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.     

A case of coexisting primary biliary cirrhosis and primary sclerosing cholangitis: a new overlap of autoimmune liver diseases

Although the etiology of AIH, PBC, and PSC remains unknown, it is apparent that these autoimmune liver diseases share many common features and can coexist in the same patient. Our patient had features of PBC and later clearly developed a picture of PSC. This case suggests that PBC, PSC, AIH, and autoimmune cholangitis are part of a spectrum of chronic autoimmune liver disease that develop in response to some yet unidentified antigen.     

Antimitochondrial antibody‐negative primary biliary cirrhosis: a subset of primary biliary cirrhosis

Objective: Antimitochondrial antibodies (AMA) are the hallmark in primary biliary cirrhosis (PBC); nevertheless, it has long been recognized that 5–10% patients with typical features compatible with PBC do not have detectable AMA, and they were referred to as ‘AMA‐negative PBC’. This study aimed to evaluate whether AMA‐negative/positive PBC represents different clinical entities. Methods: We compared the clinical, laboratory, percentage of regulatory T cells (Tregs) in peripheral blood, liver biopsy features and response to treatment of the two groups of patients. The first group was comprised of 12 patients with ‘AMA‐negative PBC’. The second was made up of another 12 PBC patients with positive AMA. Results: Antimitochondrial antibodies‐negative/positive patients were remarkably similar in terms of clinical manifestations, liver biochemistries and histological findings. The frequency of anti‐nuclear antibodies, anti‐smooth‐muscle antibody, anti‐gp210 and anti‐sp100 antibody showed no significant difference between the two groups. A significantly lower mean percentage of CD4⁺CD25^high T cells was observed in peripheral blood mononuclear cells of AMA‐negative/positive PBC patients compared with that of the 12 control subjects (5.8±1.8 and 5.4±1.4% vs. 7.6±1.7% respectively; P=0.014 and 0.004). However, no difference could be found between AMA‐negative and AMA‐positive PBC patients (P=0.599). After 1 year treatment with ursodeoxycholic acid, the two groups showed similar response. Conclusion: Antimitochondrial antibody‐negative/positive PBC patients are similar in clinical, laboratory, percentage of Treg in peripheral blood, liver biopsy features and response to treatment. This suggests that AMA‐negative PBC may be a variant of AMA‐positive PBC rather than a separate clinical entity.     

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.     

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.     

原发性胆汁性肝硬化与肝血瘀证

目的:探讨原发性胆汁性肝硬化(PBC)与肝血瘀证的关系.方法:根据我们制定的肝血瘀证辨证标准,将肝血瘀证划分为轻度、中度、重度3型,通过对84例PBC患者进行肝血瘀证辨证,探讨PBC患者肝血瘀证的发生率,且设40例正常人作为对照组,考察PBC肝血瘀证患者与非肝血瘀证患者及正常人的免疫学指标.结果:84例PBC中肝血瘀证患者71例(84.5％),其中轻度22例(26.2％),中度25例(29.8％),重度24例(28.5％);非肝血瘀证患者13例(15.5％).两组患者具体症状体征出现的频率则以舌质紫暗、舌下静脉曲张以及面部、齿龈及眼周紫黑为高,在84例PBC患者中所占比例分别为59.5％和57.1％.肝血瘀证与非肝血瘀证两组患者的免疫指标CD4+、CD8+、CD4+/CD8+、IgG、IgM、IgA、B因子均异于正常对照组(P＜0.05),但两组之间差异无显著性意义(P＞0.05);补体C3、C4不仅两组异于正常对照组(P＜0.05),且两PBC组间差异有显著性意义(P＜0.05),肝血瘀证者降低更为明显.结论:研究表明PBC患者中肝血瘀证者占84.5％,且与免疫功能异常密切相关.     

Pediatric-onset primary biliary cirrhosis

Unlike other autoimmune liver diseases, primary biliary cirrhosis (PBC) has not been reported in childhood. We report 2 cases of PBC diagnosed at 16 and 15 years of age, respectively. The first girl was noted to have increased liver enzyme levels at 16 years of age. Antimitochondrial antibody (AMA) was strongly positive, and serum quantitative immunoglobulin M level was 8.26 g/L (normal, 0.6-3 g/L). A liver biopsy specimen showed stage II PBC. Despite treatment with ursodeoxycholic acid, she developed progressive cholestasis, intractable pruritus, and a significant sensory neuropathy and weight loss eventually requiring liver transplantation. Her mother had PBC/autoimmune overlap syndrome and underwent successful liver transplantation at 34 years of age. The second girl had persistently elevated liver enzyme levels following cholecystectomy at 15 years of age for symptomatic cholelithiasis. Endoscopic retrograde cholangiopancreatography showed no abnormalities. AMA was positive at 1:160, and serum quantitative immunoglobulin was 6.96 g/L. A liver biopsy specimen showed stage II PBC, and her liver enzyme levels almost normalized after starting treatment with ursodeoxycholic acid. In conclusion, we present 2 liver biopsy-confirmed cases of pediatric-onset AMA-positive PBC. With increased awareness of early-onset PBC, further pediatric cases may be discovered.     

Clinical and pathological characteristics of the autoimmune hepatitis and primary biliary cirrhosis overlap syndrome

BACKGROUND AND AIMS: The defining of the autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) overlap syndrome as a separate clinicopathological entity has been controversial and temporally and geographically subjective. METHODS: From 1979 until 2000, 227 patients diagnosed with AIH, PBC or the overlap thereof were treated. Cases with genuine AIH/PBC overlap syndrome were sorted out using close clinical follow up and serial liver biopsies. RESULTS: Of the 227 patients, 19 (8.4%) were diagnosed with the AIH/PBC overlap syndrome. They all cleared a score >10 for the diagnosis of AIH, and tested positive for antimitochondrial antibodies during their courses. Long-term follow up with frequent histological examinations, however, established the diagnosis of AIH/PBC overlap syndrome in only two (0.8%) patients. The most powerful factor distinguishing AIH from PBC was acidophilic bodies in lobules that were detected significantly more frequently in patients with AIH than PBC or spurious overlap syndrome (39/46 [85%]vs 3/85 [4%], P < 0.001). It was more reliable than bile-duct lesions for the distinction of PBC from AIH. CONCLUSIONS: Although AIH/PBC overlap syndrome does exist, it is infrequent and needs to be diagnosed carefully using close clinical and histological follow up to enable timely and effective treatment.     

A biliary protein identified by immunoblotting stimulates proliferation of peripheral blood T lymphocytes in primary biliary cirrhosis

ABSTRACT— The source of activation of T lymphocytes in primary biliary cirrhosis (PBC) is undefined. Hence, T-cell-mediated reactivity against a biliary tract antigenic protein from human bile was studied. The bile protein was fractionated by 30–50% saturated ammonium sulphate and gel-chromatography, and analysed by SDS-PAGE and Western immunoblotting using rabbit antisera to the bile protein. The antisera reacted specifically with human bile duct epithelium. Western blotting of bile proteins showed two major bands, the B1 and B2 antigens. B1 stained for sialoglycoprotein but not lipid, but B2 was negative for both. Cell-mediated reactivity was tested by proliferation of peripheral lymphocytes against B1. Taking the upper limit of the normal range for stimulation indices (S.I.) as less than 1.89 (= mean + 2 SD), a mitogenic response was detected in 14 of 16 patients with PBC (S.I.: 11.7 to 2.3), and in 4 of 15 patients with chronic active hepatitis, but in none of 12 patients with drug-induced intrahepatic cholestasis or obstructive jaundice. The B2 protein was non-stimulatory. Lymphocyte proliferation to B1 in PBC was confined to T cell fractions of peripheral blood leucocytes. There was no cross-antigenicity between B1 and the M2 antigens, according to Western blotting using the rabbit antisera and PBC sera with anti-M2 reactivity. Thus, the B1 biliary protein is a possible source of T cell activation in PBC and hence could be an immunological co-factor in the pathogenesis of this disease.     

Fatigue in primary biliary cirrhosis

Background—Fatigue is a frequent and debilitatingsymptom in patients with primary biliary cirrhosis (PBC).
Aims—To study fatigue in relation to sleep,depression, and liver disease severity.
Methods—Patients with PBC completedvalidated self report questionnaires measuring fatigue, sleep quality,depression, and functional capacity. Verbally reported fatigue andobserver rated measure of depression and ursodeoxycholic acid (UDCA)use were recorded. Liver biochemistry and tests to rule out metaboliccauses of fatigue were performed.
Results—Mean age of the 88 patientsenrolled was 57 years; 86% were female and mean duration of diseasewas 6.6 years. Median bilirubin was 13 µmol/l (mean 18.6). Verballyreported fatigue (for more than six months) was present in 60 patients(68%). The self rated Fatigue Severity Score (FSS) correlated wellwith verbally reported fatigue (p=0.0001). The FSS did not correlatewith age, duration of disease, serum bilirubin, Mayo Risk Score, orUDCA use, but correlation was seen with sleep quality. Fatiguedpatients had more sleep problems and higher depression scores thannon-fatigued patients. Self rated depression was present in 28%(17/60) of fatigued compared with 4% (1/28) of non-fatigued patients.
Conclusions—Long term fatigue affected 68% ofthe patients with PBC but it was not related to the severity of theirliver disease. Poor sleep quality and depression were commonlyassociated with fatigue.

Keywords:primary biliary cirrhosis; fatigue; depression; sleep

     

Autoreactive CD8-specific T-cell response in primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is an autoimmune liver disease of unknown etiology. Autoimmune attack in PBC is predominantly organ-specific, despite the presence of mitochondrial autoantigens, the major targets of autoimmunity in PBC, in all nucleated cells. Cytotoxic T lymphocytes are thought to be directly involved in the tissue injury in PBC. The major histocompatibility complex (MHC) class I-restricted epitope for E2 components of pyruvate dehydrogenase complexes, namely amino acid 159–167, a region very close to the epitoperecognized by MHC class II-restricted CD4 cells and by antibody, has been characterized. In addition, there was a 10-fold increase in the frequency of autoreactive cytotoxic T lymphocytes in the liver as compared to the blood in PBC patients using tetramer technology.     

Prediction of prognosis of primary biliary cirrhosis in Japan

The clinical profile of primary biliary cirrhosis in Japan was clarified on the basis of data on 1066 patients attending 212 hospitals and institutions in this country. Six hundred and twelve patients (57.4%) were asymptomatic. The majority of the patients were middle-aged women. Pruritus was the most frequent initial symptom of symptomatic primary biliary cirrhosis. Antimitochondrial antibodies were positive in 877 patients (82.5%). Sjögren's syndrome was the most common associated autoimmune disease. Liver biopsy was performed in 753 patients at the time of diagnosis, and histological staging by Scheuer's classification indicated that 307 (43.7%) patients were in stage I and 222 (31.6%) were in stage II. The most frequent causes of death were hepatic failure and/or gastrointestinal bleeding, which affected 166 (78.3%) of the 212 patients who died. Statistical analysis using Cox's regression method revealed that the patient's age and the serum bilirubin, albumin, and total cholesterol concentrations were significant predictors of the prognosis. A prognostic index was also calculated that could be used to predict the duration of survival for patients with primary biliary cirrhosis.     

Localisation and semiquantitative assessment of hepatic procollagen mRNA in primary biliary cirrhosis

Background—Chronic liver disease ischaracterised by excessive deposition of collagen and otherextracellular matrix proteins, produced mainly, but not exclusively, byactivated hepatic stellate cells in the perisinusoidal space. Inprimary biliary cirrhosis (PBC) fibrosis is concentrated mainly aroundthe portal tracts.
Aims—To examine the hypothesisthat, in addition to hepatic stellate cells, portal tract fibroblastsmight play a significant role in the deposition of collagen in PBC.
Methods—Fifty liver biopsyspecimens from patients with PBC were studied. An in situ hybridisationtechnique was adapted to localise and measure semiquantitatively type Iprocollagen mRNA in formalin fixed, paraffin wax embedded sections,using an ³⁵S labelled cRNA probe specific for theα₁ chain of rat type I procollagen. Hepatic fibrogenicactivity was also assessed using serum type III procollagen peptide (PIIINP).
Results—In PBC, type I procollagengene expression was significantly increased. Signal was localisedmainly in and around inflamed portal tracts, to cells which had theappearances of portal fibroblasts. Signal activity in these cellscorrelated with the degree of portal fibrosis and inflammation and alsowith serum PIIINP concentrations.
Conclusions—Results are consistentwith the hypothesis that the excessive extracellular matrix, depositedwithin the liver in PBC, is synthesised not only by hepatic stellatecells but also by portal tract fibroblasts. The semiquantitativeassessment of procollagen mRNA in liver biopsy specimens may provide auseful method of evaluating the rate of synthesis of collagen andtherefore disease activity in patients with PBC.

Keywords:in situ hybridisation; procollagen peptide; primarybiliary cirrhosis; hepatic fibrosis

     

Natural history of primary biliary cirrhosis.

The natural history of primary biliary cirrhosis (PBC) has improved significantly over the last two decades. Most patients are diagnosed with asymptomatic PBC (a-PBC). The prognosis of a-PBC is usually better than that of symptomatic PBC (s-PBC). Among a-PBC patients, some remain asymptomatic, whereas others progress to s-PBC. The prognosis of s-PBC is still poor and the main cause of death in PBC is liver failure. Other complications, such as esophageal varices and hepatocellular carcinoma, also affect the prognosis of PBC patients. Ursodeoxycholic acid treatment improves the prognosis of PBC patients in the early stage. There seems to be several types of PBC progression.     

Cytotoxic activity of spleen-derived T lymphocytes against autologous biliary epithelial cells in autopsy patients with primary biliary cirrhosis

ABSTRACT— Autoimmunity against biliary epithelial cells is considered to be involved in the pathogenesis of primary biliary cirrhosis (PBC). However, cytotoxic activity of T lymphocytes against biliary epithelial cells has not previously been examined. This study has demonstrated that spleen-derived T lymphocytes were cytotoxic for autologous biliary epithelial cells in all of five patients with PBC, even though it was only detectable at high effector to target ratios. Such cytotoxicity was not found in non-PBC patients. CD8-positive T lymphocytes were shown to be responsible for the cytotoxicity by negative selection, and its inhibition was dependent on the ratio of cold to hot target cells. These observations may support a current hypothesis that the pathogenesis of PBC is partly due to T cell autoimmunity directed against the bile duct epithelium.     

原发性胆汁性肝硬化的治疗进展

原发性胆汁性肝硬化（PBC）是一种原因不明的慢性进行性肝内胆汁淤积性疾病,其发病率有逐年上升趋势。其治疗主要包括针对胆汁淤积的熊去氧胆酸、针对免疫异常发病机制的糖皮质激素或免疫抑制剂以及并发症的对症治疗,终末期患者适合肝移植。随着新药的不断研发和临床应用,对最新的治疗研究进展作一简要综述。结合近5年国内外PBC治疗的最新研究进展,观察哪一种方法可以根治PBC,不良反应最小,还须要进一步研究。     

Lack of association between appendectomy and primary biliary cirrhosis

Objective Children with inflammatory bowel disease (IBD) suffer from malabsorption and malnutrition and therefore may be at risk of developing polyunsaturated fatty acid (PUFA) deficiency. The aim of this study was to investigate PUFA status in children with IBD and the possible relationship to disease activity and nutritional status.

Material and methods We assessed the fatty acid composition of plasma phospholipids (%wt/wt) of 21 children aged 5.5–18 years with IBD (ulcerative colitis, 15; Crohn's disease, 6) with mild or moderate disease activity. The clinical symptoms and biochemical indices of disease activity and nutritional status (lean and fat body mass, Hb, albumin serum conc.) were also determined.

Results The patients had lower phospholipid PUFAs than 13 healthy, aged-matched controls (25.8±5.2 versus 34.2±5.7, M±SD, p<0.001), mainly due to lower values of linoleic acid (18:2n?6, 14.0±3.8 versus 18.3±4.3, p<0.01) and its major metabolite arachidonic acid (20:4n?6, 5.3±2.0 versus 9.3±1.9, p<0.0001). There were also higher values of α-linolenic acid (18:3n?3, 0.3±0.4 versus 0.2±0.1, p<0.01) while the long-chain n?3 PUFA-eicosapentaenoic and docosahexaenoic acids were normal. Total n?6 PUFA correlated inversely to erythrocyte sedimentation rate (p<0.01), seromucoid (p<0.05) and positively to Hb concentration (p<0.01).

Conclusions Children with inflammatory bowel disease have a high risk of n?6 PUFA depletion, which is related to disease activity.     

原发性胆汁性肝硬化外周血T细胞亚群及细胞因子的检测

目的　探讨中国人原发性胆汁性肝硬化患者的T细胞亚群及细胞因子存在状况及意义。方法　选未经特殊治疗的原发性胆汁性肝硬化 (PBC) 2 5例 ,性别、年龄匹配的健康人 2 0例作为对照组。以双抗体夹心ELISA法检测外周血细胞因子IL_2、IFN_γ、IL_4、IL_10、TNF_α水平。以S_P法检测外周血T淋巴细胞亚群。结果　与对照组比较 ,PBC患者CD+ 4 T细胞升高 ,CD+ 8T细胞下降 ,CD+ 4 /CD+ 8比值上升 (P <0 0 1)。PBC组IL_2、IFN_γ、TNF_α明显升高 (P <0 0 1) ,IL_10轻度上升 (P <0 0 5 ) ,IL_4水平与对照组比较无差异 (P >0 0 5 )。结论　PBC外周血CD+ 4 T细胞和Th1细胞因子占优势 ,提示其在PBC发病机制中发挥重要作     

Cancer risk in primary biliary cirrhosis: a study in northern England

BACKGROUND: Suggestions that breast cancer may be more common in patients with primary biliary cirrhosis (PBC) have been challenged. It has recently been proposed that total cancer rates may be higher in patients with PBC, as well as liver cancers. AIMS: To investigate these proposals on a strictly defined case series. SUBJECTS: A total of 769 prevalent or incident PBC patients with "definite" or "probable" disease detected in a defined area of the north-east of England during 1987-94. METHODS: Cancer events and deaths were identified by obtaining information from one or more of the following sources: Office for National Statistics (ONS) Central Registers, Regional Cancer Registry, and clinical case records. Standardised cancer incidence (SIR) and mortality ratios (SMR) were calculated using the local region as the standard population. RESULTS: There were 97 cancer events during 1987-96. SIR from cancer registrations for all cancers was 1.7 (95% confidence interval (CI) 1.3 to 2.2), for liver cancer was 74 (95% CI 32 to 146), and for breast cancer was 1.1 (95% CI 0.4 to 2.4). SMR for all cancers was 1. 8 (95% CI 1.4 to 2.4), for liver cancer was 39 (95% CI 20 to 68), and for breast cancer was 0.4 (95% 0.1 to 1.6). The results were similar after excluding the first year of follow up after PBC diagnosis. CONCLUSIONS: There was some evidence of a small increase in overall cancer incidence and mortality in PBC patients. With the exception of liver cancer, it is unlikely that there is a high excess incidence for PBC patients from any cancer at a particular site, and specifically breast cancer.     

Treatment of pruritus of primary biliary cirrhosis with rifampin

Pruritus can be a debilitating symptom in patients with chronic cholestasis. Based on previous reports of its efficacy, we evaluated the impact of rifampin on the pruritus associated with primary biliary cirrhosis. Fourteen patients were included in a randomized, crossover study. After a 15-day washout period, subjects were followed for three weeks. During the first and third week, patients received 600 mg of rifampin or placebo; no treatment was administered during the second week. Pruritus was subjectively scored on a scale from 0 to 100. With rifampin, pruritus disappeared in 11 patients and partially improved in three; with placebo, only two had a partial response (P<0.001). Six patients with a prior poor or no response to cholestyramine improved with rifampin. No changes in biochemical tests or side effects were observed during this period. We conclude that short-term administration of rifampin relieves pruritus in primary biliary cirrhosis. When administered over a period of eight months in an open study, the relief of pruritus was maintained, while one individual developed an allergic reaction. Rifampin appears to be a safe drug in the management of the pruritus of primary biliary cirrhosis.