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Abstract：
Hepatic chronic graft-versus-host disease (cGVHD) causes morbidity and current diagnostic criteria are nonspecific. An accurate diagnosis is imperative because overdiagnosis can lead to unnecessary treatment with immunosuppressive agents and raising the risk of opportunistic infections. We aim to characterize different patterns of liver injury and cytokine profiles associated with hepatic dysfunction in cGVHD, to evaluate the accuracy of the NIH Consensus Criteria (NCC) for hepatic cGVHD and to explore predictors for hepatic cGHVD. Patients were evaluated in this prospective cross-sectional study of patients with cGVHD recruited under a natural history protocol. Laboratory tests and cytokines were measured. The cGVHD were diagnosed and scored based on NCC. Clinically indicated liver biopsy specimens or autopsies were reviewed by an expert hepatopathologist (D.E.K.). Comparisons were made between groups, and univariable and multivariable logistic regression were calculated. Of the 302 patients enrolled, 151 fulfilled hepatic cGVHD based on NCC; however, 69% had at least 1 abnormal liver test result. Abnormal alanine aminotransferase (ALT) and aspartate aminotransferase were associated with lower platelets, higher total bilirubin (TB), total cholesterol, serum amyloid A, and IL 15. Abnormal ALP and gamma-glutamyl transpeptidase were associated with higher cholesterol, and IL7. Lower platelet count was associated with higher ALT, TB, and triglycerides and lower albumin. Of the 27 with liver tissue, 16 had histologic features of GVHD, only eight met clinical criteria for hepatic GVHD. Sensitivity and specificity of NCC in identifying hepatic GVHD were 50% and 27% (Kappa = -0.23). Only 6 had only hepatic GVHD, whereas 10 had hepatic GVHD with either iron overload, nodular regenerative hyperplasia, or steatosis. Multivariable logistic regression showed that ALP and total cholesterol were associated with hepatic GVHD and total cholesterol >220 mg/dL increased the sensitivity for histologic hepatic GVHD. In conclusion, abnormal liver enzymes in cGVHD are nonspecific and have poor correlation with histologic evidence for hepatic GVHD, highlighting the importance of histology. Cytokines provide insight into the pathogenesis of hepatic cGVHD. Decreased platelet count was associated with factors associated with liver disease including portal vein diameter, which may suggest progression of liver disease. This highlights the need of incorporating these factors in natural history study and using liver biopsy to understand the development of liver dysfunction in hematopoietic stem cell transplantation and to develop better instruments to decreased hepatic cGVHD related morbidity and mortality. The study was registered with a ClinicalTrials.gov identifier NCT00092235.
摘要：
肝慢性移植物抗宿主病（cGVHD）会导致发病，目前的诊断标准是非特异性的。准确的诊断是必要的，因为过度诊断会导致不必要的免疫抑制剂治疗，并增加机会性感染的风险。我们的目标是表征不同模式的肝损伤和细胞因子谱与肝功能障碍相关的cGVHD，评估NIH共识标准（NCC）对肝脏cGVHD的准确性，并探讨肝脏cGHVD的预测因子。在这项前瞻性横断面研究中，根据自然史方案招募了cGVHD患者，对患者进行了评估。测量实验室测试和细胞因子。诊断cGVHD并基于NCC进行评分。临床指示的肝活检标本或尸检由专家肝病理学家（D.E.K.）审查。组间进行了比较，并计算单变量和多变量逻辑回归。在登记的302名患者中，151基于NCC实现了肝cGVHD；然而，69％的人至少有1次肝脏检查结果异常。谷丙转氨酶(ALT)和谷草转氨酶异常与血小板降低有关,较高的总胆红素（TB），总胆固醇,血清淀粉样蛋白A,IL15异常的ALP和γ-谷氨酰转肽酶与高胆固醇有关，IL7较低的血小板计数与较高的ALT相关，TB,和甘油三酯和低白蛋白。在27个肝脏组织中，16具有GVHD的组织学特征，只有8人符合肝性GVHD的临床标准.NCC识别肝GVHD的敏感性和特异性分别为50％和27％（Kappa=-0.23）。只有6人只有肝脏GVHD，而10人患有肝GVHD，伴有铁过载，结节性再生增生,或者脂肪变性.多因素logistic回归分析显示，ALP和总胆固醇与肝GVHD相关，总胆固醇>220mg/dL增加了组织学肝GVHD的敏感性。总之,cGVHD的异常肝酶是非特异性的，与肝GVHD的组织学证据相关性差，强调组织学的重要性。细胞因子提供了对肝cGVHD发病机理的见解。血小板计数减少与肝脏疾病相关的因素，包括门静脉直径，这可能提示肝脏疾病的进展。这突出了将这些因素纳入自然史研究和使用肝活检的需要，以了解造血干细胞移植中肝功能障碍的发展，并开发更好的工具来降低肝脏cGVHD相关的发病率和死亡率。该研究注册了ClinicalTrials.gov标识符NCT00092235。
