Is mitochondrial antibody diagnostic of primary biliary cirrhosis?

In a series of 218 patients diagnosed as having primary biliary cirrhosis only nine exhibited a negative serum mitochondrial antibody. On examining additional specimens from these patients, seven were found to be positive, giving a final incidence of greater than 99%. The two patients whose sera remained negative for the mitochondrial antibody had liver histology compatible with the diagnosis of primary biliary cirrhosis, but a firm diagnosis could not be reached. Three additional mitochondrial antibody positive subjects who were asymptomatic and exhibited normal serum alkaline phosphatase were shown on liver biopsy to have stage I primary biliary cirrhosis. The presence of a positive serum mitochondrial antibody in a patient with or without abnormalities in liver function tests strongly suggests the diagnosis of primary biliary cirrhosis.     

Clinical significance of the serum levels of the 7S domain of type IV collagen in patients with primary biliary cirrhosis

The serum levels of the 7S domain of type IV collagen were measured with a radio-immunoassay in 42 patients with primary biliary cirrhosis (asymptomatic: n = 28; symptomatic: n = 14), 10 patients with chronic active hepatitis, 10 patients with liver cirrhosis and 10 healthy female controls. Serum levels of the 7S domain of type IV collagen were: 4.28 ng/mL (3.88-4.72 ng/mL; mean and range of mean +/- s.d.) in healthy controls; 5.97 ng/mL (5.07-7.02 ng/mL) in patients with chronic active hepatitis; 8.23 ng/mL (6.40-10.58 ng/mL) in patients with liver cirrhosis; and 6.79 ng/mL (4.76-9.67 ng/mL) in patients with primary biliary cirrhosis. Patients with liver cirrhosis and primary biliary cirrhosis had higher levels of serum 7S domain of type IV collagen than healthy controls (P < 0.001, respectively). Serum levels of the 7S domain of type IV collagen in patients with asymptomatic primary biliary cirrhosis, 5.83 ng/mL (4.55-7.48 ng/mL) were significantly lower than those in symptomatic primary biliary cirrhosis, 9.18 ng/mL (6.53-12.91 ng/mL; P < 0.001). Serum levels of the 7S domain of type IV collagen increased significantly along with advancement of the histological stages of primary biliary cirrhosis. Serum levels of the 7S domain of type IV collagen in the paired sera of eight patients with asymptomatic primary biliary cirrhosis (mean interval 30 months, range 12-48 months) showed significant rises during the intervals (P < 0.05), while serum levels of albumin and total bilirubin did not change significantly during these intervals.(ABSTRACT TRUNCATED AT 250 WORDS)     

Primary biliary cirrhosis: geographical clustering and symptomatic onset seasonality

Patients with primary biliary cirrhosis (primary non-suppurative destructive cholangitis) in the north east region of England were studied over a five year period and, to evaluate epidemicity, compared with two contemporaneous disease series of known occurrence. These were: terminal renal failure, all causes (low or absent epidemicity n = 106) and an outbreak of echovirus 19 disease (high epidemicity n = 201). Eight primary biliary cirrhosis-affected men and 109 women from an estimated catchment population of 2.08 million were identified. The current diagnosis rate was 1.0/100 000 (1.8/100 000 for women of 15 or more). There were 18 deaths, mean survival from diagnosis 4.0 years. Within the region prevalence varied from 3.7/100 000 in rural areas to 14.4/100 000 in industrial urban areas. In the conurbation, prevalence rates varied insignificantly. Here, most cases were concentrated in central districts, where the proportion of asymptomatic presentations was 50%. Outside the conurbation the asymptomatic proportion fell to 21%, suggesting low incidental diagnosis rates. When compared with echovirus 19, primary biliary cirrhosis was of low or absent epidemicity, and similar to renal failure in its uniform geographical distribution and lack of clustering. Forty three patients (37% of the total), however, had significantly seasonal symptomatic presentations (p less than 0.01), although scan statistic testing failed to show clustering of onset in time. Apparently provocative factors associated with primary biliary cirrhosis symptomatic onset were identified in only 11 (9.4%) of patients. Age-specific onset rates rose linearly between ages 35 and 65, and nearly one third of patients presented after 65 years, two thirds of deaths occurring in this age group. There is thus no evidence in north east England of geographical anomalies in the distribution of primary biliary cirrhosis. International differences may be partly explained by environmental factors influencing seasonal presentation, such as sunlight. Diagnosis rates are profoundly influenced by increased medical awareness, especially in the elderly, of this now relatively common disease and increased use of the mitochondrial (AMA) antibody test.     

A double‐blind,placebo‐controlled,randomized study to evaluate the efficacy,safety and tolerability of tegaserod in patients with irritable bowel syndrome

To determine survival and the risk factors of death in primary biliary cirrhosis, data from 52 symptomatic and 13 asymptomatic patients were analyzed. The mean follow-up time was 6.3 years (range, 0.4–23 years). The average length of survival was 18 years for the symptomatic and 8.4 years for the asymptomatic patients. By a univariate analysis, ascites, presence of esophageal varices, gastrointestinal bleeding, jaundice, hepatomegaly and the logarithms of albumin and bilirubin were all associated with a poor prognosis. A multivariate analysis of the clinical features showed that the presence of bleeding from esophageal varices and the logarithm of bilirubin were the only predictors for poor prognosis. The survival of the symptomatic patients is longer than reported previously, while the life expectancy for the asymptomatic patients seems no better than for the symptomatic group.     

The demography of primary biliary cirrhosis in Ontario, Canada

The demographics of primary biliary cirrhosis in Ontario, Canada, are described. Two hundred and twenty-five primary biliary cirrhosis patients were identified by 85 of 502 gastroenterologists (or internists) practicing in Ontario acute care hospitals that have 150 or more beds. Two hundred and six patients were verified as being antimitochondrial antibody-positive, resulting in an incidence of 3.26 per million per year and a prevalence of 22.39 per million. Questionnaire data were obtained on 88.5% of these patients. Twenty-nine percent of the patients were found to be asymptomatic. Geographical clustering and racial predisposition were not seen. No increase in breast cancer prevalence was noted. By the time the diagnosis of primary biliary cirrhosis was established, the patients had consulted a median number of 3.5 physicians. Fatigue was reported as the most disabling symptom. The diagnosis of primary biliary cirrhosis in patients referred from across the province of Ontario was independently confirmed by us, using standard criteria (antimitochondrial antibody testing and liver biopsy), and was found to be reliable.     

Asymptomatic primary biliary cirrhosis: a study of its natural history and prognosis

Objective: To document the natural history of asymptomatic primary biliary cirrhosis and identify prognostic features that would predict the development of symptomatic disease. Methods: A retrospective chart review of all patients with abnormal liver biochemical tests and antimitochondrial antibody-positive, liver biopsy-compatible primary biliary cirrhosis who were seen in a single tertiary care center between 1983 and 1994 was performed. Statistical analysis using Cox regression was employed to compare survival of the study population with an age- and gender-matched control population and to identify potential prognostic variables. Results: Ninety-one patients were included. Median age at presentation was 53.2 yr. Ninety percent were female. Median follow up was 61.2 months (range 7–206 months). Thirty-six percent (33 patients) became symptomatic with 11% (10 patients) progressing to death or liver transplant. Median predicted length of survival from onset of disease for the entire cohort was 14 yr. Patient survival was less than that predicted for an age- and gender-matched control population (   p < 0.05  ). Univariate and multivariate analysis on a broad spectrum of clinical, biochemical, and histological features at the time of initial presentation failed to reveal any prognostic variables that would distinguish those who would become symptomatic from those who would remain symptom-free. Specifically, three primary variables of interest (associated autoimmune disorders, hepatomegaly, and histological stage) were not found to predict prognosis. Conclusion: Patients who present with asymptomatic primary biliary cirrhosis have a shorter life span than the general population. Presently, there are no prognostic features that identify the patients who will develop progressive disease from those who will remain symptom-free. Therefore, treatment should be offered to all patients.     

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.     

Epidemiology of primary biliary cirrhosis in a defined rural population in the northern part of Sweden

The northern part of Sweden is sparsely populated and must be regarded as a rural region. An investigation into the incidence and prevalence of primary biliary cirrhosis was conducted and the course of the disease was followed. In total, 111 patients with primary biliary cirrhosis were identified for the 10-yr period 1973 to 1982 in the northern health region of Sweden. The mean annual incidence amounted to 13.3 per million and the point prevalence was 151 per million, which is the highest reported so far. There was a significantly higher prevalence in the most northern county of Sweden, both with respect to total number of primary biliary cirrhosis patients and symptomatic patients. Asymptomatic patients amounted to 37%. During the study period 25 patients out of the 111 died (23%), 14 as a direct consequence of the liver disease. Three patients died of primary hepatocellular carcinoma, one having an asymptomatic liver disease without cirrhosis. Primary biliary cirrhosis seems to be more common in Sweden, especially in the northern part, than it is elsewhere. A high frequency of extrahepatic symptoms (85%), mainly musculoskeletal, was recorded. These symptoms may lead to the first contact with the health service, rather than signs of liver disease. Thus, an increasing number of patients are diagnosed with asymptomatic liver disease, who must be followed to check for the eventual development of symptoms.     

LIVER INVOLVEMENT IN PRIMARY SJOGREN'S SYNDROME

Three hundred patients with primary Sjögren's syndrome(pSS) were investigated for liver involvement using clinical,biochemical, immunological and histological data. Seven percent of patients showed evidence of liver disease eithersubclinical (2%) or asymptomatic (5%) with elevated liver enzymesIn 6.6 % of patients antimitochondrial antibodies (AMA) weredetected by immunofluorescence and 27% of pSS patients showedantibodies to pyruvate dehydrogenase (a-PDH) using ELISA. AMA-positivepatients were further investigated with transcutaneous liverbiopsy. Ninety-two per cent of patients with AMA showed liverinvolvement with features of chronic cholangitis similar tostage I primary biliary cirrhosis It is concluded that liverinvolvement in pSS patients is rare and subclinical with histologicalfeatures predominantly of stage I primary biliary cirrhosisAMA is the most sensitive indicator of underlying liver pathologyin pSS patients KEY WORDS: Sjögren's syndrome, Antimitochondrial antibodies, Primary biliary cirrhosis     

Factors of prognostic importance in primary biliary cirrhosis

To determine survival and the risk factors of death in primary biliary cirrhosis, data from 52 symptomatic and 13 asymptomatic patients were analyzed. The mean follow-up time was 6.3 years (range, 0.4-23 years). The average length of survival was 18 years for the symptomatic and 8.4 years for the asymptomatic patients. By a univariate analysis, ascites, presence of esophageal varices, gastrointestinal bleeding, jaundice, hepatomegaly and the logarithms of albumin and bilirubin were all associated with a poor prognosis. A multivariate analysis of the clinical features showed that the presence of bleeding from esophageal varices and the logarithm of bilirubin were the only predictors for poor prognosis. The survival of the symptomatic patients is longer than reported previously, while the life expectancy for the asymptomatic patients seems no better than for the symptomatic group.     

Recurrence of primary biliary cirrhosis, autoimmune cholangitis and primary sclerosing cholangitis after liver transplantation

Given the usually prolonged natural history of primary biliary cirrhosis, autoimmune cholangitis, and primary sclerosing cholangitis, and the relatively recent introduction of orthotopic liver transplantation, our understanding of recurrence of these autoimmune diseases after orthotopic liver transplantation has been slow to evolve. Present data suggest that after orthotopic liver transplantation, patients with primary biliary cirrhosis will have persistence of serum antimitochondrial antibodies, develop histologic lesions suggestive of recurrent primary biliary cirrhosis with a frequency in the 8% to 16% range at 2 to 5 years after orthotopic liver transplantation, but will demonstrate little if any symptomatic disease as a consequence. Although data are extremely limited, autoimmune cholangitis patients will have a similar post-transplant course (without antimitochondrial antibodies). Recurrence of primary sclerosing cholangitis remains the most controversial, however, these patients probably develop nonanastomotic intrahepatic and extrahepatic strictures more frequently than patients without primary sclerosing cholangitis, with a frequency in the 20% to 25% range at 3 to 5 years. With longer patient follow-up and additional studies, it is hoped that our understanding of recurrent autoimmune biliary diseases will grow considerably in the future.     

Frequency and significance of antimitochondrial antibodies in severe chronic active hepatitis

Of 187 patients with severe chronic active hepatitis, 37 (20%) had antimitochondrial antibodies, usually of low titer (less than or equal to 1:40). To assess the significance of this finding and to identify differentiating features from primary biliary cirrhosis, 24 of these patients were compared to two groups of matched counterparts of which one lacked antimitochondrial antibodies and one had the antibodies together with typical primary biliary cirrhosis. Higher serum levels of alkaline phosphatase and an increased frequency of stainable hepatic copper were the only features that distinguished these patients from those without antimitochondrial antibodies. The response to corticosteroids was not influenced by antibody status. Histologic interpretation differentiated primary biliary cirrhosis from antibody-positive chronic active hepatitis in 91% of instances. High antibody levels (greater than or equal to 1:160), immunoglobulin M concentrations (greater than or equal to 6.0 mg/ml), alkaline phosphatase activity (greater than or equal to fourfold normal), and cholesterol elevations (greater than or equal to 300 mg/dl) separated the syndromes in 82% of instances. Patients with laboratory features of primary biliary cirrhosis but histologic findings of chronic active hepatitis responded to corticosteroids. We conclude that low titers of antimitochondrial antibodies are common in chronic active hepatitis, and the presence of these antibodies does not preclude a satisfactory response to corticosteroids. Histologic features are more reliable than biochemical findings in differentiating the syndromes and should be the basis for diagnosis and treatment.     

Insulin-like growth factor I gene microsatellite repeat, collagen type Ialpha1 gene Sp1 polymorphism, and bone disease in primary biliary cirrhosis

BACKGROUND: Genetic factors have been implicated in the pathogenesis of osteoporosis, a common disorder in primary biliary cirrhosis. Insulin-like growth factor I (IGF-I) gene microsatellite repeat polymorphism was found to be associated with osteoporosis in some studies, and collagen-Ialpha1 (COLIA1) Sp1 s allele was associated with lower bone mineral density in primary biliary cirrhosis. IGF-I treatment restored osteopenia and reduced fibrogenesis in experimental cirrhosis. We investigated IGF-I and COLIA1 gene polymorphisms and bone mineral density in Hungarian primary biliary cirrhosis patients. PATIENTS AND METHODS: Seventy female patients with primary biliary cirrhosis were enrolled (mean age 57.6 years, range 37-76 years; all anti-mitochondrial antibody M2-positive; stage II-IV). One hundred and thirty-nine age-matched female subjects served as controls (mean age 55.9 years, range 43-72 years). COLIA1 and IGF-I polymorphisms were determined by polymerase chain reaction. Bone mineral density was measured by dual-energy X-ray absorptiometry in the lumbar spine and femoral neck. RESULTS: The IGF-I was not different between primary biliary cirrhosis patients and controls. The genotype frequency of COLIA1 polymorphism was also not different between primary biliary cirrhosis patients and controls. However, the s allele was significantly less frequent in patients with primary biliary cirrhosis. Osteoporosis was detected in 22 patients. The IGF-I 192/192 genotype was associated with higher femoral-neck z-scores compared with other genotypes. CONCLUSION: In contrast to previous studies, the s allele was less frequent in patients with primary biliary cirrhosis, and its presence was not associated with bone mineral density. Since IGF-I polymorphism was associated with bone mineral density, it may be hypothesised that not COLIA1 but IGF-I together with other genetic and environmental factors may be involved in the complex regulation of bone mineral density in primary biliary cirrhosis.     

Immunoblotting as a confirmatory test for antimitochondrial antibodies in primary biliary cirrhosis.

Primary biliary cirrhosis is characterised by the presence of antimitochondrial antibodies which are directed against components of mitochondrial dehydrogenase complexes. The specificity of antimitochondrial antibodies for primary biliary cirrhosis as detected by immunoblotting was investigated. Commercially available preparations of pyruvate and oxo-glutarate dehydrogenases and beef-heart mitochondria were used as source of antigens. Sera from 47 primary biliary cirrhosis patients (46 of whom were antimitochondrial antibody positive by immunofluorescence), 16 non-primary biliary cirrhosis patients (antimitochondrial antibody positive by immunofluorescence), 23 liver-kidney microsomal antibody positive chronic active hepatitis patients, and 32 patients with connective tissue diseases were examined. Of the 47 subjects with primary biliary cirrhosis, 43 (91%) and 13 (28%) tested positive by immunoblotting for pyruvate and oxo-glutarate dehydrogenase, respectively. Only three primary biliary cirrhosis patients were negative for both antigens, including the only one shown to be antimitochondrial antibody negative by immunofluorescence. The other two patients were positive by immunoblotting with beef-heart mitochondria. In contrast, only three of 16 (19%) non-primary biliary cirrhosis patients who were antimitochondrial antibody positive by immunofluorescence tested positive by immunoblotting (for both pyruvate dehydrogenase and beef-heart mitochondria). None of the 23 liver-kidney microsomal antibody positive and the 32 patients with rheumatic diseases were positive by immunoblotting with any antigen. Our data show that immunoblotting with commercially available oxo-acid dehydrogenases is a reproducible method for the detection of antimitochondrial antibodies highly specific for primary biliary cirrhosis.     

Positive antimitochondrial antibody but normal alkaline phosphatase: is this primary biliary cirrhosis?

Twenty-nine patients with a positive antimitochondrial antibody titer greater than or equal to 1/40, who were detected during screening for other autoimmune disease, are described who had a normal serum bilirubin, alkaline phosphatase and transaminase and who had no symptoms of liver disease at presentation. Liver biopsies in 12 of the 29 fulfilled diagnostic criteria for primary biliary cirrhosis; a further 12 were consistent with primary biliary cirrhosis, but only 2 were normal. There was a high incidence of other autoantibodies and autoimmune diseases, especially thyroid antibodies and disorders. Sixteen of these patients have been followed for over 4 years since diagnosis (mean = 6 years, range = 4 to 9 years) and for a mean of 8.7 years since initial detection of the antimitochondrial antibody (range = 4 to 13). Five of 16 developed symptoms suggestive of primary biliary cirrhosis, and 11 of 16 developed elevation of alkaline phosphatase. The antimitochondrial antibody activity in these patients was in the same IgG subclasses (predominantly IgG1 and IgG3) as that seen in a group of 23 patients with clinically, biochemically and histologically advanced primary biliary cirrhosis. All showed the same abnormalities on quantitative estimation of the total IgG subclasses in serum; relative excess of IgG3 and, to a lesser extent, IgG2 was exhibited. It is concluded that, in this study, the finding of an antimitochondrial antibody titer greater than or equal to 1/40 is strongly suggestive of primary biliary cirrhosis even in the absence of symptoms and the presence of a normal alkaline phosphatase.     

18例无症状期原发性胆汁性肝硬化诊断特点分析

背景：原发性胆汁性肝硬化（PBC）进展缓慢,从无症状至出现症状,时间可长达数年。无症状期PBC临床表现缺乏特异性,诊断较为困难。目的：总结无症状期PBC的诊断特点。方法：纳入18例无症状期PBC患者,检测并分析其一般情况、临床、生化、病毒学、免疫学、影像学和组织学表现。结果：18例无症状期PBC患者中男2例,女16例,确诊时平均年龄47.8岁。无临床和生化异常,仅抗线粒体抗体M2亚型（AMA-M2）阳性者9例;因肝功能异常,主要是碱性磷酸酶（ALP）、γ-谷氨酰转肽酶（GGT）升高而就诊者9例,确诊时间平均8.9个月。11例（61.1%）患者AMA-M2阳性,3例gp210抗体阳性,2例SP100抗体阳性。所有患者肝穿刺病理学检查均为Ι、Ⅱ期PBC表现。结论：无症状期PBC女性多见,可仅表现为AMA-M2和（或）gp210、SP100抗体阳性,以及ALP/GGT升高。对中老年人群特别是女性,筛查肝功能和自身免疫性肝病抗体以及完善肝脏组织学检查有助于早期诊断PBC。     

Vitamin E deficiency in primary biliary cirrhosis: gastrointestinal malabsorption, frequency and relationship to other lipid-soluble vitamins

In contrast to deficiencies of vitamins A, D and K, little is known of the prevalence, clinical manifestations and mechanisms of vitamin E deficiency in adult patients with cholestasis. We measured serum vitamin E levels in 45 patients with primary biliary cirrhosis, 20 with primary sclerosing cholangitis, 9 with cryptogenic cirrhosis and 12 with alcoholic cirrhosis. To correct for the hyperlipidemia often found in patients with primary biliary cirrhosis and primary sclerosing cholangitis, total serum lipids were measured and vitamin E levels were expressed as the vitamin E/total serum lipid ratio. Serum vitamin A and D levels and prothrombin time were also determined. Six of 45 patients with primary biliary cirrhosis (13%) but none of the patients with sclerosing cholangitis, cryptogenic cirrhosis or alcoholic cirrhosis and subnormal vitamin E/total serum lipids ratios. Vitamin E deficiency was found in two of eight patients with asymptomatic primary biliary cirrhosis. There was no correlation between standard liver biochemical tests, fasting serum cholylglycine and vitamin E levels. Patients with primary biliary cirrhosis and primary sclerosing cholangitis had significantly lower vitamin E/total serum lipids ratios than patients with either cryptogenic or alcoholic cirrhosis. Twenty-three percent of patients with primary biliary cirrhosis were vitamin D deficient and 14% had low vitamin A levels. Two of the six patients with vitamin E deficiency were also deficient in vitamin D, only one was vitamin A deficient and none had prolonged prothrombin time. We also investigated the gastrointestinal absorption of vitamin E in nine patients with primary biliary cirrhosis and normal vitamin E levels as well as in six normal controls.(ABSTRACT TRUNCATED AT 250 WORDS)     

Antimitochondrial Antibody-Negative Primary Biliary Cirrhosis

Objectives : We reviewed our experience with patients who had biochemical and histological features of primary biliary cirrhosis in the absence of antimitochondrial antibodies (AMA) to better understand this variant of the syndrome. Methods : During the period between 1976 to 1992, 597 patients with clinical and histological features of primary biliary cirrhosis were seen at the Mayo Clinic. Thirty-five (5.8%) of these patients were negative for antimitochondrial antibody and had normal cholangiographic studies. The records of these patients were reviewed for this study. Results : No difference was found between the two groups with respect to age, gender, or biochemical features. IgM and γ-globulin levels were higher in the antimitochondrial antibody-positive than the antimitochondrial antibody-negative patients. What is more important, 96% of the AMA-negative patients who could be tested were positive for antinuclear antibody or anti-smooth-muscle antibodies. These tests were positive in only 56% of the antimitochondrial antibody-positive group (p < 0.05). The response of five of these patients to ursodeoxycholic acid appeared comparable to the response seen in antimitochondrial antibody-positive patients. Conclusions : Patients with histological features of primary biliary cirrhosis, whether antimitochondrial antibody positive or negative, are quite comparable with respect to clinical and biochemical features. Other autoantibodies, such as antinuclear or anti-smooth-muscle antibodies, are more common in the antimitochondrial antibody-negative group. These two conditions might be part of a spectrum that has been termed "autoimmune cholangitis" and that is characterized by chronic cholestasis, histological features of chronic nonsuppurative destructive cholangitis, and the presence of any of a variety of serum autoantibodies.     

Symptom development and prognosis in primary biliary cirrhosis: a study in two centers

The prognosis of patients with asymptomatic primary biliary cirrhosis has been uncertain. Cases of primary biliary cirrhosis in 95 patients from two centers are presented: 70 patients from a regional referral center (Freeman Hospital, FH) and 25 from an international tertiary referral center (King's College Hospital, KCH) with similar mean age at diagnosis and duration of follow-up (median, 12 months). During follow-up, 19 of 70 FH patients and 15 of 25 KCH patients developed symptoms (P less than 0.001); the mean time to symptom appearance was 43 months at FH and 35 months at KCH (P = 0.0012). Twenty-five of 95 patients died, 15 of 34 subjects who had developed symptoms (all liver-related deaths) and 10 of 61 who remained asymptomatic (all non-liver-related deaths) (P less than 0.001). Hepatic mortality was worse than among the normal population (P less than 0.05). A comparison of those patients developing symptoms with 111 at FH and 165 at KCH who presented with symptoms suggests no difference in survival once hepatic symptoms appear. In both centers, hepatic mortality was strongly related to symptom appearance in asymptomatic primary biliary cirrhosis: patients developing symptoms resemble those with symptoms at presentation. Other differences between the centers may reflect different referral patterns.     

Antinuclear antibodies in primary biliary cirrhosis

Antinuclear and antinuclear membrane autoantibodies are detected by indirect immunofluorescence in sera of 62 p. 100 of primary biliary cirrhosis patients; when anti-SS-A (Ro) and anti-SS-B (La) autoantibodies were included, 70 percent of patients had at least one type of antinuclear antibody. Of 89 patients with primary biliary cirrhosis, 30 had either Raynaud's phenomenon, Sj?gren's syndrome or the CREST syndrome. Some antinuclear antibodies, anticentromere and speckled S1 type, seem to correlate with the associated connective tissue disease. Antibodies showing the S3 pattern (multiple nuclear dots) and antibodies to nuclear membrane may be present independently of an association with connective tissue disease. In the classical technical conditions used to detect anti-tissue and anti-mitochondrial autoantibodies on tissue sections, antinuclear antibodies like anti-centromere or S3 may not be detected and/or identified. Primary biliary cirrhosis patient sera for antinuclear antibodies determination must be screened by at least two assays: indirect immunofluorescence on a human cell line, like HEp-2, and immunodiffusion. The last assay must be performed even if antinuclear antibodies are undetected by immunofluorescence.