Clinical analysis of liver transplantation in autoimmune liver diseases

Background: Autoimmune liver diseases(ALDs) consist of autoimmune hepatitis(AIH), primary biliary cirrhosis(PBC), primary sclerosing cholangitis(PSC), Ig G4-associated cholangitis and overlap syndromes.Patients with these diseases may gradually progress to end-stage liver diseases and need liver transplantation. The present study aimed to explore the prognosis of patients with ALDs after liver transplantation.Methods: The clinical data of 80 patients with ALD(24 cases of AIH, 35 of PBC, 15 of PSC and 6 of AIHPBC overlap syndromes) who underwent liver transplantation in Renji Hospital, Shanghai Jiao Tong University School of Medicine from June 2004 to September 2016 were collected retrospectively. The causes of death were analyzed and the postoperative cumulative survival rate was estimated by the Kaplan–Meier method. Recurrence and other complications were also analyzed.Results: Of the 80 patients, 18 were males and 62 were females. The average age was 50.5 years and the average Model for End-stage Liver Disease(MELD) score was 14.1. After a median follow-up of 19.8 months, 8 patients died. The 1-, 3-and 5-year cumulative survival rates were all 89.0%. Three cases of recurrent ALDs were diagnosed(3.8%) but they were not totally consistent with primary diseases. Biliary tract complication occurred in 10 patients(12.5%). The new onset of tumor was observed in 1 patient(1.3%). De novo HBV/CMV/EBV infection was found in 3, 8 and 3 patients, respectively.Conclusion: Liver transplantation is an effective and safe treatment for end-stage ALD.     

加强对自身免疫性肝病重叠综合征的认识

随着自身免疫性肝病研究的不断深入,发现许多自身免疫性肝病同时具有或随后表现出其他自身免疫性肝病的特征,临床上称为自身免疫性肝病重叠综合征.由于发病率越来越高以及本组疾病的病因不明、临床表现多样、诊断标准及治疗终点等诸多方面均有待于进一步探讨,因而加强对本组疾病的探索具有重要的意义.     

自身免疫性肝病在住院患者中的分布特征

目的研究自身免疫性肝病住院疾病谱的分布特征及变化趋势。方法回顾性分析2002年1月至2011年12月住院的4 014例自身免疫性肝病患者的疾病构成情况。结果自身免疫性肝病在住院肝病患者中的构成总体呈上升趋势,其构成比由2002年的1.76%升至2011年的3.66%;原发性胆汁性肝硬化和自身免疫性肝炎是自身免疫性肝病疾病谱中的重要组成部分,其构成比分别为51.82%和38.39%;自身免疫性肝病疾病谱中,各组患者年龄及女性构成比均差异有统计学意义（χ^2=332.51、57.36,均P〈0.01）。各组患者的治愈好转率及肝功能衰竭的发生率均差异有统计学意义（χ^2=31.52、31.63,均P〈0.01）。但各组患者出现肝功能衰竭的性别构成比之间差异无统计学意义（χ^2=5.72,P=0.126）。结论目前自身免疫性肝病已成为肝病的重要组成部分,应引起临床医师的高度重视。     

Overlap syndromes among autoimmune liver diseases

The three major immune disorders of the liver are autoimmune hepatitis（AIH）,primary biliary cirrhosis（PBC） and primary sclerosing cholangitis（PSC）.Variant forms of these diseases are generally called overlap syndromes,although there has been no standardised definition.Patients with overlap syndromes present with both hepatitic and cholestatic serum liver tests and have histological features of AIH and PBC or PSC.The AIH-PBC overlap syndrome is the most common form,affecting almost 10% of adults with AIH or PBC.Single cases of AIH and autoimmune cholangitis（AMA-negative PBC） overlap syndrome have also been reported.The AIH-PSC overlap syndrome is predominantly found in children,adolescents and young adults with AIH or PSC.Interestingly,transitions from one autoimmune to another have also been reported in a minority of patients,especially transitions from PBC to AIH-PBC overlap syndrome.Overlap syndromes show a progressive course towards liver cirrhosis and liver failure without treatment.Therapy for overlap syndromes is empiric,since controlled trials are not available in these rare disorders.Anticholestatic therapy with ursodeoxycholic acid is usually combined with immunosuppressive therapy with corticosteroids and/or azathioprine in both AIH-PBC and AIH-PSC overlap syndromes.In end-stage disease,liver transplantation is the treatment of choice.     

不同类型自身免疫性肝病患者肝组织炎症因子表达的变化

目的 探讨不同类型自身免疫性肝病(AILD)患者肝组织炎症因子表达的变化。方法 2016年12月～2018年12月我院肝病科收治的AILD患者74例,其中自身免疫性肝炎(AIH)患者19例,原发性胆汁性肝硬化(PBC)患者42例,自身免疫性肝炎/原发性胆汁性肝硬化重叠综合症(AIH/PBC OS)患者13例。采用免疫组化法检测肝穿组织白介素-12(IL-12)、IL-17和干扰素-γ(IFN-γ)表达情况。结果 AIH、PBC和AIH-PBC OS患者血清ALT水平分别为(132.5±12.5)U/L、(40.1±8.4)U/L和(166.2±16.3)U/L,AST水平分别为(120.3±11.7)U/L、(52.8±5.6)U/L和(194.7±18.3)U/L,差异显著(P<0.05);血清ALP水平分别为(98.0±9.2)U/L、(323.5±30.9)U/L和(257.1±24.1)U/L,血清GGT水平分别为(49.1±4.7)U/L、(236.8±22.6)U/L和(376.7±35.5)U/L,差异显著(P<0.05);AIH、PBC和AIH-PBC OS组患者肝组织IL-12表达阳性率无统计学差异(分别为15.8%、7.1%和15.4%,P>0.05),肝组织IL-17阳性表达率无统计学差异(分别为73.7%、76.2%和76.9%,P<0.05),肝组织IFN-γ阳性表达率无统计学差异(分别为68.4%、85.7%和76.9%,P<0.05);AIH患者血清抗肝肾微粒体I型抗体(LKM-1)、抗可溶性肝抗原/肝胰抗原抗体(SLA/LP)阳性率分别为21.1%和10.8%,均显著高于PBC组或AIH-PBC OS患者(分别为0.0%和0.0%,和0.0%和0.0%,P<0.05);PBC患者血清抗sp100抗体阳性率为19.0%,显著高于AIH组(0.0%)或AIH-PBC OS患者(7.7%,P<0.05);AIH-PBC OS组血清抗gp210抗体阳性率为38.5%,显著高于AIH组(0.0%,P<0.05),AIH-PBC OS组患者血清抗线粒体M2抗体(AMA-M2)阳性率为100.0%,显著高于AIH组(0.0%)或PBC组(73.8%,P<0.05);AIH患者血清ANA和SMA阳性率分别为94.7%和78.9%,显著高于PBC患者(分别为19.0%和19.0%,P<0.05)。结论 不同类型AILD患者血清自身抗体呈交叉阳性现象,肝组织炎性因子检测对鉴别诊断没有意义,常规肝功能指标仍对诊断起关键作用。     

Diagnostic utility of IgG and IgM immunohistochemistry in autoimmune liver disease

AIM:To assess the role of IgM and IgG immunohistochemistry(IHC) in the evaluation of autoimmune liver conditions-autoimmune hepatitis(AIH),primary biliary cirrhosis(PBC),and primary sclerosing cholangitis(PSC).METHODS:Forty one biopsies from untreated patients diagnosed with autoimmune liver disease(AIH,n = 20;PBC,n = 13;PSC,n = 8) and fourteen biopsies of patients with chronic hepatitis C were selected.IgM and IgG-positive plasma cells were counted in each sample.RESULTS:A predominance of IgG-positive plas...     

2014年自身免疫性肝病诊疗进展

<正>自身免疫性肝病(Autoimmune liver diseases,AILD)是因免疫系统过度激活从而出现肝功能异常及相应临床综合征的一组疾病,可简单分为以肝炎为主型,即自身免疫性肝炎(Autoimmune hepatitis,AIH)及以胆管损害和胆汁淤积为主型,即原发性胆汁性肝硬化(Primary biliary cirrhosis,PBC)和原发性硬化性胆管炎(Primary sclerosing cholangitis,PSC)。此外,部分     

Autoimmune liver serology：Current diagnostic and clinical challenges

Liver-related autoantibodies are crucial for the correct diagnosis and classification of autoimmune liver diseases（AiLD）,namely autoimmune hepatitis types 1 and 2（AIH-1 and 2）,primary biliary cirrhosis（PBC）,and the sclerosing cholangitis variants in adults and children.AIH-1 is specified by anti-nuclear antibody（ANA） and smooth muscle antibody（SMA）.AIH-2 is specified by antibody to liver kidney microsomal antigen type-1（anti-LKM1） and anti-liver cytosol type 1（anti-LC1）.SMA,ANA and anti-LKM antibodies can be present in de-novo AIH following liver transplantation.PBC is specified by antimitochondrial antibodies（AMA） reacting with enzymes of the 2-oxo-acid dehydrogenase complexes（chiefly pyruvate dehydrogenase complex E2 subunit） and disease-specific ANA mainly react-ing with nuclear pore gp210 and nuclear body sp100.Sclerosing cholangitis presents as at least two variants,first the classical primary sclerosing cholangitis（PSC） mostly affecting adult men wherein the only（and non-specific） reactivity is an atypical perinuclear antineutro-phil cytoplasmic antibody（p-ANCA）,also termed perinuclear anti-neutrophil nuclear antibodies（p-ANNA） and second the childhood disease called autoimmune sclerosing cholangitis（ASC） with serological features resembling those of type 1 AIH.Liver diagnostic serology is a fast-expanding area of investigation as new purified and recombinant autoantigens,and automatedtechnologies such as ELISAs and bead assays,become available to complement（or even compete with） traditional immunofluorescence procedures.We survey for the first time global trends in quality assurance impacting as it does on（1） manufacturers/purveyors of kits and reagents,（2） diagnostic service laboratories that fulfill clinicians＇ requirements,and（3） the end-user,the physician providing patient care,who must properly interpret test results in the overall clinical context.     

2008年非病毒性肝病临床进展回顾

回顾2008年关于肝豆状核变性、非酒精性脂肪肝、自身免疫性肝炎、原发性胆汁性肝硬化及原发性硬化性胆管炎在诊断、治疗及检测等方面的研究进展。     

中西医药治疗自身免疫性肝病研究进展

目的 自身免疫性肝病的发病率逐年升高,成为肝脏疾病的研究热点之一。西医治疗有明确的疗效,但中西医结合治疗能让患者有更多的获益,在提高治疗效果的同时,可以减少西药的副作用,提高西药的应答率,更好地改善患者的生存质量,延长生存时间。本文就当前西医、中医和中西医结合治疗进展进行了综述,以为临床提供可参考的中西医结合治疗方案。     

Cirrhosis and autoimmune liver disease:Current understanding

Primary biliary cirrhosis(PBC),primary sclerosing cholangitis(PSC) and autoimmune hepatitis(AIH) constitute the classic autoimmune liver diseases(AILDs).While AIH target the hepatocytes,in PBC and PSC the targets of the autoimmune attack are the biliary epithelial cells.Persistent liver injury,associated with chronic AILD,leads to un-resolving inflammation,cell proliferation and the deposition of extracellular matrix proteins by hepatic stellate cells and portal myofibroblasts.Liver cirrhosis,and the resultant loss of normal liver function,inevitably ensues.Patients with cirrhosis have higher risks or morbidity and mortality,and that in the decompensated phase,complications of portal hypertension and/or liver dysfunction lead to rapid deterioration.Accurate diagnosis and monitoring of cirrhosis is,therefore of upmost importance.Liver biopsy is currently the gold standard technique,but highly promising non-invasive methodology is under development.Liver transplantation(LT) is an effective therapeutic option for the management of endstage liver disease secondary to AIH,PBC and PSC.LT is indicated for AILD patients who have progressed to end-stage chronic liver disease or developed intractable symptoms or hepatic malignancy;in addition,LT may also be indicated for patients presenting with acute liver disease due to AIH who do not respond to steroids.     

自身免疫性肝病活检组织病理学特征分析109例

目的:分析比较自身免疫性肝炎(AIH)、原发性胆汁性肝硬化(PBC)、原发性硬化性胆管炎(PSC)及其重叠综合征的组织病理学变化,提高对自身免疫性肝病(AILD)的认识.方法:对27例AIH、67例PBC、4例PSC、1例AIH-PSC重叠综合征和10例AIH-PBC重叠综合征患者的肝穿组织病理资料进行回顾性分析.结果:AILD患者多发于中年女性(73.3%),肝组织病理变化以界面性肝炎为主(77.7%),在重度患者则出现重度界面性肝炎、桥样坏死等.PBC患者早期(Ⅰ、Ⅱ)占28.3%,而晚期(Ⅲ、Ⅳ)占71.7%,肝组织病理变化以小胆管减少甚至消失为主(62.6%).AIH-PBC重叠综合征患者并非罕见,他的肝组织病理学具有AIH和PBC的双重特征.结论:AILD是非病毒性肝病的重要组成部分,其诊断需综合临床表现、生化、免疫指标和组织学变化.     

自身免疫性肝病的回顾性研究

目的 提高对自身免疫性肝病的认识,以利于早期诊断、早期治疗.方法 回顾性对81例自身免疫性肝病患者进行诊断,比较自身免疫性肝炎(AIH)、原发性胆汁性肝硬化(PBC)及其重叠综合征(OS)的临床、血液化学及病理特点.结果 81例患者中,女性占91.4%;总体误诊率为45.7%,OS漏诊率为96.7%,初始诊断为肝硬化者60.5%(49/81),其中37%(30/81)为失代偿期肝硬化.AIH组18.2%(6/33)以急性肝功能衰竭发病,明显高于PBC、OS组,3组患者症状、体征基本一致,AIH、OS组患者丙氨酸氨基转移酶(ALT)、天冬氨酸氨基转移酶(AST)水平及抗核抗体(ANA)阳性率明显高于PBC组(Z=6.411,P=0.041;Z=7.980,P=0.019;X2=11.951,P=0.003),PBC、OS组患者血清门冬氨酸氨基转移酶(GGT)、碱性磷酸酶(ALP)、总胆固醇、载脂蛋白B水平及抗线粒体抗体(AMA)阳性率明显高于AIH组(Z=37.327,P=0.000;Z=12.929,P=0.002;Z=16.722,P=0.000;Z=6.695,P=0.035;X2=31.219,P=0.000).结论 自身免疫性肝病误诊率高.AIH、OS患者氨基转移酶升高明显,ANA阳性率高,PBC、OS患者GGT、ALP升高明显,血脂代谢障碍,AMA阳性率高.     

Liver transplantation in autoimmune liver diseases

Liver transplantation is indicated for terminal phases of autoimmune hepatitis, primary biliary cirrhosis and primary sclerosing cholangitis. Indications for transplantation in autoimmune liver diseases are similar to those used in other acute or chronic liver diseases. Therapeutic advances have reduced the need for transplantation for autoimmune hepatitis and primary biliary cirrhosis but not for primary sclerosing cholangitis. Overall, outcomes of transplantation for autoimmune liver diseases are excellent. However, recurrence of autoimmune liver diseases in the allograft has variable impacts on graft and patient survivals. Treatment of recurrent diseases requires changes in immunosuppression or addition of ursodeoxycholic acid. Among autoimmune liver diseases, only autoimmune hepatitis occurs de novo in recipients transplanted for other diseases. Patients transplanted for autoimmune hepatitis or primary sclerosing cholangitis are at risk for reactivation or de novo onset of ulcerative colitis. Better understanding of the pathogenesis of recurrent autoimmune liver diseases is needed to devise effective means of prevention and treatment.     

慢性肝病患者组织中生存素与VEGF-A的表达

目的研究慢性肝病患者组织中生存素与血管内皮生长因子-A(VEGF-A)的表达意义。方法选取2011年1月-2013年5月广西壮族自治区南溪山医院肝病科收治的原发性肝癌患者50例作为研究对象,所有患者均行手术治疗,同时经病理学检查后证实为原发性肝癌,比较乙肝肝硬化、慢性乙型肝炎、原发性肝癌患者组织中的生存素与VEGF-A的表达。结果生存素在乙肝肝硬化、慢性乙型肝炎、原发性肝癌患者组织中的阳性表达率分别为46.9%、31.6%、84.0%,在三者之间的表达,差异具有统计学意义(P0.05);VEGF-A的表达率分别为75.0%、26.3%、68.0%,VEGF-A在原发性肝癌患者中的阳性表达率比乙肝肝硬化、慢性乙型肝炎患者较高,差异具有统计学意义(P0.05)。结论将生存素与VEGF-A作为早期原发性肝癌的检测标志物,能有效提高肝癌的诊断率,值得临床推广使用。     

Risk factors for de novo hepatitis B infection in pediatric living donor liver transplantation

AIM: To investigate the incidence of de novo hepatitis B virus (HBV) infection after pediatric living donor liver transplantation (LDLT) and to analyze the risk factors associated with this de novo HBV infection.METHODS: The clinical and laboratory data of children who underwent LDLT from June 2010 to September 2012 in First Center Hospital in Tianjin, China, were retrospectively included in the study. Intrahepatic HBV DNA in donors and recipients was quantified by real-time polymerase chain reaction using DNA extracted from formalin-fixed, paraffin-embedded tissues.RESULTS: Between June 2010 to September 2012, 32 consecutive pediatric patients underwent LDLT in our institute. Thirty LDLT patients (13 girls and 17 boys) were followed up for a median of 15 mo, of whom 53.3% (16/30) were hepatitis B core antibody (HBcAb) positive and 36.7% (11/30) were hepatitis B surface antibody (HBsAb)/HBcAb positive before transplantation. Sixteen of the children received HBcAb-positive allografts, and 43.7% (7/16) of the grafts were found to be intrahepatic HBV DNA positive. De novo HBV infection developed in 16.1% (5/30) of the children within a median of 11 mo after transplantation. All five of the HBV-infected children had received HBcAb-positive allografts, four of which were intrahepatic HBV DNA positive. Two of the children developed de novo HBV infection despite the preoperative presence of both HBsAb and HBcAbCONCLUSION: In pediatric recipients, positive intrahepatic HBV DNA in allografts could be a risk factor for de novo HBV infection from HBcAb-positive allografts. HBsAb/HBcAb positivity in pediatric LDLT patients before transplantation exhibited only weak effectiveness in protecting them against de novo HBV infection from HBcAb-positive allografts.     

自身免疫性肝炎与原发性胆汁性肝硬化患者血生化和肝组织病理学分析

目的：探讨自身免疫性肝炎（AIH）与原发性胆汁性肝硬化（PBC）患者早期临床特征。方法回顾性分析我院近年来收治的42例自身免疫性肝病患者的临床资料,其中PBC组25例,AIH组17例,分别对两种疾病患者生化学、免疫学、组织学指标进行比较,找出各自的特点。结果 AIH患者总胆红素水平（53.4±28.5）μmol/L与PBC患者（62.0±34.2）μmol/L比,无统计学差异（P＞0.05）;AIH患者ALT（268.0±149.1） U/L、AST（178.7±108.4） U/L、免疫球蛋白IgG（21.7±8.6） g/L显著高于PBC患者ALT为（57.3±36.5） U/L、AST为（107.7±76.1） U/L、IgG为（11.6±5.2） g/L,两组比较具有统计学差异（P〈0.05）;PBC患者γ-GT （398.8±158） U/L、ALP（456.4±175.2） U/L、免疫球蛋白IgM（5.4±1.7） g/L显著高于AIH患者（γ-GT为（107.5±68.4） U/L、ALP为（133.0±64.5） U/L、IgM为（2.2±0.8） g/L,两组比较具有统计学差异（P〈0.01）;AIH患者抗核抗体阳性率为64.7%,PBC患者抗线粒体抗体-M2阳性率为96.0%;AIH主要表现为界面性炎症、浆细胞浸润,PBC主要表现为小胆管变性和坏死。结论通过生化学、免疫学指标、自身抗体检查及肝活检可早期对两种疾病进行诊断及鉴别。     

Gender specific medicine in liver diseases: A point of view

Gender medicine focuses on the patho-physiological, clinical, prevention and treatment differences in diseases that are equally represented in men and women. The purpose of gender medicine is to ensure that each individual man and woman receives the best treatment possible based on scientific evidence. The concept of “gender” includes not only the sexual characteristics of individuals but also physiological and psychological attributes of men and women, including risk factors, protective/aggravating effects of sexual hormones and variances linked to genetics and corporal structures that explain biological and physiological differences between men and women. It is very important to consider all the biological, physiological, functional, psychological, social and cultural characteristics to provide patients with individualized disease management. Herein, we critically analyze the literature regarding gender differences for diseases and acquired conditions of the most representative hepatic pathologies: primary biliary cirrhosis, autoimmune hepatitis, primary sclerosing cholangitis, non alcoholic fatty liver disease and alcoholic liver disease, and viral chronic hepatitis B and C. The last section addresses hemochromatosis, which is a prevalent iron overload disorder in the Caucasian population. This review aims to describe data from the literature concerning viral chronic hepatitis during pregnancy, management during pregnancy and delivery, and new effective drugs for the prevention of maternal infection transmission without significant adverse effects or complications.     

吗替麦考酚酯治疗难治性自身免疫性肝病的临床研究

目的 探讨吗替麦考酚酯(MMF)对难治性自身免疫性肝病的疗效及安全性.方法 回顾性分析6例传统治疗无效或不能耐受的自身免疫性肝病患者MMF治疗前后的疗效及生化指标的变化,记录治疗过程中出现的不良反应.结果 4例ALT增高者,3例降至正常;5例碱性磷酸酶(ALP)增高者,4例下降超过50%;5例GGT增高者,下降均超过50%;2例IgG、y-球蛋白增高者,均降至正常;2例总胆红素(TBIL)、直接胆红素(DBIL)、总胆汁酸、白细胞、血小板增高者,无变化.6例患者均未出现不良反应.结论 MMF对早期的难治性自身免疫性肝病疗效良好,毒副作用小.     

De novo autoimmune hepatitis in liver transplant: State-of-the-art review

In the two past decades, a number of communications, case-control studies, and retrospective reports have appeared in the literature with concerns about the development of a complex set of clinical, laboratory and histological characteristics of a liver graft dysfunction that is compatible with autoimmune hepatitis. The de novo prefix was added to distinguish this entity from a pre-transplant primary autoimmune hepatitis, but the globally accepted criteria for the diagnosis of autoimmune hepatitis have been adopted in the diagnostic algorithm. Indeed, de novo autoimmune hepatitis is characterized by the typical liver necroinflammation that is rich in plasma cells, the presence of interface hepatitis and the consequent laboratory findings of elevations in liver enzymes, increases in serum gamma globulin and the appearance of nonorgan specific auto-antibodies. Still, the overall features of de novo autoimmune hepatitis appear not to be attributable to a univocal patho-physiological pathway because they can develop in the patients who have undergone liver transplantation due to different etiologies. Specifically, in subjects with hepatitis C virus recurrence, an interferon-containing antiviral treatment has been indicated as a potential inception of immune system derangement. Herein, we attempt to review the currently available knowledge about de novo liver autoimmunity and its clinical management.