Wisecarver J L, Earl R A, Haven M C, Timmins P W, Shaw B W, Stratta R J, Langnas A N, Zetterman R K, Donovan J P, Shaefer M S
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, USA.
Mod Pathol. 1992 Nov;5(6):611-6.
Cyclosporine is used in the postoperative management of rejection in liver allograft recipients. Despite its efficacy in the treatment of allograft rejection, the drug exhibits toxicity at elevated whole blood concentrations including nephrotoxicity with associated histologic changes, and evidence of hepatotoxicity as determined by liver function studies. To date, there have been few published reports describing histologic changes in liver biopsies from patients with elevated blood cyclosporine levels. In the present study, we retrospectively examined biopsies from 16 liver allograft recipients, seven patients with elevated whole blood cyclosporine levels (> 1000 ng/ml) and nine control patients who had whole blood cyclosporine levels in the therapeutic range (558 to 993 ng/ml). In each case, frozen liver biopsy tissue was available to measure tissue levels of cyclosporine and metabolites. The blood and tissue drug levels were then correlated with the histologic changes present in the biopsy specimens. Patients with increased cyclosporine levels displayed histologic changes consisting of hypertrophy of the bile ductal epithelium with cytoplasmic vacuoles and the presence of "foamy" material within the hepatic sinusoids that were either absent or occurred less frequently in the control group. The histologic changes correlated best with cyclosporine metabolite levels rather than tissue levels of native drug. When liver function studies were correlated with cyclosporine levels, only gamma glutamyl transpeptidase (GGT) demonstrated a significant positive correlation with the histologic changes.(ABSTRACT TRUNCATED AT 250 WORDS)
环孢素用于肝移植受者术后排斥反应的管理。尽管其在治疗移植排斥反应方面有效，但该药物在全血浓度升高时会表现出毒性，包括肾毒性及相关的组织学改变，以及肝功能研究确定的肝毒性证据。迄今为止，很少有已发表的报告描述血中环孢素水平升高患者肝脏活检的组织学变化。在本研究中，我们回顾性检查了16例肝移植受者的活检标本，其中7例全血环孢素水平升高（>1000 ng/ml），9例对照患者全血环孢素水平在治疗范围内（558至993 ng/ml）。在每种情况下，均有冷冻的肝脏活检组织可用于测量环孢素及其代谢物的组织水平。然后将血液和组织药物水平与活检标本中存在的组织学变化相关联。环孢素水平升高的患者表现出组织学变化，包括胆管上皮细胞肥大伴细胞质空泡形成，以及肝血窦内出现“泡沫状”物质，这些在对照组中要么不存在，要么出现频率较低。组织学变化与环孢素代谢物水平的相关性最佳，而不是与原药的组织水平相关。当肝功能研究与环孢素水平相关联时，只有γ-谷氨酰转肽酶（GGT）与组织学变化呈现出显著的正相关。（摘要截短于250字）
