Hepatic veno-occlusive disease--liver toxicity syndrome after bone marrow transplantation.
Hepatic veno-occlusive disease--liver toxicity syndrome after bone marrow transplantation.
复制标题
DOI：
--
复制
发表时间：
1992-09
影响因子：
4.8
通讯作者：
H. Shulman;W. Hinterberger
中科院分区：
文献类型：
--
作者：
H. Shulman;W. Hinterberger
肝静脉闭塞性疾病（VOD）是骨髓移植（BMT）预备方案相关毒性最常见的危及生命的并发症。VOD的频率差异很大，在为地中海贫血进行小儿骨髓移植的中心，VOD的频率为1% -2%，而在一些为血液恶性肿瘤进行骨髓移植的中心，VOD的频率超过50%。肝毒性综合征是一个临床病理定义，包括肝小静脉和周围的肝窦和肝细胞的组织病理学范围。这些组织学异常在统计学上与移植后早期黄疸、腹水和肝肿大疼痛的临床综合征相关。可能有助于准确性的新方法是经静脉肝活检，同时测定楔形和自由肝静脉压之间的梯度，以及测量血液凝固成分，特别是蛋白C水平。在比较异质患者群体、患者选择方法和对照选择以及分析是单因素还是多因素时，由于缺乏明确的风险层次，对VOD临床危险因素的分析存在混淆。前瞻性多因素分析表明，发生肝毒性的风险与调节治疗的强度、移植前病毒性肝炎、使用阿昔洛韦、两性霉素或万古霉素抗菌治疗（反映发烧）以及不匹配或不相关的异体骨髓移植独立相关。这些分析加上形态学和生化数据支持这样的假设，即VOD是由肝细胞和肝腺第三区内皮细胞的细胞减原性损伤引起的，反过来又受到诱导肿瘤坏死因子- α (tnf - α)释放的因素的强烈影响，导致凝血功能增强或激活，肝窦和小静脉梗阻。作为调节剂的丁硫丹的药代动力学测量表明，高稳态丁硫丹水平与肝毒性之间存在相关性，并表明可以通过调整个体剂量和改变给药计划来获得更安全和/或更有效的血浆丁硫丹浓度。严重VOD的保守治疗，包括使用腹膜-胸膜分流术缓解腹水，是不令人满意的。针对肝素或前列腺素E1预防VOD的预防性研究结果表明，其毒性和疗效存在相当大的差异。使用tnf - α阻滞剂己酮茶碱也显示出减少点播的希望。一个统计模型，预测患者可能有不利的结果，从VOD已被用于选择有希望的新的治疗方式，如重组组织纤溶酶原激活剂的发病前患者。
Hepatic veno-occlusive disease (VOD) is the most common life threatening complication of preparative-regimen-related toxicity for bone marrow transplantation (BMT). The frequency of VOD varies greatly, from 1-2% in centers performing pediatric BMT for thalassemia to over 50% in some centers doing BMT for hematologic malignancy. The term liver toxicity syndrome is a clinicopathologic definition which encompasses the range of histopathology within the hepatic venules and surrounding sinusoids and hepatocytes. These histologic abnormalities are statistically associated with a clinical syndrome of jaundice, ascites, and painful hepatomegaly developing early post-transplant. Newer modalities which may aid accuracy are transvenous liver biopsy along with determination of the gradient between the wedged and free hepatic venous pressures, and measurement of blood coagulatory components, particularly protein C levels. Analyses of clinical risk factors for VOD are confounded by lack of a clear hierarchy of risk when comparing heterogeneous patient populations, the methods of patient selection and choice of controls, and whether analysis is univariate or multivariate. Prospective multivariate analyses indicate that the risk of developing liver toxicity is independently correlated with intensity of conditioning therapy, pre-transplant viral hepatitis, use of antimicrobial therapy with acyclovir, amphotericin, or vancomycin (reflecting fever), and mismatched or unrelated allogeneic marrow grafts. These analyses plus morphologic and biochemical data support the hypothesis that VOD is caused by cytoreductive injury to hepatocytes and endothelium in zone three of the liver acinus, and in turn strongly influenced by factors which induce the release of tumor necrosis factor-alpha (TNF-alpha) leading to enhancement or activation of coagulation with obstruction of hepatic sinusoids and venules. Pharmacokinetic measurements of busulfan as a conditioning agent demonstrate a correlation between high steady-state busulfan levels and liver toxicity and suggest that safer and/or more efficacious plasma busulfan concentrations can be obtained by making individual dose adjustments and by changing the schedule of administration. Conservative therapy of severe VOD, including the use of peritoneal-pleural shunts for relief of ascites, is unsatisfactory. Results from prophylactic studies aimed at preventing VOD by heparin or prostaglandin E1 indicate considerable differences with toxicity and efficacy. Use of the TNF-alpha blocker, pentoxifylline, has also shown promise in lessening VOD. A statistical model which predicts patients likely to have an unfavorable outcome from VOD has been used to select premorbid patients for promising new therapeutic modalities, such as recombinant tissue plasminogen activator.