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广东地区新型冠状病毒Delta变异株感染并发肝功能异常患者的临床特征分析
DOI: 10.3969/j.issn.1001-5256.2022.03.017
伦理学声明：本研究方案于2020年1月已通过广州医科大学附属市八医院伦理委员会审查，批号：202001134，所有患者均签署知情同意书。
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：林浩炜负责课题设计，撰写论文；雷燕、陈彬彬、巫培连参与临床数据的收集与统计分析；邓浩辉负责拟定写作思路，指导撰写论文，修改论文并最后定稿。
Clinical features of patients with severe acute respiratory syndrome coronavirus 2 Delta variant infection and abnormal liver function in Guangdong Province, China
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摘要:
目的 总结分析广东地区新型冠状病毒（SARS-CoV-2）Delta变异株感染并发肝功能异常患者的临床特征。 方法 选取2021年5月21日—2021年6月18日广州医科大学附属市八医院收治的广东地区（广州市和佛山市）同一传播链的SARS-CoV-2 Delta变异株感染者，肝功能指标判定标准：ALT（男/女）＞50/40 U/L，AST＞40 U/L，TBil＞26 μmol/L，GGT＞60 U/L，ALP＞125 U/L。上述指标其中1项异常，即定义为肝功能异常并纳入分析（< 18岁的患者ALP单项轻中度升高不纳入分析）。比较肝功能正常者与肝功能异常者临床资料的差异，并分析肝功能异常的病因及转归。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。 结果 166例SARS-CoV-2 Delta变异株感染者中，32例（19.3%）患者出现肝功能异常，肝功能指标均为轻度至中度升高，肝功能异常组危重型患者占比明显高于肝功能正常组（χ2=38.689，P < 0.001），前者年龄、炎症指标（C反应蛋白、血清淀粉样蛋白A和IL-6）水平亦明显高于肝功能正常组（P值均 < 0.05）。在32例肝功能异常患者中，13例患者入院时即出现肝功能异常（原发组），19例患者在入院时肝功能指标正常，但经治后复查发现肝功能异常（继发组）。原发组3例（3/13，23.1%）患者未发现其他引起肝功能异常的证据，考虑SARS-CoV-2感染直接相关的中毒性肝损伤可能性大；继发组中，轻/普通型9例（47.4%），危重型10例（52.6%），危重型患者均存在炎症因子（C反应蛋白、血清淀粉样蛋白A和IL-6）水平明显升高和低氧血症等间接引起肝损伤的证据，继发组仅1例（1/19，5.3%）患者未发现其他引起肝功能异常的证据，考虑SARS-CoV-2感染直接相关的中毒性肝损伤可能性大。32例肝功能异常的患者经护肝等治疗后肝功能指标均较峰值明显下降。 结论 在本次广东地区同一传播链的SARS-CoV-2 Delta变异株感染者中，危重型患者肝功能异常的占比明显高于其他临床分型，其肝损伤病因以SARS-CoV-2感染以外的其他因素及间接损伤为主。 Abstract:Objective To investigate the clinical features of patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Delta variant infection and abnormal liver function in Guangdong Province, China. Methods The patients with SARS-CoV-2 Delta variant infection who belonged to the same chain of transmission in Guangdong Province (Guangzhou and Foshan) and were admitted to Guangzhou Eighth People's Hospital, Guangzhou Medical University from May 21 to June 18, 2021 were enrolled in this study, and the judgment criteria for liver function were alanine aminotransferase (male/female) > 50/40 U/L, aspartate aminotransferase > 40 U/L, total bilirubin > 26 μmol/L, gamma-glutamyl transpeptidase > 60 U/L, and alkaline phosphatase (ALK) > 125 U/L. Abnormality in any one item of the above criteria was defined as abnormal liver function, and such patients were included in analysis (the patients, aged < 18 years, who had a mild or moderate increase in ALP alone were not included in analysis). Clinical data were compared between the patients with normal liver function and those with abnormal liver function, and the etiology and prognosis of abnormal liver function were analyzed. The Mann-Whitney U test was used for comparison of continuous data between two groups; the chi-square test was used for comparison of categorical data between two groups. Results Among the 166 patients with SARS-CoV-2 Delta variant infection, 32 (19.3%) had abnormal liver function with mild-to-moderate increases in liver function parameters, and compared with the normal liver function group, the abnormal liver function group had a significantly higher proportion of critical patients (χ2=38.689, P < 0.001) and significantly higher age and inflammatory cytokines [C-reactive protein type, serum amyloid A, and interleukin-6 (IL-6)](all P < 0.05). Among the 32 patients with abnormal liver function, 13 patients had abnormal liver function on admission (defined as primary group), while 19 patients had normal liver function on admission but were found to have abnormal liver function by reexamination after treatment (defined as secondary group). For the primary group, the evidence of abnormal liver function was not found for 3 patients (3/13, 23.1%), and the possibility of toxic liver injury directly associated with SARS-CoV-2 infection was considered. Among the 19 patients in the secondary group, 9 (47.4%) had mild/common type and 10 (52.6%) had critical type, and all critical patients had the evidence of liver injury indirectly caused by the significant increases in C-reactive protein type, serum amyloid A, and IL-6 and hypoxemia; the evidence of abnormal liver function was not found for only 1 patient (1/19, 5.3%), and the possibility of toxic liver injury directly associated with SARS-CoV-2 infection was considered. All 32 patients with abnormal liver function had [JP2]significant reductions in liver function parameters after treatment including liver protection. Conclusion As for the patients with SARS-CoV-2 Delta variant infection who belong to the same chain of transmission in Guangdong Province, the critical patients show a significantly higher proportion of patients with abnormal liver function than the patients with other clinical types, and other factors except SARS-CoV-2 infection and indirect injury caused by SARS-CoV-2 infection are the main cause of liver injury. -
Key words:
- 2019 Novel Coronavirus /
- Hepatic Insufficiency /
- Guangdong
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表 1 肝功能正常与异常组患者一般资料比较
临床指标 肝功能正常组(n=134) 肝功能异常组(n=32) 统计值 P值 年龄(岁) 45(24~64) 60(46~75) Z=-0.338 0.001 性别[例(%)] χ2=3.519 0.061 男 51(38.1) 18(56.3) 女 83(61.9) 14(43.8) COVID-19临床分型[例(%)] 无症状/轻型 32(23.9) 1(3.1) χ2=6.987 0.008 普通型 100(74.6) 20(62.5) χ2=1.896 0.168 重型 1(0.7) 0(0) 1.000 危重型 1(0.7) 11(34.4) χ2=38.689 < 0.001 合并HBV感染[例(%)] χ2=0 1.000 是 9(6.7) 2(6.3) 否 125(93.3) 30(93.8) 合并非酒精性脂肪肝[例(%)] χ2=1.218 0.270 是 10(7.5) 5(15.6) 否 124(92.5) 27(84.4) 炎症指标 C反应蛋白(mg/mL) 10.0(10.0~11.8) 18.0(10.0~42.8) Z=-4.594 < 0.001 血清淀粉样蛋白A(mg/mL) 10.7(5.4~44.3) 69.5(23.0~172.7) Z=-4.179 < 0.001 IL-6(pg/mL) 7.0(3.1~19.1) 21.3(12.0~48.0) Z=-4.922 < 0.001 
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表 2 原发组患者肝功能异常病因分析
肝损伤病因 例数 肝功能指标上升幅度 ALT AST GGT ALP 非酒精性脂肪肝 4 1~3×ULN 1~2×ULN < 1×ULN < 1×ULN 慢性乙型肝炎 2 1~2×ULN 1~2×ULN < 1×ULN < 1×ULN 单纯心肌细胞损伤可能1) 3 < 1×ULN 1~2×ULN < 1×ULN < 1×ULN 药物相关肝生化学检查异常2) 1 2~3×ULN 1~2×ULN < 1×ULN < 1×ULN 中毒性肝损伤 3 2~4×ULN 1~4×ULN < 1~3×ULN < 1×ULN 注：1)患者单纯AST水平升高，有心脏受损的检查证据；2)患者入院前有服用氯氮平等有肝损伤风险的药物史。ULN，正常值上限。
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表 3 继发组7例患者使用布洛芬治疗后出现肝功能指标异常的峰值和出现峰值时间
病例序号 性别 年龄(岁) ALT (U/L) AST (U/L) GGT (U/L) RUCAM评分(分) 出现峰值时间(周) 1 女 71 64 70 正常 9 1 2 女 50 96 72 95 8 2 3 男 60 51 正常 正常 9 2 4 男 45 132 66 正常 8 3 5 女 37 52 43 正常 8 3 6 男 45 243 161 74 9 1 7 女 75 54 正常 122 9 1
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表 4 继发组10例危重型患者肝功能指标异常的峰值和出现峰值时间
病例序号 性别 年龄(岁) TBil (μmol/L) ALT (U/L) AST (U/L) GGT (U/L) ALP (U/L) 出现峰值时间(周) 1 男 63 正常 正常 46 208 正常 3 2 男 69 32 103 163 333 172 1 3 女 85 正常 67 109 正常 正常 4 4 男 73 50 54 80 320 正常 1 5 女 92 正常 49 39 168 164 3 6 女 63 正常 47 46 88 正常 2 7 女 63 正常 158 159 404 302 2 8 男 75 正常 正常 正常 83 正常 4 9 男 85 正常 正常 44 正常 正常 1 10 男 80 正常 正常 54 正常 正常 1
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