No abstract

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.

Inherited deficiencies of plasma proteins involved in blood coagulation generally lead to lifelong bleeding disorders, whose severity is inversely proportional to the degree of factor deficiency. Haemophilia A and B, inherited as X-linked recessive traits, are the most common hereditary hemorrhagic disorders caused by a deficiency or dysfunction of blood coagulation factor VIII (FVIII) and factor IX (FIX). Together with von Willebrand's disease, a defect of primary haemostasis, these X-linked disorders include 95% to 97% of all the inherited deficiencies of coagulation factors. The remaining defects, generally transmitted as autosomal recessive traits, are rare with prevalence of the presumably homozygous forms in the general population of 1:500,000 for FVII deficiency and 1 in 2 million for prothrombin (FII) and factor XIII (FXIII) deficiency. Molecular characterization, carrier detection and prenatal diagnosis remain the key steps for the prevention of the birth of children affected by coagulation disorders in developing countries, where patients with these deficiencies rarely live beyond childhood and where management is still largely inadequate. These characterizations are possible by direct or indirect genetic analysis of genes involved in these diseases, and the choice of the strategy depends on the effective available budget and facilities to achieve a large benefit. In countries with more advanced molecular facilities and higher budget resources, the most appropriate choice in general is a direct strategy for mutation detection. However, in countries with limited facilities and low budget resources, carrier detection and prenatal diagnosis are usually performed by linkage analysis with genetic markers. This article reviews the genetic diagnosis of haemophilia, genetics and inhibitor development, genetics of von Willebrand's disease and of rare bleeding disorders.

Combined deficiency of factor V and factor VIII (F5F8D) is caused by mutations in one of 2 genes, either LMAN1 or MCFD2. Here we report the identification of mutations for 11 additional F5F8D families, including 4 novel mutations, 2 in MCFD2 and 2 in LMAN1. We show that a novel MCFD2 missense mutation identified here (D81Y) and 2 previously reported mutations (

Chronic infection with the hepatitis delta virus (HDV) is a risk factor for cirrhosis and hepatocellular carcinoma (HCC), but little is known whether the outcome of hepatitis is predicted by serum markers of HDV and hepatitis B virus (HBV) infection. The aim of the study was to investigate these correlations in 193 patients with chronic HDV infection who had been followed up for a median of 9.5 years (4.8–19.3). HDV-RNA was first measured by qualitative in-house nested RT-PCR and quantified by in-house real-time PCR. HDV RNA levels only appeared significantly associated to HCC (univariate analysis: OR 1.32, 95% CI 1.02–1.71; p = 0.037; multivariate analysis: OR 1.42, 95% CI 1.04–1.95; p = 0.03). In non-cirrhotics at first presentation (n = 105), HDV RNA levels were associated with progression to cirrhosis (univariate analysis: OR = 1.57, 95% CI 1.20–2.05, p<0.001; multivariate analysis: OR = 1.60, 95% CI 1.20–2.12, p = 0.007) and development of HCC (univariate analysis: OR = 1.66, 95% CI 1.04–2.65, p = 0.033; multivariate analysis: OR = 1.88, 95% CI 1.11–3.19, p = 0.019). ROC analysis showed that approximately 600,000 HDV RNA copies/mL was the optimal cut-off value in our cohort of patients for discriminating the development of cirrhosis. High levels of HDV viremia in non-cirrhotic patients are associated with a considerable likelihood of progression to cirrhosis and the development of HCC. Once cirrhosis has developed, the role of HDV replication as a predictor of a negative outcome lessens.

Summary. Inherited deficiencies of plasma proteins involved in blood coagulation generally lead to lifelong bleeding disorders. The severity of these disorders is generally inversely proportional to the degree of factor deficiency. Among all the autosomal recessive rare bleeding disorders, which include afibrinogenaemia, factor (F) II, FV, FV + VIII, FVII, FX, FXI, FXIII, the combined deficiency of coagulation FV and FVIII (F5F8D or FV + FVIII) is exceptional because it is due to mutations in genes encoding proteins involved in the FV and FVIII intracellular transport (LMAN1 and MCFD2) rather than DNA defects in the genes that encode the corresponding coagulation factors. F5F8D is estimated to be extremely rare (1:1.000.000) in the general population, but an increased frequency is observed in regions where consanguineous marriages is practiced. F5F8D is characterized by concomitantly low levels (usually between 5% and 20%) of both FV and FVIII, and is associated with a mild to moderate bleeding tendency. Treatment of bleeding episodes requires a source of both FV and FVIII; replacement of FV is achieved through the use of fresh frozen plasma, and that of FVIII by desmopressin or specific FVIII concentrates, plasma-derived or recombinant FVIII products. We focus here on the clinical, molecular, treatment-related and diagnostic features of F5F8D.

whole-blood-derived PCs and apheresis PCs are stored up to 5 days.

Rare bleeding disorders (RBDs) are inherited deficiencies of coagulation factors as fibrinogen, Factor (F) FII, FV, FVII, combined FV/FVIII, FX, FXI, and FXIII. These disorders have usually a low prevalence in the general population and constitute approximately 3 to 5% of all coagulation disorders. However, in some countries they could have the same prevalence of hemophilia B due to the practice of consanguineous marriage. The clinical picture of RBDs are highly variable and could markedly vary from mild to severe, making either diagnosis and optimal treatment quiet challenging. This review focuses on 1) efforts to establish a bleeding assessment tool adequate to RBDs, 2) the optimal management of patient affected with FXI deficiency and 3) the correlation between clinical severity and laboratory diagnosis for determining the minimum coagulant activity required to prevent bleeding in each RBD.