PG 4 PG Course 2012 Portal Hypertension 조기간성뇌증의진단과삶의질 가톨릭대학교의과대학소화기내과 윤승규 Diagnosis and Health-related Quality of Life (HRQOL) of Minimal Hepatic Ence

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1 PG 4 PG Course 2012 Portal Hypertension 조기간성뇌증의진단과삶의질 가톨릭대학교의과대학소화기내과 윤승규 Diagnosis and Health-related Quality of Life (HRQOL) of Minimal Hepatic Encephalopathy Seung Kew Yoon Division of Gastroenterology and Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea Minimal encephalopathy (MHE) is the leading cause of cognitive dysfunction in patients with liver cirrhosis who are characterized by abnormal responses to psychometric and/or neurophysiological tests without clinically abnormal feature. Patients with MHE have poor-health-related quality of life (HRQOL) and thus have difficulty to have job, resulting in poor socio-economic life. Moreover, the patients with MHE meet frequent life-threatening risk due to cognitive dysfunction throughout their life. In particular, recent reports have demonstrated that patients with MHE are unfit to drive in 52% to 100% of cases. Although there is still debate over whether active treatment for patients with MHE is needed or not in terms of cost-effectiveness, recent studies have suggested that active treatment for MHE could improve HRQOL, enhance driving ability, and eventually may prevent the development of overt hepatic encephalopathy. 서 론 간성혼수 (hepatic encephalopathy) 는크게현성간성뇌증 (overt hepatic encephalopathy, OHE) 와미세간성뇌증 (minimal hepatic encephalopathy, MHE) 로나누고, 현성간성뇌증은초기현성간성뇌증 (early OHE) 와후기현성간성뇌증 (late OHE) 으로다시나눌수있다. 하지만일반적으로초기간성뇌증은미세간성뇌증과혼용하여사용하고있는바, 미세간성뇌증은간성뇌증의임상증세는보이지않으나, 정신측정검사 (psychometric test) 혹은신경생리검사 (neurophysiologic test) 에서이상반응을보이는인지기능장애 (cognitive dysfunction) 를초래하는경우로정의한다. 또한과거미세간성뇌증은 subclinical HE로도사용되었으나최근에는잘사용되지않고있다. 1 미세간성뇌증은현성간성뇌증이없는간경변증환자의 22-74% 에서나타나는것으로보고되고있고, 발생빈도는연령, 간질환의중등도, 식도정맥류발생여부, 현성간성뇌증발생의기왕력, 수술적문맥-전신단락술 (porto-systemic shunt) 시행여부에비례하는것으로알려져있다. 2 하지만간질환의원인과미세뇌증의유병율과는상관관계가없다고보고된바있다

2 Postgraduate Course 미세간성뇌증의임상적의미와삶의질미세간성뇌증은인지기능의장애와연관되어환자의삶의질을저하시키는것으로알려져있다 (Table 1) 인지기능장애는주의력, 정보처리속도, 정신운동능력및균형조정능력등복합적인영역의장애를초래하는반면지적기능이나언어능력에는영향을미치지않는다. 따라서환자는옷을입거나화장실을이용하는등의일상생활은수행할수있지만, 자동차를운전하거나무언가를계획하는등의능력은현저히감소하게된다. 왜냐하면자동차운전은인지기능과운동수행능력과기술적인전략적사고방식이종합적으로요구되기때문이다. 미세뇌증환자의증상으로는수면장애, 기억력, 집중력및주의력감소가있으며미세뇌증환자는사회적관계, 각성, 감정행동, 업무, 가사, 오락및취미활동등의일상생활기능에현저한장애를겪는것으로보고되었다. 5,7 특히미세뇌증과동반된운전능력감소에대해서많은연구가시행되었는데, 실제 MHE를앓고있는환자에게운전을시켰을때절반이상의환자에서운전에적합하지못한것으로나타났고이들의인지기능저하로인하여교통위반및자동차사고가증가하는것이알려졌으며, 주의력및정보처리속도가감소하여교차로에서의갑작스러운끼어들기등예상치못한교통상황에적절하게반응하지못하는것으로보고되었다 미세뇌증환자는경제적인부담도증가하게된다. 실업자이거나비정규직고용자인환자의빈도가미세뇌증이없는환자에서는약 15% 인것에비해미세뇌증이있는환자에서는 50% 정도인것으로알려져있고, 20-60% 의미세뇌증환자가건강상의이유로직장을그만두게된다는연구결과도있었다. 또한 8 미세뇌증환자에서현성간성뇌증의발생과사망위험도가증가함이보고되었지만상대적인간기능저하가원인인지미세뇌증자체때문인지확실하지않다. 2. 미세간성뇌증의진단미세뇌증은현성간성뇌증환자에서흔히관찰되는지적능력장애, 인격및의식상태의변화나신경기능장애는관찰되지않으면서경한인지기능및정신운동장애만나타나므로임상적검사만으로는진단이불가능하다. 미세뇌증으로진단하기위해서는 (1) 간경변증이나문맥-전신단락등미세뇌증을유발할수 Table 1. MHE is associated with poor quality of life (QOL) Study Instrument Used Poor QOL Groeneweg Sickness Impact Profile Yes Schomerus Sickness Impact Profile Yes Bao Chronic liver disease Q, SF-36 Yes Prasad Sickness Impact Profile Yes Les Chronic liver disease Q, SF-36 Yes Sidhu Sickness Impact Profile Yes Wunsch Chronic liver disease Q, SF-36 No 120

3 윤승규 조기간성뇌증의진단과삶의질 있는질환이있고, (2) 다른신경학적질환이동반되어있지않으며, (3) 임상적검사에서의식이정상이면서 (4) 인지기능또는신경생리기능에이상이있어야한다. 정상적인의식상태를확인하기위해서는 West Haven criteria를이용하나, stage 0-2의구분에는검사자의주관적인판단이많이작용하기때문에검사자에따라차이를보일수있다. West Haven criteria stage 0과 stage 1-2를구분하는데 Mini-Mental State Examination (MMSE) 이도움이될수있으며, MMSE에서 23점이하이면인지기능에장애가있는현성간성뇌증으로간주한다. 15 의식이정상이라고판단되면미세뇌증의유무를판단하기위한검사를시행할수있다. 어떤검사가미세뇌증의진단에가장유효할것인지는확실하게밝혀지지않았으나 number-connection test (NCT)-A, NCT-B, figure connection test (FCT)-A, FCT-B, block design test 및 digit symbol test 등의신경정신검사중두가지이상을시행하거나 Psychometric Hepatic Encephalopathy Score (PHES) battery, critical flicker frequency (CFF), inhibition control test (ICT) 중한가지검사를시행할것이권장되고있다 (Figure 1). 2 신경정신검사는많은미세뇌증환자와건강한지원자들을대상으로시행되어임상적인의미가확립된검사이며외래진료시시행할수있지만많은수의검사를선택하면시행하는데시간이많이걸린다는단점이있다. 2 PHES는 NCT-A, NCT-B, line tracing test, serial dotting test 및 digit symbol test로구성된표준화된간편한검사방법으로스페인, 독일및인도등의연구에서유효성이입증되었으며운동속도와정확성, 시공간적지남력, 시각적지각능력, 주의력, 집중력, 기억력에대한평가를할수있다 최근우리나라에서도 PHES의우리나라국민에서의정상치및미세뇌증의진단에대한유효성이입증된바있다. CFF 는시각적식별력과각성여부를평가하며시행방법이간단하고미세뇌증을진단하는데있어신뢰성이높다는장점이있지만환자가컴퓨터를조작하는데어려움이있다면시행하기어렵다는단점이있다. 17,19,20 ICT는반응억제력, 주의력, 작동기억력에대하여평가할수있는방법으로교통위반및자동차사고발생증가를예 측할수있다고보고되었다. 21 ICT 는 CFF 와 마찬가지로간단히시행할수있지만환자가컴퓨터를조작하는데어려움이없어야한다는제약이있다. 그외에도 EEG를이용하여 dominant mean frequency를측정하는방법이있으며이는객관적인방법으로반복시험이 가능하다는장점이있지만고가의장비가필 요하고결과의해석을위한전문인력이필 요하다는단점이있다 (Table 2) Figure 1. Algorithm for diagnosis and treatment of minimal hepatic encephalopathy (MHE) (Adapted from Dhiman et al. J. Gastroenterol Hepatol 2010;25: ). 121

4 Postgraduate Course 2012 Table 2. Methods for Detecting MHE Methods Expense Time Validated Predicting outcomes Formal psychological assessment Neurophysiologic tests (EEG) Short Batteries (Block design tests, PHES) Computerized tests (ICT, CFF) (Adapted from Mullen KD et al. Semin Liver Dis. 2007;27: ). 미세뇌증을치료하면인지기능및삶의질이호전되고현성간성뇌증의발생을억제할수있다고보고되어, 일부에서는현성간성뇌증이없는모든간경변증환자들에서미세뇌증에대한검사를시행할것을권장하고있다. 하지만, 아직까지미세뇌증의치료가실제적으로환자의예후에도움이되는지확실하지않기때문에모든간경변증환자에서이와같은검사를권장하기는힘들것으로생각된다. 다만인지기능장애, 삶의질이나업무수행능력의저하등을호소하는경우, 자가운전자, 기계를다루는직업에종사하는환자들의경우에는미세뇌증에대한검사를고려해볼수있다. 3. 미세간성뇌증의치료현성간성뇌증과마찬가지로장에서기인한질소성물질, 특히암모니아가주된역할을하는것으로알려져있어, 미세뇌증이있는경우체내암모니아를감소시키기위한치료를시행할수있다. 가장많은연구가이루어진것은 lactulose로서하루 ml를 2-3회분복하여하루 2-3회의무른변을볼수있도록조절하여투여하며, 치료군에서는위약군에비해인지기능및삶의질의현저한호전이관찰되었다. 7 또한 prebiotics나 probiotics 및 synbiotics 등미생물제제가장내세균총을변화시켜장에서의암모니아생성을억제함으로써미세뇌증을호전시킨다고보고되었다. 25 최근에는 rifaximin 26 이정신측정검사결과를향상시키며동시에삶의질을호전시킨다는보고가있으며그외에도 L-ornithine-L-aspartate 27 나 acetyl L-carnitine 28 등이미세뇌증에효과가있다는보고가있었으나, 아직효과를입증할만한근거가부족한실정이다. 4. 미세간성뇌증의진단후치료 ; 과연필요한가? 미세간성뇌증은인지기능장애를일으켜환자의일상생활기능에현저한장애를가져오며교통위반, 자동차사고율, 실업률및경제적인부담을증가시켜삶의질의저하를초래한다. 5,8,11-14 그럼에도불구하고보편적으로 PHES, EEG 등의진단도구를이용하여미세간성뇌증을진단하고치료해야한다는데는이견이존재한다. 이증후군을진단하는데있어서현재까지 gold standard가존재하지않아비교적높은위음성및위양성율이발생하며현존하는진단방법들을시행하는데는많은시간이소요되고전문장비와결과의평가및해석을위한전문인력이필요하여대부분의병원에서는실용적이지못하다는것에대한주장이다. 19,29 따라서현시점에서미세간성뇌증을진단한후에치료하는것에대해회의적인학자들은간경변증환자들에서약 10-20% 를제외하고는미세및현성간성뇌증이결국발생한다는점에착안하여대다수의간경 122

5 윤승규 조기간성뇌증의진단과삶의질 변환자들이신경정신병적 (neuropsychiatric) 인이상이발생할가능성을받아들이고비용대비효과 (cost effectiveness ) 가크고안전한약제를모든간경변환자에게투여하는것을주장한다. 하지만아직그러한 입증된약제또한존재하지않는것이현실이다. 결 론 미세간성뇌증은인지기능장애를일으켜환자의일상생활기능에현저한장애를가져오며교통위반, 자동차사고율, 실업률및경제적인부담을증가시켜삶의질의저하를초래한다. 따라서미세뇌증은반드시치료해야할질환이다. 하지만현존하는진단방법중에는 gold standard가존재하지않고실용적이지못하여앞으로미세간성뇌증의진단및치료에대한임상적, 실험실적연구가활성화되어야할것으로생각된다. 참고문헌 1. Ferenci P, Lockwood A, Mullen K, Tarter R, Weissenborn K, Blei AT. Hepatic encephalopathy--definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, Hepatology 2002;35: Dhiman RK, Saraswat VA, Sharma BK, et al. Minimal hepatic encephalopathy: consensus statement of a working party of the Indian National Association for Study of the Liver. J Gastroenterol Hepatol 2010;25: Gitlin N, Lewis DC, Hinkley L. The diagnosis and prevalence of subclinical hepatic encephalopathy in apparently healthy, ambulant, non-shunted patients with cirrhosis. J Hepatol 1986;3: Bao ZJ, Qiu DK, Ma X, et al. Assessment of health-related quality of life in Chinese patients with minimal hepatic encephalopathy. World J Gastroenterol 2007;13: Groeneweg M, Quero JC, De Bruijn I, et al. Subclinical hepatic encephalopathy impairs daily functioning. Hepatology 1998;28: Les I, Doval E, Flavia M, et al. Quality of life in cirrhosis is related to potentially treatable factors. Eur J Gastroenterol Hepatol 2010;22: Prasad S, Dhiman RK, Duseja A, Chawla YK, Sharma A, Agarwal R. Lactulose improves cognitive functions and health-related quality of life in patients with cirrhosis who have minimal hepatic encephalopathy. Hepatology 2007;45: Schomerus H, Hamster W. Quality of life in cirrhotics with minimal hepatic encephalopathy. Metabol Br Dis 2001;16: Sidhu SS, Goyal O, Mishra BP, Sood A, Chhina RS, Soni RK. Rifaximin improves psychometric performance and health-related quality of life in patients with minimal hepatic encephalopathy (the RIME Trial). Am J Gastroenterol 2011;106: Wunsch E, Szymanik B, Post M, Marlicz W, Mydlowska M, Milkiewicz P. Minimal hepatic encephalopathy does not impair health-related quality of life in patients with cirrhosis: a prospective study. Liver Int 2011;31: Bajaj JS, Ananthakrishnan AN, McGinley EL, Hoffmann RG, Brasel KJ. Deleterious effect of cirrhosis on outcomes after motor vehicle crashes using the nationwide inpatient sample. The American journal of gastroenterology 2008;103: Bajaj JS, Hafeezullah M, Hoffmann RG, Saeian K. Minimal hepatic encephalopathy: a vehicle for accidents and traffic violations. Am J Gastroenterol 2007;102: Marottoli RA, Cooney LM, Jr., Wagner R, Doucette J, Tinetti ME. Predictors of automobile crashes and moving violations among elderly drivers. Annals of internal medicine 1994;121: Wein C, Koch H, Popp B, Oehler G, Schauder P. Minimal hepatic encephalopathy impairs fitness to drive. Hepatology 2004;39:

Postgraduate Course 2012 15. Folstein MF, Folstein SE, McHugh PR. "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician.

6 Postgraduate Course Folstein MF, Folstein SE, McHugh PR. "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. Journal of psychiatric research 1975;12: Dhiman RK, Kurmi R, Thumburu KK, et al. Diagnosis and prognostic significance of minimal hepatic encephalopathy in patients with cirrhosis of liver. Dig Dis Sci 2010;55: Romero-Gomez M, Cordoba J, Jover R, et al. Value of the critical flicker frequency in patients with minimal hepatic encephalopathy. Hepatology (Baltimore, Md) 2007;45: Weissenborn K, Ennen JC, Schomerus H, Ruckert N, Hecker H. Neuropsychological characterization of hepatic encephalopathy. J Hepatol 2001;34: Kircheis G, Wettstein M, Timmermann L, Schnitzler A, Haussinger D. Critical flicker frequency for quantification of low-grade hepatic encephalopathy. Hepatology 2002;35: Sharma P, Sharma BC, Puri V, Sarin SK. Critical flicker frequency: diagnostic tool for minimal hepatic encephalopathy. J Hepatol 2007;47: Bajaj JS, Saeian K, Schubert CM, et al. Minimal hepatic encephalopathy is associated with motor vehicle crashes: the reality beyond the driving test. Hepatology 2009;50: Amodio P, Del Piccolo F, Petteno E, et al. Prevalence and prognostic value of quantified electroencephalogram (EEG) alterations in cirrhotic patients. J Hepatol 2001;35: Amodio P, Quero JC, Del Piccolo F, Gatta A, Schalm SW. Diagnostic tools for the detection of subclinical hepatic encephalopathy: comparison of standard and computerized psychometric tests with spectral-eeg. Metabol Br Dis 1996;11: Weissenborn K, Scholz M, Hinrichs H, Wiltfang J, Schmidt FW, Kunkel H. Neurophysiological assessment of early hepatic encephalopathy. Electroencephal Clin Neurophysiol 1990;75: Bajaj JS, Saeian K, Christensen KM, et al. Probiotic yogurt for the treatment of minimal hepatic encephalopathy. Am J Gastroenterol 2008;103: Butterworth RF. Editorial: rifaximin and minimal hepatic encephalopathy. Am J Gastroenterol 2011;106: Kircheis G, Nilius R, Held C, et al. Therapeutic efficacy of L-ornithine-L-aspartate infusions in patients with cirrhosis and hepatic encephalopathy: results of a placebo-controlled, double-blind study. Hepatology 1997;25: Malaguarnera M, Gargante MP, Cristaldi E, et al. Acetyl-L-carnitine treatment in minimal hepatic encephalopathy. Dig Dis Sci 2008;53: Bajaj JS, Hafeezullah M, Franco J, et al. Inhibitory control test for the diagnosis of minimal hepatic encephalopathy. Gastroenterol 2008;135:

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A 617 Special Issue Diabetic Retinopathy Won Ki Lee, M.D. Department of Ophthalmology The Catholic University of Korea College of Medicine Kangnam St. Mary s Hospital E mail : wklee@catholic.ac.kr Abstract R