte infiltration grade in histology was associated with recurrence or re-infection. Conclusions: Neither histological findings nor gastroduodenal diseases was associated with H. pylori re-infection. The re-infection rate in this study was approximately 6.2%. This rate was slightly higher than rates reported in other recent studies in Korea. (Korean J Gastrointest Endosc 2008;37:161-166) Key Words: Helicobacter pylori, Recurrence, Reinfection, Gastroduodenal diseases, Histology 참고문헌 1. Makola D, Peura DA, Crowe SE. Helicobacter pylori infection and related gastrointestinal diseases. J Clin Gastroenterol 2007;41:548-558. 2. Malfertheiner P, Megraud F, O'Morain C, et al. Current concepts in the management of Helicobacter pylori infection: the Maastricht III Consensus Report. Gut 2007;56:772-781. 3. Gisbert JP. The recurrence of Helicobacter pylori infection: incidence and variables influencing it. A critical review. Am J Gastroenterol 2005;100:2083-2099. 4. Lee JY, Kim W, Gwak GY, et al. Alimentary tract: reinfection rate and clinical manifestation of Helicobacter pylori - positive peptic ulcer disease after triple therapy containing clarithromycin. Korean J Gastroenterol 2002;39:93-100. 5.Cheon JH, Kim N, Kim JM, et al. Recurrence rate of Helicobacter pylori and peptic ulcer after bismuth-containing second-line quadruple therapy. Korean J Helicobacter Res Prac 2005;5:151-156. 6. Na HS, Hong SJ, Yoon HJ, et al. Eradication rate of first-line and second-line therapy for Helicobacter pylori infection, and reinfection rate after successful eradication. Korean J Gastroenterology 2007;50:170-175. 7. Gómez Rodríguez BJ, Rojas Feria M, García Montes MJ, et al. Incidence and factors influencing on Helicobacter pylori infection recurrence. Rev Esp Enferm Dig 2004;96:620-623. 8. Gunaid AA, Hassan NA, Murray-Lyon IM. Recurrence of Helicobacter pylori infection 1 year after successful treatment: prospective cohort study in the Republic of Yemen. Eur J Gastroenterol Hepatol 2004;16:1309-1314. 9. Kim CT, Kang PS, Lee KS, Hwang TY. Helicobacter pylori reinfection rate and its related factors after successful eradication: 4-year follow-up in a Korean rural community. Korean J Gastroenterol 2005;46:39-47. 10. Khulusi S, Mendall MA, Patel P, Levy J, Badve S, Northfield TC. Helicobacter pylori infection density and gastric inflammation in duodenal ulcer and non-ulcer subjects. Gut 1995; 37:319-324. 11. Dixon MF, Genta RM, Yardley JH, Correa P. Classification and grading of gastritis. The updated sydney system. international workshop on the histopathology of gastritis, Houston 1994. Am J Surg Pathol 1996;20:1161-1181. 12. Bell GD, Powell KU. Helicobacter pylori reinfection after apparent eradication--the Ipswich experience. Scand J Gastroenterol 1996;215(suppl):96S-104S. 13. Go MF. Review article: natural history and epidemiology of Helicobacter pylori infection. Aliment Pharmacol Ther 2002; 16(suppl):3S-15S. 14. Yim JY, Kim N, Choi SH, et al. Seroprevalence of Helicobacter pylori in South Korea. Helicobacter 2007;12:333-340. 15. You J, Wong P, Wu J. Cost-effectiveness of Helicobacter pylori "test and treat" for patients with typical reflux symptoms in a population with a high prevalence of H. pylori infection: a Markov model analysis. Scand J Gastroenterol 2006;41: 21-29. 16. Hopkins RJ, Girardi LS, Turney EA. Relationship between Helicobacter pylori eradication and reduced duodenal and gastric ulcer recurrence: a review. Gastroenterology 1996;110: 1244-1252. 17. Cameron EA, Bell GD, Baldwin L, Powell KU, Williams SG. Long-term study of re-infection following successful eradication of Helicobacter pylori infection. Aliment Pharmacol Ther 2006;23:1355-1358. 18. Okimoto T, Murakami K, Sato R, et al. Is the recurrence of Helicobacter pylori infection after eradication therapy resultant from recrudescence or reinfection, in Japan. Helicobacter 2003;8:186-191.