Association of Histologic Disease Activity With Progression of Nonalcoholic Fatty Liver Disease
Association of Histologic Disease Activity With Progression of Nonalcoholic Fatty Liver Disease
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DOI：
10.1001/jamanetworkopen.2019.12565
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发表时间：
2019-10-01
影响因子：
13.8
通讯作者：
Yates, Katherine P.
中科院分区：
文献类型：
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作者：
Kleiner, David E.;Brunt, Elizabeth M.;Yates, Katherine P.
重要性非酒精性脂肪性肝病（NAFLD）全谱的组织学演变和与进展或消退相关的因素仍有待明确建立。目的评估NAFLD的组织学演变和与疾病严重程度随时间变化相关的因素。非酒精性脂肪性肝炎临床研究网络的一项前瞻性队列亚研究（NASH CRN）NAFLD数据库研究是一项非干预性登记研究，在8个大学医学研究中心进行。采用预先规定的方案对个体活检进行评分，对肝脏组织学标本进行盲法评估。参与者包括2004年10月27日至2013年9月13日期间参加NASH CRN数据库研究的446名NAFLD成人，他们接受了间隔1年或更长时间的2次肝活检。数据分析从2016年10月至2018年10月进行。主要结果和指标纤维化阶段的进展和消退，使用临床，实验室和组织学结果，包括NAFLD活动评分（NAS）（脂肪变性、小叶炎症和气球样变的评分总和;范围0-8分，8分表示病情较重研究了NAFLD（NAFL，86例[19.3%]）、临界NASH（84例[18.8%]）和明确NASH（276例[61.9%]）患者（平均[SD]年龄，47 [11]岁; 294例[65.9%]女性）。在平均（SD）4.9（2.8）年的活检间隔内，11例患者（12.8%）的NAFL消退，36例患者（41.9%）进展为脂肪性肝炎。24例（28.6%）临界NASH患者和61例（22.1%）明确NASH患者的脂肪性肝炎消退。分别有132名（30%）和151名（34%）参与者发生了至少1个阶段的纤维化进展或消退。代谢综合征（20 [95%] vs 108 [72%]; P = .03），基线NAS（平均值[SD]，5.0 [1.4] vs 4.3 [1.6]; P = 0.005），NAS降低幅度较小（-0.2 [2] vs -0.9 [2]; P < .001）与进展至晚期（3-4期）纤维化相关，而与未进展至3 - 4期纤维化相关。纤维化消退与较低的基线胰岛素水平相关（20 vs 33 mu U/mL; P = .02），所有NAS组分均降低（脂肪变性分级-0.8 [0.1] vs -0.3 [0.9]; P <0.001;小叶炎症-0.5 [0.8] vs -0.2 [0.9]; P <0.001;气球样变-0.7 [1.1] vs -0.1 [0.9]; P < .001）。在多变量回归分析中，仅基线天冬氨酸转氨酶（AST）水平与纤维化消退与无变化以及进展与无变化相关：基线AST（消退：条件优势比[cOR]，0.6/10 U/L AST; 95% CI，0.4-0.7; P < .001;进展：cOR，1.3; 95% CI，1.1-1.5; P = .002）。AST水平、丙氨酸氨基转移酶（ALT）水平和NAS的变化也与纤维化的消退和进展相关（Δ AST水平：回归，cOR，0.9; 95% CI，0.6-1.2; P = 0.47;进展，cOR，1.3; 95% CI，1.0-1.6; P = 0.02; Δ ALT水平：回归，cOR，0.7/10 U/L AST; 95% CI，0.5-0.9; P = 0.002;进展，cOR，1.0/10 U/L AST; 95% CI，0.9-1.2; P = 0.93; Delta NAS：回归，cOR，0.7; 95% CI，0.6-0.9; P = 0.001;进展，cOR，1.3; 95% CI，1.1-1.5;结论和相关性在NAFLD中，疾病活动性的改善或恶化可能分别与纤维化的消退或进展相关。
IMPORTANCE The histologic evolution of the full spectrum of nonalcoholic fatty liver disease (NAFLD) and factors associated with progression or regression remain to be definitively established.OBJECTIVE To evaluate the histologic evolution of NAFLD and the factors associated with changes in disease severity over time.DESIGN, SETTING, AND PARTICIPANTS A prospective cohort substudy from the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) NAFLD Database study, a noninterventional registry, was performed at 8 university medical research centers. Masked assessment of liver histologic specimens was performed, using a prespecified protocol to score individual biopsies. Participants included 446 adults with NAFLD enrolled in the NASH CRN Database studies between October 27, 2004, and September 13, 2013, who underwent 2 liver biopsies 1 or more year apart. Data analysis was performed from October 2016 to October 2018.MAIN OUTCOMES AND MEASURES Progression and regression of fibrosis stage, using clinical, laboratory, and histologic findings, including the NAFLD activity score (NAS) (sum of scores for steatosis, lobular inflammation, and ballooning; range, 0-8, with 8 indicating more severe disease).RESULTS A total of 446 adults (mean [SD] age, 47 [11] years; 294 [65.9%] women) with NAFLD (NAFL, 86 [19.3%]), borderline NASH (84 [18.8%]), and definite NASH (276 [61.9%]) were studied. Over a mean (SD) interval of 4.9 (2.8) years between biopsies, NAFL resolved in 11 patients (12.8%) and progressed to steatohepatitis in 36 patients (41.9%). Steatohepatitis resolved in 24 (28.6%) of the patients with borderline NASH and 61 (22.1%) of those with definite NASH. Fibrosis progression or regression by at least 1 stage occurred in 132 (30%) and 151 [34%] participants, respectively. Metabolic syndrome (20 [95%] vs 108 [72%]; P = .03), baseline NAS (mean [SD], 5.0 [1.4] vs 4.3 [1.6]; P = .005), and smaller reduction in NAS (-0.2 [2] vs -0.9 [2]; P < .001) were associated with progression to advanced (stage 3-4) fibrosis vs those without progression to stage 3 to 4 fibrosis. Fibrosis regression was associated with lower baseline insulin level (20 vs 33 mu U/mL; P = .02) and decrease in all NAS components (steatosis grade -0.8 [0.1] vs -0.3 [0.9]; P < .001; lobular inflammation -0.5 [0.8] vs -0.2 [0.9]; P < .001; ballooning -0.7 [1.1] vs -0.1 [0.9]; P < .001). Only baseline aspartate aminotransferase (AST) levels were associated with fibrosis regression vs no change and progression vs no change on multivariable regression: baseline AST (regression: conditional odds ratio [cOR], 0.6 per 10 U/L AST; 95% CI, 0.4-0.7; P < .001; progression: cOR, 1.3; 95% CI, 1.1-1.5; P = .002). Changes in the AST level, alanine aminotransferase (ALT) level, and NAS were also associated with fibrosis regression and progression (Delta AST level: regression, cOR, 0.9; 95% CI, 0.6-1.2; P = .47; progression, cOR, 1.3; 95% CI, 1.0-1.6; P = .02; Delta ALT level: regression, cOR, 0.7 per 10 U/L AST; 95% CI, 0.5-0.9; P = .002; progression, cOR, 1.0 per 10 U/L AST; 95% CI, 0.9-1.2; P = .93; Delta NAS: regression, cOR, 0.7; 95% CI, 0.6-0.9; P = .001; progression, cOR, 1.3; 95% CI, 1.1-1.5; P = .01).CONCLUSIONS AND RELEVANCE Improvement or worsening of disease activity may be associated with fibrosis regression or progression, respectively, in NAFLD.