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.     

复方鳖甲软肝片治疗原发性胆汁性肝硬化患者疗效分析*

目的 观察应用复方鳖甲软肝片治疗原发性胆汁性肝硬化（PBC）患者的临床疗效以及对血清肝纤维化指标的改善作用。方法 2016年1月~2017年12月在我院就诊的78例PBC患者,其中37例接受熊去氧胆酸（UDCA）胶囊治疗,另41例接受UDCA联合复方鳖甲软肝片治疗,观察24周。采用PBC-40量表评价生活质量,常规检测血清三型前胶原N端肽（PC-III）、层粘连蛋白（LN）和四型胶原（IV-C）水平。结果 在治疗后,联合治疗组疲劳、瘙痒、社交评分别为（18.5±5.5）分、（4.7±1.3）分、（14.4±3.9）分,显著低于治疗前的（25.5±7.0）分、（5.5±1.5）分、（19.2±4.6）分（P<0.05）,也显著低于对照组[（23.2±5.5）分、（5.1±1.0）分、（18.1±4.9）分,P<0.05];治疗后,联合组血清ALT、AST、GGT、AKP水平分别为（90.2±17.6） U/L、（81.5±14.8） U/L、（187.1±16.3） U/L、（117.5±28.1）IU/L,均显著低于治疗前的（133.6±24.6） U/L、（124.9±14.9） U/L、（350.4±18.9） U/L、（484.1±52.3） IU/L（P<0.05）,且显著低于对照组的（101.3±15.3） U/L、（95.3±18.0） U/L、（199.8±15.7） U/L、（152.6±21.3） IU/L（P<0.05）;治疗后,观察组血清PC-III、LN、IV-C水平分别为（120.9±20.0） μg/L、（123.4±16.9） μg/L、（92.5±18.5） μg/L,均显著低于治疗前的（193.5±30.0） μg/L、（160.4±20.1） μg/L、（180.2±21.3） μg/L（P<0.05）,且显著低于对照组的（131.6±21.5） μg/L、（136.8±15.4） μg/L、（109.4±10.0） μg/L（P<0.05）。结论 复方鳖甲软肝片对PBC患者具有较好的近期疗效,可减轻临床症状,并可能具有改善肝纤维化的作用。     

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。     

Biochemical markers for non-invasive assessment of disease stage in patients with primary biliary cirrhosis

AIM： To evaluate different biochemical markers and their ratios in the assessment of primary biliary cirrhosis （PBC） stages. METHODS： This study included 112 patients with PBC who underwent a complete clinical investigation. We analyzed the correlation （Spearman＇s test） between ten biochemical markers and their ratios with different stages of PBC. The discriminative values were compared using areas under receiver operating characteristic （ROC） curves. RESULTS： The mean age of patients included in the study was 53.88 ＋ 10.59 years, including 104 females and 8 males. We found a statistically significant correlation between PBC stage and Aspartate aminotransferase （AST）, Alanine aminotransferase （ALT） to platelet ratio （APRI）, ALT/platelet count, AST/ALT, ALT/AST and ALT/Cholesterol ratios, with the values of Spearman＇s rho of 0.338, 0.476, 0.404, 0.356, 0.351 and 0.325, respectively. The best sensitivity and specificity was shown for AST/ALT, with an area under ROC of 0.660. CONCLUSION： Biochemical markers and their ratios do correlate with different sensitivity to and specificity of PBC disease stage. The use of biochemical markers and their ratios in clinical evaluation of PBC patients may reduce, but not eliminate, the need for liver biopsy.     

抗线粒体抗体-M2阳性体检人群原发性胆汁性肝硬化相关指标的调查分析

目的 通过对抗线粒体抗体(AMA)-M2型阳性体检人群原发性胆汁性肝硬化(PBC)相关指标的分析,揭示PBC早期主要临床症状及体征的分布状况. 方法 对20 970例健康体检者进行调查,采用间接免疫荧光法检测抗核抗体(ANA);采用免疫印迹法检测AMA-M2.率的比较用x2检验,P＜ 0.05为差异有统计学意义. 结果 ANA滴度＞1∶320阳性1 243例,其中AMA-M2阳性156例,阳性率0.74％,男性阳性率为0.3 (32/10 550),女性阳性率为1.2％ (124/10 420),二者差异有统计学意义(x2=55.85,P＜0.05);肝功能异常66例,其中碱性磷酸酶升高58例,可明确诊断为PBC;血常规异常72例;有胆囊疾病病史者47例,糖尿病史者49例,过敏史者22例;有腹部不适者75例,乏力者38例,黄疸者3例,瘙痒者11例.与对照组比较,差异均有统计学意义.结论 亚健康人群如发现血常规及肝功能异常应尽早行AMA-M2等自身抗体检测,以利于PBC早期诊断及病情控制,提高患者生活质量,延长寿命.     

Biochemical markers of liver fibrosis and lymphocytic piecemeal necrosis in UDCA-treated patients with primary biliary cirrhosis.

BACKGROUND/AIM: We have previously shown that the histological stage and severity of lymphocytic piecemeal necrosis (LPN) are independent predictive factors of cirrhosis development in ursodeoxycholic acid (UDCA)-treated patients with primary biliary cirrhosis (PBC). Our aim during this study was to determine whether biochemical parameters classically used in PBC management and measured under UDCA could be considered as reliable surrogate markers for these histological prognostic indices in clinical practice. METHOD: The study included 153 patients with PBC who had undergone a control liver biopsy after 2 years of UDCA therapy. The relationships between histological and biological features were assessed by variance analysis and logistic regression. The diagnostic value of independent markers was assessed in terms of their sensitivity, specificity, positive predictive value (PPV) and negative value (NPV) and receiver-operating characteristic curves. RESULTS: Two variables were independently associated with extensive fibrosis (i.e. advanced histological stages): serum levels of bilirubin and hyaluronic acid (HA). A fibrosis index ([bilirubin (micromol/l)/14]+[HA (microg/l)/143]) higher than 1.5 exhibited good PPV and specificity (>74%) but rather poor NPV and sensitivity (<64%) regarding a diagnosis of extensive fibrosis. The only independent marker of LPN was aspartate aminotransferase (AST) activity. AST activity of more than twice the upper limit of normal showed acceptable PPV (>70%) but very low sensitivity (<25%) for a diagnosis of LPN. CONCLUSIONS: Serum bilirubin and HA levels measured under UDCA therapy are of acceptable diagnostic value for extensive fibrosis, but none of the biochemical tests commonly employed in the management of PBC can be considered as surrogate markers of LPN. Taken together with our previous results, these findings suggest that liver biopsy may be necessary to screen UDCA-treated patients who might require additional therapies.     

Serum sterols in patients with primary biliary cirrhosis and acute liver failure before and after liver transplantation

BACKGROUND/AIMS: Liver diseases modify sterol metabolism. Liver transplantation (LTX) provides a model to evaluate the impact of disease-affected liver on sterol metabolism. METHODS: We studied serum sterol profiles and their relationships to other biochemical markers in consecutive cholestatic patients with acute liver failure (ALF, n=39) and end-stage primary biliary cirrhosis (PBC, n=67) before and 27d after LTX. Accordingly, we determined serum levels of sterols, bilirubin and prealbumin. RESULTS: Due to weak cholesterol synthesis of ALF-patients before LTX, their serum levels of cholesterol, lathosterol/cholesterol, cholestanol/cholesterol and lathosterol/campesterol were 18%-41% lower (P<0.05 for each) than in PBC, but ratios of phytosterols to cholesterol were equal. In general, non-cholesterol sterol ratios reflected bilirubin and prealbumin concentrations. Interrelation of surrogate sterols showed that homeostasis of cholesterol metabolism prevailed in lowest cholestanol tertile of ALF-patients consistently, but not in PBC. After LTX, cholesterol levels and lathosterol ratios increased in both groups and phytosterol ratios decreased (P<0.01). Cholestanol decreased profoundly in PBC, but remained 26% higher than in ALF (P<0.05). CONCLUSIONS: Homeostasis of cholesterol metabolism was maintained only in ALF. Metabolism of phytosterols was equal in study groups. PBC- and ALF-patients have differential patterns in their serum sterols and cholesterol metabolism.     

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…     

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。     

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.     

FibroScan对原发性胆汁性肝硬化患者肝纤维化的诊断价值

目的探讨FibroScan对于原发性胆汁性肝硬化（primary biliary cirrhosis,PBC）肝纤维化诊断的准确性。方法选择2009年10月—2013年12月经肝脏穿刺病理诊断的PBC患者56例,进行FibroScan检测得到肝脏硬度测量（liver stiffness measurement,LSM）值。以肝脏活组织检查结果作为＂金标准＂,计算受试者工作特征曲线下面积（AUROC）,评价FibroScan对PBC肝纤维化的诊断价值。结果 LSM值平均为（13.714±7.475）kPa,与肝脏病理分期呈正相关,Kendall相关系数为0.897,P〈0.01。FibroScan诊断PBC肝纤维化≥S2期、≥S3期、S4期的AUROC分别为0.897、0.959、0.989。纤维化分期为≥F2、≥F3、F4时对应的最佳截断值分别为12.9、16.1和19.7 kPa。肝硬度、血清透明质酸、AST/PLT（APRI）均为肝脏病理分期独立相关因素。结论 FibroScan是一项方便、准确的用于诊断PBC肝纤维化程度的方法。     

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。     

Pseudolymphoma of the liver associated with primary biliary cirrhosis： A case report and review of literature

We report a case of two pseudolymphomas of the liver in a 63-year-old Japanese woman with primary biliary cirrhosis. One of the lesions was found incidentally during a medical examination, presenting as a 10 mm hypodense nodule that revealed hyperdensity in the early phase and hypodensity in the late phase in computed tomography （CT） after injection of contrast medium. Retrospectively, the 10 mm nodule had first been discovered as a 4 mm nodule during CT 4 years previously. Superparamagnetic iron oxide-enhanced MRI revealed another 4 mm hyperintense nodule in segment 6 in addition to the 10 mm hyperintense nodule in segment 7. CT during arterial portography revealed two hypointense nodules. Findings with other imaging modalities such as ultrasonography, magnetic resonance imaging, and hepatic angiography were consistent with hepatocellular carcinoma. A right posterior segmentectomy was performed, and the lesions were microscopically diagnosed as pseudolymphoma. To the best of our knowledge, only 31 other cases of this disease have ever been reported, with a highly asymmetrical male：female ratio of 1：9.7. Although we could find only one case of transformation of hepatic pseudolymphoma into lymphoma in the liver, the exact nature of development from benign pseudolymphoma to malignant lymphoma is still not fully understood and cases of hepatic lymphoma need to be followed carefully.     

Presence of disease specific autoantibodies against liver sinusoidal cells in primary biliary cirrhosis

AIM: To investigate the presence of autoantibodies directed against liver sinusoidal cells in primary biliary cirrhosis (PBC).METHODS: Liver biopsies from 21 PBC patients were studied and compared with 12 liver biopsies from disease controls [3 patients with hepatitis B (HBV) virus, 3 patients with hepatitis C virus (HCV), 3 patients with non-alcoholic steatohepatitis and 3 patients with acute alcoholic hepatitis (AAH)]. As healthy controls, we used tissue specimens adjacent to metastatic liver adenocarcinoma. Normal serum was taken from staff members of the unit. The determination of the cell type targeted by autoantibodies present in the patients sera was performed by indirect immunofluorescence (IIF) analysis using paraffin-embedded liver sections as a substrate. Sera from homologous or heterologous PBC patients or sera from the disease control group were used as primary antibodies. The presence of autoantibodies was identified using confocal microscopy.RESULTS: In total, 18/21 (85.7%) PBC patients exhibited positive staining in the sinusoidal cells, 10/21 (47.6%) in lymphocytes, 8/21 (38%) in cholangiocytes and 7/21 (33.3%) in hepatocytes, when homologous serum and fluorescein isothiocyanate-conjugated immunoglobulin type G (IgG) secondary antibody were used. PBC sections incubated with heterologous PBC serum showed reduced staining (20% for sinusoidal cells, 20% for lymphocytes, 20% for cholangiocytes and 13.3% for hepatocytes). When IgM immunoglobulin, instead of IgG, was used as secondary antibody, positive staining was observed in 75% of lymphocytes, 62.5% of cholangiocytes, 37.5% of hepatocytes and 50% of the sinusoidal cells with a much stronger staining intensity. No staining was observed when either normal or PBC sera were used as a primary antibody on liver sections from the disease control group. When PBC sera were incubated with healthy control sections, weak positive staining of cholangiocytes was observed in 3/21 (14.3%) PBC serum samples. Steatohepatitis serum on PBC sections gave a positive staining of some hepatocytes and lymphocytes but no staining on viral hepatitis sections. Incubation with HBV sera stained some hepatocytes, cholangiocytes and intra-sinusoidal or portal lymphocytes of PBC, HBV and AAH patients but not HCV patients.CONCLUSION: In this study, for the first time in diseased liver tissue, we have demonstrated that a large proportion of PBC patients have disease specific autoantibodies against liver sinusoidal cells.     

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