原发性胆汁性肝硬化自身抗体的研究进展

原发性胆汁性肝硬化（pfimary biliary cirrhosis，PBC）是一种原因不明的慢性胆汁淤积性自身免疫性肝病，其确切的发病机制尚未明确，可能涉及遗传、免疫及环境因素。其中体液免疫可能扮演了重要角色，引起了临床上的高度关注，血清中高滴度的抗线粒体抗体（antimitochondrial antibodies，AMA）已成为PBC诊断的重要指标。本文旨在探讨该领域的最新进展，以期加深对其爱病机制的理解，为临床诊治提供进一步的依据。     

53例原发性胆汁性肝硬化临床和病理分析

目的分析原发性胆汁性肝硬化（PBC）患者的临床表现、实验室检查及病理特征。方法回顾性分析53例PBC患者的临床表现、实验室检查及病理特征。结果53例PBC患者中女性46例（86．8％），发病至确诊时间（中位数）28个月，主要症状包括反复肝功能异常、乏力、黄疸、瘙痒、肝脾肿大等；53例患者GGT、ALP均有明显升高；73．6％（39／53）患者AMA和（或）AMA-M2亚型阳性，另14例血清AMA和AMA-M2亚型阴性，经病理检查证实为PBC；53例患者中Ⅰ期为13例（24．5％），Ⅱ期20例（37．7％），Ⅲ期16例（30．2％），Ⅳ期4例（7．5％）；Ⅰ期、Ⅱ期（33例）与Ⅲ期、Ⅳ期（20例）患者肝功能等计量资料只有GGT、ALP差异有显著性意义（P〈0．05），病理改变严重者GGT、ALP升高明显。结论临床判断PBC患者病情的轻重应综合分析临床症状、生化改变（尤其是GGT、ALP）、自身抗体检测以及组织学检查等，而不应局限于用黄疸作为衡量指标。     

Diagnosis of primary biliary cirrhosis

Primary biliary cirrhosis is the archetypal autoimmune liver disease, with the disease label describing a chronic granulomatous lymphocytic small bile duct cholangitis, which now most commonly presents asymptomatically and at an early pre-cirrhotic stage. Disease is more common than thought, with 1 in 1000 women over the age of 40 affected. Characteristic immunologic features of the disease assist clinicians in ready non-invasive diagnosis of patients, even if asymptomatic with only anicteric/cholestatic liver biochemical profiles. Over 90% of patients are anti-mitochondrial antibody positive, and for those negative, a significant proportion have highly specific anti-nuclear antibody profiles. Liver biopsy remains useful in certain settings where clarity is needed to confirm diagnosis, exclude alternative disease, and assess the relative contribution of PBC to other co-existent liver injury, and seeks to demonstrate in particular the classic bile duct lesions, as well as the degree of interface activity.     

Pathogenesis of primary biliary cirrhosis： A unifying model

Primary biliary cirrhosis (PBC) is a disease of unknown etiology leading to progressive destruction of small intrahepatic bile ducts and eventually to liver cirrhosis and failure. It is characterised by female predominance and serum auto-antibodies to mitochondrial antigens targeting the E2 components of the 2-oxoacid dehydrogenase complex. Although they are associated with disease pathogenesis, no concrete evidence has been presented so far. Epidemiological data indicate that a geographical clustering of cases and possible environmental factors are implicated in pathogenesis. A number of genetic factors play a role in determining disease susceptibility or progression, although no definitive conclusion has been reached so far. A key factor to immune pathogenesis is considered to be the breakdown of immune tolerance, either through molecular mimicry or through the so called determinant density model. In this review, the available data regarding the pathogenesis of primary biliary cirrhosis are described and discussed. A new unifying hypothesis based on early endothelin overproduction in primary biliary cirrhosis (PBC) is presented and discussed.     

Osteoporosis: still a typical complication of primary biliary cirrhosis?

BACKGROUND: Osteoporosis is a recognized complication of primary biliary cirrhosis but it has been suggested that its prevalence may overlap that observed among postmenopausal women. AIM: To evaluate prevalence and risk factors of osteoporosis in primary biliary cirrhosis. PATIENTS: A total of 133 female patients (age 53+/-10 years, menopausal status 70%, histological stage I-II 61%, portal hypertension 28%, Mayo Risk Score 4.11+/-0.59) were enrolled. METHODS: Dual X-ray absorptiometry of the lumbar spine. RESULTS: Mean bone mineral density, T and Z score were 0.861+/-0.160 g/cm2, -1.87+/-1.45 and -0.78+/-2.63, respectively. At multivariate analysis, bone mineral density was inversely correlated with age (p<0.05). Osteoporosis was present in 39/92 (41%) postmenopausal and 8/41 (20%) premenopausal patients. In the premenopausal group, osteoporosis was significantly correlated with serum albumin (p<0.05) and Mayo Risk score (p<0.005). No significant correlation was present in the postmenopausal group. CONCLUSIONS: Despite the accepted wisdom that osteoporosis is a common complication of primary biliary cirrhosis, its frequency in post-menopausal patients overlaps that observed in the general population, but is much more frequent in premenopausal patients, where it appears to be related to severity of liver disease and cholestasis.     

原发性胆汁性肝硬化发生失代偿的预测

目的建立原发性胆汁性肝硬化(PBC)发生失代偿的预测模型,验证并判断其预测价值。方法回顾性分析113例确诊时处于代偿期的PBC患者的人口统计学、实验室检查、临床表现及其他预后模型(Child-Pugh、MELD、Mayo模型)积分,研究终点为发生腹水、肝性脑病、食管胃底静脉曲张出血等失代偿。应用SPSS16.0统计软件,采用多因素(Cox回归、Kaplan-Meier(K-M)等方法建立发生失代偿的预测模型,采用接受者工作特征(ROC)曲线下面积比较所建模型与以往其他模型对PBC发生失代偿的预测价值。结果随访中位数时间31.2个月(3.37～122.43个月)期间,有21例(18.58%)患者达研究终点。所建立的PBC发生失代偿的预测模型(即D-PBC模型)指标包括AST/ALT比值、碱性磷酸酶(ALP)、胆碱酯酶(CHE)和血小板(PLT),PI=0.862×AST/ALT+0.003×ALP(U/L)-0.293×CHE(kU/L)-0.011×PLT(×10~9/L)。与其他模型相比,该预测模型的ROC曲线下面积较大,采用PI>-1.41预测PBC发生失代偿的敏感性高达0.91。结论 D-PBC模型能准确预测代偿期PBC患者临床失代偿的发生。     

AMA阳性的原发性胆汁性肝硬化患者的临床特征

目的探讨原发性胆汁性肝硬化(primary biliary cirrhosis,PBC)的临床特征。方法回顾36例AMA阳性的PBC患者临床资料,同期住院的36例慢性乙型肝炎肝硬化(chronic hepatitis B virus-related cirrhosis,HBV-C)患者为对照组,分析两组患者的临床特点和生物化学指标。结果 PBC组以女性(83.3%)多见,平均年龄(53.5±11.5)岁,HBV-C组主要是男性(77.8%),平均年龄(56.4±12.8)岁。黄疸(66.7%)和乏力(63.9%)是PBC组的主要表现,HBV-C组以腹水(50.0%)和上消化道出血(38.9%)常见。HBV-C组的PLT和WBC水平较PBC组显著下降(P<0.01)。两组患者均有Hb和RBC水平明显降低,PBC组更明显,但两组间差异无统计学意义。ALT、AST、GGT、ALP、TBIL和DBIL水平在PBC组中均明显升高(P<0.05),而PT在HBV-C组显著延长(P=0.000)。血脂各项指标在Child-Pugh A级中,PBC组均高于HBV-C组,但差异无统计学意义;Child-Pugh B级中,TG、TC及LDL-C水平PBC组显著高于HBV-C组(P<0.05),而HDL-C水平在PBC组显著降低(P=0.006)。结论 PBC患者具有许多独特的临床特征,包括:①常合并其他自身免疫性疾病;②更容易发生黄疸和贫血;③反映胆管功能和胆汁代谢指标明显异常;④HDL-C的下降可能是反映PBC病情进展的良好指标。     

25例原发性胆汁性肝硬化患者临床和病理特征分析

目的通过分析原发性胆汁性肝硬化患者的临床资料,旨在提高对该病的诊治水平。方法对25例原发性胆汁性肝硬化患者的临床和病理资料进行回顾性分析,总结患者的临床特征、各项生化指标、免疫学与病理学特点。结果在25例PBC患者,ALP均明显升高(524.9±214.4U/L),17例γ-GT升高(431.1±248.9U/L),8例总胆红素升高(274.1±161.6μmol/L),均以直接胆红素升高为主,21例抗核抗体(ANA)阳性;12例行肝穿刺病理检查,其中11例符合PBC;8例影像学检查显示肝内胆管扩张,走行僵直。结论PBC主要累及中老年女性,血清ALP、γ-GT水平升高,AMA阳性以及病理学与影像学检查有助于诊断本病。     

Concept on the pathogenesis and treatment of primary biliary cirrhosis

~~Concept on the pathogenesis and treatment of primary biliarycirrhosis@Vasiliy Ivanovich Reshetnyak$Scientific Research Institute of General Reaniamatology,Russia Academy of Medical Sciences,Moscow,Russia1 Loginov AC. Classification and nomenclature of c…     

Etidronate for osteoporosis in primary biliary cirrhosis: a randomized trial

BACKGROUND/AIM: Osteoporosis is a common complication of primary biliary cirrhosis but there is no accepted therapy for the osteoporosis. In this randomized controlled trial, we compared the effects of etidronate to placebo on the treatment of osteoporosis associated with primary biliary cirrhosis. METHODS: Sixty-seven patients with primary biliary cirrhosis and osteopenia, defined by bone mineral density criteria (T-score < -2.0) were enrolled. Measurements of the lumbar spine and proximal femur, as well as x-rays of the lumbar spine, were obtained. Patients received cyclical etidronate 400 mg/day for 14 days every 3 months for at least 1 year. Supplemental calcium was administered on the days patients did not receive etidronate. RESULTS: Of the 67 patients entered, 60 completed at least 1 year of therapy. There was no significant difference in changes in bone density at either the lumbar spine or femur in patients receiving etidronate when compared to placebo. Fractures occurred in eight patients, four receiving etidronate. Etidronate therapy was associated with a significant reduction in markers of bone turnover compared to placebo. These changes did not correlate with changes in bone density. CONCLUSIONS: Cyclical etidronate administered with supplemental calcium did not significantly improve bone density in patients with primary biliary cirrhosis.     

Gastric myoelectrical activity in patients with primary biliary cirrhosis

Objective  To examine gastric myoelectrical activity in patients with primary biliary cirrhosis (PBC). Materials and methods  The study comprised 11 female PBC patients (average age 53.4 years, range 43–70) and two aged-matched control groups: 11 (53.4 years, range 37–78) healthy women, and 10 female patients with chronic hepatitis C, CHC (53.9 years, range 35–66), who were examined prior to administration of an antiviral therapy. Every subject underwent an electrogastrographic recording comprising a 30-min interdigestive and a 120-min postprandial period. Results  Abnormal electrogastrograms, containing prolonged epochs of tachygastria in the postprandial phase were found in 2 out of 11 (18.2%) patients having both stage IV of the Scheuer’s PBC classification, as well as in 1 patient out of 10 (10%) with CHC at stage F2 according to the METAVIR fibrosis score. Conclusion  Electrogastrographic abnormalities do not seem to be pathognomonic for the PBC as a disease, but rather would be considered an unspecific sequel of a morbid liver affection.     

原发性胆汁性肝硬化患者60例自身抗体检测分析

目的研究原发性胆汁性肝硬化(PBC)患者自身抗体的类型。方法分析北京大学人民医院1995-01~2004-12收治的60例原发性胆汁性肝硬化患者的自身抗体检测结果和临床资料。结果60例患者中抗线粒体抗体(AMA)阳性者45例(75%),抗核抗体(ANA)阳性者36例(60%),其中斑型ANA14例(23%),多核点ANA12例(20%),核膜型ANA10例(16%),着丝点型ANA6例(10%),均质型ANA1例(1·6%),抗SSA阳性者12例(20%),抗SSB阳性者6例(10%),抗RNP阳性者1例。对比AMA阴性者中多核点型ANA阳性者3例,核膜型ANA阳性者4例。7例PBC患者存在一种以上的ANA荧光模式。AMA阳性和阴性患者临床资料,两组患者的年龄、生化及免疫学指标差异无显著性意义。结论AMA阳性和阴性患者有相似的临床表现、生化和免疫学指标。除AMA外,PBC患者可出现多种自身抗体。多核点型和核膜型ANA的检测有助于AMA阴性PBC的诊断。     

Characteristic differences according to the cirrhotic pattern of advanced primary biliary cirrhosis: Macronodular cirrhosis indicates slow progression.

It is important to evaluate advanced primary biliary cirrhosis (PBC) clinicopathologically to clarify its progressive mechanism. According to the cirrhotic pattern, 26 cases of explanted PBC were classified into non-cirrhotic (n=4), macronodular (n=4), mixed nodular (n=6), and micronodular cirrhosis (n=12), to compare their clinical and morphological features. In addition, the degree of preserved intrahepatic bile ducts and other histologic features were analyzed. Patients at living donor liver transplantation (LDLT) in the macronodular cirrhosis were significantly older than those in the micronodular cirrhosis. The mean duration between clinical presentation and LDLT in the macronodular cirrhosis was significantly longer than in the micronodular cirrhosis. The non-cirrhotic group showed a short duration between clinical presentation and LDLT. The ratio of explanted liver volume to standard liver volume (ELV/SLV) indicates that macronodular cirrhosis revealed more atrophic change than that in the other three types. The density of remnant intrahepatic bile ducts of less than 50mum per group in cases of macronodular cirrhosis was significantly higher than that in cases of micronodular cirrhosis. Therefore, different cirrhotic patterns of advanced PBC were correlated with the disease progression and the degree of bile duct disappearance. The macronodular cirrhotic patients were older, had a longer disease course, yet had less bile duct loss. We suggest that macronodular cirrhosis and micronodular cirrhosis of PBC are different type of PBC.     

High concentration of antimitochondrial antibodies predicts progressive primary biliary cirrhosis

AIM: To evaluate the serum concentration of antimitochondrial antibodies (AMAs) as a prognostic indicator of progressive primary biliary cirrhosis (pPBC). METHODS: Serum concentrations of AMA subtypes (anti-M2, anti-M4, and anti-M9), biochemical indices of liver function and Mayo risk factor (MRF) were determined in 30 women with diagnosed primary biliary cirrhosis (PBC) selected among 348 females with elevated alkaline phosphatase but without signs of hepatic decompensation. They were followed up for 5 years for possible development of hepatic decompensation. RESULTS: Anti-M2 concentration was significantly correlated with bilirubin and albumin levels as well as MRF, whereas anti-M4 was significantly correlated with albumin level, prothrombin time and MRF. During the 5-year follow-up, progressive PBC (pPBC) was diagnosed in 3 among 23 patients available for evaluation. These 3 patients were positive for both anti-M2 and anti-M4. Anti-M2 serum concentration exceeded 1 300 RU/mL in patients with pPBC and only in 1 among 20 non-progressive PBC persons (5%). Anti-M4 serum concentration exceeded 400 RU/mL in 2 of the progressive patients and none in the non-progressive group. In contrast, anti-M9 serum concentration was below 100 RU/mL in all patients with pPBC, and higher than 100 RU/mL in 11 women (55%) among the non-progressive group. CONCLUSION: Females with elevated alkaline phosphatase and high anti-M2 and anti-M4 concentrations are at a high risk for developing pPBC. Quantitative AMA detection should be considered as a method for early diagnosis of pPBC.     

老年原发性胆汁性肝硬化患者的特点

<正>原发性胆汁性肝硬化(Primary biliary cirrhosis,PBC)是肝内中小胆管慢性进行性非化脓性炎症而导致的慢性胆汁淤积性疾病。近年来,由于早期诊断及治疗的进步,疾病的缓解率已明显提高,患者也可长期无肝硬化表现,故也有观点认为应将尚未出现肝硬化的患者命名为原发性胆汁性胆管炎(Primary biliary cholangitis),仍简称为PBC。原发性胆汁性胆管炎的命名能更客观地界定疾病,避免将     

原发性胆汁性肝硬化93例临床及病理特点分析

目的总结原发性胆汁性肝硬化（PBC）患者的临床及病理学特点,以加深对该病的认识,指导临床诊疗。方法回顾性分析93例经肝活组织穿刺病理检查确诊为PBC患者的临床表现、生化指标、免疫学指标、病理学特点以及不同病理分期与生化指标相关性。结果93例患者临床症状中以乏力、皮肤瘙痒、黄疸最为常见。PBC患者均有不同程度肝功能异常,以ALP、GGT升高最为多见,异常比例分别为94．6％、95．7％。69．9％患者血清AMA和（或）AMA—M2亚型阳性,64．5％患者ANA阳性。93例肝脏病理学检查,符合I期为25例,Ⅱ期37例,Ⅲ期21例,Ⅳ期10例。病理分期与TBil、TBA呈正相关,与CHE呈负相关（P〈0．05）。结论诊断PBC应重视病理学检查,对病情及预后判断可参考TBil、TBA、CHE等指标,也应综合分析其临床症状、生化指标、自身抗体检测及组织学检查等。     

19例男性原发性胆汁性肝硬化患者临床分析

目的分析男性原发性胆汁性肝硬化(PBC)患者的临床特征及预后。方法回顾性分析19例男性PBC患者的临床资料。结果本组患者平均年龄54±17岁,其中17例(89%)为中老年;确诊时无症状者为7例(36.7%),失代偿期肝硬化9例(47.4%);100%患者血GGT和ALP升高,78.9%ALT和AST轻中度升高;2例(10.5%)合并干燥综合征;13例(68.4%)患者AMA阳性,14例(73.7%)AMA-M2阳性。经熊去氧胆酸治疗,早期患者病情有不同程度的好转。结论男性PBC患者起病隐匿,特异性自身抗体检测阳性率略低,早期诊断困难较大。     

Hyperhomocysteinemia and hypercoagulability in primary biliary cirrhosis

AIM: To assess the hypercoagulability in PBC and its relationship with homocysteine (HCY) and various components of the haemostatic system. METHODS: We investigated 51 PBC patients (43F/8M; mean age: 63±13.9 yr) and 102 healthy subjects (86 women/16 men; 63±13 yr), and evaluated the haemostatic process in whole blood by the Sonoclot analysis and the platelet function by PFA-100 device. We then measured HCY (fasting and after methionine loading), tissue factor (TF), thrombin-antithrombin complexes (TAT), D-dimer (D-D), thrombomodulin (TM), folic acid, vitamin B6 and B12 plasma levels. C677T 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphism was analyzed. RESULTS: Sonoclot RATE values of patients were significantly (P< 0.001) higher than those of controls. Sonoclot time to peak values and PFA-100 closure times were comparable in patients and controls. TAT, TF and HCY levels, both in the fasting and post-methionine loading, were significantly (P< 0.001) higher in patients than in controls. Vitamin deficiencies were detected in 45/51 patients (88.2%). The prevalence of the homozygous TT677 MTHFR genotype was significantly higher in patients (31.4%) than in controls (17.5%) (P<0.05). Sonoclot RATE values correlated significantly with HCY levels and TF. CONCLUSION: In PBC, hyper-HCY is related to hypovitaminosis and genetic predisposing factors. Increased TF and HCY levels and signs of endothelial activation are associated with hypercoagulability and may have an important role in blood clotting activation.     

原发性胆汁性肝硬化无创性肝纤维化诊断模型的验证

目的验证采用常规实验室指标建立的无创性肝纤维化诊断模型,并评判其对原发性胆汁性肝硬化(PBC)患者组织学分期的诊断价值。方法采用受试者工作特征曲线下面积(AUC)检测各项无创诊断模型对PBC患者组织学分期的诊断价值。结果各项模型均对PBC的组织学分期有一定诊断价值,其中H指数、Forns评分及RPR预测价值最为突出,AUC分别可达0.851,0.811和0.843。结论由常规实验室指标建立的肝纤维化无创诊断模型H指数、Forns评分及RPR能协助准确区分PBC患者的早期(Ⅰ-Ⅱ期)和进展期(Ⅲ-Ⅳ期)病变。     

多发性肌炎并原发性胆汁性肝硬化1例

患者,男,59岁,因"乏力6mo余"于2011-07入院,患者乏力、转氨酶升高,CT提示肝脾增大,肝裂增宽,以"慢性肝病"给予常规保肝药治疗,但肝功无明显好转且乏力症状进行性加重.进一步测定血CK明显升高,AMA-M2:(+++),肌电图提示肌源性损害(提示广泛、活动期),并行腓肠肌活检发现炎性细胞浸润,最后患者诊断为多发性肌炎并原发性胆汁性肝硬化.给予激素、免疫抑制剂及熊去氧胆酸等治疗后,症状明显改善,肝功恢复正常.本病例报道旨在唤起消化科医生对全科知识掌握的重视,从而减少误诊误治.