ASH and NASH Drug Therapy for Nonalcoholic Fatty Liver Disease(NAFLD): What is New? Yun Soo Kim Department of Gastroenterology and Hepatology, Gachon University Gil Medical Center, Korea 비알코올지방간질환의약물치료 : 새로운점은? 김연수 가천의대소화기내과 Nonalcoholic fatty liver disease (NAFLD) is one of common chronic liver disease and is associated with liver cirrhosis and hepatocellular carcinoma. Insulin resistance and oxidative stress play major role in the pathogenesis of NAFLD, and obesity and type 2 diabetes are closely associated. The principal treatment for NAFLD is life style modification by diet and exercise, and therapeutic options are not only limited but also not very effective. Currently, insulin sensitizer and antioxidant such as thiazolidinedione and vitimin E seem to be most promising for NAFLD, showing reduced hepatic steatosis and inflammation. However, these compounds can cause side effects such as weight gain, heart failure, bone density reduction and potential malignancies, and concerns have been raised as ideal pharmacologic agents. Several new drugs have recently been developed for NAFLD and type 2 diabetes. In this paper, potential drug therapies for NAFLD were reviewed. Keywords: Nonalcoholic fatty liver disease, Nonalcoholic steatohepatitis, Drug therapy, Insulin resistance 서론비알코올지방간질환 (nonalcoholic fatty liver disease, 이하 NAFLD) 은만성간질환의중요한원인이며간경변증, 간암을유발할수있다. 비알코올지방간염 (nonalcoholic steatohepatitis, 이하 NASH) 의경우 15 내지 20% 에서간경변증으로진행하며간이식의원인질환으로서그빈도가점차증가하고있다. 1 비만과제 2형당뇨병은비알코올지방간질환의발생과긴밀히관계되고있다. 따라서식생활습관의교정과운동이 NAFLD 치료의기본적인요소이다. 또한인슐린저항성과산화스트레스 (oxidative stress) 가 NASH의중요한병인으로제시되고있으나아직까지이상적으로간내지방을감소시키고염증반응과간섬유화를호전시키는약제는없는실정이다. pioglitazone과같은 thiazolidinediones과 vitamin E 가간조직학적소견을호전시키는데효과적이었다고보고되었으나 thiazolidinediones는체중증가, 골절위험증가, 그리고방광암의위험이증가 2,3 하여치료제로서제한점이있으며 vitamin E의경우도장기투여의안정성이확보되지않았고전립선암의위험을높일수있다고보고되고있다. 4 최근 NAFLD의치료제로여러약제들이보고되고있으나아직임상시험단계의약제들이다수이다. 새로운약제들의약리작용과효능그리고부작용에대하여논하고자한다. 핵수용체 (nuclear receptor) 에작용하는약제 1) Obeticholic acid 담즙산은지방흡수등의고전적인기능뿐만아니라대사기능과인슐린민감성조절기능이최근강조되고있다. 280
Obeticholic acid (OCA,; INT-747, 6α-ethyl-chenodeoxycholic acid) 는 chenodeoxycholic acid의반합성유도체로당, 지질대사를조절하는핵호르몬수용체 (nuclear hormone receptor) 인 farnesoid X receptor (FXR) 의 natural agonist 로작용한다. FXR은간, 신장, 장에서주로발현되며간에서는 gluconeogenesis 와 glycogenolysis를조절하며근육과지방조직에작용하여인슐린민감성을개선한다. 5 또한 NASH에서간내염증반응을호전시키며항섬유화효과를보인다. 5 제 2형당뇨병과 NASH가있는환자를대상으로 6주간 obeticholic acid 를투여시 GGT가의미있게감소하였으며 hyperinsulinemic-euglycemic insulin clamp 법에의한인슐린민감성이 28% (25 mg 투여군 ), 24.5% (50 mg 투여군 ) 개선되었다. 또한 FXR에의해생성되는 FGF19 (fibroblast growth factor 19) 의농도가현저히증가하는데 6 FGF는이상지질혈증, 간내지방침착, 인슐린민간성을호전시키고체중을감소시킨다고알려져있다. 7 아울러 obeticholic acid 25 mg 투여군에서는 ELF (Enhanced Liver Fibrosis) 점수로측정한간내섬유화가현저히개선되었다고보고하고있다. 그러나 50 mg 투여군에서는혈중 LDL이증가하고 HDL은감소하여이에대한추가적인연구가필요한실정이 다. 6 최근보고된 FLINT (Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis) 연구에의하면 obeticholic acid 투여는대조군에비해간기능개선뿐만아니라현저히조직학적호전을나타낸다고보고되고있다. 8 72주간 obeticholic acid를 25 mg 투여군에서는 45% (50/110) 에서 NAFLD activity score (NAS) 가 2점이상개선된반면대조군에서는 21% (23/109) 에서만개선되었다고보고되고있다 (p=0.0002). 치료중총콜레스테롤과 LDL 증가와 HDL 콜레스테롤감소가관찰되었고 23% 의환자에서소양증이나타났다. 8 2) GFT-505 Peroxisome proliferator-activated receptor (PPAR)α는지방대사에관여하는유전자발현에영향을미치나당대사에는관여하지않는반면 PPARδ 는미토콘드리아기능에영향을미치며지방산산화와인슐린민감성에영향을미치며간내염증반응을호전시킨다. 9,10 PPAR agonist중 PPARα/δ dual agonist인 GFT-505 (2-2,6 dimethyl-4-(methylthio)phenyl -3-oxo-1(E)- prophenyl phenoxyl -2-methylprophanoic acid) 는 NASH 치료에효과적일것으로제시되고있다. 복부비만과이상지질혈증이있는환자를대상으로 GFT505 80 mg을투여한 2상연구에서 GFT505 투여는심각한부작용없이인슐린저항성을개선시켰고 TG 감소와 HDL 상승, 그리고 ALT와 GGT치의유의한감소가관찰되었다. 11 GLP1 receptor agonist Glucagon-like peptide 1 (GLP1) 과같은 incretin은담즙산이 G protein-coupled receptor TGR5를활성화시켜식후위장관에서분비되는호르몬이며췌장에서인슐린분비를자극한다. 12 GLP1은인슐린민감성을호전시키며포만감을증가시키고위장관운동을억제하여체중감량효과를나타낸다. 또한간내에서지방산의산화를촉진한다고보고되고있다. 13 GLP1은 dipeptidyl peptidase-4 (DPP-4) 에의해빠르게분해되므로 GLP1 receptor agonist는 DPP-4에저항성을보인다. Liraglutide와 exenatide가이에해당되는약제인데당불내성 (glucose intolerance) 환자를대상으로 liraglutide (0.9 mg/ 일 ) 24주투여시 BMI 감소, AST/ALT, GGT가감소되었고 96주투여시간조직검사를시행한 10예중 6예에서 NAS 2점이상의감소가관찰되었다. 14 Exenatide는합성 GLP1 receptor agonist이다. 비만과 NAFLD가있는제2형당뇨병환자에서 12주간 exenatide와인슐린투여군에서인슐린투여군에비하여체중감소, AST/ALT, GGT의감소그리고초음파검사상지방간의의미있는호전이관찰되었다. 15 281
간섬유화에작용하는약제 1) GR-MD-02 Galectin-3 는염증반응, 세포자멸사 (apoptosis), 혈관형성, 세포이동 (migration) 등에관여하는다기능단백이다. 대식세포 (macrophage) 에서높게발현되며간등의장기에서섬유화에관여한다. 16 동물실험에서 GR-MD-02는 galectin-3와결합하여간내염증반응과섬유화를호전시키며문맥압항진증도개선되었다고보고하고있다. GR-MD-02 가섬유화를호전시키는기전은아직확실치않으나 collagen을분해하는대식세포의수를증가시킬것으로추측하고있다. NASH와진행성간섬유화가있는환자를대상으로시행한 1상임상시험에서간섬유화가감소하였으며염증반응과관계되는 IL-6, TNF-alpha, IL-8이현저히감소되었다고하였다. 17 약제부작용은관찰되지않았고현재 2상시험중이다. 이외에도 Lysyl oxidase-like 2 (LOXL2) 에대한단클론항체인 Simtuzumab (GS-6624) 이 NASH 에의한진행성간섬유화와간경변증환자를대상으로임상시험중이다. 18 LOXL2는 collagen과 elastin의 cross-linking에관여하는 lysyl oxidase protein family에속하며간섬유화와관계된다고알려져있다. 지질강하제 Statin은 HMG-CoA reductase 를억제하여콜레스테롤합성을저하시켜이상지질혈증에이용된다. Atorvastatin은 NAFLD 환자에서혈중지질과 aminotransferase농도를감소시키며 NAS도호전시키나일부의환자에서는간섬유화가악화되었다고보고되고있어 NASH의효과적인약제로인정받고있지못하는상태이다. 18,19 Ezetimibe는장과간의 brush border에서 Niemann-Pick C1 Like 1(NPC1L1)-dependent cholesterol transport를강력히억제하여혈청지질농도를감소시킨다. 6개월간 ezetimibe 10 mg 투여시 aminotransferases와 LDL 콜레스테롤농도가현저히감소하였다. 간조직검사상 NAS도감소되었으나섬유화정도는의미있는변화를보이지않았으며 20 치료기간을 24개월연장하였을때에도섬유화는개선되지않았다는단점이있다. 21 N-3 polyunsaturated fatty acid (n-3 PUFAs) 의경우예비연구에서는하루 eicosapentanoic acid 2,700 mg를 12 개월투여시 ALT와간내지방침착, 소엽내염증반응, 간세포풍선화변성과섬유화가의미있게호전되었다고보고 22 된바있으나최근 ethyl-eicosapentanoic acid (EPA-E) 2상연구 (EPA-E, 1,800 mg, 2,700 mg, 12개월 ) 에서는의미있는조직학적변화가관찰되지않아 NASH 치료제로서의역할은향후더많은연구가필요하리라생각된다. 23 Probiotics 사람의장내에는 10 14 개이상의세균이존재하며세균의종은 10 4 개이상존재한다고알려져있다. 장내세균총은장내면역체계를유지하는데중요한역할을하며세균총 (microbiota) 의변화는 NAFLD를비롯한다양한간질환과관계된다고보고되고있다. 24 또한마른사람의세균총을대사증후군이있는환자에게장내주입하였을때인슐린저항성이현저히호전되었다는보고는장내세균총의변화가비만과인슐린저항성에관계될가능성을시사한다. 25 또한 NAFLD 환자에서는정상인에비하여장투과성 (intestinal permeability) 이증가되어있으며문맥을통해흡수된 lipopolysaccharide (LPS) 등에의한 Toll-like receptor (TLR) signaling이간손상과관계되리라제시되고있다. 26 NASH환자에서 Lactobacillus와 Bifidobacterium이주성분인 VSL#3 투여시 lipid peroxidation의지표인 malondialdehyde (MDA) 와 4-hydroxynonenal (4-HNE) 가의미있게감소 27 되었다고하며 Bifidobacterium longum은 AST/ALT, LDL cholesterol, CRP, TNF-alpha, 그리고인슐린저항성및조직학적소견이개선되었다고보고 28 되었다. 향후 NAFLD 치료제로서 probiotics에대한많은연구가진행되리라생각된다. 282
기타약제 1) Aramchol Aramchol (3β-arachidyl-amido, 7α-12α-dihydroxy, 5β-cholan-24-oic acid) 은담즙산인 cholic acid와포화지방산인 arachidic acid의포합체 (conjugate) 로 stearoyl coenzyme A desaturase1 (SCD1) 을억제하여간내지방을제거하여인슐린저항성이호전될수있다. 2상임상시험에서 300 mg의 Aramchol을 12주간투여시 MR spectroscopy로측정한간내지방이 12.8% 감소 ( 대조군 : 6.4%) 하였다. 또한혈청 adiponectin 농도가대조군에비하여현저히증가하였고특별한부작용은관찰되지않았다. 29 2) Remogliflozin etabonate Sodium-dependent glucose transporter 2 (SGLT2) 길항제는신장에서당의재흡수를차단하여혈당을떨어뜨린다. 30 Remogliflozin etabonate은 remogliflozin의 prodrug으로 SGLT2에대한선택적이고강력한 O-glycoside 길항제이다. 인슐린민감성개선효과뿐만아니라고유의항산화제로서의작용이있어당뇨병이있는 NASH 환자에서효과가있으리라생각된다. 12주간투여로대조군에비하여 ALT치를 32 내지 42% 감소시켰다고보고되고있다. 31 맺음말 NASH는간경변과간암을유발할수있는만성간질환이므로간질환의진행을억제할수있는효과적인약제의개발이시급한실정이다. 현재 NAFLD의치료제로많은새로운약제들이소개되고있으나인슐린저항성과생화학적지표의개선과더불어간조직소견을의미있게호전시키는약제는아직개발되지못한상태이다. 향후많은임상연구를통한효과적인치료제의출현과더불어서로다른기전을가진약제들의병합치료도기대하여본다. 참고문헌 1. Agopian VG, Kaldas FM, Hong JC, Whittaker M, Holt C, Rana A, et al. Liver transplantation for nonalcoholic steatohepatitis:the new epidemic. Ann Surg 2012;256:624-633 2. Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass, NM, et al. Pioglitazone, vitamine E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010;362(18):1675-1685. 3. Lewis JD, Ferrara A, Peng T, Hedderson M, Bilker WB, Quesenberry CP, Vaughn DJ, et al. Risk of bladder cancer among diabetic patients treated with pioglitazone: interim report of a longitudinal cohort study. Diabetes Care 2011;34:916-922 4. Klein EA, Thompson Jr IM, Tangen CM, Crowley JJ, Lucia MS, Goodman PJ, et al. Vitamin E and the risk of prostate cancer: the Selenium and Vitmin E Cancer Prevention Trial(SELECT). JAMA 2011;306:1549-1556 5. Adorini L, Pruzanski M, Shapiro D. Farnesoid X receptor targeting to treat nonalcoholic steatohepatitis. Drug Discov Today 2012;17:988-997 6. Mudaliar S, Henry RR, Sanyal AJ, Morrow L, Marschall H-U, Kipnes M, et al. Efficacy and safety of th Farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology 2013;145:574-582 7. Fu L, John LM, Adams SH, Yu XX, Tomlinson E, Renz M, et al. Fibroblast growth factor 19 increases metabolic rate and reverses dietary and leptin-deficient diabetes. Endocrinology 2004;145:2594-2603 8. Neuschwander-Tetri BA, Loomba R, Sanyal AJ, Lavine JE, Van Natta ML, Abdelmal 다 MF, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis(flint): a multicentre, randomized, placebo-controlled trial. Lancet 2015;385:956-965 9. Barish GD, Narkar VA, Evans RM. PPAR delta; a dagger in the heart of the metabolic syndrome. J Clin Invest 2006;116:590-597. 10. Bojic LA, Huff MW. Peroxisome proliferator-activated receptor delta: a multifaceted metabolic player. Curr Opin Lipiodol 2013;24:171-177. 11. Cariou B, Zair Y, Staels B, Bruckert E. Effects of the new dual PPARα/δ agonist GFT505 on lipid and glucose homeostasis in abdominally obese patients with combined dyslipidemia or impaired glucose metabolism. Diabetes Care 2011;34:2008-2014 283
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