PG2 PG Course 2015 Fatty Liver Disease (ASH & NASH) 알코올성간질환의진단 : 침습적또는비침습적 건양의대소화기내과 이태희 Diagnosis of Alcoholic Liver Disease: Invasive or Non-invasive? Tae Hee Lee Konyang University Hospital, Korea Diagnosis of alcoholic liver diseases is based on the evidence of alcohol use through history taking or questionnaire, physical examinations, blood tests, imaging studies and/or liver biopsy. The liver biopsy is required when a patient may have co-existing disease, before treatment for severe alcoholic steatohepatitis, to confirm the diagnosis, and to identify an acute-on-chronic liver injury. However, it is still challenging because of no solid criteria or guidelines for them. 서 론 2011년한국인의 1인당연간알코올소비량은 14.8 l로 WHO회원국중 13위를차지하였다. 1 알코올성간질환은한국인간경변증원인의 2위, 간암원인의 3위가되며 2 2012년국민건강영양조사에서고위험음주율 [1회평균음주량이 7잔이상 ( 여자 5잔 ) 이며주 2회이상음주하는경우 ] 이남자 21.8%, 여자 6.0% 로높고중 고등학교청소년의약 55% 가 1잔이상의음주를경험하였고만취경험률은 17.5% 로우려할만한수준이다. 2 이러한알코올사용장애는알코올성간질환으로진행하여개인적으로다양한신체적, 정신적질병과연관되며, 사회적으로는문제행동, 사고, 폭력, 범죄등과도연관된다. 이글에서는알코올성간질환을진단하는방법에대해간략히논하고자한다. 본 론 1. 침습적인진단방법 ( 간조직생검 ) 알코올간질환의흔한조직학적소견으로는지방증 (steatosis), 간세포손상, 소엽의염증, 말로리-덴크소체 (Mallory-Denk bodies, MDB), 거대미토콘드리아, 담세관증식 (ductular proliferation), 담세관빌리루빈정체 (ductular bilirubinostasis), 실질내담즙정체 (intraparenchymal cholestasis), 섬유화, 간경변등이있다. 3,4 조직학적소견에근거하여알코올간질환을단순지방증또는지방간, 지방간염, 간섬유화, 간경변증으로구분하기도하지만, 이들은동일한환자에서중복되거나동시에존재할수있으며이에대한명확한분류기준은아직없다. 5 57
Postgraduate Course 2015 Table 1. Proposed Grading System of Alcoholic Liver Diseases Steatosis (0-3) 0: <5%, 1: 5%-33%, 2: 33%-66%, 3: >66% Lobular inflammation (0-3) 0: No foci, 1: <2 foci per 200 field, 2: 2-4 foci per 200 field, 3: >4 foci per 200 field Cell death (0-3) 0: none, 1: focal apoptosis, 2: many acidophil bodies, 3 confluent necrosis Ballooning (0-2) 0 None, 1 Few balloon cells, 2 Many cells/prominent ballooning Fibrosis stages (0-6) Stage 1 mild Zone 3 pericellular and/or perivenular Stage 2 marked Zone 3 fibrosis in most zones 3 Stage 3 fibrous linkage HV to septa Stage 4 fibrous linkage HV, PT and septa Stage 5 incomplete or probable cirrhosis Stage 6 definite cirrhosis Tannapfel 등은알코올성지방간에서비알코올성지방간에비해 MDB, satellitosis, sclerosing hyaline necrosis, veno-occlusive disease 등이더흔하다고하였다. 6 MDB는주로핵주변에존재하는호산성의밧줄모양물질로 misfolded and aggregated keratin filaments 들로이루어진것이다. 7 Satellitosis 는호중구가 ballooned hepatocyte를둘러싸는모습을말한다. 8 임상적으로중증알코올성간염이의심된환자들의 70% 에서만간조직검사에서알코올성간염으로확진되었다. 9 간조직생검은알코올성간질환의진단에꼭필요하지는않지만알코올성간염환자의약 20% 환자에서동반된다른질환이있을수있고 10 간손상의정도와간섬유화의정도를평가하는데도움이되고예후를아는데도일부도움이될수있다. 염증이심하고호중구가침착되며담즙정체가심하면불량한예후를나타내고 megamitochondria의존재는좋은예후를보일수있다. 11 또한알코올성간질환이의심되거나알코올성간질환과비알코올성간질환이둘다의심될때조직검사가유용할수도있고치료를계획하고있는심한알코올성간질환에서와 acute-on-chronic liver injury가의심되는경우에도도움이될수있다. 12 알코올성간질환의조직학적분류에대해서는 2006년 Yip 등이다음과같은것을제안하였다 (Table 1). 13 2. 비침습적인진단방법 1) 병력청취술의종류, 음주량, 1주간음주횟수, 음주기간등에대해자세히확인해야한다. 아직까지알코올간질환을일으키는데필요한최소음주량에대한통일된기준이없고개인차가있지만, 하루평균알코올섭취량이남자에서 40 g 이상, 여자는 20 g 이상인경우를기준으로삼는다. 14-16 표준잔의경우나라마다다르지만우리나라는 12 g을기준으로하고있으며대략소주 1잔반 (90 ml), 맥주 1캔 (355 ml), 막걸리 1사발 (230 ml), 포도주 1잔 (120 ml), 양주 1잔 (40 ml) 에해당한다. 5 여러요인들이관여하기때문에음주기간에관해서도통일된자료는확인하기어렵다. 2) 증상및진찰소견 58
Tae Hee Lee Diagnosis of Alcoholic Liver Disease: Invasive or Non-invasive? Table 2. Typical Clinical Features of Alcoholic Liver Diseases Spectrum of ALD Clinical presentation Alcoholic fatty liver Asymptomatic Alcoholic hepatitis Jaundice, Anorexia, Fever +/- RUQ/epigastric pain +/- Abdominal distention due to ascites +/- Proximal muscle weakness +/- Confusion due to HE Compensated cirrhosis Asymptomatic Anorexia, Weight loss, Weakness, Fatigue, Muscle cramps, Amenorrhea or irregular menses Impotence, infertility, loss of sexual drive Decompensated cirrhosis Jaundice, Pruritus, GI bleeding, Weight gain, Abdominal distention due to ascites, Lower extremity edema, Easy bruising, Sleep disturbances, Confusion ALD: Alcoholic liver disease; GI: Gastrointestinal; RUQ: Right upper quadrant; HE: Hepatic encephalopathy 증상은무증상부터간부전이나사망까지다양하게나타날수있다 (Table 2). 17 상복부불쾌감, 고열, 피로, 식욕부진, 권태, 체중감소, 압통이동반된간종대, 황달, 지주상혈관, 악액질, 여성화소견및우상복부잡음등이나타날수있으나비특이적이다. 급성중증알코올간염이나간경변에서복수, 다리의부종, 간성뇌증및식도정맥류출혈등을보인다. 5 3) 혈액검사만성음주력을판단할수있는혈액검사로혈청아스파르테이트아미노전달효소 (aspartate aminotransferase, AST), 알라닌아미노전달효소 (alanine aminotransferase, ALT), gamma glutamyl transpeptidase(ggt), 평균적혈구용적 (mean corpuscular volume, MCV) 및탄수화물결핍트랜스페린 (carbohydrate deficient transferrin, CDT) 등이있는데어느한가지지표보다여러가지를종합하는것이판단에도움이된다 (Table 3). 18-21 이외에도혈액검사로다른가능한원인에대해배제가필요하다. 예를들면 B, C형간염, 자가면역성간염, 혈색소증, 알파-1 안티트립신결핍증, 윌슨씨병등에대한혈액검사를꼭시행하여확인하여야한다. 17 한편알코올의대사는대부분산화과정을통해이루어지지만소량은비산화과정을통해이루어져서 (Figure 1) 22,23 혈중뿐만아니라소변이나모발등에서대사물을확인할수있다. 24 Table 3. Sensitivity and Specificity of Biomarkers in detecting Harmful or Heavy Alcohol Consumption 18-21 Tests AST ALT MCV CDT CDT + GGT CDT + GGT + MCV Sensitivity 47~68% 32~50% 45~48% 63~84% 83~90% 88% Specificity 80~95% 87~92% 52~94% 92~98% 95~98% 95% AST: aspartate aminotransferase; ALT: alanine aminotransferase; GGT: gamma glutamyl transpeptidase; MCV: mean corpuscular volume; CDT: carbohydrate deficient transferrin 59
Postgraduate Course 2015 Figure 1. Oxidative and non-oxidative pathways for alcohol metabolism (modified from ref 22, 23). 4) 영상검사초음파, CT, MRI 등의영상검사는지방증을선별하고간질환의진행정도와합병증여부를평가하며, 담도질환, 간종양등다른원인질환을배제할수있다. 그러나영상검사만으로간질환의원인이알코올이라고확진할수없다. 5 초음파검사는첫검사로흔히이용되며간이 30% 이상지방으로차있다면 91%, 93% 의민감도와특이도를보이나 30% 미만의경우에는민감도가 64% 정도로떨어진다. 25 CT는간과비장의 Hounsfield unit (HU) 차이를구하여 10 HU 이상이면강력하게지방간 (30% 이상 ) 을의심할수있다고하였다. 26 MRI는 in and out of phase technique을이용하면지방간에대한민감도와특이도가 95%, 98% 에이른다고하였다. 27 이외에도 transient elastography를이용한 Controlled attenuation parameter (CAP) 으로지방증의정도를파악하려는시도 28-30 와 MRI를이용한 spectroscopy 30-32 도소개되고있다. 섬유화의정도도 transient elastography 33,34, MR elastography 35,36, acoustic radiation force impulse (ARFI) 37 등이소개되었으나아직충분히검증되지않았다. 결 론 알코올성간질환의진단은충분한양의알코올섭취를확인하는병력청취가꼭필요하며혈액검사로만성음주력을판단하는데도움을얻을수있다. 간질환의증거를찾기위해신체검사, 혈액검사및영상검사가필요하며다른질환이나다른질환과의공존이의심되거나또는심한알코올성간질환을확진하기위해서, 간손상의정도와섬유화의정도를파악하기위해서는간조직생검을시행할수있다. 60
Tae Hee Lee Diagnosis of Alcoholic Liver Disease: Invasive or Non-invasive? 참고문헌 1. WHO. Global status report on alcohol and health. 2011. 2. 한국인간질환백서. 대한간학회. 2013. 3. Lefkowitch JH. Morphology of alcoholic liver disease. Clin Liver Dis 2005;9:37-53. 4. MacSween RN, Burt AD. Histologic spectrum of alcoholic liver disease. Semin Liver Dis 1986;6:221-232. 5. 2013 대한간학회알코올간질환진료가이드라인. 6. Tannapfel A, Denk H, Dienes HP, Langner C, Schirmacher P, Trauner M, et al. Histopathological diagnosis of non-alcoholic and alcoholic fatty liver disease. Virchows Arch 2011;458:511-523. 7. Denk H, Stumptner C, Zatloukal K. Mallory bodies revisited. J Hepatol 2000;32:689-702. 8. Lefkowitch JH. Morphology of alcoholic liver disease. Clin Liver Dis 2005;9:37-53. 9. Levin DM, Baker AL, Riddell RH, Rochman H, Boyer JL. Nonalcoholic liver disease. Overlooked causes of liver injury in patients with heavy alcohol consumption. Am J Med 1979;66:429-434. 10. O 'Shea RS, Dasarathy S, McCullough AJ; Practice Guideline Committee of the American Association for the Study of Liver Diseases; Practice Parameters Committee of the American College of Gastroenterology. Alcoholic liver disease. Hepatology 2010;51:307-328. 11. Chedid A, Mendenhall CL, Tosch T, Chen T, Rabin L, Garcia-Pont P, et al. Significance of megamitochondria in alcoholic liver disease. Gastroenterology 1986;90:1858-1864. 12. Sakhuja P. Pathology of alcoholic liver disease, can it be differentiated from nonalcoholic steatohepatitis? World J Gastroenterol 2014;20:16474-16479. 13. Yip WW, Burt AD. Alcoholic liver disease. Semin Diagn Pathol 2006;23:149-160. 14. Becker U, Deis A, Sorensen TI, Gronbaek M, Borch-Johnsen K, Muller CF, et al. Prediction of risk of liver disease by alcohol intake, sex, and age: a prospective population study. Hepatology 1996;23:1025-1029. 15. McQuade WH, Levy SM, Yanek LR, Davis SW, Liepman MR. Detecting symptoms of alcohol abuse in primary care settings. Arch Fam Med 2000;9:814-821. 16. Eckardt MJ, Rawlings RR, Martin PR. Biological correlates and detection of alcohol abuse and alcoholism. Prog Neuropsychopharmacol Biol Psychiatry 1986;10:135-144. 17. Torruellas C, French SW, Medici V. Diagnosis of alcoholic liver disease. World J Gastroenterol 2014;20:11684-11699. 18. Rinck D, Frieling H, Freitag A, Hillemacher T, Bayerlein K, Kornhuber J, et al. Combinations of carbohydrate-deficient transferrin, mean corpuscular erythrocyte volume, gamma-glutamyltransferase, homocysteine and folate increase the significance of biological markers in alcohol dependent patients. Drug Alcohol Depend 2007;89:60-65. 19. Madhubala V, Subhashree AR, Shanthi B. Serum carbohydrate deficient transferrin as a sensitive marker in diagnosing alcohol abuse: a case - control study. J Clin Diagn Res 2013;7:197-200. 20. Hock B, Schwarz M, Domke I, Grunert VP, Wuertemberger M, Schiemann U, et al. Validity of carbohydrate-deficient transferrin (% CDT), gamma-glutamyl transferase (gamma-gt) and mean corpuscular erythrocyte volume (MCV) as biomarkers for chronic alcohol abuse: a study in patients with alcohol dependence and liver disorders of non-alcoholic and alcoholic origin. Addiction 2005;100:1477-1486. 21. Hietala J, Koivisto H, Anttila P, Niemelä O. Comparison of the combined marker GGT-CDT and the conventional laboratory markers of alcohol abuse in heavy drinkers, moderate drinkers and abstainers. Alcohol Alcohol 2006;41:528-533. 22. http://pubs.niaaa.nih.gov/publications/arh294/245-255.htm. 23. http://www.wardelab.com/19-3.html. 24. Litten RZ, Bradley AM, Moss HB. Alcohol biomarkers in applied settings: recent advances and future research opportunities. Alcohol Clin Exp Res 2010;34:955-967. 25. Palmentieri B, de Sio I, La Mura V, Masarone M, Vecchione R, Bruno S, et al. The role of bright liver echo pattern on ultrasound B-mode examination in the diagnosis of liver steatosis. Dig Liver Dis 2006;38:485-489. 26. Limanond P, Raman SS, Lassman C, Sayre J, Ghobrial RM, Busuttil RW, et al. Macrovesicular hepatic steatosis in living related liver donors: correlation between CT and histologic findings. Radiology 2004;230:276-280. 27. Borra RJ, Salo S, Dean K, Lautamaki R, Nuutila P, Komu M, et al. Nonalcoholic fatty liver disease: rapid evaluation of liver fat content 61
Postgraduate Course 2015 with in-phase and out-of-phase MR imaging. Radiology 2009;250:130-136. 28. Sasso M, Beaugrand M, de Ledinghen V, Douvin C, Marcellin P, Poupon R, et al. Controlled attenuation parameter (CAP): a novel VCTE guided ultrasonic attenuation measurement for the evaluation of hepatic steatosis: preliminary study and validation in a cohort of patients with chronic liver disease from various causes. Ultrasound Med Biol 2010;36:1825-1835. 29. de Lédinghen V, Vergniol J, Foucher J, Merrouche W, le Bail B. Non-invasive diagnosis of liver steatosis using controlled attenuation parameter (CAP) and transient elastography. Liver Int 2012;32:911-918. 30. Karlas T, Petroff D, Garnov N, Böhm S, Tenckhoff H, Wittekind C, et al. Non-invasive assessment of hepatic steatosis in patients with NAFLD using controlled attenuation parameter and 1H-MR spectroscopy. PLoS One. 2014;9(3):e91987. 31. Longo R, Pollesello P, Ricci C, Masutti F, Kvam BJ, Bercich L, et al. Proton MR spectroscopy in quantitative in vivo determination of fat content in human liver steatosis. J Magn Reson Imaging. 1995;5:281-285. 32. Georgoff P, Thomasson D, Louie A, Fleischman E, Dutcher L, Mani H, et al. Hydrogen-1 MR spectroscopy for measurement and diagnosis of hepatic steatosis. AJR Am J Roentgenol. 2012;199:2-7. 33. Nahon P, Kettaneh A, Tengher-Barna I, Ziol M, de Lédinghen V, Douvin C, et al. Assessment of liver fibrosis using transient elastography in patients with alcoholic liver disease. J Hepatol. 2008;49:1062-1068. 34. Janssens F, de Suray N, Piessevaux H, Horsmans Y, de Timary P, Stärkel P. Can transient elastography replace liver histology for determination of advanced fibrosis in alcoholic patients: a real-life study. J Clin Gastroenterol. 2010 ;44:575-582. 35. Huwart L, Peeters F, Sinkus R, Annet L, Salameh N, ter Beek LC, et al. Liver fibrosis: non-invasive assessment with MR elastography. NMR Biomed. 2006;19:173-179. 36. Yin M, Talwalkar JA, Glaser KJ, Manduca A, Grimm RC, Rossman PJ, et al. Assessment of hepatic fibrosis with magnetic resonance elastography. Clin Gastroenterol Hepatol. 2007;5:1207-1213. 37. Crespo G, Fernández-Varo G, Mariño Z, Casals G, Miquel R, Martínez SM, et al. ARFI, FibroScan, ELF, and their combinations in the assessment of liver fibrosis: a prospective study. J Hepatol 2012;57:281-287. 62