PG 2 PG Course 2014 Treatments of ASH, NASH and AIH 비알코올지방간염의치료표적과치료방법 한양대학교의과대학 1 내과학교실, 2 구리병원소화기내과 김선민 1, 손주현 2 Therapeutic Targets and Management of Non-Alcoholic Steatohepatitis Sunmin Kim 1, Joo Hyun Sohn 2 1 Department of Internal Medicine, College of Medicine, Hanyang University, Seoul, Korea; 2 Hanyang University Guri Hospital, Guri, Korea Non-alcoholic fatty liver disease (NAFLD) is one of most common liver diseases in the world and Korea but to date its efficient therapies are still insufficient. Recently, pathophysiological understanding has been much developed. Insulin resistance with the derangement of glucose and lipid metabolism has a principal role in the development of NAFLD and other many factors such as lipotoxicity, oxidative injury, mitochondrial dysfunction, inflammatory cytokines, hepatic fibrosis, hepatocyte apoptosis, innate immunity and the gut microbiota are also involved, especially in the pathogenesis of non-alcoholic steatohepatitis (NASH). Based on the pathophysiologic advance, these factors become attractive targets for NAFLD/NASH treatment. In this lecture, current and future treatment options will be discussed shortly, focusing mainly on the recently developing promising candidates such as probiotics, incretin mimetics, farnesoid X receptor agonist, anti-apoptosis agents, peroxisome proliferator activated receptor-α/δ agonists and adiponectin receptor agonists. 서 론 비알코올지방간질환 (non-alcoholic fatty liver disease, NAFLD) 은영상의학적으로또는조직학적으로간내지방침착이있으면서이를일으킬만한약물의사용력, 의미있는음주력, 그리고유전적인질환이동반되지않은경우로정의된다. 1 NAFLD는비만, 당뇨, 이상지질혈증등이포함되는대사증후군에서동반될수있는간질환으로단순지방간에서보다진행된지방간염 (nonalcoholic steatohepatitis, NASH) 과간경변, 간세포암을모두포함하는포괄적인용어이다. 2,3 최근비만, 당뇨를포함한대사증후군의증가와함께그유병률이급격히증가하고있으며실제최근우리나라에서진행된대규모연구에서유병률이 19-33% 로보고된바가있다. 4-6 NASH는간내지방침착을보이면서간세포손상 ( 풍선변형 ) 을동반한염증소견이있는경우로정의하며, 단순지방간은 10-20% 정도에서 NASH 로진행할수있다. 7 특히 NASH 는단순지방간과달리간경변과간세포암으로의진행가능성이높아서 8-13년에걸쳐서약 15% 에서간경변으로진행하며, 또다른보고에의하면, 4년간추적관찰했을때 25-30% 에서간경변으로진행한다. 7,8 게다가 NAFLD는당뇨및심혈관질환의위험요인으로도널리알려져있다. 5,8 43
Postgraduate Course 2014 이와같이 NASH는간경변, 간암으로의진행위험뿐아니라심혈관과내분비질환의위험이있어서치료가필요한질환으로최근유병율도증가하는등임상적인중요성이높아지고있어서본소고를통해지금까지알려진 NASH의치료표적과치료방법에대해간략히정리하고자한다. 특히 2013년비알코올지방간질환진료가이드라인이발표되었으므로, 치료에대한전체적인내용은간략히소개하면서진료가이드라인에서다루기힘든최근새롭게등장하고있는치료제에대한것을주로소개하고자한다. 치료표적과치료방법 NASH의치료목표는지방간염자체의치료를통한간질환의진행을억제하는방향과기저질환인대사증후군의치료를통해심혈관질환등의합병증을예방하는방향으로이루어져야한다. 치료방법은크게생활습관의교정, 약물치료, 그리고수술적치료로나눌수있다. 1. 생활습관교정 NASH의가장기본적인병인은인슐린저항성이다. 그위에지방조직의과도한축적과지방산의과다, 지방산의과다로인한미토콘드리아의기능이상, 지방조직의미세저산소증, 산화스트레스, 단백질합성을담당하는세포질세망 (endoplasmic reticulum, ER) 의스트레스와전신적염증반응등에의해유발된다. 또한 22번염색체의 PNPLA3 domain 같은유전적인인자도지방간염의발병에기여할수있다. 9 인슐린저항성은유리지방산을지방조직에서간으로보내는기능을한다. 10 그리고간세포에서지방산과그대사물의축적이지방산의과산화와지방간염을일으키는지방독성의기본이되고염증성 cytokine의분비를통해 DNA의손상을입혀서미토콘드리아의기능이상까지초래하게된다. 10 이러한측면에있어서치료의표적은지방조직에서의인슐린저항성을개선시키고부적절한지방의분해를억제함으로써간내지방산을낮추는것이고그원인이되는과도한칼로리, 지방및탄수화물의섭취를줄이는식이요법과체중감량그리고근육의당섭취를증가시키기위한운동요법이중요한치료방법이된다. 11,12 1) 체중감량비만인 NASH 환자에서적절한체중감량은 MRI를이용해서측정했을때간내지방량을감소시킬수있었고, 13 조직검사를통해서측정했을때에도간내지방량을감소시킬수있었다. 14 체중감소와간조직소견의관계에대해서 7-10% 의체중감량은간내지방침착, 염증, 및풍선변성등의소견을호전시켰다. 15,16 그러나대상환자가적어서추가적인연구가필요하며체중조절과 ALT에대해서는체중감소가 ALT를낮췄다는보고들이있긴하지만아직논란이있다. 16-18 그래서현재로서는체중감량은간내지방량을감소시킬수있으나간조직소견과간효소수치에미치는영향에대해서는아직추가적인연구가필요하다. 19 2) 식이요법 NASH의식이요법으로는총에너지섭취를줄이는것이가장중요한데구체적으로하루권장에너지섭취량과비교하여 25% 정도줄이는것이추천된다. 20 91명의 NAFLD 환자를대상으로시행한연구에의하면탄수화물의섭취량은대사증후군의동반여부및간내지방침착, 염증의정도와관련이있었다. 21 또최근에식이에관해서중요성이강조되는것으로과당이있다. 이는인스턴트식품에서단맛을내는데사용되는것으로인슐린분비를덜촉진시키고세포의사멸을유도하며포만감을느끼지못하게하는등의기전을통해 NAFLD 44
김선민, 손주현 비알코올지방간염의치료표적과치료방법 의발생에영향을미친다. 국내의연구에서도탄수화물특히과당의섭취가증가하면간효소수치가증가하고지방간의유병률이증가하였으며저탄수화물식이교육이저지방식이교육보다간내지방감소와간효소수치의감소에효과적이었다는보고가있었다. 22 이는한국인이서양에비해전체에너지섭취량중에탄수화물의비율이높기때문일것이며그래서한국인에서는저탄수화물및저과당식이가특히추천될것이다. 23 3) 운동요법운동요법은운동에의한체중감소가동반되지않은경우에도인슐린저항성과대사증후군의개선에도움이된다. 운동요법이간내지방량에미치는영향에대해알아본연구들에서는대체로운동요법자체가간내지방량의감소에도움이된다고밝혀졌으나, 14,24-26 ALT 감소에는영향을미치지못하는것으로보고되었다. 27 아직운동요법의종류와강도및시간에대해서는합의된바가없다. 다만기존의연구에의하면일주일에 2회이상, 매회 30-60분동안최대심박수의 50-70% 정도가되도록하는유산소운동을 6주이상지속할것을추천할수있겠다. 14,24-26 2. 약물요법앞서기술한대로 NAFLD을일으키는가장기본적인기전은인슐린저항성이며그외에산화스트레스, ER 스트레스, 지방산의과다, 지방조직의축적및전신적인염증반응등이영향을미친다. 따라서약물치료의표적은크게두가지로나누어질수있다. 한가지는원인이되는간내지방을줄여서지방간염을호전시키는것이되겠고다른한가지는지방을직접줄이진않지만산화스트레스, apoptosis, 전신적염증반응, 그리고인슐린저항성등을억제해서지방간염을호전시키는것이되겠다. 그외에동반된대사증후군을조절함으로써합병증발생을예방하는것도고려해야하겠다. 1 1) 항산화제간세포는미토콘드리아의베타산화를통해지방산을산화하여에너지를생산하는데지방산이과다할경우과산화소체에서도베타산화가일어나고이때생기는유리산소기는간세포를손상시킬수있다. 10 따라서이러한산화반응을억제하는것이치료의표적이된다. 대표적항산화제인비타민 E는지방간염을악화시키는산화스트레스와지질의과산화를억제하여지방간염과섬유화소견을호전시킬수있다고생각되어왔다. 28 최근의연구에서고용량비타민 E (800 IU/day for 96 days) 는당뇨가없는 NASH 환자에서간내지방량, 염증의정도, 그리고간효소수치를감소시켰으나섬유화의호전에영향을미치지못했고다른연구에서는고용량비타민 E를투여해서간염은호전되었으나간효소수치는호전되지않았다. 29,30 한편 NASH 환자에게매일 1000 IU의비타민 E와 1000mg의비타민 C를함께투여한연구가있는데이연구에서간효소수치와염증의정도는개선되지않았으나섬유화점수에서호전이있었다고보고했다. 31 부작용에대해서는 35000여명의건강한남성을대상으로진행한연구결과에서비타민 E를사용한그룹은대조군과비교해서전립선암의발생이증가하는것으로확인되었다. 32 따라서고용량의비타민 E는 NASH 환자에서간내지방량을감소시키고염증을호전시킬수있으나장기간투여시전립선암등의부작용이생길수있으므로주의가필요하겠다. 33 그외의기타항산화제로 N-acetylcysteine, betaine, probucol, viusid 등에대한연구가진행중이나아직까지효과가입증된것은없다. 2) 인슐린저항성개선제앞에서언급한대로인슐린저항성은지방조직에서지방산을간으로이동시키고간세포에서지방산과그대 45
Postgraduate Course 2014 사물을축적시킴으로써지방간염을일으킨다. 따라서 10 인슐린저항성을개선하는것은지방간염의중요한치료표적이되며, 이러한대표적인약물로 thiazolidinedione과 metformin이있다. (1) Thiazolidinedione 우선 thiazolidinedione계약물인 pioglitazone은 peroxisome proliferator-activated receptor-γ (PPAR-γ) 작용제 (agonist) 로지방조직과근육, 간에서인슐린저항성을개선하고, 염증을억제하는 adiponectin의분비를촉진하여, 간내지방을감소시키고풍선변성과소엽염증같은간세포의손상을감소시킬수있다. 10,29,34 그외에규모가작은연구이긴하지만 pioglitazone이간내지방량과간효소수치의호전과함께섬유화를개선시켰다는연구도있었다. 35 또다른연구들에의하면 pioglitazone은간효소수치와간내지방량을감소시키며염증을의미있게호전시켰으나섬유화에대해서는통계적으로의미없는호전경향만을보였다. 34,36 게다가 PPAR-γ 작용제는 Kupffer cell을 M1에서항염증기능을갖는 M2 대식세포로활성화시키는역할도하므로비만으로인한간의인슐린저항성의개선에더욱도움이될수있을것이다. 12 그러나 pioglitazone을사용하다가중지하면 NASH 가재발하므로장기간의사용이필요하다는부정적인보고도있다. 37 한편, thiazolidinedione의부작용으로는체중증가, 골절, 하지부종, 근육경련, 심부전등이있었고특히 rosiglitazone 은심부전과심근경색등의부작용으로사용중지권고가있었다. 38,39 따라서 pioglitazone은 NASH 환자에서간효소수치와간내지방량의감소를일으키고염증을호전시키나섬유화의호전과부작용에대해서는아직추가적인연구가필요하다고할수있다. (2) Metformin Metformin 은간과근육에서인슐린저항성을개선하고, 간에서지방의생산을억제하여 NASH의치료에도움이될것으로생각되었다. 40,41 실제로 metformin의사용이간효소수치를감소시켰다는보고가있었다. 42 하지만최근의연구에의하면 thiazolidinedione에 metformin을추가하는것은 thiazolidinedione 단독에비해조직학적측면에서추가적인이득을보이지않았으며, 43 다른연구들에서도 metformin 은간효소수치, 간내지방량의감소또는염증과섬유화의호전에있어서아무런영향을미치지못했다. 44-46 따라서현재까지 metformin은 NASH에서간효소수치와지방량및조직소견에큰영향을미치지못하므로당뇨를동반한 NASH 환자에서당뇨에대한치료약으로서우선적으로고려할수있는정도라고하겠다. 33 3) 고지혈증치료제 NASH 환자는심혈관질환의위험이증가하며실제로가장중요한사망원인은관상동맥질환이다. 따라서 47 NASH 환자에서심혈관질환의위험요인을감소시키는것도중요한치료표적이될수있다. 이를위해다양한고지혈증약제들을치료제로고려할수있다. 1 (1) Statins 처음에 statins은간독성이있는것으로알려져간질환환자에서투약에장애가되었다. 그러나최근의연구들을보면일시적인간효소수치의증가는있을수있으나치명적인간손상을일으키는경우는드물고특히 NASH 환자에서비교적안전하게사용될수있다고한다. 48,49 규모가작은일부연구에서간손상을일으키지않고간조직소견과간효소수치를호전시켰다는결과가나왔으며 48 반대로간효소수치와염증, 섬유화의정도에서효과를보이지않았다는연구 50 도있었으므로아직까진지방간염의치료자체보다는심혈관질환의합병증을감소시키기위해서적응증이될경우사용할수있겠다. 46
김선민, 손주현 비알코올지방간염의치료표적과치료방법 (2) Omega-3 polyunsaturated fatty acids (n-3 PUFA) 고중성지방혈증의치료에사용되고있는 n-3 PUFA를 NAFLD 환자에게 12개월간매일 1g 투여시간효소수치와초음파소견에의한간내지방량의감소를일으켰다. 51 그러나최근의메타분석에의하면 n-3 PUFA는 NASH에서유의한효과를보이지못했고다른연구에서도 ALT와초음파에서지방간의소견을호전시켰으나조직검사를시행하지않았기때문에효과를받아들이고권장하기에는근거가아직부족하다 52. 53 따라서 NASH 환자에서고중성지방혈증이있을때에치료약제로고려할수있겠다. (3) Ezetimibe 간과장세포 (enterocytes) 에서콜레스테롤의흡수를억제하는 ezetimibe는 NASH 환자에서 ALT와염증소견, 풍선변성, NAFLD fibrosis score 등을호전시켰으나섬유화를개선시키진못했다는보고가있다. 54,55 하지만규모가작은연구이므로현재로서는대규모의무작위대조군연구결과가필요하다. 4) Pentoxifylline NASH 의악화요인으로대식세포와염증성 cytokine인 TNF-α가있다. 대식세포는지방세포의기능장애와인슐린저항성, 지방산의분비와간내지방침착등을일으킨다. 지방조직에서는 M1 대식세포에의해염증성 cytokine이분비되고 M2 대식세포가항염증효과를발휘하며간에서는 M1 Kupffer 세포가염증성 cytokine을분비하고지방간염의발병에기여한다. 12 그러므로염증성 cytokine의작용을억제하는것이치료표적이될수있다. Pentoxifylline은 TNF-α의분비를억제함으로써산화스트레스, apoptosis, 간세포손상, 염증과섬유화반응을감소시켜서지방간염의치료에도움이될수있을것이라여겨져왔다. 56 또최근에는 pentoxifylline이지방의산화를감소시켜서산화부산물에의한간손상을막는다는의견도제기되고있다. 57 여러가지기존의연구들에서 pentoxifylline은간효소수치의호전과인슐린저항성의개선효과를보였다. 58,59 한편다른연구에서는 NAFLD fibrosis score, 간내지방량, 그리고소엽염증의호전을보였으나풍선변성과섬유화에서는의미있는호전을보이지못했다고보고하였다. 56 그러나지금까지축적된근거자료로는 pentoxifylline을 NASH의치료에단독으로사용하는것은권장되지않는다. 5) Ursodeoxycholic acid (UDCA) UDCA는유해성담즙의농도를낮추고 apoptosis 와산화스트레스를억제하기때문에 NASH 치료에효과가있을것으로생각되었다. 60 그러나기존의연구에서하루 13-15mg/kg 의용량으로는간효소수치와조직소견모두에서의미있는호전을보이지않았다. 61,62 또한최근의이중맹검무작위대조군연구에서고용량의 UDCA 의사용이소엽염증이외의다른지표를호전시키지못함이확인되었고 60 2011년에무작위대조군연구를통해서고용량 UDCA의투약이 ALT와혈청섬유화지표의호전에인슐린저항성까지개선시켰으나조직검사를시행하지않았다는제한점이있었다. 62 그러므로현재까지의연구들에의하면고용량의 UDCA도 NASH 치료에있어서추천되지않으며효과를입증하기위해서는대규모의장기간에걸친연구가필요하다. 33 6) 최근연구진행중인전망있는새로운치료제현재까지 NASH 의치료로효과가입증된표준치료제가거의없기때문에많은치료제들이연구되고개발되고있다. 이들중에는 prebiotics와 probiotics, angiotensin II receptor blockers (ARB), incretin 유사체 (mimetics), farnesoid X receptor (FXR) 작용제 (agonist), apoptosis 억제제 (inhibitors), PPAR-α/δ 작용제, adiponectin receptors 작용제등이있으며, 이들중몇가지를간략히소개하고자한다. 47
Postgraduate Course 2014 (1) Prebiotics and Probiotics NASH 환자에서장벽의투과성증가와혈중세균내독소가증가되어있으며이로인한 TNF-α와같은염증성 cytokines의증가및지방간환자에서일부대변내세균의조성이변화가생긴다는연구가있다. 이러한자료들은장내세균총의변화를가져오는 prebiotics 또는 probiotics이 NASH의새로운치료표적으로등장할수있는근거가된다. 63,64 Prebiotics는대장내세균의성장과활동성 (activity) 에영향을미치는비흡수성당류로서, 지방간질환환자에서투여후간효소수치를낮추고체지방량의감소, 체중감소와혈당조절의호전을일으켰다는연구들이있다. 65,66 또생균제 (live microorganism) 인 probiotics도장내세균총의조성을변화시길수있는데, 실제로동물실험에서 probiotics의사용이간내지방산을감소시키고간효소수치와조직소견을호전시켰다는연구가있고 67 사람을대상으로한연구에서도 probiotics의사용이간내중성지방과간효소수치를호전시켰다는보고가있다. 68 그러나이러한약제들이일부연구에서효과가입증되었지만아직은대규모의임상연구가필요한단계이다. 33 (2) Angiotensin II receptor blockers (ARB) 지방간염에서속발되는간섬유화의진행억제도치료표적이될수있다. ARB는간성상세포의활성도와증식을억제하여간내염증과간섬유화의진행을억제하는기능이있을것으로여겨진다. 그래서 NASH에섬유화가동반된고혈압환자들을대상으로 2년간 losartan을투여하여섬유화의진행을지연시키는효과가있는지에대한 3상연구가현재진행중이다. 2 (3) Incretin mimetics Incretin은음식물이소화될때장에서분비되는 peptide 호르몬으로서 glucagon-like peptide-i (GLP-I) 와 gastric inhibitory peptide (GIP) 가있으며췌장베타세포에서인슐린생성과분비를촉진하며식욕저하작용이있다. 69 한편 incretin 유사체에는 GLP-I 작용제와 dipeptidyl peptidase 4 (DPP4) 억제제가있고인슐린저항성을개선하고체중감소에효과가있다. 실제동물실험을통해간내지방의감소, 간효소수치의감소에효과가있음이밝혀졌다. 이중 70 GLP-I 작용제인 exenatide는포도당에의한인슐린생성을증가시키는것으로 pioglitazone과병합하여사용시 MR spectroscopy 를통해측정한간내지방감소에대조군과비교해서유의한차이를보인연구가있으며간내유리지방산의침착이감소됨을조직소견으로확인한보고도있다. 71,72 또한현재 NASH 환자에서 48주간또다른 GLP-I 작용제인 liraglutide의사용으로간조직소견, NAFLD activity score, serum steatosis marker, 간탄성도, 인슐린저항성, 체중과 ALT, 혈중지질에미치는영향에대해알아보기위한 2상연구가진행중이다. 73 한편, GLP-I 은 DPP4에의해분해된다. 따라서 DPP4의억제가 GLP-I 의반감기를줄임으로써혈당의조절에도움이될수있다. 실제로동물실험에서 DPP4 억제제의사용이간내지방과인슐린저항성을개선시킨다는연구결과가있으나아직연구결과가부족한실정이다. 69 (4) FXR agonist: obeticholic acid 요즘연구되고있는약물중가장전망이있는것중하나는반합성담즙산인 6α-ethyl chenodeoxycholic acid (obeticholic acid; INT-747) 이며이는 FXR 작용제이다. FXR은간에서담즙산의합성조절, 포도당과지질의대사를조절하며근육과지방조직에서인슐린감수성의조절에관여하는것으로알려져있다. 74 이미동물실험에서 WAY-362450이라는합성 FXR 작용제의사용으로 methionine choline deficient diet를시행한 male mice에서간내염증과섬유화의정도가호전되는것을확인했으며 FXR의결핍이간내지방의증가와고지혈증을일으키고 FXR의과발현은간내중성지방침착과고지혈증을호전시킨다는보고도있다. 75,76 또한실제임상시험으로도당뇨병이있는 NASH 환자에서체중을감소시키고섬유화표지자를개선시킬수있는것이확인되 48
김선민, 손주현 비알코올지방간염의치료표적과치료방법 었다. 77 그리고최근의 2상연구에서당뇨병에 NASH가동반된환자를대상으로 obeticholic acid의 6주간처방이대조군과비교해서간효소수치와혈청섬유화표지자및인슐린저항성을개선시키는것으로확인되었다. 74 (5) Anti-apoptosis agents 비알코올성지방간염에서나타나는간세포의 apoptosis 는결국간의염증과섬유화를유발하게되므로중요한치료표적이될수있다. Caspase 는 apoptosis에관여하는효소인데특히 caspase 8이필수적이다. 따라서 caspase 8을선택적으로억제하면질환의진행을막을수있을것이다. 실제로최근연구중에 caspase 1,8,9를선택적으로억제하는 GS-9450이비알코올성지방간염환자에서혈청 ALT 수치의감소를가져올수있다는보고가있다. 78 또한 pancaspase inhibitor인 IDN-6556 이간내지방의감소, 간섬유화의개선과인슐린저항성을개선시킨다는보고도있다. 79 (6) Adiponectin receptor agonist Adiponectin은지방조직에서생성되어항염증작용을갖는 adipocytokine이다. 또비만이나 80 NAFLD과같은비만과관련된질환에서감소되며 adiponectin의감소가염증을일으키는시발점으로여겨진다. 80,81 합성 adiponectin-specific receptor 작용제인 AdipoRon 은 adiponectin 수용체에결합하면간에서포도당과지질대사, 산화스트레스및염증과정을조절할수있고, 69,80 간, 골격근, 그리고지방조직에서인슐린저항성과 glucose tolerance를개선시킬수있는것으로알려져있어서 NASH 치료에효과적일것으로주목받고있다. 82 하지만 adiponectin의과발현은골밀도나종양발생등에있어서부작용을일으킬수있다는보고가있어서아직더많은연구결과가요구된다. 80 (7) PPAR-α/δ agonist PPAR-α/δ 이중작용제인 GFT505는동물실험에서간내지방의감소와염증과섬유화의호전을일으키는것으로알려져있다. 83 이러한항염증, 항섬유화효과로인해 GFT505 를 NASH 치료에사용하려는시도가이어지고있으며이미임상시험을통해 GFT505가간과말초의인슐린저항성의개선과간효수수치, 중성지방과저밀도콜레스테롤의감소및전신염증의호전에효과가있음이증명되었다. 84,85 현재는 NASH 환자를대상으로한 2상연구가진행중이며결과에대한관심이모아지고있다. 80 (8) IKK2 inhibitor 끝으로 IKK2는만성염증및인슐린저항성과관련된것으로동물실험에의하면간에서 IKK2의 deletion은인슐린저항성을개선시킨다는연구가있으며 IKK2의억제는간의지방변성과염증을호전시키고항산화반응까지도개선시켰다는보고도있다. 86 3. 수술적치료 NASH 치료는가장우선적으로생활습관의교정을통한체중감소가있어야하며, 다음으로약물치료를선택할수있으나이러한보존적치료만으로적정체중을유지하기는어렵다. 또한간혹건강을위협할만큼의심한비만이동반된경우가있어서이러한환자들을대상으로심혈관질환의위험을낮추고생존률을향상시키기위한체중감소목적의수술이치료방법이될수있다. 87,88 실제체중감소를위한위장관수술이간조직소견에미치는효과를알아보기위한연구가여러차례시행되었는데대체로수술후조직검사에대한자료가충분하지않았다. 1 그러나수술후조직검사에대한자료를충분히확인할수있었던한연구의결과를보면간내지방량, NAFLD activity score, 풍선변성등이호전되었 49
Postgraduate Course 2014 으나섬유화에있어서는오히려악화를보였다고한다. 87 또한 NASH에서위장관수술의효과에대한두개의메타분석에의하면한분석에서는간내지방량, 염증및섬유화의감소에효과적이라고보고했으나 89 다른분석에서는아직잘디자인된무작위대조군연구가없어서결론내릴수없다고하였다. 90 게다가급격한체중감소로인한간부전의위험이있고간경변이동반된환자에서수술을진행할때안전성에대해서도아직논란이남아있으며우회수술로인한영양결핍과, dumping syndrome의합병위험이있고수술후의장기추적결과에대한보고가부족하기때문에아직일차적인치료법으로권고되지않고종합적으로고려해서신중히결정을해야하겠다. 91,92 참고문헌 1. Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology 2012;55:2005-2023. 2. Korean Association for the Study of the, Liver. KASL clinical practice guidelines: management of nonalcoholic fatty liver disease. Clin Mol Hepatol 2013;19:325-348. 3. Park SH. Nonalcoholic steatohepatitis: pathogenesis and treatment. Korean J Hepatol 2008;14:12-27. 4. Bae JC, Cho YK, Lee WY, Seo HI, Rhee EJ, Park SE, et al. Impact of nonalcoholic fatty liver disease on insulin resistance in relation to HbA1c levels in nondiabetic subjects. Am J Gastroenterol 2010;105:2389-2395. 5. Choi SY, Kim D, Kim HJ, Kang JH, Chung SJ, Park MJ, et al. The relation between non-alcoholic fatty liver disease and the risk of coronary heart disease in Koreans. Am J Gastroenterol 2009;104:1953-1960. 6. Park SH, Jeon WK, Kim SH, Kim HJ, Park DI, Cho YK, et al. Prevalence and risk factors of non-alcoholic fatty liver disease among Korean adults. J Gastroenterol Hepatol 2006;21:138-143. 7. Ekstedt M, Franzen LE, Mathiesen UL, Thorelius L, Holmqvist M, Bodemar G, et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 2006;44:865-873. 8. Musso G, Gambino R, Cassader M, Pagano G. Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity. Ann Med 2011;43:617-649. 9. Sookoian S, Pirola CJ. Meta-analysis of the influence of I148M variant of patatin-like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease. Hepatology 2011;53:1883-1894. 10. Lomonaco R, Sunny NE, Bril F, Cusi K. Nonalcoholic fatty liver disease: current issues and novel treatment approaches. Drugs 2013;73:1-14. 11. Neuschwander-Tetri BA. Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: the central role of nontriglyceride fatty acid metabolites. Hepatology 2010;52:774-788. 12. Cusi K. Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications. Gastroenterology 2012;142:711-725 e716. 13. Kantartzis K, Thamer C, Peter A, Machann J, Schick F, Schraml C, et al. High cardiorespiratory fitness is an independent predictor of the reduction in liver fat during a lifestyle intervention in non-alcoholic fatty liver disease. Gut 2009;58:1281-1288. 14. Jin YJ, Kim KM, Hwang S, Lee SG, Ha TY, Song GW, et al. Exercise and diet modification in non-obese non-alcoholic fatty liver disease: analysis of biopsies of living liver donors. J Gastroenterol Hepatol 2012;27:1341-1347. 15. Promrat K, Kleiner DE, Niemeier HM, Jackvony E, Kearns M, Wands JR, et al. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology 2010;51:121-129. 16. Harrison SA, Fincke C, Helinski D, Torgerson S, Hayashi P. A pilot study of orlistat treatment in obese, non-alcoholic steatohepatitis patients. Aliment Pharmacol Ther 2004;20:623-628. 17. Suzuki A, Lindor K, St Saver J, Lymp J, Mendes F, Muto A, et al. Effect of changes on body weight and lifestyle in nonalcoholic fatty liver 50
김선민, 손주현 비알코올지방간염의치료표적과치료방법 disease. J Hepatol 2005;43:1060-1066. 18. Hickman IJ, Jonsson JR, Prins JB, Ash S, Purdie DM, Clouston AD, et al. 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 2004;53:413-419. 19. Thoma C, Day CP, Trenell MI. Lifestyle interventions for the treatment of non-alcoholic fatty liver disease in adults: a systematic review. J Hepatol 2012;56:255-266. 20. World Gastroenterology Organisation (WGO). Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis. WGO web site, http://www.worldgastroenterology.org/assets/export/userfiles/2012_nash%20and%20nafld_final_long.pdf>. Accessed 2013. 21. Kang H, Greenson JK, Omo JT, Chao C, Peterman D, Anderson L, et al. Metabolic syndrome is associated with greater histologic severity, higher carbohydrate, and lower fat diet in patients with NAFLD. Am J Gastroenterol 2006;101:2247-2253. 22. National Institute of Food and Drug Safety Evaluation (NIFDS). Influence of dietary intake on non-alcoholic fatty liver disease in Korean. NIFDS web site, <http://rnd.mfds.go.kr/ >. Accessed 2013. 23. Korea Centers for Disease Control and Prevention (KCDC). Korea Health Statistics 2009: Korea National Health and Nutrition Examination Survey.KCDC web site, < http://knhanes.cdc.go.kr/knhanes/index.do >. Accessed 2013. 24. van der Heijden GJ, Wang ZJ, Chu ZD, Sauer PJ, Haymond MW, Rodriguez LM, et al. A 12-week aerobic exercise program reduces hepatic fat accumulation and insulin resistance in obese, Hispanic adolescents. Obesity (Silver Spring) 2010;18:384-390. 25. Johnson NA, Sachinwalla T, Walton DW, Smith K, Armstrong A, Thompson MW, et al. Aerobic exercise training reduces hepatic and visceral lipids in obese individuals without weight loss. Hepatology 2009;50:1105-1112. 26. Shojaee-Moradie F, Baynes KC, Pentecost C, Bell JD, Thomas EL, Jackson NC, et al. Exercise training reduces fatty acid availability and improves the insulin sensitivity of glucose metabolism. Diabetologia 2007;50:404-413. 27. Keating SE, Hackett DA, George J, Johnson NA. Exercise and non-alcoholic fatty liver disease: a systematic review and meta-analysis. J Hepatol 2012;57:157-166. 28. Hasegawa T, Yoneda M, Nakamura K, Makino I, Terano A. Plasma transforming growth factor-beta1 level and efficacy of alpha-tocopherol in patients with non-alcoholic steatohepatitis: a pilot study. Aliment Pharmacol Ther 2001;15:1667-1672. 29. Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010;362:1675-1685. 30. Lavine JE, Schwimmer JB, Van Natta ML, Molleston JP, Murray KF, Rosenthal P, et al. Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. JAMA 2011;305:1659-1668. 31. Harrison SA, Torgerson S, Hayashi P, Ward J, Schenker S. Vitamin E and vitamin C treatment improves fibrosis in patients with nonalcoholic steatohepatitis. Am J Gastroenterol 2003;98:2485-2490. 32. Klein EA, Thompson IM, Jr., Tangen CM, Crowley JJ, Lucia MS, Goodman PJ, et al. Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 2011;306:1549-1556. 33. Schwenger KJ, Allard JP. Clinical approaches to non-alcoholic fatty liver disease. World J Gastroenterol 2014;20:1712-1723. 34. Belfort R, Harrison SA, Brown K, Darland C, Finch J, Hardies J, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med 2006;355:2297-2307. 35. Promrat K, Lutchman G, Uwaifo GI, Freedman RJ, Soza A, Heller T, et al. A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis. Hepatology 2004;39:188-196. 36. Aithal GP, Thomas JA, Kaye PV, Lawson A, Ryder SD, Spendlove I, et al. Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology 2008;135:1176-1184. 37. Lutchman G, Modi A, Kleiner DE, Promrat K, Heller T, Ghany M, et al. The effects of discontinuing pioglitazone in patients with nonalcoholic steatohepatitis. Hepatology 2007;46:424-429. 38. Mahady SE, Webster AC, Walker S, Sanyal A, George J. The role of thiazolidinediones in non-alcoholic steatohepatitis-a systematic review and meta analysis. J Hepatol 2011;55:1383-1390. 39. Lipscombe LL, Gomes T, Levesque LE, Hux JE, Juurlink DN, Alter DA. Thiazolidinediones and cardiovascular outcomes in older patients with diabetes. JAMA 2007;298:2634-2643. 40. Lin HZ, Yang SQ, Chuckaree C, Kuhajda F, Ronnet G, Diehl AM. Metformin reverses fatty liver disease in obese, leptin-deficient mice. Nat 51
Postgraduate Course 2014 Med 2000;6:998-1003. 41. Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 2001;108:1167-1174. 42. Bugianesi E, Gentilcore E, Manini R, Natale S, Vanni E, Villanova N, et al. A randomized controlled trial of metformin versus vitamin E or prescriptive diet in nonalcoholic fatty liver disease. Am J Gastroenterol 2005;100:1082-1090. 43. Torres DM, Jones FJ, Shaw JC, Williams CD, Ward JA, Harrison SA. Rosiglitazone versus rosiglitazone and metformin versus rosiglitazone and losartan in the treatment of nonalcoholic steatohepatitis in humans: a 12-month randomized, prospective, openlabel trial. Hepatology 2011;54:1631-1639. 44. Uygun A, Kadayifci A, Isik AT, Ozgurtas T, Deveci S, Tuzun A, et al. Metformin in the treatment of patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2004;19:537-544. 45. Omer Z, Cetinkalp S, Akyildiz M, Yilmaz F, Batur Y, Yilmaz C, et al. Efficacy of insulin-sensitizing agents in nonalcoholic fatty liver disease. Eur J Gastroenterol Hepatol 2010;22:18-23. 46. Shields WW, Thompson KE, Grice GA, Harrison SA, Coyle WJ. The Effect of Metformin and Standard Therapy versus Standard Therapy alone in Nondiabetic Patients with Insulin Resistance and Nonalcoholic Steatohepatitis (NASH): A Pilot Trial. Therap Adv Gastroenterol 2009;2:157-163. 47. Targher G, Day CP, Bonora E. Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N Engl J Med 2010;363:1341-1350. 48. Chalasani N. Statins and hepatotoxicity: focus on patients with fatty liver. Hepatology 2005;41:690-695. 49. Lewis JH, Mortensen ME, Zweig S, Fusco MJ, Medoff JR, Belder R, et al. 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 2007;46:1453-1463. 50. Nelson A, Torres DM, Morgan AE, Fincke C, Harrison SA. A pilot study using simvastatin in the treatment of nonalcoholic steatohepatitis: A randomized placebo-controlled trial. J Clin Gastroenterol 2009;43:990-994. 51. Capanni M, Calella F, Biagini MR, Genise S, Raimondi L, Bedogni G, et al. Prolonged n-3 polyunsaturated fatty acid supplementation ameliorates hepatic steatosis in patients with non-alcoholic fatty liver disease: a pilot study. Aliment Pharmacol Ther 2006;23:1143-1151. 52. Parker HM, Johnson NA, Burdon CA, Cohn JS, O'Connor HT, George J. Omega-3 supplementation and non-alcoholic fatty liver disease: a systematic review and meta-analysis. J Hepatol 2012;56:944-951. 53. Zhu FS, Liu S, Chen XM, Huang ZG, Zhang DW. Effects of n-3 polyunsaturated fatty acids from seal oils on nonalcoholic fatty liver disease associated with hyperlipidemia. World J Gastroenterol 2008;14:6395-6400. 54. Yoneda M, Fujita K, Nozaki Y, Endo H, Takahashi H, Hosono K, et al. Efficacy of ezetimibe for the treatment of non-alcoholic steatohepatitis: An open-label, pilot study. Hepatol Res 2010;40:566-573. 55. Park H, Shima T, Yamaguchi K, Mitsuyoshi H, Minami M, Yasui K, et al. Efficacy of long-term ezetimibe therapy in patients with nonalcoholic fatty liver disease. J Gastroenterol 2011;46:101-107. 56. Zein CO, Yerian LM, Gogate P, Lopez R, Kirwan JP, Feldstein AE, et al. Pentoxifylline improves nonalcoholic steatohepatitis: a randomized placebo-controlled trial. Hepatology 2011;54:1610-1619. 57. Zein CO, Lopez R, Fu X, Kirwan JP, Yerian LM, McCullough AJ, et al. Pentoxifylline decreases oxidized lipid products in nonalcoholic steatohepatitis: new evidence on the potential therapeutic mechanism. Hepatology 2012;56:1291-1299. 58. Adams LA, Zein CO, Angulo P, Lindor KD. A pilot trial of pentoxifylline in nonalcoholic steatohepatitis. Am J Gastroenterol 2004;99:2365-2368. 59. Satapathy SK, Garg S, Chauhan R, Sakhuja P, Malhotra V, Sharma BC, et al. Beneficial effects of tumor necrosis factor-alpha inhibition by pentoxifylline on clinical, biochemical, and metabolic parameters of patients with nonalcoholic steatohepatitis. Am J Gastroenterol 2004;99:1946-1952. 60. Leuschner UF, Lindenthal B, Herrmann G, Arnold JC, Rossle M, Cordes HJ, et al. High-dose ursodeoxycholic acid therapy for nonalcoholic steatohepatitis: a double-blind, randomized, placebo-controlled trial. Hepatology 2010;52:472-479. 61. Lindor KD, Kowdley KV, Heathcote EJ, Harrison ME, Jorgensen R, Angulo P, et al. Ursodeoxycholic acid for treatment of nonalcoholic 52
김선민, 손주현 비알코올지방간염의치료표적과치료방법 steatohepatitis: results of a randomized trial. Hepatology 2004;39:770-778. 62. Ratziu V, de Ledinghen V, Oberti F, Mathurin P, Wartelle-Bladou C, Renou C, et al. A randomized controlled trial of high-dose ursodesoxycholic acid for nonalcoholic steatohepatitis. J Hepatol 2011;54:1011-1019. 63. Daubioul CA, Horsmans Y, Lambert P, Danse E, Delzenne NM. Effects of oligofructose on glucose and lipid metabolism in patients with nonalcoholic steatohepatitis: results of a pilot study. Eur J Clin Nutr 2005;59:723-726. 64. Spencer MD, Hamp TJ, Reid RW, Fischer LM, Zeisel SH, Fodor AA. Association between composition of the human gastrointestinal microbiome and development of fatty liver with choline deficiency. Gastroenterology 2011;140:976-986. 65. Li Z, Yang S, Lin H, Huang J, Watkins PA, Moser AB, et al. Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease. Hepatology 2003;37:343-350. 66. Parnell JA, Raman M, Rioux KP, Reimer RA. The potential role of prebiotic fibre for treatment and management of non-alcoholic fatty liver disease and associated obesity and insulin resistance. Liver Int 2012;32:701-711. 67. Miele L, Valenza V, La Torre G, Montalto M, Cammarota G, Ricci R, et al. Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology 2009;49:1877-1887. 68. Wong VW, Won GL, Chim AM, Chu WC, Yeung DK, Li KC, et al. Treatment of nonalcoholic steatohepatitis with probiotics. A proof-of-concept study. Ann Hepatol 2013;12:256-262. 69. Takaki A, Kawai D, Yamamoto K. Molecular Mechanisms and New Treatment Strategies for Non-Alcoholic Steatohepatitis (NASH). Int J Mol Sci 2014;15:7352-7379. 70. Samson SL, Bajaj M. Potential of incretin-based therapies for non-alcoholic fatty liver disease. J Diabetes Complications 2013;27:401-406. 71. Gupta NA, Mells J, Dunham RM, Grakoui A, Handy J, Saxena NK, et al. Glucagon-like peptide-1 receptor is present on human hepatocytes and has a direct role in decreasing hepatic steatosis in vitro by modulating elements of the insulin signaling pathway. Hepatology 2010;51:1584-1592. 72. Samson SL, Sathyanarayana P, Jogi M, Gonzalez EV, Gutierrez A, Krishnamurthy R, et al. Exenatide decreases hepatic fibroblast growth factor 21 resistance in non-alcoholic fatty liver disease in a mouse model of obesity and in a randomised controlled trial. Diabetologia 2011;54:3093-3100. 73. Armstrong MJ, Barton D, Gaunt P, Hull D, Guo K, Stocken D, et al. Liraglutide efficacy and action in non-alcoholic steatohepatitis (LEAN): study protocol for a phase II multicentre, double-blinded, randomised, controlled trial. BMJ Open 2013;3:e003995. 74. Mudaliar S, Henry RR, Sanyal AJ, Morrow L, Marschall HU, Kipnes M, et al. Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology 2013;145:574-582 e571. 75. Zhang S, Wang J, Liu Q, Harnish DC. Farnesoid X receptor agonist WAY-362450 attenuates liver inflammation and fibrosis in murine model of non-alcoholic steatohepatitis. J Hepatol 2009;51:380-388. 76. Xiong X, Wang X, Lu Y, Wang E, Zhang Z, Yang J, et al. Hepatic steatosis exacerbated by endoplasmic reticulum stress-mediated downregulation of FXR in aging mice. J Hepatol 2014;60:847-854. 77. Sanyal AJ, Mudaliar S, Henry R, Marschall H-U, Morrow L, Sciacca CI, et al. A new therapy for nonalcoholic fatty liver disease and diabetes? INT-747-the first FXR hepatic therapeutic study. Hepatology 2009;50:389-390A. 78. Ratziu V, Sheikh MY, Sanyal AJ, Lim JK, Conjeevaram H, Chalasani N, et al. A phase 2, randomized, double-blind, placebo-controlled study of GS-9450 in subjects with nonalcoholic steatohepatitis. Hepatology 2012;55:419-428. 79. Barreyro FJ, Holod S, Finocchietto PV, Camino AM, Aquino JB, Avagnina A, et al. The Pan-Caspase Inhibitor Emricasan (IDN-6556) Decreases Liver Injury and Fibrosis in a Murine Model of Non-Alcoholic Steatohepatitis. Liver Int 2014 [Epub ahead of print]. 80. Tilg H, Moschen AR. Evolving therapies for non-alcoholic steatohepatitis. Expert Opin Drug Discov 2014 [Epub ahead of print]. 81. Tilg H, Moschen AR. Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol 2006;6:772-783. 82. Okada-Iwabu M, Yamauchi T, Iwabu M, Honma T, Hamagami K, Matsuda K, et al. A small-molecule AdipoR agonist for type 2 diabetes and short life in obesity. Nature 2013;503:493-499. 83. Staels B, Rubenstrunk A, Noel B, Rigou G, Delataille P, Millatt LJ, et al. Hepatoprotective effects of the dual peroxisome proliferator-activated receptor alpha/delta agonist, GFT505, in rodent models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Hepatology 2013;58:1941-1952. 53
Postgraduate Course 2014 84. Cariou B, Zair Y, Staels B, Bruckert E. Effects of the new dual PPAR alpha/delta agonist GFT505 on lipid and glucose homeostasis in abdominally obese patients with combined dyslipidemia or impaired glucose metabolism. Diabetes Care 2011;34:2008-2014. 85. Cariou B, Hanf R, Lambert-Porcheron S, Zair Y, Sauvinet V, Noel B, et al. Dual peroxisome proliferator-activated receptor alpha/delta agonist GFT505 improves hepatic and peripheral insulin sensitivity in abdominally obese subjects. Diabetes Care 2013;36:2923-2930. 86. Beraza N, Malato Y, Vander Borght S, Liedtke C, Wasmuth HE, Dreano M, et al. Pharmacological IKK2 inhibition blocks liver steatosis and initiation of non-alcoholic steatohepatitis. Gut 2008;57:655-663. 87. Mathurin P, Hollebecque A, Arnalsteen L, Buob D, Leteurtre E, Caiazzo R, et al. Prospective study of the long-term effects of bariatric surgery on liver injury in patients without advanced disease. Gastroenterology 2009;137:532-540. 88. NIH conference. Gastrointestinal surgery for severe obesity. Consensus Development Conference Panel. Ann Intern Med 1991;115:956-961. 89. Mummadi RR, Kasturi KS, Chennareddygari S, Sood GK. Effect of bariatric surgery on nonalcoholic fatty liver disease: systematic review and meta-analysis. Clin Gastroenterol Hepatol 2008;6:1396-1402. 90. Chavez-Tapia NC, Tellez-Avila FI, Barrientos-Gutierrez T, Mendez-Sanchez N, Lizardi-Cervera J, Uribe M. Bariatric surgery for non-alcoholic steatohepatitis in obese patients. Cochrane Database Syst Rev 2010:CD007340. 91. Car Peterko A, Kirac I, Gaurina A, Diklic D, Bekavac-Beslin M. Diagnosis and management of acute and early complications of/after bariatric surgery. Dig Dis 2012;30:178-181. 92. Hammer HF. Medical complications of bariatric surgery: focus on malabsorption and dumping syndrome. Dig Dis 2012;30:182-186. 54