Cirrhosis is a milieu that develops hepatocellular carcinoma (HCC), the second most lethal cancer worldwide. HCC prediction and prevention in cirrhosis are key unmet medical needs. Here we have ...established an HCC risk gene signature applicable to all major HCC etiologies: hepatitis B/C, alcohol, and non-alcoholic steatohepatitis. A transcriptome meta-analysis of >500 human cirrhotics revealed global regulatory gene modules driving HCC risk and the lysophosphatidic acid pathway as a central chemoprevention target. Pharmacological inhibition of the pathway in vivo reduced tumors and reversed the gene signature, which was verified in organotypic ex vivo culture of patient-derived fibrotic liver tissues. These results demonstrate the utility of clinical organ transcriptome to enable a strategy, namely, reverse-engineering precision cancer prevention.
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•Clinically applicable pan-etiology HCC risk biomarker was established•Global transcriptome map of cirrhosis identified HCC chemoprevention targets•Global transcriptome map of cirrhosis identified clinically relevant animal models•LPA pathway inhibitors were verified as HCC chemopreventive and anti-fibrotic drugs
Nakagawa et al. establish a hepatocellular carcinoma (HCC) risk gene signature applicable to all major HCC etiologies and identify the lysophosphatidic acid pathway as a central chemoprevention target, pharmacological inhibition of which reduces tumors and reverses the gene signature in preclinical models.
Large cohort studies have disclosed the association between obesity and rheumatoid arthritis (RA) risk. The sarcopenia prevalence in RA patients can be up to 31%. However, there is little information ...linking adipokines to sarcopenia in RA, so this study aimed to investigate whether adipokines were indeed involved in secondary sarcopenia in RA with a focus on non‐obese females. Sixty‐four female patients and 36 controls were included in this study. The serum adipokine levels (leptin and adiponectin) were determined by ELISA kits. The impacts of adipokines on muscle atrophy and potential autophagy were examined in mouse myoblasts, C2C12, upon treatment with recombinant leptin and adiponectin agonist (AdipoRan). Interestingly, serum adiponectin was significantly increased but the ratio of leptin/adiponectin was dramatically decreased in the RA patients with sarcopenia. After normalization by body mass, serum leptin was positively associated but adiponectin was negatively associated with muscle mass respectively, even after adjustment for fat mass. Treating C2C12 cells with leptin and AdipoRan inhibited proliferation of mature myotube respectively, as did treatment with the serum from RA patients. A combination of low leptin and high AdipoRan greatly decreased myogenin, but instead increased MAFbx and MuRF‐1 as well as increased Beclin 1, Atg5, and LC3β. Taken together, our study reveals that secondary sarcopenia of RA females may be an imbalance of RA‐related, but not obesity‐related, increase in adipokine production; additionally, the reduced leptin/adiponectin ratio could be a better indicator in monitoring sarcopenia in non‐obese RA females. Moreover, adipokine imbalance may promote muscle atrophy through inducing autophagy.
Abstract Background and Aim Among low viral load (DNA of hepatitis B virus (HBV) was < 2000 IU/mL), the factor of the loss of hepatitis B surface antigen (HBsAg) remained elusive. Methods The ...retrospective study recruited patients with chronic hepatitis B (CHB) who were negative low for hepatitis B e‐antigen (HBeAg), had a low viral load, and experienced HBsAg loss during follow‐up. CHB patients with low‐viral load but without consequent HBsAg loss were also enrolled at the ratio of 1:4. The factors contributing to HBsAg loss were analyzed. Results A total of 80 patients were recruited for the current study, with a mean age of 63.9 years and 61.3% being male. Among them, 62.5% patients (50/80) were treated with potent nucleoside/nucleotide analogues (NAs) during the follow‐up period. Additionally, 12.5% patients (10/80) had a prior history of NAs treatment before enrolment. During the follow‐up, HBsAg loss occurred in 17 patients (21.3%). Compared with patients without HBsAg loss, those with HBsAg loss were younger (57.9 years vs 65.5 years; P = 0.01), had lower HBV DNA levels (1.3 log 10 IU/mL vs 2.3 log 10 IU/mL; P = 0.003), and higher proportion of prior NAs‐treated history. Logistic regression analysis revealed that the factors associated with factors associated with HBsAg loss were age < 60 years (OR/CI: 3.95/1.15–13.60, P = 0.03), prior NAs‐treated history (OR/CI: 7.59/1.42–40.51, P = 0.01) and current NAs‐treated (OR/CI: 0.19/0.05–0.71, P = 0.01). Conclusions In the study, older age and prior NAs were positively associated with HBsAg loss, and current NAs was negatively associated with HBsAg loss. Additionally, some patients experienced HBsAg loss during the NAs therapy.
ObjectiveHCV prevails in uremic haemodialysis patients. The current study aimed to achieve HCV microelimination in haemodialysis centres through a comprehensive outreach programme.DesignThe ERASE-C ...Campaign is an outreach programme for the screening, diagnosis and group treatment of HCV encompassing 2323 uremic patients and 353 medical staff members from 18 haemodialysis centres. HCV-viremic subjects were linked to care for directly acting antiviral therapy or received on-site sofosbuvir/velpatasvir therapy. The objectives were HCV microelimination (>80% reduction of the HCV-viremic rate 24 weeks after the end of the campaign in centres with ≥90% of the HCV-viremic patients treated) and ‘No-C HD’ (no HCV-viremic subjects at the end of follow-up).ResultsAt the preinterventional screening, 178 (7.7%) uremic patients and 2 (0.6%) staff members were HCV-viremic. Among them, 146 (83.9%) uremic patients received anti-HCV therapy (41 link-to-care; 105 on-site sofosbuvir/velpatasvir). The rates of sustained virological response (SVR12, undetectable HCV RNA 12 weeks after the end of treatment) in the full analysis set and per-protocol population were 89.5% (94/105) and 100% (86/86), respectively, in the on-site treatment group, which were comparable with the rates of 92.7% (38/41) and 100% (38/38), respectively, in the link-to-care group. Eventually, the HCV-viremic rate decreased to 0.9% (18/1,953), yielding an 88.3% reduction from baseline. HCV microelimination and ‘No-C HD’ were achieved in 92.3% (12/13) and 38.9% (7/18) of the haemodialysis centres, respectively.ConclusionOutreach strategies with mass screenings and on-site group treatment greatly facilitated HCV microelimination in the haemodialysis population.ClinicalTrials.gov identifier NCT03803410 and NCT03891550
Background and Aim
The prevalence of metabolic dysfunction‐associated fatty liver disease (MAFLD) and its interplay with hepatitis B virus (HBV) and hepatitis C virus (HCV) in terms of liver disease ...severity is elusive.
Methods
A mass surveillance program was conducted in a viral hepatitis endemic area. The objective was to identify MAFLD/non‐MAFLD subjects with advanced liver disease.
Results
Two thousand two hundred and forty‐two (41.7%) of the 5378 subjects were identified as having MAFLD, and 375 (7.0%) had advanced liver disease. The proportions of anti‐HCV and HBsAg seropositivity were 19.3% and 9.7%, respectively. The proportions of advanced fibrosis in subjects with non‐viral hepatitis (NBNC), HBV and HCV infection were 2.8%, 5.7% and 23.4%, respectively. Subjects with MAFLD had a significantly higher proportion of advanced fibrosis (8.7% vs 5.7%, P < 0.001). Factors associated with advanced fibrosis included age (odds ratio OR/95% confidence interval CI: 4.8/3.7–6.0, P < 0.001), male sex (OR/CI: 1.3/1.0–1.7, P = 0.019), anti‐HCV seropositivity (OR/CI: 5.9/4.6–7.5, P = 0.019), MAFLD‐lean metabolic dysregulation (MS) (OR/CI: 2.6/1.3–5.2, P = 0.005; compared with the non‐MAFLD group) and MAFLD‐diabetes (OR/CI: 1.5/1.1–2.1, P = 0.008; compared with the non‐MAFLD group). MAFLD did not aggravate liver disease severity in patients with viral hepatitis. However, among NBNC subjects, factors associated with advanced liver disease included MAFLD‐lean MS group (OR/CI: 9.1/2.4–34.6, P = 0.001; compared with non‐MAFLD group) and MAFLD‐DM group (OR/CI: 2.0/1.2–3.2, P = 0.004; compared with non‐MAFLD group).
Conclusions
MAFLD patients with diabetes and metabolic dysregulation had a higher risk of advanced liver disease. The effect was more significant in non‐viral hepatitis subjects in a community level.
Globally, hepatitis B virus (HBV) affects over 250 million people, whereas hepatitis C virus (HCV) affects approximately 70 million people, posing major public health challenges. Despite the ...availability of vaccines and treatments, a lack of comprehensive diagnostic coverage has left many cases undiagnosed and untreated. To address the need for sensitive, specific, and accessible diagnostics, this study introduced a multiplex loop‐mediated isothermal amplification assay with lateral flow detection for simultaneous HBV and HCV testing. This assay achieved exceptional sensitivity and was capable of detecting HBV and HCV concurrently in a single tube and on a single strip within 25 min, achieving the required clinical sensitivity (10 and 103 genomic copies/reaction for HBV and HCV, respectively). The method was validated in clinical samples of various viral genotypes, achieving an equivalent limit of detection. Additionally, a custom portable heating device was developed for field use. The assay developed here, capable of direct viral detection on the strip, shows promise in supplanting current methods that solely identify antibodies and necessitate additional qPCR for viral activity assessment. This economical and rapid assay aligns with point‐of‐care testing needs, offering significant advancements in enhancing viral hepatitis diagnostics in settings with limited resources.
Age and hepatic fibrosis are the factors that increase the risk of hepatocellular carcinoma over time. We aimed to explore their impact at the initiation of antiviral therapy on hepatocellular ...carcinoma among chronic hepatitis C (CHC) patients.
A total of 1,281 biopsy-proven CHC patients receiving IFN-based therapy were followed for a mean period of 5.5 years.
The 5-year cumulative incidence of hepatocellular carcinoma did not differ between non-sustained virological response (SVR) and SVR patients who were <40 years old (7.7% vs. 0.5%,
= 0.1) but was significantly higher in non-SVR patients between 40 and 55 years old (18.0% vs. 1.3%,
< 0.001) and >55 years old (15.1% vs. 7.9%,
= 0.03). Compared with SVR, non-SVR was independently predictive of hepatocellular carcinoma in patients 40 to 55 years old HR/95% confidence intervals (CI), 10.92/3.78-31.56;
< 0.001 and >55 years old (HR/CI, 1.96/1.06-3.63;
= 0.03) but not in patients <40 years old (HR/CI, 2.76/0.41-18.84;
= 0.3). The 5-year cumulative incidence of hepatocellular carcinoma did not differ between non-SVR and SVR patients whose fibrosis stage was F0-1 (4.6% vs. 1.9%,
= 0.25) but was higher in non-SVR patients with F2-3 (21.4% vs. 4.3%,
< 0.001) or F4 (33.5% vs. 8.4%,
= 0.002). Compared with SVR, non-SVR was independently predictive of hepatocellular carcinoma in patients with F2-3 (HR/CI, 4.36/2.10-9.03;
< 0.001) and F4 (HR/CI, 3.84/1.59-9.30;
= 0.03) but not in those with F0-1 (HR/CI, 1.53/0.49-4.74;
= 0.47).
Delayed hepatitis C virus clearance for patients with CHC >40 years old or with a fibrosis stage >2 increases the risk of hepatocellular carcinoma over time.
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Protein induced by vitamin K absence or antagonist II (PIVKA-II) is a promising serum marker for hepatocellular carcinoma (HCC). There are limited data on its cutoff value in HCC for Taiwanese ...cirrhosis patients. This study aimed to investigate the diagnostic value of PIVKA-II levels in patients with suspected HCC. In total, 88 patients with chronic hepatitis and suspected HCC by ultrasound, elevated α-fetoprotein (AFP) or PIVKA-II levels were consecutively enrolled. Their baseline characteristics and findings on dynamic phases of computed tomography (CT) or magnetic resonance imaging (MRI) were examined. Sixty participants had cirrhosis and 34 had HCC. The median levels of PIVKA-II in non-cirrhosis and cirrhosis patients without or with HCC were 28.0, 48.0, and 847.0 mAU/mL, respectively. The optimal cutoff value of PIVKA-II in predicting HCC was 78.0 mAU/mL. Combining AFP with PIVKAII mildly increased its diagnostic performance for HCC, yielding higher specificity and positive predictive value. Significant factors predicting HCC in multivariate regression analysis were PIVKA >78.0 mAU/mL and fatty liver. Monitoring PIVKA-II level is suitable for noninvasively assessing HCC in patients with chronic hepatitis, particularly with AFP.
The predictive factors of overall survival after hepatectomy for HCC remain controversial and need to be investigated.
In total, 535 consecutive HCC patients undergoing resection were included and ...their clinicopathological data and overall survival were recorded. Both the tumor and adjacent non-tumor (ANT) tissues were subjected to immunohistochemistry analysis for the expression of autophagy-related markers.
Death was observed for 219 patients, and the cumulative overall survival rates at 1, 3, 5 and 7 years were 91.0%, 72.3%, 58.8%, and 27.7%, respectively. In the multivariate analysis, mortality was significantly associated with the following: diminished LC3 expression in both the tumor and ANT tissues, in the HCC tissues alone and in the ANT tissues alone (hazard ratio/95% confidence interval: 6.74/2.052-22.19, 6.70/1.321-33.98 and 2.58/1.499-4.915, respectively); recurrent HCC (5.11/3.136-8.342); HBV infection (2.75/1.574-4.784); cirrhosis (1.78/1.059-2.974); and antiviral therapy (0.42/0.250-0.697). The 5-year overall survival rates were 70.2%, 57.3%, 49.6% and 10.7% for patients with positive LC3 expression in both tissue types, in the HCC tissues alone, in the ANT tissues alone, and in neither tissue type, respectively. The 5-year overall survival rates were 56.7%, 47.3%, 51.2% and 38.7% for patients with HBV-related HCC, cirrhosis, no antiviral therapy, and recurrent HCC, respectively, and these rates were significantly lower than those in their counterparts.
Patients with recurrent HCC, HBV-related HCC, cirrhosis, and the absence of antiviral therapy showed significantly lower overall survival rates. Furthermore, LC3 expression in both the tumor and liver microenvironments were significantly predictive of overall survival after resection for HCC.
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality in Taiwan. To help clinical physicians to manage patients with HCC, the Taiwan Liver Cancer Association and the ...Gastroenterological Society of Taiwan produced the management consensus guideline for HCC.
The recommendations focus on nine important issues on management of HCC, including surveillance, diagnosis, staging, surgery, local ablation, transarterial chemoembolization/transarterial radioembolization/hepatic arterial infusion chemotherapy, systemic therapy, radiotherapy, and prevention.
The consensus statements were discussed, debated and got consensus in each expert team. And then the statements were sent to all of the experts for further discussion and refinement. Finally, all of the experts were invited to vote for the statements, including the level of evidence and recommendation.
With the development of the management consensus guideline, HCC patients could benefit from the optimal therapeutic modality.
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