New Opportunities in the Systemic Treatment of Hepatocellular Carcinoma-Today and Tomorrow.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer. Liver cirrhosis, hepatitis B, hepatitis C, and non-alcoholic fatty liver disease represent major risk factors of HCC. Multiple different treatment options are available, depending on the Barcelona Clinic Liver Cancer (BCLC) algorithm. Systemic treatment is reserved for certain patients in stages B and C, who will not benefit from regional treatment methods. In the last fifteen years, the arsenal of available therapeutics has largely expanded, which improved treatment outcomes. Nevertheless, not all patients respond to these agents and novel combinations and drugs are needed. In this review, we aim to summarize the pathway of trials investigating the safety and efficacy of targeted therapeutics and immunotherapies since the introduction of sorafenib. Furthermore, we discuss the current evidence regarding resistance mechanisms and potential novel targets in the treatment of advanced HCC.

Possible Therapies for Hepatocellular Carcinoma-Preparing for the Modern War with the Insidious Enemy.

Hepatocellular carcinoma (HCC) accounts for 7% of all malignancies and about 90% of all primary liver malignancies, making it the most common type of malignant liver neoplasm [...].

New Options for Systemic Therapies in Intrahepatic Cholangiocarcinoma (iCCA).

Intrahepatic cholangiocarcinoma (iCCA) is a malignant neoplasm of the biliary tract, the incidence of which has increased in recent years. The etiopathogenesis is not fully elucidated, but the greatest association has been shown with inflammatory changes within the biliary tract. Surgical treatment is the main therapeutic modality; however, less than 30% of its are resectable at diagnosis, with the majority of patients requiring systemic treatment. Chemotherapy with capecitabine is the standard adjuvant therapy. For patients with inoperable tumors or metastatic lesions, chemotherapy alone or in combination with immunotherapy (durvalumab, pembrolizumab) is used. There is a need to provide systemic treatment in patients with progression after first-line treatment in good performance status. New therapeutic pathways for the treatment of this tumor type are still being identified with new emerging potential targets such as isocitrate dehydrogenase (IDH), fibroblast growth factor receptor 2 (FGFR2), or BRAF mutation.

Intrahepatic Cholangiocarcinoma-Where Are We Now and Where Are We Going to?

Cholangiocarcinomas (CCAs) are a heterogeneous group of malignancies originating from the biliary tract epithelium [...].

Shadows Behind Using Simple Risk Models in Selection of Hepatocellular Carcinoma Patients for Liver Transplantation.

OBJECTIVE: To assess the potential influence of replacing Milan criteria with simple risk scores on outcomes of hepatocellular carcinoma (HCC) patients undergoing liver transplantation. SUMMARY BACKGROUND DATA: Several risk scores combining morphological and biological features were recently proposed for precise selection of HCC patients for transplantation. METHODS: This retrospective study included 282 HCC liver transplant recipients. Recurrence-free survival (RFS), the primary outcome measure, was evaluated according to Metroticket 2.0 model and French AFP model with Milan criteria serving as benchmark. RESULTS: Patients were well stratified with respect to RFS by Milan criteria, Metroticket 2.0 criteria, and AFP model cut-off ≤2 points (all P < 0.001) with c-statistics of 0.680, 0.695, and 0.681, respectively. Neither Metroticket 2.0 criteria (0.014, Z = 0.023; P = 0.509) nor AFP model (-0.014, Z = -0.021; P = 0.492) provided significant net reclassification improvement. Both patients within the Metroticket 2.0 criteria and AFP model ≤2 points exhibited heterogeneous recurrence risk, dependent upon alpha-fetoprotein (P = 0.026) and tumor number (P = 0.024), respectively. RFS of patients beyond Milan but within Metroticket 2.0 criteria (75.3%) or with AFP model ≤2 points (74.1%) was inferior to that observed for patients within Milan criteria (87.1%; P = 0.067 and P = 0.045, respectively). Corresponding microvascular invasion rates were 37.2% and 50.0%, compared with 13.6% in patients within Milan criteria (both P < 0.001). Moreover, Milan-out status was associated with significantly higher recurrence risk in subgroups within Metroticket 2.0 criteria (P = 0.021) or AFP model ≤2 points (P = 0.014). CONCLUSION: Utilization of simple risk scores for liver transplant eligibility assessment leads to selection of patients at higher risk of posttransplant HCC recurrence.

Prognostic Relevance of a Complete Pathologic Response in Liver Transplantation for Hepatocellular Carcinoma.

BACKGROUND: A complete pathologic response (CPR) after neoadjuvant treatment is reported to be associated with an exceptionally low risk of recurrence after liver transplantation for hepatocellular carcinoma (HCC). This study aimed to evaluate the prognostic role of CPR in liver transplantation for HCC. METHODS: This retrospective cohort study was based on 222 HCC transplant recipients. Incidence of recurrence and survival at 5 years were the primary and secondary outcome measures, respectively. Competing risk analyses were applied to evaluate recurrence incidence and its predictors. Propensity score matching was performed to compare the outcomes for patients after neoadjuvant treatment with and without CPR. RESULTS: Neoadjuvant treatment was performed for 127 patients, 32 of whom achieved CPR (25.2%). Comparison of baseline characteristics showed that the patients with CPR were at lowest baseline recurrence risk, followed by treatment-naïve patients and patients without CPR. Adjusted for potential confounders, CPR did not have any significant effects on tumor recurrence. No significant net reclassification improvement was noted after addition of CPR to existing criteria. Neoadjuvant treatment without CPR was associated with increased risk of recurrence in subgroups within the Milan criteria (p = 0.016), with alpha-fetoprotein concentration (AFP) model not exceeding 2 points (p = 0.021) and within the Warsaw criteria (p = 0.007) compared with treatment-naïve patients who were at risk similar to those with CPR. The 5-year incidences of recurrence in propensity score-matched patients with and without CPR were respectively 14.0% and 15.9% (p = 0.661), with corresponding survival rates of 73.2% and 67.4%, respectively (p = 0.329). CONCLUSIONS: The findings showed that CPR is not independently associated with long-term outcomes after liver transplantation for HCC.

Immunosuppressive treatment with everolimus in patients after liver transplant: 4 years of single-center experience.

INTRODUCTION: Everolimus after liver transplant (LT) has been used to minimize the use of calcineurin inhibitors (CNIs), optimize renal function, and prevent recurre nce of hepatocellular carcinoma (HCC). OBJECTIVES: We aimed to analyze a single­center experience with switching from CNIs to everolimus in immunossupressive treatment of LT recipients. PATIENTS AND METHODS: A total of 108 LT recipients (men, 65.7%; mean [SD] age, 53.2 [11.1] years) were prospectively enrolled into the study. In all patients, everolimus and CNIs were introduced (target trough levels of 3 to 6 ng/ml and 3 to 5 ng/ml, respectively). After 3 months, CNIs were discontinued in patients who tolerated everolimus well, while everolimus dosage was increased (blood trough levels, 6-12 ng/ml). RESULTS: Everolimus monotherapy was introduced in 32 patients (29.6%), while a combination therapy with everolimus and CNIs was continued in 76 patients (70.4%). However, during a mean follow­up of 27 months (range, 4-50 months), everolimus was withdrawn in 25 patients (33%) due to side effects. In the everolimus­monotherapy group, all patients continued the therapy (P <0.005), but dyslipidemia was more frequent than in patients receiving everolimus and CNIs (40.6% vs 14.5%; P <0.03). Creatinine levels improved significantly in both groups: combination therapy, from 1.58 mg/dl to 1.24 mg/dl after 3 months, and everolimus monotherapy, from 1.19 mg/dl to more than 1 mg/dl. Renal function in the everolimus group was better than in the combination-therapy group (P <0.04). Recurrence of HCC was observed in both groups: combination therapy (9/46 [19.6%]) and everolimus monotherapy (1/17 [5.9%]; P <0.01). CONCLUSIONS: This study showed that switching from CNIs to everolimus after LT allowed a safe weaning of CNIs and an improvement in creatinine levels. In patients on everolimus monotherapy, we observed dyslipidemia as a dose­dependent side effect of the drug as well as a lower risk of HCC recurrence.

Extremes of Liver Transplantation for Hepatocellular Carcinoma.

The aim of this retrospective observational study was to evaluate outcomes of patients with extremely advanced hepatocellular carcinoma (HCC) after liver transplantation. A total of 285 HCC patients after liver transplantation were screened for eligibility based on either intrahepatic dissemination (≥10 tumors) or macrovascular invasion. Tumor recurrence was the primary end-point. The study cohort comprised 26 patients. Median recurrence-free survival was 23.2 months with hepatitis B virus (HBV) infection (p = 0.038), higher AFP model score (p = 0.001), prolonged graft ischemia (p = 0.004), and younger donor age (p = 0.016) being significant risk factors. Median recurrence-free survival of HBV-negative and HBV-positive patients was 29.8 and 9.3 months, respectively (p = 0.053). In patients with macrovascular invasion, recurrence-free survival at 3 years was 46.3% with no specific predictors. Tumor size (p = 0.044), higher AFP model score (p = 0.019), prolonged graft ischemia (p = 0.016), and younger donor age (p = 0.041) were significant risk factors in patients with intrahepatic dissemination. Superior 3-year outcomes were observed in patients with intrahepatic dissemination and tumor size <3.5 cm (83.3%, p = 0.027) and HBV-negative patients with ischemia <9.7 h (85.7%, p = 0.028). In conclusion, patients with extremely advanced HCCs are remarkably heterogeneous with respect to their profile of tumor recurrence risk. This heterogeneity is largely driven by factors other than standard predictors of post-transplant HCC recurrence.

Successful Hepatoatrial Anastomosis During a Consecutive Liver Retransplant in the Same Patient Shows Good Long-Term Results: Case Report and 2-Year Follow-Up.

Liver retransplant is the last and only treatment for patients with irreversible graft failure. It is recognized as a high-risk procedure; thus surgical difficulties are multiplied with every successive liver transplant. Liver retransplant is a demanding technical procedure for the surgeon, with no guarantee of postoperative and long-term survival. Here, we report a 29-year-old male patient who underwent a liver transplant in April 2009 due to primary sclerosing cholangitis with overlapping autoimmune hepatitis. The patient underwent liver retransplant in May 2012 due to graft failure. A second liver retransplant was performed in April 2013 using the classical technique. An inflammatory process involving the inferior vena cava and diaphragm forced the surgeon to open the pericardium from the diaphragm and clamp the cuff of the right atrium to perform a hepatoatrial anastomosis of the inferior vena cava. The next steps were performed as for a typical liver transplant. Postoperative stay was free of complications and was not prolonged. Immunosuppression regimen was kept standard. During our follow-up of more than 32 months, the patient continued to show good results. A consecutive hepatectomy in the same recipient is associated with an increased risk of intraoperative complications. When excessive adhesions limit a safe and functioning cavocaval anastomosis, a hepatectomy with the excision of the intrahepatic inferior vena cava and end-to-end anastomosis through a pericardial window for the extension of the recipient's' vena cava cuff are feasible options. We found that a hepatoatrial anastomosis does not impair good overall outcomes and long-term results.

Ischemia-reperfusion injury and the risk of hepatocellular carcinoma recurrence after deceased donor liver transplantation.

This study aimed to evaluate the effects of ischemia-reperfusion injury (IRI) on the risk of hepatocellular carcinoma (HCC) recurrence after liver transplantation. Data of 195 patients were retrospectively analysed. Post-reperfusion aspartate (AST), alanine transaminase, and lactate dehydrogenase (LDH) levels were the primary measures of IRI. Tumour recurrence was the primary endpoint. Post-reperfusion AST was a continuous risk factor for tumour recurrence in patients within Milan criteria (p = 0.035), with an optimal cut-off of 1896 U/L. Recurrence-free survival of patients within Milan criteria and post-reperfusion AST of <1896 and ≥1896 U/L was 96.6% and 71.9% at 5 and 3.7 years, respectively (p = 0.006). Additionally, post-reperfusion AST and LDH exceeding the upper quartile significantly increased the risk of HCC recurrence in patients within Milan criteria (p = 0.039, hazard ratio [HR] = 5.99 and p = 0.040, HR = 6.08, respectively) and to a lesser extent, in patients within Up-to-7 criteria (p = 0.028, HR = 3.58 and p = 0.039, HR = 3.33, respectively). No other significant IRI effects were found in patients beyond the Up-to-7 criteria and in analyses stratified for independent risk factors for recurrence: tumour number and differentiation, alpha-fetoprotein, and microvascular invasion. Thus, IRI exerts major negative effects on the risk of HCC recurrence after liver transplantation in patients within standard and extended criteria.

Challenging the principle of utility as a barrier for wider use of liver transplantation for hepatocellular cancer.

BACKGROUND: Although transplant benefit appears superior for patients with advanced hepatocellular cancer (HCC), liver transplantation remains limited to selected low-risk HCC patients to keep their outcomes similar to heterogeneous group of non-HCC patients. The purpose of this study was to assess the rationale for current policy of restricting access to liver transplantation to minority of HCC patients based on utility principle. METHODS: This retrospective cohort study comprised 1246 liver transplant recipients, including 206 HCC and 1040 non-HCC patients. Patient survival was the primary outcome measure. Patients with HCC and benign diseases were divided into low-, moderate-, and high-risk subgroups basing on independent risk factors for disease-free survival and model for end-stage liver disease (MELD) score (<30, 30-40, >40), respectively. RESULTS: MELD (p < 0.001) and presence of HCC (p = 0.008) were independent risk factors for early and late mortality, respectively. Total tumor volume (p = 0.008) and alpha-fetoprotein (p = 0.013) were independent predictors of recurrence and mortality used for division of HCC patients into low-, moderate-, and high-risk subgroups, with disease-free survival rates of 74.9% (5 years), 51.7% (5 years), and 8.0% (3 years), respectively (p < 0.001). There were no differences in 5-year overall survival between low-risk HCC (74.9%) and non-HCC (81.9%) patients (p = 0.210), moderate-risk HCC (63.3%) and non-HCC (68.0%) patients (p = 0.372), and high-risk HCC (55.0%) and non-HCC (56.0%) patients (p = 0.559). CONCLUSIONS: The principle of utility is unequally applied for restriction of access to liver transplantation for HCC patients. The results provide rationale for discussion on reinitiation of liver transplantation for advanced HCCs.

Effects of continuous use of probiotics before liver transplantation: A randomized, double-blind, placebo-controlled trial.

BACKGROUND & AIMS: Although there is increasing evidence for the benefits of probiotics in patients with liver diseases, data on the benefits of pre-LT administration of probiotics are lacking. The aim of this study was to evaluate the effects of continuous administration of probiotics before liver transplantation (LT) on pre- and post-transplant patient outcomes. METHODS: In this randomized, double-blind, and placebo-controlled trial adult cirrhotic patients listed for LT received a 4-strain probiotic preparation or placebo daily from enrollment until LT. The primary outcome measures were postoperative mortality and infection rates. The secondary outcome measures were 5-day post-transplant aspartate and alanine aminotransferase activities, bilirubin concentration, and international normalized ratio; waiting-list mortality; pre-transplant Model for End-stage Liver Disease score and Child-Turcotte-Pugh class changes; and pre-transplant infections. RESULTS: A total of 55 patients were randomized. The 90-day postoperative mortality rates were 0% and 4.3% in the probiotic and placebo groups, respectively (p > 0.99). Patients receiving probiotics had significantly reduced 30-day (4.8% versus 34.8%, p = 0.02) and 90-day (4.8% versus 47.8%, p = 0.002) infection rates, lower post-LT bilirubin concentration (p = 0.02), and more rapid decrease of aspartate (p = 0.03) and alanine (p = 0.03) aminotransferase activities. Probiotics did not have significant effects on other secondary outcome measures. CONCLUSIONS: Although continuous administration of probiotics before LT does not appear to affect postoperative mortality, it effectively prevents postoperative infections and improves early biochemical parameters of allograft function. CLINICALTRIALS. GOV IDENTIFIER: NCT01735591.

A novel approach to genome-wide association analysis identifies genetic associations with primary biliary cholangitis and primary sclerosing cholangitis in Polish patients.

BACKGROUND: Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are forms of hepatic autoimmunity, and risk for both diseases has a strong genetic component. This study aimed to define the genetic architecture of PBC and PSC within the Polish population. METHODS: Subjects were 443 women with PBC, 120 patients with PSC, and 934 healthy controls recruited from Gastroenterology Departments in various Polish hospitals. Allelotyping employed a pooled-DNA sample-based genome-wide association study (GWAS) approach, using Illumina Human Omni2.5-Exome BeadChips and the following novel selection criteria for risk loci: blocks of at least 10 single nucleotide polymorphisms (SNPs) in strong linkage disequilibrium, where the distance between each adjacent SNP pair in the block was less than 30 kb, and each SNP was associated with disease at a significance level of P < 0.005. A selected index SNP from each block was validated using TaqMan SNP genotyping assays. RESULTS: Nineteen and twenty-one SNPs were verified as associated with PBC and PSC, respectively, by individual genotyping; 19 (10/9, PBC/PSC) SNPs reached a stringent (corrected) significance threshold and a further 21 (9/12, PBC/PSC) reached a nominal level of significance (P < 0.05 with odds ratio (OR) > 1.2 or < 0.83), providing suggestive evidence of association. The SNPs mapped to seven (1p31.3, 3q13, 6p21, 7q32.1, 11q23.3, 17q12, 19q13.33) and one (6p21) chromosome region previously associated with PBC and PSC, respectively. The SNP, rs35730843, mapping to the POLR2G gene promoter (P = 1.2 × 10-5, OR = 0.39) demonstrated the highest effect size, and was protective for PBC, whereas for PSC respective SNPs were: rs13191240 in the intron of ADGRB3 gene (P = 0.0095, OR = 0.2) and rs3822659 (P = 0.0051, OR = 0.236) along with rs9686714 (P = 0.00077, OR = 0.2), both located in the WWC1 gene. CONCLUSIONS: Our cost-effective GWAS approach followed by individual genotyping confirmed several previously identified associations and discovered new susceptibility loci associated with PBC and/or PSC in Polish patients. However, further functional studies are warranted to understand the roles of these newly identified variants in the development of the two disorders.

Limitations of predicting microvascular invasion in patients with hepatocellular cancer prior to liver transplantation.

Microvascular invasion (MVI) is well known to negatively influence outcomes following surgical treatment of hepatocellular cancer (HCC) patients. The aim of this study was to evaluate the rationale for prediction of MVI before liver transplantation (LT). Data of 200 HCC patients after LT were subject to retrospective analysis. MVI was present in 57 patients (28.5%). Tumor number (p = 0.001) and size (p = 0.009), and alpha-fetoprotein (p = 0.049) were independent predictors of MVI used to create a prediction model, defined as: 0.293x(tumor number) + 0.283x(tumor size in cm) + 0.164xloge(alpha-fetoprotein in ng/ml) (c statistic = 0.743). The established cut-off (≥2.24) was associated with sensitivity and specificity of 72%. MVI was not an independent risk factor for recurrence (p = 0.307), in contrast to tumor number (p = 0.047) and size (p < 0.001), alpha-fetoprotein (p < 0.001) and poor differentiation (p = 0.039). Recurrence-free survival at 5 years for patients without MVI was 85.9% as compared to 83.3% (p = 0.546) and 55.3% (p = 0.001) for patients with false negative and true positive prediction of MVI, respectively. The use of both morphological and biological tumor features enables effective pre-transplant prediction of high-risk MVI. Provided that these parameters are combined in selection of HCC patients for LT, pre-transplant identification of all patients with MVI does not appear necessary.

Plasmapheresis exerts a long-lasting antipruritic effect in severe cholestatic itch.

BACKGROUND & AIMS: The amelioration of refractory cholestatic pruritus after plasmapheresis has been reported in single patients. Here, we analyse the efficacy of plasmapheresis in a cohort of patients with primary biliary cholangitis (PBC). METHODS: Seventeen consecutive patients with PBC (age range 39-85 years, 16 females, 9 with cirrhosis) and refractory pruritus underwent 129 plasmapheresis procedures during 40 admissions. Pruritus was quantified by the 10-point numeric rating scale (NRS) before and after plasmapheresis, as well as ~30 and ~90 days later. RESULTS: The mean pruritus before plasmapheresis did not differ between patients with and without cirrhosis (P>.05). Cirrhotics presented, however, with significantly higher serum alanine aminotransferase (ALT), aspartate transaminase (AST), gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP) and bilirubin before plasmapheresis. Plasmapheresis decreased itching to NRS≤5 in all but five admissions: Mean pruritus decreased from 8.3±1.4 to 3.1±2.2 (P<.0001) in the entire cohort. It also led to a significant decrease in serum ALT, ALP, AST, GGT (all P<.001) and bilirubin (P=.002). Antipruritic effect persisted throughout the 90-days follow-up (P<.0001). The amelioration of pruritus was not affected by the presence of cirrhosis. CONCLUSIONS: Plasmapheresis is a promising method for reducing intractable itch in a significant proportion of PBC patients regardless of liver fibrosis. Long-lasting improvement of symptoms requires repeated procedures.

Evolution Of The Results Of 1500 Liver Transplantations Performed In The Department Of General, Transplant And Liver Surgery Medical University Of Warsaw.

UNLABELLED: Liver transplantation is a well-established treatment of patients with end-stage liver disease and selected liver tumors. Remarkable progress has been made over the last years concerning nearly all of its aspects. The aim of this study was to evaluate the evolution of long-term outcomes after liver transplantations performed in the Department of General, Transplant and Liver Surgery (Medical University of Warsaw). MATERIAL AND METHODS: Data of 1500 liver transplantations performed between 1989 and 2014 were retrospectively analyzed. Transplantations were divided into 3 groups: group 1 including first 500 operations, group 2 including subsequent 500, and group 3 comprising the most recent 500. Five year overall and graft survival were set as outcome measures. RESULTS: Increased number of transplantations performed at the site was associated with increased age of the recipients (p<0.001) and donors (p<0.001), increased rate of male recipients (p<0.001), and increased rate of piggyback operations (p<0.001), and decreased MELD (p<0.001), as well as decreased blood (p=0.006) and plasma (p<0.001) transfusions. Overall survival was 71.6% at 5 years in group 1, 74.5% at 5 years in group 2, and 85% at 2.9 years in group 3 (p=0.008). Improvement of overall survival was particularly observed for primary transplantations (p=0.004). Increased graft survival rates did not reach the level of significance (p=0.136). CONCLUSIONS: Long-term outcomes after liver transplantations performed in the Department of General, Transplant and Liver Surgery are comparable to those achieved in the largest transplant centers worldwide and are continuously improving despite increasing recipient age and wider utilization of organs procured from older donors.

NOD2/CARD15 mutations in Polish and Bosnian populations with and without Crohn's disease: prevalence and genotype-phenotype analysis.

Data on prevalence and phenotypic consequences of nucleotide-binding oligomerisation domain 2/caspase recruitment domains 15 (NOD2/CARD15) variants in Crohn's disease (CD) population in Poland and Bosnia and Herzegovina (B&H) are nonexistent. We aimed to determine the prevalence of NOD2/CARD15 mutations and their association with disease phenotype in Polish and Bosnian patients with CD and in healthy controls. We prospectively recruited 86 CD patients and 83 controls in Poland and 30 CD patients and 30 controls in B&H, 229 in total. We determined the prevalence of NOD2/CARD15 mutations and their association with the disease phenotype according to Montreal classification. Participants were genotyped for Leu1007fsinsC and Gly908Arg mutations. At least one CD-associated allele was found in 29/86 (33.7%) of Polish CD patients and in 9/83 (10.8%) of healthy controls (p<0.001). In both CD patients and controls in Bosnian sample, at least one NOD2 mutation was found in equal number of patients (3/30; 10%) with all of the NOD2 mutation positive CD patients being homozygous, while controls being heterozygous. In Polish sample, perianal disease was less frequent in CD patients with any NOD2 mutation (1/21; 4.8%) compared to those without (11/41; 26.8%; p=0.046). Higher percentage of patients with NOD2 mutations had history of CD related surgery when compared with those without mutations (66.7% vs. 43.3%; p=0.05). The risk for CD is increased in patients with NOD2 mutations (Poland) and especially in the presence of homozygous NOD2 mutations (Poland and Bosnia). The presence of variant NOD2 alleles is associated with increased need for surgery and reduced occurrence of perianal disease.

TRAF1 gene polymorphism correlates with the titre of Gp210 antibody in patients with primary biliary cirrhosis.

BACKGROUND: Polymorphisms of TRAF1 (Tumor necrosis factor receptor-associated factor 1) are associated with rheumatoid arthritis (RA). Whether TRAF1 polymorphisms confer increased risk for primary biliary cirrhosis (PBC), an autoimmune liver disease which can co-exist with RA, is unknown. AIM OF THE STUDY: To assess the frequency of the RA-conferring susceptibility TRAF1 polymorphisms rs3761847 and rs2900180 in a cohort of PBC patients. The association of TRAF1 polymorphisms with clinical features and autoantibody markers was also analyzed. METHODS: We studied 179 PBC patients and 300 controls. Samples were genotyped for TRAF1 gene polymorphisms by real-time PCR. Autoantibodies were tested by ELISA. RESULTS: The frequency of rs3761847 and rs2900180 polymorphisms did not differ between patients and controls. Laboratory or clinical features were not associated with specific polymorphisms. Gp210 autoantibody titres were conspicuously higher among GG homozygotes of rs3761847 as compared with AA homozygotes (P = 0.02). In contrast, antichromatin titers were higher in AA compared to GG rs3761847 homozygotes (P = 0.04). Rheumatoid factor IgG titres were significantly higher in rs2900180 TT homozygotes than CC homozygotes (P = 0.02). CONCLUSIONS: TRAF1 polymorphisms occur with the similar frequency in PBC patients and in the general population, but their presence is probably involved in the regulation of specific PBC-related autoantibodies.