원저 Lab Med Online Vol. 2, No. 1: 15-19, January 임상화학 케톤뇨의임상적유용성의평가 Evaluation of the Clinical Significan

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1 원저 Lab Med Online Vol. 2, No. 1: 15-19, January 2012 임상화학 케톤뇨의임상적유용성의평가 Evaluation of the Clinical Significance of Ketonuria 정혜원 1 박일규 2 Hae-Won Jung, M.D. 1, Ile-Kyu Park, M.D. 2 한양대학교병원진단검사의학과 1, 한양대학교구리병원진단검사의학과 2 Department of Laboratory Medicine 1, Hanyang University Hospital, Seoul; Department of Laboratory Medicine 2, Hanyang University Kuri Hospital, Guri, Korea Background: Urine ketone test is commonly used to screen for diabetic ketoacidosis (DKA). Ketonuria also develops in patients with disease conditions other than DKA. However, the prevalence of DKA in patients with ketonuria is not known. We investigated the prevalence of ketonuria and characteristics of patients with ketonuria and estimated the prevalence of DKA among them to study the clinical significance of ketonuria as an indicator of DKA. Methods: We studied 1,314 adult and 1,027 pediatric patients who underwent urinalysis. The prevalence of ketonuria in the different groups of patients, classified according to the types of their visits to the institution, was investigated, and the relationships between ketonuria and albuminuria, glycosuria, and bilirubinuria were evaluated. Results: The overall prevalence of ketonuria was 9.1%. The prevalences of ketonuria in adult and pediatric patients were 4.3% and 15.2%, respectively. The prevalences of ketonuria were the highest in the adult (9.7%) and pediatric (28%) patients in the group that had visited the emergency department. Among patients with ketonuria, 7% adult and 3.8% pediatric patients showed glycosuria. Conclusions: This study showed that the prevalence of DKA in patients with ketonuria, defined as the simultaneous presence of ketone bodies and glucose in urine, was only 7%. Therefore, we concluded that ketonuria might be clinically significant as an indicator of acute or severe disease status rather than of DKA. Key Words: Ketonuria, Urine ketone, Diabetic ketoacidosis 서론 케톤체는조직세포의주에너지원인포도당의사용이불가능할 때지방산으로부터생성되는대사산물이다. 간에서생산되는케 톤체는포도당결핍시지방산을직접에너지원으로사용할수없 는뇌에서대체에너지원으로사용된다 [1, 2]. 케톤체는혈중에서 Corresponding author: Ile-Kyu Park, M.D. Department of Laboratory Medicine, Hanyang University Kuri Hospital, Gyomun-dong, Guri , Korea Tel: , Fax: , ikpark@hanyang.ac.kr Received: March 28, 2011 Revision received: September 19, 2011 Accepted: September 19, 2011 This article is available from , Laboratory Medicine Online This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 정상적으로소량존재하며요에서는발견되지않지만, 케톤체의생산과제거가균형을이루지못하면케톤혈증이초래되고소변에서도발견된다. 현재요케톤검사는주로당뇨병케톤산증 (diabetic ketoacidosis; DKA) 환자의조기선별을위한검사로쓰인다 [3, 4]. 그러나요케톤은당뇨병케톤산증이외에알코올성케톤산증 [5, 6], 살리실산중독 [7], 급성췌장염 [8], 글리코겐축적증 [9], 소아에서구토와설사를동반하는열성질환 [10] 이나간 [11] 또는신장질환 [12] 등여러질환에서양성이며임신 [13] 이나심한운동 [14], 저탄수화물식이 [15], 금식 [16-18], 마취후상태 [19] 등다양한생리적상태에서도양성을보이는것으로보고되고있다. 이처럼케톤뇨가발견되는다양한질병이나임상상태가보고되고있어전체케톤뇨환자중당뇨병케톤산증이차지하는비율은낮을것으로예상되나실제조사된바는없다. 요케톤검사에관한기존의연구들은단순당뇨병과당뇨병케톤산증을구별할때의유용성과 [10, 20-23] 당뇨병케톤산증이외의요케톤양성을보인질환에관한단발적인증례보고들이대부분이었다 [7-9, 11, 15, 17]. eissn

2 본연구에서저자들은 3차병원에서실시한요검사중요케톤검사의재원형태별양성률을조사하여케톤뇨를보이는환자의질환특성을파악하여보았다. 또한, 함께시행한요검사항목과상관성을조사하여케톤양성을보이는환자중요당양성을기준으로당뇨병케톤산증이의심되는환자가전체재원환자중차지하는비율을파악해보았고이를통해요케톤검사의임상적의미를평가하고자하였다. 대상및방법 2010년 10월중 6일간본원을방문한성인환자와 9월부터 11월까지방문한소아환자중요시험지봉검사를시행한모든환자를대상으로하였다. 성인환자는총 1,314 명이었고이중남자가 544명, 여자가 770명이었으며나이는 51.8±15.8 세였다. 총소아환자는 1,027명으로그중남자가 550명, 여자가 477명이었으며나이는 6.5 ±4.4세였다. 요화학검사는 Multistix 10 SG 요시험지봉 (Siemens, Germany) 을이용해시행하였다. 요시험지봉검사는 Aution Max Ax-4030 (Arkray, Japan) 을이용하였고검사시약은개봉후 1일내에모두소모되었다. 모든요검사는동일한장소에서시행하였다. 재원형태에따른케톤뇨증의빈도를보기위해성인은응급실, 건강검진, 외래, 입원의 4군의재원형태로소아는응급실, 외래, 입원의 3군의재원형태로분류하였다. 요케톤검사와요단백, 요당, 그리고요빌리루빈검사와의관계를비교하였으며. 재원형태별요케톤양성률비교및요케톤양성과다른요검사와의상관성비교를위해카이제곱검정및다중비교를시행했다. 3군이상의카이제곱검정에서는자유도를군수-1로증가시켜검정했으며이어지는다중비교에서도같은자유도를사용하였다. 결과 본원에내원한총 2,341명의성인또는소아환자중 213명 (9.1%) 이요케톤양성을보였다. 성인에서는총 1,314 명의환자중 57명 (4.3%) 이요케톤양성소견을보였으며건강검진대상자를제외한환자 1,185 명중에서는 50명 (4.2%) 이요케톤양성을보였다. 건강검진대상자 129명중 7명 (5.4%), 응급실환자 144명중 14명 (9.7%), 외래환자 858명중 27명 (3.1%), 입원환자 183명중 9명 (4.9%) 이요케톤양성소견을보여응급실환자에서요케톤양성률이가장높았다 (Table 1). 성인환자의네군전체카이제곱검정결과 P값은 <0.01로통계적으로유의하였고재원형태간다중비교에서 P값은응급실과외래, 응급실과입원, 응급실과건강검진간비교에서각각 <0.01, <0.05, <0.01로응급실환자군은모든재원형태와의비교에서통계적으로유의하게높은요케톤양성률을보였다. 반면외래와건강검진, 외래와입원, 입원과건강검진간비교에서는 P값은각각 0.10, 0.38, 0.80으로통계적으로유의한차이를보이지않았다. 소아환자에게서의요케톤검사결과총 1,027명의환자중 156명 (15.2%) 이양성소견을보여성인환자군 (4.4%) 에서보다높은케톤뇨의빈도를보였다. 소아환자들은응급실환자 189명중 53명 (28%), 외래환자 372명중 23명 (6.2%), 입원환자 466명중 80명 (17.2%) 이케톤뇨소견을보여성인에서와같이응급실환자군에서가장높은양성률을보였다 (Table 2). 소아환자의세군전체카이제곱검정결과 P값은 <0.01로통계적으로유의하였고재원형태간다중비교에서 P값은모두 <0.01로각각의재원형태는서로유의한요케톤양성률의차이를보였다. 총 57명의성인요케톤양성환자들중요단백, 요빌리루빈, 요당양성인환자들은각각 8명 (14.0%), 17명 (29.8%), 4명 (7.0%) 이었고이중요빌리루빈만이요케톤음성군보다양성군에서통계적으로유의하게높은양성률을보였다 (Table 3). 반면 156명의요케톤양성소아환자들중요단백, 요빌리루빈, 요당양성환자는각각 9명 (5.8%), 15명 (10.6%), 6명 (3.8%) 이었고요당과요빌리루빈이요케톤음성군보다요케톤양성군에서통계적으로유의하게높은양성률을보였다 (Table 4). 고찰 Table 1. Ketonuria in adult patients classified according to the types of their visits to the hospital Urine ketone test ED (%) OP (%) IP (%) Total excluding C/U (%) C/U (Adult) (%) Total including C/U (%) Positive 14 (9.7) 27 (3.1) 9 (4.9) 50 (4.2) 7 (5.4) 57 (4.3) Negative 130 (90.3) 831 (96.9) 174 (95.1) 1135 (95.8) 122 (94.6) 1257 (95.7) Total 144 (100) 858 (100) 183 (100) 1185 (100) 129 (100) 1314 (100) Chi-square test between the 4 groups (P <0.01). Abbreviations: ED, emergency department; OP, outpatient; IP, inpatient; C/U, check-up. 성인에서재원상태별로환자들의요케톤검사결과를살펴본 Table 2. Ketonuria in pediatric patients classified according to the types of their visit to the hospital Urine ketone test ED (%) OP (%) IP (%) Total (%) Positive 53 (28) 23 (6.2) 80 (17.2) 156 (15.2) Negative 136 (72) 349 (93.8) 386 (82.8) 871 (84.8) Total 189 (100) 372 (100) 466 (100) 1,027 (100) Chi-square test between the 3 groups (P <0.01). Abbreviations: ED, emergency department; OP, outpatient; IP, inpatient. 16

3 Table 3. Association between ketonuria and albuminuria, glycosuria, and bilirubinuria in 1,314 adult patients Urine ketone test (%) Positive Negative P value of chi square test Albumin (N=1,314) Positive 8 (14.0) 109 (8.7) Negative 49 (86.0) 1,148 (91.3) Glucose (N=1,314) Positive 4 (7.0) 77 (6.1) Negative 53 (93.0) 1,180 (93.9) Bilirubin (N=1,314) Positive 17 (29.8) 37 (2.9) <0.01 Negative 40 (70.2) 1,220 (97.1) Total 57 (100) 1,257 (100) Table 4. Association between ketonuria and albuminuria, glycosuria, and bilirubinuria in 1,027 pediatric patients Urine ketone test (%) Positive Negative P value of chi square test Albumin (N=1,027) Positive 9 (5.8) 32 (3.7) 0.22 Negative 147 (94.2) 839 (96.3) Glucose (N=1,027) Positive 6 (3.8) 9 (1.0) <0.01 Negative 150 (96.2) 862 (99.0) Bilirubin (N=854) Positive 15 (10.6) 14 (2.0) <0.01 Negative 126 (89.4) 699 (98.0) 결과응급실환자의요케톤양성률은 9.7% 로다른재원형태에비하여월등히높았다. 본연구에서응급실환자를급성병적상태의환자로, 그리고입원환자를중증질환에해당하는환자로추측및분류하였는데이는재원형태의특성상응급실환자들은급성병적증상을호소하고입원환자들은증상이가볍고통원치료가가능한외래환자들보다중증질환자에해당한다고생각되기때문이다. 따라서저자는응급실환자의요케톤양성률이월등히높은것을미루어요케톤검사결과가환자의급성병적상태에서의대사변화와연관이있다고추측하였다. 또한, 검사를위한잠시의금식으로도요케톤이검출된다는보고가있어 [23] 질병에의한영향을비교적적게받으며검사를위해 8-12시간의금식이요구되는건강검진환자의결과를관찰한결과 5.4% 에서케톤뇨가관찰되어기저질환이없는건강인에서도금식에의해케톤뇨가나타남을알수있었다. 다른요화학검사결과와케톤뇨검사를비교한결과, 요케톤양성성인환자에서요빌리루빈양성소견을보인경우가 29.8% (P <0.01) 로요케톤은폐쇄성간담도질환등직접빌리루빈이증가하는환자상태와자주동반된것으로추측되었다. 당뇨병케톤산증은혈당이 250 mg/dl 이상이며혈중산도가 7.3 이하이고케톤혈증이동반될때로정의할수있다. 그러나저자는소변에서케톤과당이동시에발견되는상태를당뇨병케톤산증의심소견으로판단하였다. 요당은혈중산도, 혈당, 혈중케톤처럼당뇨병케톤산증을진단하는데필수적인검사소견이아니며 [23] 수시간전의혈당을반영하며혈당과의상관관계가뚜렷하지않고혈당이약 180 mg/dl 이상이되지않으면소변에서검출되지않는다는제한점이있다 [24, 25]. 그러나, 요당은당뇨병이나그합병증을진단하고추적및관찰하는데널리쓰이는지표중하나이며요케톤과함께발견되면당뇨병케톤산증을의심할수있는데 [4, 26, 27] 그이유는 DKA 환자는심한고혈당을동반하므로대부분요당이검출되며 [28] DKA가아닌케톤증에서는요당이케톤뇨와동시에발견되는경우는매우드물기때문이다 [29]. 성인에서케톤 양성환자중요당양성을보인 DKA 의심환자는 4명 (7%) 뿐이었고케톤양성환자군과케톤음성환자군간의요당양성률이유의한차이를보이지않아성인에서의케톤뇨소견은당뇨병케톤산증보다는다른원인에의한것이더많을것으로예상하였다. 소아환자의요케톤양성률은 15.2% 로성인환자에비해월등히높은것으로조사되었다. 이미알려진바와같이간에서의글리코겐저장량이성인보다낮고성인보다상대적으로큰중추신경계를유지하므로포도당결핍시에너지원을뇌에공급하기위해지방으로부터의케톤생산이성인보다높아생리적으로케톤증에더욱취약한것이그이유중하나로생각된다 [1]. 소아환자군에서도재원상태별요케톤양성률의차이는뚜렷했다. 소아환자에서는응급실환자군에서양성률이가장높았고입원환자의양성률은외래환자보다현저히높았다. 따라서소아에서는급성상태뿐만아니라중증병적상태로인한대사변화에의한케톤뇨도흔한것으로생각되었다. 또한, 요케톤양성소아환자에서요당양성률은 3.8% 로성인의 7% 와마찬가지로낮아전체요케톤양성소견은 DKA보다는다른원인에의함을파악할수있었다. 본연구는환자의질환의급성, 중증도, 금식정도를구체적으로조사하지않고재원형태에따라추측하였다. 또한, 당뇨병케톤산증의진단기준인혈액산도검사, 혈중케톤과혈당검사없이요케톤과요당만으로당뇨병케톤산증여부를판단하고그빈도를추측한제한점이있다. 또한제한적으로요케톤과요당이동시에양성인환자들의당뇨병케톤산증여부만조사하였다. 그러나내원한전체환자를대상으로요케톤양성률을조사하는방법을선택함으로써기존의연구와는다른다음과같은결과를얻었다. 첫째, 내원한환자의전체요케톤양성률은약 9% 이었다. 둘째, 요케톤양성환자중당뇨병케톤산증으로추측되는환자의빈도는성인과소아모두에서매우낮았다. 셋째, 성인에서요케톤은질환의급성상태와연관성이있을것으로추측되었으며소아에서는질환의급성상태와중증상태모두와연관이있을것으로추측되었다. 결론적으로전체환자에서요케톤은당뇨병케톤산증보다는다른질환과의연관성이더많을것으로예상되었다. 그러므로요 17

4 케톤검사를 DKA의지표로만의미를두지않고급성또는중증질환을가진환자를선별하는지표로서이용한다면또다른임상적유용성을찾을수도있을것으로생각되었다. 요약 배경 : 요케톤검사는주로당뇨병케톤산증의선별검사로쓰인다. 케톤뇨는당뇨병케톤산증이외의다양한질환에서도양성을보이는것으로보고되고있지만케톤뇨를보이는환자중당뇨병케톤산증이차지하는비율은아직알려진바없다. 이에저자들은요케톤검사의양성비율과양성을보이는환자들의특징을알아보고또한당뇨병케톤산증이차지하는비율을추측하여요케톤검사의임상적유용성을평가하고자하였다. 방법 : 본원을방문한성인환자 1,314 명과소아환자 1,027명중요화학검사를시행한모든환자들을대상으로연구를시행하였다. 요케톤양성률을성인과소아에서각각의응급실, 외래, 입원등의재원형태에따라분류하였고요케톤검사결과와요단백, 요당, 그리고빌리루빈검사결과와의관계를서로비교하였다. 결과 : 케톤뇨의전체양성률은 9.1% 이었고성인과소아의요케톤양성률은각각 4.3%, 15.2% 였다. 응급실에서의성인과소아의요케톤양성률은각각 9.7%, 28% 로재원형태중가장높은양성률을보였다. 전체케톤뇨환자중성인의 7%, 소아의 3.8% 에서요당양성을보였다. 결론 : 케톤뇨환자에서재원형태와요당의존재를근거로추측한당뇨병케톤산증의유병률은비교적낮게관찰되었고케톤뇨는당뇨병케톤산증보다는급성질환, 중증질환등다른질환과의연관성이더클것을시사하였다. 그러므로요케톤검사를당뇨병케톤산증의지표로만평가하지말고급성중증질환을가진환자를선별하는지표로서이용한다면충분한임상적유용성이있을것으로생각되었다. 참고문헌 1. Laffel L. Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes. Diabetes Metab Res Rev 1999;15: McGarry JD and Foster DW. Regulation of hepatic fatty acid oxidation and ketone body production. Annu Rev Biochem 1980;49: Hendey GW, Schwab T, Soliz T. Urine ketone dip test as a screen for ketonemia in diabetic ketoacidosis and ketosis in the emergency department. Ann Emerg Med 1997;29: Schwab TM, Hendey GW, Soliz TC. Screening for ketonemia in patients with diabetes. Ann Emerg Med 1999;34: Platia EV and Hsu TH. Hypoglycemic coma with ketoacidosis in nondiabetic alcoholics. West J Med 1979;131: Ngatchu T, Sangwaiya A, Dabiri A, Dhar A, McNeil I, Arnold JD. Alcoholic ketoacidosis with multiple complications: a case report. Emerg Med J 2007;24: Brenner BE and Simon RR. Management of salicylate intoxication. Drugs 1982;24: Kabadi UM. Pancreatic ketoacidosis: ketonemia associated with acute pancreatitis. Postgrad Med J 1995;71: Bock DE, Rupar CA, Prasad C. Asymptomatic critical hypoglycemia: a dangerous presentation of glycogen storage disease type Ib in infancy. Acta Paediatr 2011;100:e Rewers M, Pihoker C, Donaghue K, Hanas R, Swift P, Klingensmith GJ. Assessment and monitoring of glycemic control in children and adolescents with diabetes. Pediatric Diabetes 2007;8: Weinstein DA, Correia CE, Saunders AC, Wolfsdorf JI. Hepatic glycogen synthase deficiency: an infrequently recognized cause of ketotic hypoglycemia. Mol Genet Metab 2006;87: Mangione F, Calcaterra V, Esposito C, Dal Canton A. Renal blood flow redistribution during acute kidney injury. Am J Kidney Dis 2010;56: Chez RA and Curcio FD 3rd. Ketonuria in normal pregnancy. Obstet Gynecol 1987;69: Chalmers RJ, Sulaiman WR, Johnson RH. The metabolic response to exercise in chronic alcoholics. Q J Exp Physiol Cogn Med Sci 1977;62: Shah P and Isley WL. Ketoacidosis during a low-carbohydrate diet. N Engl J Med 2006;354: Féry F and Balasse EO. Ketone body production and disposal in diabetic ketosis. A comparison with fasting ketosis. Diabetes 1985;34: Patel A, Felstead D, Doraiswami M, Stocks GM, Waheed U. Acute starvation in pregnancy: a cause of severe metabolic acidosis. Int J Obstet Anesth 2011;20: Reichard GA Jr, Owen OE, Haff AC, Paul P, Bortz WM. Ketone-body production and oxidation in fasting obese humans. J Clin Invest 1974; 53: Minnitt RJ. A successful treatment for toxic symptoms resulting from ether anaesthesia, based on a biochemical investigation. Proc R Soc Med 1933;26: Lee JI, Sohn TS, Chang SA, Lee JM, Cha BY, Son HY, et al. Clinical 18

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Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee University College of Medicine & Hospital E mail : ycell2@yahoo.co.kr Abstract