<303320C6AFC1FD20B9DABBF3C8C62E687770>

Transcription

1 대한내과학회지 : 제 79 권제 5 호 2010 특집 (Special Review) - 지방간질환 (nonalcoholic fatty liver disease, NAFLD) 비알코올성지방간질환의치료 한림대학교의과대학강남성심병원소화기내과 박상훈 Nonalcoholic fatty liver disease: treatment Sang Hoon Park, M.D., Ph.D. Department of Internal Medicine, Hallym University Medical Center, Hallym University College of Medicine, Seoul, Korea Recently, nonalcoholic fatty liver disease (NAFLD) is highly prevalent even in Korea, which has the potential to progress to cryptogenic cirrhosis and hepatocellular carcinoma. It is not only regarded as a hepatic component of the metabolic syndrome but also as an independent risk factor and a marker for increase in cardiovascular disease. We should keep in mind the NAFLD is a treatable and have to treat disease to prevent early death from liver and cardiovascular complications. Weight loss via lifestyle modification remains the most common and fundamental therapy advocated for reducing hepatic lipid in NAFLD. There is increasing evidence that exercise or physical activity beneficially modulates liver fat independent of weight loss. Although reduced total calorie intake potentially plays a role in the treatment of NAFLD, dietary macronutrient composition may also play a role. Low-carbohydrate and low-fructose diets are of particular benefit to reduce steatosis and improve biochemical tests. Polyunsaturated fatty acid (n3-pufa) and monounsaturated fatty acid (MUFA) may play a protective role against increase liver fat. Limitation of Saturated fat and trans-fatty acids intake is very recommendable. Even lifestyle modifications continued to be the cornerstone of therapy in NAFLD, some insulin-sensitizing drug may be a more effective means in the treatment of NAFLD. Vitamin E and statins have demonstrated promising initial results in improving liver enzymes or features of liver histology. Bariatric surgery is very useful treatment option for morbidly obese NAFLD patients. However, weight loss medication is not recommended which have shown varying degrees of side effects for the treatment of NAFLD. (Korean J Med 79: , 2010) Key Words: Nonalcoholic fatty liver disease; Nonalcoholic steatohepatitis ; Treatment 서론비알코올성지방간질환 ( 이하, 지방간질환으로함 ) 은앞에서언급되었듯이서구여러나라뿐아니라국내에서도가장높은유병률을보이는질환이며, 최근의여러보고에의하면간경변증, 간암을일으키는주요한원인질환이다 1-7). 그러나아직까지일반사람들이나심지어이러한질환을치료해야되는의사들도 치료를왜해야하는가? 혹은치료를꼭해야만하는가? 라는환자의물음에자신있게치료해야한다 고대답하는내과의사는많지않은실정이다. 그것은지방간질환이천천히나빠지고, 증상이없는경우가대부분인특성이있기때문이기도하지만아직까지치료의당위성을입증할수있는충분한증거 ( 연구결과 ) 가부족한이유가클것으로생각된다. 지방간질환이심한간질환을유발하고간질환에의한사망률을증가시킨다는보고가활발해지기시작한것이벌써 10년이넘었다 8). 또한최근에는이러한지방간질환이대사증후군의일부분으로생각되고심혈관질환의위험을증가

2 - The Korean Journal of Medicine: Vol. 79, No. 5, 시킨다는보고도있는실정이다 9-12). 따라서간질환의진행, 심혈관질환의악화등에의한유병률, 사망률을억제하기위해지방간질환의적절한치료는꼭필요하다고생각된다. 지방간질환의적절한치료시작시점은아직까지알수없다. 그렇지만, 지방간염 (nonalcoholic steatohepatitis) 으로진단된환자에서간경변증, 간암으로진행하는경우가대부분으로알려져있고일반적으로간경변증으로진행되면회복되지않기때문에간경변증이없는지방간염환자가주된치료의대상이될수있을것으로생각된다. 그러나임상적으로단순지방간과지방간염을조직검사없이감별하기가쉽지않으며, 지방간질환에의한간경변증도치료후에호전되었다는보고가있어치료시작시점을단정적으로말할수없을것으로생각된다 13). 따라서현재까지는임상적으로지방간질환으로진단받은환자는가능한빠른시기 ( 단순지방간, 지방간염 ) 에치료를시작하는것이좋을것으로생각된다. 본종설에서는최근까지지방간질환의치료로연구되었던 생활습관의개선 중에서임상적으로비교적쉽게접할수있는체중감소, 운동, 식이요법에대해서자세히알아보고, 약물치료 에서는최근에연구가활발하였던 thiazolidinedione (TZD), vitamin-e, ursodeoxychilic acid (UDCA) 등에대해알아보고자한다. 1. 생활습관의변화 (life style modification) 1) 체중감소 (weight loss) 지방간질환의주된발병기전은간내지방의축적 (steatosis) 에서출발한다 14). 따라서간내지방을감소시키는것은근본적인치료가될수있다. 체중감소는지방조직, 근육에서인슐린감수성을증가시켜간으로유리지방산 (free fatty acid) 의유입을적게하며, 간에서새로운지방산의생산을억제하여지방의축적을감소시키고간기능 (ALT) 을호전시킨다. 최근간내중성지방을조직검사없이비교적정확하게측정할수있는 proton magnetic resonance spectroscopy ( 1 H-MRS) 를이용하여측정한결과체중이약 2.6% 감소할경우간내중성지방은약 20% 감소한다는보고가있어체중의감소와간내지방의감소가밀접한관련이있는것으로확인되었다 15). 체중감소는 6개월동안, 1주에 500 gm에서 1 kg을감량하여치료시작당시체중의 10% 감량을목표로한다. 체중감소효과는연구에따라다른데, 적게는 3% 에서많게는 10% 의체중감소로간내중성지방의감소와간조직검사에서간내염증및섬유화의호전을보였다 16-19). 너무짧은기간에많은양의체중감소는오히려간내염증이나섬유화를증가시 킨다는보고가있다. 체중감소는음식, 운동등의생활습관의개선혹은체중감소를위한약물이나수술 (bariatric surgery) 하는방법이있다. 생활습관의개선을통한체중감소는가장인체생리에맞으면서상대적으로부작용이적은적절한치료방법이긴하지만치료받은환자의 80% 내외에서 1~3년이내에원래체중으로돌아와체중감소를유지하지못한다는보고가있었다 20). 따라서최근에는영양사, 심리학자, 운동요법트레이너 (exercise supervisor) 등과함께유기적으로협조하여행동치료를통해생활습관을개선하여지방간질환을치료하자는주장도있는실정이다 21). 식이조절이나운동은아래에서자세히살펴보기로하고여기서는체중조절에도움을줄수있다고알려진약물과수술요법에대해알아본다. (1) 체중감소약물 (weight loss medication) 체중을조절할수있는약제는 orlistat (Xenical ), sibutramine (Reductil ), rimonabant (Acomplia ) 등이다. Orlistat는위와췌장에서분비되는 lipase 를억제하여지방의흡수를감소시켜체중감소를유도한다. 지방간질환에서체중감소와함께 ALT의감소, 간내지방의감소, 섬유화호전등의소견을보이나심한지방변 (steatorrhea), oily spotting 등으로지속복용이어렵고 (compliance 감소 ) 장기간복용시에지용성비타민결핍등이올수있는단점이있다 22-24). Sibutramine은 norepinephrine과 serotonin의재흡수를억제하여식욕을억제하여체중을조절한다. 지방간질환에서 orlistat과비슷한효과를얻었으나, 심혈관계및뇌혈관질환의부작용으로유럽에서사용이금지되었고, 미국 FDA에서는경과기간을두고사용하면서관찰하기로결정되었으나회사에서자진철수하기로하였다. 이에따라우리나라식약청에서도처방을규제하기로하였다. Rimonabant는음식섭취와체중조절에관여하는 endocannabinoid (EC) 계에서 cannabinoid-1 receptor (CB1) 에선택적으로작용하여식욕을억제하여체중을감소시킨다 25). 지방간질환에서체중감소와함께중성지방의감소, ALT 의호전등을보고한연구가있어장기간, 많은환자를대상으로연구가진행중이었으나최근심한정신질환 ( 우울증, 자살 ) 등의부작용으로연구가중지되었다 26-28). 현재유럽에서는사용이중지되었고, 미국 FDA에서는통과되지못했다. 따라서현재까지는체중감소약물을이용한지방간질환의치료는권고되지않고있는실정이다

3 - Sang Hoon Park. Nonalcoholic fatty liver disease: treatment - (2) 수술요법 (bariatric surgery) BMI (body mass index) > 35 kg/m 2 이상인환자가대상이며, 가장효과적이고지속가능한치료로입증되어있다 29-32). 비만수술요법으로는 1) 조기포만감을유도하여음식섭취를줄이는시술 (gastric banding) 2) 소장을우회시켜흡수불량을유도하는시술 (jejunoileal bypass) 3) 위두가지모두의효과를얻기위한시술 (Roux-en-Y gastric bypass, bilopancreatic diversion) 이있다. 최근에는복강경을이용한 gastric banding 시술이덜침습적이면서수술후발생되는영양결핍등이상대적으로적은효과적인수술법으로알려져있다 33). 수술후장기간관찰에서도간내지방뿐아니라섬유화도 80% 환자에서호전되었다는보고가있다 34). 2) 식이조절 (diet) 식이조절을통한지방간질환의치료에서가장중요한것은저칼로리식이 (hypocaloric diet) 이다. 단기간의저칼로리식이라도체중변화없이간내중성지방을감소시키고인슐린저항성을개선시켜간기능의호전을보인다는보고가있다 35). 기본적으로섭취하던양에서매일 500~1,000 칼로리를적게조정하거나, 영양사와상의하여비만한여자는 1,000~1,200, 남자는 1,200~1,600 칼로리를유지하게하여체중감소를유도한다 16,36,37). 지방간질환에서탄수화물 (carbohydrates) 이전체칼로리에서차지하는비중이낮을수록간내지방이감소하고간기능이호전된다는연구가있으나, 극단적인탄수화물의감소보다는전체칼로리의 50~60% 정도가적당하다고생각된다 38). 저탄수화물식이는특히우리나라와같은탄수화물섭취가많은나라에서필요할것으로생각된다. 저자는환자들에게저녁식사에서 밥 양을반으로줄일것을권한다. 탄수화물중에서최근문제가되는것은과당 (fructose) 이다 39). 과당은포도당 (glucose) 이나자당 (sucrose) 보다인슐린분비가적어간내지방의축적을증가시킨다 40). 과당은대부분의음료수나과자등의인스턴트식품에맛을내는성분 (high-fructose corn syrup, HFCS) 으로이러한식품들의과다섭취는지방간질환을유발하거나지방간질환환자에서섬유화를악화시킬수있다 41,42). 고지방 (high-fat diet) 식이는잘알려진대로간내지방을증가시키고지방간염으로진행시킬수있다 43). 포화지방 (saturated fat) 은당뇨, 심혈관질환, 대사증후군과밀접한관계가있으며, 동물실험에서 SREBP, ER stress 등을촉진시켜 간세포에염증이나 apoptosis를유발하는것으로밝혀졌다 44). 그러나사람에서포화지방식이에의한간내지방의증가는연구자마다다른결과를보고하였다. 그것은포화지방의증가와그에따른칼로리의증가에의한영향을완전히구분할수없기때문이다. 최근문제가되고있는트랜스지방산 (trans-fatty acid) 은한개이상의이중결합 (double bond) 을갖는불포화지방산으로액체상태의불포화지방산을반고체상태로만들때산에의해손상되는것을막기위해수소를첨가 (hydrogenation) 해서만들어지는일종의인공적인지방산이다. 대표적으로쇼트닝 (shortening oil, 경화유 ), 마가린 (margarine) 등이다. 이들은주로튀김, 마요네즈, 수프, 케이크, 쿠키, 아이스크림, 햄, 소시지등을만들때이용되며, 당뇨, 심혈관질환유발과관련이입증되어있다 45). 실험동물에서는트랜스지방산의과다한섭취가간내지방의증가를가져오는것이확인되었으나, 사람에서의직접적인연구는부족한실정이다. 견과류나생선에많은오메가-3 혹은 n-3 고도불포화지방산 (polyunsaturated fatty acid, PUFA) 과올리브, 해바라기씨등에많은단일불포화지방산 (monounsaturated fatty acid, MUFA) 은지방간질환에서지방산의생성을억제하고분해를촉진하여간내지방축적을예방한다 46-48). 최근한연구에서매일 2 gm의 n-3 PUFA 를복용한지방간질환환자에서간내지방이감소되는것을확인하였다 49). MUFA 의섭취는복부지방을감소시키고인슐린저항성을개선시킨다는보고가있었다 50). 그렇지만지방간질환환자들에게치료목적으로이러한 n-3 PUFA 등의지속적인투약은제조회사마다순도나용량등이일정하지않고, 아직도명백한증거가부족해좀더많은연구가진행된후에시행되어야할것으로생각된다. 지방간질환에서식이단백질 (protein) 에의한영향은잘알려져있지않다. 그러나고단백식이가고칼로리 / 고지방식이보다는간내지방침착이적었고인슐린저항성이개선되었다는보고가있었다 51). 결론적으로지방간질환환자는저칼로리의저탄수화물, 저지방음식을기본으로, n-3 PUFA 나 MUFA 등이많이포함된식품의섭취를늘리고, 포화지방산, 트랜스지방산, HFCS 등이많이포함된음식은피해야한다 52). 3) 운동 (physical activity, exercise) 지방간질환의치료에서중요한체중감소를위해서는식이조절과함께운동 (exercise) 이중요한역할을한다. 활동이부족한사람이나운동을하지않는사람에서지방간의유병

4 - 대한내과학회지 : 제 79 권제 5 호통권제 603 호 률이높았고, 식이조절을통한체중감소없이운동만으로도간내지방의감소와인슐린저항성의호전등을보인연구결과가있었다 53-56). 우리가흔히하는유산소운동 (aerobic exercise) 은지방조직에서인슐린감수성을증가시켜유리지방산의생성을감소시켜간으로지방산의유입을감소시키고, 간내에서미토콘드리아에의한지방산의산화 (mitochondrial β-oxidation) 를증가시켜중성지방이만들어지는양을줄인다 57). 또한, 중성지방을배출시키는 VLDL의분비를촉진하여간밖으로중성지방의배출을돕는다. 결과적으로, 내장지방 (visceral adipose tissue) 의부피 (volume) 가줄고간내중성지방의양이감소하게된다. 운동의강도나시간등은 ACSM (American College of Sports Medicine) 에서권고한심폐단련 (cardiorespiratory fitness) 프로그램을제안한다 58). 1) 운동빈도 : 3~5일 / 주 2) 강도 : 최대심박수 (HR max) 의 55/65~90% 혹은최대산소흡수능력 (V O 2R) 의 40/50~85% 3) 시간 : 하루에 20~60분을지속적혹은간헐적인운동 4) 운동방식 : 큰근육들을사용하는리드미컬하고유산소성격의모든운동, 예 ) 걷기-하이킹, 달리기-조깅, 자전거타기, 에어로빅댄스, 조정 (rowing), 계단오르기, 수영, 스케이트타기등이다. 일반적으로중간이상의 ( 최대심박수의 60~70% 정도 ) 강도로주 (week) 에 150분이상의운동을권한다. 운동의종류는유산소전신운동이가장효과적이지만, 역기등을이용해서근육운동을하는저항력훈련 (resistance training) 도체중감소없이지방간질환에효과가있는것으로알려져있다 59). 또한지속적인저강도의신체활동 ( 정원가꾸기, 가사노동, 요가등 ) 이나최대한숨이찰정도의유산소운동을아주짧은시간 ( 약 10~ 30초 ) 동안 5~8회반복하는것도효과가있다는연구가있다 58-60). 운동만으로체중을줄이기위해서는최소일주일에 150분이상의운동이필요하며, 식이조절없이운동만으로체중을줄여서지방간을치료하는것은상당히어려우며지속하기도매우어렵다 58). 따라서각자에맞는지속가능하고재미있는운동을선택하여식이조절과병행하여꾸준히할수있도록운동트레이너와영양사의도움을받는것이필요하다 21,57). 2. 약물치료 (insulin sensitizers, anti-oxidants, lipid-lowering agents, and others) 위에서언급하였듯이지방간질환의가장중요한치료는 생활습관의개선 에의한치료지만, 운동, 식이조절, 체중 감량등에오랜시간과많은참을성을필요로하여치료성공가능성이떨어진다. 또한치료에성공하였던대부분의환자에서일정시간이지나면다시원래의생활습관으로돌아갈정도로지속성이떨어진다. 이러한이유로약물을이용한지방간질환의치료를시도하게되었다. 단편적으로많은연구가되었지만, 장기간사용에도안전하고부작용이없는것으로알려진약물은거의없는실정이다. 여기에서는최근까지비교적안전하고치료효과가있다고알려진대표적인약제를소개하고자한다. 1) 인슐린저항성개선약물 (insulin sensitizers) 대표적인약물로 thiazolidinediones (TZDs, rosiglitazone, pioglitazone) 등과 metformin이다. TZDs 는 PPAR-γ agonist로지방조직과근육, 간에서인슐린저항성개선하고, 염증을억제하는 adipokine 분비를촉진하여간내지방을감소시키고, 동물실험에서간내섬유화를유발하는간성상세포의활성화와콜라젠합성을억제시키는좋은결과를보였다 61). 1999년 rosiglitazone, pioglitazone 등이당뇨치료목적으로허가를받았으며 2001년부터지방간질환특히지방간염에대한치료제로연구가시작되었다. 초기연구에서는 1년치료로조직검사에서간내지방, 염증, 섬유화등에서모두호전되는결과를보였으나, 최근의연구에서는지방및염증소견은호전되었으나섬유화의호전은없었다는연구가대부분이다 62-64). 또한 1년간치료후에중단하면짧은시간에다시치료전상태로돌아가는단점이있어장기치료가필요한약제로생각되었다 65). 그러나 Ratziu 등은지방간염환자에서 rosiglitazone으로 2년간치료한후에도간내지방의감소및염증등은 1년치료와차이가없다고보고하여, 장기치료효과에의문을제기하였다 66). TZDs의부작용으로는체중증가 (70% 환자에서 2~6 kg) 가가장흔하며, 하지부종, 근육경련, 장기간사용시에골절위험의증가와함께울혈성심부전 (congestive heart failure) 등이보고되어있다. Rosiglitazone ( 상용량 8 mg, Avandia ) 과 pioglitazone (30~45 mg, Actos ) 은작용기전이거의동일하지만 rosiglitazone은울혈성심부전을경험했다는보고가있는데반해서, pioglitazone은혈중 HDL을높이고 LDL은감소시키며, 오히려심혈관계를보호하는기능을하는것으로알려져있다. 저자는조직검사에서확인된지방간염환자를대상으로 rosiglitazone 4 mg ( 일반적인지방간염치료용량의 1/2) 으로단기간사용하였더니경미한체중증가와함께인슐린저항

5 - 박상훈. 비알코올성지방간질환의치료 - 성의개선, ALT 의호전을경험하였다. 현재까지의연구결과로는치료기간, 치료용량, 치료효과를예측하는인자등에대한연구가부족한실정이지만, 더좋은약제가나오거나혹은지방간질환의새로운병리기전이나타나기전까지 TZDs는인슐린저항성이확인된지방간질환환자에서매우유용한약물로생각된다 67). 최근 rosiglitazone은우리나라식약청에서부작용우려에따른사용중지권고가있어앞으로지방간질환치료제로선택에제한을받게되었다. 당뇨병치료에사용되는 metformin은간과근육에서인슐린저항성을개선하고, 간내 AMPK (adenosine monophosphateactivated protein kinase) 를활성화시켜간에서새로운지방의생산을억제하여지방간질환의치료에도움이된다 68,69). 초기에는당뇨병을동반한지방간질환환자의치료에서효과가있었으며, 최근에는당뇨병이없는환자에서도간내지방의감소, ALT의정상화를보였다 70). 그러나 metformin (1,500~ 2,000 mg) 의치료효과에대한보고는연구자마다다르며, 장기치료도단기치료보다효과적이지못하다는연구도있다 71). 따라서현재까지는당뇨가있는지방간질환환자에서다른치료와함께병합치료제의한가지로 metformin을선택할수있을것으로생각된다. 2) 항산화제 (anti-oxidants) 와간세포보호제항산화제는지방간질환을악화시키는산화스트레스 (oxidative stress) 를감소시키고간내염증을줄일것으로생각되어사용되었다. 그러나대부분의약제는치료효과를입증할만한대규모연구가부족한실정이다. 비타민 E ( 알파토코페롤 ) 는소규모연구에서지방간치료에효과가없다는보고와함께장기간사용시사망률을증가시킨다는연구가있어지방간질환의치료에적절치못할것으로생각되었다 72). 그러나최근지방간염환자에서비타민 E와 pioglitazone의효과를비교한장기간의연구에서비타민 E가 pioglitazone 과비슷한효과를보였으며, 부작용도적다는보고가있었다 73). 이러한연구가몇차례더발표된다면, 앞으로비타민 E가지방간질환의치료에상당한역할을할수있을것으로생각된다. 간세포보호제로대표적인약물이 UDCA (urosodeoxycholic acid) 다. UDCA는여러가지기전으로지방간질환에도움이될것으로생각되었고, 특히고용량을장기간투여해도부작용이없다는장점때문에지방간치료에도움이될것으로생각되었다. 그러나대규모연구에서는만족스럽지못한결과를보였으며, 최근고용량 (23~28 mg/kg) 의 UDCA 치료에서도대조군과차이가없었다 74,75). 그렇지만, 장기간서서히 진행하는지방간질환의특성때문에부작용이적고작용기전이다양한 UDCA를아직도많은수의지방간연구자들이완전히포기하지못하고처방하고있는실정이다. 앞으로는 UDCA의단독치료보다는 pioglitazone 등이나다른약제들과의병합치료를연구해야할것으로생각된다 76). 3) 고지혈증치료제 (lipid-lowering agents) 과거에는 gemfibrozil, fenofibrate 등의 fibrate 계열의약제가연구되었으나, 최근에는 HMG-CoA reductase 인 statin (atorvastatin, pravastatin, rosuvastatin) 이주목을받고있다. Statin이지방간질환에서 ALT를정상화시키고간내지방을감소시킨다는보고가있으나반대로간기능이상을초래한다는보고도있어사용이조심스러웠다 77,78). 그러나최근에는 statin 복용으로인한간기능악화는단순히경미한 ALT의상승뿐이고심한간손상은거의없으므로약간의 ALT 상승에도지속처방이가능하다고알려져있다 79). 현재까지는지방간질환치료에서 statin에대한결정적이고결론을내릴만한연구는부족한실정이며, 고지혈증을동반한지방간질환환자에서다른약제와병합투여를고려해볼수있을것으로생각된다. 4) 기타약제 Angiotensin receptor blocker (ARB, losartan 등 ) 는지방간염환자에서간내섬유화와염증을줄여준다는연구가있어고혈압이동반된지방간질환환자에서우선적으로선택될수있는약제이다 80). Polyunsaturated fatty acid (PUFA, 오메가 -3 fatty acid) 는 ALT 및중성지방을낮추어주고간내지방을감소시킨다 49). 그러나아직치료제로단독으로처방하기에는연구가부족한실정이다. 결론단순지방간, 지방간염은치료가가능한만성질환이다. 지방간의치료는단기적으로는환자의삶의질 (quality of life) 을개선시키고, 장기적으로는간경변증, 간암으로진행을예방하여간질환으로인한사망을감소시킬수있으며, 동반되는심혈관계질환의위험성을감소시킬수있다. 생활습관의변화를통한체중감소, 운동, 식이조절이치료의근간을이루며, 약물치료는당뇨, 고지혈증, 고혈압등의기저질환이동반된경우나지방간염으로진단된경우에추천되며고도비만이동반된환자는비만수술이효과적이다

6 - The Korean Journal of Medicine: Vol. 79, No. 5, 앞으로치료효과를지속적으로유지하기힘든운동이나식이요법등을좀더효과적으로수행할수있는다학제적인 (multi-disciplinary) 치료가도입되어야할것으로생각되며, 장기치료에도안전하고효과적인약제가개발될것을기대해본다. 중심단어 : 비알콜성지방간질환 ; 비알콜성지방간염 ; 치료 REFERENCES 1) Clark JM, Brancati FL, Diehl AM. The prevalence and etiology of elevated aminotransferase levels in the United States. Am J Gastroenterol 98: , ) Falck-Ytter Y, Younossi ZM, Marchesini G, McCullough AJ. Clinical features and natural history of nonalcoholic steatosis syndromes. Semin Liver Dis 21:17-26, ) Park SH, Jeon WK, Kim SH, Kim HJ, Park DI, Cho YK, Sung IK, Sohn CI, Keum DK, Kim BI. Prevalence and risk factors of non-alcoholic fatty liver disease among Korean adults. J Gastroenterol Hepatol 21: , ) Starley BQ, Calcagno CJ, Harrison SA. Nonalcoholic fatty liver disease and hepatocellular carcinoma: a weighty connection. Hepatology 51: , ) Kawada N, Imanaka K, Kawaguchi T, Tamai C, Ishihara R, Matsunaga T, Gotoh K, Yamada T, Tomita Y. Hepatocellular carcinoma arising from non-cirrhotic nonalcoholic steatohepatitis. J Gastroenterol 44: , ) Michitaka K, Nishiguchi S, Aoyagi Y, Hiasa Y, Tokumoto Y, Onji M. Etiology of liver cirrhosis in Japan: a nationwide survey. J Gastroenterol 45:86-94, ) Oh KC, Park SH, Park JC, Jin DK, Park CS, Kim KO, Jang HJ, Lee JY, Park CH, Han TH, Yoo KS, Kim JH, Kim DJ, Lee MS, Park CK. Is the prevalence of cryptogenic hepatocellular carcinoma increasing in Korea? Korean J Gastroenterol 45:45-51, ) Ekstedt M, Franzén LE, Mathiesen UL, Thorelius L, Holmqvist M, Bodemar G, Kechagias S. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 44: , ) Targher G, Bertolini L, Poli F, Rodella S, Scala L, Tessari R, Zenari L, Falezza G. Nonalcoholic fatty liver disease and risk of future cardiovascular events among type 2 diabetic patients. Diabetes 54: , ) Kim HJ, Kim HJ, Lee KE, Kim DJ, Kim SK, Ahn CW, Lim SK, Kim KR, Lee HC, Huh KB, Cha BS. Metabolic significance of nonalcoholic fatty liver disease in nonobese, nondiabetic adults. Arch Intern Med 164: , ) Choi SY, Kim D, Kang JH, Park MJ, Kim YS, Lim SH, Kim CH, Lee HS. Nonalcoholic fatty liver disease as a risk factor of cardiovascular disease: relation of non-alcoholic fatty liver disease to carotid atherosclerosis. Korean J Hepatol 14:77-88, ) Targher G, Day CP, Bonora E. Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N Engl J Med 363: , ) Kral JG, Thung SN, Biron S, Hould FS, Lebel S, Marceau S, Simard S, Marceau P. Effects of surgical treatment of the metabolic syndrome on liver fibrosis and cirrhosis. Surgery 135:48-58, ) Day CP, James OF. Steatohepatitis: a tale of two "hits"? Gastroenterology 114: , ) Tamura Y, Tanaka Y, Sato F, Choi JB, Watada H, Niwa M, Kinoshita J, Ooka A, Kumashiro N, Igarashi Y, Kyogoku S, Maehara T, Kawasumi M, Hirose T, Kawamori R. Effects of diet and exercise on muscle and liver intracellular lipid contents and insulin sclsitivity in type 2 diabetic patients. J Clin Endocrinol Metab 90: , ) Ueno T, Sugawara H, Sujaku K, Hashimoto O, Tsuji R, Tamaki S, Torimura T, Inuzuka S, Sata M, Tanikawa K. Therapeutic effects of restricted diet and exercise in obese patients with fatty liver. J Hepatol 27: , ) Palmer M, Schaffner F. Effect of weight reduction on hepatic abnormalities in overweight patients. Gastroenterology 99: , ) Kantartzis K, Thamer C, Peter A, Machann J, Schick F, Schraml C, Königsrainer A, Königsrainer I, Kröber S, Niess A, Fritsche A, Häring HU, Stefan N. High cardiorespiratory fitness is an independent predictor of the reduction in liver fat during a lifestyle intervention in non-alcoholic fatty liver disease. Gut 58: , ) Hickman IJ, Jonsson JR, Prins JB, Ash S, Purdie DM, Clouston AD, Powell EE. Modest weight loss and physical activity in overweight patients with chronic liver disease results in sustained improvements in alanine aminotransferase, fasting insulin, and quality of life. Gut 53: , ) Franz MJ, VanWormer JJ, Crain AL, Boucher JL, Histon T, Caplan W, Bowman JD, Pronk NP. Weight-loss outcomes: a systematic review and meta-analysis of weight-loss clinical trials with a minimum 1-year follow-up. J Am Diet Assoc 107: , ) Bellentani S, Dalle Grave R, Suppini A, Marchesini G. Behavior therapy for nonalcoholic fatty liver disease: the need for a multidisciplinary approach. Hepatology 47: , ) Harrison SA, Ramrakhiani S, Brunt EM, Anbari MA, Cortese C, Bacon BR. Orlistat in the treatment of NASH: a case series. Am J Gastroenterol 98: , ) Zelber-Sagi S, Kessler A, Brazowsky E, Webb M, Lurie Y, Santo M, Leshno M, Blendis L, Halpern Z, Oren R. A double-blind randomized placebo-controlled trial of orlistat for the treatment of nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 4: ,

7 - Sang Hoon Park. Nonalcoholic fatty liver disease: treatment - 24) Harrison SA, Fecht W, Brunt EM, Neuschwander-Tetri BA. Orlistat for overweight subjects with nonalcoholic steatohepatitis: a randomized, prospective trial. Hepatology 49:80-86, ) Després JP, Golay A, Sjöström L. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med 353: , ) Banasch M, Goetze O, Schmidt WE, Meier JJ. Rimonabant as a novel therapeutic option for nonalcoholic steatohepatitis. Liver Int 27: , ) Van Gaal LF, Scheen AJ, Rissanen AM, Rössner S, Hanotin C, Ziegler O. Long-term effect of CB1 blockade with rimonabant on cardiometabolic risk factors: two year results from the RIO-Europe study. Eur Heart J 29: , ) Pi-Sunyer FX, Aronne LJ, Heshmati HM, Devin J, Rosenstock J. Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients: RIO-North America: a randomized controlled trial. JAMA 295: , ) Dixon JB, Bhathal PS, Hughes NR, O'Brien PE. Nonalcoholic fatty liver disease: improvement in liver histological analysis with weight loss. Hepatology 39: , ) O'Brien PE, Dixon JB, Laurie C, Skinner S, Proietto J, McNeil J, Strauss B, Marks S, Schachter L, Chapman L, Anderson M. Treatment of mild to moderate obesity with laparoscopic adjustable gastric banding or an intensive medical program: a randomized trial. Ann Intern Med 144: , ) Mathurin P, Hollebecque A, Arnalsteen L, Buob D, Leteurtre E, Caiazzo R, Pigeyre M, Verkindt H, Dharancy S, Louvet A, Romon M, Pattou F. Prospective study of the long-term effects of bariatric surgery on liver injury in patients without advanced disease. Gastroenterology 137: , ) Liu X, Lazenby AJ, Clements RH, Jhala N, Abrams GA. Resolution of nonalcoholic steatohepatits after gastric bypass surgery. Obes Surg 17: , ) Chapman AE, Kiroff G, Game P, Foster B, O'Brien P, Ham J, Maddern GJ. Laparoscopic adjustable gastric banding in the treatment of obesity: a systematic literature review. Surgery 135: , ) de Almeida SR, Rocha PR, Sanches MD, Leite VH, da Silva RA, Diniz MT, Diniz Mde F, Rocha AL. Roux-en-Y gastric bypass improves the nonalcoholic steatohepatitis (NASH) of morbid obesity. Obes Surg 16: , ) Kirk E, Reeds DN, Finck BN, Mayurranjan SM, Patterson BW, Klein S. Dietary fat and carbohydrates differentially alter insulin sensitivity during caloric restriction. Gastroenterology 136: , ) Okita M, Hayashi M, Sasagawa T, Takagi K, Suzuki K, Kinoyama S, Ito T, Yamada G. Effect of a moderately energy-restricted diet on obese patients with fatty liver. Nutrition 17: , ) Huang MA, Greenson JK, Chao C, Anderson L, Peterman D, Jacobson J, Emick D, Lok AS, Conjeevaram HS. One-year intense nutritional counseling results in histological improvement in patients with non-alcoholic steatohepatitis: a pilot study. Am J Gastroenterol 100: , ) Hollingsworth KG, Abubacker MZ, Joubert I, Allison ME, Lomas DJ. Low-carbohydrate diet induced reduction of hepatic lipid content observed with a rapid non-invasive MRI technique. Br J Radiol 79: , ) Kawasaki T, Igarashi K, Koeda T, Sugimoto K, Nakagawa K, Hayashi S, Yamaji R, Inui H, Fukusato T, Yamanouchi T. Rats fed fructose-enriched diets have characteristics of nonalcoholic hepatic steatosis. J Nutr 139: , ) Ouyang X, Cirillo P, Sautin Y, McCall S, Bruchette JL, Diehl AM, Johnson RJ, Abdelmalek MF. Fructose consumption as a risk factor for non-alcoholic fatty liver disease. J Hepatol 48: , ) Assy N, Nasser G, Kamayse I, Nseir W, Beniashvili Z, Djibre A, Grosovski M. Soft drink consumption linked with fatty liver in the absence of traditional risk factors. Can J Gastroenterol 22: , ) Abdelmalek MF, Suzuki A, Guy C, Unalp-Arida A, Colvin R, Johnson RJ, Diehl AM. Increased fructose consumption is associated with fibrosis severity in patients with nonalcoholic fatty liver disease. Hepatology 51: , ) Westerbacka J, Lammi K, Hakkinen AM, Rissanen A, Salminen I, Aro A, Yki-Jarvinen H. Dietary fat content modifies liver fat in overweight nondiabetic subjects. J Clin Endocrinol Metab 90: , ) Funaki M. Saturated fatty acids and insulin resistance. J Med Invest 56:88-92, ) Micha R, Mozaffarian D. Trans fatty acids: effects on metabolic syndrome, heart disease and diabetes. Nat Rev Endocrinol 5: , ) Clarke SD. Nonalcoholic steatosis and steatohepatitis: I. molecular mechanism for polyunsaturated fatty acid regulation of gene transcription. Am J Physiol Gastrointest Liver Physiol 281:G865-G869, ) Xu J, Cho H, O'Malley S, Park JH, Clarke SD. Dietary polyunsaturated fats regulate rat liver sterol regulatory element binding proteins-1 and -2 in three distinct stages and by different mechanisms. J Nutr 132: , ) Garg A. High-monounsaturated-fat diets for patients with diabetes mellitus: a meta-analysis. Am J Clin Nutr 67:S577-S582, ) Spadaro L, Magliocco O, Spampinato D, Piro S, Oliveri C, Alagona C, Papa G, Rabuazzo AM, Purrello F. Effects of n-3 polyunsaturated fatty acids in subjects with nonalcoholic fatty liver disease. Dig Liver Dis 40: , ) Paniagua JA, Gallego de la Sacristana A, Romero I, Vidal-Puig A, Latre JM, Sanchez E, Perez-Martinez P, Lopez-Miranda J,

8 - 대한내과학회지 : 제 79 권제 5 호통권제 603 호 Perez-Jimenez F. Monounsaturated fat-rich diet prevents central body fat distribution and decreases postprandial adiponectin expression induced by a carbohydrate-rich diet in insulin-resistant subjects. Diabetes Care 30: , ) Tremblay F, Lavigne C, Jacques H, Marette A. Role of dietary proteins and amino acids in the pathogenesis of insulin resistance. Annu Rev Nutr 27: , ) Sullivan S. Implications of diet on nonalcoholic fatty liver disease. Curr Opin Gastroenterol 26: , ) Church TS, Kuk JL, Ross R, Priest EL, Biltoft E, Blair SN. Association of cardiorespiratory fitness, body mass index, and waist circumference to nonalcoholic fatty liver disease. Gastroenterology 130: , ) Perseghin G, Lattuada G, De Cobelli F, Ragogna F, Ntali G, Esposito A, Belloni E, Canu T, Terruzzi I, Scifo P, Del Maschio A, Luzi L. Habitual physical activity is associated with intrahepatic fat content in humans. Diabetes Care 30: , ) St George A, Bauman A, Johnston A, Farrell G, Chey T, George J. Independent effects of physical activity in patients with nonalcoholic fatty liver disease. Hepatology 50:68-76, ) Johnson NA, Sachinwalla T, Walton DW, Smith K, Armstrong A, Thompson MW, George J. Aerobic exercise training reduces hepatic and visceral lipids in obese individuals without weight loss. Hepatology 50: , ) Johnson NA, George J. Fitness versus fatness: moving beyond weight loss in nonalcoholic fatty liver disease. Hepatology 52: , ) Donnelly JE, Blair SN, Jakicic JM, Manore MM, Rankin JW, Smith BK. American College of Sports Medicine Position Stand: appropriate physical activity intervention strategies for weight loss and prevention of weight regain for adults. Med Sci Sports Exerc 41: , ) Zelber-Sagi S, Nitzan-Kaluski D, Goldsmith R, Webb M, Zvibel I, Goldiner I, Blendis L, Halpern Z, Oren R. Role of leisure-time physical activity in nonalcoholic fatty liver disease: a population-based study. Hepatology 48: , ) Burgomaster KA, Howarth KR, Phillips SM, Rakobowchuk M, Macdonald MJ, McGee SL, Gibala MJ. Similar metabolic adaptations during exercise after low volume sprint interval and traditional endurance training in humans. J Physiol 586: , ) Galli A, Crabb DW, Ceni E, Salzano R, Mello T, Svegliati-Baroni G, Ridolfi F, Trozzi L, Surrenti C, Casini A. Antidiabetic thiazolidinediones inhibit collagen synthesis and hepatic stellate cell activation in vivo and in vitro. Gastroenterology 122: , ) Neuschwander-Tetri BA, Brunt EM, Wehmeier KR, Oliver D, Bacon BR. Improved nonalcoholic steatohepatitis after 48 weeks of treatment with the PPAR-gamma ligand rosiglitazone. Hepatology 38: , ) Promrat K, Lutchman G, Uwaifo GI, Freedman RJ, Soza A, Heller T, Doo E, Ghany M, Premkumar A, Park Y, Liang TJ, Yanovski JA, Kleiner DE, Hoofnagle JH. A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis. Hepatology 39: , ) Belfort R, Harrison SA, Brown K, Darland C, Finch J, Hardies J, Balas B, Gastaldelli A, Tio F, Pulcini J, Berria R, Ma JZ, Dwivedi S, Havranek R, Fincke C, DeFronzo R, Bannayan GA, Schenker S, Cusi K. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med 355: , ) Lutchman G, Modi A, Kleiner DE, Promrat K, Heller T, Ghany M, Borg B, Loomba R, Liang TJ, Premkumar A, Hoofnagle JH. The effects of discontinuing pioglitazone in patients with nonalcoholic steatohepatitis. Hepatology 46: , ) Ratziu V, Charlotte F, Bernhardt C, Giral P, Halbron M, Lenaour G, Hartmann-Heurtier A, Bruckert E, Poynard T. Long-term efficacy of rosiglitazone in nonalcoholic steatohepatitis: results of the fatty liver improvement by rosiglitazone therapy (FLIRT 2) extension trial. Hepatology 51: , ) Harrison SA. Thiazolidinedione therapy for nonalcoholic steatohepatitis: go, stop, or proceed with caution? Hepatology 51: , ) Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, Musi N, Hirshman MF, Goodyear LJ, Moller DE. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 108: , ) Lin HZ, Yang SQ, Chuckaree C, Kuhajda F, Ronnet G, Diehl AM. Metformin reverses fatty liver disease in obese, leptin-deficient mice. Nat Med 6: , ) Marchesini G, Brizi M, Bianchi G, Tomassetti S, Zoli M, Melchionda N. Metformin in non-alcoholic steatohepatitis. Lancet 358: , ) Nair S, Diehl AM, Wiseman M, Farr GH Jr, Perrillo RP. Metformin in the treatment of non-alcoholic steatohepatitis: a pilot open label trial. Aliment Pharmacol Ther 20:23-28, ) Miller ER 3rd, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med 142:37-46, ) Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, Neuschwander-Tetri BA, Lavine JE, Tonascia J, Unalp A, Van Natta M, Clark J, Brunt EM, Kleiner DE, Hoofnagle JH, Robuck PR. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 362: , ) Lindor KD, Kowdley KV, Heathcote EJ, Harrison ME, Jorgensen R, Angulo P, Lymp JF, Burgart L, Colin P. Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial. Hepatology 39: , ) Leuschner UF, Lindenthal B, Herrmann G, Arnold JC, Rossle M,

9 - 박상훈. 비알코올성지방간질환의치료 - Cordes HJ, Zeuzem S, Hein J, Berg T. High-dose ursodeoxycholic acid therapy for nonalcoholic steatohepatitis: a double-blind, randomized, placebo-controlled trial. Hepatology 52: , ) Kashi MR, Torres DM, Harrison SA. Current and emerging therapies in nonalcoholic fatty liver disease. Semin Liver Dis 28: , ) Ekstedt M, Franzén LE, Mathiesen UL, Holmqvist M, Bodemar G, Kechagias S. Statins in non-alcoholic fatty liver disease and chronically elevated liver enzymes: a histopathological follow-up study. J Hepatol 47: , ) Bhardwaj SS, Chalasani N. Lipid-lowering agents that cause drug-induced hepatotoxicity. Clin Liver Dis 11: , ) Lewis JH, Mortensen ME, Zweig S, Fusco MJ, Medoff JR, Belder R. Efficacy and safety of high-dose pravastatin in hypercholesterolemic patients with well-compensated chronic liver disease: results of a prospective, randomized, double-blind, placebo-controlled, multicenter trial. Hepatology 46: , ) Yokohama S, Yoneda M, Haneda M, Okamoto S, Okada M, Aso K, Hasegawa T, Tokusashi Y, Miyokawa N, Nakamura K. Therapeutic efficacy of an angiotensin II receptor antagonist in patients with nonalcoholic steatohepatitis. Hepatology 40: ,