Abstract
Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by arterial or venous thrombosis and obstetric complication in association with the presence of anti-phospholipid antibodies (anti-PL Abs). Anti-PL Abs are directed against complexes of negatively charged phospholipids and plasma proteins (co-factors). According to the recently established criteria, only anticardiolipin antibodies (anti-CL Abs) or lupus anti-coangulant (LA), are considered as laboratory criteria for anti-PL Abs positivity in APS. It seems that co-factors such beta-2-glycoprotein I (β-2-GPI) must be present for the anti-PL Abs to bind to phospholipids in APLS patients. In other chronic inflammatory conditions, such as ulcerative colitis or infectious diseases, anti-CL Abs seem to be of non-pathogenic origin (co-factor independent or non-thrombogenic).The principal immune-mediated liver diseases are autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). ...
Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by arterial or venous thrombosis and obstetric complication in association with the presence of anti-phospholipid antibodies (anti-PL Abs). Anti-PL Abs are directed against complexes of negatively charged phospholipids and plasma proteins (co-factors). According to the recently established criteria, only anticardiolipin antibodies (anti-CL Abs) or lupus anti-coangulant (LA), are considered as laboratory criteria for anti-PL Abs positivity in APS. It seems that co-factors such beta-2-glycoprotein I (β-2-GPI) must be present for the anti-PL Abs to bind to phospholipids in APLS patients. In other chronic inflammatory conditions, such as ulcerative colitis or infectious diseases, anti-CL Abs seem to be of non-pathogenic origin (co-factor independent or non-thrombogenic).The principal immune-mediated liver diseases are autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). AIH is a chronic liver disorder defined as an unresolving, predominantly periportal hepatitis that is usually associated with hypergammaglobulinaemia, tissue autoantibodies, a strong genetic predisposition and in most cases, responsiveness to immunosuppressive therapy. PBC is a chronic, autoimmune, cholestatic liver disease, which predominantly affects middle-aged women and is characterized by destruction of the small intrahepatic bile ducts by chronic, often granulomatous, inflammation. Ninety-five per cent of patients are tested positive for antimitochondrial antibodies. PSC is a chronic cholestatic disorder characterized by inflammation and fibrosis of the intra- and extrahepatic bile ducts. The autoimmune liver diseases (ALD) have been associated with several other autoimmune diseases and/or syndromes. In AIH, these include autoimmune thyroid diseases, ulcerative colitis, autoimmune hemolytic anaemia, Sjogren’s and sicca syndrome, rheumatoid arthritis. Patients with PBC may also have a variety of associated autoimmune features such as sicca syndrome, Raynaud phenomenon, CREST syndrome, autoimmune thyroid diseases, arthritis, renal tubular acidosis, scleroderma, Biermer anaemia. In addition, approximately 70% of patients with PSC have ulcerative colitis while there is a strong association with other autoimmune diseases such as Sjogren syndrome, Riedel’s thyroiditis, Crohn’s disease, systemic lupus erythematosus (SLE), polyositis. However, only a very few case reports on the association between ALD and the presence of antiphospholipid antibodies (anti-PL Abs) and/or antiphospholipid syndrome (APS) have been reported so far. The aims of the present study were:1. To evaluate the prevalence and the clinical significance of IgG and IgM isotype-specific anti-CL Abs in a consecutive series of AIH, PBC and PSC patients and in patients with other hepatic diseases, as well as in healthy control.2. To evaluate whether these antibodies are pathogenic (thrombogenic) or not. In order to address this point, we investigated their co-factor dependency and avidity (low or high resistance of anti-CL Abs binding to dissociating agents such as urea) because co-factor dependency or increased resistance of anti-CL Abs to urea is associated with the occurrence of APS features.3. To evaluate the parameters, that are possibly correlated with the presence of the anti-CL Abs. For this reason, the presence of the anti-CL Abs was associated with certain demographical, epidemiological, clinical, laboratory, histological and virologic characteristics of patients. It was found that a significant proportion of patients with ALD had detectable IgG and/or IgM anti-CL Abs ( 50.8% in AIH, 45% in PBC and 26.8 in PSC patients). In addition the majority of the IgG anti-CL Abs patients were consistently positive in at least two subsequent testings, 6 week apart. Positivity for IgG, IgM or for at least one anti-CL Abs isotype was not associated with sex, alcohol abuse, disease duration, the presence of extrahepatic autoimmune diseases and the reported thrombotic events and foetal losses in the past. Neither positivity nor the titre of other autoantibodies tested or the presence of markers of past HBV or HCV infection were associated with positivity for any isotype of the anti-CL Abs. Among the parameters studied, statistically significant association was found: a) in AIH patients, between the positivity for IgG or for at least one isotype of anti-CL Abs and the presence of cirrhosis, clinically active disease and biochemical activity (increased mean levels of AST and ALT in positive patients); b) in patients with PBC, between the positivity of anti-CL Abs and the presence of cirrhosis, the advanced age, the increase level of bilirubin and the decrease level of albumin and also with poor outcome (as reflected by the increase value of Mayo Risk Score). Furthermore, in the group of PBC patients the presence of anti-CL Abs was associated with lower platelets counts, as well as the presence of thrombocytopenia. We also showed that anti-CL Abs in ALD patients are most likely non pathogenic as demonstrated by the absence of anti-β2 GPI IgG Abs (only 2 patients with AIH, 2 with PBC and 1 with PSC tested positive but all of them without any clinical evidence suggestive of APS). In the contrary, the resistance to dissociation of the IgG anti-CL Abs from the respective antigen, as illustrated by the RA% values, was similar with that observed in APLS patients. This production of high avidity anti-CL Abs in our ALD patients may be of particular interest, raising questions on the possibility of developing APS features during the time course of the disease. In conclusion, our report is the first to demonstrate a significantly higher prevalence of anti-CL Abs in autoimmune liver diseases, especially in AIH and PBC, compared to that found in patients with other liver disorders. From the clinical point of view, in patients with AIH, anti-CL Abs appear to be associated with the clinical activity and the stage of the disease. Furthermore, in patients with PBC the presence of anti-CL Abs seems to be correlated to the presence of thrombocytopenia and more severe disease (advanced age, increase level of bilirubin and decrease level of albumin and increased Mayo Risk Score). These autoantibodies were not correlated with the known APS features and appear to be non-pathogenic. However, the avidity of IgG anti-CL Abs in patients with autoimmune liver diseases was comparable with the reported for APS patients. Taking into account the results mentioned above, as well as the known propensity of ALD to be associated with extrahepatic immune-mediated syndromes, we believe that multicenter prospective studies with long-term follow-up of anti-CL Abs positive patients are needed in order to address definitely whether these autoantibodies have any clinical importance being able to contribute to the progression of disease and the appearance of APS or they are simply an epiphenomenon associated with the endothelial dysfunction and tissue damage.
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