Department of Infectious Disease and Liver Disease, The Second Hospital of Nanjing, Affiliated to Nanjing University of Chinese Medicine, Nanjing, China.
Department of Infectious Diseases, Jurong People's Hospital, Jiangsu University, Zhenjiang, China.
Clin Res Hepatol Gastroenterol. 2024 Nov;48(9):102472. doi: 10.1016/j.clinre.2024.102472. Epub 2024 Sep 25.
There is no conventional treatment for patients with severe drug-induced liver injury (DILI) except for discontinuation of liver injury drugs and symptomatic supportive therapy. Opinions on whether corticosteroids can be used to treat severe DILI are conflicting, and most of the relevant clinical studies are case reports or retrospective studies, which still need to be supported by high-level evidence-based medical studies. This study aimed to evaluate the effect and tolerance of corticosteroids in patients with severe DILI. Risk factors associated with patient failure to cure were also explored.
Propensity score matching based on nearest-neighbor 1:1 matching was used to screen severe DILI patients in the corticosteroids and control groups. Severe DILI was defined as elevated serum ALT and/or ALP with TBIL≥5 ULN (5 mg/dL or 85.5 μmol/L) with or without INR ≥1.5. Patients were treated with conventional therapy combined with corticosteroids in the corticosteroids group and only conventional therapy in the control group.
A total of 146 patients, 73 each in the corticosteroids and control groups, were included in this study. By analyzing the entire cohort, we found no significant difference in cure rates between patients in the corticosteroid group and control group (34.2% vs. 20.5 %, p = 0.095), and there was no significant difference in the incidence of adverse effects between the two groups (20.5% vs. 20.5 %, p = 1.000). However, TBIL decreased more in the corticosteroids group on day 7 (89.2 ± 107.6 μmol/L vs. 58.8 ± 70.7 μmol/L, p = 0.046). In subgroup analyses, patients whose TBIL remained elevated despite conventional treatment had a higher TBIL decline on day 7,14 after use of corticosteroid (99.2 ± 98.5μmol/L vs. -23.3 ± 50.4μmol/L, p < 0.001; 120 ± 119.1μmol/L vs. 61.2 ± 98.5μmol/L, p = 0.047). The cure rate of patients in the corticosteroid group was significantly higher than that of the control group (36.1 % versus 4.5 %, p = 0.016). The proportion of patients with TBIL <85.5 μmol/L was also significantly higher in the corticosteroid group than in the control group at day 7 (p = 0.016) and day 14 (p = 0.004) after treatment. In the subgroup analysis of patients with different clinical phenotypes, the causative agent was herbal, autoimmune antibody-positive and 40 % < PTA ≤ 50 % of patients, corticosteroid use did not increase the cure rate of the patients. Univariate and multifactorial analyses found corticosteroid use to be a protective factor for failure to cure in patients with severe DILI (p < 0.001, OR:0.191,95 % CI:0.072-0.470), and peak TBIL to be a risk factor (p = 0.003, OR:1.016,95 % CI:1.007-1.028).
The addition of corticosteroids could not increase the cure rate in patients with severe DILI, but it could rapidly reduce the patient's TBIL at an earlier stage. Corticosteroids could also promote curing in patients with elevated TBIL after conventional treatment. Corticosteroid use was a protective factor for failure to cure in patients with severe DILI and peak TBIL was a risk factor.
对于严重药物性肝损伤（DILI）患者，除了停用肝损伤药物和对症支持治疗外，目前尚无常规治疗方法。对于是否可以使用皮质类固醇治疗严重 DILI，意见不一，而且大多数相关的临床研究都是病例报告或回顾性研究，仍需要高水平的循证医学研究来支持。本研究旨在评估皮质类固醇在严重 DILI 患者中的疗效和耐受性，并探讨与患者治疗失败相关的危险因素。
采用最近邻 1:1 匹配的倾向评分匹配方法筛选皮质类固醇组和对照组的严重 DILI 患者。严重 DILI 定义为血清 ALT 和/或 ALP 升高，TBIL≥5 ULN（5mg/dL 或 85.5μmol/L），伴或不伴 INR≥1.5。皮质类固醇组患者在常规治疗的基础上加用皮质类固醇，对照组仅给予常规治疗。
共纳入 146 例患者，皮质类固醇组和对照组各 73 例。对整个队列进行分析，发现皮质类固醇组和对照组患者的治愈率无显著差异（34.2% vs. 20.5%，p=0.095），两组不良反应发生率也无显著差异（20.5% vs. 20.5%，p=1.000）。然而，皮质类固醇组患者在第 7 天的 TBIL 下降更明显（89.2±107.6μmol/L 比 58.8±70.7μmol/L，p=0.046）。亚组分析显示，常规治疗后 TBIL 持续升高的患者，使用皮质类固醇后第 7 天和第 14 天的 TBIL 下降更明显（99.2±98.5μmol/L 比-23.3±50.4μmol/L，p<0.001；120±119.1μmol/L 比 61.2±98.5μmol/L，p=0.047）。皮质类固醇组患者的治愈率明显高于对照组（36.1% vs. 4.5%，p=0.016）。治疗后第 7 天和第 14 天，皮质类固醇组患者的 TBIL<85.5μmol/L 的比例也明显高于对照组（p=0.016 和 p=0.004）。在不同临床表型的亚组分析中，病因是草药、自身抗体阳性和 40%<PTA≤50%的患者，使用皮质类固醇并不能提高患者的治愈率。单因素和多因素分析发现，使用皮质类固醇是严重 DILI 患者治疗失败的保护因素（p<0.001，OR：0.191，95%CI：0.072-0.470），峰值 TBIL 是危险因素（p=0.003，OR：1.016，95%CI：1.007-1.028）。
在严重 DILI 患者中，加用皮质类固醇并不能提高治愈率，但可在早期阶段迅速降低患者的 TBIL。皮质类固醇还可以促进常规治疗后 TBIL 升高的患者治愈。皮质类固醇的使用是严重 DILI 患者治疗失败的保护因素，而峰值 TBIL 是危险因素。
