PG 3 PG Course 2013 Non Alcoholic Fatty Liver Disease 아주대학교의과대학외과학교실 변철수, 한상욱 The Impact of Bariatric Surgery in Non-alcoholic Fatty Liver Disease (NAFLD) Cheulsu Byun, Sang-Uk Han Department of Surgery, School of Medicine, Ajou University, Suwon, Korea Nonalcoholic fatty liver disease (NAFLD) comprises a spectrum of disorders ranging from simple steatosis, nonalcoholic steatohepatitis (NASH) to fibrosis, which may even lead to cirrhosis, hepatocellular carcinoma, and end-stage liver disease. The current best treatment of NAFLD is weight reduction through lifestyle modifications, drug therapy and bariatric surgery. However, it is often difficult to achieve sustained weight loss in morbidly obese patients with diet and exercise alone. Bariatric surgery is an effective treatment option for individuals who are severely obese and provides for long-term weight loss and resolution of obesity-associated diseases in most patients. The most commonly performed bariatric surgeries are Roux-en-Y gastric bypass (RYGB), adjustable gastric banding (AGB) and sleeve gastrectomy (SG). Thus, in this article, we describe the current options for bariatric surgery and the outcomes of bariatric surgery on NAFLD patients. Key words: Bariatric surgery, Non-alcoholic fatty liver disease (NAFLD), Non-alcoholic steatohepatitis (NASH) 서 론 비알코올성지방간질환 (nonalcoholic fatty liver disease, NAFLD) 은알코올섭취나간염, 약물, 유전등의원인이없이발생한간질환을의미하며단순지방증 (simple steatosis) 에서부터비알코올성지방간염 (nonalcoholic steatohepatitis, NASH), 간경변까지의스펙트럼이포함된다. 1,2 현재 NAFLD는대사증후군이간에서발현되는양상으로받아들여지며, 최근비만과제2형당뇨병이증가하면서 NAFLD의유병률이증가하고있다. 3,4 성인인구에서 NAFLD의유병률은미국, 이탈리아, 우리나라에서각각 30%, 25%, 16% 로알려져있으며, 5-7 이는비만환자에서 70%, 병적비만환자에서 85-90% 로그빈도가비만도에비례하여증가한다. 8 전향적연구에서 NASH 환자의 30% 는 5년내에간이조직학적으로섬유화가진행되며, 15년이내에 11% 의환자에서간경변증이발생한다. 9 NAFLD의명확한발병기전이밝혀지지않았으며, 이를치료하기위한공인된투약제제는없다. 식이요법이나운동등의생활습관개선을통한체중감소가NAFLD 의치료방법으로받아들여지고있으나, 10 식이요법및및생활습관개선을통한체중감소는어려우며, 특히이를장기간유지하기는더욱어렵다. 11 배리아트릭수술 52
한상욱 은위의용적을줄여섭취를제한하거나위장관을우회하여흡수를제한하여체중감소를유도함으로써비만치료에있어다른어떤치료보다단기적, 장기적으로효과가있다. 12 현재보편적으로시행되는배리아트릭수술은조절형위밴드술 (adjustable gastric banding), 루와이위우회술 (Roux-en-Y gastric bypass), 위소매절제술 (sleeve gastrectomy) 이며이들수술은대부분복강경으로안전하게시행되며체중감소효과가우수하다. 최근수술이후 2형당뇨병및대사증후군의개선효과가지속적으로보고되고있어배리아트릭수술은대사수술 (metabolic surgery) 로확대되고있으며, 13 배리아트릭수술이후 NAFLD의개선에대한보고가있으나, 현재까지국내에서보고된바는없다. 따라서본종설에서는문헌고찰을통하여최근의배리아트릭수술의종류및방법과 NAFLD과의관계에대해기술하고자한다. 본 론 1. 배리아트릭수술의종류및방법현재세계적으로가장많이시행되는수술은루와이위우회술과조절형위밴드삽입술이며, 최근위소매절제술이새롭게대두되고있다. 11 이상의수술은복강경수술법의도입으로기존의개복수술시발생하였던수술상처감염, 탈장등이감소하였으며, 14 이는비만치료에있어수술의빈도를폭발적으로많게하는혁명을가져오게된다. 15 1) 복강경루와이위우회술 (laparoscopic Roux-en-Y gastric bypass, LRYGB) 루와이위우회술은식도위경계부하방의위를소만곡쪽으로 15-30 ml 정도의위주머니 (gastric pouch) 만남기고나머지위와절제분리한이후트라이츠인대 (Treitz ligament) 후방 30-70 cm 에서절단된공장의원위부와위공장문합을시행하고, 절단된공장의근위부를위공장문합부 75-150 cm 하방의공장에문합함으로써식이제한과흡수제한을유도하는수술술식으로복강경수술의도입으로 1990년대말부터미국에서급속도로증가되었으며현재표준비만수술로인정받고있다. 16 루와이위우회술은수술현재까지연구가가장많이된수술술식으로장절제및문합과관련하여문합부유출, 문합부협착, 출혈, 내부탈장등의조기합병증이발생할수있으며 17,18 사망률은 0.4% 로보고된다. 19 수술이후기능적으로반복적인구토나덤핑증후군이발생할수있으며, 20 장기적으로위우회로인한철분, 비타민 B12, 칼슘등의결핍이일어날수있다. 수술이후개별적인영양상태평가및이에따른필수영양소보충등의관리가요구된다. 21 2) 복강경조절형위밴드술 (laparoscopic adjustable gastric banding, LAGB) 조절형위밴드술은 Kuzmak이 1986년에개발한이후임상에도입되었고, 1993년복강경랩밴드 (Lap-Band) 가보급된이후급속히대중화되었다. 실리콘재질의팔찌모양밴드가위상부에삽입되고관을통해복벽내설치된포트에연결되며, 이포트에생리식염수를주입하여위밴드의풍선이부풀게하여위상부를조임으로써음식섭취가제한이되게한다. 이수술은위나소장의절단및문합이없으므로, 수술의편리성이높고안정성이높게보이며랩밴드제거시원상복귀가가능한장점으로보편화되었다. 하지만밴드와관련된이탈, 탈출, 위미란등의합병증이있으며사망률은 0.05% 로보고된다. 22 53
Postgraduate Course 2013 3) 복강경위소매절제술 (laparoscopic sleeve gastrectomy, LSG) 위소매절제술은위의소만부쪽으로 40Fr 정도의부지관을삽입한이후자동문합기를이용하여부지관을따라절제하여위대만부를제거하고원통모양의위를만들어주는수술이다. 이수술은초기에는초고도비만환자에서보다복잡한고도비만수술을하기에안전한체중을만들기위한중간단계수술이었으나, 23,24 최근에는위소매절제술단독으로도충분한체중감소와더불어비만과동반된질환이개선되는것이관찰되면서 25,26 하나의독립적인고도비만수술법으로받아들여지고있다. 27 위소매절제술은위의종단면을길게절단함에따라수술초기에절단부분을따라누출 (0-2.4%) 28 과출혈 (0-1.6%) 29 이발생할수있으며후기에협착과위식도역류가발생할수있다. 이수술은비만의표준수술인루와이위우회술과달리위장관문합술이필요치않으므로문합부유출이나협착이생기지않고기술적인어려움이적다. 이런장점으로루와이위우회술을대신하여위소매절제술을선택하는경우가많으며같은수술자에의해시행되어비교된주요합병증을보면위소매절제술에서는 4.6%, 루와이위우회술에서는 10.6% 로위소매절제술의합병증이낮았다. 30 또한수술시간과수술이후병원입원기간도유의하게감소되었으며이런이유들로최근이수술의빈도가늘어나고있다. 31 2. NAFLD 치료에있어서배리아트릭수술의효능 NAFLD 치료에있어배리아트릭수술의효능에대한보고는아직까지많지않으며최근 Rabl 등 32 과 Hafeez 등 33 이문헌고찰을하였다. 현재까지배리아트릭수술과 NAFLD 에관한전향적무작위대조연구결과에대한보고는없다. 1) 복강경루와이위우회술 5개의후향적연구 34-38 와 7개의전향적연구 8,39-44 에서수술전과수술후체중감소가된이후시점에서간조직생검을통해루와이위우회술과 NAFLD 의개선효과가있음을보고하였다. Furuya 등 44 은병적비만한자 18 명을수술이후 24개월에추적관찰하면서간조직생검을시행하였고, 89% 에서간지방증 (steatosis), 79% 에서간섬유화 (fibrosis) 그리고 50% 의환자에서간세포풍선변형 (ballooning) 의개선효과를보고하였다. 또한 Clack, 8 de Almeida, 43 Weiner 37 등의연구에서도모든환자에있어루와이위우회술은체중감소와함께간지방증, 간염증, 간섬유화의개선효과를관찰하였다. 하지만 Barker, 41 Csendes, 42 Moretto 38 등의연구에서간지방증, 간염증은모든환자에서개선되었으나 10.5%, 6.7%, 11.6% 의환자에서간섬유화가증가되거나새롭게발생하였다. 수술이후간섬유화가악화된환자들의공통점은이들이수술전에간섬유화가이미진행되어있었으며, 수술후급격한체중감소와영양소및미세영양소결핍이있었다. 2) 복강경조절형위밴드술 Dixon 등 45,46 이 36명과 60명을대상으로한전향적연구결과를두차례보고하였으며, 수술이후체중감소와함께 NAFLD 가개선됨을관찰하였다. 2006년보고에서수술전 30예 (50%) 의환자에서 NASH 에합당한조직소견을관찰하였으나수술이후체중감소이후 6예 (10%) 의환자에서만 NASH 에합당한조직소견을관찰하였다. Mathurin 등 47 은 381명의환자 (AGB: 56.2%, biliointestinal bypass: 22.8%, RYGB: 21%) 들의수술이후 5년추적관찰결과, 수술이후 1년조직생검상간지방증은 37.4% 에서 16% 로감소하였으나간염증은변화를보이지않았으며, 간섬유화는 20% 의환자에서급격히증가하였다. 간섬유화의진행은체중감소와별다른차이를보이지않았다 (-18% ± 10.7% vs. -20.7% ± 12.7%). 또한수술방법에따른 NAFLD 차이는보이지않았으며수술이후 1년이경과한후 5년까지별다른변화를보이지않았다고한다. 54
한상욱 3) 복강경위소매절제술 2000년대중반에서야위소매절제술이독립적인배리아트릭수술로받아들여짐에따라현재까지위소매절제술전후로간조직생검을한보고는많지않다. Matter 등 39 은NAFLD 진단기준에적합한70명 (41: LRYBG, 23: LSG, 6: AGB) 환자에서추적관찰기간에간조직검사를추가시행하였고, 대사증후군 (70% to 14%), 간지방증 (88% to 8%), 간염증 (23% to 2%), 그리고간섬유화 (31% to 13%) 의개선을보고하였다. 또한간염증및간섬유화는 37%, 20% 에서관해를나타내었다. 결 론 NAFLD는만성간질환의가장흔한원인이며비만과대사증후군이증가하면서유병률이증가한다. NAFLD치료에있어체중감소는가장중요한영역이며약물및생활습관개선을통한체중감소및유지는어렵다. 배리아트릭수술은체중감소및유지에가장효과적인방안이며 BMI 40 kg/m 2, 이상이거나, 35 kg/m 2 이상이면서대사관련동반질환이있을때권고되며, 최근미국 FAD에서 BMI 30 kg/m 2 이상이면서대사증후군이동반될경우복강경위조절형밴드술을승인하였다. 현재복강경루와이위우회술, 복강경조절형위밴드술, 복강경위소매절제술이보편적으로이용되고있으며, 배리아트릭수술이후대사질환개선효과가보고되면서그적용범위가늘어나고있다. 일부예에서수술이후급속한간섬유화가진행함을보여주므로급속한체중감소및영양결핍, 대사변화는주의가필요하겠지만, 현재까지의전후향코호트연구대부분에서배리아트릭수술이후 NAFLD 의개선효과를보여주고있으므로 NAFLD의치료에있어배리아트릭수술의역할은확대될것이다. 비만환자에있어배리아트릭수술의 NAFLD 치료에대한대규모연구가필요하겠다. 참고문헌 1. Harrison SA, Kadakia S, Lang KA, et al. Nonalcoholic steatohepatitis: what we know in the new millennium. Am J Gastroenterol 2002;97:2714-24. 2. Angulo P. Nonalcoholic fatty liver disease. N Engl J Med 2002;346:1221-31. 3. Bellentani S, Marino M. Epidemiology and natural history of non-alcoholic fatty liver disease (NAFLD). Ann Hepatol 2009;8 Suppl 1:S4-8. 4. Anstee QM, McPherson S, Day CP. How big a problem is non-alcoholic fatty liver disease? BMJ 2011;343:d3897. 5. Browning JD. Statins and hepatic steatosis: perspectives from the Dallas Heart Study. Hepatology 2006;44:466-71. 6. Bedogni G, Miglioli L, Masutti F, et al. Prevalence of and risk factors for nonalcoholic fatty liver disease: the Dionysos nutrition and liver study. Hepatology 2005;42:44-52. 7. Park SH, Jeon WK, Kim SH, et al. Prevalence and risk factors of non-alcoholic fatty liver disease among Korean adults. J Gastroenterol Hepatol 2006;21:138-43. 8. Clark JM, Alkhuraishi AR, Solga SF, et al. Roux-en-Y gastric bypass improves liver histology in patients with non-alcoholic fatty liver disease. Obes Res 2005;13:1180-6. 9. Angulo P. Long-term mortality in nonalcoholic fatty liver disease: is liver histology of any prognostic significance? Hepatology 2010;51:373-5. 10. Ahmed MH, Byrne CD. Current treatment of non-alcoholic fatty liver disease. Diabetes Obes Metab 2009;11:188-95. 11. Buchwald H, Oien DM. Metabolic/Bariatric surgery worldwide 2011. Obes Surg 2013;23:427-36. 12. Sjostrom L, Lindroos AK, Peltonen M, et al. Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. N Engl J 55
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