Incidence Of Primary Biliary Cirrhosis Research Articles

Primary biliary cirrhosis in early childhood - A rare case report.

Introduction and importancePrimary biliary cirrhosis (PBC) is a chronic and progressive autoimmune liver disease with no known etiology. This disease is mainly characterized by granulomatous destruction of intrahepatic biliary ducts, severe peri-portal inflammation, and ultimate progress to liver fibrosis and cirrhosis. Here, we report a five-year-old girl diagnosed with PBC, presented to us with end-stage liver disease for liver transplantation. Our patient successfully underwent liver transplantation with an uneventful recovery. This case highlights the need for awareness to report further PBC cases in the pediatric age group.Case presentationA five-year old female child presented with a 6 months history of progressive jaundice. She had multiple admissions for hepatic encephalopathy and this time she was admitted for hepatic transplantation. On examination, she was icteric and had hepatomegaly. After thorough workup, she underwent successful hepatic transplantation and was alright post-operatively. At 6 months follow up, she is doing well.ConclusionPBC is rare in childhood. The natural history and exact incidence of PBC in childhood are not known. Hence, there is a need for awareness to report further PBC cases in the pediatric age group.

Primary Biliary Cirrhosis

Primary biliary cirrhosis (PBC) is an inflammatory disease or chronic liver inflammation, with slow progressive characteristic and is an unknown cholestatic liver disease and commonly happen in middle-aged women. The incidence of PBC is 0.03 – 5.8 per 100,000 people per year, prevalence of 1.91-40.2 per 100,000 people and continues to increase. Based on the American Association for Study of Liver Disease criteria, the diagnosis of PBC is made in the presence of two out of three criteria, which are increase of alkaline phosphatase, positive antimitochondrial antibodies (AMA), and histopathology examination.We reported a case which is very rarely found; a 47-year-old women with the chief complaints of decrease consciousness and jaundice. In physical examination, there were anaemic conjunctiva, icteric sclera, hepatosplenomegaly, palmar erythema, and liver nails. In the patient, there was no evidence of obstruction in imaging with two-fold increase of alkaline phosphatase and positive AMA test. Patient was hospitalised to slow down the progression of the disease and to overcome the signs (e.g. pruritus, osteoporosis and sicca syndrome).

A62 CANADIAN POPULATION-BASED EVALUATION OF THE NATURAL HISTORY OF PRIMARY BILIARY CHOLANGITIS OVER THE LAST DECADE

Abstract Background Few studies have evaluated the epidemiology of primary biliary cirrhosis (PBC) in North America. Ursodeoxycholic acid (URSO) improves outcomes amongst PBC patients. Aims Therefore, we undertook this study to determine the epidemiology of PBC in Canada, and impact of URSO on clinical outcomes, two decades after URSO approval in North America. Methods We used our previously validated coding algorithm to identify PBC patients in population based administrative databases in the Calgary Health Zone (population ~1.5 million) from 2005–2015. Multiple sources of data including inpatient, ambulatory, physician billing, laboratory, and pharmaceutical were linked. Annual prevalence and incidence were estimated using Poisson regression. Age/sex adjusted rate ratios were calculated. We used Cox regression models to estimate: all-cause mortality, liver transplant and decompensated cirrhosis free survival. In our models, we adjusted for demographic and clinical variables including response to URSO. Results During the study period over 11 years, the overall annual age/sex adjusted PBC incidence was 29.5 cases per million (48.3 and 9.9 per million for women and men, respectively). The highest incidence rate was observed among women aged 60–79 (90.9 per million) with an incidence rate ratio of 10.4 (95%: 6.83–15.9) compared to those aged 20–39. While incidence rate remained stable, prevalence rate increased significantly from 242 to 343 cases/ million, between 2005 and 2015 (P<0.01). Prevalence rate was highest at 965 cases/ million amongst women aged 60–79. We identified 299 incident PBC cases with a median follow up of 5.1 years (IQR 2.9–8.3). 87 (29.1%) of these incident cases developed decompensated cirrhosis or HCC, 10 patients (3.4%) underwent liver transplantation, and 44 (14.7%) patients died. The annual mortality rate was 2.9% (95%CI: 2.1- 3.8) compared to 3.4% (2.3–4.9%) a decade ago (P=0.04). The estimated 5-year survival rate was 87.6% (82.6- 91.3). Standardized mortality rate was 3.2 (95%CI: 2.2–4.1). Overall, 25% of our incident cohort were not prescribed URSO. Patients not prescribed URSO were more likely to be male, older age, have normal ALP and had decompensated cirrhosis at diagnosis (P<0.01 for all). Among those who used URSO, response rate was 86%. Response to URSO was an independent predictor of reduced risk of decompensated cirrhosis and liver transplant, and higher survival (aHR: 0.46, 0.29–0.74). Conclusions PBC prevalence is increasing in this North American population. While mortality rate decreases in our PBC cohort, survival was suboptimal compared to the general population, mainly due to late presentation at diagnosis. Therefore, better surveillance and early detection of possible PBC patients in the primary care setting are essential to improve PBC outcomes. Funding Agencies None

CLINICAL AND LABORATORY FEATURES OF ANTICENTROMERE ANTIBODY-POSITIVE SJö GREN’S SYNDROME

Objective: to study the clinical and laboratory features of patients with anticentromere antibody (ACA) positive Sjö gren’s syndrome (SjS); to assess the spectrum of autoantibodies in patients of this group; to determine the frequency with which the SjS patients who are highly positive for ACA, meet the international classification criteria for SjS and systemic sclerosis (SS); to reveal the incidence of MALT lymphomas in this patient group; to estimate the incidence of primary biliary cirrhosis (PBC)/biliary lesions as part of autoimmune epithelitis in SjS in this patient group.Material and methods. A total of 83 patients with ACA positive SjS were comprehensively examined at the V.A. Nasonova Research Institute of Rheumatology during the period 2012 to 2018. The inclusion criteria were con formity to the 2001 Russian SjS criteria and a high ACA level. MALT lymphomas were diagnosed on the basis of histological and immunohistochemical studies and polymerase chain reaction-based determination of B-cell clonality in the biopsy samples of affected organs according to the World Health Organization classification of Hematopoietic Tumors. The diagnosis of PBC/biliary lesions was made on the basis of histological and immunohistochemical studies of liver biopsy specimens.Results and discussion. The investigation revealed low detection rates for anti-Ro antibodies (32.5%), anti-La antibodies (7.2%) and rheumatoid factor (RF) (21.7%), which were typical for the classical SjS immunophenotype), increased ESR (14%), leukopenia (7%), hypergammaglobulinemia (17.6%), elevated levels of IgG (9.5%) and IgA (18.7%), and hypocomplementemia (16.1%) in the ACA positive SjS patients. Despite the low detection rate of RF, 15 (18%) patients in this group developed MALT lymphomas: 14 patients had salivary gland MALT lymphoma and one patient had tonsil MALT lymphoma with peripheral lymph node involvement (generalized marginal zone lymphoma). Also, the patients of this group showed high detection rates for AMA antibodies (34.6%), increased IgM level (29.7%) and a higher risk for PBC/biliary lesions as a manifestation of autoimmune epithelitis in SjS (14.5%). AMA-antibodies were absent in only two patients who were diagnosed with liver disease according to biopsy specimens. Nervous system and renal lesions, antiphospholipid syndrome, rheumatoid arthritis, hypergammaglobulinemic purpura, and cryoglobulinemic vasculitis were much less common and sporadic. Also ACA-positive SjS patients often have Raynaud’s phenomenon (54.9%) with scleroderma-type capillaroscopic changes (68%) and a limited form of SS (24%) according to the 2013 ACR criteria.Conclusion. ACA-positive SjS is a subtype of the disease, which is significantly different from the classic one in a number of clinical and laboratory signs and characterized by an increased risk for SS, MALT lymphomas, and PBC/biliary lesions as a manifestation of autoimmune epithelitis in SjS which in some cases leads to the underdiagnosis of SjS. ACA should be considered as pathogenetically related to SjS autoantibodies; and all patients who are seropositive for ACA should be examined for SjS and PBC/biliary lesions as a manifestation of autoimmune epithelitis in SjS regardless of whether they have SS or not, as well as complaints of dry mouth and eyes. Patients with significantly enlarged salivary glands should undergo biopsy to rule out or confirm MALT lymphoma before initiating hormonal, antilymphoproliferative, and anti-B-cell therapy.

National incidence of autoimmune liver diseases and its relationship with the human development index.

ObjectivePrimary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), autoimmune hepatitis (AIH) and immunoglobulin G4 related cholangitis represent the major autoimmune liver diseases (AILD). However, the relationship between AILD incidence and socioeconomic development levels is yet to be explored.ResultsA total of 43 studies were included. There was a positive but not significant correlation between the PBC incidence and HDI on a global level (r=0.348, P=0.082). However, in Europe, a significantly positive correlation existed between the PBC incidence and HDI (r=0.455, P=0.044). No statistical correlation between PSC incidence and HDI was observed (r=0.116, P=0.706). The incidence of AIH revealed a positive correlation with the national HDI both globally (r=0.638, P=0.014) and in Europe (r=0.644, P=0.045). Moreover, the PBC incidence demonstrated a positive correlation with the health index (r=0.422, P=0.036), but a negative correlation with the education index (r= −0.650, P<0.01). Moreover, the income index presented a positive correlation with both the PSC incidence (r=0.599, P=0.031) and the AIH incidence (r=0.649, P=0.012).MethodsPubMed was searched to identify relevant epidemiological studies on AILD. The human development index (HDI) was applied as an indicator for socioeconomic development. HDI data were obtained and calculated based on the 2014 Human Development Report. Pearson coefficient and linear regression analysis were conducted to estimate the correlation between incidence and HDI.ConclusionsThere is positive association between the national incidence of AILD and the socioeconomic status, as measured by HDI. In less-developed countries, the incidence of AILD, especially PBC and AIH, might be less common.

Low incidence of primary biliary cirrhosis (PBC) in the first-degree relatives of PBC probands after 8 years of follow-up.

Primary biliary cirrhosis (PBC) is characterized by chronic cholestasis and disease-specific antimitochondrial antibodies (AMA). A high prevalence of AMAs in first-degree relatives (FDRs) of PBC probands has been reported, although the natural history of such patients has not been described. We aimed to assess the risk of developing PBC in AMA+ FDRs of patients with PBC. First-degree relatives recruited to the Mayo Clinic PBC Genetic Epidemiology Registry and Biorepository were followed for disease onset after recruitment. Development of PBC was ascertained via self-report during a telephone interview and/or via proband report on a questionnaire. Chi-squared test and t-test were used to assess the differences between categorical and continuous variables respectively. A mixed-effects model was used to assess the change in biochemical profiles over time. Forty AMA+ and 423 AMA- subjects were included and followed for a median of 8.9 and 8.4 years respectively. Overall, 3% (n = 15) of FDRs were diagnosed with PBC, and AMA+ FDRs had a higher risk than AMA- FDRs (24% vs. 0.7%, P < 0.01). However, among undiagnosed FDRs, only 4% of AMA+ (n = 1) and 0.4% of AMA- (n = 1) FDRs were diagnosed with PBC (P = 0.17) during the follow-up period. None of the AMA+ FDRs with normal alkaline phosphatase at baseline developed PBC in follow-up. Our results suggest a low risk of developing PBC over time in FDRs of patients with PBC, particularly those without biochemical evidence of cholestasis at baseline. These data are useful in counselling and reassuring relatives of their overall favourable prognosis.

Mo1001 Low Incidence of Primary Biliary Cirrhosis (PBC) in First Degree Relatives (FDRs) of Patients With PBC With Long Term Follow Up

Mo1001 Low Incidence of Primary Biliary Cirrhosis (PBC) in First Degree Relatives (FDRs) of Patients With PBC With Long Term Follow Up

Geoepidemiology and space–time analysis of Primary biliary cirrhosis in Crete, Greece

The prevalence of Primary biliary cirrhosis varies in different geographical areas. This might reflect genetic or environmental risk factors. We aimed to define Primary biliary cirrhosis prevalence and incidence, describe patient's spatial distribution, generate prediction maps and detect any possible routing pattern of time-spatial appearance of the disease in Crete, Greece. From 1990-2010, 245 Primary biliary cirrhosis patients diagnosed and followed up at the Gastroenterology Department of the University Hospital and the District Hospitals of the island, were contacted and 222 were included in the time-spatial analysis. To map their spatial distribution per 5-year periods, geospatial models were applied in Gis-ArcMap 9.3 software. Kriging Interpolation methods were used to generate prediction maps for the disease in Crete. Areas of high and low probability of disease occurrence were estimated through multicriteria modelling. The disease route was defined by Gis-ArcMap's toolbox. Prevalence was found to be 365 cases per million, with a mean incidence of 20.88 (range 3.79-35.99). Prediction map estimates from 1.22 to 11 patients per 50 km2 all over Crete. Areas of high risk of disease occurrence are located in the Eastern part, while low risk in the Western part of the island. Prevalence and incidence of Primary biliary cirrhosis in Crete are among the higher published in Europe. Given the homogeneous and stable study population and the geopolitics of the island, the heterogeneity in the time-spatial distribution and the route of disease appearance strongly suggest a role for environmental causative agents.

No Rise in Incidence but Geographical Heterogeneity in the Occurrence of Primary Biliary Cirrhosis in North East England

In this study, we examined temporal changes in the incidence of primary biliary cirrhosis (PBC) and investigated associations between PBC incidence and sociodemographic factors and spatial clustering. We included 982 patients aged ≥40 years from North East England with incident PBC diagnosed during 1987–2003. Age-standardized incidence rates with 95% confidence intervals were calculated. Negative binomial regression was used to analyze incidence and socioeconomic deprivation. Clustering analysis was performed using point process methods, testing the null hypothesis that disease risk does not vary spatially and that PBC cases occur independently. The age-standardized incidence rate was 53.50 per million persons per year (95% confidence interval: 48.65, 58.35) in 1987–1994 and 45.09 per million persons per year (95% confidence interval: 41.10, 49.07) in 1995–2003. Risk of PBC increased in areas with higher levels of socioeconomic deprivation (P = 0.035). More specifically, risk increased in areas with higher levels of overcrowded homes (P = 0.040), higher levels of households without cars (P < 0.001), and higher levels of non-owner-occupied homes (P < 0.001). Overall, there was evidence of spatial clustering (P = 0.001). The findings confirm that overall incidence of PBC did not rise over time, but sociodemographic variations suggest that certain aspects of deprivation are involved in its etiology.

Primary biliary cirrhosis in Southern Israel: A 20 year follow up study

BackgroundThe epidemiology of primary biliary cirrhosis (PBC) in Israel is unknown. We aimed to determine the epidemiology, long-term survival and outcomes of PBC in Southern Israel from 1990 to 2010. MethodsCase-finding methods and population-based administrative data were used to estimate and evaluate the incidence, prevalence and prognostic factors of outcome in our PBC cohort. Results138 cases of PBC were identified. The average annual prevalence of PBC was 255 cases per million. The overall age/sex-adjusted annual incidence of PBC was 10 cases per million from 1990 through 1999 and 20 cases per million from 2000 to 2010.Among 138 incident cases with a total follow-up of 960 persons-years from diagnosis, 30 patients (21.7%) died. Survival in PBC patients was significantly lower than that of the age/sex-matched Israeli population. Mortality was significantly increased in patients with an initial MELD score greater than 8 (P<0.001), with portal hypertension (P<0.001), and in non-responders to ursodeoxycholic acid (UDCA) therapy according to Barcelona criteria (P=0.005).Out of 138 patients, 95 patients (68.0%) responded to UDCA therapy according to Barcelona and Paris criteria. None of the responders died during the follow-up period as opposed to 30 out of 43 (69.8%) of non-responders. In multivariate analysis the factors associated with response to UDCA were: albumin levels above 3.5g/dL (P<0.001) and lower degree of fibrosis per liver biopsy (P=0.003). ConclusionsThis study addresses the increasing burden of PBC in Israel and confirms the importance of some clinical and therapeutic factors as predictors of long-term prognosis.

Epidemiology and natural history of primary biliary cirrhosis in a Canadian health region: A population-based study

The recent epidemiology and outcomes of primary biliary cirrhosis (PBC) in North America are incompletely described, partly due to difficulties in case ascertainment. In light of their availability, broad coverage, and limited expense, administrative databases may facilitate such investigations. We used population-based administrative data (inpatient, ambulatory care, and physician billing databases) and a validated International Classification of Diseases coding algorithm to describe the epidemiology and natural history of PBC in the Calgary Health Region (population approximately 1.1 million). Between 1996 and 2002, the overall age/sex-adjusted annual incidence of PBC was 30.3 cases per million (48.4 per million in women, 10.4 per million in men). Although the incidence remained stable, the prevalence increased from 100 per million in 1996 to 227 per million in 2002 (P < 0.0005). Among 137 incident cases with a total follow-up of 801 person-years from diagnosis (median 5.8 years), 27 patients (20%) died and six (4.4%) underwent liver transplantation. The estimated 10-year probabilities of survival, liver transplantation, and transplant-free survival were 73% (95% confidence interval [CI] 60%-83%), 6% (95% CI 2.5%-12.6%), and 68% (95% CI 55%-78%), respectively. Survival in PBC patients was significantly lower than that of the age/sex-matched Canadian population (standardized mortality ratio 2.87; 95% CI 1.89-4.17); male sex (hazard ratio [HR] 3.80; 95% CI 1.85-7.82) and an older age at diagnosis (HR per additional year, 1.06; 95% CI 1.03-1.10) were independent predictors of mortality. This population-based study demonstrates that the burden of PBC in Canada is high and growing. Survival of PBC patients is significantly lower than that of the general population, emphasizing the importance of developing new therapies for this condition.

Prevalence and incidence of primary biliary cirrhosis are increasing in Finland

Objective. To examine the epidemiology of primary biliary cirrhosis (PBC) in Finland and to evaluate whether the possible increase in prevalence was attributable to the increasing incidence, better survival, or both. Material and methods. The Hospital Discharge Register, pathology registers, and death certificates for the years 1988–99 were scrutinized, and the patients identified were followed-up for survival until 31 October 2004. The study area covered four university hospital districts: a total of 25 hospitals. The diagnosis of PBC was regarded as definite (or probable) if three (or two) of the following criteria were fulfilled: positive antimitochondrial antibodies, constantly elevated alkaline phosphatase, and compatible liver histology. Results. In the total population of the study areas, the age-standardized prevalence of PBC increased during the study period from 103 (95% CI: 97–110) to 180 (172–189) per million inhabitants. Incidence increased from 12 (10–14) to 17 (15–20) per million inhabitants per year. The annual average increase in prevalence was 5.1% (4.2–5.9%, p<0.0001) and in incidence 3.5% (0.9%–6.0%, p=0.008). In gender-specific analyses among women, the prevalence of PBC increased from 161 (151–171) to 292 (277–207) per million during the study period and the incidence from 20 (16–24) to 27 (23–32) per million per year. The death rate was 4% per year and half the deaths were from liver-related causes. Survival after diagnosis during the study period lengthened. Conclusions. The prevalence of PBC increased in Finland during 1988–99, owing to both the increased incidence and the prolonged survival.

Living near toxic-waste sites linked to increased incidence of primary biliary cirrhosis

Living near toxic-waste sites linked to increased incidence of primary biliary cirrhosis

The geographical distribution of primary biliary cirrhosis in a well-defined cohort

The incidence of primary biliary cirrhosis (PBC) varies widely between regions. However, little is known about variation within regions and the degree to which this may reflect environmental risk factors. The aim of this study was to describe the spatial distribution of cases of PBC in a defined region of Northeast England over a defined period, and to assess the magnitude of any departure from random spatial distribution. Seven hundred seventy patients with established PBC were identified in a previous comprehensive case finding study. A total of 3,044 control locations were randomly selected from postcode (zip code) data weighted for number of drop off points per postcode. Geographical analysis was performed by testing both for spatial variation in risk and local clustering by using previously described point process methods. Both tests used the same null hypothesis that risk of disease does not vary spatially and cases occur independently of each other. Statistically significant spatial variations in risk were found in the whole study region (P [lt ] .001) and in the major urban area within the region (P [lt ] .004). Risk was higher in the urban area of Tyneside than in the surrounding rural area. Within the rural area, spatial variation in risk was equivocal (P = .012), but there was significant (P = .001) clustering of cases (estimated average cluster effect approximately 10 excess cases within a 7-km radius). PBC occurred to a density of 10.7 cases/km2 in the highest risk areas. In conclusion, PBC is unevenly distributed in Northeast England. This may reflect one or more environmental risk factors in its etiology. (HEPATOLOGY 2001;34:1083-1088.)

Cholangiocytes and primary biliary cirrhosis: prediction and predication

Although there have been descriptions of primary biliary cirrhosis (PBC) for more than 100 years, this condition first attracted the attention of immunologists in 1965, when patients’ sera were found to have antimitochondrial antibodies (AMAs) (1). The mitochondrial autoantigens, which are highly conserved among mitochondria and even chloroplasts (2) of divergent species, have been identified as the E2 components of the 2-oxo-acid dehydrogenase family — particularly the 74-kDa E2 subunit of the pyruvate dehydrogenase complex, which catalyzes the formation of acetyl CoA. The structurally and functionally related mitochondrial proteins BCOADC-E2 and OGDC-E2, as well as the E3 binding protein (3), are also found as autoantigens in PBC patients. Work with recombinant autoantigens has shown that the presence of AMAs is virtually diagnostic of PBC and that, while they may be detected in the sera of asymptomatic people years before the clinical diagnosis of PBC, they are very rarely found in non-PBC individuals (4, 5). The B cell epitope of PDC-E2 is found on the lipoyl domains, and antibody binding occurs when the antigen is complexed with lipoic acid (6). In fact, there are only five proteins in mammals that contain lipoic acid, and four of the five are autoantigens in PBC. Lipoic acid is bound to the lysine residue of the inner lipoyl domain, where it functions as a swinging arm to capture electrons during oxidative phosphorylation. Related work using cloned PDC-E2–specific T cell lines shows that the immunodominant T cell epitope also falls within the lipoyl domains. Interestingly, the frequency of PDC-E2–specific CD4+ T cell precursors is 100-fold higher in the liver than in PBMCs (7) in PBC patients, suggesting that these cells are recruited to the liver during the progression of the disease. However, the precise pathogenic role of these T cells is still under investigation. Despite the advances in the molecular characterization of immunoreactivity, a number of unexplained questions remain regarding the epidemiology and tissue specificity of this disease (3). Why is PBC overwhelmingly more common in women? Why is PBC not found in childhood? Why are granulomas found, and why is eosinophilia present in periductal inflammatory infiltrates? Why is PBC relatively more specific for small bile ducts than large bile ducts? Why should PBC recur following liver transplantation? Why is the incidence of PBC so much higher in families with an index case, even when there is no obvious MHC class I or class II association? What is the significance of the observation that some monoclonal antibodies to mitochondria appear to uniquely stain the bile duct cells in patients with PBC? Finally, why does the immune response induce damage to only a minor population of cells, those of the small ducts and ductules of the biliary and salivary epithelia?

Epidemiology and natural history of primary biliary cirrhosis in a U.S. community

Background & Aims: The epidemiology of primary biliary cirrhosis (PBC) has not been studied systematically in the United States. We report the incidence and prevalence of this condition in the general population. We also examined the validity of the Mayo natural history model for PBC among these unselected patients from the community. Methods: The Rochester Epidemiology Project entails a computerized index of diagnoses from the health care encounters of residents of Olmsted County, Minnesota. For potential cases identified using this database, the complete (inpatient and outpatient) medical records were reviewed to verify the diagnosis and extract information necessary for the application of the Mayo model. We estimated the incidence and prevalence of PBC in this population and compared the actual survival of patients with PBC in the community with the survival predicted for PBC patients by the Mayo natural history model. Results: The age-adjusted (to 1990 U.S. whites) incidence of PBC per 100,000 person-years for years 1975–1995 was 4.5 (95% confidence interval [CI], 3.1–5.9) for women, 0.7 (95% CI, 0.1–1.3) for men, and 2.7 (95% CI, 1.9–3.5) overall. The age- and sex-adjusted prevalence per 100,000 persons as of 1995 was 65.4 (95% CI, 43.0–87.9) for women, 12.1 (95% CI, 1.1–23.1) for men, and 40.2 (95% CI, 27.2–53.1) overall. The Mayo natural history model accurately predicted the actual survival of these patients. Conclusions: This first description of the epidemiology of PBC in the United States indicates that its incidence and prevalence in this country are among the highest reported. Outcomes among these unselected patients from a community population further validated the Mayo natural history model of PBC.GASTROENTEROLOGY 2000;119:1631-1636

Tumour necrosis factor-a promoter polymorphisms in primary biliary cirrhosis

Background/aims: The incidence of primary biliary cirrhosis (PBC) is increased in the close relatives of patients, suggesting that genetic factors play a role in disease susceptibility. Decreased in vitro production of tumour necrosis factor (TNF)-α has been reported in PBC patients, suggesting a potential aetiological role for this cytokine. The aim of this study was to examine two biallelic polymorphisms in the promoter region of the TNF-α gene, which may play a role in the control of TNF-α secretion, as candidate susceptibility loci in PBC.Methods: The polymorphisms at positions −238 and −308 in the TNF-α promoter region were analysed by polymerase chain reaction in 168 unrelated PBC patients and 145 local unrelated, geographically matched normal individuals. All PBC subjects were also genotyped for HLA DR8, a previously identified susceptibility locus in PBC.Results: The −308 TNF1/TNF1 genotype was seen in a similar proportion of PBC patients (66%) and controls (60%). However, this genotype was found significantly more frequently in the 95 PBC patients with more advanced disease (histological stage III/IV) (77%) than in either controls (p<0.01, OR=2.2 [1.2–4.0]) or the PBC patients with earlier disease (38/73 (52%), p=0.001 OR 3.1 [1.6–5.9]). Linkage between TNF −308 and HLA DR8 was not seen. No association was found between PBC and the biallelic −238 TNF-α polymorphism, either in the whole PBC population or the histological Stage III/IV subgroup.Conclusions: Our study provides no evidence for involvement of the TNF-α −308 or −238 promoter polymorphisms in genetic predisposition to PBC. However, the significantly increased frequency of the −308 TNF1/TNF1 genotype seen in 95 patients with more advanced disease raises the possibility that this allele may be linked to disease progression rather than susceptibility. The finding of different allele frequencies in PBC patients in different disease subgroups emphasises the importance of clinical phenotype/case-mix in the design of disease association studies.

No evidence for involvement of the interleukin-10 −592 promoter polymorphism in genetic susceptibility to primary biliary cirrhosis

Background/Aims: Primary biliary cirrhosis is a chronic cholestatic liver disease with an autoimmune aetiology. Family studies, which have shown a significantly increased incidence of primary biliary cirrhosis in the close relatives of patients, suggest that genetic factors play a significant role in determining disease susceptibility. Several studies have previously identified loci which appear to play a role in determining this susceptibility, including the MHC class II allele HLA DR8, and the class III encoded C4A null allele (C4AQ0). Here, we have studied another candidate susceptibility locus in primary biliary cirrhosis, an apparently functional biallelic polymorphism at position −592 in the promoter region of the gene encoding the immuno-modulatory cytokine interleukin-10. Interleukin-10 plays an important role in the functional control, in vivo, of autoreactive Th-1 type CD4+ T-cells, with experimental manipulation of interleukin-10 leading to significant modulation of disease development in animal models of autoimmunity. Methods: Interleukin-10 −592 genotypes were studied by polymerase chain reaction in 171 well-characterised, histologically-staged, primary biliary cirrhosis patients and 141 locally matched controls. Results: Of 171 primary biliary cirrhosis patients, 99 were homozygous for the commoner allele (C/C), 68 171 (40%) were heterozygotes (A/C), whilst 4 171 (2%) were homozygous for the rarer allele (A/A). These genotype frequencies were not significantly different from those seen in controls ( p=0.49, odds ratio 1.2 [0.8–1.9]). Conclusions: These findings, in the first study of IL-10 as a candidate locus in a human autoimmune disease, suggest that IL-10 −592 is not a susceptibility locus in primary biliary cirrhosis.

Primary biliary cirrhosis in Estonia. With special reference to incidence, prevalence, clinical features, and outcome.

Primary biliary cirrhosis (PBC) is a liver disease of unknown etiology, whose occurrence varies greatly between different regions. For a long time there have been no published data about the incidence and prevalence of PBC from Eastern Europe countries. The incidence and prevalence of PBC have been investigated in the Estonian population during the period 1973-92. Two sources of information were used: an information circular/questionnaire was sent to all district hospitals and gastroenterologists, and the case histories of all patients with a positive antimitochondrial antibody titer of 1:40 or more were reexamined. During this period 69 cases of PBC were diagnosed. The male to female ratio was 1:22; 13% of the patients were asymptomatic. The mean annual incidence was 2.27 per million, and on 31 December 1992 the point prevalence was 26.9 per million. There were differences in prevalence among the various districts of Estonia. Associated autoimmune conditions were reported in 32% of the patients. Mean survival from the time of diagnosis was 52.5 months. The incidence of PBC in Estonia is at the lower end of the range reported in the world literature. This has probably partly been caused by a low percentage of asymptomatic and male patients.

Incidence and prevalence of primary biliary cirrhosis in a defined population in Sweden.

The incidence and prevalence of antimitochondrial antibody-positive primary biliary cirrhosis (PBC) has been studied within a defined area in Sweden served by one hospital. During the period 1976-1983 the yearly incidence of PBC was 1.4/10(5) inhabitants, and on 31 December 1983 the prevalence was 12.8/10(5) inhabitants. The prevalence is the highest reported so far. At the time of diagnosis half of the patients were clinically asymptomatic. Two of the patients also had celiac disease with osteomalacia responding to a gluten-free diet. Gallstone disease occurred in 30% of the patients. Four patients died--two of liver-related complications, one of colonic carcinoma, and one of staphylococcal septicemia and endocarditis. One further patient, who is still alive, developed hypernephroma. Our results indicate that PBC is a fairly benign disease in most patients, with a slow progress during which they lead a fairly normal life.