肝移植术后糖尿病发病机制研究进展

肝移植术后糖尿病(PTDM)是一种发生于肝移植术后的继发性糖尿病,其发生机制与糖皮质激素和钙调磷酸酶抑制剂等免疫抑制剂的应用、肝功能损害、丙型肝炎病毒(HCV)感染、器官失神经等有关.PTDM的发病率高,严重影响移植物的存活和受者的长期生存.现结合近年相关研究和报道就其发病机制作一综述.     

供肝脂肪变性与肝移植术后糖尿病发病风险的关系

目的探讨肝移植术后糖尿病（PTDM）发病的危险因素以及供肝脂肪变性对PTDM发病风险的影响。方法回顾性分析2001年4月至2008年12月438例接受肝移植患者的术前、术后的临床资料。采用2006年中华医学会肝脏病学分会制定的非酒精性脂肪性肝病（NAFLD）诊疗指南的组织病理评分标准判定供肝脂肪变性程度，肝功能状态判定采用Child—Pugh评分系统。根据术后空腹血糖将患者分为非PTDM组（n=298，男250例，女48例，平均年龄48岁）与PTDM组（n=140，男120例，女20例，平均年龄50岁）。对PTDM可能的危险因素，包括年龄、性别、空腹血糖、体质指数、术前肝功能、供肝脂肪变性、术后抗排异药种类、白细胞介素-2受体拮抗剂（IL-2RA）应用等进行单因素分析。在单因素分析基础上进行logistic多元回归分析。结果非PTDM组供肝脂肪变性者占34．6％（103／298），PTDM组供肝脂肪变性者占44．3％（62／140），2组无显著差别（X^2=3．83，P=0．05）。单因素分析提示术前空腹血糖（F=23．38，P〈0．05）、术前肝功能、IL-2RA、免疫抑制剂类型与PTDM显著相关（X^2值分别为7．69、8．30、0．02，均P〈0．05），而供肝脂肪变性与PTDM相关性处于临界水平（X^2=3．83，P=0．05）。logistic多元回归分析提示术前空腹血糖异常（OR=1．853，P〈0．01）、供肝脂肪变性（OR=1．80，P〈0．05）可提高PTDM患病风险，而使用IL．2RA（OR=0．43，P〈0．01）可降低PTDM患病风险。结论供肝脂肪变性、术前空腹血糖异常为PTDM的危险因素，而IL-2RA应用则可降低PTDM发生风险，术前肝功能异常可能增加PTDM的发生风险，免疫抑制剂与PTDM的关系有待进一步研究。     

肝移植术后肾功能衰竭的发生率明显增高

据好医生网8月23日报道，肝移植术后。肾功能衰竭的发生率明显增高。[第一段]     

乙型肝炎病毒感染患者肝移植术后再感染及其机制

肝移植已成为终末期肝脏疾病的一个重要治疗手段。但是，乙型肝炎病毒(HBV)相关性肝病患者肝移植术后，乙型肝炎的复发率达70％～80％，严重地影响了肝移植术的远期效果，成为亟待解决的一个问题。作者在对肝移植患者HBV再感染随访观察的基础上，采集外周血单个核淋巴细胞(PBMC)，进行HBV DNA定量检测和HBV共价闭合环状DNA(cccDNA)的定性检测，对肝移植术后患者HBV再感染的状况及其机制进行了探讨。     

肝移植术后脑血管并发症9例分析

肝移植术后神经系统并发症发生率为8％～47％，其中脑血管疾病发生率约占整个神经系统并发症的50％。我院自1993年1月至2004年11月，共实施原位肝移植术487例，其中9例术后出现脑血管并发症，现报道如下。     

肝移植后丙型肝炎的复发及治疗

肝移植后丙型肝炎的复发可导致肝脏损伤加速、移植物失活及患者生存率大幅度下降。但遗憾的足目前还没有有效的治疗方法治疗丙型肝炎的复发，成为当前医生面临的挑战性问题之一。     

免疫抑制剂与器官移植后糖尿病相关性机制研究进展

正贵州医科大学附属医院内分泌代谢病科     

CENPM表达在肝移植术后肝癌复发患者中的临床意义

［摘要］　目的　研究促肝癌基因着丝粒蛋白M（CENPM）在肝移植术后肝癌复发患者中表达与临床特征的相关性以及对预后的影响。方法　纳入肝移植术后肝癌复发患者82例,未复发组40例,对切除肝标本进行免疫组织化学染色观察CENPM表达水平,收集患者临床资料及预后情况,分析高表达组与低表达组临床特征、复发特征和预后的差异。结果　复发患者82例中位随访时间为22（8～38）个月,CENPM高表达比例为70.7%,而未复发组为50.0%,差异有统计学意义(P=0.025)。复发患者中,高表达组与低表达组相比,无疾病生存时间差异有统计学意义(P=0.036);高表达组总体生存时间低于低表达组,差异有统计学意义(P=0.019)。结论　CENPM表达与肝移植术后肝癌较快复发及转移有关,并影响患者预后。     

卒中后抑郁的发病机制

抑郁是卒中的一种常见并发症,它与卒中互相影响,进一步降低了患者的生活质量。对于卒中后抑郁的发病机制尚无统一定论,可能与神经递质、颅内病变部位、炎性细胞因子和精神社会心理等因素有关。     

肝移植术后再住院患者住院费用分析

目的分析肝移植术后再住院患者住院费用的特点和影响因素。方法对84例肝移植术后再住院患者的住院费用进行了回顾性分析。结果肝移植术后再住院患者平均住院费用为23235.20元,其中西药费、检查费和床位费分别占66.61%、18.02%和7.45%;患者以退休人员为多,住院次数多,并发症多。结论控制病人并发症的发生对降低肝移植术后再住院患者的医疗费用具有重要的意义。     

肾移植术后空腹血糖变化规律及其对预后的影响分析

目的 探讨肾移植术后存活1年以上患者空腹血糖变化规律及其对预后的影响.方法 收集446例1993年1月至2008年12月接受肾移植手术且移植肾存活1年以上患者的临床资料,根据术前空腹血糖,将患者分为移植前糖尿病、空腹血糖受损、空腹血糖正常3组,观察各组术后空腹血糖变化规律.对428例术前非糖尿病患者,根据空腹血糖分析术后移植后糖尿病( PTDM)发生及转归,比较持续性PTDM和一过性PTDM临床特点,并比较PTDM组和非PTDM组术后并发症及生存率的差异.结果 肾移植后患者血糖整体呈先升高后下降的趋势.428例术前非糖尿病患者,共有87例(20.3％)发生PTDM,其中15例(占总PTDM的17.2％)在随访中转为空腹血糖正常或空腹血糖受损.与持续性PTDM相比,一过性PTDM患者急性排斥反应发生率更高(P=0.043).与非PTDM组相比,PTDM组术后感染、高血压和脂代谢紊乱发生率更高(P＜0.05).平均随访(5.65±3.68)年,两组患者生存率和生存时间未见明显差异.结论 PTDM并非持续存在,在病程中有可能转为空腹血糖受损或空腹血糖正常.急性排斥反应是一过性血糖升高的危险因素.肾移植后PTDM患者术后更容易发生感染、高血压、高血脂等并发症,但本组术后随访,存活率未受明显影响.     

Prevalence and long-term glucose metabolism evolution of post-transplant diabetes mellitus in Chinese renal recipients

Aim

To assess the prevalence and predictors of post-transplant diabetes mellitus (PTDM) in Chinese renal recipients and describe their long-term evolution of glucose metabolism.

Methods

887 non-diabetic Chinese adult renal recipients were studied retrospectively, with a median follow-up of 7 years. PTDM patients were categorized into transient PTDM and permanent PTDM. The cumulative incidence and risk factors of PTDM were estimated by Kaplan-Meier and Cox regression.

Results

The cumulative incidence of PTDM at 3 months, 1, 3, 5, 10, 15 and 20 years post-transplant was 10.4%, 11.4%, 13.4%, 15.2%, 22.7%, 27.9% and 38.3%, respectively. 61.9% of PTDM cases were diagnosed within the first three months and 61.6% of them developed persistent diabetes in the future. Risk factors for all PTDM included older age, body mass index (BMI) ≥ 25 kg/m², triglycerides ≥ 1.5 mmol/L, rejection, the use of tacrolimus and diltiazem. The predictors of permanent PTDM included age >50 years (RR = 2.322, 95% CI 1.255-4.296, P = 0.007), BMI ≥ 25 kg/m² (RR = 1.699, 95% CI 1.014-2.846, P = 0.044) and the use of tacrolimus (RR = 1.835, 95% CI 1.181-2.851, P = 0.007).

Conclusions

Patients were most susceptible to PTDM within the first three months post-transplant and more than half of them developed persistent diabetes in the future. Age >50 years, overweight and tacrolimus application were risk factors for both PTDM and permanent PTDM.     

肝病伴糖代谢异常患者的临床分析

目的探讨肝病伴糖代谢异常的临床特点及其可能机制.方法分别对29例慢性乙型肝炎伴糖代谢异常患者及62例乙型肝炎后肝硬化伴糖代谢异常患者进行相关分析.结果 （1）乙型肝炎后肝硬化患者中肝源性糖耐量减低（IGT）及肝源性糖尿病（DM）发生率高于慢性乙型肝炎患者（20.53%对3.82%,P＜0.05;24.11%对1.64%,P＜0.01）.（2）慢性乙型肝炎及乙型肝炎后肝硬化伴肝源性IGT或DM患者均无糖尿病症状,而19例慢性乙型肝炎伴原发性DM者中12例有症状,12例乙型肝炎后肝硬化伴原发性DM者中6例有症状.（3）慢性乙型肝炎伴肝源性IGT或DM者,空腹血糖（FPG）、餐后血糖（PPG）水平均低于伴原发性DM者（P＜0.05）;但前者葡萄糖负荷后胰岛素（PINS）及C肽（PCP）分泌水平高于后者（P＜0.05）.（4）乙型肝炎后肝硬化伴肝源性DM与伴原发性DM患者的FPG、PPG水平差异均无统计学意义,伴肝源性DM患者空腹胰岛素（FINS）、PINS、空腹C肽（FCP）及PCP水平高于伴原发性DM患者（P＜0.05）,但两者的PINS/FINS、PCP/FCP值差异无统计学意义,且小于5;伴肝源性DM患者其FPG、PPG水平均显著高于伴肝源性IGT者（P＜0.05）,FINS、PINS及FCP、PCP水平均低于肝源性IGT患者（P＜0.05,P＜0.01）.结论肝病继发糖代谢异常者多发生于肝硬化患者,且以肝功能损害较重者为主,多无症状;慢性乙型肝炎伴肝源性DM患者胰岛β细胞分泌胰岛素的功能增强,而乙型肝炎后肝硬化伴肝源性DM患者则减弱.     

Outcomes of liver transplantation in patients with hepatorenal syndrome

Hepatorenal syndrome (HRS) plays an important role in patients with liver cirrhosis on the wait list for liver transplantation (LT). The 1 and 5-year probability of developing HRS in cirrhotic with ascites is 20% and 40%, respectively. In this article, we reviewed current concepts in HRS pathophysiology, guidelines for HRS diagnosis, effective treatment options presently available, and controversies surrounding liver alone vs simultaneous liver kidney transplant (SLKT) in transplant candidates. Many treatment options including albumin, vasoconstrictors, renal replacement therapy, and eventual LT have remained a mainstay in the treatment of HRS. Unfortunately, even after aggressive measures such as terlipressin use, the rate of recovery is less than 50% of patients. Moreover, current SLKT guidelines include: (1) estimation of glomerular filtration rate of 30 mL/min or less for 4-8 wk; (2) proteinuria > 2 g/d; or (3) biopsy proven interstitial fibrosis or glomerulosclerosis. Even with these updated criteria there is a lack of consistency regarding long-term benefits for SLKT vs LT alone. Finally, in regards to kidney dysfunction in the post-transplant setting, an estimation of glomerular filtration rate < 60 mL/min per 1.73 m² may be associated with an increased risk of patients having long-term end stage renal disease. HRS is common in patients with cirrhosis and those on liver transplant waitlist. Prompt identification and therapy initiation in transplant candidates with HRS may improve post-transplantation outcomes. Future studies identifying optimal vasoconstrictor regimens, alternative therapies, and factors predictive of response to therapy are needed. The appropriate use of SLKT in patients with HRS remains controversial and requires further evidence by the transplant community.     

稳定型冠心病及合并糖尿病危险因素的高血压患者糖代谢异常筛查

目的调查在心内科门诊中既往无糖代谢异常病史的稳定型冠心病及合并糖尿病危险因素的高血压患者的糖代谢异常发生情况。方法对入选患者进行空腹或餐后毛细血管血糖检测,空腹血糖≥6.1 mmol/L或餐后随机血糖≥7.8 mmol/L的患者再进行口服葡萄糖耐量试验(OGTT)。结果共1412例患者进行毛细血管血糖检测,其中939例患者进行空腹血糖检测,281例(29.9%)患者空腹血糖≥6.1 mmol/L并且<7.0 mmol/L,105例(11.2%)患者空腹血糖≥7.0 mmol/L;473例患者进行餐后随机血糖检测,123例(26.0%)患者随机血糖≥7.8 mmol/L并且<11.1 mmol/L,43例(9.1%)患者随机血糖≥11.1 mmol/L。入选患者共552例(39.1%)毛细血管空腹血糖≥6.1 mmol/L或随机血糖≥7.8 mmol/L,其中298例患者又进行了OGTT,正常糖耐量(NGT)66例(22.1%),糖调节受损(IGR)132例(44.3%),其余100例(33.6%)患者新诊断为糖尿病。结论对既往无糖代谢异常病史的稳定型冠心病及合并糖尿病危险因素的高血压患者进行毛细血管血糖筛查及OGTT有助于早期发现糖代谢异常。     

肾移植术后糖尿病的发病及其危险因素分析

目的 探讨肾移植术后存活1年以上患者中根据空腹血糖(FPG)异常诊断的移植后糖尿病(PTDM)的发病及其相关危险因素.方法 对1993年1月至2008年12月接受肾移植手术的428例术前非糖尿病患者进行随访,根据FPG分析术后PTDM发生率及其相关危险因素.结果 428例术前非糖尿病患者,平均随访(5.65±3.68)年,共有87例(20.3％)发生PTDM,其中57例(占总PTDM的65.5％)发生于术后1年内.单因素分析提示年龄、体重指数(BMI)、吸烟史、糖尿病家族史、尸体供肾、乙型肝炎病毒(HCV)感染、巨细胞病毒感染、术前和术后1周FPG、术前高脂血症、术后环孢素A转换为他克莫司(FK506)、术后6个月和1年环孢素A峰浓度与PTDM明显相关(P＜0.05).由环孢素A转换为FK506的患者PTDM患病率升高,而由环孢素A转换为雷帕霉素的患者PTDM患病率无明显变化.多因素分析提示术前FPG、年龄、BMI、HCV感染、尸体供肾是PTDM的独立危险因素(P＜0.05或P＜0.01).结论 肾移植患者中有较高的PTDM发生率,应早期预防、早期诊断、早期治疗.     

肝移植病人术后他克莫司剂量的个体化调整

目的了解肝移植后肝脏功能和血药浓度的共同检测对指导个体化抗排异减量的意义。方法动态随访检测15例肝移植病人肝功能与他克莫司（FK506）血药浓度,根据检测结果进行FK506剂量的个体化调整。结果15例病人在联合检测行FK506个体化的减量过程中均获得成功。结论肝移植病人术后,通过肝脏功能和FK506血药浓度的共同检测,可以指导抗排异药物达到合理、有效、个体化的调整使用,值得临床推广。     

Minimizing tacrolimus decreases the risk of new-onset diabetes mellitus after liver transplantation

AIM: To investigate the impact of minimum tacrolimus(TAC) on new-onset diabetes mellitus(NODM) after liver transplantation(LT).METHODS: We retrospectively analyzed the data of 973 liver transplant recipients between March 1999 and September 2014 in West China Hospital Liver Transplantation Center. Following the exclusion of ineligible recipients, 528 recipients with a TAC-dominant regimen were included in our study. We calculated and determined the mean trough concentration of TAC(c TAC) in the year of diabetes diagnosis in NODM recipients or in the last year of the follow-up in nonNODM recipients. A cutoff of mean c TAC value for predicting NODM 6 mo after LT was identified using a receptor operating characteristic curve. TAC-related complications after LT was evaluated by χ~2 test, and the overall and allograft survival was evaluated using the Kaplan-Meier method. Risk factors for NODM after LT were examined by univariate and multivariate Cox regression.RESULTS: Of the 528 transplant recipients, 131(24.8%) developed NODM after 6 mo after LT, and the cumulative incidence of NODM progressively increased. The mean c TAC of NODM group recipients was significantly higher than that of recipients in the non-NODM group(7.66 ± 3.41 ng/m L vs 4.47 ± 2.22 ng/m L, P 0.05). Furthermore, NODM group recipients had lower 1-, 5-, 10-year overall survival rates(86.7%, 71.3%, and 61.1% vs 94.7%, 86.1%, and 83.7%, P 0.05) and allograft survival rates(92.8%, 84.6%, and 75.7% vs 96.1%, 91%, and 86.1%, P 0.05) than the others. The best cutoff of mean c TAC for predicting NODM was 5.89 ng/m L after 6 mo after LT. Multivariate analysis showed that old age at the time of LT( 50 years), hypertension pre-LT, and high mean c TAC(≥ 5.89 ng/m L) after 6 mo after LT were independent risk factors for developing NODM. Concurrently, recipients with a low c TAC( 5.89 ng/m L) were less likely to become obese(21.3% vs 30.2%, P 0.05) or to develop dyslipidemia(27.5% vs 44.8%, P 0.05), chronic kidney dysfunction(14.6% vs 22.7%, P 0.05), and moderate to severe infection(24.7% vs 33.1%, P 0.05) after LT than recipients in the high mean c TAC group. However, the two groups showed no significant difference in the incidence of acute and chronic rejection, hypertension, cardiovascular events and newonset malignancy. CONCLUSION: A minimal TAC regimen can decrease the risk of long-term NODM after LT. Maintaining a c TAC value below 5.89 ng/m L after LT is safe and beneficial.     

Utility of liver biopsy in predicting clinical outcomes after percutaneous angioplasty for hepatic venous obstruction in liver transplant patients

AIM: To determine utility of transplant liver biopsy in evaluating efficacy of percutaneous transluminal angioplasty(PTA) for hepatic venous obstruction(HVOO). METHODS: Adult liver transplant patients treated with PTA for HVOO(2003-2013) at a single institution were reviewed for pre/post-PTA imaging findings, manometry(gradient with right atrium), presence of HVOO on prePTA and post-PTA early and late biopsy(EB and LB, or 60 d after PTA), and clinical outcome, defined as good(no clinical issues, non-HVOO-related death) or poor(surgical correction, recurrent HVOO, or HVOOrelated death). RESULTS: Fifteen patients meeting inclusion criteria underwent 21 PTA, 658 ± 1293 d after transplant.In procedures with pre-PTA biopsy(n = 19), no difference was seen between pre-PTA gradient in 13/19 procedures with HVOO on biopsy and 6/19 procedures without HVOO(8 ± 2.4 mm Hg vs 6.8 ± 4.3 mm Hg; P = 0.35). Post-PTA, 10/21 livers had EB(29 ± 21 d) and 9/21 livers had LB(153 ± 81 d). On clinical follow-up(392 ± 773 d), HVOO on LB resulted in poor outcomes and absence of HVOO on LB resulted good outcomes. Patients with HVOO on EB(3/7 good, 4/7 poor) and no HVOO on EB(2/3 good, 1/3 poor) had mixed outcomes. CONCLUSION: Negative liver biopsy greater than 60 d after PTA accurately identifies patients with good clinical outcomes.