Lindor, Keith D.

Abstract Background: Differences in body fat (BF) distribution in patients with normal body mass index (BMI) with elevated alanine aminotransferase (ALT) remains poorly described. Objective: To determine the relationship between total BF, waist circumference (WC), insulin resistance (IR), and cardiometabolic risk profile in subjects with elevated ALT and normal BMI. Methods: We analyzed cross-sectional data from 4,914 US participants in the third National Health and Nutrition Examination Survey database, who were ≥20 years of age, had normal BMI, and had body composition assessed by bioimpedance. Results: Mean ± SD age was 41.4 ± 0.3 years, and 58% participants were women. BF was 20 ± 0.1% in men and 29.9 ± 0.1% in women. As total BF increased by tertiles, there was a tendency towards a higher prevalence of nonalcoholic fatty liver disease in men (6.1%, 6.5%, 9.5%, P = 0.13), but not in women (8.7%, 8.2%, 10.7%, P = 0.71). As WC increased by tertiles, there was a higher prevalence of elevated ALT in men (2.6%, 8.6%, 6.6%, P < 0.0001), but not in women. As ALT increased, men had significantly higher levels of nonhigh density lipoprotein cholesterol (HDL-C), increased apolipoprotein B, increased IR, and lower levels of C-reactive protein, whereas, women had higher levels of non-HDL-C and increased IR. Conclusion: In subjects with normal BMI, increased WC is associated with a higher prevalence of elevated ALT in men, but not in women. Higher levels of ALT correlated with a poor cardiometabolic risk profile.

Objective Hepatocellular carcinoma (HCC) is an infrequent yet critical event in primary biliary cirrhosis (PBC); however, predictive tools remain ill-defined. Our objective was to identify candidate risk factors for HCC development in patients with PBC. Design Risk factor analysis was performed in over 15 centres from North America and Europe spanning >40 years observation period using Cox proportional hazards assumptions, logistic regression, and Kaplan-Meier estimates. Results Of 4565 patients with PBC 123 developed HCC, yielding an incidence rate (IR) of 3.4 cases/1000 patient-years. HCC was significantly more common in men (p<0.0001), and on univariate analysis factors at PBC diagnosis associated with future HCC development were male sex (unadjusted HR 2.91, p<0.0001), elevated serum aspartate transaminase (HR 1.24, p<0.0001), advanced disease (HR 2.72, p=0.022), thrombocytopenia (HR 1.65, p<0.0001), and hepatic decompensation (HR 9.89, p<0.0001). As such, non-treatment with ursodeoxycholic acid itself was not associated with cancer development; however, 12-month stratification by biochemical non-response (Paris-I criteria) associated significantly with future risk of HCC (HR 4.52, p<0.0001; IR 6.6 vs 1.4, p<0.0001). Non-response predicted future risk in patients with early stage disease (IR 4.7 vs 1.2, p=0.005), advanced disease (HR 2.79, p=0.02; IR 11.2 vs 4.4, p=0.033), and when restricting the analysis to only male patients (HR 4.44, p<0.001; IR 18.2 vs 5.4, p<0.001). On multivariable analysis biochemical non-response remained the most significant factor predictive of future HCC risk (adjusted HR 3.44, p<0.0001). Conclusions This uniquely powered, internationally representative cohort robustly demonstrates that 12-month biochemical non-response is associated with increased future risk of developing HCC in PBC. Such risk stratification is relevant to patient care and development of new therapies.

Primary sclerosing cholangitis (PSC) is a rare, chronic, cholestatic liver disease in which emerging data suggest that oral antibiotics may offer therapeutic effects. We enrolled patients with PSC in a 12-week, open-label pilot study to investigate the efficacy and safety of 550 mg of oral rifaximin twice daily. The primary end point was serum alkaline phosphatase (ALK) at 12 weeks. Secondary end points included (1) serum bilirubin, gamma-glutamyl transpeptidase, and Mayo PSC risk score; (2) fatigue impact scale, chronic liver disease questionnaire, and short form health survey (SF-36) scores; and (3) adverse effects (AEs). Analyses were performed with nonparametric tests. Sixteen patients were enrolled, among whom the median age was 40 years; 13 (81%) were male, 13 had inflammatory bowel disease, and baseline ALK was 342 IU/mL (interquartile range, 275–520 IU/mL). After 12 weeks of treatment, there were no significant changes in ALK (median increase of 0.9% to 345 IU/mL; P = 0.47) or any of the secondary biochemical end points (all P > 0.05). Similarly, there were no significant changes in fatigue impact scale, chronic liver disease questionnaire, or SF-36 scores (all P > 0.05). Three patients withdrew from the study due to AEs; 4 others reported mild AEs but completed the study. In conclusion, although some antibiotics may have promise in treating PSC, oral rifaximin, based on the results herein, seems inefficacious for this indication. Future studies are needed to understand how the antimicrobial spectra and other properties of antibiotics might determine their utility in treating PSC.

Introduction Hepatocellular carcinoma (HCC) is an important but infrequent outcome in primary biliary cirrhosis (PBC). Improved risk evaluation is an important goal for stratified surveillance. Methods Risk-factor analysis of the ‘Global PBC Study Group’ comprising 15 centres across North America and Europe spanning >40-years follow-up was performed using Cox proportional hazards model, logistic regression and Kaplan-Meier estimates (SPSSv21). Results Of 3546 patients with PBC (med. follow-up 8.6 yrs; IQR 4.4–14.1), 131 developed HCC. Excluding those who developed HCC within 12 months of PBC diagnosis (n = 23), median time to HCC was 12.7 yrs (6.9–16.8) and subsequent survival 1.1 yrs. (0.2–2.7). At diagnosis, factors associated with HCC development were male gender (adj. HR: 4.4;1.4–12.2, p = 0.014) and thrombocytopenia (adj. HR: 4.5;1.4–14.8, p = 0.012). Use of ursodeoxycholic acid per-se was not associated with future risk of HCC, but stratification of risk by biochemical response at 12 months was effective by Rotterdam (adj. HR: 8.9;2.1–37.3, P = 0.003), Paris-I (adj. HR: 7.6;2.0–29.0, p = 0.003) or Toronto criteria (HR: 5.6;1.6–18.8, P = 0.006). Five (4.6 vs. 0.2%) and 10-year (13%vs.1.9%) HCC incidence was significantly increased for biochemical non-responders (p = 2.2 × 10 –9 ), and by multivariate analysis non-response remained the only significant risk factor. Conclusion Our uniquely powered cohort allows robust demonstration that 12-month biochemical non-response is associated with an increased risk of developing HCC in PBC. Routine surveillance in those achieving biochemical response is unlikely cost-effective. Disclosure of Interest None Declared.

Primary sclerosing cholangitis (PSC) is an idiopathic, progressive, cholestatic liver disease with considerable morbidity and mortality and no established pharmacotherapy. In addition to the long-recognized association between PSC and inflammatory bowel disease, several lines of preclinical and clinical evidence implicate the microbiota in the etiopathogenesis of PSC. Here we provide a concise review of these data which, taken together, support further investigation of the role of the microbiota and antibiotics in PSC as potential avenues toward elucidating safe and effective pharmacotherapy for patients afflicted by this illness.

Summary Background Emerging data suggest that oral antibiotics may have therapeutic effects in primary sclerosing cholangitis ( PSC ), but published studies are limited. Aims To investigate the safety and efficacy of oral vancomycin and metronidazole in patients with PSC . Methods Thirty‐five patients with PSC were randomised in a double‐blind manner into four groups: vancomycin 125 mg or 250 mg four times/day, or metronidazole 250 mg or 500 mg three times/day for 12 weeks. The primary endpoint was decrease in alkaline phosphatase ( ALK ) at 12 weeks. Secondary end points included serum bilirubin and Mayo PSC risk score; pruritus; and adverse effects ( AE s). Nonparametric tests were used for analysis. Results The primary endpoint was reached in the low‐dose (−43% change in ALK , P = 0.03) and high‐dose (−40%, P = 0.02) vancomycin groups, with two patients in the former experiencing ALK normalisation. Bilirubin decreased significantly in the low‐dose metronidazole group (−20%, P = 0.03) and trended towards significance in the low‐dose vancomycin group (−33%, P = 0.06). Mayo PSC risk score decreased significantly in the low‐dose vancomycin (−0.55, P = 0.02) and low‐dose metronidazole group (−0.16, P = 0.03). Pruritus decreased significantly in the high‐dose metronidazole group (−3.4, P = 0.03). AE s led to medication discontinuation in six patients, four of whom were receiving metronidazole. Conclusions Both vancomycin and metronidazole demonstrated efficacy; however, only patients in the vancomycin groups reached the primary endpoint, and with less adverse effects. Larger, longer‐term studies are needed to further examine the safety and efficacy of antibiotics as a potential treatment for patients with primary sclerosing cholangitis ( clinicaltrials.gov NCT01085760 ).

AbstractThe accuracy of theFramingham risk score (FRS) in identifying patients with nonalcoholic fatty liver disease (NAFLD) at higher 10‐year coronary heart disease (CHD) risk remains unknown. We aimed at evaluating both the baseline probability ofCHDas predicted by theFRSand the actual long‐term occurrence ofCHDinNAFLDpatients. This was a longitudinal study of a community‐based cohort. A total of 309NAFLDpatients were followed up for 11.5 ± 4.1 years (total 3554 person‐years). The overall calculated 10‐yearCHDrisk was significantly higher in theNAFLDcohort than the absoluteCHDrisk predicted by theFRSfor persons of the same age and gender (10.9 ± 9.3% vs. 9.9 ± 5.9%, respectively,P < 0.0001), and higher in men than women (12.6 ± 10.3% vs. 9.6 ± 8.1%, respectively,P = 0.006). New onsetCHDoccurred in 34 patients (11% vs. 10.9% predicted at baseline,P = NS), whereas 279 (89%) patients did not developCHD. Using multivariable analysis, theFRSwas the only variable significantly associated with new onsetCHD(OR = 1.13, 95%CI = 1.05–1.21;P = 0.001). AFRScut‐point of 11 in women, and 6 in men had a sensitivity of 80% and 74%, respectively, and a negative predictive value of 97% and 93% respectively.NAFLDpatients have a higher 10‐yearCHDrisk than the general population of the same age and gender. TheFRSaccurately predicts the higher 10‐yearCHDrisk inNAFLDpatients, and helps identify those patients expected to derive the most benefit from early intervention to preventCHDevents.