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1 대한내과학회지 : 제 93 권제 6 호 In-depth review 고중성지방혈증급성췌장염의최신지견 단국대학교의과대학내과학교실 김홍자 An Update on Hypertriglyceridemia-Induced Acute Pancreatitis Hong Ja Kim Department of Internal Medicine, Dankook University College of Medicine, Cheonan, Korea Hypertriglyceridemia a major cause of acute pancreatitis, accounting for up to 10% of all cases. The pathophysiological mechanism of hypertriglyceridemia-induced acute pancreatitis (HTGP) is presumed to involve the hydrolysis of triglycerides by pancreatic lipase resulting in an excess of free fatty acids and elevated chylomicrons, which are thought to increase plasma viscosity and induce ischemia and inflammation in pancreatic tissue. Although the clinical course of HTGP is similar to other forms of acute pancreatitis, the clinical severity and associated complications are significantly higher in patients with HTGP. Therefore, an accurate diagnosis is essential for treatment and prevention of disease recurrence. At present, there are no approved guidelines for the management of HTGP. Different treatment modalities such as apheresis/plasmapheresis, insulin, heparin, fibric acids, and omega-3 fatty acids have been successfully implemented to reduce serum triglycerides. Following acute phase management, lifestyle modifications including dietary adjustments and drug therapy are important for the long-term management of HTGP and the prevention of relapse. Additional studies are required to produce generalized and efficient treatment guidelines for HTGP. (Korean J Med 2018;93: ) Keywords: Hypertriglyceridemia; Acute pancreatitis 서론급성췌장염은 1-2일이면회복되는경미한염증부터다발성장기부전과동반된심한궤사로 20-50% 이상의사망률을보이는중증의췌장염까지다양한임상경과를보이는췌 장의급성염증성질환이다 [1-3]. 담석과알코올이가장흔한원인이며생활습관의서구화로증가하고있는대사증후군의일환인고중성지방혈증 (hypertriglyceridemia) 은급성췌장염원인의 10% 이상을차지한다 [4-9]. 고중성지방혈증이원인이되어발생하는고중성지방혈증 Received: Accepted: Correspondence to Hong Ja Kim, M.D. Department of Internal Medicine, Dankook University College of Medicine, 201 Manghyang-ro, Dongnam-gu, Cheonan 31116, Korea Tel: , Fax: , hjkimjung@hotmail.com Copyright c 2018 The Korean Association of Internal Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

2 - Hong Ja Kim. Hypertriglycerimedia-induced acute pancreatitis - 급성췌장염 (hypertriglyceridemia-induced acute pancreatitis, HTGP) 의정확한병태생리학적기전은아직도명확하지않으나췌장에서분비된리파아제가과도한중성지방을가수분해할때방출된과량의유리지방산 (free fatty acids, FFA) 과카일로마이크론 (chylomicron) 이혈장점도를증가시키고이는췌장조직의국소적인허혈과췌장의염증을촉발시키는것으로알려져있다 [9,10]. HTGP 의임상증상은다른원인에의한급성췌장염과유사하나임상경과가더중하여더높은합병증과사망률, 재발률을보이므로 [5-9], 초기의정확한진단은적절한치료와재발예방에필수적이다. 이논고에서는급성 HTGP의원인, 임상특징, 치료및관리에대하여알아보고자한다. 본론고중성지방혈증및고중성지방혈증췌장염의정의고중성지방혈증은공복시혈중중성지방의농도가 150 mg/dl 이상일때로정의한다. 증가된정도에따라, 경도, 중증도, 고도, 최고도로나눌수있으며각각에대한혈중중성지방의기준은아래와같다 [9]. 경도중성지방혈증 ; mg/dl, mmol/l 중등도중성지방혈증 ; mg/dl, mmol/l 고도중성지방혈증 ; 1,000-1,999 mg/dl, mmol/l 최고도중성지방혈증 ; 2,000 mg/dl, > 22.6 mmol/l HTGP는통상적으로 1,000 mg/dl 이상의고도중성지방혈증소견을보이며췌장염을유발할만한다른원인 ( 담석, 음주, 약물및기타 ) 이동반되지않은급성췌장염으로정의한다. 일반적으로중성지방농도가증가할수록급성췌장염의발생위험도는증가하는것으로알려져있어, 보고에따르면경도의고중성지방혈증의경우급성췌장염발생위험은낮으나, 혈중중성지방이 500 mg/dl 이상일때수치증가와함께췌장염발생의위험도도점진적으로증가하여 1,000 mg/dl 이상에서는위험도가급격히증가한다. 급성췌장염발생의위험은혈청중성지방 > 1,000 mg/dl인경우약 5%, 중성지방이 > 2,000 mg/dl인경우에는 10-20% 로보고되고있다 [9-12]. 그러나 HTGP 의진단시 1,000 mg/dl의수치는절대적기준은아니며연구자에따라조금씩다른기준값을사용하여정의하고있다 [13]. 고중성지방혈증의원인다양한일차성 ( 유전성 ) 고중성지방혈증및중성지방증가를유발하는질환에의한이차성고중성지방혈증이급성췌장염발생과관련이있다. Fredrickson 분류에따른 5형의고지혈증중특히 I형고지혈증 ( 카일로마이크론, 중성지방증가 ), IV형고지혈증 ( 극저밀도지단백질 [very low-density lipoprotein, VLDL], 중성지방증가 ) 및 V형고지혈증 ( 카일로마이크론, VLDL 증가 ) 시동반되는고중성지방혈증이급성췌장염의위험을증가시킨다 [14]. I형고지혈증은 lipoprotein lipase의상염색체열성유전인자결핍에기인한가족성고카일로마이크론혈증으로, 흔히유아기에다른악화요인없이급성췌장염이발생하는반면, IV형및 V형고지혈증환자의혈중중성지방은환경적또는호르몬적요인이동반되지않은경우일반적으로급성췌장염을일으킬정도로충분히상승하지않으며대개성인기에다른요인이동반되면급성췌장염이발현된다. 중성지방증가를초래하는질환에의하여이차적으로고중성지방혈증이발생하는경우로는조절되지않은당뇨, 임신, 과도한알코올섭취, 약물, 비만등이있다 [15-18]. 흔히이차성고중성지방혈증단독으로는 HTGP 를초래할만큼의과도한고중성지방혈증이발생하지않으나일차성고지혈증이동반된경우혈중중성지방상승이증강되어 HTGP 를유발할수있다. 조절되지않는당뇨병 (1형및 2형 ) 과당뇨병성케톤산증이 HTGP를유발할수있다 [16,19]. 1형당뇨병의인슐린의결핍은지방조직에서지방분해를유도하여 FFA를방출시키고, 간으로의증가된 FFA의전달은말초조직에서 lipoprotein lipase의활성저하와 VLDL의고출력을유도하여고중성지방혈증을초래한다. 2형당뇨병의고인슐린혈증및인슐린저항성역시중성지방생성증가와혈중중성지방제거저하로고중성지방혈증을유발한다. 낮은혈청 ph (7.1 이하 ) 와높은음이온갭으로특징지어지는중증대사산증인당뇨병케톤산증은혈청중성지방의현저한상승을촉발하고이는급성췌장염을유발시킬수있다. 임신중발생하는대부분의 HTGP 의경우는가족성고중성지방혈증과관련되어있다 [20]. 임신중분비된에스트로젠에의한 lipoprotein lipase 활성도감소와 VLDL 합성증가는카일로마이크론과중성지방의증가를초래하는데이는임신후반기의태아의정상적성장및발달에필요하다. 일반적으로임신 3기의혈중중성지방수치는비임신기의 2-3배

3 - 대한내과학회지 : 제 93 권제 6 호통권제 685 호 까지증가하지만총혈중중성지방수치는 300 mg/dl를초과하지않고이는급성췌장염을유발하기에충분하지않은수준이다. 그러나가족성고중성지방혈증이동반된경우현저한중성지방의상승으로 HTGP 발생위험이있으며, 드물게임신전이상지질병력이없는경우에서도급성췌장염의발생보고가있다 [21]. 알코올이직접적으로 HTGP 를유발하는지는불분명하다. 7,915명의남성과여성을대상으로한알코올섭취량과혈액생화학지표와의관계를본연구에따르면거의음주하지않은군과하루 3-9회이상음주군을비교하였을때 227 mg/dl 이상의고중성지방혈증유병률이 8% 에서 20% 로증가하여알코올은혈중중성지방농도를용량의존적으로증가시킨다고보고하였으나 [22], 또다른연구에따르면알코올섭취에의한중성지방의상승은일시적이며췌장염의원인보다는부수현상 (epiphenomenon) 으로추정되어, 알코올과 HTGP 가직접적으로관련되어있기보다평소고지혈증이있던환자가음주와함께섭취한고지방식이등악화요인이동반될경우현저한고중성지방혈증이초래되고이는 HTGP를촉발할수있는것으로추정된다 [23]. 에스트로겐및선택적에스트로겐수용체조절제인호르몬보충제 tamoxifen은혈청중성지방수치를높여주의를요하는데타목시펜복용후유발된급성췌장염에대한보고들이있다 [17]. 그외혈청중성지방농도를증가시킬수있는약물들로클로미펜, 프로테아제억제제, 항레트로바이러스제제, 프로포폴, 올란자핀, 미르타자핀, 레티노이드, 티아지드이뇨제및베타차단제등이있으며이들약물복용후유발된급성췌장염의보고들이있다 [24-26]. 병인 HTGP의병인은아직도불분명하나 2가지병인이유력하게제시되고있다. 첫째, HTGP의유발원인으로중성지방의분해산물인독성 FFA가 HTGP 를촉발한다는가설로, 혈중 FFA는적정농도를넘어선고농도에서혈소판, 혈관내피및췌장선포세포 (acinar cell) 의손상을유발하여췌장허혈및산증이발생하고이는췌장내트립시노오젠을활성화시켜급성췌장염을촉발시킨다는가설이다. 둘째, 중성지방의분해로증가된카일로마이크론이혈액의점도를높이고이는모세혈관의폐색과허혈을유도하여급성췌장염을촉발시킨다는가설이다. 두가지가함께 HTGP 발생에기여할가능성이높다 [27,28]. 임상특징 HTGP 는모든급성췌장염중 1-14%, 임신중급성췌장염의 56% 를차지한다 [3,5,6]. HTGP 와다른원인의췌장염사이에는몇몇인구통계학적차이가있는데일례로 400건의급성췌장염에대한전향적연구에서 HTGP 환자는더젊고 (44세 vs. 52세 ), 남성에호발하며 (65% vs. 45%), 비만인경우 (57% vs. 34%), 당뇨병이동반된경우 (38% vs. 17%) 에흔히발생하였다 [29]. HTGP 의초기증상은심한상복부복통, 메스꺼움및구토등다른원인으로인한급성췌장염과유사하다. 메타분석을위하여선택된연구들간의 HTGP 정의나췌장염중증도정의등이표준화되지않아논란은있으나 HTGP에관한 34개연구를메타분석한보고에따르면, HTGP는다른췌장염과비교하여더중증의경과를보이는것으로추정된다 [9]. 고중성지방혈증과췌장염중증도의상관관계를보기위하여 400명의급성췌장염환자를대상으로한코호트연구에서고중성지방혈증의정도에따라정상적인중성지방수치의환자와비교할때지속적인장기기능부전을일으킬가능성이더높음을보고하였고 ( 정상중성지방 17%; 경도중성지방 30%; 중증도중성지방 39%; 고도, 최고도중성지방 48%; p trend < 0.001) [29], 1,539명의급성췌장염환자를대상으로중성지방의수치와췌장염과의관계를조사한다른연구에서도중증췌장염의발생빈도 ( 경도중성지방 4% vs. 중증도중성지방 8% vs. 고도, 최고도중성지방 12%; p trend < 0.001) 및지속적인장기부전, 다발성장기부전및지속적인전신염증반응증후군을가진환자의비율이고중성지방혈증의정도에따라증가하여 (p trend < 0.001), 혈중중성지방이급성췌장염의중증도및예후와관련가능성을제시하였다 [6]. 그러나 HTGP 의중증도는중성지방가수분해로인한지방독성뿐아니라췌장리파아제활성정도, 혈청에서 FFA 제거효율및췌장염자체에의한염증반응정도등여러요소에영향을받는것으로알려져혈중중성지방수치뿐아니라다양한요소들이중증도에기여할것으로추정된다 [30,31]. 진단 HTGP 의진단은다른병인의급성췌장염과동일하여 ; 1) 급성상복부통증, 2) 혈청아밀라아제나리파제가정상상한치의 3배이상상승, 3) 조영증강 CT 또는복부초음파검사에서급성췌장염의특징적영상소견존재의 3항목중 2가지이상을만족할때로정의한다 [1]. 급성췌장염및고중성지방

4 - 김홍자. 고중성지방혈증급성췌장염의최신지견 - 혈증의위험인자, 즉당뇨병, 과도한음주, 비만, 임신, 이전의췌장염, 고중성지방혈증의가족력이있는경우 HTGP 를의심해야한다. 고중성지방혈증이급성췌장염의근본적인병인으로간주되기위해서는혈청중성지방농도 > 1,000 mg/dl (11.2 mmol/l) 이며담석, 음주, 약물등의다른췌장염의원인요인이없는경우진단할수있다. 그러나 500 mg/dl 이상으로상승된중성지방수치는아밀라아제및리파제활성도측정에간섭을일으켜효소수치가실제보다낮게측정될수있어결과해석에주의를요한다. 이경우혈청아밀라아제시료를연속희석하면중성지방간섭을줄일수있다 [29,32]. 또한대부분의경우, 중성지방혈증은일시적이며금식할경우빠르게회복되어병인에따라 2-3일이내에거의정상으로회복되므로췌장염의원인으로고중성지방혈증이의심되는경우복통발생시부터 24시간이내에혈중중성지방을측정하는것이효과적이다. 치료법및치료전략 HTGP의초기치료는다른원인에의한췌장염치료와동일하게금식, 초기대량정맥수액공급, 통증조절, 적절한영양공급등이필수적이다. 이와더불어병인인중성지방제거치료가필요한데 HTGP 환자에서중성지방감소를위한주요치료법으로혈장교환술 (therapeutic plasma exchange, TPE), 인슐린, 헤파린등이제시되고있으나치료법에대한무작위대조군연구등적절한임상연구가부족하여현재까지공인된 HTGP 치료가이드라인은없다 [33,34]. TPE, apheresis/plasmapheresis 혈중중성지방을낮추고중성지방의분해독소산물인 FFA를제거하는것을목표로하는 TPE는고농도의중성지방을단기간에효과적으로제거하기위하여선택할수있다. 실제 TPE의효과는중성지방의제거뿐아니라급성췌장염의초기에방출되는전신염증매개체인 interlukin-1과 tumor necrosis factor-α 의제거에도기여한다는보고등을근거로중성지방혈증 2,000 mg/dl이면서 2012년개정된아틀란타분류에따른중증췌장염에해당할경우 TPE를 1차치료중하나로권하고있다 [35-37]. 그러나 HTGP 환자에서혈장교환의유용성을뒷받침하는증거는대부분관찰연구나증례보고를근거로하고있고무작위시험은부족한실정이다 [38-42]. TPE는고가의치료이며중심정맥관의삽입에따른감염, 아나필락시스, 항응고 제사용에따른출혈의위험성등을내포하고있을뿐아니라, 94명의 HTGP 환자를대상으로 TPE를시행한 60명과시행하지않은 34명을비교한연구에서 TPE 여부에따른합병증발생률, 사망률차이는발견되지않았다는 Chen 등의보고및유사한결과를보인몇몇연구결과를감안해볼때 [43,44], 향후 TPE가표준치료로인정받기위해서는무작위임상시험이필요하며이를통하여적절한적응증, 방법등에대한정립이필요하다. 인슐린인슐린은카일로마이크론과 VLDL의대사를촉진하여글리세롤과지방산으로분해시키는역할을하는 lipoprotein lipase를활성화시킴으로써혈중중성지방을감소시키며, 또한지방세포에서중성지방을분해하여혈중으로 FFA를방출시키는주요효소인지방세포의리파아제를억제하여혈중중성지방을감소시킨다 [45,46]. HTGP 가조절되지않는당뇨병환자에게동반되는경우가흔하고이경우인슐린투여는중성지방및혈당을동시에저하시킬수있어효과적이다. 인슐린의중성지방감소효과는주로증례보고를통하여증명되어있으며 3.5-4일에걸쳐중성지방수치를 500 mg/dl 미만으로낮추는데, 정맥인슐린주입이 HTGP 에서피하인슐린보다적정농도조절에더효과적인것으로보고되고있다 [47,48]. 일반적으로 units/kg/hour의속도로규칙적인인슐린을정맥주사하여 mg/dl 혈당치도달을목표로하며저혈당예방을위하여별도의 5% 포도당수액주입이필요하다. 그러나현재까지인슐린의중성지방감소효과는대부분작은규모의증례보고수준이므로일차치료로확립되기위해서는잘계획된무작위연구가필요하다. 헤파린 HTGP 치료로항응고제인헤파린사용은논란의여지가있다. 헤파린은이론적으로혈관내피에존재하는 lipoprotein lipase 의방출을자극하여중성지방을 FFA로분해함으로써중성지방의혈중농도를감소시킨다 [49]. 그러나혈중 lipoprotein lipase의증가는간에서 lipoprotein lipase의파괴를증가시키고이는오히려혈중 lipoprotein lipase의감소와이로인한혈중카일로마이크론의증가를촉발한다. 이처럼사용초기단기간에만관찰되는일시적경향의중성지방감소효과와 HTGP의병인으로주목되는 FFA의역설적증가, 헤파린사용에따른출혈의위험성등으로 HTGP 치료로헤파

5 - The Korean Journal of Medicine: Vol. 93, No. 6, 린단독사용은다소유보적이다. 그러나최근중증의 HTGP 환자에서치료효과를강화하고헤파린의지연부작용은최소화하는방법으로, 인슐린과함께치료초기단기간의헤파린의병용사용이시도되어좋은효과를보고하고있다 [50,51]. 향후 HTGP 에서의헤파린사용에대해서는무작위대조임상연구가필요하다. 치료전략혈청중성지방농도 > 1,000 mg/dl 이상의 HTGP 환자로전신염증또는장기기능장애악화또는다발성장기부전의징후가있는환자의경우조기 TPE는일차치료로권고되며중성지방수치가 < 500 mg/dl 이하가될때까지시행하는것이도움이된다. 심각한중증도가아닌경우정맥내인슐린치료가권고되나인슐린과단기간의헤파린병용투여도한방법이다. 모든과정은지속적인혈중중성지방의모니터링이필요하며중성지방수치가 500 mg/dl일때중단하는것이안전하다. 고중성지방혈증의장기관리데이터베이스를이용한연구에따르면평균혈중중성지방을 500 mg/dl 미만으로낮추지못할경우췌장염발생가능성이유의하게높았고 (hazard ratio 1.79, 95% CI ) [52], 후속연구에서혈중중성지방이 500 mg/dl 이상인환자에서중성지방수치를 200 mg/dl 미만으로낮출경우그렇지못한경우보다급성췌장염의빈도를 100인년 (person-year) 당 1.1회에서 0.4회로낮춤을보고하였다 (adjusted incidence rate ratio 0.45; 95% CI, ) [53]. 이러한연구결과들을바탕으로 HTGP의초기치료후일단중성지방수치가 500 mg/dl 이하로떨어지고나면 HTGP 합병증예방및재발예방을위하여혈청중성지방수치를 200 mg/dl 이하로유지하는치료를시작하는것이권장되며약물치료와식이지방제한, 체중조절, 유산소운동, 혈중중성지방증가약물회피, 금주, 당뇨병환자의엄격한혈당조절등비약물적중재가포함된다. 약물적치료로지질강하제중 fibrates가가장효과적인 1차치료제로추천된다 [54]. Fibrates, statins, niacin과 omega-3 지방산은중성지방수치를각각 36.3%, 10-18%, 20%, % 낮춘다 [55,56]. Fibrates의약부작용으로근육병증, 담석증, 일시적크레아틴의상승등이있으나심각한부작용은드물며 statin과병용하는경우횡문근융해증의위험도가증가하므로주의를요한다. Omega-3 지방산은비교적안전하고효과적인약제로중 간사슬중성지방과함께 omega-3 지방산을병용치료한임상연구에서 1주사용후중성지방수치의 67% 가감소함을보고하였다 [57]. 고농도 niacin 치료도비교적효과적인중성지방감소를보이나소양감, 위장관불편감, 고혈당, 간효소수치상승과같은잦은약제부작용으로사용이제한된다. 결 일차성 ( 유전성 ) 고중성지방혈증또는조절되지않은당뇨병, 과도한음주, 임신등에의하여유발된이차성고중성지방혈증은 HTGP 를초래할수있다. 비록 HTGP의증상은다른원인에의한췌장염과유사하나더중증의임상경과를보이므로정확한진단및이에따른적절한치료가예후향상에필수적이다. 급성기치료법으로금식, 수액, 통증조절등의통상적인췌장염치료와함께혈중중성지방제거치료로 TPE, 인슐린, 헤파린등이적절하게사용될수있으며재발예방을위하여지속적인지질강하제의복용과생활습관개선을위한노력이필요하다. 아직까지 HTGP 의치료에관한만족스러운무작위대조군임상시험이부족하며이로인하여치료에관한인정받는가이드라인이없어향후관련연구가시급하다. 론 중심단어 : 고중성지방혈증 ; 급성췌장염 REFERENCES 1. Lankisch PG, Apte M, Banks PA. Acute pancreatitis. Lancet 2015;386: Xiao AY, Tan ML, Wu LM, et al. Global incidence and mortality of pancreatic diseases: a systematic review, meta-analysis, and meta-regression of population-based cohort studies. Lancet Gastroenterol Hepatol 2016;1: Zhu Y, Pan X, Zeng H, et al. A study on the etiology, severity, and mortality of 3260 patients with acute pancreatitis according to the revised Atlanta classification in Jiangxi, China over an 8-year period. Pancreas 2017;46: Fortson MR, Freedman SN, Webster PD 3rd. Clinical assessment of hyperlipidemic pancreatitis. Am J Gastroenterol 1995;90: Koutroumpakis E, Slivka A, Furlan A, et al. Management and outcomes of acute pancreatitis patients over the last decade: a US tertiary-center experience. Pancreatology 2017;17:

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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