We would like, however, to highlight some key points. PBC is characterized by a long natural history that is influenced by a number of factors that modulate mortality risk, including: clinical symptoms/signs of liver disease, associated autoimmune conditions, comorbidity with other nonautoimmune-associated conditions (i.e., osteoporosis), and response to ursodeoxycholic acid (UDCA). Table 1 summarizes the 10 most important studies dealing with the incidence of HCC in PBC patients, also reported in Liang et

al.’s review article,[1] for a total of 6,040 PBC patients. Five studies report a relationship between HCC and BMS-907351 clinical trial PBC histological stage; all of them clearly indicate that HCC arises in advanced histological stages. This behavior is most commonly observed in all types of liver disease in Western countries, with viral and nonviral selleck products etiology, with only very few exceptions. These data also confirm our previous observation, i.e., that the relative risk for HCC in female patients with stage IV PBC is similar to that of female patients with cirrhosis of different etiologies.[2] Only a few studies report a statistical analysis of the risk factors associated with

HCC development. The most impressive data regard the association with male gender and the lack of response to UDCA (although these data should be considered with caution). In our opinion it is remarkable that UDCA may favorably influence the natural history of PBC in responders. There are no sufficient elements to consider UDCA as a protective agent toward HCC, however. Screening for HCC with cross-sectional imaging, with or without alpha-fetoprotein at 6-month intervals, should be recommended for PBC patients with much advanced stage disease

(histological stage IV or Mayo prognostic score >4.1), or evidence of portal hypertension. Due to the lack of an evidence-based association with other extrahepatic liver malignancies, cancer screening in PBC patients should not differ from what is indicated in the general population. Having said that, it must be also kept in mind that, overall, PBC-related HCC appears to be a low-impact problem, since in a consecutive series of about 3,000 consecutive cases of HCC diagnosed in Italy and registered in the ITA.LI.CA database, only 10 (0.03%) are diagnosed in PBC patients. ANNAROSA FLOREANI, M.D. “
“The histone H3-lysine-4 methyltransferase mixed-lineage leukemia-3 (MLL3) and its closest homolog MLL4 (aka KMT2D) belong to two homologous transcriptional coactivator complexes, named MLL3- and MLL4-complexes, respectively. We previously reported that MLL3 plays crucial roles in multiple metabolic processes. However, the physiological roles of MLL4 in metabolism and the relationship between MLL3 and MLL4 in metabolic gene regulation remained unclear. To address these issues, we analyzed the phenotypes of newly generated MLL4 mutant mice, along with MLL3 mutant and MLL3;MLL4 compound mutant mice.