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1 대한내과학회지 : 제 81 권제 1 호 2011 특집 (Special Review) - 프로톤펌프억제제장기사용에대한논쟁 : Safe vs. Unsafe 영양, 대사및감염에미치는프로톤펌프억제제의영향 : Safe 측면 연세대학교의과대학내과학교실 김지현 The Effect of Proton Pump Inhibitors on Nutrition, Metabolism, Infection and Small Intestinal Bacterial Overgrowth: Safe Perspective Jie-Hyun Kim Department of Internal Medicine, Institute of Gastroenterology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea Proton pump inhibitors (PPIs) have been widely used to treat patients with acid-related disorders because they are perceived to be safe and effective. However, they have the potential for side effects. Many studies have examined the side effects of long-term PPI exposure. We review the side effects of long-term PPIs, focusing on nutrition, metabolism, and infection. (Korean J Med 2011;81:11-16) Keywords: Proton pump inhibitors; Side effects; Safety; Nutrition; Infection 서론프로톤펌프억제제 (proton pump inhibitor, PPI) 는소화성궤양, 역류성식도염등위산관련질환에서사용되는약제로, 국내에서도역류성식도염의발생빈도가증가하고있어이약제의장기사용증가가예상된다. PPI 투여의부작용에대해서는 1986년부터꾸준히연구가되었으나특히최근에보고가증가하는추세이다 [1]. PPI 부작용에대한인지는약제의사용빈도증가뿐아니라긴혈중반감기와좀더강하게산을억제하는약제들이개발되는현시점에서중요할수있다. PPI 부작용은약제의특성을고려할때, 산억제에대한영향, 간의 cytochrome P450 과의상호작용에대한영향등에의하여발생할수있으며, 따라서카르시노이드종양, 위축성위염, 위암, 위저선용종, 흡수장애, 감염, 약물상호작용등이부작용으로알려져있다 [1,2]. 이중위산저하에의한흡수및대사장애즉영양적측면과위산저하에의한감염적측면에서 PPI 부작용을살펴봄으로써 PPI 장기사용에대한안전성을검토해보고자한다. 본론영양적측면 PPI의위산억제에의한비타민및미네랄흡수장애가발 Correspondence to Jie-Hyun Kim, M.D. Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, 712 Eonju-ro, Gangnam-gu, Seoul , Korea Tel: , Fax: , otilia94@yuhs.ac

2 - The Korean Journal of Medicine: Vol. 81, No. 1, 생할수있으며, 특히칼슘흡수장애로골 (bone) 에대한영향을생각해볼수있다. 비타민및미네랄흡수장애비타민 B 12 위의산성도는비타민 B 12 흡수에중요하다. 음식물에서비타민 B 12 는단백과강하게결합되어있는데, 위산과펩신에의해단백과분리되어타액 R 단백과결합하게되므로, PPI 사용에의한위산억제는비타민 B 12 흡수를저해하게된다. 또한, 위산감소에의해소장의세균과다증식이발생하게되면세균에의한비타민 B 12 소비증가가발생하여비타민 B 12 결핍이발생할수있다. 이와같이이론적으로 PPI 사용에의한위산억제는비타민 B 12 결핍을초래할수있으나임상적으로 PPI 장기사용에의한비타민 B 12 결핍은뚜렷하지않다. 6개의 PPI 장기사용에따른혈청비타민 B 12 농도를측정한연구중 5개의연구에서혈청비타민 B 12 농도는감소하지않았으며, 감소를보인연구는 Zollinger-Ellison 증후군환자를대상으로장기간동안고용량의 PPI를사용한것이었다 [3-10]. 하지만노인을대상으로한연구에서는 PPI를장기사용하였을경우혈청비타민 B 12 감소가능성을보여주었다 [11-13]. 따라서일반적으로 PPI 장기사용이혈청비타민 B 12 감소를유발할가능성은적으나, 노인들의경우는이미위의위축성변화가동반되었을가능성이있기때문에 PPI 장기사용에있어비타민 B 12 감소될가능성이있으므로주의를요하며, Zollinger-Ellison 증후군환자와같이 PPI를고농도로장기사용할경우에도혈청비타민 B 12 감소가능성을염두에두어야하겠다. 철 (iron) PPI 장기사용과철흡수에대한연구를많지않다. 이론적으로 PPI 장기사용에의한위산감소는철흡수를감소시킬수있다. 음식물에포함된철은 non-heme (66%) 또는 heme 철 (32%) 로존재하게되는데, 위산은 non-heme 철이포함된음식물에서철염을분리하고용해하도록도와준다. PPI 장기사용과철흡수감소에대한보고는증례보고정도만이있는상태로, 철보충제에반응이적던철결핍성빈혈환자가 PPI 중단이후호전된경우이다 [3]. 이외에다른연구들에서는임상적으로 PPI 장기사용이철흡수감소에뚜렷한 영향을보여주지못하였다 [14,15]. 마그네슘 PPI 사용시저마그네슘혈증이유발됨이보고되고있으며, 증상을유발하는심한저마그네슘혈증및저칼륨혈증이나고칼슘혈증의동반도보고되고있다 [16-20]. 이와같은환자들은위장내흡수장애나신장소실의증거가없이저마그네슘이발생한경우로 PPI의중단또는 H2RA로의교체 1-2주만에정상으로회복되었다. 따라서 PPI 사용에의한저마그네슘혈증이발생하였음을알수있으나, 이에대한기전은밝혀진것이없다. 특이약물반응가능성이제기되기도하며, 저마그네슘혈증을유발할수있는다른위험인자와의반응등이제기되기도하나현재까지밝혀진기전은없는상태이다. 따라서저마그네슘혈증을유발할가능성이높은환자들선정을위한연구가추후필요한상태이며, 현재까지는 PPI 사용에있어저마그네슘혈증이동반될가능성을염두에두는것이중요하다고하겠다. 칼슘및골 (bone) 에대한영향위산은음식물의칼슘염용해와관계된다는점에서칼슘흡수에중요하다고하겠다. 따라서 PPI에의한위산억제는칼슘흡수의저하를유발할수있고이는임상적으로골밀도감소와연관될수있다. 하지만위산의골밀도에대한영향은칼슘에의해서만영향을받는것은아니다. PPI가골 (bone) 에영향을미치는기전은여러가지로보고되고있다. 파골세포 (osteoclast) 에존재하는프로톤펌프에작용하여오히려골흡수를저해한다는보고도있지만, PPI 에의해골밀도가감소하는여러가지기전에의해 PPI 장기사용에따른골밀도저하, 이에따른골절여부가임상적으로중요한부분이라하겠다. PPI에의해골강도가감소하는기전은그림 1과같다 [1]. 환자, 대조군연구에따르면 PPI 사용과골절의위험도증가는 PPI의용량및사용기간과연관이있다고알려져있다 [21]. 즉, 한연구에서는 5년이상 PPI를복용하였을때골다공증에의한골절의위험도가 1.62배증가하였다고보고하였으며, 다른연구에서는 7년이상복용하였을때고관절골절의위험도가 4.55배증가하였다고보고하였다 [22,23]. 하지만이와같은환자, 대조군연구에서골절의위험도증가를

- Jie-Hyun Kim. PPI on nutrition and infection - Figure 1. Pathways through which proton pump inhibitor therapy can decrease bone strength.

그러나대부분의연구들이골절과관련된다른위험인자들이배제가된후 PPI와골절과의연관관계만을분석하지는못하였다 [24,25]. 따라서캐나다소화기학회 (The Canadian Association of Gastroenterology, CAG) 에서는현재까지의연구들은 PPI를처방함에있어고관절골절의위험성을고려할근거가부족하다고언급하였다 [26].

따라서 PPI 장기사용이골절과연관이있을수있지만모든 PPI 사용자를대상으로고려하였을때임상적으로미치는위험도는적다고하겠다. 이미골다공증위험인자를가지고있는경우 PPI 장기사용시골절의위험도를인지하는 것이중요할수있으며되도록가장효과적이면서적은용량의 PPI 사용이골절예방에도움이될수있겠다.

3 - Jie-Hyun Kim. PPI on nutrition and infection - Figure 1. Pathways through which proton pump inhibitor therapy can decrease bone strength. PPI, proton pump inhibitor; Vit, vitamin; vbmd, volumetric bone mineral density. 분석함에있어중요한것은다른골다골증골절의위험인자가배제된즉, PPI 사용과골절여부만의새로운연관관계를제대로분석하였느냐가중요할수있을것이다. 그러나대부분의연구들이골절과관련된다른위험인자들이배제가된후 PPI와골절과의연관관계만을분석하지는못하였다 [24,25]. 따라서캐나다소화기학회 (The Canadian Association of Gastroenterology, CAG) 에서는현재까지의연구들은 PPI를처방함에있어고관절골절의위험성을고려할근거가부족하다고언급하였다 [26]. 가장최근의연구를살펴보면, 2년이상 PPI를장기복용한환자들에서고관절골절의정도를다른골절의위험인자와같이분석하여보았을때 1개이상의골절의위험인자를가진환자들에서만 1.25배로골절의위험도가증가함을보고하면서산억제는골다공증의위험인자를가지고있는사람들에게있어골절의위험도를증가시킬수있다고결론지었다 [27]. 따라서 PPI 장기사용이골절과연관이있을수있지만모든 PPI 사용자를대상으로고려하였을때임상적으로미치는위험도는적다고하겠다. 이미골다공증위험인자를가지고있는경우 PPI 장기사용시골절의위험도를인지하는 것이중요할수있으며되도록가장효과적이면서적은용량의 PPI 사용이골절예방에도움이될수있겠다. 감염적측면위산은상부위장관에서세균집락형성에대한장벽역할을하며, 장의상재균구성에영향을미치는것으로알려져있다. 따라서, PPI에의한위산저하는위장관내세균감염및집락형성을유발할수있으며이의역류에의한호흡기감염을유발할수있고, 장의상재균구성변화및세균성위장염을일으킬가능성이있다. 폐렴이론적으로는 PPI에의한위산저하가폐렴을유발할수있으나이에대한임상적근거는희박한상태이다. 지역사회획득폐렴 (community-acquired pneumonia, CAP) 의경우현재 PPI 사용여부및 PPI 사용기간과 CAP 발생사이에연관성이부족한상태이다. 즉, 현재 PPI를사용하는경우 CAP가발생할가능성이 1.89배인데반해이전에 PPI를사용한경우에도 CAP 발생가능성이 1.5배로 PPI 사용여부와 CAP 발생

4 - 대한내과학회지 : 제 81 권제 1 호통권제 611 호 사이의연관성이부족하며, PPI 사용이짧을수록 CAP 발생가능성이높아진다는결과가보고된것에서도 PPI 사용과 CAP 발생사이의연관성을찾기는부족하다하겠다 [28-30]. 실제로한메타연구에서는 CAP와 PPI 사이에의미있는관련이없다고결론지었다 [30]. 원내폐렴 (nosocomial pneumonia, NP) 의경우에는오히려 PPI 사용이 NP를증가시키지않는다고보고되고있다 [31-33]. 한연구에서는 PPI를비위관으로주입하였을때 NP의위험성이감소한다고보고하였다 [34]. 담즙산농도증가에의한삼투압증가및장운동의증가로설사가많이동반될수있다고보고되었다 [40,41]. 따라서이와같이 PPI 사용과 SIBO, 이에의한과민성장증후군과같은증상에대해과민성장증후군환자들에서 PPI 를사용할경우과민성장증후군증상의악화를유발할수있으며, 과민성장증후군환자에서 SIBO를고려하여항생제를사용하기전에 PPI를사용중일경우 PPI 중단을먼저고려하여야할가능성에대해언급되기도한다 [42]. 하지만이에대해서는추후연구가필요하겠다. Clostridium difficile 관련설사 (Clostridium difficileassociated diarrhea, CDAD) CDAD의발생위험인자로항생제사용, 나이, 감염환자와의접촉, 위생, 환자의면역력정도등다양한인자들이보고되어있다. CDAD와 PPI와의관련성을분석함에있어서이와같은다른위험인자들을배제하는것이중요할수있다. 실제로만성신부전환자에서 CDAD와 PPI 사용과의연관성을본연구에서는 CDAD 발생이 5.7배로증가함을보고하였지만 [35], 메타분석에서는 PPI 사용의경우 CDAD 발생이 1.96배로증가함을보고하였다 [36]. 하지만이메타분석에서몇몇연구들은굉장히강한독성의 Clostridium difficile 을대상으로연구가진행되었으며, 실제항생제사용과같은다른위험인자를고려하였을때 PPI 사용과 CDAD와는관련성이없다고하였다 [36]. 즉, 아직까지는 PPI 장기사용이 CDAD 발생을증가시킨다는확실한근거는없다고하겠다. 소장세균과다증식증 (Small intestinal bacterial overgrowth, SIBO) PPI 사용에의한위산억제는위, 십이지장, 장관내세균구성에변화를가져올수있으며이에의한 SIBO의위험인자임이보고되었다 [37]. 실제로십이지장액을배양하여보았을때 PPI 사용군에서더많은세균과다증식증이확인되었다 [38]. SIBO 를포도당호기검사로측정하여본연구에서도 PPI 사용군에서과민성장증후군이나대조군과비교하였을때의미있게포도당호기검사가양성임을보고하였으며 PPI 사용기간에대해분석하여보았을때 13개월이상복용한경우의미있게 SIBO가증가함을보여주었다 [39]. 이와같은 PPI 관련 SIBO에의해발생하는증상은과민성장증후군과비슷한증상을유발할수있으며, 특히 PPI에의해비결합 결 영양, 대사및감염에미치는연구결과들을보았을때 PPI 장기사용은이와같은측면에서보면비교적안전하다고할수있다. PPI 사용이절대적적응증이된다면아직까지는이와같은부작용을고려하여 PPI 사용을저해할만한근거는부족하겠다. 하지만 PPI 장기사용에따른부작용에대한인지는 PPI 사용에있어적절한적응증의선택, 효과를나타내는최소용량및적절한기간에대한중요성을한번더인식할수있다는점에서매우의미있는일이다. 또한, 이론적으로가능한부작용에대하여임상적고위험군선정에대한추후연구가필요하다고하겠다. 중심단어 : 프로톤펌프억제제 ; 부작용 ; 안정성 ; 영양 ; 감염 론 REFERENCES 1. Yang YX, Metz DC. Safety of proton pump inhibitor exposure. Gastroenterology 2010;139: Kahrilas PJ, Shaheen NJ, Vaezi MF. American Gastroenterological Association Institute technical review on the management of gastroesophageal reflux disease. Gastroenterology 2008;135: , 1413.e1-e5. 3. Sharma VR, Brannon MA, Carloss EA. Effect of omeprazole on oral iron replacement in patients with iron deficiency anemia. South Med J 2004;97: den Elzen WP, Groeneveld Y, de Ruijter W, et al. Long-term use of proton pump inhibitors and vitamin B12 status in elderly individuals. Aliment Pharmacol Ther 2008;27: Howden CW. Vitamin B12 levels during prolonged treatment with proton pump inhibitors. J Clin Gastroenterol 2000;30: Maton PN, Vinayek R, Frucht H, et al. Long-term efficacy and safety of omeprazole in patients with Zollinger-Ellison syndrome: a prospective study. Gastroenterology 1989;97:

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A 617 Special Issue Diabetic Retinopathy Won Ki Lee, M.D. Department of Ophthalmology The Catholic University of Korea College of Medicine Kangnam St. Mary s Hospital E mail : wklee@catholic.ac.kr Abstract R