However, we could not find the possible major source of heterogeneity by the Galbraith plot and by the meta-regression (Fig. 2 and Table 2). Furthermore, we conducted subgroup meta-analyses by region, case ascertainment, mTOR inhibitor type of effect size, sex, and age. The increased risk did not change significantly in various subgroups, with

the exception of one subgroup for studies with RR as measurement of risk. There was no significant risk increase in this subgroup, which may have to do with the small number of studies (only three studies) with significant heterogeneity (I2 = 52.4%) (Table 2). As shown in Table 3, because of severe heterogeneity (I2 = 79.1%, P < 0.001), a random-effect model was used to evaluate the association of PBC with HCC risk. The pooled RR with 95% CI was 18.80 (95% CI, 10.81-26.79) for PBC patients compared with the general population. In addition, find protocol the Galbraith

plot was performed to analyze the source of heterogeneity; however, we could not find the possible major source of heterogeneity, because it plotted too many studies as the outliers (Fig. 3). Furthermore, a meta-regression including region, case ascertainment, type of effect size, and age was also performed to analyze the source of heterogeneity. The results indicate that only the type of effect size was significantly associated with the heterogeneity (P < 0.1). When conducting subgroup meta-analyses by these factors, PBC still remained significantly associated with an increased risk of HCC in various subgroup analyses with the exception of two, one for the studies in the USA population (pooled RR 23.88, 95%CI, -9.14-56.89), the other for mafosfamide the population-based studies (pooled RR 8.61, 95%CI, -4.18-21.40), which might result from too small number of studies (only three studies for each subgroup) with significant heterogeneity (Table 2). As shown in Table 3, there were nine studies reporting RRs or giving information with which SIRs could be calculated for breast cancer risk; five for kidney cancer risk; five for colon cancer risk; four for stomach cancer risk; three

for pancreatic cancer, lung cancer, non-Hodgkin lymphoma and colorectal cancer risk; and two for esophageal cancer, rectal cancer, uterine cancer, cervical cancer, prostate cancer, bladder cancer, skin melanoma, skin nonmelanoma, Hodgkin disease, and thyroid cancer risk. Because of no significant heterogeneity (all I2 values were <20% and all P values were >0.1), fixed-effect models were conducted to evaluate the association between PBC and various cancer risks, with the exception of stomach cancer and pancreatic cancer. The results indicate that PBC was not with increased risk of breast cancer, kidney cancer, or colon cancer, as well as other malignancies. For breast cancer, we also conducted subgroup analyses by region, case ascertainment, type of effect size, and age.