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1 Towards a Better Understanding of Non-Alcoholic Fatty Liver Disease in 2018 Clinical management and decision of NAFLD with metabolic syndrome 조은영원광대학교의과대학내과 Eun Young Cho Department of Internal Medicine, Wonkwang University College of Medicine, Korea. NAFLD can be a hepatic expression of the metabolic syndrome, and NAFLD may also be a predictor of the development of metabolic syndrome such as type 2 diabetes. Patients with NAFLD may be associated with factors of metabolic syndrome such as abdominal obesity, lipid abnormality, diabetes and hypertension, etc., as liver fibrosis can progress rapidly, and risks such as the incidence of CVD or cancer, etc. can become high, additional screening and diagnosis of these risk factors in NAFLD patients, education about life-style correction, and treatment of each factor are needed. There is the absence of a specific treatment for NAFLD or NASH, it is thought that attention to these factors and therapeutic intervention are very important. Recently, it is true that chronic viral hepatitis has also been successfully treated, and that the increased prevalence of obesity and its effective treatment are minimal. As nonalcoholic liver disease is expected to be a major cause of advanced liver disease (liver cirrhosis, liver cancer), therefore attention and active intervention is needed. 서 론 비알콜성지방간질환 (nonalcoholic fatty liver disease, 이하 NAFLD) 의국내유병율은연구방법에따라 6~51% 까지보고되어있는데, 1-4 NAFLD진단에가장많이사용하는복부초음파를진단기준으로할때유병율은 16~33% 로보고되었다. 3,4 비만과대사증후군의유병율도이와비슷해서 2008년에서 2010년까지한국국민건강영양조사를통해남자의 35%, 여자의 29% 가비만 ( BMI가 25 kg/m2) 에해당하였으며, 년자료에서는남자의 25%, 여자의 24% 가대사증후군의기준에해당한다고보고하였다. 6 즉, 전인구의 1/3이비알코올성지방간질환과대사증후군에해당한다고할수있는데이는서구의보고와유사한수치이다. 최근만성바이러스성간염이성공적으로치료되고있고, 증가된비만유병률과이에대한효과적치료가미미하여, 비알코올성간질환은추후진행된간질환 ( 간경변, 간암 ) 의주요원인이될것으로예상되므로이에대한관심과적극적개입이필요하다. 이강좌에서는 대사증후군이동반된비알코올성지방간환자를어떻게치료할것인가? 에대해논의해보기로하겠다. 41

2 2018 대한간학회추계 Single Topic Symposium Table 1. 대사증후군의임상진단기준 구성요소복부비만상승된공복혈당상승된중성지방저하된고밀도지질단백질콜레스테롤상승된혈압 기준점인종별기준점제시 100 mg/dl 또는고혈당조절을위해약물투여중인상태 150 mg/dl 또는고중성지방혈증치료를위해약물투여중인상태남성 <40 mg/dl; 여성 <50 md/dl 수축기 130mmHg 및 / 또는이완기 85mmHg 또는고혈압치료를위해약물투여중인상태 인종에따른상승된허리둘레의정의 : (1) 백인 : 남성 102cm, 여성 88cm (2) 아시아인 : 남성 90cm, 여성 80cm (3) 중동, 지중해, 아프리카 : 남성 94cm, 여성 80cm (4) 중남미 : 남성 90cm, 여성 80cm 대사증후군의요소와 NAFLD 대사증후군은중심성비만, 지질이상, 당대사이상, 고혈압의복합체이며, 2형당뇨병과심혈관계질환의위험성을높인다. 지난수십년간다양한그룹이모두서로다른진단기준을제시했었는데, 2009년에 International diabetes federation: American heart association; national heart, lung, blood institute, world heart federation; international atherosclerosis society international association for the study of obesity를주축으로 consensus criteria 를만들었다 (Table 1). 7 대사증후군은아래기준에서 3가지이상을만족하면진단이가능하다. NAFLD 가대사증후군의선행질환인지대사증후군이 NAFLD의원인인지는명확하지않으나 NAFLD는비만, 당뇨병, 이상지질혈증등과더불어대사증후군의중요한요소로인식되고있으며, 대사증후군환자대부분에서 NAFLD가동반된다. NAFLD 에서각각의대사증후군요소를동반할때치료에대한최근까지의 update내용들을알아보겠다. 1. 복부비만 NAFLD은체질량지수보다복부비만과더연관이깊다. NAFLD 의결정요소에전체지방질량보다는지방의분포가더중요하다고알려져있으며, 특히증가된내장지방은비알콜성지방간염 (nonalcoholic steatohepatitis, 이하 NASH) 에서섬유화진행과연관되어있다. 따라서복부비만을조절하는것은 NAFLD 의진행을막는데중요하다고할수있다. 이러한복부비만을조절하기위한방법으로체중을감량시키는약제복용과비만수술이있다. 최근비만조절약제에대한 meta-analysis 가있었는데 orlistat, lorcaserin, naltrexone-bupropion, liraglutide 및 phentermine-topiramate 등현재사용이가능한체중감량약제들이포함되었다. 8 각약제복용군에서 5% 이상체중감량한비율은위약 23%, phentermine-topiramate 75%, liraglutide 63%, naltrexone-bupropion 55%, lorcaserin 49%, orlistat 44% 였고, 1년간평균체중감량은 phentermine-topiramate 8.8kg, liraglutide 5.3kg, naltrexone-bupropion 5.0kg, lorcaserin 3.2kg, orlistat 42 대한간학회 Korean Association for the Study of the Liver

3 조은영 Clinical Management and Decision of NAFLD with metabolic syndrome 2.6kg였다. 이중 naltrexone-bupropion 은우울감, 지살충동, 고혈압, 및빈맥등의부작용으로, liraglutide는심한오심, 구토등의위장관장애로치료를중단하는경우가많았다. NAFLD에서연구된비만조절약제는 orlistat, liraglutide, lorcaserin이다. orlistat는전반적으로는 NAFLD 의호전이나인슐린저항성의개선을보이지않았으나 sub-group analysis 에서는 5% 이상체중감량이있었던군에서인슐린저항성의호전과 steatosis의개선을보이고, 9% 이상의체중감소를보인군에서인슐린저항성의호전과 NAFLD activity score(nas) 의감소및 adiponectin 수치의증가를보이며 NAFLD 가개선되었다. 9 Liraglutide 의 NAFLD 에대한치료효과에대한대표적연구는 Armstrong의 LEAN 연구로 52명비만한인슐린저항성환자들을 48주간치료하여간과지방조직에서인슐린민감성의회복및 39% 에서 NASH의개선을확인하였고, 간섬유화도덜진행함을보고하였다. 10 Lorcaserin은심각한부작용이없는비교적안전한약으로, NASH에서진행된 decompensated LC환자에 9개월간하루 2회 10mg의 lorcaserin 을투여하여체질량지수의감소와혈소판증가및 MELD 점수의감소를보인증례가보고되어 NASH로인한말기간질환에서간이식의 bridge therapy 로서의가능성을보여주었다. 11 복부비만을해결하기위해서는체중감량을위한치료와더불어식이와운동습관을비롯한생활습관을교정이중요하다. 칼로리섭취를 750~100kcal/day로제한하는것이인슐린저항성과간내지방증을호전시켰고, 6 METs 이상강도의운동시 NASH의개선을보였다는연구결과가있다. 국내연구에서도주 5회, 중증도강도의운동을하면 NAFLD의개선및예방하는효과가있음을보고하였다. 12 이러한치료로체중을 7~10% 이상감량하면간내지방증과인슐린저항성호전뿐아니라간문맥염증과섬유화등 NASH의모든양상이개선되지만 12개월간생활습관교정한결과 7% 이상체중감량한환자는절반정도에불과했다. 13 고도비만환자에서비만수술은관련합병증을호전또는소멸시키고, 심혈관계질환 (cardiovascular disease, 이하 CVD) 과각종암으로생기는사망률을감소시켜장기생존률을개선시킨다 체중조절을위한약물치료와생활습관교정으로 NAFLD 의개선이미미한경우비만수술을시행할수있으며, 또한약물치료와생활습관교정으로감량한체중을유지하는것이매우어려운데, 비만수술은체중감량의유지에도도움이된다. 최근발표된가이드라인을보면유럽간학회는비만수술이비만과당뇨병을개선함으로써간내지방을줄이고 NASH 진행을감소시키며섬유증을포함한모든조직학적개선을보여 B1등급으로권고하고있었고, 18 미국간학회는 NASH개선에대한 2개의대규모코호트연구를근거로 foregut 비만수술을비만한 NAFLD 또는 NASH환자에고려할수있으나아직 NASH의치료option 으로권고하기는근거가부족하다고하였고, 특히간경변환자에서는수술종류, 안전성, 효과가아직정립되어있지않아개별화된전략으로의접근이필요하다고하였다 당뇨와내당능장애 NAFLD 환자는 2 형당뇨병의유병율이높다. 20 NASH 의병인으로인슐린저항성과지질독성이주된역할 43

4 2018 대한간학회추계 Single Topic Symposium 을하고있고 NAFLD 환자에서 2형당뇨병이생기면섬유화및간경화의진행과간암발생을촉진시킨다. 21 따라서 NAFLD환자에서인슐린저항성의개선와지질독성의역전 (reversal) 은중요한치료목표라고할수있다. 인슐린감작제 (sensitizer) 로는 metformin, pioglitazone, liraglutide 등이있다. metformin 은 AMPK (AMP-activated protein kinase) 활성화하여포도당합성을저해하고체내지질생성을조절한다. metformin은간기능수치의호전과인슐린저항성개선에는일부효과가있었으나대다수의연구에서 NASH환자간조직에조직학적개선을시키는지는못했다. 22,23 따라서 metformin은간조직소견의개선이나간기능호전효과가명확하지않으므로 NASH치료제로권고하지는않으나, 당뇨병이있는 NAFLD환자에서당뇨병치료제로우선고려해볼수있다. 19 Pioglitazone은 thiazolidinediones계약제로 peroxisome proliferator-activated receptor (PPAR)-ɣ 작용제로가장많이연구된인슐린감작제이다. 내당능장애나당뇨가있는 NASH환자를대상으로한 Belfort연구 24 와 Cusi 연구 25 에서인슐린민감성, 간기능호전및 NAS 점수의호전을보였고, 특히 Cusi의연구에서는 51% 의환자에서 NASH의 resolution과 fibrosis 의호전이보였고이러한효과는치료 36개월동안유지되었다. NAFLD 환자의 Pioglitazone 치료효과는당뇨가없는 NASH환자를대상으로도연구되었다. 초기무작위대조시험에서 pioglitazone을 12개월간투여한결과간내지방의유의한감소는없었으나간세포손상과섬유화는호전을보였다. 26 PIVENS 연구는 247명의당뇨없는 NASH환자를대상으로 2년간 pioglitazone (30 mg/day), 비타민 E (800 IU/day) 와위약을투약해그효과를비교하는연구로 34% 의 pioglitazone과 43% 의비타민 E에서간섬유화의악화없이 NAS 점수가 2점이상개선되었다 ( 위약은 19%). 27 Pioglitazone의부작용은체중증가 (2.5~4.7kg, 12~36개월동안 ) 가가장흔하고, 여성에서의골소실, 드물게울혈성심부전이생길수있으며방광암발생의위험성은아직명확하지않다 Pioglitazone은당뇨유무에관계없이조직학적으로확진된 NASH에서조직소견개선을보이므로이러한환자에우선적으로사용하도록권고하고있으나아직적정사용기간등에대한자료가부족하다. 18,19 최근출시된새로운계열의당뇨약들중 SGLT2 저해제와 GLP 1 작용제는체중감량을유도하므로 NAFLD에대한치료로활발히연구되고있다. Sodium-glucose transport protein 2 (SGLT 2) 저해제 (gliflozin) 는신장의근위세뇨관에서포도당재흡수의억제로고혈당을조절하는데, 평균 3kg의체중감소와 3~4mmHg 의혈압저하를보인다. 최근 66명의 NAFLD와 2형당뇨가있는환자를대상으로 ipragliflozin 50mg과 pioglitazone 15~30mg의효과를비교한연구가진행되었고 primary outcome은 liver-to-spleen attenuation ratio (L/S ratio) 의기저치로부터의변화였다. 32 Ipragliflozin 군과 pioglitazone군모두에서 L/S ration의증가가있었고, 혈청 AST, ALT 와공복혈당및 HbA1c 의감소가있었으나, 체중감소와내장지방의의미있는감소는 Ipragliflozin 군에서만보였으며, 두군모두에서심각한부작용은없었다. 따라서 NAFLD가있는당뇨환자에서 SGLT 2 저해제는혈당조절뿐아니라 NAFLD 호전에효과가있음이확인되었으나, 당대사에이상이없는 NAFLD 환자의치료 44 대한간학회 Korean Association for the Study of the Liver

5 조은영 Clinical Management and Decision of NAFLD with metabolic syndrome 제로사용가능한지는추가연구가필요하다. 다음으로 incretin 기반약제인 glucagon like peptide 1 (GLP 1) agonist 역시혈당개선뿐아니라평균 3.7kg의의미있는체중감소를보이고, 동물연구에서도 NASH의호전을보여 NAFLD 치료효과에대해연구되었다. 앞서소개한 LEAN 연구가 NASH환자에서 GLP1 agonist의효과와안전성을본대표적인연구로 liraglutide군에서섬유화의진행없이 39% 의환자에서 NASH의 resolution이확인되었다. 10 그러나 liraglutide군의 81% 가설사, 변비, 식욕부진등의위장관증상을호소하였다. Liraglutide는 NASH치료제로써의가능성이있으나그근거가부족해아직 NASH 치료제로권고하고있지않다 고혈압고혈압은대사증후군의한요소이고, NAFLD 와 NASH환자를대상으로한간섬유화의진행에대한연구에서동맥고혈압이있으면섬유화진행속도가빨라진다고하여 33 고혈압은 NAFLD 또는 NASH의발생또는진행과연관성이있으며, 그기전은고인슐린혈증으로인해증가된 Na재흡수증가, 인슐린자극에의한혈관확장능의손상등으로설명하고있다. 34,35 NASH 조직에는활성화된간성상세포의증가를보이는데 losartan 으로 48주간치료시활성화된간성상세포가유의하게감소되어, 안지오텐신 II 수용체길항제 (angiotensin II receptor blockers, 이하 ARBs) 에항섬유화효과가있을것으로기대되었다. 이에따라 NASH 환자에서 losartan이간섬유화에미치는효과를알아보기위해 3상무작위배정위약대조연구가진행되었다. 36 이연구는 214명의환자를등록할계획이었으나 45명만등록되었고의미있는결과를얻지못했다. 환자등록이어려웠던이유로대부분의대상환자군들이이미 ACEI 또는 ARBs를복용하고있었기때문으로설명하고있었다. 비록 ARBs의항섬유효과에대한연구에서유의미한결과를얻지는못했으나, ARBs는효과적인항고혈압제이며인슐린감수성을향상시킬수있기때문에 NAFLD 환자의고혈압치료로 ARBs를권고하고있다 이상지질혈증과심혈관계질환 NAFLD/NASH환자의사망원인은 liver-related disease가아닌심혈관계질환과암이다. 스웨덴에서실시한연구에서 NAFLD환자의사망원인으로가장흔한것이 CVD였고, 37 최근실시된 34,043명의성인을대상으로한메타연구에서도 NAFLD 환자는 CVD event가더많이발생했고 (OR 1.64; 95% CI ), NAFLD가심할수록 CVD event가더잘생기는경향을보였다 (OR 2.58; 95% CI ). 38 이처럼 NAFLD와 CVD발생과강하게연관되어있는데, NAFLD 환자에서보이는내장비만, 인슐린저항성, 증가된염증반응, 혈관내피세포의기능부전등으로인해무증상의심근리모델링과기능부전이관찰되고, 39 carotid artery intimal medial thickness (CIMT) 가증가되며, 40 관상동맥의죽상경화증이유의하게증가되는등의가속화된죽상경화증으로관상동맥질환과뇌졸증등의혈관질환이유의하게증가된다고설명하고있다. 41,

6 2018 대한간학회추계 Single Topic Symposium 따라서 NAFLD환자와대사증후군환자에서죽상경화증을유발하는이상지질혈증을치료하는것은 CVD 발생위험도를감소시켜장기사망률을감소시킬수있다. 이상지질혈증의치료는 7-10% 체중감량을목표로생활습관을교정함과더불어약물치료로 fibrate, statin, omega 3, Ezetimibe 등을사용해볼수있다. 먼저 statin은이상지질혈증치료로가장많이사용되며일반적으로 LDL-cholesterol 을감소시켜 CVD 를예방하는것으로잘알려져있으나 NAFLD 나 NASH의특이적치료제로는근거가부족하다. 그러나여러연구에서고강도 / 고용량의 statin 을복용하면간효소수치의호전, 간의조직학적개선및 CVD 발생을감소시키며, 더불어몇몇연구에서간세포암 (hepatocellular carcinoma) 발생도감소시킨다는보고가있어, NAFLD/NASH 환자에서 statin사용은분명한이득이있다. 만성간질환환자에서 statin의안전성이문제가될수있는데, 간효소수치가상승된 NAFLD/NASH환자는 statin사용시는오히려간효소수치의호전을보여 NAFLD/NASH환자에서 statin사용은비교적안전한것으로보인다. 다만비대상성간경변환자의경우는되도록사용을피하되, 반드시사용해야하는경우는저용량으로사용하고혈청 creatinine phosphokinase 값을모니터링하면서주의하여사용해야한다. 56 다음 ezetimibe 는장에서콜레스테롤을재흡수하는과정에작용하는데장세포 (enterocytes) 에위치한콜레스테롤운반체인 NPC1L1 (Niemann-Pick C1 Like 1 Protein) 을차단하여콜레스테롤재흡수를차단한다. Ezetimibe 단독치료에대한초기무작위대조시험에서는 6개월간투여하여의미있는간의조직학적호전 (ballooning, fibrosis) 을보였으나 57 최근진행된 MOZART (Magnetic Resonance imaging and elastography in ezetimibe versus placebo for assessment of response to treatment in NASH) trial에서는간조직의호전이나 MR-liver stiffness 의호전을보이지않았다. 58 또한이들임상시험중 ezetimibe 투여군에서 HgbA1C 의상승을보여 NAFLD/NASH 환자에서 ezetimibe 단독치료는아직권하기어려우며추가적대규모연구가필요하다. Ezetimibe 과 statin병합치료는콜레스테롤대사과정의두주요 pathway 를차단하기때문에추가적이득이있을것을예상해볼수있다. 전임상연구에서 Ezetimibe과 atorvastatin 병합치료시간효소수치를정상화시키고간조직소견을호전시켰고, 45명의 NAFLD와당뇨및이상지질혈증이있는환자에서 Ezetimibe과 statin의병합치료하여의미있는 LDL-cholesterol의감소를보였으나 CVD risk를줄이는지는명확하지않았다. 59,60 그러나이후진행된 IMPROVE-IT(Improved Reduction of Outcomes: Vytorin Efficacy International Trial) 연구에서 Ezetimibe과 simvastatin 병합치료가 LDL-cholesterol의유의미한감소뿐아니라급성관상동맥증후군등의심혈관계 event를의미있게감소시켜 61 CVD의고위험군인경우 Ezetimibe과 statin병합치료를지속하는것이이득이있음을보여주었다. Fibrate는 PPAR-α 작용제로중성지방을감소시키는데유용하고간효소수치의호전을보이지만간의조직학적인호전 (steatosis, fibrosis 등 ) 을보이지않아 NAFLD/NASH의치료제로는아직근거가부족하다 최근조직검사로확진된 NAFLD환자 16명에 200mg/day의 fenofibrate를 48주간투여하는연구에 46 대한간학회 Korean Association for the Study of the Liver

7 조은영 Clinical Management and Decision of NAFLD with metabolic syndrome 서도중성지방, 혈당, 간효소수치의호전을보였으나이연구에서도간조직의조직학적인호전은없었다. 65 Omega-3 fatty acids는고중성지방혈증치료에널리사용되고있는데, NAFLD 환자에투여시간질환의호전을보인다는 review article 이있었으나 66 여기에포함된연구는모두대상인원이적은연구들이었다. 최근진행된 welcome 연구 (n=103) 와 EPE-A 연구 (n=157) 에서는 NAFLD/NASH환자에서 omega-3의치료의이득을증명하는데실패하였다. 67,68 결 론 NAFLD는대사증후군의간내표현이라고할수있고, 또한 NAFLD 가 2형당뇨와같은대사증후군의발생을예측할수있는요인일수있다. NAFLD 환자에서복부비만, 지질이상, 당뇨, 고혈압등의대사증후군요소들이동반되면간섬유화가빠르게진행될수있고 CVD나암발생등의위험이높아지므로 NAFLD환자에서이들위험요소들에대한추가적인검사와진단및생활습관교정에대한교육및각요소들에대한치료가필요하다. 아직은 NAFLD나 NASH에대한특이적치료제가없는현실에서이들요소에대한관심과치료적개입이매우중요할것으로생각된다. REFERENCES 1. Lee JW, Cho YK, Ryan M, Kim H, Lee SW, Chang E, et al. Serum uric Acid as a predictor for the development of nonalcoholic Fatty liver disease in apparently healthy subjects: a 5-year retrospective cohort study. Gut Liver 2010;4: Lee JY, Kim KM, Lee SG, Yu E, Lim YS, Lee HC, et al. Prevalence and risk factors of non-alcoholic fatty liver disease in potential living liver donors in Korea: a review of 589 consecutive liver biopsies in a single center. J Hepatol 2007;47: 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: 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: Lee YH, Lee SG, Lee MH, Kim JH, Lee BW, Kang ES, et al. Serum cholesterol concentration and prevalence, awareness, treatment, and control of high low-density lipoprotein cholesterol in the Korea National Health and Nutrition Examination Surveys : Beyond the Tip of the Iceberg. J Am Heart Assoc 2014;3: Park E, Kim J. Gender- and Age-Specific Prevalence of Metabolic Syndrome Among Korean Adults:Analysis of the Fifth Korean National Health and Nutrition Examination Survey. J Cardiovasc Nurs. 2015;30: Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 2009;120: Khera R, Murad MH, Chandar AK, Dulai PS, Wang Z, Prokop LJ, et al. Association of Pharmacological Treatments for Obesity With Weight Loss and Adverse Events: A Systematic Review and Meta-analysis. JAMA 2016;315: Harrison SA, Fecht W, Brunt EM, Neuschwander-Tetri BA. Orlistat for overweight subjects with nonalcoholic steatohepatitis: 47

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