Sarcopenia is associated with nonalcoholic fatty liver disease (NAFLD). This study investigated whether sarcopenia is associated with significant liver fibrosis in subjects with NAFLD. Data from the ...Korean National Health and Nutrition Examination Surveys 2008‐2011 database were analyzed. NALFD was defined by NAFLD liver fat score, comprehensive NAFLD score, or hepatic steatosis index. Degree of liver fibrosis was assessed by NAFLD fibrosis score (NFS), FIB‐4, and Forns index. Significant liver fibrosis was defined as FIB‐4 ≥2.67 and the highest quartile values of NFS and Forns index. Sarcopenia index (= total appendicular skeletal muscle mass kg/body mass index (kg/m2) was calculated using dual‐energy X‐ray absorptiometry. Using the NAFLD liver fat score, NAFLD was identified in 2761 (28.5%) of 9676 subjects. Of subjects with NAFLD, sarcopenia was identified in 337 (12.2%). Sarcopenia was significantly associated with significant liver fibrosis assessed in fibrosis prediction models (all P < 0.05). In subgroups stratified according to body mass index and homeostasis model assessment of insulin resistance, a significant association between sarcopenia and significant liver fibrosis by NFS was consistently present (odds ratio = 1.76‐2.68 depending on the subgroup, all P < 0.05). Multivariate logistic regression analysis demonstrated an independent association between SI and significant liver fibrosis by NFS after adjusting for other confounders (odds ratio = 0.52‐0.67, all P < 0.01). Other NAFLD (comprehensive NAFLD score, hepatic steatosis index) and fibrosis prediction models (FIB‐4 and Forns index) produced similar results. Conclusion: Sarcopenia is associated with significant liver fibrosis in subjects with NAFLD, and the association is independent of obesity and insulin resistance. (Hepatology 2016;63:776–786)
The knowledge and understanding of all aspects of liver cancer this including hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA) have experienced a major improvement in the ...last decades. New laboratory technologies have identified several molecular abnormalities that, at the very end, should provide an accurate stratification and optimal treatment of patients diagnosed with liver cancer. The seminal discovery of the
TP53
hotspot mutation
1
,
2
was an initial landmark step for the future classification and treatment decision using conventional clinical criteria blended with molecular data. At the same time, the development of ultrasound, computed tomography (CT) and magnetic resonance (MR) has been instrumental for earlier diagnosis, accurate staging and treatment advances. Several treatment options with proven survival benefit if properly applied are now available. Major highlights include: i) acceptance of liver transplantation for HCC if within the Milan criteria
3
, ii) recognition of ablation as a potentially curative option
4
,
5
, iii) proof of benefit of chemoembolization (TACE),
6
and iv) incorporation of sorafenib as an effective systemic therapy
7
. These options are part of the widely endorsed BCLC staging and treatment model (
Fig. 1
)
8
,
9
. This is clinically useful and it will certainly keep evolving to accommodate new scientific evidence.
This review summarises the data which are the basis for the current recommendations for clinical practice, while simultaneously exposes the areas where more research is needed to fulfil the still unmet needs (
Table 1
).
Several risk prediction models have been created to predict hepatitis B virus (HBV)‐related hepatocellular carcinoma (HCC) occurrence, with promising results. However, their prognostic performances ...need to be validated in the era of antiviral therapy. From 2006 to 2011, patients with chronic HBV infection were recruited and those with a history of HCC or hepatic decompensation were excluded. At enrollment, liver stiffness (LS) was measured using transient elastography. We assessed the performances of conventional HCC prediction models (CU‐HCC, GAG‐HCC, REACH‐B, and LSM‐HCC scores) and the modified REACH‐B (mREACH‐B) score where LS values were incorporated into REACH‐B score instead of serum HBV‐DNA levels. Of 1,308 subjects analyzed, the median age was 50.0 years (883 men). During the follow‐up (median, 75.3 months), HCC developed in 125 (9.6%) patients. mREACH‐B score had the highest areas under the receiver operating characteristic curves (AUROCs) for the prediction of HCC development at 3/5 years (0.828/0.806), compared with LSM‐HCC (0.777/0.759), GAG‐HCC (0.751/0.757), REACH‐B (0.717/0.699), and CU‐HCC (0.698/0.700) scores, respectively, with statistical significances (all P values <0.05 vs. mREACH‐B). When serum HBV‐DNA levels were excluded from the formula for REACH‐B score, AUROCs for HCC development at 3/5 years improved paradoxically (from 0.717/0.699 to 0.757/0.732, respectively). In patients with antiviral therapy (n = 848), mREACH‐B score had the better prognostic performances for HCC development at 3/5 years, compared to other prediction models. However, in patients without antiviral therapy (n = 460), it had the prognostic performances comparable to those of other prediction models. Conclusions: Prognostic performances of mREACH‐B score seemed better compared to conventional models. In the era of antiviral therapy, incorporation of serum HBV‐DNA level should be applied cautiously and individual risks should be assessed effectively based on the fibrotic burden.(Hepatology 2015;62:1757–1766)
Summary Background There is no standard of care for adjuvant therapy for patients with hepatocellular carcinoma. This trial was designed to assess the efficacy and safety of sorafenib versus placebo ...as adjuvant therapy in patients with hepatocellular carcinoma after surgical resection or local ablation. Methods We undertook this phase 3, double-blind, placebo-controlled study of patients with hepatocellular carcinoma with a complete radiological response after surgical resection (n=900) or local ablation (n=214) in 202 sites (hospitals and research centres) in 28 countries. Patients were randomly assigned (1:1) to receive 400 mg oral sorafenib or placebo twice a day, for a maximum of 4 years, according to a block randomisation scheme (block size of four) using an interactive voice-response system. Patients were stratified by curative treatment, geography, Child-Pugh status, and recurrence risk. The primary outcome was recurrence-free survival assessed after database cut-off on Nov 29, 2013. We analysed efficacy in the intention-to-treat population and safety in randomly assigned patients receiving at least one study dose. The final analysis is reported. This study is registered with ClinicalTrials.gov , number NCT00692770. Findings We screened 1602 patients between Aug 15, 2008, and Nov 17, 2010, and randomly assigned 1114 patients. Of 556 patients in the sorafenib group, 553 (>99%) received the study treatment and 471 (85%) terminated treatment. Of 558 patients in the placebo group, 554 (99%) received the study treatment and 447 (80%) terminated treatment. Median duration of treatment and mean daily dose were 12·5 months (IQR 2·6–35·8) and 577 mg per day (SD 212·8) for sorafenib, compared with 22·2 months (8·1–38·8) and 778·0 mg per day (79·8) for placebo. Dose modification was reported for 497 (89%) of 559 patients in the sorafenib group and 206 (38%) of 548 patients in the placebo group. At final analysis, 464 recurrence-free survival events had occurred (270 in the placebo group and 194 in the sorafenib group). Median follow-up for recurrence-free survival was 8·5 months (IQR 2·9–19·5) in the sorafenib group and 8·4 months (2·9–19·8) in the placebo group. We noted no difference in median recurrence-free survival between the two groups (33·3 months in the sorafenib group vs 33·7 months in the placebo group; hazard ratio HR 0·940; 95% CI 0·780–1·134; one-sided p=0·26). The most common grade 3 or 4 adverse events were hand-foot skin reaction (154 28% of 559 patients in the sorafenib group vs four <1% of 548 patients in the placebo group) and diarrhoea (36 6% vs five <1% in the placebo group). Sorafenib-related serious adverse events included hand-foot skin reaction (ten 2%), abnormal hepatic function (four <1%), and fatigue (three <1%). There were four (<1%) drug-related deaths in the sorafenib group and two (<1%) in the placebo group. Interpretation Our data indicate that sorafenib is not an effective intervention in the adjuvant setting for hepatocellular carcinoma following resection or ablation. Funding Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals.
Summary Background Therapy for chronic hepatitis B reduces the risk of progressing to hepatocellular carcinoma (HCC); however, there is no suitable and accurate means to assess risk. This study aimed ...to develop and validate a simple scoring system to predict HCC risk in patients with chronic hepatitis B. Methods The development cohort consisted of 3584 patients without cirrhosis from the community-based Taiwanese REVEAL-HBV study (of whom 131 developed HCC during follow-up), and a validation cohort of 1505 patients from three hospitals in Hong Kong and South Korea (of whom 111 developed HCC during follow-up). We used Cox multivariate proportional hazards model to predict risk of HCC at 3, 5, and 10 years. Variables included in the risk score were sex, age, serum alanine aminotransferase concentration, HBeAg status, and serum HBV DNA level. We calculated the area under receiver operating curve (AUROC) and calibration of predicted and observed HCC risk. Findings A 17-point risk score was developed, with HCC risk ranging from 0·0% to 23·6% at 3 years, 0·0% to 47·4% at 5 years, and 0·0% to 81·6% at 10 years for patients with the lowest and highest HCC risk, respectively. AUROCs to predict risk were 0·811 (95% CI 0·790–0·831) at 3 years, 0·796 (0·775–0·816) at 5 years, and 0·769 (0·747–0·790) at 10 years in the validation cohort, and 0·902 (0·884–0·918), 0·783 (0·759–0·806), and 0·806 (0·783–0·828), respectively, after exclusion of 277 patients in the validation cohort with cirrhosis. Predicted risk was well calibrated with Kaplan-Meier observed HCC risk. Interpretation A simple-to-use risk score that uses baseline clinical variables was developed and validated. The score accurately estimates the risk of developing HCC at 3, 5, and 10 years in patients with chronic hepatitis B. Clinicians can use this score to assess risk of HCC in patients with chronic hepatitis B and subsequently make evidence-based decisions about their clinical management. Funding The Academia Sinica; the National Health Research Institute, Taiwan; and Bristol-Myers Squibb.
Summary
Background
Anti‐viral therapy is not indicated for patients with chronic hepatitis B (CHB) in the immune‐tolerant phase.
Aims
To investigate the cumulative incidence of phase change and ...hepatocellular carcinoma (HCC) and independent predictors for phase change in patients with CHB in immune‐tolerant phase.
Methods
In total, 946 patients in immune‐tolerant phase, defined as hepatitis B e antigen positivity, HBV‐DNA >20 000 IU/mL and alanine aminotransferase (ALT) ≤40 IU/L, between 1989 and 2017 were enrolled from eight institutes.
Results
The mean age of study population (429 men and 517 women) was 36.7 years. The mean ALT and HBV‐DNA levels were 24.6 IU/L and 8.50 log10 IU/mL, respectively. Of the study population, 476 (50.3%) patients remained in immune‐tolerant phase throughout the study period (median: 63.6 months). The cumulative incidence rates of phase change and HCC at 10 years were 70.7% and 1.7%, respectively. Multivariate analyses revealed that HBV‐DNA level >107 IU/mL was associated independently with a reduced risk of phase change (hazard ratio HR = 0.734, P = 0.008), whereas a high ALT level, above the cut‐off recommended in the Korean Association for the Study of the Liver guidelines (34 IU/L for men and 30 IU/L for women), was associated independently with a greater risk of phase change (HR = 1.885, P < 0.001).
Conclusions
The criterion of HBV‐DNA level > 107 IU/mL may be useful to define immune‐tolerant phase. In addition, an extremely low risk of HCC development was observed in patients with CHB in immune‐tolerant phase.
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•The hepatocellular carcinoma risk was not statistically different between the ETV and TDF groups.•The death or liver transplant risk was not statistically different between the 2 ...groups.•These results were consistently reproduced after adjusting for confounding variables.
It is currently unclear which antiviral agent, entecavir (ETV) or tenofovir disoproxil fumarate (TDF), is superior for improving prognosis in patients with chronic hepatitis B (CHB). Here, we assessed the ability of these 2 antivirals to prevent liver-disease progression in treatment-naïve patients with CHB.
From 2012 to 2014, treatment-naïve patients with CHB who received ETV or TDF as a first-line antiviral agent were recruited from 4 academic teaching hospitals. Patients with decompensated cirrhosis or hepatocellular carcinoma (HCC) at enrollment were excluded. Cumulative probabilities of HCC and death or orthotopic liver transplant (OLT) were assessed.
In total, 2,897 patients (1,484 and 1,413 in the ETV and TDF groups, respectively) were recruited. The annual HCC incidence was not statistically different between the ETV and TDF groups (1.92 vs. 1.69 per 100 person-years PY, respectively; adjusted hazard ratio HR 0.975 p = 0.852 by multivariate analysis). Propensity score (PS)-matched and inverse probability of treatment weighting (ITPW) analyses yielded similar patterns of results (HR 1.021 p = 0.884 and 0.998 p = 0.988, respectively). The annual incidence of death or OLT was not statistically different between the ETV and TDF groups (0.52 vs. 0.53 per 100 PY, respectively; adjusted HR 1.202 p = 0.451). PS-matched and ITPW analyses yielded similar patterns of results (HR 1.248 p = 0.385 and 1.239 p = 0.360, respectively). These findings were consistently reproduced in patients with compensated cirrhosis (all p >0.05).
The overall prognosis in terms of HCC and death or OLT was not statistically different between the ETV and TDF groups. Further studies are needed to validate our results.
It is currently unclear which antiviral agent, entecavir or tenofovir disoproxil fumarate, is superior for improving prognosis in patients with chronic hepatitis B virus infection. In this analysis we found that there was no difference in terms of overall prognosis, including risk of hepatocellular carcinoma, death, or the need for a liver transplant, in patients receiving either antiviral.
In a phase 2 trial, lenvatinib, an inhibitor of VEGF receptors 1–3, FGF receptors 1–4, PDGF receptor α, RET, and KIT, showed activity in hepatocellular carcinoma. We aimed to compare overall survival ...in patients treated with lenvatinib versus sorafenib as a first-line treatment for unresectable hepatocellular carcinoma.
This was an open-label, phase 3, multicentre, non-inferiority trial that recruited patients with unresectable hepatocellular carcinoma, who had not received treatment for advanced disease, at 154 sites in 20 countries throughout the Asia-Pacific, European, and North American regions. Patients were randomly assigned (1:1) via an interactive voice–web response system—with region; macroscopic portal vein invasion, extrahepatic spread, or both; Eastern Cooperative Oncology Group performance status; and bodyweight as stratification factors—to receive oral lenvatinib (12 mg/day for bodyweight ≥60 kg or 8 mg/day for bodyweight <60 kg) or sorafenib 400 mg twice-daily in 28-day cycles. The primary endpoint was overall survival, measured from the date of randomisation until the date of death from any cause. The efficacy analysis followed the intention-to-treat principle, and only patients who received treatment were included in the safety analysis. The non-inferiority margin was set at 1·08. The trial is registered with ClinicalTrials.gov, number NCT01761266.
Between March 1, 2013 and July 30, 2015, 1492 patients were recruited. 954 eligible patients were randomly assigned to lenvatinib (n=478) or sorafenib (n=476). Median survival time for lenvatinib of 13·6 months (95% CI 12·1–14·9) was non-inferior to sorafenib (12·3 months, 10·4–13·9; hazard ratio 0·92, 95% CI 0·79–1·06), meeting criteria for non-inferiority. The most common any-grade adverse events were hypertension (201 42%), diarrhoea (184 39%), decreased appetite (162 34%), and decreased weight (147 31%) for lenvatinib, and palmar-plantar erythrodysaesthesia (249 52%), diarrhoea (220 46%), hypertension (144 30%), and decreased appetite (127 27%) for sorafenib.
Lenvatinib was non-inferior to sorafenib in overall survival in untreated advanced hepatocellular carcinoma. The safety and tolerability profiles of lenvatinib were consistent with those previously observed.
Eisai Inc.
Background and Aims
The modified PAGE‐B (mPAGE‐B) score comprising age, gender, platelet count and albumin was recently proposed to predict hepatocellular carcinoma (HCC) risk among chronic hepatitis ...B (CHB) patients undergoing antivirals. Here, in the independent cohort, we externally validated the predictive performance of the mPAGE‐B score and compared it with those of conventional HCC prediction models.
Methods
We consecutively recruited CHB patients treated with lamivudine, entecavir or tenofovir as the first‐line antiviral regimen. Patients with decompensated cirrhosis or HCC at baseline were excluded. Predictive performances of the mPAGE‐B score and other models were assessed with comparison.
Results
Among 1330 patients, 9.6% developed HCC during follow‐up. The mPAGE‐B score provided the highest Harrell's c‐index (0.769), followed by the GAG‐HCC (0.751), PAGE (0.744), REACH‐B (0.686) and CU‐HCC (0.618) scores. The mPAGE‐B score showed the similar performance to the PAGE‐B and GAG‐HCC scores and the better performance than the REACH‐B and CU‐HCC scores. Cumulative HCC probabilities at 5‐ and 7‐years were 0.0% and 0.0% in low‐risk group (mPAGE‐B score ≤ 8), 6.1% and 10.8% in intermediate‐risk group (mPAGE‐B score 9‐12) and 18.7% and 26.7% in high‐risk group (mPAGE‐B score ≥ 13) respectively (both P < 0.001 between adjacent two groups). C‐indices of the mPAGE‐B score were 0.785 and 0.724 among subgroups treated with entecavir or tenofovir (n = 1011) and with lamivudine (n = 319), respectively, which are overall similar to those of the PAGE‐B score.
Conclusion
The mPAGE‐B score showed acceptable predictive performances. Compared to the PAGE‐B score, addition of albumin as a constituent provided the marginal benefit.
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