肝移植术后丙型肝炎病毒的再感染与丙肝复发

丙肝肝炎后肝移植病人均伴随不同程度的丙型肝炎病毒(HCV)复发,其发病机制因疾病的不同阶段而不同.影响复发的因素包括HCV基因型、病毒载量、供体和受体HLA匹配情况、复发的时间、供体的年龄等,而免疫抑制剂的使用是最重要的影响因素.治疗的效果通过持续病毒学应答来评价.目前认为聚二乙醇干扰素联合利巴韦林是治疗慢性丙型肝炎最好的选择和最佳的治疗方案.     

DR antigens influence graft outcome and HCV recurrence after liver transplantation

Hepatitis C (HCV) recurrence following liver transplantation is universal. However, the severity of recurrence is highly variable between patients. We speculated that recipient DR antigens or the level of DR mismatching between the recipient and the donor might affect the severity of HCV recurrence and allograft survival. Clinical outcome was compared between HCV+ recipients with DR2, DR3, or DR5 versus HCV+ recipients with all other DR antigens. Recipients with DR3 had reduced allograft survival (P < .02), a higher rate of HCV recurrence (P < .05), and more severe liver disease (P < .05). Recipients with DR5 had superior allograft survival (P < .05), low rates of HCV recurrence (P < .05), and benign liver disease (P < .05). Clinical outcome of recipients with DR2 was equivalent (P = Ns) to the non-DR2, -3, -5 recipients. The incidence of acute rejection was equivalent (P = Ns) in all groups. The level of DR mismatching between donor and recipient did not affect HCV recurrence or severity. However, allograft survival was better (P < .05) in recipients with zero DR mismatches. The data show that host genetic factors play an important role in HCV recurrence and allograft outcome after liver transplantation. In addition, identification of DR antigens may help predict an HCV+ patient's relative risk for severe HCV recurrence.     

The effect of recurrence of HCV infection of life after liver transplantation

Abstract The present study evaluated the quality of life (QOL) of adult cirrhotic patients before orthotopic liver transplantation (OLT), the effect of OLT on QOL in the long-term and the effect of HCV recurrence within medical complications on QOL. Three groups of patients were studied: 19 pre-OLT, 33 during the first year post-OLT and 41 1 to 5 years post-OLT. The patients completed questionnaires on QOL and underwent liver function tests, immunosuppressive drug blood level determinations and medical complications evaluation. Somatization and depression and anxiety scores improved significantly during the first year post-OLT compared with pre-OLT, but they worsened again during the 1–5-year period post-OLT. Physical functioning and life satisfaction scores improved significantly during the first year post-OLT compared with pre-OLT and the improvement persisted 1–5-year during the period post- OLT. Patients with HCV recurrence compared with patients without HCV recurrence during the first year post-OLT showed a significant worsening of most of the domains of QOL. In conclusion, OLT improved most of the domains of QOL by the end of the first post-transplant year, though the improvements did not all persist in the long-term. Recurrence of HCV infection plays a major role in the impairment of QOL after OLT.     

The effect of recurrence of HCV infection of life after liver transplantation

The present study evaluated the quality of life (QOL) of adult cirrhotic patients before orthotopic liver transplantation (OLT), the effect of OLT on QOL in the long-term and the effect of HCV recurrence within medical complications on QOL. Three groups of patients were studied: 19 pre-OLT, 33 during the first year post-OLT and 41 1 to 5 years post-OLT. The patients completed questionnaires on QOL and underwent liver function tests, immunosuppressive drug blood level determinations and medical complications evaluation. Somatization and depression and anxiety scores improved significantly during the first year post-OLT compared with pre-OLT, but they worsened again during the 1–5-year period post-OLT. Physical functioning and life satisfaction scores improved significantly during the first year post-OLT compared with pre-OLT and the improvement persisted 1–5-year during the period post-OLT. Patients with HCV recurrence compared with patients without HCV recurrence during the first year post-OLT showed a significant worsening of most of the domains of QOL. In conclusion, OLT improved most of the domains of QOL by the end of the first post-transplant year, though the improvements did not all persist in the long-term. Recurrence of HCV infection plays a major role in the impairment of QOL after OLT.     

Tumor recurrence after liver transplantation for hepatocellular carcinoma: recurrence pathway and prognostic factors

INTRODUCTION: Liver transplantation (OLT) has been advocated as a good management option for patients with carcinoma hepatocellular (HCC). More recurrences are extrahepatic due to many pathological factors. PATIENTS AND METHODS: From April 1986 to December 2003, we performed 95. OLTs for HCC including 73% men of mean age of 54.7 years and 25.3% not filling Mazzaferro's criteria. RESULTS: The recurrence incidence was 15.8% (n = 15), including only extrahepatic lesions in 11 (mainly lung recurrence, seven) and hepatic plus extrahepatic in four. Main late mortality was due to tumor recurrence (n = 12, 33.3%). No differences were observed among sex, preoperative chemoembolization, age, Child, Okuda, etiology, or satellite nodules. A greater incidence of tumor recurrence was observed with a preoperative biopsy (45.5% vs 5.9%, P = .0001); and alpha fetoprotein (AFP) > 200 ng/mL (37.5% vs 13.3%, P = .08); known HCC (25.5% vs 3.1%, P = .008); vascular invasion (42.1% vs 10.3%, P = .001); > 5 cm single nodule (50% vs 13%, P = .004); more than three nodules (50% vs 13.9%, P = .01); moderately to poorly differentiated tumors (37.5% vs 12.7%, P = .01); pTNM IV (50% vs 8.7%, P = .0001); and not meeting Milan criteria (40.9% vs 9.2%, P = .001). These are the same factors for extrahepatic recurrence. For hepatic recurrence the prognostic factors were: vascular invasion (15.8% vs 1.5%, P = .008), more than three nodules (25% vs 2.5%, P = .004), moderately to poorly differentiated tumors (18.8% vs 1.4%, P = .003), pTNM IV (16.7% vs 1.4%, P = .006), and not meeting Milan criteria (13.6% vs 1.5%, P = .01). CONCLUSIONS: Recurrence incidence with Milan criteria was less than 10%, mainly extrahepatic (lung). Prognostic factors for tumor recurrence were pathological features, namely vascular invasion, more than three nodules, size larger than 5 cm, moderately to poorly differentiated tumors, pTNM IV stage. The use of preoperative chemoembolization did not decrease the recurrence rate. A preoperative biopsy increased the incidence of extrahepatic recurrence.     

Allograft TNFbeta and IL16 polymorphisms influence HCV recurrence and severity after liver transplantation.

Hepatitis C (HCV) recurrence after liver transplantation is universal although severity varies. We explored whether certain donor cytokine gene polymorphisms may be useful markers of susceptibility to severe recurrence. Allograft tumor necrosis factor (TNF) beta and interleukin (IL) 16 gene polymorphisms were correlated with l-yr clinical outcome among HCV+ recipients. Recipients of donor TNFbeta(2,2) (n = 8) experienced less recurrence (50% vs. 71%, P < 0.05), less fibrosis (25% vs. 76%, P < 0.01), and less rejection (25% vs. 71%, P < 0.01) than donor TNFbeta(1,1) (n = 19). Recipients of donor TNFbeta(1,2) (n = 27) demonstrated an intermediate picture with less fibrosis (56%, P < 0.01) and less rejection (37%, P < 0.01) than TNFbeta(1,1). Recipients with donor IL16(TC) (n = 22) showed less recurrence (65% vs. 78%, P = 0.05), less fibrosis (53% vs. 67%, P = 0.06), and less rejection (41% vs. 55%, P = 0.06) than IL16(TT) (n = 32) genotype. Recipients of the combination TNFbeta(2,2)/IL16(TC) donor genotype had the most benign clinical outcome with less recurrence (33% vs. 75%, P < 0.01), no fibrosis (0% vs. 50%, P < 0.001), and fewer rejections (33% vs. 75%, P < 0.01) than donor TNFbeta(1,1)/IL16(TT) genotype. In vitro production of cytokines correlated with genotype. Release of soluble TNFbeta for TNFbeta(1,1) vs. TNFbeta(1,2) and TNFbeta(2,2) was 4803 +/- 2142 pg/mL vs. 5629 +/- 3106 (P = not significant [ns]) and 7180 +/- 3005 (P = ns). Release of soluble IL16 for IL16(TT) vs. IL16(TC) was 437 +/- 86 pg/mL vs. 554 +/- 39 (P = 0.06). In conclusion, allograft TNFbeta and IL16 gene polymorphisms may be useful markers to predict the severity of disease recurrence among HCV+ patients after liver transplantation.     

Immunosuppression and donor age with respect to severity of HCV recurrence after liver transplantation.

In HCV cirrhotic patients after liver transplantation, survival and recurrence of HCV appears to be worsening in recent years. Donor age has been suggested as a cause. However, it is not clear if early and/or late mortality is affected and whether donor age is a key factor, as opposed to changes in immunosuppression. The aim of this study was to assess impact of donor age and other factors with respect to the severity of HCV recurrence posttransplant. A consecutive series of 193 HCV cirrhotic patients were transplanted with cadaveric donors, median age 41.5 years (13-73) and median follow-up of 38 months (1-155). Donor age and other factors were examined in a univariate/multivariate model for early/late survival, as well as fibrosis (grade 4 or more, Ishak score) with regular biopsies, 370 in total, from 1 year onwards. Results of the study indicated that donor age influenced only short-term (3 months) survival, with no significant effect on survival after 3 months. Known HCC independently adversely affected survival, as did the absence of maintenance azathioprine. Severe fibrosis (stage > or = 4) in 51 patients was related to neither donor age nor year of transplantation, but it was independently associated with combined biochemical/histological hepatitis flare (OR 2.9, 95% CI 1.76-4.9) whereas maintenance steroids were protective (OR 0.4, 95% CI 0.23-0.83). In conclusion, in this cohort donor age did not influence late mortality in HCV transplanted cirrhotic patients or development of severe fibrosis, which was related to absence of maintenance steroids and a hepatitis flare. Maintenance azathioprine gave survival advantage.     

Effect of nonviral factors on hepatitis C recurrence after liver transplantation

OBJECTIVE: Hepatitis C (HCV) is now the most common indication for orthotopic liver transplantation (OLT). While graft reinfection remains universal, progression to graft cirrhosis is highly variable. This study examined donor, recipient, and operative variables to identify factors that affect recurrence of HCV post-OLT to facilitate graft-recipient matching. METHODS: Retrospective review of 307 patients who underwent OLT for HCV over a 10-year period at our center. Recurrence of HCV was identified by the presence of biochemical graft dysfunction and concurrent liver biopsy showing diagnostic pathologic features. Time to recurrence was the endpoint for statistical analysis. Five donor, 6 recipient, and 2 operative variables that may affect recurrence were analyzed by univariate comparison and Cox proportional hazard regression models. RESULTS: Recurrence-free survival in the 307 study patients was 69% and 34% at 1 and 5 years, respectively. Four predictive variables related to either donor or recipient characteristics were identified. Advanced donor age, prolonged donor hospitalization, increasing recipient age, and elevated recipient MELD scores were found to increase the relative risk of HCV recurrence. Examination of HLA disparity between donors and recipients demonstrated no correlation between class I or class II mismatches and recurrence-free survival. CONCLUSIONS: We have identified donor and recipient characteristics that significantly predict hepatitis C recurrence following liver transplantation. These factors are identifiable before transplant and, if considered when matching donors to HCV recipients, may decrease the incidence of HCV recurrence after OLT. A change in the current national liver allocation system would be needed to realize the full value of this benefit.     

肝移植后丙型肝炎复发患者肝脏纤维化进展与肝内免疫细胞分布

目的 了解肝移植术后丙型肝炎复发患者肝脏纤维化进展情况及其与肝组织中免疫细胞分布的关系.方法 对2005年4月至2012年12月解放军第三○二医院34例肝移植术后丙型肝炎复发患者的58次肝脏穿刺(肝穿)组织和15份非移植慢性丙型肝炎患者的肝组织进行病理分析,行Metavir评分,同时对其中15例行2～4次肝穿的39份样本做CD4+、CD8+、CD20+、CD57+细胞的免疫组织化学染色.采用x2检验和方差分析肝纤维化进展情况与病理特点、CD4+、CD8+T淋巴细胞,B淋巴细胞和NK细胞分布的关系.结果 34例肝移植术后丙型肝炎复发患者肝纤维化发展速度中位数为1/年,其中9例(26.47％)为快进展型,移植术后1年内肝纤维化发展速度＞2(Metavir评分),其余25例(73.53％)慢进展型患者肝纤维化发展速度中位数为0.6/年.与非移植慢性丙型肝炎患者肝脏病理学改变相比,移植后丙型肝炎复发患者肝脏病理改变以汇管区水肿、小叶间胆管损伤、界面炎、小叶内凋亡小体增多为特点,其中界面炎随肝纤维化加重而增多(x2=9.656,P=0.008).肝组织中CD4+、CD8+T淋巴细胞,B淋巴细胞的表达量随肝脏纤维化程度加重而增多,NK细胞表达量则随肝脏纤维化程度加重而减少.相同纤维化程度的快进展型与慢进展型患者,肝组织中免疫细胞的数量差异无统计学意义(P值均＞0.05).结论 肝移植术后部分丙型肝炎复发患者肝纤维化发展速度较快.随肝脏纤维化程度加重,肝组织中CD4+、CD8+T淋巴细胞,B淋巴细胞的表达增多,NK细胞表达减少.     

Minimization of immunosuppression with thymoglobuline pre-treatment and HCV recurrence in liver transplantation

Induction with thymoglobuline, a potent anti-thymocyte polyclonal antibody, has been recently reported to allow minimization of postoperative immunosuppression in organ transplantation. The relationship with recurrence of hepatitis C virus (HCV) after liver transplantation (LTx) has never been investigated. We report here on the outcome in 22 HCV+ patients receiving thymoglobuline pre-treatment and minimal immunosuppression after LTx. Patient survival and acute rejection rates were good, and remarkably low dosages and levels of immunosuppression were achieved with thymoglobuline, without exposing patients to an elevated risk of rejection. A progressive weaning of the primary immunosuppressor was also possible in the majority of patients without complications. The HCV recurrence rate was similar to what is reported in the literature, although lower HCV-RNA viral loads were obtained with thymoglobuline, with a mild histologic course. Although our results need to be validated in large cohort studies, our experience shows that minimization of immunosuppression with thymoglobuline is effective in protecting against rejection and demonstrated a positive impact on HCV recurrence that deserves further investigation.     

Risk factors for recurrence of primary sclerosing cholangitis after liver transplantation.

Liver transplantation (LT) is the only therapeutic option for end-stage primary sclerosing cholangitis (PSC), but PSC can recur (rPSC) in some patients after LT. The aim of our study was to evaluate the risk factors associated with rPSC. Between 1989 and 2004, 69 patients receiving transplantation for PSC (42 male, mean age 41.9 yr). Clinical and laboratory data, activity/extension and treatment of ulcerative colitis (UC), post-LT cytomegalovirus (CMV) infection, and immunosuppression were evaluated. Determination of rPSC was made by radiological and histological findings. Exclusion criteria were ABO blood group incompatibility, hepatic artery stenosis, and biliary strictures occurring in <3 months post-LT. A total of 48 (70%) patients had PSC and UC pre-LT. rPSC occurred in 7 of 53 (13.5%, 2 patients with de novo UC) who were alive 1 yr after LT and/or met inclusion/exclusion criteria: median 60 (4-120) months. No patient without post-LT UC had rPSC: 0 of 20 vs. 7 of 26 with post-LT UC (P = 0.027). The multivariate logistic regression analysis showed that maintenance steroids for UC (>3 months) post-LT was the only risk factor significantly associated with rPSC (P = 0.025). In conclusion, the presence of UC post-LT, and the need for maintenance steroids post-LT, which is an independent factor, are associated with rPSC. These findings could help elucidate a possible mechanism of PSC pathogenesis.     

Noninvasive tests for evaluation of fibrosis in HCV recurrence after liver transplantation: a systematic review

Noninvasive tests (NIT) for evaluation of hepatic fibrosis have not been evaluated extensively in liver transplantation. We systematically reviewed the literature regarding NIT after liver transplantation. We identified 14 studies evaluating NIT based on serum markers and/or liver imaging techniques: 10 studies assessed NIT in recipients with recurrent HCV infection for fibrosis and four studies evaluated predictors of progression of fibrosis in recurrent HCV. Transient Elastography (TE) had good discrimination for significant fibrosis (median AUROC: 0.88). Among the serum NIT, APRI had good performance (median AUROC: 0.75). TE performed better than serum (direct and indirect) NIT for significant fibrosis with median AUROC 0.88 (vs. 0.66, P < 0.001), median sensitivity 0.86 (vs. 0.56, P = 0.002), median NPV 0.90 (vs. 0.74, P = 0.05) and median PPV 0.80 (vs. 0.63, P = 0.02). TE compared to indirect serum NIT, had better performance, but was not superior to APRI score. Finally, direct, compared to indirect NIT, were not significantly different except for specificity: median: 0.83 vs. 0.69, respectively, P = 0.04. In conclusion, NIT could become an important tool in clinical management of liver transplant recipients, but whether they can improve clinical practice needs further evidence. Their optimal combination with liver biopsy and assessment of collagen content requires investigation.     

肝移植术后乙型肝炎复发2例临床分析

拉米夫定联合乙型肝炎高效价免疫球蛋白(hepatitis b immunoglobulin,hbig)可有效预防原位肝移植术后乙型肝炎复发.然而,移植后核苷(酸)类药物使用不规范及疗程的不确切性给广大医务人员及患者带来诸多困扰.本文介绍2例乙型肝炎相关性终末期肝病患者行原位肝移植术后坚持拉米夫定治疗6年出现乙型肝炎复发的病例,为预防肝移植术后乙型肝炎复发及核苷(酸)类药物使用疗程提供借鉴.     

肝脏恶性肿瘤肝移植术后肿瘤复发的临床研究

目的 总结肝脏恶性肿瘤患者行肝移植术后肿瘤复发的临床特点,探讨术后复查的规范方法和治疗复发肿瘤的措施.方法 回顾性分析215例原位肝移植患者的临床资料,分析其中81例复发患者的肿瘤复发时间、复发部位和治疗效果.结果 81例患者的随访时间为6～108个月.首次发现肿瘤复发的时间为肝移植术后3～20个月,常见的复发部位为肺、腹腔种植或淋巴结转移、移植肝内复发和骨转移.复发肿瘤的治疗以局部治疗为主,包括肺转移瘤切除术6例次、伽马刀治疗74例次;腹盆腔转移癌切除术10例次,腹腔淋巴结伽马刀治疗8例次;肝转移癌切除术6例次、消融治疗5例次、伽马刀治疗15例次、TACE 33例次,二次肝移植3例次;骨转移瘤切除术15例、伽马刀治疗16例次以及病理性骨折内固定术3例;脑转移瘤伽马刀治疗4例次.本组患者治愈3例,带瘤生存6例,已存活21～56个月,中位生存时间为39个月.死亡72例,中位生存时间为15个月.结论 肝移植术后对恶性肿瘤患者要进行有针对性的规范检查、积极治疗复发肿瘤,尽量延长患者的生存时间.