Current status of research on the prognostic markers for acute-on-chronic liver failure

Jian LI; Yaqiu DU; Dezhao LI; Huifan JI; Chenggang ZHANG; Qingxia LIU; Xiaolin GUO

doi:10.3969/j.issn.1001-5256.2021.11.047

Volume 37 Issue 11

Nov. 2021

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References

Article Navigation > Journal of Clinical Hepatology > 2021 > 37(11): 2701-2705

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Current status of research on the prognostic markers for acute-on-chronic liver failure

DOI: 10.3969/j.issn.1001-5256.2021.11.047

Department of Hepatology, The First Hospital of Jilin University, Changchun 130021, China

Research funding:

National Key Research Plan "Precision Medicine Research" Key Project (2017YFC0908104)

Received Date: 2021-03-26
Accepted Date: 2021-04-13
Published Date: 2021-11-20

Abstract

Abstract

Acute-on-chronic liver failure (ACLF) is a syndrome characterized by multiple organ failure and high short-term mortality rate, and it has always been a research hotspot in the field of severe liver diseases. Therefore, early and accurate risk stratification and timely intervention are of great significance to improve prognosis. This article summarizes the serum biomarkers identified in recent years for evaluating the prognosis of patients with ACLF, and it is pointed out that new serum biomarkers have an important guiding significance in the prognostic evaluation of ACLF patients.
- Acute-On-Chronic Liver Failure,
- Prognosis,
- Biomarkers

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非酒精性脂肪性肝病(NAFLD)是指除外酒精和其他明确的损肝因素所致肝脏细胞内脂肪过度沉积(＞5%)为主要特征的一种临床病理综合征^[1]。NAFLD是与胰岛素抵抗和遗传易感性密切相关的一种获得性代谢应激性肝损伤^[2]，随着肥胖及其相关代谢综合征全球化的流行趋势，NAFLD现已成为欧美等发达国家和我国相对富裕地区慢性肝病的重要病因。NAFLD疾病谱包括非酒精性肝脂肪变、非酒精性脂肪性肝炎(NASH)、肝硬化和肝细胞癌(HCC)^[3]。

尿酸是内源性和外源性嘌呤核苷酸代谢的终产物，血清尿酸(serum uric acid，sUA)产生过多或排泄减少可导致sUA升高，即为高尿酸血症(hyperuricemia，HUA)。HUA可引起全身系统的损害，并与代谢综合征密切相关。研究^[4]显示，sUA/肌酐(serum creatinine，Cr)比值与代谢综合征显著相关。本研究着眼于sUA/Cr与NAFLD发生的相关性，以期对NAFLD的诊疗提供进一步的依据。

1. 资料与方法

1.1 研究对象

回顾性选取2020年1月—2020年12月就诊于本院的97例NAFLD患者(NAFLD组)。另选取同期于本院体检的36例健康成人作为对照组。NAFLD诊断标准：根据《非酒精性脂肪性肝病防治指南(2018年更新版)》^[2]中相关诊断标准，年龄≥18岁。排除标准：(1)已确诊的糖尿病、高血压患者，慢性肾功能衰竭(肾小球滤过率＜30 mL/min)、肿瘤等严重的急慢性病患者；(2)酒精性、病毒性、药物性、自身免疫性、全胃肠外营养等明确病因所致肝脏疾病患者。

1.2 NAFLD超声分级标准

(1) 肝肾对比或肝肾回声差异，肝实质回声明显大于肾实质回声；(2)肝脏近场和远场回声差异，近场回声增强，远场则衰减；(3)肝内管道结构特别是静脉内径变细，显示不清；(4)肝脏各径线测值存在不同程度增大；(5)彩色血流显示肝脏中血流信号不同程度存在减少；(6)肝右叶包膜及横膈回声显示不清晰。轻度脂肪肝：满足(1)与其余任何一项的情况。中度脂肪肝：满足(1)以及其余任何2项的情况。重度脂肪肝：满足(1)及其余任何3项的情况^[5]。

1.3 资料收集

收集所有研究对象的性别、年龄、空腹血糖(fasting blood sugar，FBS)、ALT、AST、TC、TG、高密度脂蛋白胆固醇(HDL)、低密度脂蛋白胆固醇(LDL)、GGT、sUA、sCr、sUA/Cr，以及腹部超声结果。

1.4 伦理学审查

本研究方案经由首都医科大学附属北京天坛医院伦理委员会审批，批号：KY2016-042-01。

1.5 统计学方法

采用SPSS 18.0软件对所有数据进行统计学分析。正态分布的计量资料以x ±s表示，2组间比较采用独立样本t检验，3组间比较采用方差分析；非正态分布数据以M(P₂₅~P₇₅)表示，组间比较采用Mann-Whitney U检验；计数资料组间比较采用χ²检验；相关性分析采用Spearman检验。采用logistic回归分析NAFLD相关的危险因素。P＜0.05为差异有统计学意义。

2. 结果

2.1 一般资料

NAFLD组ALT、AST、TG、GGT、sUA、sUA/Cr水平均显著高于健康对照组，而HDL水平则显著低于健康对照组(P值均＜0.05)(表 1)。

表 1 NAFLD组与健康对照组临床资料比较

项目	NAFLD组(n=97)	健康对照组(n=36)	统计值	P值
男性[例(%)]	62(63.9)	25(69.4)	χ²=0.354	0.682
年龄(岁)	44(34~55)	39(34~52)	Z=-1.353	0.176
FBS(mmol/L)	5.15(4.69~6.28)	5.05(4.78~5.39)	Z=-1.473	0.141
ALT(U/L)	36.7(21.5~58.6)	14.6(11.6~20.0)	Z=-4.881	＜0.001
AST(U/L)	23.6(18.4~35.7)	15.6(13.5~17.8)	Z=-4.616	＜0.001
TC(mmol/L)	4.53(3.66~5.37)	4.67(3.88~5.23)	Z=-0.765	0.444
TG(mmol/L)	1.71(1.03~2.72)	0.95(0.62~1.32)	Z=-4.221	＜0.001
HDL(mmol/L)	1.14(1.00~1.38)	1.58(1.43~1.88)	Z=-5.682	＜0.001
LDL(mmol/L)	2.70±0.97	2.69±0.93	t=0.003	0.958
GGT(U/L)	39.46(20.31~55.72)	19.21(11.95~31.05)	Z=-3.563	＜0.001
sUA(μmmol/L)	363.46±95.75	294.27±92.36	t=12.974	＜0.001
sCr(μmmol/L)	63.20±19.19	58.37±14.93	t=1.723	0.192
sUA/Cr	6.04±1.60	5.05±1.11	t=10.710	0.001

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2.2 NAFLD脂肪肝严重程度与各指标相关性分析

随着脂肪肝严重程度的加重，NAFLD患者ALT、AST、TC、TG、LDL、GGT水平均显著升高(P值均＜0.05)(表 2)。相关性分析显示，NAFLD的脂肪肝严重程度(轻中重)与ALT(r=0.291，P=0.004)、TC(r=0.272，P=0.010)、LDL(r=0.253，P=0.017)水平呈正相关。

表 2 轻中重度NAFLD患者临床资料比较

项目	轻度NAFLD组(n=33)	中度NAFLD组(n=31)	重度NAFLD组(n=33)	统计值	P值
男性[例(%)]	23(69.7)	21(67.7)	18(54.5)	χ²=1.931	0.381
年龄(岁)	54(44~60)	42(34~61)	38(32~52)	Z=7.574	0.023
FBS(mmol/L)	5.11(4.39~6.12)	5.34(4.79~7.28)	5.29(4.76~6.12)	Z=2.937	0.230
ALT(U/L)	20.23(14.05~32.45)	45.30(24.20~76.51)	46.55(33.65~77.88)	Z=19.181	＜0.001
AST(U/L)	19.20(15.25~25.65)	26.40(20.00~41.30)	29.55(21.58~46.83)	Z=11.969	0.003
TC(mmol/L)	4.07(3.44~4.73)	4.62(3.57~4.97)	5.03(4.27~5.64)	Z=9.097	0.011
TG(mmol/L)	1.32(0.85~2.39)	1.41(1.05~2.12)	2.16(1.25~2.89)	Z=6.333	0.042
HDL(mmol/L)	1.13(0.98~1.35)	1.14(1.00~1.38)	1.23(1.02~1.45)	Z=1.100	0.577
LDL(mmol/L)	2.51±1.00	2.48±0.85	3.10±0.93	F=4.175	0.019
GGT(U/L)	24.30(16.05~47.80)	40.6(30.00~65.70)	42.15(30.05~57.45)	Z=7.667	0.022
sUA(μmmol/L)	349.55±109.80	368.60±100.52	372.28±76.64	F=0.466	0.629
sCr(μmmol/L)	62.44±16.03	68.21±24.99	59.08±14.32	F=1.855	0.162
sUA/Cr	5.72±1.48	5.95±1.86	6.45±1.42	F=1.648	0.199

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2.3 NAFLD发生的危险因素logistic回归分析

多因素logistic回归分析结果显示，年龄、HDL水平、sUA/Cr是发生NAFLD的独立影响因素(P值均＜0.05)(表 3)。

表 3 NAFLD发生的影响因素logistic回归分析

因素	OR	95%CI	B值	Wald值	P值
年龄(岁)	1.056	1.005~1.109	0.055	4.735	0.030
HDL(mmol/L)	0.023	0.003~0.186	-3.788	12.423	＜0.001
sUA/Cr	1.885	1.162~3.060	0.634	6.584	0.010

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3. 讨论

NAFLD是全球最常见的慢性肝病之一，世界范围内约有25%的人罹患NAFLD^[6]。近几十年来，随着人们生活方式、饮食结构的改变，NAFLD发病率不断上升，已成为我国第一大慢性肝病以及健康体检肝生物化学指标异常的最常见原因。目前认为，NAFLD与代谢综合征、胰岛素抵抗、糖尿病以及心血管疾病的风险增加有关^[7]。近10年间，NASH所致的肝移植率已从1.2%增加至9.7%^[8]。因此，寻找高效的NAFLD发生风险预测工具成为目前研究的热点。

尿酸主要由腺苷酸和鸟嘌呤分解后形成。研究^[9]显示，高尿酸血症是高血压病、脑卒中、动脉粥样硬化的独立危险因素。高尿酸血症也是代谢综合征的重要组分之一。尿酸在脂肪代谢中具有重要作用。即使是正常范围内sUA的水平升高，也与高脂血症、动脉硬化等具有显著相关性^[10]。Ali等^[11]研究指出，高尿酸血症是脂肪组织中促炎性细胞分泌失衡的重要介质，sUA与TG、TC和LDL水平呈显著正相关，与HDL呈负相关。诸多研究提示血尿酸水平与NAFLD具有显著的相关性。Afzali等^[12]研究指出，sUA与肝硬化的发展及肝酶升高具有显著相关性。尿酸的代谢与肾脏功能密切相关，尿酸经肾脏排出减少即会引起高尿酸血症。Kawamoto等^[13]指出，sUA/Cr水平是代谢综合征的独立预测因子。目前，国内尚未有sUA/Cr与NAFLD相关性的研究。

本研究NAFLD组ALT、AST、TG、GGT、sUA水平均显著高于健康对照组，HDL水平显著低于健康对照组，FBS、TC、LDL、GGT及sCr水平无明显差异。既往有Hwang等^[14]以及Moon等^[15]的研究已经指出sUA与NAFLD的相关性，本研究结果同样证实了这一结论。氧化应激是NAFLD发生的关键因子^[16]，sUA可能通过起到促氧化剂的作用，并与氧化剂发生反应，诱导产生自由基和氧化应激，从而影响NAFLD的发生。Xu等^[17]研究显示，NAFLD显著增加了高尿酸血症的发病风险，并指出黄嘌呤氧化酶可能是介导NAFLD患者发生高尿酸血症的重要因子。sUA通肾脏排泄，sUA的清除通常受肾功能的影响，而既往研究大都没有考虑到肾脏的影响。sUA/Cr较sUA更能准确地反映内源性UA水平。本研究结果显示，NAFLD组sUA/Cr水平均显著高于健康对照组。而多因素logistic回归分析结果显示，sUA/Cr是NAFLD的独立危险因素。Seo等^[18]研究显示，健康成人sUA/Cr升高与NAFLD具有显著相关性，故指出sUA/Cr可作为预测NAFLD的可靠指标。这与本研究结果一致。根据腹部超声检测结果，根据脂肪肝严重程度分为轻、中、重度3组，结果显示，随着NAFLD患者脂肪肝严重程度的加重，其ALT、AST、TC、TG、LDL、GGT水平显著升高。相关性分析结果显示，ALT、TC、LDL与NAFLD的严重程度呈正相关。因此，虽然sUA/Cr是NAFLD的独立危险因素，尚无法通过检测sUA/Cr水平来预测NAFLD的严重程度。

综上所述，鉴于NAFLD在世界范围内的高发病率，亟需一种非侵入性、成本效益高的筛查工具来预测存在潜在NAFLD风险的患者。本研究结果显示，sUA/Cr水平升高与成人罹患NAFLD有很强的相关性。NAFLD受试者的sUA水平和sUA/Cr均显著升高，即使校正了混杂因素，NAFLD的患病风险也与sUA/Cr升高有关。因此，可以通过监测sUA/Cr水平判断NAFLD的风险，以早期采取改善生活方式乃至药物等有效的干预措施预防NAFLD的发生，延缓NAFLD进展并改善患者预后。

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Current status of research on the prognostic markers for acute-on-chronic liver failure

DOI: 10.3969/j.issn.1001-5256.2021.11.047