Hepatic copper content is normal in early primary biliary cirrhosis and primary sclerosing cholangitis

In previous studies, the majority of patients with the cholestatic liver diseases, primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC), had increased hepatic copper (Cu) levels even in early stages of disease. We prospectively measured hepatic copper content by atomic absorption spectrophotometry in 55 patients with PBC, 6 patients with PSC, and 29 patients with other chronic noncholestatic liver diseases. Hepatic Cu content was normal in 22/61 (36%) of patients with PBC or PSC; 18 of the 22 did not have cirrhosis (82%). Hepatic Cu content increased with increasing stage of disease (r=0.61,P<0.001) and was positively correlated with serum total bilirubin (r=0.6,P<0.0001) and alkaline phosphatase (r=0.5,P<0.001). All patients with stage I and II disease had hepatic Cu<150 µg/g dry weight, and all patients with hepatic Cu>150 µg/g dry weight had stage III and IV disease. Hepatic Cu content is normal in early PBC and PSC. Copper accumulation in the liver in these cholestatic liver diseases is secondary to cholestasis rather than a primary phenomenon.Supported by General Research Center grant MOIRR0054 from the National Institutes of Health.     

Osteoporosis in primary biliary cirrhosis revisited

BACKGROUND: Primary biliary cirrhosis (PBC) is increasingly being diagnosed in the earlier non-cholestatic stages of disease. Accepted wisdom has been that PBC is frequently complicated by osteoporosis. Whether this association holds true for the broader spectrum of PBC patients now recognised has not as yet been studied. AIMS: To examine the extent to which osteoporosis occurs more commonly in PBC patients than in normal individuals of the same age and sex. DESIGN: Retrospective review of a large cohort of well characterised PBC patients. PATIENTS: A total of 272 PBC patients with definite or probable PBC followed up for a mean of 10.1 years (total follow up 2726 patient years) who had at least one bone mineral density measurement (BMD). RESULTS: In this unselected group of PBC patients, mean Z scores (number of SDs from age and sex matched normal mean values) at the neck of femur (NOF) and lumbar spine (LS) at first BMD measurement (7 (6) years after PBC diagnosis) were -0.1 (1.4) and 0.1 (1.4), respectively. At first BMD measurement, 18 PBC patients had Z scores less than -2.0 and 85 had T scores less than -2.5. No factors predictive of osteoporosis were found in affected patients. A total of 957 BMD measurements were performed (0.35 per patient year of follow up); 220 patients had two or more measurements. No patient went on to develop de novo osteoporosis during follow up. In the 51 patients (who were clinically representative of the whole group) who received no PBC or bone related treatment during follow up, %BMD changes per year at the NOF and LS were -1.6 (3.2) and 0.1 (2.2), respectively. No variance in this "natural" rate of BMD measurement was seen in patients receiving PBC modulating agents (including prednisolone and UDCA) or osteoporosis prophylaxis/therapy. Significant improvement at the LS was seen in patients undergoing liver transplantation. CONCLUSIONS: Osteoporosis is not a specific complication of PBC.     

原发性胆汁性肝硬化的治疗进展

原发性胆汁性肝硬化（PBC）是一种慢性肝内胆汁淤积性疾病。熊去氧胆酸（UDCA）是惟一经随机对照临床试验证实的治疗PBC安全有效的药物。经UDCA治疗1年后有较好生化应答的患者,其长期预后较好。目前,对UDCA应答欠佳患者的治疗方法尚不确定。肝移植是治疗终末期PBC患者惟一有效的方法     

Transplantation in primary biliary cirrhosis

Improved immunosuppressive regimens, better postoperative intensive care and judicious patient selection have all resulted in increased patient survival following orthotopic liver transplantation (OLT), which has become the preferred option for most patients with end-stage primary biliary cirrhosis (PBC). As with most other clinical series, PBC is now the most common indication for OLT in the King's College hospital and Cambridge programmes. To date (30 July 1990), 129 patients with PBC have been transplanted, with overall actual 1 and 5 year survival rates of 65 and 63% respectively. When patients transplanted since 1985 are considered, both the 1 and 2 year survival rates are 78%. Immediate operative mortality was 4.5%, generally due to uncontrollable bleeding, while further mortality within 30 days of operation--mainly consequent upon infection and multi-organ failure--has fallen from 40% prior to 1985 to 9% since 1988. Thirteen per cent of patients have been retransplanted for vanishing bile duct syndrome, manifest in this series invariably within the first 6 months following OLT. Although rehabilitation in this series was excellent, a significant percentage of cases have continuing problems with metabolic bone disease, hypertension and renal impairment, mainly due to cyclosporin toxicity.     

Long-term outcomes in antimitochondrial antibody negative primary biliary cirrhosis

Objectives Antimitochondrial antibodies (AMA) are a sensitive and specific marker for primary biliary cirrhosis (PBC). AMAs are present in 95% of patients with PBC. However, 5% do not have AMAs and data on these patients is scarce. We aim to evaluate the long-term outcomes of patients with AMA negative PBC. Methods A retrospective chart review of 71 AMA negative PBC patients. Disease presentation, laboratory results, and clinical endpoints were recorded. AMA negative patients were matched on year of diagnosis to a control group of 71 AMA positive patients. Results Ninety-six percent of the AMA negative patients were of female gender with a median age at diagnosis of 55 years and a length of follow-up of 7.5 years vs. 86% females, a median age of 56 and a follow-up of 8.3 years in the control group. Mean total bilirubin and alkaline phosphatase levels were 0.7?mg/dL vs. 0.6 and 570?U/L vs 341, in AMA negative vs. AMA positive patients at presentation, respectively (p?=?NS). AMA negative patients did not differ in terms of age, serum IgM levels, ANA status, or length of follow-up. Notably, AMA negative patients had a significantly reduced survival free of liver-related complications including transplantation and death compared to AMA positive patients (p?=?0.0182). Conclusion In this large experience, AMA negative PBC patients had a significantly worse prognosis compared to AMA positive PBC patients. The reason for the difference in prognosis is unclear, as it may be true difference or reflect delays in case detection among AMA negative patients.     

Altered biliary epithelial cell and monocyte responses to lipopolysaccharide as a TLR ligand in patients with primary biliary cirrhosis

Objective. Many reports indicate the importance of active treatment for hepatocellular carcinoma (HCC), but there are few studies available that address the impact of delayed therapy on survival or take the lead-time bias into account. The objective of this study was to investigate whether patients with delayed locoregional therapy for HCC truly have a shortened survival from the time of diagnosis. Material and methods. Survival rates were compared between 48 HCC patients with treatment delay and 96 age- and gender-matched controls without delay. All patients underwent transarterial chemoembolization or percutaneous ethanol or acetic acid injection for HCC. Treatment delay was defined as a >2 months’ time interval between diagnosis and treatment. Results. Baseline comparison showed that patients with treatment delay had higher scores in the model for endstage liver disease compared with those of patients without delay (12.3±1.8 versus 11.1±2.5, p=0.01). In the Cox multivariate model, advanced cancer stage (relative risk (RR): 2.66, p=0.001), Child-Turcotte-Pugh class B (RR: 3.81, p<0.001), tumor size >5 cm (RR: 2.02, p=0.011) and treatment delay (RR: 2.91, p=0.001) were independent poor prognostic predictors. Among patients with treatment delay, disease progression was registered in 30 (63%) patients. Patients with prolonged treatment delay (>3 months) were more likely to have tumor progression (p=0.013). In the Cox model, a treatment delay of >3 months independently predicted a poor rate of survival (RR: 3.67, p=0.002). Conclusions. Delayed HCC treatment is linked with shortened overall survival unrelated to the lead-time bias in patients undergoing locoregional therapy. Prolonged treatment delay of more than 3 months in these patients may worsen the long-term outcome.     

原发性胆汁性肝硬化的过去、现在与未来

原发性胆汁性肝硬化(PBC)是近百年间发现的一种与免疫相关的慢性进行性胆汁淤积性肝病,其病因及发病机制至今不详。对PBC的命名由来、近年来针对PBC的相关研究进展以及未来PBC患者治疗的展望进行概述,认为熊去氧胆酸可有效改善PBC胆汁淤积状态。但无论是PBC的命名、发病相关危险因素,还是应答标准及治疗等都仍需进一步探讨与深入研究。     

PDC-E3BP is not a dominant T-cell autoantigen in primary biliary cirrhosis.

BACKGROUND: Autoantibody responses reactive with the E2 and E3BP components of pyruvate dehydrogenase complex (PDC), which characterise primary biliary cirrhosis (PBC) crossreact, precluding the identification, from serological studies, of the antigen to which the principal breakdown of tolerance occurs. Although autoreactive T-cell responses to PDC-E2 have been well characterised it is, at present, unclear whether T-cell tolerance breakdown also occurs to PDC-E3BP. The aims of this study were to characterise autoreactive T-cell responses to PDC-E3BP in PBC and potential factors regulating their expression. METHODS: Peripheral blood T-cell proliferative responses to purified recombinant human PDC-E2 and PDC-E3BP at a range of concentrations were characterised in PBC patients and control subjects. RESULTS: T-cell proliferative responses to both E2 and E3BP were absent from control subjects (median peak stimulation index (SI) to PDC-E2 1.2 [range 0.3-1.9], 0/10 positive (SI>2.32), median peak SI to PDC-E3BP 1.1 [0.7-2.1]], 0/10 positive). Significant responses to PDC-E2 were seen in the majority of patients (median peak SI 11.4 [0.4-24.4], 17/20 (85%) positive) but to PDC-E3BP in only a minority (median peak SI 1-9 [0.6-9.95], 8/20 (40%) positive). Where responses to PDC-E3BP were seen they were universally secondary to responses to PDC-E2. CONCLUSIONS: Despite the presence of antibodies reactive with PDC-E3BP in the majority of PBC patients this self-protein is not a dominant T-cell autoantigen in PBC.     

Familial primary biliary cirrhosis and autoimmune cholangitis

AIM: Autoimmune cholangitis has been proposed as a separate disease entity from primary biliary cirrhosis without serum antimitochondrial antibodies. The ultimate answer to the question of whether autoimmune cholangitis and primary biliary cirrhosis are distinct will require detailed comparison of aetiologic factors and pathogenic mechanisms. METHODS AND RESULTS: Two families are described each of which has one member with classical antimitochondrial antibody positive biopsy-proven primary biliary cirrhosis and a first degree relative with antimitochondrial antibody negative but antinuclear antibody positive autoimmune cholangitis (biopsy proven in one case). Study of such families should allow analysis of the contribution of shared genetic risk factors versus varying environmental triggering mechanisms to disease pathogenesis. CONCLUSIONS: We suggest a European registry of families, such as the two described, which are rare within one centre, to facilitate elucidation of pathogenetic factors.     

Hepatic Met‐enkephalin immunoreactivity is enhanced in primary biliary cirrhosis

Abstract: Background/aims: In contrast to the normal adult liver, the fetal human and rat livers, and the liver of rats with cholestasis secondary to bile duct resection (BDR) express the preproenkephalin (ppENK) mRNA, which codes for the endogenous opioid peptide Met‐enkephalin. In addition, Met‐enkephalin immunoreactivity (MEIR) is detected in hepatocytes and in proliferating bile ductules in the cholestatic rat liver. These data suggest that cholestasis is associated with the resurgence of cells that produce Met‐enkephalin. To explore further the status of opioids in cholestasis, we studied the expression of MEIR in liver tissue. Methods: The MEIR was sought in paraffin‐preserved liver tissues from patients with primary biliary cirrhosis (PBC) (n = 10). Results: The MEIR was detected in all the PBC livers. Its intensity varied from weak to strong on hepatocytes and bile ducts and the strongest expression appeared as coarse granules. The MEIR was either absent or only faintly expressed by some hepatocytes from disease and nondisease control biopsies, but absent from bile ducts. Conclusion: These results suggest that the human liver in cholestasis may be a source of endogenous opioids.     

Aminoterminal propeptide of type III procollagen and hyaluronan in patients with primary biliary cirrhosis: Markers of fibrosis in primary biliary cirrhosis

The aminoterminal propeptide of type III procollagen (PIIINP) and hyaluronan have previously been studied in different liver diseases. The results of these studies are controversial. The aim of the present study was to examine the relationship between PIIINP and hyaluronan levels and the clinical, biochemical and histological features of primary biliary cirrhosis (PBC) and its prognosis. Fifty-five PBC patients were studied at the time of diagnosis of PBC and were followed up for a mean of 58 months. During the follow-up period 21 patients died. In addition, 30 healthy subjects were examined in the present study. Hyaluronan and PIIINP were measured by radioimmunoassay and the levels of both PIIINP and hyaluronan were higher in PBC patients than in healthy volunteers (P< 1.8 times 10^-6 and 1.6 times 10^-9, respectively). Hyaluronan and PIIINP levels were above normal values in 82 and 84% of PBC patients, respectively. There were correlations between PIIINP and hyaluronan and the histological stage of PBC (r=0.44, P< 0.004 and r=0.56, P< 0.00001, respectively). The correlation between PIIINP and hyaluronan was 0.46 (P< 0.0035). In symptomatic patients, both PIIINP and hyaluronan values were higher than in controls (P< 0.002 and P< 0.006, respectively). The levels of PIIINP correlated significantly with bilirubin (r=0.43, P< 0.006), while hyaluronan was correlated with age (r=0.33, P< 0.015), pruritus (r=0.32, P< 0.02), fatigue (r=0.41, P< 0.003), hepatomegaly (r=-0.46, P< 0.0008), the presence of oesophageal varices (r=0.34, P< 0.002), weight loss (r=0.29, P< 0.05), bilirubin (r=0.54, P< 0.0001), albumin (r=-0.30, P< 0.04), extent of fat excretion (r=0.53, P< 0.009) and length of symptomatic period before diagnosis of PBC (r=0.43, P< 0.002). Using Cox's logistic regression analysis, survival was found to be influenced by bilirubin concentration but not by hyaluronan, PIIINP, age, albumin or histological stage. Therefore, hyaluronan is a more sensitive marker for predicting advanced PBC than is PIIINP. However, neither hyaluronan nor PIIINP gave any indication of prognostic outcome.     

Primary biliary cirrhosis in India

BACKGROUND: Primary biliary cirrhosis (PBC) is a rare cause of chronic liver disease in India. We analyzed the clinical, biochemical, serological and histological features of patients with PBC for over a 10-year period. METHODS: PBC was diagnosed by the presence of raised level of serum alkaline phosphatase (ALP), anti-mitochondrial antibody (AMA) positivity (1:40 dilution), and/or diagnostic liver histology. RESULTS:Fifteen female patients with mean age of 46.5±11 years were studied. Pruritis (80%) followed by jaundice (67%), skin changes (pigmentation, coarsening, xanthelesma and vitiligo) (67%) and fatigue (60%) were common symptoms. The mean duration of the symptoms was 3.5± 5.4 years (3 months to 20 years). Dryness of eyes was observed in only 2 patients. Hepatomegaly was noted in 87% of the patients and ascites at presentation in 40%. Mean levels of bilirubin and albumin at the time of diagnosis were 3.4±3.3 mg/dl and 3.5±0.8 g/dl, respectively. The level of serum ALP ranged from 54 to 2400 IU/L, with a median being 552 IU/L (2×ULN). In all the 15 patients with AMA positive, 8(53%) were also positive for either anti-nuclear or anti-smooth muscle antibodies. Two patients presented with persistently elevated SAP after an acute hepatitic illness. Liver biopsy was available in 13 patients, diagnostic of PBC Ⅱ & Ⅲ(8) and with evidence of cirrhosis (5). Associated autoimmune disorders were observed in 5 patients (33%). The mean time for follow-up was 26±21 months (1 to 87 months). In 4 deaths, 3 were due to liver related causes. CONCLUSION: PBC is a rare cause of chronic liver disease in India. PBC in India, unlike in the West, presents late, often with features of cirrhosis and decompensation.     

原发性胆汗性肝硬化中B细胞免疫的研究进展

原发性胆汁性肝硬化（PBC）以肝内小胆管的损伤为特征,但其损伤机制尤其是B细胞免疫在其中发挥的作用尚不明确。从B细胞和浆细胞在PBC肝组织中的分布、B细胞清除、PBC血清中异常增高的IgM产生机制及其组织器官来源、线粒体抗体的产生机制以及在胆管损伤中的可能作用、PBC中特征性的自身抗体等方面,回顾了B细胞免疫在PBC发病机制中的可能作用。通过以上分析,认为B细胞免疫的确在PBC的发病机制中发挥了重要作用,但仍有很多关键的问题尚未得到阐明。     

原发性胆汗性肝硬化的药物治疗研究进展

原发性胆汁性肝硬化（PBC）是一种自身免疫性疾病,熊去氧胆酸（UDCA）是唯一经随机对照临床试验证实治疗PBC安全有效的一线治疗药物,对于UDCA反应不佳者亟需其他有效的药物治疗。回顾了UDCA的疗效,重点叙述了对UDCA反应不佳者的备选治疗和辅助治疗的分类和最新研究进展,评估了药物的疗效和治疗前景,但布地奈德、依那西普等免疫抑制剂和其他类药物的疗效有待更多长期临床试验来验证。一些新兴的PBC分子疗法正处于积极的临床研究中。目前,对UDCA反应欠佳者的药物治疗方法尚不确定,尽管研究表明部分药物可以改善肝功能和肝脏生化指标,尚无确切的证据证明可改善长期预后。     

Transverse myelitis occurring in association with primary biliary cirrhosis and Sjogren's syndrome

Transverse myelitis (TM) as a manifestation of an autoimmune disorder is relatively rare. In Sjogren's syndrome (SS), the occurrence of TM is remarkably uncommon. Only three cases have been reported associated with primary biliary cirrhosis (PBC). Here we report the fourth case of TM occurring in association with SS and PBC. Patients with unexplained transverse myelitis require a careful search for an underlying etiology to include the findings of SS and PBC. The precise pathogenesis of TM in patients with SS is unknown. Most show good response to steroids. Cyclophosphamide and chlorambucil may be useful in those who respond poorly to steroids.     

亚洲地区原发性胆汁性肝硬化的诊疗现状

原发性胆汁性肝硬化（PBC）是一种慢性淤胆性疾病,其病理特点表现为肝内小胆管的病变。本病多见于女性,临床特点为碱性磷酸酶（ALP）、γ-谷氨酰转肽酶（GGT）明显升高,抗线粒体抗体（AMA）和（或）AMA—M2阳性。过去认为PBC是主要于西方国家的一种自身免疫性肝病,但近年来亚洲地区所发表的文献中有关PBC的报道也不断增多,故本文对亚洲地区PBC的诊疗现状做一简介。     

原发性胆汁性肝硬化肝功能衰竭患者48例临床分析

观察肝衰竭期合并腹水的原发性胆汁性肝硬化患者(PBC组)临床特征,及其与肝衰竭期乙型肝炎肝硬化(HBV组)合并腹水患者的异同点。分析48例PBC组和33例HBV组入院时(治疗前)临床症状及血常规、肝功能等化验指标的差异。两组患者最常见的临床症状均为腹胀、乏力、纳差、皮肤瘙痒,PBC组患者皮肤瘙痒、肝脏肿大比例明显高于乙型肝炎组(P＜0．05)。对Child-Pugh计数分级法为C级的PBC组28例患者与HBV组26例患者的实验室指标进行t检验,PBC组患者ALT、AST、GLO、Tcho、TG、CHE、Bil、TBA、PA、ALP、GGT、WBC、PLT等水平均高于HBV组(P＜0．05)。PBC肝功能衰竭的患者在临床表现及实验室检查方面均与乙型肝炎后肝硬化有所不同,了解这些特点将有助于及早诊断和治疗。     

原发性胆汁性肝硬化的流行病学与自然史变迁

原发性胆汁性肝硬化(PBC)是一种自身免疫介导的胆汁淤积性肝病。全面介绍了不同国家和不同地区PBC的流行病学情况,并针对熊去氧胆酸药物广泛应用前后,PBC自然史的变迁进行了分析,同时对我国近些年在PBC研究领域所取得的成绩进行了总结。尽管我国在PBC的诊疗方面取得了很大的进步,但仍然与西方国家存在差距。认为进一步提高基层医生和患者自身对该疾病的认识、成立中国多中心联合的PBC研究组、深入探索PBC的发病机制,将为我国PBC患者的有效治疗奠定重要的基础。     

原发性胆汁性肝硬化的细胞免疫学发病机制

原发性胆汁性肝硬化（PBC）是一种器官特异性的进行性自身免疫疾病,常见于女性,以肝脏门脉周围的淋巴细胞浸润,胆管上皮细胞特异性损伤以及血清中高滴度抗线粒体抗体（AMA）为主要特征。最新的PBC研究采用了CD4启动子控制下的TGFβ受体2显性失活（dnTGFβRⅡ）小鼠模型,这种小鼠模型很好地模拟了PBC患者的典型特征。在这种小鼠的基因背景下,通过分别敲除Rag1,μ以及CD1d基因建立了多种双基因缺陷鼠,通过研究发现T细胞,B细胞以及CD1d限制的NKT细胞等对肝脏淋巴细胞浸润,胆管上皮细胞损伤以及AMA的产生发挥着重要的作用。一系列的细胞免疫学实验结果显示,是CD8＋T细胞而非CD4＋T细胞在肝脏损伤过程中起着决定性的作用,而B细胞除分泌抗自身抗体之外,还具有抑制PBC发生的免疫调节作用。这些机制的研究为揭示人类PBC疾病的细胞免疫学致病机理提供了有力的证据和依托