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1 대한내과학회지 : 제 79 권제 5 호 2010 특집 (Special Review) - 지방간질환 (Nonalcoholic fatty liver disease, NAFLD) 비알코올성지방간질환의진단 인하대학교의학전문대학원내과학교실 이진우 The diagnosis of nonalcoholic fatty liver disease Jin Woo Lee, M.D., Ph.D. Department of Internal Medicine, Inha University School of Medicine, Incheon, Korea It is important to have a safe and effective diagnostic tool for liver fibrosis. Currently, liver biopsy is the technique of choice for determining hepatic fat deposition and the stage of fibrosis. However, it is an invasive procedure and its use is limited. It may also be subject to sampling error. Because of need for less invasive techniques, new diagnostic modalities are emerging to replace biopsy. In the present review, available new techniques are introduced and the advantages and disadvantages of each one are discussed. Although none of these non-invasive techniques is able to differentiate between steatosis and steatohepatitis and to reveal all features visible using histology, the proposed diagnostic modalities offer a wide range of additional information instead of liver biopsy. (Korean J Med 79: , 2010) Key Words: Nonalcoholic fatty liver disease; Diagnosis; Liver biopsy; Non-invasive test 서론비알코올성지방간질환 (Nonalcoholic fatty liver disease, NAFLD) 이란알코올남용력이없으면서알코올성간염과유사한조직학적변화를보이는질환으로여기에는단순지방증 (steatosis), 비알코올성지방간염 (Nonalcoholic steatohepatitis, NASH), 간섬유증및간경변증과같은광범위한질환들이모두포함된다. NASH의진단기준은다음세가지조건을충족시켜야한다 1-3). 첫째, 하루 20 g 이상의알코올을섭취하지않아야하고, 둘째간조직검사에서지방간염소견을보이며, 셋째혈청학적검사와병력청취결과바이러스성간염, 자가면역성간염, 윌슨병, 헤모크로마토시스, 약물성간염등다른만성간질환의원인을배제할수있어야한다. NAFLD 의진단을위한방법에는크게침습적방법과비침습적방법이있다. 아직까지는간조직생검이 NAFLD 의 감별및중등도진단을위한절대적표준으로여겨지고있으나침습적방법으로인한합병증및표본오차등의문제점으로인해 NAFLD 의선별검사로는적절치못하다고알려져있다 4). 비침습적방법으로는간기능검사및이를이용한진단알고리즘들이개발되었고, 복부초음파와 CT, MRI 등의방사선검사등이이용되고있다. 최근에는간조직생검을대체할수있는비침습적방법으로서간섬유화의병리기전에관여하는혈청학적표지자및 transient elastography 등에대한연구가활발히진행되고있다. 간조직생검 NAFLD 가의심되는환자에서간조직생검을하는목적은크게세가지이다. 첫째, NAFLD 의확진및다른질환을배제하는것이고둘째, 단순지방증과 NASH를구분하기위해서이며셋째로는간섬유화정도의단계를알기위해서이다 5)

2 - The Korean Journal of Medicine: Vol. 79, No. 5, NASH의조직학적진단기준은 1980년 Ludwig 등이처음기술한이래로 20년간계속해서개정되어왔다. NASH 진단의최소한의필수소견으로는지방증, 간세포의풍선변성, 간소엽내염증이있다 6,7). 지방증은주로간소엽의제3대 (zone 3) 에집중되며대공포지방증혹은대공포및소공포혼합지방증으로나타난다. 풍선변성은간세포손상의한형태로간세포의종창과세포질의다공포변화를보이며말로리소체를함유한세포에서더욱뚜렷하다. 염증은주로림프구및중성구가침윤하는데주로소포제3대에서흔하다. 그외에말로리소체, 거대미토콘드리아, 호산성소체등도 NASH 에서관찰될수있다. 섬유화는소엽제3대의말단세정맥주변이나간세포주변에서먼저나타나고, 섬유화가진행됨에따라서문맥역끼리나중심- 문맥역의가교상섬유화가발생하여구조적재형성을거쳐간경변증으로진행한다. NASH Clinical Research Network (CRN) 는 2005년에 NAFLD 등급을구분하기위하여 NAFLD activity score (NAS) 를고안하였다 ( 표 1) 6). NAS가 5 이상인경우 NASH의진단과거의일치하나 NAS가 3 미만인경우는대부분 NASH가아니고, 3~4점은경계부위이다. 하지만 NAS는 NASH의병리진단자체보다는치료에대한반응으로서병리소견의변화를측정하는데의의가있으며, 흔히사용되는 H-E 염색과 Masson s trichrome 염색등으로간편하게측정이가능하여현재많이이용되고있다 6-9). 한편간생검에는여러제한점이있다. 첫째, 침습적술기로인하여 0.5% 이하에서합병증이발생하였다고보고되고있으며 4), 둘째전체간의 1/50,000 이하의작은부분만이생검되므로표본오차가발생할수있으며지방증이나섬유화에서보다괴사염증반응이나간세포풍선변성의진단에서이런표본오차가발생할가능성이더크다. 셋째, 조직검사의판독이병리의사의기술과경험에영향을받아관찰자간의변이가있을수있다. 이러한제한점으로인해 NAFLD 환자에서모두간조직생검을시행하는것은적절치않으며, 간조직생검을통하여얻은정보가환자의치료에도움이되는경우에간조직생검을시행하는것이바람직하다. NAFLD 환자의간조직생검적응증은아직까지완전히정립되지는않았으나간섬유화의위험인자로평가되는비만, 45세이상의고령, 당뇨병이있는환자에서 3~6개월동안식습관조절이나운동, 당뇨조절등의치료를했음에도불구하고 alanine aminotransferase (AST) 나 aspartate aminotransferase (ALT) 가계속높거나복부초음파에서여전히지방증이지속될경우생검을고려하게된다. 특히, 간의변연이딱딱하거나 AST보다 ALT가더높을때그리고혈청생화학검사에서낮은알부민및혈소판수치를보이는등진행된간섬유화를시사하는소견이보이는경우에는보다조기에간조직생검을시행하여야한다 10-13). Table 1. NAS (NAFLD activity score) definition 6,8) Item Definition Score Steatosis Low to medium power evaluation of parenchymal involvement by steatosis Grade <5% 0 5~33% 1 >33~66% 2 >66% 3 Lobular inflammation Overall assessment of all inflammatory foci No foci 0 <2 foci per 200 field 1 2~4 foci per 200 field 2 >4 foci per 200 field 3 Ballooning None 0 Few balloon cells 1 Many cells/prominet ballooning 2 NAS Not NASH 0~2 Borderline 3, 4 NASH 5~

3 - Jin Woo Lee. The diagnosis of nonalcoholic fatty liver disease - 임상적특징과혈청생화학적검사및진단알고리즘 NAFLD 진단을위해서는알코올성간질환배제를위해알코올섭취여부를확인해야하고, NAFLD 의위험요인이되는식사, 신체활동, 체중변화등의자세한병력과가족력청취및증상에대한문진이필요하며키, 몸무게, 배둘레, 허리-배비율, 혈압등의신체검사를하여야한다. 지방증 NAFLD 환자에서피곤함, 우상복부통증, 간비대등이나타날수도있지만특징적인증상이나징후가없는경우가대부분이다 14,15). 간기능검사로흔히사용되고있는 AST, ALT, alkaline phosphatase (ALP), gamma-glutamyl-transpeptidase (GGT) 등의혈청검사가 NAFLD 환자에서약간증가하는소견을보이기도한다. 하지만 AST, ALT 가정상상한치의 5배이상증가하는경우는드물며 NASH 환자의 3분의 2 이상에서는정상범위내에서변화를보인다 16-18). 최근에는현재사용되는 ALT의정상범위가너무높아실제간질환환자를발견하지못하는경우가많으므로, 적정 ALT의역치를 25~30% 낮게하여남자에서는 30 U/L, 여자에서는 19 U/L로재조정해야한다는연구가설득력을얻고있다 19-21). 알부민, prothrombin time, 빌리루빈등은말기간경변성 NAFLD 에서나증가하며대부분의 NAFLD 환자에서는거의정상범위이다. 또한바이러스성간염, 자가면역성간염, 윌슨병등을배제하기위해간염바이러스검사, 항평활근항체, 항핵항체, 구리, ceruloplasmin 등의혈청학적검사도필요하다. 혈청학적검사들의민감도와특이도, 음성예상치가낮은단점을극복하고자혈청학적검사에나이, 성별, 신체질량지 수, 인슐린저항성, 당뇨같은대사증후군과관련된지표들을포함하여여러변수를복합적으로이용하여 NASH 진단알고리즘들이개발되었다 ( 표 2) 9). Dixon 등 13) 과 Palekar 등 22), Gholam 등 23) 은 NASH 진단을위해여러지표를이용하여진단알고리즘을개발하였고, 이들은대략적으로비슷한진단율을보였으나그타당성은아직확실하게정립되지않은상태이다. NAFLD 환자의섬유화진단에보다중점을둔진단알고리즘들도개발이되었는데 ( 표 3), Ratziu 등 11) 이개발한 BAAT를비롯하여 FibroTest 24), NAFLD fibrosis score 25), OELF 26), ELF 27) 등이있다. 이들연구들은섬유화를시사하는임상적지표와생화학적지표및혈청표지자들을조합하여섬유화정도를진단하는것으로서이러한진단알고리즘들이 NAFLD 의감별진단및중등도진단에도움이되지만, 이런연구들모두단면조사연구방식으로만연구되었다는제한이있으며, 질환의예후및치료반응정도를감시하는표지자로서의역할은아직분명치않다 24-27). 따라서아직까지이러한진단알고리즘들이 NAFLD 진단으로서간조직생검을대체하기는부족한상황이다. 영상학적검사여러영상학적검사중에서복부초음파검사는안전성, 반복성및경제적인장점으로인해 NAFLD 의영상학적진단에우선적으로가장많이이용되고있다 19). 복부초음파에서간실질의에코음영증가와불명확한혈관경계등으로지방간을진단할수있다. 여러연구들에의하면지방간진 Table 2. Panel markers for NASH diagnosis 9) Test N AUC for NASH diagnosis Components Dixon et al (CI: Non stated) HTN, ALT, IR Palekar et al (CI: 0.65, 0.87) Age, female gender, AST, BMI, AST/ALT ratio, HA Gholam et al (CI: Non stated) AST, diabetes Poynard et al (CI: 0.69, 0.86) * Same as Fibro Test plus six other components (Nash Test) 0.79 (CI: 0.67, 0.87) (Total of 13 measurements) Zeim et al (CI: 0.81, 0.93) * Age, HOMA, Log (ASTxALT), female sex, BMI 0.85(CI: 0.75, 0.95) * Training set. Validation set. Other component include height, weight, serum levels of triglycerides, cholesterol, ALT and ALT. AUC, area under the curver; CI, confidence interval; HTN, hypertension; ALT, alanine aminotransferase; IR, insulin resistance; AST, aspartate aminotransferase; BMI, body mass index; HA, hyaluronic acid; HOMA, homeostatic model assessment

4 - 대한내과학회지 : 제 79 권제 5 호통권제 603 호 Table 3. Panel markers for Fibrosis 9) Test Staging system N AUC for NASH diagnosis Components BAAT score Metavir (CI: Non stated) Age, BMI, ALT, serum triglycerides FibroTest Modified Brunt (CI: 0.77, 0.91) * Age, sex, alpha2-marcroglobulin, apolipoprotein A (CI: 0.61, 0.83) Haptoglubulin, total bilirubin, GGT NAFLD fibrosis Modified Brunt (CI: 0.85, 0.92) * Age, BMI, platelet count, albumin, AST/ALT ratio, Score 0.82 (CI: 0.76, 0.88) IFG/diabetes OELF Scheuer (CI: 0.66, 1.0) Age, HA, PIIINP, TIMP-1 ELF Modified Brunt (CI: 0.84, 0.96) HA, PIIINP, TIMP-1 * Training set. Validation set. Other component include height, weight, serum levels of triglycerides, cholesterol, ALT and ALT. AUC, area under the curver; CI, confidence interval; BMI, body mass index; ALT, alanine aminotransferase; AST, aspartate aminotransferase; IFG, increase fasting glucose; HA, hyaluronic acid; PIIINP, aminoterminal peptide of procollagen III; TIMP-1, Tissue 1 inhibitor of metalloproteinase. 단에복부초음파는 60~90% 의민감도와 84~95% 의특이도를가지나 28-31), 다음과같은제한점을지니기도한다. 초음파결과가시술자에의존적이어서시술자간차이가있을수있고지방침윤의정량적측정이불가능하다. 그리고지방침윤이 30% 이하인경우에는민감도가급격히감소하며 32), 비만환자에서도민감도가 40% 이하로감소한다 33). 또한 NASH와간섬유화진단에는민감도와특이도가떨어진다는치명적제한점이있다. 통상적인 CT와 MRI도 NAFLD 진단에유용한영상학적방법이기는하지만복부초음파보다우월하지는않다 34). CT는간과비장의감쇠 (attenuation) 비를비교하여지방증의정도를평가할수있지만민감도와특이도가높지않고방사선노출위험등의문제로인해 NAFLD 진단에일차적으로추천되지않는다 19). Magnetic resonance spectroscopy (MRS) 가간의중성지방을측정하는데있어조직생검의중성지방측정치와거의일치할만큼의정확성을보이지만 35-37), 지방증과 NASH, 섬유화를감별하기어렵다는한계가있다. 최근에는 transient elastography가 NAFLD 진단에서각광을받고있다. transient elastography는초음파탐색자를통해진동을발생시켜간으로전파되는파동의속도를다시초음파로측정하여탄력도를평가함으로써섬유화를추정하는방법이다. Wong 등에의하면 cutoff 값을 7.9 kpa으로할때 3단계이상의간섬유화에대한민감도, 특이도, 양성예측치, 음성예측치는각각 91%, 75%, 52%, 97% 로서 NAFLD 환자에서진행성섬유화를배제할수있는선별검사로 transient elastography가 매우유용하다고보고하였다 38). 하지만복부비만인 NAFLD 환자에서는기술적으로 transient elastography를제대로시행할수없다는한계가있으며, ALT 가높거나지방증이있는경우 transient elastography 결과에영향을미칠수있고 38,39), 관찰자내변동성이보고되는등 40) 의제한점으로인해 NAFLD 진단에있어서간조직생검을완전히대체하지는못하고있다. 이를보완하여 Magnetic resonance elastography (MRE) 는비만인 NAFLD 환자에서중등도이상의섬유화를진단하는데유용하며단순지방증은정상대조군과같은간의경직도를보인다는새로운연구도발표되었다 41). 새로운혈청학표지자 NAFLD 진행과정에포함된병태생리학적기전을연구하면서이에바탕한새로운혈청학표지자들이 NAFLD 진단에사용되고있다. Hyaluronic acid, TNF-α, adiponectin, type VI collagen 7S, type III collagen, cytokeratin-18, tissue inhibitor of matrix metalloproteinase A 등이 NAFLD 에서간의섬유화를예측하는혈청학표지자로제시되고연구되고있다 42-46). 결론 NAFLD 는현재유병률이높고또한계속증가하고있는추세이다. NAFLD 는단순지방증부터 NASH 및간섬유증과간경변증까지포함하며각단계별로예후에큰차이가있다

5 - 이진우. 비알코올성지방간질환의진단 - NAFLD 진단을위한비침습적방법들에는간기능검사및이를이용한진단알고리즘들, 복부초음파와 CT, MRI 등의방사선검사등이이용되어왔으나진단의정확성에한계가있어아직까지는간조직생검이 NAFLD 의감별및중등도진단에꼭필요하다고알려져있다. 그러나어떤환자를대상으로생검을시행하여야하는지는아직논란이되고있으며, 생검에의한합병증및표본오차등의문제점으로인하여최근에는간조직생검을대체할수있는새로운비침습적진단법이연구되고있다. 간섬유화의병리기전에관여하는새로운혈청학적표지자및 transient elastography, magnetic resonance elastography 같은새로운영상학적방법들이소개되었고이에대한연구가활발히진행되고있다. 중심단어 : 비알코올성지방간질환 ; 진단 ; 간조직생검 ; 비침습적검사 REFERENCES 1) Ludwig J, Viggiano TR, McGill DB, Oh BJ. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc 55: , ) Brunt EM. Pathology of nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol 7: , ) Abrams GA, Kunde SS, Lazenby AJ, Clements RH. Portal fibrosis and hepatic steatosis in morbidly obese subjects: a spectrum of nonalcoholic fatty liver disease. Hepatology 40: , ) Piccinino F, Sagnelli E, Pasquale G, Giusti G. Complications following percutaneous liver biopsy: a multicentre retrospective study on 68,276 biopsies. J Hepatol 2: , ) Sorbi D, McGill DB, Thistle JL, Therneau TM, Henry J, Lindor KD. An assessment of the role of liver biopsies in asymptomatic patients with chronic liver test abnormalities. Am J Gastroenterol 95: , ) Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, Ferrell LD, Liu YC, Torbenson MS, Unalp-Arida A, Yeh M, McCullough AJ, Sanyal AJ. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 41: , ) Jeen YM, Jin SY. Pathology of nonalcoholic steatohepatitis. Korean J Hepatol 15: , ) Lee KH, Park SH, Kim YJ, Huh KR, Min KS, Jun SY, Kim KO, Park CH, Hahn T, Yoo KS, Kim JH, Lee MS, Park CK. Validity and reliability of the nonalcoholic fatty liver diseases activity score (NAS) in Korean NAFLD patients and its correlation with clinical factors. Korean J Hepatol 16:29-37, ) Wieckowska A, Feldstein AE. Diagnosis of nonalcoholic fatty liver disease: invasive versus noninvasive. Semin Liver Dis 28: , ) Angulo P, Keach JC, Batts KP, Lindor KD. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology 30: , ) Ratziu V, Giral P, Charlotte F, Bruckert E, Thibault V, Theodorou I, Khalil L, Turpin G, Opolon P, Poynard T. Liver fibrosis in overweight patients. Gastroenterology 118: , ) Marceau P, Biron S, Hould FS, Marceau S, Simard S, Thung SN, Kral JG. Liver pathology and the metabolic syndrome X in severe obesity. J Clin Endocrinol Metab 84: , ) Dixon JB, Bhathal PS, O'Brien PE. Nonalcoholic fatty liver disease: predictors of nonalcoholic steatohepatitis and liver fibrosis in the severely obese. Gastroenterology 121:91-100, ) Ong JP, Younossi ZM. Approach to the diagnosis and treatment of nonalcoholic fatty liver disease. Clin Liver Dis 9: , ) Adams LA, Talwalkar JA. Diagnostic evaluation of nonalcoholic fatty liver disease. J Clin Gastroenterol 40(Suppl 1):S34-S38, ) Yano E, Tagawa K, Yamaoka K, Mori M. Test validity of periodic liver function tests in a population of Japanese male bank employees. J Clin Epidemiol 54: , ) Nomura K, Yano E, Shinozaki T, Tagawa K. Efficacy and effectiveness of liver screening program to detect fatty liver in the periodic health check-ups. J Occup Health 46: , ) Ipekci SH, Basaranoglu M, Sonsuz A. The fluctuation of serum levels of aminotransferase in patients with nonalcoholic steatohepatitis. J Clin Gastroenterol 36:371, ) Loria P, Adinolfi LE, Bellentani S, Bugianesi E, Grieco A, Fargion S, Gasbarrini A, Loguercio C, Lonardo A, Marchesini G, Marra F, Persico M, Prati D, Baroni GS. Practice guidelines for the diagnosis and management of nonalcoholic fatty liver disease. A decalogue from the Italian Association for the Study of the Liver (AISF) Expert Committee. Dig Liver Dis 42: , ) Prati D, Taioli E, Zanella A, Della Torre E, Butelli S, Del Vecchio E, Vianello L, Zanuso F, Mozzi F, Milani S, Conte D, Colombo M, Sirchia G. Updated definitions of healthy ranges for serum alanine aminotransferase levels. Ann Intern Med 137:1-10, ) Zeuzem S, Alberti A, Rosenberg W, Marcellin P, Diago M, Negro F, Prati D, Puoti C, Roberts SK, Shiffman ML. Review article: management of patients with chronic hepatitis C virus infection and "normal" alanine aminotransferase activity. Aliment Pharmacol Ther 24: , ) Palekar NA, Naus R, Larson SP, Ward J, Harrison SA. Clinical model for distinguishing nonalcoholic steatohepatitis from simple steatosis in patients with nonalcoholic fatty liver disease. Liver Int 26: , ) Gholam PM, Flancbaum L, Machan JT, Charney DA, Kotler DP. Nonalcoholic fatty liver disease in severely obese subjects. Am J Gastroenterol 102: ,

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<30382EC0C7C7D0B0ADC1C22E687770> 대한내과학회지: 제 76 권 제 2 호 2009 의학강좌-개원의를 위한 모범처방(Current Clinical Practice) 간기능검사의 이해와 적용 인제대학교 의과대학 일산백병원 내과학교실 김 경 아 Understanding and application of liver function tests Kyung-Ah Kim, M.D. Department of