Low circulating levels of dehydroepiandrosterone in histologically advanced nonalcoholic fatty liver disease
Low circulating levels of dehydroepiandrosterone in histologically advanced nonalcoholic fatty liver disease
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DOI：
10.1002/hep.22063
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发表时间：
2008-02-01
期刊：
影响因子：
13.5
通讯作者：
Lindor, Keith
中科院分区：
文献类型：
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作者：
Charlton, Michael;Angulo, Paul;Lindor, Keith
非酒精性脂肪性肝病(NAFLD)组织学进展的变异性的生物学基础尚不清楚。脱氢表雄酮(DHEA)是体内含量最丰富的类固醇激素，可影响机体对氧化应激的敏感性、胰岛素敏感性以及过氧化物酶体增殖物激活受体α和前胶原信使RNA的表达。我们的目的是确定组织学上更晚期的NAFLD是否与循环中低水平的脱氢表雄酮有关。在439例NAFLD患者(初始队列中78例，验证队列中361例)和44例胆汁淤积性肝病对照组中，前瞻性地在肝脏活检时采集血清样本。NAFLD以轻度[单纯性脂肪变性或非酒精性脂肪变性(NASH)伴纤维化0~2期]或晚期(NASH伴纤维化3~4期)为特征。采用双抗体夹心法测定血清硫酸脱氢表雄酮(脱氢表雄酮-S)水平。晚期非酒精性脂肪肝患者的血浆脱氢表雄酮-S水平低于轻度非酒精性脂肪肝患者(P<；0.001)和验证队列(0.47+/-0.06vs0.99+/-0.04mU g/mL，P<；0.001)。肝纤维化0、1、2、3、4期的平均脱氢表雄酮-S浓度分别为1.03+/-0.05、0.96+/-0.07、0.83+/-0.11、0.66+-0.11、0.35+/-0.06微克/毫升，呈剂量效应。进展期非酒精性脂肪性肝病组两个队列中的所有患者的脱氢表雄酮-S水平都较低，大多数患者在肾上腺皮质下范围内。在调整了年龄因素后，脱氢表雄酮-S与非酒精性脂肪肝的严重程度之间的关联仍然存在。在胆汁淤积性肝病患者中，未发现疾病/纤维化程度与脱氢表雄酮-S水平的关系。结论NASH伴晚期纤维化提示NAFLD的发生与低循环DHEA-S密切相关。这些数据为组织学晚期NASH患者相对缺乏脱氢表雄酮-S提供了新的证据。
The biological basis of variability in histological progression of nonalcoholic fatty liver disease (NAFLD) is unknown. Dehydroepiandrosterone (DHEA) is the most abundant steroid hormone and has been shown to influence sensitivity to oxidative stress, insulin sensitivity, and expression of peroxisome proliferator-activated receptor alpha and procollagen messenger RNA. Our aim was to determine whether more histologically advanced NAFLD is associated with low circulating levels of DHEA. Serum samples were obtained prospectively at the time of liver biopsy in 439 patients with NAFLD (78 in an initial and 361 in validation cohorts) and in controls with cholestatic liver disease (n = 44). NAFLD was characterized as mild [simple steatosis or nonalcoholic steatobepatitis (NASH) with fibrosis stage 0-2] or advanced (NASH with fibrosis stage 3-4). Serum levels of sulfated DHEA (DHEA-S) were measured by enzyme-linked immunosorbent assay. Patients with advanced NAFLD had lower plasma levels of DHEA-S than patients with mild NAFLD in both the initial (0.25 +/- 0.07 versus 1.1 +/- 0.09 mu g/mL, P < 0.001) and validation cohorts (0.47 +/- 0.06 versus 0.99 +/- 0.04 mu g/mL, P < 0.001). A "dose effect" of decreasing DHEA-S and incremental fibrosis stage was observed with a mean DHEA-S of 1.03 +/- 0.05, 0.96 +/- 0.07, 0.83 +/- 0.11, 0.66 +/- 0.11, and 0.35 +/- 0.06 mu g/mL for fibrosis stages 0, 1, 2, 3, and 4, respectively. All patients in both cohorts in the advanced NAFLD group had low DHEA-S levels, with the majority in the hypoadrenal range. The association between DHEA-S and severity of NAFLD persisted after adjusting for age. A relationship between disease/fibrosis severity and DHEA-S levels was not seen in patients with cholestatic liver diseases. Conclusiom More advanced NAFLD, as indicated by the presence of NASH with advanced fibrosis stage, is strongly associated with low circulating DHEA-S. These data provide novel evidence for relative DHEA-S deficiency in patients with histologically advanced NASH.