A genome-wide association screen for primary biliary cirrhosis risk alleles was performed in an Italian cohort. The results from the Italian cohort replicated IL12A and IL12RB associations, and a combined meta-analysis using a Canadian dataset identified newly associated loci at SPIB (P = 7.9 × 10–11, odds ratio (OR) = 1.46), IRF5-TNPO3 (P = 2.8 × 10–10, OR = 1.63) and 17q12-21 (P = 1.7 × 10–10, OR = 1.38).

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery datasets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5×10−8) and used pathway analysis to identify JAK-STAT/IL12/IL27 signaling and cytokine-cytokine pathways, for which relevant therapies exist.

Reports from North America and Northern Europe have suggested that antimitochondrial antibody (AMA) negative primary biliary cirrhosis (PBC) is a distinct chronic cholestatic liver disease with high prevalence of serum non‐organ‐specific autoantibodies other than AMA. To evaluate if such a peculiar serum immunoreactivity is associated with clinically relevant characteristics, we reviewed our experience with 297 Italian patients who have had a clinical and histological diagnosis of PBC and were regularly followed‐up at our Center from June 1974 to June 1994. AMA‐negative and AMA‐positive patients were compared in terms of biochemical and clinical features, and clinical outcome of the disease. At presentation, 30 of 297 patients (10%) tested negative for AMA by indirect immunofluorescence. Six of them tested positive for antimitochondrial M2 antibodies (AMA‐M2) by immunoblotting analysis, therefore, diagnosis of AMA‐negative PBC was made in 24 patients (8%). At the initial visit, AMA‐negative and AMA‐positive patients were similar in terms of biochemical and clinical features. Antinuclear and anti‐smooth‐muscle antibodies (ANA and ASMA) were more frequently positive in the AMA‐negative patients (71% vs. 31%, and 37% vs. 9%; both P = .0002). Incidence of complications of cirrhosis and development of liver failure resulting in death or referral for liver transplantation did not differ significantly between the two populations. In conclusion, data from this historical cohort study suggest that the distinct serological features of AMA‐negative PBC are not associated with substantial differences in the clinical spectrum or course of the disease.

The majority of human autoimmune diseases are characterized by female predominance. Although sex hormone influences have been suggested to explain this phenomenon, the mechanism remains unclear. In contrast to the role of hormones, it has been suggested, based on pilot data in primary biliary cirrhosis, that there is an elevation of monosomy X in autoimmune disease. Using peripheral white blood cells from women with systemic sclerosis (SSc), autoimmune thyroid disease (AITD), or healthy age-matched control women, we studied the presence of monosomy X rates using fluorescence in situ hybridization. We also performed dual-color fluorescence in situ hybridization analysis with a chromosome Y α-satellite probe to determine the presence of the Y chromosome in the monosomic cells. In subsets of patients and controls, we determined X monosomy rates in white blood cell subpopulations. The rates of monosomy X increased with age in all three populations. However, the rate of monosomy X was significantly higher in patients with SSc and AITD when compared with healthy women (6.2 ± 0.3% and 4.3 ± 0.3%, respectively, vs 2.9 ± 0.2% in healthy women, p &lt; 0.0001 in both comparisons). Importantly, X monosomy rate was more frequent in peripheral T and B lymphocytes than in the other blood cell populations, and there was no evidence for the presence of male fetal microchimerism. These data highlight the thesis that chromosome instability is common to women with SSc and AITD and that haploinsufficiency for X-linked genes may be a critical factor for the female predominance of autoimmune diseases.

Although there have been significant advances in understanding the clinical and biochemical features of primary biliary cirrhosis (PBC), there is still a paucity of data on the usefulness of biomarkers as prognostic indicators. This is particularly important at the time of initial diagnosis. Indeed, the widespread use of antimitochondrial antibody testing has led to an earlier diagnosis of asymptomatic PBC and it is difficult to predict which patients will experience a benign versus a rapidly progressive course. To address this issue, we examined a unique population of 127 newly diagnosed patients with PBC during a 15-year period of observation that began in January 1990. Sera from these patients were analyzed for antimitochondrial, antinuclear, and anti-smooth muscle antibodies, and immunoblotting was performed for nuclear pore complex (NPC). The patients were then followed up longitudinally using biochemical liver function tests. No patient was under any medical therapy for PBC at the time of the initial sera collection. Data were analyzed based not only on the clinical features, but also the Mayo score and specific outcome measures, including time to death, need for liver transplantation, and complication free survival. Among patients with early disease, bilirubin increased to >2 mg/dL in the anti-NPC(؉) patients (26% vs. 5%, P ‫؍‬ .019). Anti-NPC antibodies remained stable or slightly increased over the period of observation. In conclusion, anti-NPC identifies patients likely to experience an unfavorable clinical course and more rapid disease progression. (HEPATOLOGY 2006;43:1135-1144