台灣非酒精性脂性肝病之臨床和實驗室研究

Abstract

背景 非酒精性脂性肝病在已開發國家是一個常見的疾病，且與第二型糖尿病、肥胖與高脂血症有關，但非酒精性脂性肝病也可發生在非肥胖或沒有糖尿病的族群。由文獻中發現非酒精性脂性肝病可能為隱晦性肝炎或肝硬化的原因之一，但病程的發展是否與HFE基因有關仍有爭議性。此外，脂肪細胞激素中的脂締素(adiponectin)雖在肝臟中有抗發炎和改善脂肪代謝的作用，但在肥胖或糖尿病患者中脂締素常比非肥胖或非糖尿病患者為低，我們預期在非酒精性脂性肝病患者中脂締素濃度可能亦較低。 目的 （1）評估在台灣非酒精性脂性肝病的臨床和實驗室特點以及與HFE基因的相關性 （2）比較非酒精性脂性肝病與正常成人控制組或B型肝炎帶原組在脂締素濃度上 之差異性。 材料與方法 共有57位受試者（46位男性與11位女性）參與本研究計畫。研究設計上共分為三組，第一組為正常成人控制組、第二組為B型肝炎帶原組、第三組為非酒精性脂性肝病患者。第一組共有15位，男女別為11比4，平均年齡為33.5歲，平均身高173.2公分，平均體重為65.3公斤，平均BMI為21.8。此15位參加者都無慢性B型或C型肝炎、無飲酒過量（每天少於20公克）或糖尿病或高血壓病史、無自體免疫肝炎(autoimmune hepatitis)、原發性膽道肝硬化(primary biliary cirrhosis)和威爾森氏症(Wilson’s disease)。第二組共有20位，男女別為16比4，平均年齡為35歲，平均身高170.1公分，平均體重為69.9公斤，平均BMI為23.8。此20位慢性B型肝炎患者都無慢性C型肝炎、無飲酒過量史、無自體免疫性肝炎和威爾森氏症。第三組共有22位，男女別為19比3，平均年齡為44歲，平均身高165.2公分，平均體重為77.2公斤， 平均BMI為27.9。此22位非酒精性脂性肝病患者都無慢性B型或C型肝炎、無飲酒過量、無自體免疫性肝炎和威爾森氏症。實驗室檢驗包括血清鐵（iron），全鐵結合量（total iron binding capacity；TIBC），鐵蛋白（ferritin），空腹胰島素 （fasting insulin level）， 空腹血糖（fasting glucose level），麩胺酸苯醋酸轉氨酶（AST），麩胺酸丙酮酸轉氨酶（ALT），總膽紅素（T-bilirubin），直接型膽紅素（D-bilirubin），鹼性磷酸酶（ALP），麩胺轉酸酶（γGT）， 總膽固醇（total cholesterol），三酸甘油酯 （triglyceride ），低密度膽固醇（LDL-C），高密度膽固醇（HDL-C），尿酸 （uric acid）。採用Homeostasis model assessment（HOMA）來評估胰島素阻抗（insulin resistance）。利用Human Adiponectin ELISA Kit (B-Bridge International, Inc.)檢測血清中脂締素濃度。利用聚合酶連鎖反應併限制酶片段長度多形性(polymerase chain reaction-restriction fragment length polymorphism, PCR-RFLP)法檢測HFE基因突變。 結果 於第三組(非酒精性脂性肝病)與第一組(正常成人控制組)作統計學分析後發現兩組之間在身體質量指數（body mass index；BMI）、鐵蛋白、總膽固醇、三酸甘油酯、低密度脂蛋白膽固醇、高密度脂蛋白膽固醇、胰島素抗性、空腹胰島素值、尿酸、脂締素濃度、麩胺酸苯醋酸轉氨酶（AST），麩胺酸丙酮酸轉氨酶（ALT）和鹼性磷酸酶（ALP）等項目有明顯統計學上差異。在合併糖尿病分析上，非酒精性脂性肝病患者在趨勢上比一般民眾高 (P=0.06)。在第三組(非酒精性脂性肝病)與第二組(B型肝炎帶原組)比較分析發現兩組之間在身體質量指數、總膽固醇、脂締素濃度、麩胺轉酸酶（γGT）和麩胺酸丙酮酸轉氨酶（ALT）等項目有明顯統計學上差異。但低密度脂蛋白膽固醇、飯前胰島素值和胰島素抗性，雖然沒有達到明顯統計學差異，但達到臨界邊緣(=0.05)。57位受試者中只有控制組中之一位有HFE基因之heterozygote H63D突變，其他56位均無此基因之突變。第三組（非酒精性脂性肝病患者）的脂締素濃度明顯低於第一組（正常成人控制組）或第二組（B型肝炎帶原組）(P<0.05)。 結論 台灣的非酒精性脂性肝病與代謝症候群有密切相關，且非酒精性脂性肝病患者有較低濃度之脂締素。非酒精性脂性肝病之HFE基因突變率與一般民眾或B型肝炎帶原者相似，因此HFE基因突變對非酒精性脂性肝病之發生並無明顯影響。

論文英文簡述 Background: Nonalcoholic fatty liver disease (NAFLD) is not an uncommon disease in developed countries. NAFLD is frequently associated with type II DM, obesity, dyslipidemia, but some patients with NAFLD still have normal glucose tolerance or normal body weight. In the literatures, NAFLD may be a common cause of cryptogenic hepatitis or even cirrhosis and the relationship between NAFLD and HFE gene mutations (C282Y and H63D) remains controversial. Adiponectin has antilipogenic effects that may protect nonadipocytes tissues such as liver against lipid accumulation. In addition, the conditions most associated with the development of NAFLD, namely, obesity, insulin resistance, type 2 diabeties and dyslipidemia, all have reduced adiponectin levels. Aims: (1) To determine the clinical and laboratory characteristics in Taiwanese patients with NAFLD and the correlation between NAFLD and HFE gene mutation. (2) To compare the plasma adiponectin levels between NAFLD patients, normal controls and HBV carriers. Materials and Methods: From January to October 2004, 57 consecutive subjects were collected and into 3 groups. Group I (healthy control): 11 males and 4 females with mean age of 33.5±7.8 years. Group II (HBV carriers): 16 males and 4 females with mean age of 36.1±8.7 years. Group III (NAFLD): 19 males and 3 females with mean age of 34.3±11.3 years and serum ALT, AST at least 1.5 X the upper limit of normal. Viral hepatitis, autoimmune hepatitis, primary biliary cirrhosis, Wilson’s disease, hemochromatosis and alcohol abuse were excluded. Clinical and biochemical characteristics such as gender, age, body mass index (BMI), AST, ALT, γGT, ALP, total cholesterol, triglyceride, HDL, LDL, uric acid, fasting glucose, fasting insulin, insulin resistance, iron, total iron binding capacity, ferritin, total and direct bilirubin and adiponectin were measured. HFE gene (C282Y and H63D) mutations were detected by PCR- restriction fragment length polymorphisms (RFLP).

Results: There were significant differences between Group I and III in terms of BW, BH, BMI, TIBC, ferritin, Total cholesterol, TG, HDL, LDL, AST, ALT, ALP, insulin and insulin resistance (P＜0.05). There were also significant differences between group III and II with respect to BH, BMI, Total cholesterol, AST, ALT, γGT and fasting sugar (P＜0.05). Borderline significance of fasting sugar (p=0.05) and DM (p=0.06) were noted between group III and group I. Borderline significance (p=0.05) of LDL, insulin resistance and insulin were noted between group III and group II. All 57 patients received PCR-RFLP analysis and only one has HFE (H63D) mutation was detected. Plasma adiponectin level was significantly lower in group III compared to group I or II. Conclusions: In Taiwan, NAFLD is correlated with metabolic syndrome (obesity, dyslipidemia, DM, insulin resistance) and low adiponectin. The frequency of HFE gene mutations in NAFLD patients is comparable to that in healthy adults or HBV carriers, suggesting a minimal role of HFE gene mutations in the pathogenesis of NAFLD.