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1 CLINICAL HEPATOLOGY UPDATE 1 Clinical Hepatology Update 1 Hepatic Encephalopathy: Pathophysiology and Diagnosis 최대희강원대학교의학전문대학원소화기내과 Dae Hee Choi Department of Internal Medicine, Kangwon National University School of Medicine, Chuncheon, Korea Hepatic encephalopathy (HE, also knownas portosystemic encephalopathy) is a serious neuropsychiatric complication as a result of liver dysfunction. This disease encompasses a broad range of symptoms characterized by personality changes, intellectual impairment, and a depressed level of consciousness with varying severity. Patients with HE have high mortality and poor quality of life, however, burden of this disease is increasing. Therefore, this review focused on the pathogenesis and diagnosis of HE. Although the precise molecular mechanisms are unclear, HE is the synergistic effects of excess ammonia and inflammation cause astrocyte swelling and cerebral edema. It is theorized that neurotoxic substances, including ammonia and manganese, may gain entry into the brain in the setting of liver failure. Also, it is known that neurosteroids, altered neurotransmission and oxidative stress involved in the pathogenesis of HE. The diagnosis of HE performed by a number of investigations, including clinical scales, neuropsychometric tests, neurophysiologic tests and brain imaging. Clinically, HE is best diagnosed by excluding other acute and chronic causes of altered mental status and confirming the diagnosis by a positive response to empiric treatment. Key words: Hepatic encephalopathy, Pathogenesis, Diagnosis 1. 서론 간성뇌증 (hepatic encephalopathy, portosystemic encephalopathy) 은간기능저하상태에서발생하는의식및지남력장애, 각종신경학적이상을특징으로하는신경정신학적증후군이다. 1) 간성뇌증은원인간질환에따라 3개유형으로분류되고, C형간성뇌증은신경학적증상의지속기간및양상에따라간헐적 (episodic), 지속적 (persistent), 미세 (minimal) 간성뇌증으로나눈다 (Table 1). 간경변증환자에서간성뇌증발생시 1년생존률이 42% 에불과하다는보고에서처럼, 2) 이질환은간경변증환자에서여명을좌우하는매우중요한문제이지만, 뚜렷한증상없이환자삶의질을현저히낮추는경한형태간성뇌증의발생또한중요한임상문제로대두되고있다. 이글에서는간성뇌증의병태생리학적발생기전에대해최근까지발표된내용을정리하고임상에서이용할수있는진단방법에대해논하고자한다. Table 1. 간성뇌증의유형분류 1 Type Nomenclature Subcategory Subdivisions A B HE associated with acute liver failure HE associated with portal-systemic bypass and no intrinsic hepatocellular disease The Liver Week

2 C HE associated with cirrhosis and portal hypertension/or systemic shunts HE, hepatic encephalopathy Episodic HE Persistent HE Minimal HE Precipitated Spontaneous Recurrent Mild Severe Treatment-dependent 2. 병태생리 간성뇌증의병태생리학적기전은아직도밝혀지지않은부분이있으나, 뇌부종, 뇌관류이상, 신경전달물질이상등의기전이연관되며일부는겹쳐져작동할것으로추측된다. 간성뇌증에서뇌기능과관련된자료는대부분동물실험결과로서이글에서는다루지않고간성뇌증의발생에있어중요한역할을하는대사성요인들, 즉암모니아와신경전달물질의이상을중심으로정리하고자한다. 1) 신경독소 (Neurotoxins) (1) 암모니아 (Ammonia) 암모니아는급만성간부전환자에서뇌에축적되어간성뇌증을유발시키는잘알려진신경독소이다. 1896년문맥대정맥단락술을받은개에서고기를먹이면뇌증이유발되고혈액보다뇌에서암모니아농도가현저히증가되었다는사실과 1950년대간경변증환자에서복수치료를위해암모니움이온교환수지를사용하면간성뇌증또한호전이있었다는보고는암모니아가간성뇌증의원인임을추측하게하는근거가되었다. 3 암모니아의주요한원천은위장관으로, 장관세포에서글루타민으로부터생성되거나질소산물이장내세균으로부터이화되어생성된다. 배설과정은간에서요소와글루타민으로, 근육과뇌에서는글루타민으로전환되는데, 4 대부분은간에서요소로생성되어신장으로배설되나급성간부전환자에서는골격근과뇌가배설과정에더많이관여한다. 5 가. 성상세포내삼투압증가뇌에서암모니아를대사시킬수있는유일한세포가별아교세포 (astrocyte) 인데이세포의세포질그물에있는글루타민합성효소 (glutamine synthetase) 는글루탐산과암모니아를글루타민으로전환시킴으로써이들사이의농도를유지하는데중요한역할을한다. 간부전으로인해암모니아의농도가상승하면세포내글루타민농도가상승하게되고이는삼투물질로서별아교세포내로물을이동시켜결과적으로뇌부종과뇌압상승을유도하게된다. 6 별아교세포를고농도의암모니아에노출시켰을때흥분성신경전달물질인글루탐산이방출됨으로써불안, 혼동, 경련, 혼수등의 type A 간성뇌증의증상을유발시킴을확인하는실험결과가있었다. 7 그러나 type C 간성뇌증에서는경도의뇌부종과함께신경억제성상태가유지되는데, 이런경우별아교세포에서는오랜기간고농도암모니아에노출됨으로써별아교세포의부종또한 myoinositol 이나 taurine 같은삼투물질이세포외부로방출됨으로써보상기전을갖는것으로추측된다. 8 또한시냅스후부판에서글루탐산수용체의활성이하향조정되고별아교세포막에서글루탐산이동체 (transporter) 가비활성화되는기전이작동한것으로설명할수있다. 9 글루타민은단순한삼투성물질로만작용하지는않는다. 별아교세포내새로생성된글루타민의많은부분은 300 The Liver Week 2014

3 히스티딘민감성글루타민운반체를통해세포질로부터미토콘드리아로이동하여글루탐산과암모니아를생성하고이로인해미토콘드리아투과성변화, 자유라디컬생성및미토콘드리아구조물에산화성손상을유발시킨다. 10 그래서글루타민은 트로이의목마 에비교되기도하는데, 암모니아를미토콘드리아내부로이동시키는운반체역할을하지만미토콘드리아내부에서글루타민으로부터생성된암모니아가세포부종을포함한별아교세포의기능이상을오히려발생시키는매개체가되기때문이다. 암모니아로부터유발된산화성스트레스는미토콘드리아의투과성을증가시키고, mitogen-activated protein kinase를활성화시킴으로써별아교세포부종을유도한다. 11 혈관확장은급성간부전환자에서뇌압상승을유발하는또다른기전이다. 암모니아로부터생성된글루탐산방출과글루탐산배설장애가세포외글루탐산을증가시키고이것은 N-methyl-D-aspartate (NMDA) 수용체과흥분, 산화질소합성효소활성화를유도하고이로부터생성된산화질소가혈관확장을유발한다. 12 위의기전과함께문맥전신단락의발생은뇌증의중요한기전중하나인데문맥대정맥단락술을시술한쥐에서암모니움아세테이트를주입했을때뇌압이현저히상승하고뇌증이발생했다는결과가이를뒷받침한다. 13 나. 아미노산이동이상유발고암모니아혈증시암모니아제거를위해생성된글루타민이뇌에서혈액으로이동하면뇌혈액장벽에서 L-아미노산수송체활성을증강시키고이는 tyrosine, phenylalanine, tryptophan 등의아미노산의뇌흡수를증가시킴으로써 dopamine, norepinephrine, serotonin같은신경전달물질의합성에영향을미친다. 14 (2) 망간 (Manganese) 망간은뇌의기저핵에잘침착하는신경독소로서간경변증환자의 80% 이상에서 T1강조자기공명영상소견상침착이관찰되었다. 15 망간은별아교세포의수송체단백을자극하여신경스테로이드합성증가와 GABAergic tone을증강시키고, 기저핵의별아교세포가알츠하이머 Ⅱ형유형으로변하도록한다. 그럼으로써간성뇌증환자에서파킨슨병에서보이는운동실조와같은증상을유발한다. 16 2) 신경전달계의이상 (1) GABA- 벤조디아제핀신경전달계이상 γ-aminobutyric acid type A (GABA A ) 수용체복합체는동물뇌에서중요한억제성신경전달계로서, 전격성간부전동물모델에서신호전달을항진시키는 barbiturate 나벤조디아제핀수용체작용물질을투여했을 17, 18 때간성뇌증에서발생하는시각유발전위가관찰되어이와관련된가설이제시되었다. 가. GABA의시냅스내이용도증가정상적으로비지질성극성물질인 GABA의혈액-뇌장벽투과성은낮으나, 급성간부전의경우투과성이증가한다. 혈액-뇌장벽의투과성이증가에대한기전은잘알려진바없으나, 급성간부전동물모델에서다양한추적물질의뇌흡수증가가관찰되었고 19 그리하여다양한독성물질에뇌가노출될수있음이알려졌다. 한편또다른동물모델에서는 GABA transaminase의뇌내활성이감소하고피질에서 GABA의방출이증가하는것이관찰되었는데, 20 이러한현상은시냅스전 GABAb 수용체소실로의해발생한피질 GABA 방출의수용체전되먹이억제소실과관련되어 21 결과적으로간부전에서시냅스내 GABA 농도를상승시킨다. The Liver Week

4 나. 내인성벤조디아제핀축적중추벤조디아제핀리간드수용체에작용리간드가결합하면 GABA A 수용체복합체형태변화를통해 GABA 활성이증가된다. 급성또는만성간부전환자의간성뇌증에서 flumazenil을투여하면일시적인임상호전을보인다는결과들이있었는데, 22 이러한결과는간성뇌증에서중추벤조디아제핀수용체에작용리간드가결합되어 GABA 효과를증강시킴으로써임상증상이유발되었을것이라는가설을뒷받침한다. 내인성벤조디아제핀의원천은알려지지않았지만장내세균이벤조디아제핀의전구체를합성하거나음식을통해적은양의벤조디아제핀을섭취할수있을것으로추측한다. 23 (2) 신경스테로이드 (Neurosteroids) 신경스테로이드는중추신경계에서자체생성되는스테로이드를말하며프로게스테론의대사물질과내인성신경활성물질이다. 간성뇌증환자에서 18kDa 수송단백 ( 말초성벤조디아제핀수용체 ) 은염증에의해미세아교세포 (microglial cell) 에서수용체수가증가하는데이수용체가발현증가되면미토콘드리아내신경스테로이드합성이증가된다. 24 신경스테로이드는별아교세포의미토콘드리아소포체에서합성되고수송단백은별아교세포의미토콘드리아막에위치하여신경스테로이드합성을조절한다. 간부전환자에서증가하는암모니아와망간은수송단백을활성화시킴으로써신경스테로이드합성을증가시킨다. 25 Allopregnanolone과 tetrahydrodeoxycorticosterone은강력한선택적인gaba A 수용체복합체의입체구조조절자로서이러한스테로이드의투여는간성뇌증에서신경억제효과로나타나는증상인 sedation등의행동상이상을유도한다. (3) 글루탐산매개성흥분신경전도글루탐산은대표적인흥분성신경전달물질이다. 26 간부전에서는뇌내암모니아의상승이별아교세포특이적인효소인글루타민합성효소에의해이화되면서글루탐산을글루타민으로전환합성한다. 간부전모델에서글루탐산의대뇌피질방출이증가하고, 글루탐산의 (astroglia-specific glutamate transporter, GLT-1 의발현감소가매개된 ) 별아교세포및뉴런재흡수가감소하는데, 27 이러한현상이뇌내세포외액에서자유글루탐산의증가를유발한다. 28,29 시냅스내글루탐산이증가하면글루탐산수용체인 N-methyl-A-aspartate (NMDA), KA/ AMPA 와 G protein-linked metabotropic receptor의보상적감소를유도하게된다. 간부전에서글루탐산수용체의감소는글루탐산매개성흥분성신경전도감소로이어지고이는억제성신경전달상승과같은효과이므로, 간성뇌증의증상은억제성신경전달의증가효과처럼나타나는것이다. 전격성간부전동물모델에서 NMDA의경쟁적길항제인memantine을투여하면간성뇌증의증상및전기생리학적이상이경감되고뇌척수액에서글루탐산의감소가관찰된다는실험이이를뒷받침한다. 30 (4) Catecholamines 간성뇌증을보이는간경변증환자및급성간부전동물모델의뇌내에는도파민의대사산물인 homovanilic acid와노르에피네프린의대사산물인 3-methoxy-4-hydroxyphenylglycol이유의하게증가되어있다. 31 이는이들환자에서 catecholamine 의대사전환이항진되어있음을의미하는것이다. 도파민량은간경변증환자의뇌에서는큰변화가없었으며간성뇌증으로사망한간경변증환자에서는담창구 (globus pallidus) 의도파민 D2 수용체가감소되어있었다 The Liver Week 2014

5 (5) Serotonin 세로토닌은섭식, 수면등의생체조절과정서에관여하는신경전달물질로서간성뇌증환자의뇌척수액내에는전구물질인 tryptophan과 hydroxyindoleacetic acid 등의대사산물도증가되어있다. 이는세로토닌의대사전환이증가되어있음을시사하는것이며, MAO A의활성이증가된것과관련있을수있다. 33 그결과세포외세로토닌의농도는큰변화가없거나만성간부전의경우에는오히려감소해있는것으로보인다. 또한세로토닌수용체는농도가증가해있고세로토닌저해제에의해간성뇌증을유발할수있다는보고가있다. 33 3) 감염에대한전신반응 감염은잘알려진간성뇌증의유발인자이나그기전은완전히밝혀지지는않았다. 간경변증환자는면역억제상태로감염에취약하나감염자체가간성뇌증을악화시키는지이로인한염증반응이간성뇌증을악화시키는지는불확실하다. 간경변증환자에서전신염증반응증후군은미세또는현증간성뇌증모두를악화시키는데한보고에서는간성뇌증의정도가심해질수록동맥혈암모니아농도보다전신염증반응증후군및호중구증가증과관련이높다고보고하였다. 34 또다른강력한인자는장내세균의이동인데이것이만성적인내독소혈증을유발시켜 proinflammatory cytokine, chemokine, Toll-like and chemokine receptor를통한호중구를활성화시킨다. 35 간성뇌증환자에서글루타민길항제인 memantine 또는비스테로이드성항염증제인 ibuprofen을투여하면학습및기억력장애가호전됨을관찰한바있다. 36 4) 세균과증식 소장세균과증식이미세간성뇌증발생에관여할것이라는가설이있지만관련성을입증할충분한연구가더필요한실정이다. 37 장내세균microbiome analysis가다양한질환의발생기전을밝히는데이용되고있는데, 간경변증환자에서는 Enterobacteriaceae, Alcaligenaceae, Fusobacteriaceae, Ruminococcaceae, Lachnospiracease 가정상대조군에비해많다. 간경변증환자에서 Alcaligenaceae와 Porphyromonadaceae는인지기능장애와연관이있고, Fusobacteriaceae, Veillonellaceae와 Enterobacteriaceae는염증성마커와연관이있었다 진단 간성뇌증은간질환환자에서신경정신학적이상을보일때다른뇌질환을배제함으로써진단할수있으나실제임상에서의진단이간단하지않을수있다. 현재까지간성뇌증의진단과정도의평가를위한다양한신경정신학적, 신경생리학적방법들이발전되어왔으나표준화된진단방법이없고임상적척도가최선의방법으로간주되는경우가많다. 실제로간성뇌증환자의 80% 이상에서유발인자가확인되므로병력청취때위장관출혈, 요독증, 향정신성약제사용, 이뇨제사용, 단백질과다섭취, 감염, 변비, 탈수, 전해질불균형등의유발인자유무를확인해야한다. 39 이글에서는간성뇌증의진단방법으로알려진임상적척도, 신경정신학적검사, 신경생리학적및영상검사에대해정리하고자한다. 1) 임상적척도 임상적척도에는 West-Haven (WH) criteria, Hepatic Encephalopathy Scoring Algorism (HESA), Glasgow Coma Scale (GCS) 및 Clinical Hepatic Encephalopathy Staging Scale (CHESS) 등이있다. WH criteria는 30년이상사용되어온척도로, 환자의의식상태, 지적능력, 습관및신경운동학적기능의변화에따라정상상태부터혼수상태까지 The Liver Week

6 분류한다 ( 표2). 이기준은현증간성뇌증에대한많은연구에서사용되어왔으나, 경한정도의간성뇌증진단시는관찰자간평가의차이가있을수있어유용하지않다. 39 HESA는 WH criteria의중증도평가에대한부정확성을개선하기위해고안된방법으로임상적인평가와신경정신학적평가를통해간성뇌증환자를 4등급으로나눈다. 40 WH criteria에서취약한부분인경도의간성뇌증환자에대한더정확한평가를위해신경정신학적검사가추가되었으나 Grade Ⅰ 간성뇌증이나미세뇌증진단시에는큰도움이되지않을수있다. CHESS는 WH criteria에서논란이되는부분인정의의모호함을보정하기위해개발된방법으로, 9개문항에대해예 / 아니오로답하여 0~9 점까지산출하여간성뇌증의정도를평가한다. 41 경한간성뇌증환자의구분에 WH criteria 에서보다우월한결과가보고된바가있으나미세뇌증의진단에는의미가없어CHESS 0점인경우에는진단을위한다른검사를요한다. 한편뇌외상환자들의상태를평가하기위해개발된 GCS는환자의언어적, 시각적, 운동반응을평가하는데주로심한간성뇌증환자를평가하는데도움을받을수있다고알려져있다. 42 Table 2. 간성뇌증의 West Haven Criteria 39 Grade Consciousness Intellect and Behavior Neurologic Findings 0 Normal Normal 1 Mild lack of awareness Shortened attention span; impaired addition or subtraction Normal examination; if impaired psychomotor testing then MHE Mild asterixis or tremor 2 Lethargic Disoriented; inappropriate behavior Obvious asterixis; slurred speech 3 Somnolent but arousable Gross disorientation; bizarre behavior Muscular rigidity and clonus; hyperreflexia 4 Coma Coma Decerebrate posturing MHE, minimal hepatic encephalopathy 2) 신경정신학적검사 신경정신학적검사를이용하면임상적으로보기에는별이상이없거나경한간성뇌증환자에서인지기능을평가하는데유용하다. 신경정신학적검사는크게 paper-pencil test와computerized psychometric test로나눌수있다. Paper-pencil test는 Psychometric Hepatic Encephalopathy Score (PHES) 와 Repeatable Battery for Assessment of Neuropsychological Status (RBANS), computerized psychometric test로는 Inhibitory Control Test (ICT), cognitive drug research system이있다. 여러진료지침에서 PHES 가미세뇌증의표준진단방법으로추천되고있는데, 이방법은다음의 6가지항목과 canceling d-test로구성된다. 1,43,44 Number Connection Test (NCT)-A는 psychomotor speed, visual scanning efficiency, sequencing, attention, concentration, NCT-B는 attention set shifting ability, psychomotor speed, visual scanning efficiency, sequencing, attention, concentration, digit symbol test (DST) 는 associative learning, graphomotor speed, cognitive processing speed, visual perception, working memory, serial dotting test (SDT) 는 motor speed, line tracing test (LTT) 는 motor speed 및 accuracy를평가한다. 그러나이들검사중민감도가낮은일부의검사와좀더간단한방법에대한요구가있어개정된배터리가 portosystemic encephalopathy (PSE) syndrome test 로서, NCT-A, NCT-B, LTT, SDT, DST 만으로구성되어있다. 45 RBANS는list learning, story memory, figure copy, line orientation, picture naming, semantic fluency, digit span, coding, list recall, list recognition, story recall, figure recall 등 12 subset으로구성되어있는데말기간질환환자에서인지기능장애의평가에유용함이보고되었으나간성뇌증의진단및평가에서의 304 The Liver Week 2014

7 유용성이아직완전히확립되지는않았다. 46 자동화된컴퓨터화검사중 ICT는각성, 지속집중력, 반응억제력, 작업기억력을평가하는데교통사고발생위험및간성뇌증재발예측에유용하고검사의재연성도높아우수한검사로알려졌으나영어로진행되는검사이므로우리나라에서그대로이용하기가어렵다. 47,48 Portosystemic Encephalopathy Index (PSEI) 는 Conn 등에의해최초로소개된방법으로, 신경정신학적인기준인 Trail-making Test (TMT), 신경생리학적검사인 electroencephalogram (EEG), 생화학적검사 ( 동맥혈암모니아 ), 정신상태의임상평가, asterixis 정도평가로간성뇌증을평가하는방법이다. 49 그러나이지표에서연령이나교육정도에따른교정이포함되지않으며각각의검사들이서로독립적이지않고질병특이적이지도않아 1998 consensus group에서는 episodic acute encephalopathy에서임상적평가보다이득이없으며만성간성뇌증임상연구에서뇌증의정량화를연구하는경우에만제한하여사용할것이권고하였다. 1 3) 신경생리학적검사 간성뇌증의진단에이용되는신경생리학적검사로는EEG와 critical flicker fusion frequency (CFF) 가있다. 간성뇌증의진단및평가시 EEG 이용에대한연구는비교적많이시행되었으며경한간성뇌증에서는 α rhythm slowing과 θ와 δ wave의점차적인소실이특징적이고, 간성뇌증이심한상태로진행하면 high-amplitude irregular δ activity가특징적이다. 50 EEG의간성뇌증의진단민감도는 % 로알려져있으나, 이검사는대뇌피질만의기능을평가하며다른종류의뇌손상에의해서도영향을받기때문에간성뇌증이없는환자의 8-40% 에서도관찰될수있다. 43 CFF는깜박거리는불빛의깜박이는빈도를증가시키면서불빛이깜박거린다고느끼지못하는최대진동수를의미하는데, 대뇌피질기능에문제가있는경우낮아지므로집중력저하가동반되는간성뇌증환자의진단에사용할수있다. 현성뇌증에서는 100% 의높은진단적정확도를보였으나미세뇌증진단에는정확도가떨어져 55% 의민감도와 100% 의특이도를보였으며눈으로불빛을보고판단해야하므로양안시력이유지되고환자의협조가이루어지는경우에만시행할수있다. 51 4) 영상의학적진단 간세포기능부전또는문맥전신단락으로인한결과로뇌에는영상학적검사로확인할수있는구조적기능적이상이발생한다. 적당한도구로는전산화단층촬영술, 자기공명촬영술, magnetic resonance spectroscopy (MRS), positron emission tomography (PET), single-photon emission computed tomography (SPECT) 등을고려할수있는데이러한방법들이객관적이고재현가능하며비침습적인방법이므로간성뇌증을진단하고모니터하는데유용할수있다. 그러나뇌내대사물질의정량화등의방법은아직은진단적목적으로보편화되어있지않고 PET 및 SPECT는유용할것으로생각되나비용이상당한연구방법이다. 전산화단층촬영술은급성간부전의뇌부종이나만성간질환환자에서의병적인뇌질환을감별하는데유용하나낮은민감도와연구목적의반복적인촬영시발생할수있는방사선의노출로인한제한점이있다. 자기공명촬영술에서간성뇌증의전형적인소견은 T1 강조영상에서양측기저핵이대칭적으로고강도신호를보인다. 52 간세포에서배설이덜된망간이혈액이풍부한기저핵에축적됨으로써고강도신호를보인다는가설인데간이식후망간의혈액내농도가감소하고기저핵의망간축적이감소되는것이확인된몇연구에의해확인되었다. 53 Fluid-attenuated inversion recovery sequences (FLAIR) T2 강조영상은대뇌백질의전반적인고강도신호를확인하는데민감한검사인데이병변은가역적인뇌부종과비가역적인뉴런손상으로인해나타난다. Cordoba 등은만성간질환환자에서FLAIR T2 강조영상에서corticospinal tract을따라고강도신호와간이식후정상화됨을확인한바있다. 54 The Liver Week

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

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