Primary Biliary Cirrhosis: Family Stories

Primary biliary cirrhosis (PBC) is a chronic immune-mediated cholestatic liver disease of unknown aetiology which affects mostly women in middle age. Familial PBC is when PBC affects more than one member of the same family, and data suggest that first-degree relatives of PBC patients have an increased risk of developing the disease. Most often, these familial clusters involve mother-daughter pairs, which is consistent with the female preponderance of the disease. These clusters provide evidence towards a genetic basis underlying PBC. However, clusters of nonrelated individuals have also been reported, giving strength to an environmental component. Twin studies have demonstrated a high concordance for PBC in monozygotic twins and a low concordance among dizygotic twins. In conclusion, studies of PBC in families clearly demonstrate that genetic, epigenetic, and environmental factors play a role in the development of the disease

Primary Biliary Cirrhosis Associated with Systemic Sclerosis: Diagnostic and Clinical Challenges

Patients with primary biliary cirrhosis (PBC) often have concurrent limited systemic sclerosis (SSc). Conversely, up to one-fourth of SSc patients are positive for PBC-specific antimitochondrial antibodies (AMA). The mechanisms responsible for the co-occurrence of these diseases are largely unknown. Genetic, epigenetic, environmental, and infectious factors appear to be important for the pathogenesis of the disease, but the hierarchy of events are not well defined. Patients with SSc and PBC have an increased morbidity and mortality compared with the general population, but whether the presence of both diseases in an affected individual worsens the prognosis and/or outcome of either disease is not clear. Some case reports suggested that the presence of SSc in PBC patents is associated with a more favorable prognosis of the liver disease, whereas others report an increased mortality in patients with PBC and SSc compared to patients with PBC alone. This paper discusses the features of patients with PBC-associated SSc. Our aims are to clarify some of the pathogenetic, diagnostic, and clinical challenges that are currently faced in the routine management of these patients. We also intend to provide some practical hints for practitioners that will assist in the early identification of patients with PBC-associated SSc

Sex Differences Associated with Primary Biliary Cirrhosis

Primary biliary cirrhosis (PBC) is a cholestatic liver disease of autoimmune origin, characterised by the destruction of small intrahepatic bile ducts. The disease has an unpredictable clinical course but may progress to fibrosis and cirrhosis. The diagnostic hallmark of PBC is the presence of disease-specific antimitochondrial antibodies (AMA), which are pathognomonic for the development of PBC. The disease overwhelmingly affects females, with some cases of male PBC being reported. The reasons underlying the low incidence of males with PBC are largely unknown. Epidemiological studies estimate that approximately 7–11% of PBC patients are males. There does not appear to be any histological, serological, or biochemical differences between male and female PBC, although the symptomatology may differ, with males being at higher risk of life-threatening complications such as gastrointestinal bleeding and hepatoma. Studies on X chromosome and sex hormones are of interest when studying the low preponderance of PBC in males; however, these studies are far from conclusive. This paper will critically analyze the literature surrounding PBC in males

Epstein-Barr Virus as a Trigger of Autoimmune Liver Diseases

The pathogenesis of autoimmune diseases includes a combination of genetic factors and environmental exposures including infectious agents. Infectious triggers are commonly indicated as being involved in the induction of autoimmune disease, with Epstein-Barr virus (EBV) being implicated in several autoimmune disorders. EBV is appealing in the pathogenesis of autoimmune disease, due to its high prevalence worldwide, its persistency throughout life in the host's B lymphocytes, and its ability to alter the host's immune response and to inhibit apoptosis. However, the evidence in support of EBV in the pathogenesis varies among diseases. Autoimmune liver diseases (AiLDs), including autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC), have a potential causative link with EBV. The data surrounding EBV and AiLD are scarce. The lack of evidence surrounding EBV in AiLD may also be reflective of the rarity of these conditions. EBV infection has also been linked to other autoimmune conditions, which are often found to be concomitant with AiLD. This paper will critically examine the literature surrounding the link between EBV infection and AiLD development. The current evidence is far from being conclusive of the theory of a link between EBV and AiLD

Immunopathogenesis of primary biliary cirrhosis: an old wives' tale

Primary biliary cirrhosis (PBC) is a cholestatic liver disease characterised by the autoimmune destruction of the small intrahepatic bile ducts. The disease has an unpredictable clinical course, but may progress to fibrosis and cirrhosis. Although medical treatment with urseodeoxycholic acid is largely successful, some patients may progress to liver failure requiring liver transplantation. PBC is characterised by the presence of disease specific anti-mitochondrial (AMA) antibodies, which are pathognomonic for PBC development. The disease demonstrates an overwhelming female preponderance and virtually all women with PBC present in middle age. The reasons for this are unknown; however several environmental and immunological factors may be involved. As the immune systems ages, it become less self tolerant, and mounts a weaker response to pathogens, possibly leading to cross reactivity or molecular mimicry. Some individuals display immunological changes which encourage the development of autoimmune disease. Risk factors implicated in PBC include recurrent urinary tract infection in females, as well as an increased prevalence of reproductive complications. These risk factors may work in concert with and possibly even accelerate, immune system ageing, contributing to PBC development. This review will examine the changes that occur in the immune system with ageing, paying particular attention to those changes which contribute to the development of autoimmune disease with increasing age. The review also discusses risk factors which may account for the increased female predominance of PBC, such as recurrent UTI and oestrogens

Diagnostic and clinical significance of Crohn’s disease-specific anti-MZGP2 pancreatic antibodies by a novel ELISA:New anti-MZGP2 ELISA in Crohn’s

The recent identification of the pancreas major zymogen granule membrane glycoprotein 2 (MZGP2) as the major autoantigen of pancreatic autoantibody (PAB) has led to the appreciation of anti-MZGP2 antibodies as specific markers of Crohn’s disease (CrD). We have recently developed new, robust, highly sensitive and specific IgA and IgG anti-MZGP2 antibody ELISAs and assessed their clinical relevance in the largest inflammatory bowel disease (IBD) cohort tested to date for anti-MZGP2 antibodies. In contrast to currently available anti-MZGP2 ELISAs, the new QUANTA Lite® MZGP2 ELISA (INOVA Diagnostics, San Diego, CA) utilizes the eukaryotically-expressed specific isoform 4 of human GP2 UniProtKB: P55259. A total of 832 sera were studied including 617 consecutive IBD patients (323 CrD and 294 UC) under regular follow-up in a tertiary centre, 112 patients with various diseases, and 103 healthy blood donors. The new ELISA’s calculated AUC was 0.5968, 95% CI (0.5552, 0.6383) for IgA anti-MZGP2 [CD vs non-CD (UC plus controls)] and 0.6236, 95% CI (0.5813, 0.6659) for IgG anti-MZGP2. The sensitivity of IgA anti-MZGP2 for CrD in the IBD population was 15% and the specificity was 98% (95, 99), while the sensitivity and specificity of IgG anti-MZGP2 was 27% and 97%. IgA and IgG anti-MZGP2 combined testing led to a sensitivity of 31% and specificity of 96%. Positivity for either ASCA (IgA or IgG) or anti-MZGP2 (IgA or IgG) showed a sensitivity of 75% (70, 80) and specificity of 84% (79, 89). Of clinical relevance, IgA anti- MZGP2 antibodies were more prevalent in patients with early disease onset (Montreal classification A1, p=0.011), while patients with localised colonic disease were less likely to be IgG anti-MZGP2 positive. Anti-MZGP2 positive patients more frequently had extensive disease with ileal involvement and stricture formation. Patients with longer disease duration were more likely to have IgG anti-MZGP2 or IgA ASCA antibodies. In conclusion, the new IgA and IgG anti-MZGP2 antibody ELISAs allow accurate autoantibody determination, and can be used as a tool to study the clinical significance and utility of these autoantibodies in patients with IBD

Hepatic Transcriptome Analysis of Hepatitis C Virus Infection in Chimpanzees Defines Unique Gene Expression Patterns Associated with Viral Clearance

Hepatitis C virus infection leads to a high rate of chronicity. Mechanisms of viral clearance and persistence are still poorly understood. In this study, hepatic gene expression analysis was performed to identify any molecular signature associated with the outcome of hepatitis C virus (HCV) infection in chimpanzees. Acutely HCV-infected chimpanzees with self-limited infection or progression to chronicity were studied. Interferon stimulated genes were induced irrespective of the outcome of infection. Early induction of a set of genes associated with cell proliferation and immune activation was associated with subsequent viral clearance. Specifically, two of the genes: interleukin binding factor 3 (ILF3) and cytotoxic granule-associated RNA binding protein (TIA1), associated with robust T-cell response, were highly induced early in chimpanzees with self-limited infection. Up-regulation of genes associated with CD8+ T cell response was evident only during the clearance phase of the acute self-limited infection. The induction of these genes may represent an initial response of cellular injury and proliferation that successfully translates to a “danger signal” leading to induction of adaptive immunity to control viral infection. This primary difference in hepatic gene expression between self-limited and chronic infections supports the concept that successful activation of HCV-specific T-cell response is critical in clearance of acute HCV infection

Państwo, gospodarka, społeczeństwo w integrującej się Europie TOM 1

Ze wstępu: "III Międzynarodowa Konferencja Naukowa, jaką w pierwszych dniach czerwca 2003 roku zorganizowała Krakowska Szkoła Wyższa, poświęcona była uczczeniu wyjątkowego jubileuszu 500-lecia urodzin jej patrona - Andrzeja Frycza Modrzewskiego. Jednak to nie myśl polityczna tego wielkiego Polaka i reformatora stała się wiodącym tematem konferencji. W centrum zainteresowań znalazły się zagadnienia 0 wiele bardziej aktualne, dotyczące bowiem integracji europejskiej. Problematyka tym bardziej żywotna, gdyż dotykająca bieżącego życia politycznego - zwłaszcza w kontekście referendum akcesyjnego, które odbyło się w równy tydzień po konferencji. Tak więc jej uczestnicy mieli doskonałą okazję do podjęcia interesujących rozważań związanych z perspektywą rozwoju państwa, gospodarki i społeczeństwa w warunkach integracji europejskiej."(...