HBV相关慢加急性肝衰竭患者血清抗延胡索酸水合酶自身抗体的表达及对临床预后的预测价值

摘要/Abstract

摘要： 目的探究抗FH自身抗体(抗FH抗体)在HBV相关慢加急性肝衰竭(HBV-ACLF)血清中的表达,并确定其是否可作为评估HBV-ACLF预后的生物标志物。方法选取2019年1月—2021年12月期间南京中医药大学附属南京医院(南京市第二医院) 诊治慢性乙型肝炎(CHB)患者43例、乙肝相关肝硬化(HBV-LC)40例和HBV-ACLF患者46例,比较CHB、HBV-LC、HBV-ACLF抗FH抗体及一般资料,随访观察,将HBV-ACLF患者分为好转组、死亡组,比较两组抗FH抗体、实验室指标、MELD评分,通过绘制ROC曲线分析血清抗FH抗体对HBV-ACLF预后的预测价值。结果 HBV-ACLF组ALT、AST、TBil和DBil为72(36.5,103.7)U/L、88(43.1,145.6)U/L、145.8(100.2,223.8)μmol/L和101.9(88.2,163.9)μmol/L,分别显著高于HBV-LC组[32(27.2,58.4)U/L、33(25.3,44.3)U/L、35.4(20.3,51.6)μmol/L和17.1(14.9,30.7)μmol/L]、CHB组[17(19.3,31.6)U/L、15(18.8,32.4)U/L、20.1(9.4,32.1)μmol/L和12.9(10.5,26.3)μmol/L]。HBV-ACLF组ALB、PLT为26.1(14.2,38.7)g/L、(90.3±4.6)×10⁹/L,分别显著低于HBV-LC组[38.2(19.8,60.2)g/L、(104.4±1.4)×10⁹/L]、CHB组[40.1(21.4,56.8)g/L、(146.6±0.3)×10⁹/L],差异具有统计学意义(P<0.05)。CHB组、HBV-LC组和HBV-ACLF组血清抗FH抗体含量为(3.5±1.2)mg/L、(25.3±12.5)mg/L及(53.7±11.4)mg/L,差异具有统计学意义(P<0.05)。根据HBV-ACLF组患者随访结束的结局分为好转组(n=31)和死亡组(n=15)。好转组抗FH抗体、ALT、AST、Alb、TBil、DBil、PT、AFP和MELD评分为(13.6±6.8)mg/L、69.4(30.6,80.3)U/L、79.1(38.5,97.8)U/L、29.3(23.7,33.4)g/L、146.6(124.7,200.9)μmol/L、63.5(52.2,93.2)μmol/L、14.3(12.0,26.8)s、29(21.2,30.4)ng/mL及1.0(0.0,2.4)分,与死亡组[(50.8±25.5)mg/L、109.9(68.9,163.1)U/L、143.8(70.3,193.9)U/L、16.7(9.85,30.4)g/L、297.4(208.7,374.2)μmol/L、86.7(53.7,99.4)μmol/L、26.8(20.6,45.5)s、3.5(2.1,7.3)ng/mL及14.2(6.03,20.4)分]比,差异具有统计学意义(P<0.05)。抗FH抗体预测HBV-ACLF患者死亡发生的ROC曲线下面积为0.751,最佳截断值29.8 mg/L(P<0.05),其敏感性和特异性分别为73.3%和67.7%。结论抗FH抗体在HBV-ACLF患者血清中表达水平增高,可有效评估患者的病情严重程度,可作为预后判断的重要指标。

关键词: HBV相关慢加急性肝衰竭, 抗FH自身抗体, 预后

Abstract: Objective To investigate the expression of anti-fumarate hydratase autoantibodies (anti-FH antibodies) in the serum of patients with chronic hepatitis B-related acute-on-chronic liver failure (HBV-ACLF), and assess their potential as a biomarker for predicting the prognosis of HBV-ACLF. Methods Between January 2019 and December 2021, 43 patients with chronic hepatitis B (CHB), 40 patients with hepatitis B-related liver cirrhosis (HBV-LC), and 46 patients with HBV-ACLF were enrolled. Anti-FH antibody levels in CHB, HBV-LC and HBV-ACLF patients were compared, and general clinical data were collected for followed-up. Patients with HBV-ACLF were further categorized into an improvement group and a death group, and comparisons were made between the two groups. Results In the HBV-ACLF group, the levels of ALT, AST, TBil and DBil were 72 (36.5, 103.7) U/L, 88 (43.1, 145.6) U/L, 145.8 (100.2, 223.8) μmol/L and 101.9 (88.2, 163.9) μmol/L, respectively. These values were significantly higher than those in the HBV-LC group [32 (27.2, 58.4) U/L, 33 (25.3, 44.3) U/L, 35.4 (20.3, 51.6) μmol/L and 17.1 (14.9, 30.7) μmol/L] and the CHB group [17 (19.3, 31.6) U/L, 15 (18.8, 32.4) U/L, 20.1 (9.4, 32.1) μmol/L and 12.9 (10.5, 26.3) μmol/L], with the differences being statistically significant (P<0.05). The Alb and PLT levels in the HBV-ACLF group were 26.1 (14.2, 38.7) g/L and (90.3±4.6) ×10⁹/L, which were significantly lower than those in the HBV-LC group [38.2 (19.8, 60.2) g/L and (104.4±1.4) ×10⁹/L and the CHB group [40.1 (21.4, 56.8) g/L, (146.6±0.3) ×10⁹/L]. The Anti-FH antibody levels in the CHB group, HBV-LC group and HBV-ACLF groups were (3.5±1.2) mg/L, (25.3±12.5) mg/L and (53.7±11.4) mg/L, respectively. With statistically significant differences(P<0.05). Patients in HBV-ACLF group were categorized into an improvement group (n=31) and a death group (n=15) based on follow-up outcomes. The anti-FH antibody levels, ALT, AST, Alb, TBil, DBil, PT, AFP and MELD scores in the improved group were (13.6±6.8) mg/L, 69.4 (30.6, 80.3) U/L, 79.1 (38.5, 97.8) U/L, 29.3 (23.7, 33.4) g/L, 146.6 (124.7, 200.9) μmol/L, 63.5 (52.2, 93.2) μmol/L, 14.3 (12.0, 26.8), 29 (21.2, 30.4) ng/mL and 1.0 (0.0, 2.4) points, respetively. These values were significantly different from those in the death group, where the values were [ (50.8±25.5) mg/L, 109.9 (68.9, 163.1) U/L, 143.8 (70.3, 193.9) U/L, 16.7 (9.8, 30.4) g/L, 297.4 (208.7, 374.2) μmol/L, 86.7 (53.7, 99.4) μmol/L, 26.8 (20.6, 45.5) seconds, 3.5 (2.1, 7.3) ng/mL and 14.2 (6.0, 20.4) points, with all differences being statistically significant (P<0.05). The area under the ROC curve (AUC) for anti-FH antibodies in predicting mortality in HBV-ACLF patients was 0.751, with an optimal cutoff value of 29.8 mg/L (P<0.05). The sensitivity and specificity at this cutoff were 73.3% and 67.7% respectively. Conclusion The serum expression level of anti-FH antibodies is elevated in patients with HBV-ACLF making it a valuable marker for assessing disease severity and serving as an important prognostic indicator.

Key words: Chronic hepatitis B-acute-on-chronic liver failure, Anti-fumarate hydratase autoantibody, Prognosis

付鲁渝, 熊志强, 刘兰侠, 刘杜先, 熊清芳, 张杰东. HBV相关慢加急性肝衰竭患者血清抗延胡索酸水合酶自身抗体的表达及对临床预后的预测价值[J]. 肝脏, 2024, 29(10): 1256-1259.

FU Lu-yu, XIONG Zhi-qiang, LIU Lan-xia, LIU Du-xian, XIONG Qing-fang, ZHANG Jie-dong. Serum anti-fumarate hydratase autoantibodies in hepatitis-B-associated acute-on-chronic liver failure: changes and their prognostic value[J]. Chinese Hepatolgy, 2024, 29(10): 1256-1259.

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参考文献

[1] Li Q, Wang J, Lu M, et al. Acute-on-chronic liver failure from chronic-hepatitis-B, who is the behind scenes[J]. Front Microbiol,2020,11:583423.
[2] Li J, Liang X, You S, et al. Development and validation of a new prognostic score for hepatitis B virus-related acute-on-chronic liver failure[J]. J Hepatol,2021,75:1104-1115.
[3] Wu T, Li J, Shao L, et al. Development of diagnostic criteria and a prognostic score for hepatitis B virus-related acute-on-chronic liver failure[J]. Gut,2018,67:2181-2191.
[4] Zhang L, Hu J, Gou C, et al. Serum interleukins as potential prognostic biomarkers in HBV-related acute-on-chronic liver failure[J]. Mediators Inflamm,2022,2022:7794890.
[5] Cheng D, Wu C, Li Y, et al. METTL3 inhibition ameliorates liver damage in mouse with hepatitis B virus-associated acute-on-chronic liver failure by regulating miR-146a-5p maturation[J]. Biochim Biophys Acta Gene Regul Mech,2022,1865:194782.
[6] Luo J, Liang X, Xin J, et al. Predicting the onset of hepatitis B virus-related acute-on-chronic liver failure[J]. Clin Gastroenterol Hepatol,2023,21:681-693.
[7] Ramzan M, Iqbal A, Murtaza HG, et al. Comparison of CLIF-C HBV-ACLF score and MELD score in predicting ICU mortality in patients with acute-on-chronic liver failure[J]. Cureus,2020,12:e7087.
[8] Ueno T, Takase K, Deguchi K, et al. Early detection of liver fibrosis with serum Mac-2 binding protein glycosylation-modified isomer (M2BPGi) during follow-up intestinal failure patients without intestinal failure-associated liver disease (IFALD)[J]. Pediatr Surg Int,2022,38:1807-1813.
[9] Arroyo V, Moreau R, Jalan R. Acute-on-chronic liver failure[J]. N Engl J Med,2020,382:2137-2145.
[10] Xie Z, Violetta L, Chen E, et al. A prognostic model for hepatitis B acute-on-chronic liver failure patients treated using a plasma exchange-centered liver support system[J]. J Clin Apher,2020,35:94-103.
[11] Xiao ZX, Miller JS, Zheng SG. An updated advance of autoantibodies in autoimmune diseases[J]. Autoimmun Rev,2021,20:102743.
[12] 徐小元, 丁惠国, 李文刚, 等. 肝硬化诊治指南[J]. 实用肝脏病杂志,2019,22:770-786.
[13] 中华医学会感染病学分会肝衰竭与人工肝学组, 中华医学会肝病学分会重型肝病与人工肝学组. 肝衰竭诊治指南(2018年版)[J]. 中华肝脏病杂志,2019,27(1):18-26.
[14] Tang X, Qi T, Li B, et al. Tri-typing of hepatitis B-related acute-on-chronic liver failure defined by the World Gastroenterology Organization[J]. J Gastroenterol Hepatol,2021,36:208-216.
[15] Sun Z, Liu X, Wu D, et al. Circulating proteomic panels for diagnosis and risk stratification of acute-on-chronic liver failure in patients with viral hepatitis B[J]. Theranostics,2019,9:1200-1214.
[16] 孙梦滢, 陈备金, 李浩, 等. 晚期乙型肝炎相关慢加急性肝衰竭患者预后相关因素分析[J]. 中华肝脏病杂志,2021,29(10):983-986.
[17] Zhao Y, Li Y, Zhao D, et al. Fumarate hydratase-specific T cell response in Chinese patients with autoimmune hepatitis[J]. Clin Res Hepatol Gastroenterol,2018,42:339-346.
[18] Sun G, Zhang X, Liang J, et al. Integrated molecular characterization of fumarate hydratase-deficient renal cell carcinoma[J]. Clin Cancer Res,2021,27:1734-1743.
[19] Noguchi S, Ishikawa H, Wakita K, et al. Direct and quantitative analysis of altered metabolic flux distributions and cellular ATP production pathway in fumarate hydratase-diminished cells[J]. Sci Rep,2020,10:13065.
[20] Yang Y, Lane AN, Ricketts CJ, et al. Metabolic reprogramming for producing energy and reducing power in fumarate hydratase null cells from hereditary leiomyomatosis renal cell carcinoma[J]. PLoS One,2013,8(8):e72179.