PG 3 PG Course 2013 Non Alcoholic Fatty Liver Disease 한림대학교강남성심병원소화기내과 박상훈 Pharmacotherapy of Nonalcoholic Steatohepatitis Sang Hoon Park Department of Internal Medicine, Hallym University Medical Center, Seoul, Korea Weight loss via lifestyle modification remains the most common and fundamental therapy advocated for reducing hepatic lipid in NAFLD. Even weight loss and physical activity continued to be the cornerstone of therapy in NAFLD, but reaching a long-term lifestyle modification is not free from difficulties. Pharmacologic treatment should be considered for patients with NASH unable to achieve or maintain lifestyle-induced weight loss. Unfortunately, there is no approved pharmacological therapy for NASH at this point. Pioglitazone improved steatosis, hepatocellular ballooning and inflammation and have been demonstrated to reduce the risk of fibrosis progression in several randomized-controlled trials (RCTs). In a large RCT, large dose of vitamin E improved all histological lesions except for fibrosis. Metformin had a beneficial effect on ALT, but did not improve liver histology compared with placebo. Recently, one well-designed RCT demonstrated that pentoxifylline improves steatosis and lobular inflammation and can affect the progression of liver fibrosis in NASH and it was well tolerated in patients with NASH. Higher doses (25-30 mg/kg) of ursodeoxycholic acid (UDCA) showed a modest benefit for ALT and lobular inflammation. Some lipid-lowering drugs (statins, ezetimibe) improved ALT and radiological steatosis. Here, we systemically reviewed the effect of current pharmacological treatments for the NAFLD. Key words: NASH, Pharmacological, Treatment 서 론 지방간염을약물로치료하려는시도가 20년이되어가지만아직도입증된치료라할만한약제는없는실정이다. 그것은질환의진행속도가느려자연경과와비교가어렵고비교적양성질환이기때문에부작용이있을것으로추정되는약제의임상시험을쉽게시작하지못하는이유도있을것으로생각된다. 또한현재까지지방간염의진단에간조직검사가꼭필요하며, 치료효과를판정하는데있어서도조직검사소견이 ALT나초음파를포함하는방사선소견과일치하지않기때문에비교적침습적인간조직검사를반복해서할수밖에없기때문이다. 1 지방간질환의가장중요한치료는운동, 식이조절등을통한체중감량이지만, 치료를시작한환자중에서단지 50% 이하의환자에서만목표체중감량에성공하였고, 치료에성공하였던대부분의환자에서일정시간이 46
박상훈 지나면다시원래의체중으로돌아갈정도로지속성이떨어진다. 2 따라서생활습관의변화만을고집해서는지방간질환을치료할수없으며, 여기에안전하고부작용이적은약제를개발하여치료에활용해야한다. 지방간염을치료하는약제는크게두가지로나누어볼수있는데, 일차적으로병의원인이되는간내지방을줄여서지방간염을호전시키는약제와간내지방은줄이지않으면서산화스트레스 (oxidative stress), 인슐린저항성, apoptosis, 염증성 cytokine 등을호전시켜지방간염을치료하는약제로나누어볼수있다. 최근우리나라에서도지방간연구가활발해지면서마침내우리의독자적인임상진료가이드라인을발표하게되어지방간을연구하는연구자의한사람으로매우기쁘게생각하며본소고에서는지금까지보고된지방간염에대한약물치료를간단히요약하고자한다. 1. 체중감소약물체중을감소시키는약제는이차적으로간내지방을감소시키므로이론적으로지방간염의치료에효과적일것으로생각되었다. 그러나 sibutramine (Reductil R ), rimonabant (Acomplia R ) 등은심한부작용으로시장에서퇴출되었으며, orlistat (Xenical R ) 은드물지만심한간손상을일으킨다는보고가있다. 최근에는 rimonabant와유사하지만말초신경에작용하는 endocannabinoid 길항제에대한연구가진행중이다. 3,4 2. 인슐린저항성개선약물 Pioglitazone은 PPAR-γ agonist로지방조직과근육, 간에서인슐린저항성개선하고, 염증을억제하는 adiponectin 의분비를촉진하여, 간내지방을감소시키고간세포의손상을대변하는 hepatocyte ballooning, lobular inflammation을감소시킨다. 5,6 그렇지만간질환진행을예견하는중요한지표인간섬유화의호전은없거나아주적은호전을보였다. 5-7 Pioglitazone의부작용으로는체중증가 (70% 환자에서평균 4 kg 정도 ) 8 가가장흔하며, 하지부종, 근육경련, 장기간사용시에골절위험의증가, 9 방광암위험의증가 10 등이보고되어있으며치료를중단하면대부분의환자에서는지방간염이재발된다. 같은 thiazolidinedione (TZD) 인 rosiglitazone은 pioglitazone과작용기전이거의동일하지만심부전을경험했다는보고가있으며우리나라식약청에서투여중지권고가있어앞으로지방간질환치료제로선택에제한을받게되었다. 11,12 당뇨병치료에사용되는 metformin은간과근육에서인슐린저항성을개선하고, 간내 AMPK (adenosine monophosphate-activated protein kinase) 를활성화시켜간에서새로운지방의생산을억제하여지방간질환의치료에도움이될것으로생각된다. 초기에는당뇨병을동반한지방간질환환자의치료에서효과가있었으며, 최근에는당뇨병이없는환자에서도간내지방의감소, ALT의정상화를보였다. 13-15 또한 metformin 치료가체중감소효과가있어 TZD와병합투여서 TZD의단점인체중증가를상쇄시킬수있다는보고가있어, rosiglitazone과 metformin 두가지약제의병합투여에대한연구가있었으나 rosiglitazone 단독투여에비해치료효과가우월하지못하였고 TZD의부작용인체중증가를상쇄하는효과도없었다. 16 최근몇가지 RCT (randomized-controlled trial) 에서 metformin은지방간염환자에서조직소견을개선시키는효과가없는것으로확인되었다. 17 따라서현재까지는당뇨병이있는지방간염환자에서병합치료의한가지로 metformin을선택할수있을것으로생각된다. 3. 항산화제 항산화제는지방간염을일으키는산화스트레스를감소시키고염증성 cytokine을줄여서지방간염의치료에효과가있을것으로생각되어사용되었다. 대표적인항산화제로는비타민 E, 비타민 C, 베타인 (betaine) 등이다. 47
Postgraduate Course 2013 비타민 E ( 알파토코페롤 ) 는소규모연구에서지방간치료에효과가없다는보고와함께장기간사용시사망률을증가시킨다는연구가있어지방간염의치료에적절치못할것으로생각되었다. 18-20 그러나, 최근대규모 RCT인 PIVENS 연구에서는고용량의비타민 E (800 IU/ 일 ) 투여가대조군에비해간내조직소견의개선을보였다. 또한장기간, 고용량의비타민 E 투여는대조군이나 pioglitazone군과비교해도심각한부작용의발생은없었다. 6 TONIC 연구는 8세에서 17세사이의소아지방간염 173명의환자를대상으로고용량비타민 E (800 IU/ 일 ) 와 metformin (1,000 mg/ 일 ), 대조군의효과를비교한대규모 RCT로비록대조군에비해 ALT의호전은보이지않았으나, 지방간염이호전된환자의수는의미있게높았고, 소아에서도고용량의비타민 E 투여는안전하다는결과를보고하였다. 21 최근, 35,533명의건장한남성을대상으로비타민 E (400 IU/ 일 ) 와셀레니엄의효과를장기간비교한 SELECT 연구에서는비타민 E를투여한환자에서대조약을투여한환자에비해전립선암의발생률이높았다 (HR, 1.17;99% CI, 1.004-1.36, p=0.008). 22 이상의결과를살펴보면고용량의비타민 E는지방간염치료에서 pioglitazone과유사한효과를보이며우려했던사망률의증가는보이지않았다. 그러나아직도장기간의고용량투여에서안전성에대한우려는있는실정이다. 4. 간세포보호제 UDCA는여러가지작용기전으로지방간염에도움이될것으로생각되었고, 특히고용량을장기간투여해도부작용이없다는장점때문에지방간염치료에도움이될것으로생각되었다. 최근 Ratziu 등은고용량 (28-35 mg/kg/day) 의 UDCA 치료에서는대조군에비해 ALT 수치의호전을보였으며인슐린저항성을개선시켰으나조직소견을비교한결과는없었다. 23 한편 Leuschner 등은고용량 (23-28 mg/kg/day) 의 UDCA군과대조군을비교한결과 lobular inflammation이개선되는것이외의효과는없었다고보고하였다. 24 PSC (primary sclerosing cholangitis) 환자를대상으로한고용량의 UDCA (28-30 mg/kg/day) 연구에서는대조군에비해 UDCA 군에서심한부작용이많았고, 사망률혹은간이식을시행한환자가많아연구가조기에종료되었다. 25 따라서, 장기간서서히진행하는지방간염의특성때문에, 부작용이적고작용기전이다양한 UDCA를많은수의지방간연구자들이처방하고있는실정이나앞으로 UDCA의효과를입증하기위해서는다양한 UDCA의작용기전중에서지방간염에도움을주는기전이좀더명확히밝혀져야하며, 많은수의환자를대상으로장기간의연구가이루어져야할것으로생각된다. Pentoxifylline은비선택적 TNF-α 길항제 (non-selective TNF-α antagonist) 로지방간염을악화시키는기전에중요한역할을하는대표적인염증성 cytokine인 TNF-α의분비를억제하여산화스트레스와 apoptosis를감소시켜지방간질환의치료에도움이될것으로생각된다. 26 이와함께최근에는 pentoxifylline이지방의산화를감소시켜지방의산화부산물 (oxidized lipid products) 에의한간손상을억제시킨다는연구가있다. 27 소수의지방간염환자를대상으로한 pilot 연구에서는 ALT/AST 수치의호전과인슐린저항성을개선하는효과를보였다. 최근 Zein 등은 55명의지방간염환자를 12개월동안 pentoxifylline군과대조군으로나누어 RCT를진행하였다. 1차평가지표인 NAS 수치가 2점이상개선된환자는 pentoxifylline군에서 38.5%, 대조군에서 13.8% 로유의한차이를보였고, per protocol 분석에서는 pentoxifylline군에서 50%, 대조군에서 15.4% 였다. 그렇지만풍선변성과섬유화의호전을보인환자수는유의한차이를보이지않았다 28. 두가지 RCT 연구 (Van Wagner와 Zein) 에서장기간의 pentoxifylline (1,200 mg, 400 mg씩하루 3회 ) 의투여에도심각한부작용의발생은대조군과차이가없었다. 28,29 48
박상훈 5. 고지혈증치료제대표적인약제는 statin (atorvastatin, pravastatin, rosuvastatin 등 ) 이다. Statin이지방간질환에서 ALT를정상화시키고간내지방을감소시킨다는보고가있으나반대로간기능이상을초래한다는보고도있어사용이조심스러웠다. 그러나최근에는 statin 복용으로인한간기능악화는단순히경미한 ALT의상승뿐이고심한간손상은거의없으므로약간의 ALT 상승에도지속처방이가능하다고알려져있다. 30 현재까지는지방간염치료에서 statin에대한결정적이고결론을내릴만한연구는부족한실정이다. 유일한무작위대조군연구에서는 16명의환자를 simvastatin 40 mg 복용군과대조군으로나누어 12개월간연구가진행되었으나간조직검사에서지방침착, 염증, 섬유화모두에서호전을보여주지못하였다. 31 현재까지 statin은심혈관질환의위험이있는지방간염환자에서는효과적으로심혈관질환을예방할수있을것으로생각된다. Ezetimibe은식이나 bile에있는 cholesterol의흡수를억제하여최근지방간염의병리기전인 lipotoxicity를막아줄수있는것으로생각된다. 최근연구에서혈중 LDL 수치를호전시키며, hepatocyte ballooning과섬유화를호전시켰다는보고가있었다. 32 6. 연구가진행되고있는약제 Angiotensin receptor blocker (ARB) 는지방간염환자에서간내성상세포의활성화를억제하여섬유화와염증을줄여줄수있을것으로생각된다. 33 이들중에서 telmisartan은 PPAR-γ를조절하는기능이있어인슐린저항성을개선하는효과도있는것으로생각되며, 다른 ARB에비해지방간염치료에효과적이라는보고가있었다. 34 현재지방간염환자에서 losartan이간섬유화에미치는효과를알아보기위한 3상무작위대조군연구 (FELINE study) 가진행중이다. 현재까지의연구로는지방간염환자의단독치료로사용하기는연구가부족한실정이며, 고혈압이동반된지방간염환자에서우선적으로선택될수있는약제이다. Incretin mimetics (exenatide, liraglutide) 는 glucagon-like protein-1 receptor agonist로작용하여인슐린분비를촉진하고 gastric emptying을늦추어인슐린저항성을개선하고체중을감소시킨다. 35 최근 pioglitazone과 exenatide 를병합하여 pioglitazone 단독투여와비교한소규모연구에서는 MR spectroscopy 검사에서간내지방감소가병합치료군에서 pioglitazone 단독투여군에비해효과적이었다. 그렇지만간조직소견을직접비교하지는않았다. 36 Semi-synthetic 담즙산인 obeticholic acid (INT-747) 는 FXR (farnesoid X receptor) agonist로당뇨병이있는지방간질환환자에서인슐린저항성을개선시키고체중을감소시키는효과가있다. 37 현재 2상연구가진행중이다. Selective caspase inhibitor인 GS-9450는 124명의지방간염환자를대상으로 2상 RCT 연구가진행중이다. 38 참고문헌 1. Torres DM, Williams CD, Harrison SA. Features, diagnosis, and treatment of nonalcoholic fatty liver disease. Clinical Gastroenterology and Hepatology 2012;10:837-858. 2. Bellentani S, Dalle Grave R, Suppini A, Marchesini G. Behavior therapy for nonalcoholic fatty liver disease: The need for a multidisciplinary approach. Hepatology 2008;47:746-754. 3. Jourdan T, Demizieux L, Gresti J, Djaouti L, Gaba L, Verges B, et al. Antagonism of peripheral hepatic cannabinoid receptor-1 improves liver lipid metabolism in mice: evidence from cultured explants. Hepatology 2012;55:790-799. 4. Tam J, Cinar R, Liu J, Godlewski G, Wesley D, Jourdan T, et al. Peripheral cannabinoid-1 receptor inverse agonism reduces obesity by reversing leptin resistance. Cell Metabolism 2012;16:167-179. 49
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