APRI、FIB-4和GPR对慢性乙型肝炎肝脏炎症程度的诊断价值

周新兰; 马鑫; 王雁冰; 李秀芬; 黄丹; 陆伟; 张占卿; 丁荣蓉

doi:10.3969/j.issn.1001-5256.2021.09.013

APRI、FIB-4和GPR对慢性乙型肝炎肝脏炎症程度的诊断价值

DOI: 10.3969/j.issn.1001-5256.2021.09.013

a.
上海市公共卫生临床中心肝胆内科，上海 201508
b.
上海市公共卫生临床中心超声科，上海 201508

利益冲突声明：本研究不存在研究者、伦理委员会成员、受试者监护人以及与公开研究成果有关的利益冲突。

作者贡献声明：周新兰、马鑫负责课题设计，资料分析及撰写论文；王雁冰、李秀芬、黄丹、陆伟参与数据收集和分析；张占卿、丁荣蓉负责拟定写作思路及修改论文；丁荣蓉指导撰写文章并最后定稿。

详细信息

通信作者:
丁荣蓉，dingrongrong@shphc.org.cn

周新兰与马鑫对本文贡献相同，同为第一作者

中图分类号: R512.62
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出版历程
- 收稿日期: 2021-01-25
- 录用日期: 2021-03-03
- 出版日期: 2021-09-20

Value of aspartate aminotransferase-to-platelet ratio index, fibrosis-4, and gamma-glutamyl transpeptidase-to-platelet ratio in diagnosis of liver inflammation grade in patients with chronic hepatitis B

a.
Department of Hepatobiliary Medicine, Shanghai Public Health Clinical Center Affiliated to Fudan University, Shanghai 201508, China
b.
Department of Ultrasound, Shanghai Public Health Clinical Center Affiliated to Fudan University, Shanghai 201508, China

摘要

摘要: 目的评价AST/PLT指数(APRI)、纤维化指数(FIB-4)、GGT/PLT比值(GPR)对慢性乙型肝炎(CHB)患者肝组织炎症分级的诊断价值。方法选取2016年10月—2019年10月在上海市公共卫生临床中心住院期间接受经皮肝组织活检及常规实验室检查的CHB患者545例。依据Scheuer方法进行炎症分级(G)，并依据临床指标分别计算APRI、FIB-4、GPR。正态分布计量资料2组间比较采用t检验；非正态分布计量资料2组间比较采用Mann-Whitney U检验。计数资料2组间比较采用χ²检验。两变量间相关性应用Spearman相关分析。血清无创诊断模型对肝组织炎症活动度分级的诊断性能评价采用受试者工作特征曲线法(ROC曲线)。采用Delong检验比较血清无创模型的ROC曲线下面积(AUC)。结果 545例患者中肝组织炎症分级G0~1级224例，G2级209例，G3级112例。Spearman相关分析结果显示，APRI、FIB-4和GPR值与肝组织炎症分级均呈正相关(r值分别为0.611、0.470、0.563，P值均＜0.001)。APRI、FIB-4和GPR诊断肝炎症分级G≥2的AUC分别为0.820、0.719、0.782；临界值分别为0.53、1.48和0.20；GPR诊断G≥2的效能优于FIB-4(P=0.01)，但略低于APRI(P=0.048)。基于ALT水平分层分析，在ALT ≤1×ULN组、1~2×ULN组和2~5×ULN组，APRI诊断G≥2的AUC分别为0.847、0.786和0.724，FIB-4分别为0.777、0.729和0.626，GPR分别为0.801、0.781和0.607；亚组结果显示除在2~5×ULN组GPR诊断效能低于APRI(P=0.042), 其余ALT分层组GPR和APRI、FIB-4诊断性能相似。APRI、FIB-4和GPR诊断肝炎症分级G≥3的AUC分别为0.791、0.725、0.801；临界值分别为0.66、1.49和0.25；GPR诊断炎症分级G≥3的效能与APRI相似，但优于FIB-4(P=0.006)。基于ALT水平分层分析，在ALT ≤1×ULN组、1~2×ULN组和2~5×ULN组，APRI诊断G≥3的AUC分别为0.900、0.742和0.693，FIB-4分别为0.874、0.683和0.644，GPR分别为0.890、0.805和0.668。亚组结果显示除在1~2×ULN组GPR诊断效能优于FIB-4(P=0.015)，其余ALT分层组GPR和APRI、FIB-4诊断性能相似。结论 APRI、FIB-4和GPR可较准确地诊断CHB肝脏炎症坏死程度，有助于监测CHB疾病进展，并对抗病毒治疗时机的确定有重要意义。
- 慢性乙型肝炎 /
- 炎症 /
- 诊断
Abstract: Objective To investigate the value of aspartate aminotransferase-to-platelet ratio index (APRI), fibrosis-4 (FIB-4) score, and gamma-glutamyl transpeptidase-to-platelet ratio (GPR) in diagnosis of liver inflammation grade in patients with chronic hepatitis B (CHB). Methods A total of 545 patients with CHB who underwent percutaneous liver biopsy and routine laboratory examinations during hospitalization in Shanghai Public Health Clinical Center Affiliated to Fudan University from October 2016 to October 2019 were enrolled. Inflammation grade (G) was determined according to the Scheuer scoring system, and APRI, FIB-4, and GPR were calculated based on related clinical indicators. The t-test was used for comparison of normally distributed continuous data between two groups, and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups; the chi-square test was used for comparison of categorical data between two groups. A Spearman correlation analysis was used to investigate the correlation between two variables. The receiver operating characteristic (ROC) curve was used to evaluate the diagnostic performance of the three serum noninvasive diagnostic models in determining liver inflammation grade, and the Delong test was used for comparison of the area under the ROC curve (AUC). Results Among the 545 patients, 224 had grade G0-1 liver inflammation, 209 had grade G2 liver inflammation, and 112 had grade G3 liver inflammation. The Spearman correlation analysis showed that APRI, FIB-4, and GPR were positively correlated with liver inflammation grade (r=0.611, 0.470, and 0.563, all P < 0.001). APRI, FIB-4, and GPR had an AUC of 0.820, 0.719, and 0.782, respectively, in the diagnosis of G≥2 liver inflammation, with optimal cut-off values of 0.53, 1.48, and 0.20, respectively; for the diagnosis of G≥2 liver inflammation, GPR had a better performance than FIB-4 (P=0.01) and a slightly lower performance than APRI (P=0.048). The stratified analysis based on alanine aminotransferase (ALT) level showed that in the ≤1×upper limit of normal (ULN) group, the (1-2)×ULN group, and the (2-5)×ULN group, APRI had an AUC of 0.847, 0.786, and 0.724, respectively, in the diagnosis of G≥2 liver inflammation, FIB-4 had an AUC of 0.777, 0.729, and 0.626, respectively, and GPR had an AUC of 0.801, 0.781, and 0.607, respectively; the subgroup analysis showed that GPR had a similar diagnostic performance to APRI and FIB-4 in all ALT stratification groups except the (2-5)×ULN group, in which GPR had a lower diagnostic performance than APRI (P=0.042). APRI, FIB-4, and GPR had an AUC of 0.791, 0.725, and 0.801, respectively, in the diagnosis of G≥3 liver inflammation, with optimal cut-off values of 0.66, 1.49, and 0.25, respectively; in the diagnosis of G≥3 liver inflammation, GPR had a similar diagnostic performance to APRI and a better diagnostic performance than FIB-4 (P=0.006). The stratified analysis based on ALT level showed that in the ≤1×ULN group, the (1-2)×ULN group, and the (2-5)×ULN group, APRI had an AUC of 0.900, 0.742, and 0.693, respectively, in the diagnosis of G≥3 liver inflammation, FIB-4 had an AUC of 0.874, 0.683, and 0.644, respectively, and GPR had an AUC of 0.890, 0.805, and 0.668, respectively. The subgroup analysis showed that GPR had a similar diagnostic performance to APRI and FIB-4 in all ALT stratification groups except the (1-2)×ULN group, in which GPR had a better diagnostic performance than FIB-4(P=0.015). Conclusion APRI, FIB-4, and GPR may accurately diagnose liver inflammation grade in CHB patients, which helps to monitor the progression of CHB and determine the timing of antiviral therapy.
- Chronic Hepatits B /
- Inflammation /
- Diagnosis

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表 1 研究对象的临床资料

指标	所有患者(n=545)	炎症分级		统计值	P值
指标	所有患者(n=545)	G0~1(n=224)	G2~3(n=321)	统计值	P值
年龄(岁)	37(30~44)	37(31~46)	36(30~44)	Z=-1.863	0.062
男性[例(%)]	454(83.3)	148(66.2)	206(64.2)	χ²=0.198	0.656
HBeAg阳性[例(%)]	284(52.1)	84(37.5)	200(62.4)	χ²=20.785	＜0.001
HBV DNA(log₁₀ IU/ml)	6.3(4.1~7.3)	4.9(3.0~7.3)	6.6(5.3~7.4)	Z=6.295	＜0.001
ALT(U/L)	63.0(32.0~163.0)	37.0(18.0~71.0)	106.5(48.3~286.0)	Z=10.735	＜0.001
AST(U/L)	46.0(26.0~98.0)	28.0(20.0~45.5)	75.5(42.0~170.0)	Z=12.814	＜0.001
ALP(U/L)	76.0(63.0~95.0)	70.0(59.0~85.0)	83.0(68.0~103.5)	Z=6.052	＜0.001
GGT(U/L)	38.0(19.0~79.5)	22.0(14.5~39.0)	63.0(32.3~112.7)	Z=11.479	＜0.001
TBil(μmol/L)	15.1(11.1~20.7)	14.3(11.1~17.9)	15.9(11.3~22.0)	Z=3.976	＜0.001
Alb(g/L)	41.5(38.5~44.0)	42.8(40.5~45.6)	40.0(37.0~43.5)	Z=-8.173	＜0.001
Glo(g/L)	29.0(26.9~33.0)	29.0(26.0~32.0)	30.0(27.0~33.7)	Z=5.282	＜0.001
尿素氮(μmol/L)	4.6(3.8~5.5)	4.8(4.0~5.5)	4.5(3.7~5.5)	Z=-2.049	0.040
肌酐(μmol/L)	64.9(54.6~74.7)	63.6(54.7~73.9)	66.3(54.5~75.6)	Z=0.694	0.488
INR	1.1(1.0~1.1)	1.0(1.0~1.1)	1.1(1.0~1.2)	Z=6.477	＜0.001
WBC(×10⁹/L)	5.1(4.1~6.1)	5.4(4.1~6.3)	5.0(4.2~6.0)	Z=-3.131	0.002
RBC(×10⁹/L)	2.7(2.1~3.5)	3.0(2.2~3.8)	2.5(2.0~3.2)	Z=-3.852	＜0.001
PLT(×10⁹/L)	157(124~192)	177(148~201)	142(110~177)	Z=-7.628	＜0.001
APRI	0.81(0.40~1.65)	0.41(0.27~0.75)	1.34(0.73~2.37)	Z=13.991	＜0.001
FIB-4	1.41(0.97~2.39)	1.09(0.80~1.52)	1.81(1.24~3.38)	Z=10.142	＜0.001
GPR	0.25(0.12~0.66)	0.13(0.08~0.23)	0.40(0.23~1.10)	Z=12.444	＜0.001

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表 2 血清参数对肝组织炎症分级G≥2级的诊断价值

指标	ALT分层	AUC(95% CI)	P值	截断值	敏感度(%)	特异度(%)	准确度(%)
APRI	所有患者(n=545)	0.820(0.781~0.855)	＜0.000 1	0.53	80.4	69.4	75.1
	≤1×ULN (n=208)	0.847(0.785~0.896)	＜0.000 1	0.34	87.7	73.6	78.1
	1~2×ULN (n=167)	0.786(0.708~0.852)	＜0.000 1	0.58	80.5	65.5	74.5
	2~5×ULN (n=170)	0.724(0.639~0.799)	＜0.000 1	0.98	72.2	62.5	69.2
FIB-4	所有患者(n=545)	0.719(0.675~0.760)	＜0.000 1	1.48	56.8	77.3	66.7
	≤1×ULN (n=208)	0.777(0.709~0.836)	＜0.000 1	1.35	71.9	75.2	74.2
	1~2×ULN (n=167)	0.729(0.647~0.802)	＜0.000 1	1.41	62.2	72.7	66.4
	2~5×ULN (n=170)	0.626(0.537~0.709)	＜0.000 1	0.92	84.4	40.0	70.8
GPR	所有患者(n=545)	0.782(0.741~0.819)	＜0.000 1	0.20	74.7	71.3	73.1
	≤1×ULN (n=208)	0.801(0.735~0.857)	＜0.000 1	0.15	73.7	78.5	77.0
	1~2×ULN (n=167)	0.781(0.702~0.847)	＜0.000 1	0.25	69.5	80.0	73.7
	2~5×ULN (n=170)	0.607(0.517~0.691)	0.052 7	0.27	66.7	55.0	63.1

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表 3 血清参数模型对肝组织炎症分级G≥3级的诊断价值

指标	ALT分层	AUC(95% CI)	P值	截断值	敏感度(%)	特异度(%)	准确度(%)
APRI	所有患者(n=545)	0.791(0.750~0.827)	＜0.000 1	0.66	89.2	60.1	64.9
	≤1×ULN (n=208)	0.900(0.846~0.940)	＜0.000 1	0.53	93.3	83.4	84.3
	1~2×ULN (n=167)	0.742(0.660~0.813)	＜0.000 1	0.64	86.2	55.6	62.1
	2~5×ULN (n=170)	0.693(0.606~0.771)	＜0.000 1	1.37	60.0	72.0	69.2
FIB-4	所有患者(n=545)	0.725(0.681~0.766)	＜0.000 1	1.49	70.3	66.0	66.7
	≤1×ULN (n=208)	0.874(0.816~0.919)	＜0.000 1	1.76	93.3	80.9	82.0
	1~2×ULN (n=167)	0.683(0.598~0.760)	＜0.000 1	1.41	72.4	58.3	61.3
	2~5×ULN (n=170)	0.644(0.555~0.726)	＜0.000 1	1.13	83.3	41.0	50.8
GPR	所有患者(n=545)	0.801(0.761~0.837)	＜0.000 1	0.25	86.5	65.2	68.8
	≤1×ULN (n=208)	0.890(0.835~0.932)	＜0.000 1	0.17	98.0	73.4	74.7
	1~2×ULN (n=167)	0.805(0.729~0.868)	＜0.000 1	0.28	93.1	67.6	73.0
	2~5×ULN (n=170)	0.668(0.580~0.748)	0.001 8	0.30	76.7	53.0	58.5

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参考文献(18)

[1]	SHIH C, YANG CC, CHOIJILSUREN G, et al. Hepatitis B virus[J]. Trends Microbiol, 2018, 26(4): 386-387. DOI: 10.1016/j.tim.2018.01.009.
[2]	LAMPERTICO P, INVERNIZZI F, VIGANÒ M, et al. The long-term benefits of nucleos(t)ide analogs in compensated HBV cirrhotic patients with no or small esophageal varices: A 12-year prospective cohort study[J]. J Hepatol, 2015, 63(5): 1118-1125. DOI: 10.1016/j.jhep.2015.06.006.
[3]	KIM WR, LOOMBA R, BERG T, et al. Impact of long-term tenofovir disoproxil fumarate on incidence of hepatocellular carcinoma in patients with chronic hepatitis B[J]. Cancer, 2015, 121(20): 3631-3638. DOI: 10.1002/cncr.29537.
[4]	KEW MC. Serum aminotransferase concentration as evidence of hepatocellular damage[J]. Lancet, 2000, 355(9204): 591-592. DOI: 10.1016/S0140-6736(99)00219-6.
[5]	NGUYEN MH, GARCIA RT, TRINH HN, et al. Histological disease in Asian-Americans with chronic hepatitis B, high hepatitis B virus DNA, and normal alanine aminotransferase levels[J]. Am J Gastroenterol, 2009, 104(9): 2206-2213. DOI: 10.1038/ajg.2009.248.
[6]	DONG M, WU J, YU X, et al. Validation and comparison of seventeen noninvasive models for evaluating liver fibrosis in Chinese hepatitis B patients[J]. Liver Int, 2018, 38(9): 1562-1570. DOI: 10.1111/liv.13688.
[7]	LEMOINE M, SHIMAKAWA Y, NAYAGAM S, et al. The gamma-glutamyl transpeptidase to platelet ratio (GPR) predicts significant liver fibrosis and cirrhosis in patients with chronic HBV infection in West Africa[J]. Gut, 2016, 65(8): 1369-1376. DOI: 10.1136/gutjnl-2015-309260.
[8]	WU X, CAI B, SU Z, et al. Aspartate transaminase to platelet ratio index and gamma-glutamyl transpeptidase-to-platelet ratio outweigh fibrosis index based on four factors and red cell distribution width-platelet ratio in diagnosing liver fibrosis and inflammation in chronic hepatitis B[J]. J Clin Lab Anal, 2018, 32(4): e22341. DOI: 10.1002/jcla.22341.
[9]	WANG L, LI J, YANG K, et al. Comparison and evaluation of non-invasive models in predicting liver inflammation and fibrosis of chronic hepatitis B virus-infected patients with high hepatitis B virus DNA and normal or mildly elevated alanine transaminase levels[J]. Medicine (Baltimore), 2020, 99(23): e20548. DOI: 10.1097/MD.0000000000020548.
[10]	Chinese Society of Hepatology and Chinese Society of infectious Diseases, Chinese Medical Association. The guideline of prevention and treatment for chronic hepatitis B: A 2015 update[J]. J Cin Hepatol, 2015, 31(12): 1941-1960. DOI: 10.3969/j.issn.1001-5256.2015.12.002. 中华医学会肝病学分会, 中华医学会感染病学分会. 慢性乙型肝炎防治指南(2015年更新版)[J]. 临床肝胆病杂志, 2015, 31(12): 1941-1960. DOI: 10.3969/j.issn.1001-5256.2015.12.002.
[11]	SCHEUER PJ. The nomenclature of chronic hepatitis: Time for a change[J]. J Hepatol, 1995, 22(1): 112-114. DOI: 10.1016/0168-8278(95)80269-x.
[12]	KOYAMA Y, BRENNER DA. Liver inflammation and fibrosis[J]. J Clin Invest, 2017, 127(1): 55-64. DOI: 10.1172/JCI88881.
[13]	HUANG H, SUN Z, PAN H, et al. Serum metabolomic signatures discriminate early liver inflammation and fibrosis stages in patients with chronic hepatitis B[J]. Sci Rep, 2016, 6: 30853. DOI: 10.1038/srep30853.
[14]	LAI M, HYATT BJ, NASSER I, et al. The clinical significance of persistently normal ALT in chronic hepatitis B infection[J]. J Hepatol, 2007, 47(6): 760-767. DOI: 10.1016/j.jhep.2007.07.022.
[15]	World Health Organization. Guidelines for the prevention, care and treatment of persons with chronic hepatitis B infection[R]. Geneva: WHO, 2015.
[16]	LIU DP, LU W, ZHANG ZQ, et al. Comparative evaluation of GPR versus APRI and FIB-4 in predicting different levels of liver fibrosis of chronic hepatitis B[J]. J Viral Hepat, 2018, 25(5): 581-589. DOI: 10.1111/jvh.12842.
[17]	LI Q, LI W, HUANG Y, et al. The gamma-glutamyl transpeptidase-to-platelet ratio predicts liver fibrosis and cirrhosis in HBeAg-positive chronic HBV infection patients with high HBV DNA and normal or mildly elevated alanine transaminase levels in China[J]. J Viral Hepat, 2016, 23(11): 912-919. DOI: 10.1111/jvh.12563.
[18]	WANG J, XIA J, YAN X, et al. The gamma-glutamyl transpeptidase to platelet ratio predicts liver inflammation in chronic hepatitis B with normal or mildly elevated alanine transaminase[J]. Clin Res Hepatol Gastroenterol, 2020, 44(6): 913-922. DOI: 10.1016/j.clinre.2020.01.011.