METHOTREXATE INDUCED LIVER-CIRRHOSIS - STUDIES INCLUDING SERIAL LIVER BIOPSIES DURING CONTINUED TREATMENT
METHOTREXATE INDUCED LIVER-CIRRHOSIS - STUDIES INCLUDING SERIAL LIVER BIOPSIES DURING CONTINUED TREATMENT
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DOI：
10.1111/j.1365-2133.1980.tb06553.x
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发表时间：
1980-01-01
影响因子：
10.3
通讯作者：
SOGAARD, H
中科院分区：
文献类型：
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作者：
ZACHARIAE, H;KRAGBALLE, K;SOGAARD, H
对 328 名接受甲氨蝶呤治疗或考虑接受甲氨蝶呤或补骨脂素和长波紫外线全身治疗的银屑病患者进行了肝活检 [764]。 21 名患者经组织学诊断为肝硬化。两名患者在甲氨蝶呤治疗前活检中发现肝硬化，未给予甲氨蝶呤治疗。其余的人在甲氨蝶呤前活检中均未显示出肝硬化或纤维化的迹象。甲氨蝶呤治疗的银屑病患者与甲氨蝶呤前组之间的差异非常显着。在 39 名治疗时间超过 5 年的患者中，10 名患者发展为肝硬化（25.6%）。几乎所有患者均采用分剂量间歇性口服给药方案。首次发现肝硬化时甲氨蝶呤的累积剂量范围为590-8105mg，平均剂量为2200mg。在这项研究中，导致肝硬化的其他因素似乎是先前接受过 As 治疗、先前摄入酒精和肾功能降低。随后对 14 名患者进行的连续活检数据（其中 11 名患者因非常严重的银屑病而继续接受甲氨蝶呤治疗）似乎表明甲氨蝶呤诱发的肝硬化并不具有非常严重的性质。当盲法评估时，大多数后来的活检没有发现进展，并且由纤维化、膜界限评估、纤维破坏和再生的组合分级组成的累积肝硬化指数显示出下降的趋势。 3 名患者的最新系列活检显示没有肝硬化。继续甲氨蝶呤治疗的观察期为1-7年。肝硬化患者评估肝损伤的实验室结果与其余服用甲氨蝶呤的患者没有差异，除了血清谷氨酸丙酮转氨酶短暂升高外，没有发现任何异常。这些数据支持肝活检对于控制甲氨蝶呤治疗的银屑病的必要性。至少应对甲氨蝶呤累积剂量超过 1.5 g 的所有银屑病患者进行肝活检。数据还表明，如果剂量保持尽可能低并避免饮酒，则在适应症足够强的患者中，甲氨蝶呤可以至少持续一段时间。 1968年开始报道甲氨蝶呤治疗银屑病患者出现肝硬化的孤立病例。后来的合作研究和单独研究均证实甲氨蝶呤可能引起肝损伤，在某些患者中会导致纤维化或肝硬化。国际合作研究的数据表明，累积剂量增加、糖尿病和肥胖合并、酒精摄入量增加和年龄增加与甲氨蝶呤治疗患者的肝损伤相关。对甲氨蝶呤诱发的肝硬化的长期观察尚未发表，也没有研究报告对肝硬化诊断确定后继续服用甲氨蝶呤的患者进行进一步肝活检的结果。在某些患者中，银屑病的严重程度可能导致尽管观察到肝损伤，仍需要继续治疗。该论文报告了这些患者中随着甲氨蝶呤累积剂量的增加，出现肝硬化的频率增加，以及对已确诊的甲氨蝶呤诱发肝硬化患者进行连续肝活检的结果。
Liver biopsies [764] were performed in 328 psoriatics on treatment with methotrexate or being considered for systemic treatment either with methotrexate or with psoralens and long-wave UV light. The diagnosis of cirrhosis was established histologically in 21 patients. Two patients had cirrhosis in their premethotrexate biopsy and were not given methotrexate. The remainder all showed no signs of cirrhosis or fibrosis in their premethotrexate biopsy. The difference between the methotrexate treated psoriatics and the premethotrexate group was highly significant. Among 39 patients treated for more than 5 yr, 10 developed cirrhosis (25.6%). Almost all patients were on a divided dose intermittent oral dosage schedule. The cumulative dose of methotrexate, when cirrhosis was first found, ranged from 590-8105 mg, with an average dosage of 2200 mg. Other factors contributing to cirrhosis in this study seem to be previous treatment with As, a previous intake of alcohol and lowered renal function. Data on later serial biopsies from 14 patients, of which 11 continued to receive methotrexate due to very severe psoriasis, seem to indicate that methotrexate-induced liver cirrhosis is not of a very aggressive nature. When evaluated blind no progression was found in most of the later biopsies, and a cumulative cirrhosis index composed of the combined gradings for fibrosis, assessment of membrana limitans, fibrous destruction and regeneration showed a tendency to decrease. In 3 patients the latest of the serial biopsies showed no cirrhosis. The observation period on continued methotrexate therapy ranged from 1-7 yr. None of the patients with cirrhosis differed from the remaining patients on methotrexate in their laboratory results for evaluating liver damage, and apart from transient increases in serum glutamic pyruvic transaminases no abnormalities were found. The data support the necessity of liver biopsies in the control of psoriatics treated with methotrexate. Liver biopsies should be performed at least in all psoriatics in whom a cumulative dosage of methotrexate exceeds 1.5 g. The data also indicate that methotrexate can be continued at least for a while in patients where the indication is strong enough, if the dosage is maintained as low as possible and alcohol consumption avoided. Isolated cases of cirrhosis of the liver in methotrexate treated psoriatics were reported beginning in 1968. Later cooperative as well as single studies have confirmed that methotrexate may induce liver damage, which in some patients will lead to fibrosis or cirrhosis. Data from the international cooperative study indicated that increasing cumulative dosage, the combination of diabetes mellitus and obesity, increasing alcohol intake and increasing age were associated with liver damage in methotrexate treated patients. Long-term observations on methotrexate induced cirrhosis have not been published and no studies have reported results on further liver biopsies taken from patients who continued to take methotrexate after the diagnosis of cirrhosis had been established. In some patients the severity of psoriasis may be such that continued treatment may be indicated in spite of the observed liver damage. The paper reports the increased frequency of cirrhosis appearing with increased cumulative dosage of methotrexate in these patients, and results of serial liver biopsies in patients with established methotrexate-induced cirrhosis.