At diagnosis, many patients are asymptomatic diagnosed at a routine check by an increase in cholestatic liver enzymes. and progression of PBC is usually believed to be a multifactorial process with strong infuences from the patients genetic background and by various environmental factors. The role of innate and adaptive immunity, including cytokines, chemokines, macrophages and the involvement of apoptosis and reactive oxygen species are outlined in detailed. The current pathogenetic aspects are presented and a novel pathogenetic theory unifying the accumulated clinical information with and data is usually formulated. A review of clinical manifestations and immunological and pathological diagnosis was presented. Treatment modalities, including the multiple mechanisms of action of ursodeoxycholate were finally discussed. and data is usually formulated. A review of clinical manifestations and immunological and pathological diagnosis was presented. Treatment modalities, including the multiple mechanisms of action of ursodeoxycholate are discussed. INTRODUCTION Primary biliary cirrhosis (PBC), also known as chronic non-suppurative destructive intrahepatic cholangitis is usually characterized by a gradual destruction of small intrahepatic bile ducts. Addison et al[1] in 1851 published the first report of a patient with obstructive jaundice without evidence of large bile duct abnormalities. Dauphinee et al[2] in 1949 first used the term PBC but it was Ahrens et al[3] in 1950 that reported on a group of Rabbit Polyclonal to Cyclin E1 (phospho-Thr395) older women with progressive jaundice, pruritus, and hepatosplenomegaly. The basic histological description as chronic intrahepatic non-suppurative destructive cholangitis was reported by Rubin et al[4] in 1965. Autoimmune mechanisms have been implicated to explain the disease evolution of a condition which is in fact a member of the wider vanishing bile duct syndrome. Many epitopes and autoantigens have been reported as crucial in the pathophysiology of the disease and T and B cells abnormalities have been described, the exact pathways leading to the destruction of small intrahepatic ductules are mostly speculative. However the underlying pathways leading to liver damage are still under investigation. In this review, we examine epidemiological, pathogenetic and clinical characteristics of PBC. Finally we compile the clinical information and the novel data gathered from and studies that are presented in this review in order to propose a unifying hypothesis for the pathogenesis of this complex disease. EPIDEMIOLOGY There is a large variation of the incidence and prevalence of PBC worldwide (Table ?(Table1).1). Moreover there is a tendency to increase over the years. Thus, studies from the region of Victoria in Australia exhibited that in an earlier population-based survey a prevalence of 19.1 per million was reported[5] while ten years later in the same region a 10-fold higher incidence was reported[6]. In a review of 37 older and more recent published studies the incidence of PBC ranged from 0.7 to 49 per million per year and the prevalence was estimated to range from 6.7 to 402 per million, with a tendency for higher values in the most recent studies[7]. Table 1 Indicative studies and metanalysis reporting incidence and prevalence of primary biliary cirrhosis (was found in fecal samples from 25% of patients with PBC as well as in controls. PDC-E2 from this bacteria has high homology to human PDC-E2, and AMAs in serum samples from patients with PBC have a 1000-fold stronger reaction against 12-O-tetradecanoyl phorbol-13-acetate PDC-E2 than against PDC-E2[56,57]. Based on these clinical studies the group of Gershwin has reported on a mouse model of a liver disease closely resembling human PBC, initially brought on by 12-O-tetradecanoyl phorbol-13-acetate this bacterium[58]. The pathology of liver lesions and the presence of anti-PDC-E2 antibodies were related to the mouse genetic background, the liver persistence of Novosphingobium and the liver infiltration by NKT-cells activated by Novosphingobium glycosphingolipids. The conversation of glycosphingolipids of the Novosphingobium with NKT-cells may be the link between an environmental pathogen and the immune reactions that have been described in PBC. A previously unidentified, contamination with Novosphingobium might also explain the reported redistribution 12-O-tetradecanoyl phorbol-13-acetate of NKT-cells from the blood to the livers of PBC patients and the biliary epithelial expression of CD1d[59,60]. Other infective factors associated with PBC include lipopolysaccharide (LPS), lipoteichoic acid, and and data indicate its.