Clin Gastroenterol H：治疗抗TNF所致肝损伤可考虑使用类固醇
2013-05-06 Clin Gastroenterol Hepatol MedSci原创
印第安纳大学的Marwan Ghabril博士及其同事在5月刊《临床胃肠病学与肝脏病学》杂志上发表文章指出，继发于抗肿瘤坏死因子α(抗TNFα)药物治疗的肝损伤患者，常常表现出与自发性自身免疫性肝炎相似的组织学改变。 为了确定抗TNF药物性肝损伤的表现、损伤模式、疾病过程和治疗，Gh
印第安纳大学的Marwan Ghabril博士及其同事在5月刊《临床胃肠病学与肝脏病学》杂志上发表文章指出，继发于抗肿瘤坏死因子α(抗TNFα)药物治疗的肝损伤患者，常常表现出与自发性自身免疫性肝炎相似的组织学改变。
为了确定抗TNF药物性肝损伤的表现、损伤模式、疾病过程和治疗，Ghabril博士等人研究了来自美国药物诱发性肝损伤网络(DILIN)数据库、可能继发于抗TNF治疗的6例肝损伤患者。另外还用“肝毒性”、“肝损伤”、“肿瘤坏死因子”等关键词和所有抗TNFα药物的通用名，从PubMed文献综述中筛选出了28例患者。
在所有患者中，英夫利昔是最常见的致病药物，其次为依那西普和阿达木单抗，没有因那他珠单抗、戈利木单抗或赛妥珠单抗引起的病例。使用抗TNF药物治疗的疾病包括强直性脊柱炎、克罗恩病、慢性溃疡性结肠炎、青少年炎症性关节炎、银屑病关节炎、银屑病和类风湿性关节炎。
Ghabril博士等人首先分析了来自DILIN数据库的6例患者。这些患者在发生肝损伤之前用药的中位时间为16周(范围：2~52周)。这些患者在就诊时，半数有黄疸，半数有恶心，但仅有1例发热，无1例有皮疹或嗜酸性粒细胞增多的免疫-过敏表现。仅有1例发生了明显的凝血功能障碍，INR为3.5。无1例发生腹水或其他肝衰竭征象。ALT峰值介于384~1,687 U/L，胆红素峰值介于1.5~27.7 mg/dl。“这6例患者中有5例接受皮质类固醇治疗。1例为迁延性疾病，但所有患者最终均康复并且能够撤出皮质类固醇治疗而无复发。”
然后，研究者将注意力转向PubMed病例。“血清ALT峰值介于140~2,250 U/L，胆红素介于正常与27.7 mg/dl之间。”多数患者(n=22)在临床过程中的某些时间点有自身免疫性血清学标志物和(或)组织学表现。12例患者停用抗TNF药物，启动了皮质类固醇治疗(口服或胃肠外)，这些患者均康复。其余患者在停用抗TNF药物之后未接受类固醇治疗，其病情均好转，只有1例患者因潜在肝硬化而需要接受肝移植。值得注意的是，部分患者能继续使用另一种抗TNF药物而不再发生肝损伤。事实上，“3例患者在停用英夫利昔或阿达木单抗之后可以耐受依那西普治疗而未出现肝损伤复发，1例患者成功地从阿达木单抗改为阿巴西普”。
最后，研究者对有血清学或组织学自身免疫表现的患者和没有任何自身免疫特征的患者进行了对比。结果显示，自身免疫患者倾向于有更长的潜伏期。从开始用药到发生肝损伤的中位间隔时间，自身免疫患者为16周，非自身免疫患者为10周(P=0.17)。自身免疫患者还有更高的ALT峰值(中位峰值：784 vs. 528；P=0.03)。
“TNFα拮抗剂导致药物诱发性肝损伤的机制尚不清楚。由于仅仅1次注射之后就可能发生这类损伤，因此不太可能是剂量依赖性毒性。似乎最可能是无法预测的特质性药物诱发性肝损伤，因为上述患者中无1例发生皮疹或嗜酸粒细胞增多，仅有1例出现发热。有必要进一步研究，看看能否找出TNFα拮抗剂相关性肝毒性的遗传学或其他标志物。”
与肝损伤相关的拓展阅读：
Liver Injury From Tumor Necrosis Factor-α Antagonists: Analysis of Thirty-four Cases.
BACKGROUND & AIMS
Tumor necrosis factor (TNF)-α antagonists have been associated with drug-induced liver injury (DILI). We reviewed cases of DILI in the United States to identify those associated with use of TNF-α antagonists.
METHODS
We searched the U.S. DILI Network (DILIN) database, from 2003 to 2011, for cases associated with TNF-α antagonists. Mean Roussel-Uclaf Causality Assessment Method scores were calculated. A DILIN severity score was assigned according to a previously published scale, and we identified 6 subjects likely to have DILI associated with use of TNF-α antagonists. We also searched PubMed for articles that reported hepatotoxicity from TNF-α antagonists, identifying 28 additional cases suitable for analysis.
RESULTS
The drugs presumed to have caused DILI were infliximab (n = 26), etanercept (n = 4), and adalimumab (n = 4). The anti-TNF-α agent was the probable cause of 12 cases of DILI (35%), a very likely cause for 21 (62%), and a definite cause for 1 (3%). Median latency was 13 weeks (range, 2-104); however, 7 cases (20%) had latency periods longer than 24 weeks. Twenty-two of 33 subjects who underwent serologic analysis (67%) tested positive for anti-nuclear and/or smooth muscle antibodies. Of these 22, 17 underwent liver biopsy; 15 subjects had clear features of autoimmunity. The 22 subjects with autoimmune features had longer median latency (16 vs 10 weeks) and higher peak levels of alanine aminotransferase (784 vs 528 U/L) than the 12 without such features. There was 1 case of severe cholestasis. All but one subject improved after discontinuation of the implicated drug; 12 subjects received corticosteroid therapy. No deaths were attributed to liver injury, although one patient with preexistent cirrhosis required liver transplantation.
CONCLUSIONS
Acute liver injury caused by TNF-α antagonists may be a class effect because multiple agents in this category have been implicated. The most common presentation is an autoimmune phenotype with marked hepatocellular injury, but a mixed non-autoimmune pattern or predominant cholestasis also occurs. The prognosis is usually good after drug discontinuation, although some patients may benefit from a course of corticosteroids. ClinicalTrials.gov: Number, NCT00345930.
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#抗TNF#
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#GAS#
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#Gastroenterol#
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#AST#
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#类固醇#
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#肝损伤#
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#损伤#
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#TNF#
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