대한내과학회지 : 제 86 권제 4 호 2014 http://dx.doi.org/10.3904/kjm.2014.86.4.425 특집 (Special Review) - 비알코올지방간질환 비알코올지방간질환의약물치료 한림대학교의과대학강남성심병원소화기내과 박상훈 Pharmacologic Therapy for Nonalcoholic Fatty Liver Disease Sang Hoon Park Division of Gastroenterology, Department of Internal Medicine, Hallym University Medical Center, Hallym University College of Medicine, Seoul, Korea Weight loss via lifestyle modification remains the most efficient treatment for NAFLD. Weight loss and exercise are the cornerstones of therapy, but achieving long-term lifestyle modification is not free from difficulties. Pharmacologic therapy should be considered for patients with NAFLD unable to achieve or maintain lifestyle-induced weight loss. Unfortunately, there is no approved drug for NAFLD currently. Current treatment methods for NAFLD can be divided roughly into those methods that target components of metabolic syndrome using weight reduction and insulin sensitizers (pioglitazone) and those that use antioxidants (Vitamin E) to benefit the liver. Pioglitazone has been shown to improve steatosis, hepatocellular ballooning, and inflammation and also to reduce the risk of fibrosis progression in several randomized-controlled trials (RCTs). In a large RCT, large doses of vitamin E improved all histological lesions except for fibrosis. Compared with a placebo, Metformin lowered ALT, but did not improve liver histology. Recently, novel anti-diabetic agents (GLP-1 analogues, DPP IV inhibitors) and probiotics that alter the gut microbiome were shown to mildly benefit ALT and liver histology. In this report, we systemically review current pharmacologic therapies and other promising agents that were not considered in the most recent guidelines for the treatment of NAFLD. (Korean J Med 2014;86:425-431) Keywords: Nonalcoholic fatty liver disease; Pharmacologic therapy; Investigational drugs 서론일반적으로지방간질환에서단순지방간 (simple steatosis) 과지방간염 (nonalcoholic steatohepatitis) 의예후는매우다르며단순지방간이간경변증이나간암으로진행하는경우는드 문것으로알려져있다 [1]. 따라서지방간질환치료는단순지방간에서지방간염으로진행하지않도록하는것과지방간염으로진단된경우라면섬유화가진행되어간경변증혹은간암으로이환되지않도록하는것을목표로한다. 지방간질환의가장중요한치료는운동, 식이조절등을통한체 Correspondence to Sang Hoon Park, M.D. Division of Gastroenterology, Department of Internal Medicine, Hallym University Medical Center, Hallym University College of Medicine, 1 Singil-ro, Youngdeungpo-gu, Seoul 150-950, Korea Tel: +82-2-829-5121, 5493, Fax: +82-2-846-4669, E-mail: sanghoon@hallym.or.kr Copyright c 2014 The Korean Association of Internal Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution - 425 - Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
- The Korean Journal of Medicine: Vol. 86, No. 4, 2014 - 중감량이지만치료를시작한환자중에서단지 50% 이하의환자에서만목표체중감량에성공하였고치료에성공하였던대부분의환자에서일정시간이지나면다시원래의체중으로돌아갈정도로지속성이떨어진다 [2]. 따라서생활습관의변화만을고집해서는지방간질환을치료할수없으며여기에안전하고부작용이적은약제를개발하여치료에활용해야한다. 그러나아쉽게도지금까지지방간질환치료에인정된약제는없는실정이다. 그것은지방간질환의진행속도가느려치료환자와대조군의비교에시간이많이필요하기때문이며비교적양성질환이기때문에부작용이있을것으로추정되는약제의임상시험을쉽게시작하지못하는이유도있을것으로생각된다. 또한질환경과를예측하거나치료효과를판정할수있는진단검사법이간조직검사를대신할만한비침습적인검사가없는실정으로비교적침습적인간조직검사를반복해서할수밖에없기때문이다 [3,4]. 지방간질환을치료하는약제는크게두가지로나누어볼수있는데, 일차적으로병의원인이되는간내지방을줄여서지방간질환을호전시키는약제와간내지방은줄이지않으면서간에직접작용하여산화스트레스 (oxidative stress), 인슐린저항성, apoptosis, 염증성 cytokine 등지방간질환을악화시키는기전에작용하여지방간질환을치료혹은진행을억제하는약제로나누어볼수있다. 최근우리나라에서도지방간연구가활발해지면서마침내우리의독자적인임상진료가이드라인을발표하게되어지방간을연구하는연구자의한사람으로매우기쁘게생각하며, 본소고에서는지금까지보고된지방간질환에대한약물치료를간단히요약하고더불어최근관심을끌고있는 probiotics 혹은 prebiotics를통한장내세균총 (microbiome) 의변화를유도하는치료와새로운당뇨병치료제인 incretin mimetics (GLP-1 analogues, DPP-IV inhibitors) 의지방간질환치료효과에대해간략히알아보고자한다. 체중감소약물체중을감소시키는약제는이차적으로간내지방을감소시키므로이론적으로지방간염의치료에효과적일것으로생각되었다. 그러나 sibutramine (Reductil R ), rimonabant (Acomplia R ) 등은심한부작용으로시장에서퇴출되었으며 orlistat (Xenical R ) 은드물지만심한간손상을일으킨다는보고가있다. 최근에는 rimonabant와유사하지만말초신경에작용하는 endocannabinoid 길항제에대한연구가진행중이다 [5,6]. 한편미국에서체중감량을촉진하는새로운약제로최근판매를시작한세로토닌수용체 2C agonist인 locarserin (Belviq R ) [7] 과 sympathomimetic amine인 phentermine과항전간제인 topiramate의복합제 (Osymia R ) [8] 의지방간질환에대한치료효과는좀더연구가필요할것으로생각된다. 인슐린저항성개선약물 Pioglitazone은 PPAR-γ agonist로지방조직과근육, 간에서인슐린저항성을개선하고염증을억제하는 adiponectin의분비를촉진하여간내지방을감소시키고간세포의손상을대변하는 hepatocyte ballooning, lobular inflammation을감소시킨다 [9,10]. 그렇지만간질환진행을예견하는중요한지표인간섬유화의호전은없거나아주적은호전을보였다 [9-11]. Pioglitazone의부작용으로는체중증가 (70% 환자에서평균 4 kg 정도 ) [12] 가가장흔하며하지부종, 근육경련, 장기간사용시에골절위험의증가 [13], 방광암위험의증가 [14] 등이보고되어있으며치료를중단하면대부분의환자에서는지방간염이재발된다. 같은 thiazolidinedione (TZD) 인 rosiglitazone은 pioglitazone과작용기전이거의동일하지만심부전을경험했다는보고가있으며우리나라식약청에서투여중지권고가있어앞으로지방간질환치료제로선택에제한을받게되었다 [15,16]. 대한간학회지방간질환가이드라인에서 pioglitazone은조직검사로확인된비알코올지방간염환자에서 ALT 수치의호전을보이고간내지방의침착및염증소견을개선시키는효과가있어치료제로사용될수있지만, 적절한투여기간이나치료용량, 장기간치료시부작용에대한연구는더필요하다고권고하였다 [17]. 당뇨병치료에사용되는 metformin은간과근육에서인슐린저항성을개선하고간내 AMPK (adenosine monophosphateactivated protein kinase) 를활성화시켜간에서새로운지방의생산을억제하여지방간질환의치료에도움이될것으로생각된다. 초기에는당뇨병을동반한지방간질환환자의치료에서효과가있었으며최근에는당뇨병이없는환자에서도간내지방의감소, ALT 의정상화를보였다 [18-20]. 또한 metformin 치료가체중감소효과가있어 TZD와병합투여시 TZD의단점인체중증가를상쇄시킬수있다는보고가있어 rosiglitazone과 metformin 두가지약제의병합투여에대한연구가있었으나 rosiglitazone 단독투여에비해치료 - 426 -
- Sang Hoon Park. Pharmacologic therapy for nonalcoholic fatty liver disease - 효과가우월하지못하였고 TZD의부작용인체중증가를상쇄하는효과도없었다 [21]. 최근몇가지 RCT (randomizedcontrolled trial) 에서 metformin은지방간염환자에서조직소견을개선시키는효과가없는것으로확인되었다 [22]. 따라서현재까지는당뇨병이있는지방간질환환자에서병합치료의한가지로 metformin을선택할수있을것으로생각된다. 항산화제항산화제는지방간염을일으키는산화스트레스를감소시키고염증성 cytokine을줄여서지방간염의치료에효과가있을것으로생각되어사용되었다. 대표적인항산화제로는비타민 E, 비타민 C, 베타인 (betaine) 등이다. 비타민 E ( 알파토코페롤 ) 는소규모연구에서지방간치료에효과가없다는보고와함께장기간사용시사망률을증가시킨다는연구가있어지방간염의치료에적절치못할것으로생각되었다 [23-25]. 그러나최근대규모 RCT인 PIVENS 연구에서는고용량의비타민 E (800 IU/day) 투여가대조군에비해간내조직소견의개선을보였다. 또한장기간고용량의비타민 E 투여는대조군이나 pioglitazone군과비교해도심각한부작용의발생은없었다 [10]. TONIC 연구는 8세에서 17세사이의소아지방간염 173명의환자를대상으로고용량비타민 E (800 IU/day) 와 metformin (1,000 mg/day), 대조군의효과를비교한대규모 RCT로비록대조군에비해 ALT의호전은보이지않았으나지방간염이호전된환자의수는의미있게높았고소아에서도고용량의비타민 E 투여는안전하다는결과를보고하였다 [26]. 최근 35,533명의건장한남성을대상으로비타민 E (400 IU/day) 와셀레니엄의효과를장기간비교한 SELECT 연구에서는비타민 E를투여한환자에서대조약을투여한환자에비해전립선암의발생률이높았다 (HR, 1.17;99% CI, 1.004-1.36, p = 0.008) [27]. 이상의결과를살펴보면고용량의비타민 E는지방간염치료에서 pioglitazone과유사한효과를보이며우려했던사망률의증가는보이지않았다. 그러나아직도장기간의고용량투여에서안전성에대한우려는있는실정이다. 대한간학회지방간질환가이드라인에서고용량의비타민 E (800 IU/day) 는조직검사로확인된비알코올지방간염환자에서간조직소견을개선하고지방간염을호전시켜치료제로사용할수있으나장기간투여시안전성에대한우려가있다고권고하였다 [17]. 간세포보호제 Ursodeoxycholic acid (UDCA) 는여러가지작용기전으로지방간염에도움이될것으로생각되었고특히고용량을장기간투여해도부작용이없다는장점때문에지방간염치료에도움이될것으로생각되었다. 최근 Ratziu 등 [28] 은고용량 (28-35 mg/kg/day) 의 UDCA 치료에서는대조군에비해 ALT 수치의호전을보였으며인슐린저항성을개선시켰으나조직소견을비교한결과는없었다. 한편 Leuschner 등 [29] 은고용량 (23-28 mg/kg/day) 의 UDCA군과대조군을비교한결과 lobular inflammation이개선되는것이외의효과는없었다고보고하였다. PSC (primary sclerosing cholangitis) 환자를대상으로한고용량의 UDCA (28-30 mg/kg/day) 연구에서는대조군에비해 UDCA 군에서심한부작용이많았고사망률혹은간이식을시행한환자가많아연구가조기에종료되었다 [30]. 따라서장기간서서히진행하는지방간염의특성때문에부작용이적고작용기전이다양한 UDCA를많은수의지방간연구자들이처방하고있는실정이나앞으로 UDCA의효과를입증하기위해서는다양한 UDCA의작용기전중에서지방간염에도움을주는기전이좀더명확히밝혀져야하며많은수의환자를대상으로장기간의연구가이루어져야할것으로생각된다 [31]. 최근발표된미국간학회지방간질환가이드라인에서는 UDCA가효과없는것으로치료에권고되지않는다고하였다 [32]. Pentoxifylline 은비선택적 TNF-α 길항제 (non-selective TNF-α antagonist) 로지방간염을악화시키는기전에중요한역할을하는대표적인염증성 cytokine인 TNF-α의분비를억제하여산화스트레스와 apoptosis를감소시켜지방간질환의치료에도움이될것으로생각된다 [33]. 이와함께최근에는 pentoxifylline이지방의산화를감소시켜지방의산화부산물 (oxidized lipid products) 에의한간손상을억제시킨다는연구가있다 [34]. 소수의지방간염환자를대상으로한 pilot 연구에서는 ALT/AST 수치의호전과인슐린저항성을개선하는효과를보였다. 최근 Zein 등 [35] 은 55명의지방간염환자를 12개월동안 pentoxifylline 군과대조군으로나누어 RCT를진행하였다. 1차평가지표인 NAS 수치가 2점이상개선된환자는 pentoxifylline군에서 38.5%, 대조군에서 13.8% 로유의한차이를보였고, per protocol 분석에서는 pentoxifylline 군에서 50%, 대조군에서 15.4% 였다. 그렇지만풍선변성과섬유화의호전을보인환자수는유의한차이를보이지않았다. 두가지 RCT 연구 (Van Wagner 와 - 427 -
- 대한내과학회지 : 제 86 권제 4 호통권제 644 호 2014 - Zein) 에서장기간의 pentoxifylline (1,200 mg, 400 mg씩하루 3 회 ) 의투여에도심각한부작용의발생은대조군과차이가없었다 [35,36]. 지금까지의연구결과로는 pentoxifylline을지방간질환의치료에사용하기는이른것으로생각된다. 고지혈증치료제대표적인약제는 statin (atorvastatin, pravastatin, rosuvastatin 등 ) 이다. Statin이지방간질환에서 ALT를정상화시키고간내지방을감소시킨다는보고가있으나반대로간기능이상을초래한다는보고도있어사용이조심스러웠다. 그러나최근에는 statin 복용으로인한간기능악화는단순히경미한 ALT의상승뿐이고심한간손상은거의없으므로약간의 ALT 상승에도지속처방이가능하다고알려져있다 [37]. 현재까지는지방간염치료에서 statin에대한결정적이고결론을내릴만한연구는부족한실정이다. 유일한무작위대조군연구에서는 16명의환자를 simvastatin 40 mg 복용군과대조군으로나누어 12개월간연구가진행되었으나간조직검사에서지방침착, 염증, 섬유화모두에서호전을보여주지못하였다 [38]. 현재까지 statin은고지혈증이있는지방간질환환자에서는효과적으로심혈관질환을예방할수있을것으로생각된다. Ezetimibe은식이나 bile에있는 cholesterol의흡수를억제하여최근지방간염의병리기전인 lipotoxicity를막아줄수있는것으로생각된다. 최근발표된 RCT에서간내풍선양변화와섬유화는개선되었으나 HbA1c와간내 long-chain fatty acid가증가되었다는연구가있어향후연구가더필요할것으로생각된다. 최근연구가진행되고있는약제 a) Angiotensin receptor blocker (ARB) 는지방간염환자에서간내성상세포의활성화를억제하여섬유화와염증을줄여줄수있을것으로생각된다 [39]. 이들중에서 telmisartan 은 PPAR-γ 를조절하는기능이있어인슐린저항성을개선하는효과도있는것으로생각되며다른 ARB에비해지방간염치료에효과적이라는보고가있었다 [40]. 현재지방간염환자에서 losartan이간섬유화에미치는효과를알아보기위한 3상무작위대조군연구 (FELINE study) 가진행중이다. 현재까지의연구로는지방간염환자의단독치료로사용하기는연구가부족한실정이며고혈압이동반된지방간염환 자에서우선적으로선택될수있는약제이다. b) 최근지방간질환에서장내세균총 (gut microbiome) 에대한연구가가파르게증가하고있다 [41]. 비만한사람과마른사람의장내세균총의구성이다르고지방간염환자에서도염증을일으키는장내세균총이관찰된다는연구가있어장내세균의변화를통해지방간을치료하려는연구가최근활기를띠고있다 [42,43]. 동물실험에서는고과당식이 (high fructose diet) 혹은 MCD-diet 로발생되는지방간염이 lactobacillus casei shirota 라는 probiotics를투여하면예방되었다는연구가있으며 [44,45] 사람에서는 lactobacilli와 bifidobacteria 를포함한 probiotics를지방간염환자에투여하였더니간내지방이감소하고 ALT도호전되었다는보고가있다 [46,47]. 최근에는정상인마른사람의대변을인슐린저항성이있는환자에게투여 (fecal transplantation) 하여인슐린저항성이개선되었다는놀라운연구가보고되었다 [48]. 이것은지방간질환의주된기전인인슐린저항성이장내세균총의변화와밀접한관계가있는것을시사하며장내세균총을변화시킬수있는 probiotics, prebiotics [49] 혹은두가지가합쳐진 synbiotics를지방간질환의치료에이용할수있을것으로생각된다. c) glucagon-like peptide-1 (GLP-1) 은 incretin의일종으로음식의섭취에의해소장에서분비되어식후인슐린분비를촉진하며식욕을억제하는작용을한다 [50]. 지방간질환환자에서당 (glucose) 에의한 GLP-1의분비가감소되어있으며 [51], 사람의간세포에 GLP-1 수용체가존재하고인슐린전달신호에관여하여간내지방축적에관여한다는연구가있다 [52,53]. GLP-1 analogues (exenatide, liraglutide) 와 GLP-1 의분해를저해하는 DPP-IV inhibitors (sitagliptin, saxagliptin, vildagliptin) 는인슐린분비를촉진하고 gastric emptying을늦추어 ALT의호전을보이며간내조직소견의개선을보였다 [54-57]. 최근까지연구에서는 GLP-1 analogue인 exenatide 에대한연구가상대적으로많으며직접적인비교는아니지만 DPP-IV inhibitor에비해간조직소견의개선효과도크고체중을감소시키는효과도있는것으로알려져있다 [58]. 앞으로당뇨병이없는지방간질환환자에서도효과가있는지확인이필요하며좀더많은환자를대상으로비교연구가필요할것으로생각된다. d) Chenodeoxycholic acid로부터유도된 semi-synthetic 담즙산인 obeticholic acid (OCA; INT-747) 는 FXR (farnesoid X - 428 -
- 박상훈. 비알코올지방간질환의약물치료 - receptor) agonist로최근발표된 2상연구에서당뇨병이있는지방간질환환자의인슐린저항성을개선시키고체중을감소시키며간내섬유화를나타내는혈중지표들의개선효과를보여대조군과직접적인효과를비교하기위한 3상연구가시작되었다 [59,60]. 중심단어 : 비알코올지방간질환 ; 약물치료 ; 새로운약제 REFERENCES 1. Starley BQ, Calcagno CJ, Harrison SA. Nonalcoholic fatty liver disease and hepatocellular carcinoma: a weighty connection. Hepatology 2010;51:1820-1832. 2. Bellentani S, Dalle Grave R, Suppini A, Marchesini G; Fatty Liver Italian Network. Behavior therapy for nonalcoholic fatty liver disease: the need for a multidisciplinary approach. Hepatology 2008;47:746-754. 3. Torres DM, Williams CD, Harrison SA. Features, diagnosis, and treatment of nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2012;10:837-858. 4. Schuppan D, Schattenberg JM. Non-alcoholic steatohepatitis: pathogenesis and novel therapeutic approaches. J Gastroenterol Hepatol 2013;28(Suppl 1):68-76. 5. Jourdan T, Demizieux L, Gresti J, et al. Antagonism of peripheral hepatic cannabinoid receptor-1 improves liver lipid metabolism in mice: evidence from cultured explants. Hepatology 2012;55:790-799. 6. Tam J, Cinar R, Liu J, et al. Peripheral cannabinoid-1 receptor inverse agonism reduces obesity by reversing leptin resistance. Cell Metab 2012;16:167-179. 7. Smith SR, Weissman NJ, Anderson CM, et al. Multicenter, placebo-controlled trial of lorcaserin for weight management. N Engl J Med 2010;363:245-256. 8. Gadde KM, Allison DB, Ryan DH, et al. Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial. Lancet 2011;377:1341-1352. 9. Belfort R, Harrison SA, Brown K, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med 2006;355:2297-2307. 10. Sanyal AJ, Chalasani N, Kowdley KV, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010;362:1675-1685. 11. Aithal GP, Thomas JA, Kaye PV, et al. Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology 2008; 135:1176-1184. 12. 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. 13. Kahn SE, Zinman B, Lachin JM, et al. Rosiglitazone-associated fractures in type 2 diabetes: an Analysis from A Diabetes Outcome Progression Trial (ADOPT). Diabetes Care 2008;31:845-851. 14. Lewis JD, Ferrara A, Peng T, 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. 15. Lincoff AM, Wolski K, Nicholls SJ, Nissen SE. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA 2007;298:1180-1188. 16. Lipscombe LL, Gomes T, Lévesque LE, Hux JE, Juurlink DN, Alter DA. Thiazolidinediones and cardiovascular outcomes in older patients with diabetes. JAMA 2007;298: 2634-2643. 17. Korean Association for the Study of the Liver (KASL). KASL clinical practice guidelines: management of nonalcoholic fatty liver disease. Clin Mol Hepatol 2013;19: 325-348. 18. Marchesini G, Brizi M, Bianchi G, Tomassetti S, Zoli M, Melchionda N. Metformin in non-alcoholic steatohepatitis. Lancet 2001;358:893-894. 19. Bugianesi E, Gentilcore E, Manini R, 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. 20. Uygun A, Kadayifci A, Isik A, et al. Metformin in the treatment of patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2004;19:537-544. 21. 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, open-label trial. Hepatology 2011;54: 1631-1639. 22. Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther 2011;34:274-285. 23. Musso G, Gambino R, Cassader M, Pagano G. A meta-analysis of randomized trials for the treatment of nonalcoholic fatty liver disease. Hepatology 2010;52:79-104. 24. Bjelakovic G, Gluud LL, Nikolova D, Bjelakovic M, Nagorni A, Gluud C. Meta-analysis: antioxidant supplements for liver diseases-the Cochrane Hepato-Biliary Group. Aliment - 429 -
- The Korean Journal of Medicine: Vol. 86, No. 4, 2014 - Pharmacol Ther 2010;32:356-367. 25. 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 2005;142:37-46. 26. Lavine JE, Schwimmer JB, Van Natta ML, 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. 27. Klein EA, Thompson IM Jr, Tangen CM, et al. Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 2011;306:1549-1556. 28. Ratziu V, de Ledinghen V, Oberti F, et al. A randomized controlled trial of high-dose ursodesoxycholic acid for nonalcoholic steatohepatitis. J Hepatol 2011;54:1011-1019. 29. Leuschner UF, Lindenthal B, Herrmann G, et al. High-dose ursodeoxycholic acid therapy for nonalcoholic steatohepatitis: a double-blind, randomized, placebo-controlled trial. Hepatology 2010;52:472-479. 30. Lindor KD, Kowdley KV, Luketic VA, et al. High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis. Hepatology 2009;50:808-814. 31. Xiang Z, Chen YP, Ma KF, et al. The role of Ursodeoxycholic acid in non-alcoholic steatohepatitis: a systematic review. BMC Gastroenterol 2013;13:140. 32. Chalasani N, Younossi Z, Lavine JE, 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. 33. Strieter RM, Remick DG, Ward PA, et al. Cellular and molecular regulation of tumor necrosis factor-alpha production by pentoxifylline. Biochem Biophys Res Commun 1988; 155:1230-1236. 34. Zein CO, Lopez R, Fu X, et al. Pentoxifylline decreases oxidized lipid products in nonalcoholic steatohepatitis: new evidence on the potential therapeutic mechanism. Hepatology 2012;56:1291-1299. 35. Zein CO, Yerian LM, Gogate P, et al. Pentoxifylline improves nonalcoholic steatohepatitis: a randomized placebo-controlled trial. Hepatology 2011;54:1610-1619. 36. Van Wagner LB, Koppe SW, Brunt EM, et al. Pentoxifylline for the treatment of non-alcoholic steatohepatitis: a randomized controlled trial. Ann Hepatol 2011;10:277-286. 37. Chalasani N, Aljadhey H, Kesterson J, Murray MD, Hall SD. Patients with elevated liver enzymes are not at higher risk for statin hepatotoxicity. Gastroenterology 2004;126: 1287-1292. 38. 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. 39. Yokohama S, Yoneda M, Haneda M, et al. Therapeutic efficacy of an angiotensin II receptor antagonist in patients with nonalcoholic steatohepatitis. Hepatology 2004;40:1222-1225. 40. Georgescu EF, Ionescu R, Niculescu M, Mogoanta L, Vancica L. Angiotensin-receptor blockers as therapy for mild-to-moderate hypertension-associated non-alcoholic steatohepatitis. World J Gastroenterol 2009;15:942-954. 41. Vos MB. Nutrition, nonalcoholic fatty liver disease and the microbiome: recent progress in the field. Curr Opin Lipidol 2014;25:61-66. 42. Rabot S, Membrez M, Bruneau A, et al. Germ-free C57BL/ 6J mice are resistant to high-fat-diet-induced insulin resistance and have altered cholesterol metabolism. FASEB J 2010;24:4948-4959. 43. Zhu L, Baker SS, Gill C, et al. Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: a connection between endogenous alcohol and NASH. Hepatology 2013;57:601-609. 44. Wagnerberger S, Spruss A, Kanuri G, et al. Lactobacillus casei Shirota protects from fructose-induced liver steatosis: a mouse model. J Nutr Biochem 2013;24:531-538. 45. Okubo H, Sakoda H, Kushiyama A, et al. Lactobacillus casei strain Shirota protects against nonalcoholic steatohepatitis development in a rodent model. Am J Physiol Gastrointest Liver Physiol 2013;305:G911-918. 46. Mencarelli A, Cipriani S, Renga B, et al. VSL#3 resets insulin signaling and protects against NASH and atherosclerosis in a model of genetic dyslipidemia and intestinal inflammation. PLoS One 2012;7:e45425. 47. Wong VW, Won GL, Chim AM, et al. Treatment of nonalcoholic steatohepatitis with probiotics: a proof-of-concept study. Ann Hepatol 2013;12:256-262. 48. Vrieze A, Van Nood E, Holleman F, et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology 2012;143:913-916.e7. Erratum in: Gastroenterology 2013;144:250. 49. 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. 50. Holst JJ. Incretin hormones and the satiation signal. Int J Obes (Lond) 2013;37:1161-1168. 51. Bernsmeier C, Meyer-Gerspach AC, Blaser LS, et al. Glucose-induced glucagon-like Peptide 1 secretion is deficient in patients with non-alcoholic Fatty liver disease. - 430 -
- Sang Hoon Park. Pharmacologic therapy for nonalcoholic fatty liver disease - PLoS One 2014;9:e87488. 52. Gupta NA, Mells J, Dunham RM, 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. 53. Svegliati-Baroni G, Saccomanno S, Rychlicki C, et al. Glucagon-like peptide-1 receptor activation stimulates hepatic lipid oxidation and restores hepatic signalling alteration induced by a high-fat diet in nonalcoholic steatohepatitis. Liver Int 2011;31:1285-1297. 54. Trevaskis JL, Griffin PS, Wittmer C, et al. Glucagon-like peptide-1 receptor agonism improves metabolic, biochemical, and histopathological indices of nonalcoholic steatohepatitis in mice. Am J Physiol Gastrointest Liver Physiol 2012; 302:G762-772. 55. Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 2006;368:1696-1705. 56. Iwasaki T, Yoneda M, Inamori M, et al. Sitagliptin as a novel treatment agent for non-alcoholic Fatty liver disease patients with type 2 diabetes mellitus. Hepatogastroenterology 2011;58:2103-2105. 57. Kenny PR, Brady DE, Torres DM, Ragozzino L, Chalasani N, Harrison SA. Exenatide in the treatment of diabetic patients with non-alcoholic steatohepatitis: a case series. Am J Gastroenterol 2010;105:2707-2709. 58. Vilsbøll T, Christensen M, Junker AE, Knop FK, Gluud LL. Effects of glucagon-like peptide-1 receptor agonists on weight loss: systematic review and meta-analyses of randomised controlled trials. BMJ 2012;344:d7771. 59. Hollman DA, Milona A, van Erpecum KJ, van Mil SW. Anti-inflammatory and metabolic actions of FXR: insights into molecular mechanisms. Biochim Biophys Acta 2012; 1821:1443-1452. 60. Mudaliar S, Henry RR, Sanyal AJ, 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.e1. - 431 -