대한내과학회지 : 제 73 권제 6 호 2007 체내철저장상태와비알코올지방간발생과의연관성 성균관대학교의과대학강북삼성병원내과학교실 황상준 조용균 오세용 최효선 박정식 김신연박정호 김홍주 박동일 손정일 전우규 김병익 =Abstract= Relationship of body iron stores with the development of nonalcoholic fatty liver disease. Sang Jun Hwang, M.D., Yong Kyun Cho, M.D., Se Yong Oh, M.D., Hyo Sun Choi, M.D., Jeong Sik Park, M.D., Shin Yun Kim, M.D., Jung Ho Park, M.D., Hong Joo Kim, M.D., Dong Il Park, M.D., Chong Il Sohn, M.D., Woo Kyu Jeon, M.D. and Byung Ik Kim, M.D. Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea Background : Although numerous reports have shown the influence of the iron overload state on the development of nonalcoholic fatty liver disease (NAFLD), there have been few reports on the prevalence of NAFLD according to the body iron stores. The aim of the present study was to determine the relationship of body iron stores with the development of NAFLD in apparently healthy women. Methods : The present cross-sectional study was performed with data obtained from 5,249 women (mean age: 40.6±8.9 years), that received an annual health check-up. All components of metabolic syndrome criteria, anthropometric parameters, fasting insulin levels, level of C-reactive protein and serum iron tests were measured in each subject. Results : The prevalence of NAFLD was significantly different according to body iron status (normal iron store/iron store depletion/iron deficient erythropoiesis/iron deficiency anemia: 10.6%/4.1%/6.5%/11.2%, p<0.001). Multivariate analysis revealed that age (odds ratio [OR]=1.284; 95% confidence interval [CI]: 1.1161.507) per 10 years), being overweight (OR=1.952; 95% CI: 1.3952.732), diabetes mellitus (OR=1.694; 95% CI: 1.198-2.397), hypertriglyceridemia (OR=2.434; 95% CI: 1.737-3.409), abdominal obesity (OR=3.559; 95% CI: 2.538-4.992), insulin resistance (OR=2.665; 95% CI: 1.979-3.587), anemia (OR=2.015; 95% CI: 1.150-3.532) and stored iron depletion (OR=0.580; 95% CI: 0.405-0.830) were profoundly associated with the development of NAFLD. Conclusion : The present study reveals a possible correlation between the development of NAFLD and body iron stores, and stored iron depletion and anemia seem to be key factors for this correlation. (Korean J Med 73:587-595, 2007) Key Words : Nonalcoholic fatty liver disease, Iron status, Iron deficiency, Anemia Received : 2007. 1. 7 Accepted : 2007. 4. 30 Correspondence to : Yong Kyun Cho, M.D., Division of Gastroenterology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 108 Pyung-dong, Jongro-gu, Seoul 110-746, Korea E-mail : choyk2004.cho@samsung.com *This work was supported by the Hyoseok Research Fund. - 587 -
-The Korean Journal of Medicine : Vol. 73, No. 6, 2007 - 서론체내철과잉상태는조직내과다한양의철침착을초래하여조직손상과이로인한장기부전을야기할수있다. 간실질의철침착으로인한간손상에대해서는유전질환인혈색소침착증 (hemochromatosis) 에서잘밝혀져있으며, 바이러스성간질환과알코올성간질환에서도간내철의과부하가간섬유화및병의진행에기여한다고알려져있다 1-3). 비알코올지방간질환 (nonalcoholic fatty liver disease, NAFLD) 에서도체내저장철의지표인혈청페리틴농도가증가되어있는경우가많으며 4, 5), 혈색소침착증과관련된유전자 (HFE) 의돌연변이가비교적흔하게관찰되어 6, 7), 간내철의침착이비알코올지방간질환의발생과진행에관여될가능성을확인하기위한여러연구들이있었으나, 아직까지확실한결론에도달하지못하였다 5-9). 최근정기적인수혈및정맥절개술 (phlebotomy) 을통해인슐린저항성및제 2형당뇨병의발생을감소시킬수있다는연구결과들이보고되었다 10, 11). 또한비알코올간질환환자에서정맥절개술을통해생화학지표의호전및인슐린저항성의감소가관찰되었으며 12), 조직학적인호전을보였다는연구결과도보고되었다 13). 이러한결과들은체내철상태가비알코올지방간의병인인인슐린저항성과관계될수있으며, 철과잉상태가비알코올지방간의위험인자일가능성이있듯이철결핍상태가방어인자로작용할가능성이있음을시사한다. 이번연구에서는외견상건강한건강검진수진자들중철결핍의빈도가상대적으로높은여성수진자들을대상으로철대사와관련된생화학지표들을측정하여체내철저장상태를구분하고, 이에따라인슐린저항성및비알코올지방간질환의유병율를비교함으로써체내철저장상태및인슐린저항성이비알코성지방간의발생에미치는영향을알아보고자하였다. 대상및방법 1. 연구대상 2006년 1월부터 8월까지일개대학병원종합검진센터에내원하여건강검진을받은 27,948명의외견상건강한성인여성수진자들을대상으로하였다. 이중 10,429명은복부초음파검사를시행받지않아제외하였다. 추가적으로설문지와문진을통해하루 20 g 이상의음주력및최 근 3주이상의철분제제복용이나약인성간염의과거력이있는경우와면역혈청검사상 B형간염표재성항원 (HBs Ag), C형간염항체 (anti-hcv) 양성또는류마티스유사인자 (rheumatoid factor) 가양성으로판정된 7,623명도제외하였다. 마지막으로철대사와관련된생화학적검사들 ( 혈청페리틴, 혈청청, 트랜스페린포화도 ) 을받지않았거나, 체내철상태의범주에분류되지않는경우및대사증후군의판정에필요한자료가불충분한 4,647명을제외시켜, 최종적으로 5,249명의수진자들을연구에포함시켰다. 2. 연구방법 1) 간지방증 (hepatic steatosis) 의평가건강검진수진자를대상으로한연구의특성상비침습영상검사인복부초음파 (ASPEN; Acuson, Pennsylvania, USA) 를시행하여간지방증을평가하였다. 3.5 MHz의탐촉자로 1인의방사선과전문의에의하여시행되었으며간지방증의진단은우측신장의피질에비교한간반향의증가및혈관의불명료성 (vascular blurring), 심부반향의감쇠 (deep-echo attenuation) 등의소견들을고려하였다 14). 2) 신체계측신장체중자동측정기 (FA-94H, Fanics, Korea) 를이용하여탈의후검진용가운을입은상태에서신발을벗고신장은 0.1 cm까지체중은 0.1 kg까지측정하였으며체중을신장의제곱으로나누어체질량지수를계산하였다. 허리둘레는직립자세에서늑골최하단부위와장골능최상단부위의중간지점에줄자를대고가볍게숨을내쉰상태에서측정하였다. 혈압은최소 10분이상안정을취하게한후측정하였으며, 의자에앉은상태에서수은주혈압계를이용하여두차례측정하여평균값을구하였다. 3) 혈액검사아침식전공복상태에서혈액을채취하여공복혈당, 혈중인슐린및알부민, 총빌리루빈, AST, ALT, γ-gt 등간기능검사, 그리고지질검사등을시행하였다. 8시간금식후혈액을채취하여혈당은 hexokinase method 로측정하였고, 인슐린은 BioSource INS-IRMA kit (BioSource, Belgium) 를사용하여방사면역계수측정법 (immunoradiometric assay) 으로측정하였고, 변이계수 (coefficient of variation) 는 intra-assay 1.6~2.2%, inter- - 588 -
-Sang Jun Hwang, et al : Body iron stores in NAFLD - assay 9.1-6.5% 이었다. 12시간금식후공복혈액을채혈하여총콜레스테롤과중성지방은 enzymatic calorimetric test로측정하였고, 고밀도지단백콜레스케롤은 homogenous enzymatic calorimetric test로측정하였다. 인슐린저항성정도를알아보기위한지표로서 HOMA-IR (homeostasis model assessment insulin resistance) 를다음계산식으로구하였다. HOMA-IR: [fasting insulin (μiu/ml) X fasting glucose (mmol/l)] / 22.5 인슐린저항성의존재는 HOMA-IR 수치를삼분위수 (tertile) 로나누어, 최상위삼분위수에해당되는경우로하였다. 4) 대사증후군의정의대사증후군의진단은 2005년 International Diabetes Federation 에서정한기준을사용하였고 15), 복부비만항목은인종간차이를고려하여아시아-태평양지역의허리둘레기준을이용하였다 16). 다음의다섯가지항목중복부비만은반드시포함하면서나머지네가지항목중두가지이상을만족하는경우를대사증후군으로정의하였다. (1) 복부비만 : 허리둘레 90 cm ( 남자 ), 80 cm ( 여자 ) (2) 혈압 130/85 mmhg 또는기존에진단된고혈압으로치료를받고있는경우 (3) 공복혈당 100 mg/dl 또는기존에당뇨병으로진단된경우 (4) 중성지방 150 mg/dl 또는고중성지방혈증으로치료를받고있는경우 (5) 고밀도지단백콜레스테롤 <40 mg/dl( 남자 ), <50 mg /dl( 여자 ) 5) 체내철저장상태 (status of body iron stores) 체내철저장상태를구분하기위하여철대사와관련된생화학지표들로서혈청페리틴, 혈청철, 트랜스페린포화도를측정하였다. 철결핍 (iron deficiency) 의단계는크게 3단계로나누어, 제1단계는저장철의고갈 (iron store depletion) 상태로혈청페리틴의감소되어있으나혈청철, 트랜스페린포화도및혈색소치는정상인경우로, 제2단계는철결핍성적혈구조혈이상 (iron-deficient erythropoiesis) 상태로혈청페리틴및혈청철, 트랜스페린포화도는감소되어있으나혈색소치는정상인경우로, 제3단계는철결핍성빈혈 (iron deficiency anemia) 상태로 혈청페리틴, 혈청철, 트랜스페린포화도, 혈색소치모두감소되어있는경우로정의하였다 17). 철과잉상태는혈청페리틴이증가되어있으면서 (>200 ng/ml), 트랜스페린포화도가 45% 를초과한경우로하였다 18, 19). 3. 통계처리대상자의측정치중정규분포하는경우는평균및표준편차로, 정규분포하지않는경우는중간값및사분위수로표기하였으며, 비알코올지방간유무에따른이들변수들의비교에서는 t-test와 Mann-Whitney test를각각시행하였다. 측정치중빈도의분석에서는카이자승법을시행하였으며, 경향분석이필요한경우선형대선형결합 (linear by linear association) 으로근사적접근을시도하였다. 체내철저장상태의구분에따른측정치의비교에서는분산분석법및 Kruskal-Wallis test를시행하였다. 비알코올지방간의발생위험도에대한다변량분석에는선형로지스틱회귀분석법을시행하였다. 통계적인유의수준은 0.05 이하로하였고, 통계분석은 SPSS for windows V11.0 (SPSS Inc., USA) 를이용하여처리하였다. 4. 결과 1) 비알코올지방간유무에따른비교대상자 5,249명 ( 평균연령 40.6±8.9세, 연령대 15-82 세 ) 중 451명 (8.6%) 이비알코올지방간으로진단받았다. 대상자들에서비알코올지방간유무에따라인구학적, 생화학적변수들을비교하였을때, 연령 (p<0.001), 체질량지수 (p<0.001), 중성지방 (p<0.001), 고밀도콜레스테롤 (p=0.004), 공복혈당 (p=0.006), 허리둘레 (p<0.001), 수축기혈압 (p=0.046), 이완기혈압 (p=0.013), HOMA-IR (p< 0.001), C-reactive protein (p<0.001), 혈청페리틴 (p<0.001) 등에서유의한차이를보였다. 또한당뇨병 (p<0.001) 과고혈압 (p<0.001), 대사증후군 (p<0.001) 의유병율이비알코올지방간군에서유의하게높았다. 철대사와관련된생화학지표들중에서는혈청페리틴만이유의한차이를보였으며 (p<0.001), 철결핍의빈도는비알코올지방간군에서낮았으나 (p<0.001), 철결핍성빈혈의빈도는유의한차이가없었다 ( 표 1). 2) 체내철저장상태에따른비알코올지방간의유병율대상자 5,249명중 2,964명 (56.5%) 이정상체내철저 - 589 -
- 대한내과학회지 : 제 73 권제 6 호통권제 568 호 2007 - Table 1. Clinical, laboratory, and metabolic data for subjects with NAFLD and subjects without NAFLD * Characteristic Percent of population (%) Age (yr) Diabetes mellitus (%) Hypertension (%) Body mass index (kg/m 2 ) Triglyceride (mg/dl) HDL-cholesterol (mg/dl) Fasting glucose (mg/dl) Waist circumference (cm) Systolic BP (mmhg) Diastolic BP (mmhg) Metabolic syndrome (%) HOMA-IR hs-crp (mg/l) Serum iron (ug/dl) Serum ferritin (ng/ml) Transferrin saturation (%) Iron deficiency (%) Iron deficiency anemia (%) No NAFLD n=4798 91.4 40.0±8.5 43 (0.9) 326 (6.8) 22.7±2.6 78.0 (60.0-104.0) 61.4±12.7 88.0 (84.0-93.0) 72.4±7.6 108.0±12.9 68.4±9.0 187 (3.9) 1.79 (1.50-2.22) 0.020 (0.015-0.050) 99.9±41.5 23.1 (10.2-41.0) 32.2±13.6 2147 (44.7) 372 (7.8) Total, N=5249 NAFLD n=451 8.6 46.8±10.3 27 (6.0) 103 (22.8) 25.0±2.8 123.0 (94.0-170.0) 53.3±10.7 93.0 (89.0-101.0) 82.5±7.2 116.7±15.1 74.6±10.3 118 (26.1) 2.45 (1.91-3.11) 0.060 (0.030-0.110) 101.0±43.1 35.5 (14.7-64.4) 31.5±13.8 138 (30.6) 47 (10.4) p NA.004.006.046.013.596.311.056 Data are expressed as the mean±sd, medians (interquartile ranges) for skewed variables, or number of patients and prevalence for categorical variables. * Differences were assessed using the t-test or Mann-Whitney test for continuous variables and χ 2 -test for categorical variables. NAFLD, nonalcoholic fatty liver disease; HDL-cholesterol, high density lipoprotein cholesterol; HOMA-IR, homeostasis model assessment-insulin resistance; hs-crp, high sensitivity C-reactive protein; Systolic BP, systolic blood pressure; Diastolic BP, diastolic blood pressure; NA, not applicable 장상태를보였으며, 이중 313명 (10.6%) 에서비알코올지방간이있었다. 철결핍을 3단계로구분하였을때 1,232 명 (23.5%) 이저장철의고갈상태, 634명 (12.1%) 이철결핍성적혈구조혈이상상태, 419명 (8.0%) 이철결핍성빈혈상태에해당되었으며, 철과잉상태에해당되는경우는없었다. 체내철저장상태에따른비알코올지방간의유병율을비교하였을때, 저장철고갈상태 (4.1%) 에서가장낮은유병율을보이다가철결핍성적혈구조혈이상상태 (6.5%) 및철결핍성빈혈상태 (11.2%) 로진행함에따라유병율이다시증가되는양상을보였다 (p<0.001)( 표 2). 3) 체내철저장상태에따른대사관련지표들의비교체내철저장상태에따라대사관련지표들의평균치를비교하였을때, 모두에서유의한차이를보였다. 철결 핍성빈혈상태에서가장낮은값을보인혈청페리틴을제외하고는저장철고갈상태에서가장낮은값 ( 연령, 체질량지수, 중성지방, 공복혈당, 허리두레, 수축기및이완기혈압, HOMA-IR, C-reactive protein) 또는가장높은값 ( 고밀도지단백콜레스테롤 ) 을보였다 ( 표 3). 4) 비알코올지방간발생의위험인자들비알코올지방간발생에영향을미치는위험인자들을알아보기위하여, 기존에알려진위험인자들과단변량분석에서비알코올지방간발생과유의한상관관계를보였던변수들로다변량분석을시행하였을때, 연령 (odds ratio [OR]=1.284; 95% confidence interval [CI]: 1.116-1.507) per 10 years), 과체중 (OR=1.952; 95% CI: 1.395-2.732), 당뇨 (OR=1.694; 95% CI: 1.198-2.397), 고중성지방 - 590 -
- 황상준외 11 인 : 비알코올지방간에서의체내철저장상태 - Table 2. Prevalence of nonalcoholic fatty liver disease according to body iron stores SI (ug/dl) Serum iron tests TS TIBC (%) SF (ng/ml) NAFLD (%) p Normal 50-150 300-360 30-50 50-200 313/2964 (10.6) Iron deficiency ISD 50-150 >360 30-50 <20 50/1232 (4.1) IDE <50 >380 <20 <15 41/634 (6.5) IDA <30 >400 <10 <15 47/419 (11.2) Iron overload NA NA >45 >200 0 SI, serum iron; TIBC, total iron binding capacity; TS, transferrin saturation; SF, serum ferritin; NAFLD, nonalcoholic fatty liver disease; ISD, iron store depletion; IDE, iron deficient erythropoiesis; IDA, iron deficiency anemia; NA, not applicable Table 3. Comparison of the metabolic and biochemical data according to body iron stores Body iron stores IDA IDE ISD normal p Age (yr) Body mass index (kg/m 2 ) Triglyceride (mg/dl) * HDL cholesterol (mg/dl) Fasting glucose (mg/dl) * 40.3±6.6 22.1±2.8 91.2±47.2 59.6±12.6 90.4±11.0 38.5±6.6 21.9±2.9 93.2±47.6 61.0±12.4 90.3±10.3 38.2±6.4 21.6±2.5 86.3±38.9 62.3±12.0 87.9±7.4 42.0±10.1 22.2±2.8 95.0±50.8 60.1±13.0 90.3±12.0.001 Waist circumference (cm) Systolic BP (mmhg) Diastolic BP (mmhg) HOMA IR * hs CRP (mg/l) * Ferritin (ng/ml) * 72.7±7.3 110.5±12.9 68.5±9.0 2.12±0.77 0.05±0.12 3.5±1.9 72.6±7.6 109.0±12.6 69.2±9.1 2.16±0.79 0.09±0.29 7.7±3.1 71.5±7.5 106.9±11.5 67.8±8.6 1.90±0.59 0.04±0.07 13.0±4.2 74.4±8.4 109.2±14.1 69.4±9.6 1.96±0.66 0.07±0.17 48. 1±27.1 NAFLD, nonalcoholic fatty liver disease; ISD, iron store depletion; IDE, iron-deficient erythropoiesis; IDA, iron-deficiency anemia; BMI, body mass index; HOMA-IR, homeostasis model assessment-insulin resistance; ALT, alanine aminotransferase * Overall significance of differences between the four groups according to the Kruskal Wallis test 혈증 (OR=2.434; 95% CI: 1.737-3.409, 복부비만 (OR=3.559; 95% CI: 2.538-4.992), 인슐린저항성 (OR=2.665; 95% CI: 1.979-3.587), 빈혈 (OR=2.015; 95% CI: 1.150-3.532), 저장철고갈 (OR=0.580; 95% CI: 0.405-0.830) 등이유의한연관성을보였다. 고찰이번연구에서체내철저장상태와비알코올지방간발생과의연관성을확인할수있었으며, 저장철의고갈및빈혈발생여부가비알코올지방간의발생과관련된중요한인자임을알수있었다. 비알코올지방간의발생및진행을설명하기위한가 설로제안된 Two hit theory 에서는첫째단계로인슐린저항성에의해간세포내에지방축적이발생하게되어간손상에관련된기전들에취약해지며, 둘째단계로여러요인들에의해간세포내산화적스트레스 (oxidative stress) 가증가되어활성산소종 (reactive oxygen species) 의생성이나간성상세포 (hepatic stellate cell) 의활성화를통해간섬유화를진행시킨다고하였다 20). 간내철은이러한과정에서중요한역할을하는것으로간주되어, 이에대한다양한연구들이진행되어왔다. 간내철은지질과산화과정에관여하여이로인해생성된 malondialdehyde 나 4-hydroxynonenal 등이간의성상세포를활성화시키고, 이로인해성상세포에서교원질생성을증가시킬수 - 591 -
-The Korean Journal of Medicine : Vol. 73, No. 6, 2007 - Table 4. Multivariate relationship between risk factors and-non-alcoholic fatty liver disease (NAFLD) Variables Age (per 10 years) Body mass index ( 25 kg/m 2 ) High fasting glucose or medication High blood pressure or medication HDL-C (<50 mg/dl) Triglycerides ( 150 mg/dl) Waist circumference ( 80 cm) HOMA IR ( 2.10) C-reactive protein ( 1.7 mg/l) Hemoglobin (<12 g/dl) Serum ferritin (<12ng/mL) Odds ratio (95% confidence interval) 1.284 (1.116-1.507) 1.952 (1.395-2.732) 1.694 (1.198-2.397) 1.002 (0.719-1.397) 1.207 (0.886-1.644) 2.434 (1.737-3.409) 3.559 (2.538-4.992) 2.665 (1.979-3.587) 1.124 (0.719-1.768) 2.015 (1.150-3.532) * 0.580 (0.405-0.830) * p<0.05, p<0.001. High fasting glucose, fasting glucose 110 mg/dl. High blood pressure, systolic/diastolic blood pressure 130/85 mmhg. HDL-C, high density lipoprotein-cholesterol; HOMA-IR, homeostasis model assessment insulin resistance 있다 21, 22). 또한간내철은쿠퍼세포에서산소라디칼과사이토카인의생성을유도하여간세포손상을야기할수있다 23). 간내철은또한비알코올지방간의중요한병인인인슐린저항성의증가와관련될수있다. 실제로혈색소침착증환자의경우체내저장철이증가함에따라간에서의인슐린작용이감소하여, 고인슐린혈증이발생한다고알려져있다 24). 간조직검사를시행하여간섬유화정도에영향을미치는인자들을확인한연구들에서인슐린저항성지표는간섬유화정도를예측할수있는독립인자였다 8, 25). 따라서체내철과잉상태는비알코올지방간발생과진행에있어중요한역할을할것으로생각된다. 체내철과잉상태는체내철상태의항상성유지를위한철대사 (iron metabolism) 에서생리적배설기전이없기때문에주로철의흡수와저장에관련된기전의장애로발생한다 19). 서구의경우이러한철대사장애의대표질환인혈색소침착증과관련된유전자 (HFE) 돌연변이가비교적높게관찰되며음식물을통한철섭취의양이많기때문에체내철과잉상태가비교적흔하게발견된다. 그러나우리나라를비롯한동양의경우혈색소침착증과관련된유전자돌연변이가극히드물게발견되며 26, 27). 또한식생활이점차서구화되는상황이기는하나, 음식물을통한철섭취의양이서구인들에비해상대적으로적기때문에철과잉상태의빈도는상대적으로낮을것으로판단된다. 따라서우리나라일반대중에서는철과잉이 외의체내철상태에서체내철이비알코올지방간발생에영향을미치는지여부가더중요할수있다. 이를확인하기위하여, 이번연구에서는대부분에서체내철저장상태가정상이거나결핍된소견을보이는건강검진여성수진자들을대상으로비알코올지방간의발생과체내철저장상태와의연관성을분석하였다. 체내철저장상태를구분하여비알코올지방간의유병율을비교하였으며, 철결핍상태에서모두정상적인체내철저장상태에비해비알코올지방간의유병율이낮았으나, 저장철의고갈상태에서가장낮았다가적혈구조혈이상및철결핍성빈혈상태로진행하면서오히려유병율이증가하는것을관찰할수있었다. 이러한유병율의변화를설명하기위하여, 비알코올지방간의발생에영향을미치는것으로알려진연령, 체질량지수, 대사증후군의각요소들, HOMA-IR, C-reactive protein 등의인자들을체내철상태에따라비교하였을때 28), 비알코올지방간의유병율변화와유사한양상을관찰할수있었다. 이는이들인자들이인슐린저항성과관련됨을고려할때, 체내철저장상태에따른비알코올지방간의발생에인슐린저항성이영향을미친다는것을시사한다. 체내철상태를반영하는철대사의지표들과비알코올지방간의발생에영향을미치는것으로알려진위험인자들중단변량분석에서비알코올지방간의발생과유의한연관성을보인변수들로다변량분석을시행하였을때, 연령, 비만, 당뇨, 고중성지 - 592 -
-Sang Jun Hwang, et al : Body iron stores in NAFLD - 방혈증, 복부비만, 인슐린저항성등기존에알려진위험인자들외에, 저장철고갈및빈혈등체내철저장상태와관련된변수들에서도유의한연관성을확인할수있었다. 저장철의고갈은비알코올지방간의발생위험도를감소시키는결과를보였으며, 이는수혈및정맥절개술을통해체내철저장량을감소시킴으로써, 인슐린저항성이감소되고비알코올지방간의조직학적인소견이호전되었음을보고한기존의연구들을고려할때 10-12), 철에의한직접적인간독성및인슐린저항성의감소가비알코올지방간의발생을억제하는것으로설명될수있을것이다. 철결핍성빈혈에서비알코올지방간의발생위험도가높아지는것도인슐린저항성의증가와연관될가능성이있다. 만성빈혈에의한인슐린저항성증가에대해서는지중해빈혈증 (thalassemia major) 환자에서잘밝혀져있으며 29), 혈액투석환자들을대상으로한연구들에서빈혈의정도에따라인슐린저항성이증가하며, erythropoietin 으로빈혈을교정할경우체내철상태와관계없이인슐린저항성이호전됨을보고하고있다 30-32). 조직내저산소증 (tissue hypoxia) 은세포내미토콘드리아의전자전달회로 (mitochondrial electron transport chain) 의이상을일으켜활성산소종의생성을증가시킴으로써산화적스트레스를초래할수있으며, 이로인해인슐린저항성을악화시킬수있음을고려할때 33, 34), 만성빈혈은인슐린저항성을유발하여비알코올지방간발생에기여할수있을것으로사료된다. 이번연구는단면적연구였기때문에체내철저장상태와비알코올지방간발생의연관성에대한인과관계를판단할수는없었다. 또한건강검진수진자들을대상으로한연구였기때문에간조직생검대신비침습검사인복부초음파로비알코올지방간여부를판단하였다는제한점이있었다. 복부초음파는간의지방침착이적은경우간지방증진단의민감도가떨어지고, 관찰자간변이 (interobserver variation) 가있을수있어비알코올지방간의정확한진단에는한계가있다 14). 뿐만아니라, 간의염증및섬유화의유무를평가할수없기때문에임상적으로더중요한비알코올지방간염 (nonalcoholic steatohepatitis, NASH) 을구분하여분석할수없었다. 또한한국에서비교적드문간질환인원발성담관성간경변증 (primary biliary cirrhosis), 원발성경화쓸개관염 (primary sclerosing cholangitis), 윌슨병 (Wilson s disease) 에대한검사는시행되지않아, 이환여부를확인할수없었다. 이러한제한에도불구하고, 체내철저장상태에따른비알코올지방간발생의차이를보여준이번연구는실제로우리나라일반대중에서상대적으로흔한철결핍이비알코올지방간발생의방어인자로작용할가능성을제시하였다는데의미가있을것이다. 그러나철결핍이진행하여철결핍성빈혈상태가되면오히려비알코올지방간의발생위험도를증가시킬수도있다는점을고려할때, 비알코올지방간의발생이나진행을억제하기위한철고갈치료 (iron depletion therapy) 의시도는신중하게이루어져야할것으로보인다. 결론적으로체내철저장상태가비알코올지방간발생에영향을미칠수있으며, 특히저장철고갈및빈혈발생에의한인슐린저항성의변화가비알코올지방간의발생과관련되는것으로생각되며, 이에대해서전향연구가필요할것으로사료된다. 요약 목적 : 비알코올간질환의발생과진행에있어체내철과잉상태가영향을미치는지에대한연구가다양하게이루어지고있지만, 체내철저장상태의단계에따라비알코올지방간의발생을비교한연구는부족하였다. 이에이번연구는건강검진수진자중철결핍의빈도가상대적으로높은여성수진자를대상으로체내철저장상태가비알코올지방간발생에미치는영향을평가하고자하였다. 방법 : 일개대학병원에서건강검진을받은여성수진자들중의미있는알코올섭취 ( 하루 20 g 이상 ) 자, HBsAg 양성자, anti-hcv 양성자등을제외한 5,259명 ( 평균연령 : 40.6±8.9세 ) 을연구에포함시켰다. 임상양상, 복부초음파검사, 인슐린저항성및철대사와관련된생화학검사를포함한혈액검사소견을파악하여비알코올지방간발생과체내철저장상태와의연관성을분석하였다. 결과 : 체내철저장상태에따른비알코올지방간의유병율을비교하였을때, 정상체내철저장상태 (10.6%), 저장철고갈상태 (4.1%), 철결핍성적혈구조혈이상상태 (6.5%) 및철결핍성빈혈상태 (11.2%) 간에유의한차이를보였다 (p<0.001). 비알코올지방간발생에영향을미치는인자들을알아보기위하여, 다변량분석을시행하였을때, 연령 (odds ratio [OR]=1.284; 95% confidence interval [CI]: 1.116-1.507) per 10 years), 과체중 (OR= 1.952; 95% CI: 1.395-2.732), 당뇨병 (OR=1.694; 95% CI: 1.198-2.397), 고중성지방혈증 (OR=2.434; 95% CI: 1.737- - 593 -
- 대한내과학회지 : 제 73 권제 6 호통권제 568 호 2007-3.409, 복부비만 (OR=3.559; 95% CI: 2.538-4.992), 인슐린저항성 (OR=2.665; 95% CI: 1.979-3.587), 빈혈 (OR=2.015; 95% CI: 1.150-3.532), 저장철고갈 (OR=0.580; 95% CI: 0.405-0.830) 등이유의한연관성을보였다결론 : 체내철저장상태가비알코올지방간의발생에영향을미칠수있으며, 특히저장철의고갈및빈혈발생에의한인슐린저항성의변화가비알코올지방간발생과관련되는것으로사료된다. 중심단어 : 비알코올지방간, 철상태, 철결핍, 빈혈 REFERENCES 1) Bacon BR. Hemochromatosis: diagnosis and management. Gastroenterology 120:718-725, 2001 2) Casaril M, Stanzial AM, Tognella P, Pantalena M, Capra F, Colombari R, Corrocher R. Role of iron load on fibrogenesis in chronic hepatitis C. Hepatogastroenterology 47:220-225, 2000 3) Reif DW. Ferritin as a source of iron for oxidative damage. Free Radic Biol Med 12:417-427, 1992 4) Bacon BR, Farahvash MJ, Janney CG, Neuschwander- Tetri BA. Nonalcoholic steatohepatitis: an expanded clinical entity. Gastroenterology 107:1103-1109, 1994 5) Angulo P, Keach JC, Batts KP, Lindor KD. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology 30:1356-1362, 1999 6) Bonkovsky HL, Jawaid Q, Tortorelli K, LeClair P, Cobb J, Lambrecht RW, Banner BF. Non-alcoholic steatohepatitis and iron: increased prevalence of mutations of the HFE gene in non-alcoholic steatohepatitis. J Hepatol 31:421-429, 1999 7) George DK, Goldwurm S, MacDonald GA, Cowley LL, Walker NI, Ward PJ, Jazwinska EC, Powell LW. Increased hepatic iron concentration in nonalcoholic steatohepatitis is associated with increased fibrosis. Gastroenterology 114:311-318, 1998 8) Chitturi S, Weltman M, Farrell GC, McDonald D, Kench J, Liddle C, Samarasinghe D, Lin R, Abeygunasekera S, George J. HFE mutations, hepatic iron, and fibrosis: ethnic-specific association of NASH with C282Y but not with fibrotic severity. Hepatology 36:142-149, 2002 9) Younossi ZM, Gramlich T, Bacon BR, Matteoni CA, Boparai N, O Neill R, McCullough AJ. Hepatic iron and nonalcoholic fatty liver disease. Hepatology 30: 847-850, 1999 10) Ascherio A, Rimm EB, Giovannucci E, Willett WC, Stampfer MJ. Blood donations and risk of coronary heart disease in men. Circulation 103:52-57, 2001 11) Ferna ndez-real JM, Pen arroja G, Castro A, Garcı a- Bragado F, Herna ndez I, Ricart W. Blood letting in high-ferritin type 2 diabetes mellitus: effects on insulin sensitivity and β-cell function. Diabetes 51: 1000-1004, 2002 12) Facchini FS, Hua NW, Stoohs RA. Effect of iron depletion in carbohydrate-intolerant patients with clinical evidence of nonalcoholic fatty liver disease. Gastroenterology 122:931-939, 2002 13) Riquelme A, Soza A, Nazal L, Martinez G, Kolbach M, Patillo A, Arellano JM, Duarte I, Martinez J, Molgo M, Arrese M. Histological resolution of steatohepatitis after iron depletion. Dig Dis Sci 49:1012-1015, 2004 14) Saadeh S, Younossi ZM, Remer EM, Gramlich T, Ong JP, Hurley M, Hurley M, Mullen KD, Cooper JN, Sheridan MJ. The utility of radiological imaging in nonalcoholic fatty liver disease. Gastroenterology 123: 745-750, 2002 15) The IDF consensus worldwide definition of the metabolic syndrome. International Diabetes Federation, 2005 16) Anuurad E, Shiwaku K, Nogi A, Kitajima K, Enkhmaa B, Shimono K, Yamane Y. The new BMI criteria for Asians by the regional office for the western pacific region of WHO are suitable for screening of overweight to prevent metabolic syndrome in elder Japanese workers. J Occup Health 45:335-343, 2003 17) Ernest B. Disorders in iron metabolism. In: Marshall AL,, Thomas JK, Uri S, Kenneth K, Josef TP, eds. Williams hematology. 7th ed. p. 1642-1645, New York, McGraw Hill, 2006 18) Beutler E, Felitti V, Ho N, Gelbart T. Relationship of body iron stores to levels of serum ferritin, serum iron, unsaturated iron binding capacity and transferrin saturation in patients with iron storage disease. Acta Haematol 107:145-149, 2002 19) Heeney MM, Andrews NC. Iron homeostasis and inherited iron overload disorders: an overview. Hematol Oncol Clin North Am 18:1379-1403, 2004 20) Day CP, James OF. Steatohepatitis: a tale of two hits? Gastroenterology 114:842-845, 1998 21) Lee KS, Buck M, Houglum K, Chojkier M. Activation of hepatic stellate cells by TGF alpha and collagen type I is mediated by oxidative stress through c-myb expression. J Clin Invest 96:2461-2468, 1995 22) Bedossa P, Houglum K, Trautwein C, Holstege A, Chojkier M. Stimulation of collagen alpha 1(I) gene expression is associated with lipid peroxidation in hepatocellular injury: a link to tissue fibrosis? - 594 -
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