Hepatitis-related Hepatocellular Carcinoma Research Articles

Impact of the COVID-19 pandemic on hospitalizations with hepatocellular carcinoma in the United States

ABSTRACT Background We studied the temporal trends of hepatocellular carcinoma (HCC)-related hospitalizations and potential predictors of in-hospital mortality around the COVID-19 pandemic. Research design and methods Using the International Classification of Diseases code, we used the National Inpatient Sample 2019–2020 and defined HCC and its underlying etiology. To assess the impact of the COVID-19 pandemic on hospitalization and in-hospital mortality, the study period was divided into the pre-COVID-19 era (2019 Q1–2020 Q1) and the COVID-19 era (2020 Q2–2020 Q4). Quarterly trends in etiology-based hospitalizations with HCC and predictors of in-hospital mortality among hospitalizations with HCC were determined. Results Hospitalization rates for HCC, as well as viral hepatitis-related HCC hospitalization rates, remained stable, while hospitalizations with alcohol-related liver disease (ALD, quarterly percentage change [QPC]: 2.1%; 95% confidence interval [CI]: 0.1%-4.2%) increased steadily. Hospitalization related to nonalcoholic fatty liver disease (NAFLD)-related HCC increased significantly steeper in the COVID-19 era (QPC: 6.6%; 95% CI: 4.0%-9.3%) than in the pre-COVID-19 era (QPC: 0.7%; 95% CI: 0.2%-1.3%). COVID-19 infection was independently associated with in-hospital mortality among hospitalizations with HCC (odds ratio: 1.94, 95% CI: 1.30–2.88). Conclusion Hospitalization rates for viral hepatitis-related HCC remained stable, while those for HCC due to ALD and NAFLD increased during the COVID-19 pandemic.

A Systematic Review of the Impact of Resveratrol on Viral Hepatitis and Chronic Viral Hepatitis-related Hepatocellular Carcinoma.

Resveratrol (RSV) is used for the treatment of various diseases due to their anti-inflammatory and antioxidant activities. However, its beneficial aspects on viral hepatitis have been less investigated. This report reviews the impact of resveratrol on viral hepatitis and chronic viral hepatitis-related hepatocellular carcinoma (HCC). The systematic review was performed and reported according to the PRISMA 2020 statement. Several core databases, such as Cochrane Library, PubMed, Web of Science, EMBASE, and Scopus, were used for search on September 6, 2023. After extraction of the data, the desired information of the full text of the studies was recorded in Excel, and the outcomes and mechanisms were reviewed. RSV inhibits viral replication through anti-HCV NS3 helicase activity, maintains redox homeostasis via glutathione (GSH) synthesis, improves T and B cell activity, and suppresses miR-155 expression. It also enhances viral replication by enhancing hepatitis C virus (HCV) RNA transcription, activating sirtuin-1 (SIRT1), which can increase peroxisome proliferator-activated receptor (PPAR), and SIRT1 activates the HBV X protein (HBx). Moreover, RSV is responsible for hepatitis-related HCC proliferation via suppression of mammalian target of rapamycin (mTOR), SIRT1 up-regulation, inhibiting expression of HBx, and reducing expression of cyclin D1. Despite the promising properties of RSV in inhibiting hepatitis-related HCC cell proliferation, its antiviral effects in viral hepatitis are controversial. The antihepatitis behaviors of RSV are mainly dose-dependent, and in some studies, activating some hepatoprotective pathways increases the transcription and replication of chronic HBV and HCV. Therefore, healthcare providers should be aware of viral hepatitis before using RSV supplements.

Survival Improvements in Advanced Hepatocellular Carcinoma with Sequential Therapy by Era

Treatment modalities for advanced hepatocellular carcinoma (HCC) have changed dramatically, with systemic therapy as the primary option. However, the effect of sequential treatment on prognosis remains unclear. This retrospective study included patients who began systemic therapy between 2009 and 2022. The patients were separated into three groups according to systemic therapy commencement. The number of therapy lines, treatment efficacy, and overall survival (OS) were compared. Multivariate analyses of the prognostic factors were analyzed using the Cox proportional hazards model. Overall, 336 patients were included (period 1: 2009–2013, n = 86; period 2: 2014–2018, n = 132; period 3: 2019–2022, n = 118). A significant etiological trend was observed with decreasing viral hepatitis-related HCC and increasing non-viral hepatitis-related HCC. Across periods 1–3, the proportion of patients who were administered >2 lines progressively increased (1.2%, 12.9%, and 17.0%, respectively; p < 0.001) and the median OS was significantly prolonged (14.3, 16.8, and 31.0 months; p < 0.001). The use of <3 lines, the non-complete and partial response of the first line, modified albumin–bilirubin at grade 2b or 3, an intrahepatic tumor number ≥ 5, extrahepatic metastasis, and alpha-fetoprotein at ≥400 ng/mL were the strongest factors associated with shorter OS. Sequential therapies have contributed to significant improvements in HCC prognosis, suggesting that sequential treatment post-progression is worthwhile for better survival.

Utility of a microRNA panel in diagnosis and prognosis of hepatitis C-associated hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and the leading cause of cancer mortality. Various studies have linked dysregulated microRNA expression to liver cancers, but those related to viral hepatitis-related HCC are limited. We investigated the diagnostic and prognostic roles of circulating miR-331-3p, miR-23b-3p, and miR-3194-5p in EDTA-treated blood samples of 50 hepatitis C virus (HCV) HCC patients, 50 HCV cirrhotic patients, and 50 healthy controls using quantitative real-time polymerase chain reaction. We found that miR-23b-3p and miR-3194-5p were significantly downregulated, whereas miR-331-3p was upregulated in HCC patients compared with controls. Also, these miRNAs were significantly dysregulated in HCC compared with cirrhotic patients. For the diagnosis of HCC, miR-331-3p and the combined miRNAs panel had the highest area under the curve (AUC), followed by miR-3194-5p. The highest AUC for differentiating metastatic from nonmetastatic patients was shown by miR-331-3p and the combined miRNAs panel, followed by miR-23b-3p. Dysregulation of miRNAs was associated with poor clinicopathological manifestations. Finally, miR-331-3P was found to be an independent risk factor for metastatic lesions in HCC. Overall, the assessed miR-331-3p, miR-23b-3p, and miR-3194-5p were significantly associated with poor clinicopathological features of HCC and could be used to discriminate HCV-related HCC patients from cirrhosis and differentiating metastatic from nonmetastatic patients, primarily miR-331-3p along with combined miRNAs. Moreover, miR-331-3p was found to be an independent factor for metastatic lesions.

FRI-320 - Comparison of clinical manifestations and outcomes between non-viral-related and viral hepatitis-related hepatocellular carcinoma

FRI-320 - Comparison of clinical manifestations and outcomes between non-viral-related and viral hepatitis-related hepatocellular carcinoma

Perspectives on the Underlying Etiology of HCC and Its Effects on Treatment Outcomes.

Hepatocellular carcinoma (HCC) continues to be a serious medical problem with poor prognosis worldwide. The distribution of the major etiologies of HCC is changing due to the progress of anti-viral treatments, including hepatitis B virus (HBV) suppression by nucleoside/nucleotide analogues (NAs) and increased sustained virologic response (SVR) rates by direct-acting antivirals (DAAs) for hepatitis C virus (HCV), as well as the rising trend of nonviral liver disease. Although viral hepatitis remains the most common cause of HCC, non-alcoholic liver disease (NAFLD) with metabolic syndrome and alcohol-associated liver disease (ALD) are increasing. Effective and well-tolerated NAs treatment can slow the disease progression of chronic HBV infection to cirrhosis, end-stage liver disease, and reduce HCC risk. Treatment with NAs is also associated with significant improvement in the long-term survival of patients with HBV infection who already have HCC. DAAs have achieved viral elimination in almost all patients with HCV without significant adverse events, even in patients with decompensated liver cirrhosis and HCC. Similarly, DAA therapy can reduce disease progression, liver and non-liver complications, and improve the long-term survival of patients with chronic HCV infection with or without HCC. Meanwhile, NAFLD is a rapidly increasing cause of HCC along with the epidemics of obesity and type 2 diabetes globally. NAFLD-related HCC can occur in patients without cirrhosis and is known to have a lower survival rate than viral hepatitis-related HCC. Since there is currently no specific pharmacotherapy effective for NAFLD, lifestyle modification and prevention of complications are important to improve prognosis. Additionally, ALD is the second fastest-growing cause of HCC-related deaths, especially with an accelerated trend since the COVID-19 pandemic. This review provides an overview of the epidemiologic trends in the etiologies of HCC, and the progress of treatments for each etiology and the impact on outcome in the patients with HCC.

Identification of prognosis-related cyclin-dependent kinases and potential response drugs in hepatocellular carcinoma.

Which cyclin-dependent kinases (CDKs) involved in the progress of hepatocellular carcinoma (HCC) need to be further clarified. To identify prognostic-relevant biomarkers in HCC through a systematic investigation of the prognostic value of CDKs. We explored the relationship between CDKs expression and the prognosis of patients with HCC using multiple online databases. In addition, their biological functions and correlation with the immune system and drug response were investigated. Among the 20 CDKs (CDK1 ~20) altered in HCC, the significantly high expression of CDK1 and CDK4 in patients with HCC was significantly associated with worse prognosis. Interestingly, CDK1 had significant co-occurrence with CDK4 and CDK1-related and CDK4-related signaling pathways are closely related to hepatitis virus-related HCC. We identified multiple transcription factors of CDK1 and CDK4; of those, only four (E2F1, PTTG1, RELA, and SP1) were significantly associated with the prognosis of HCC patients. Genetic alterations in CDKs were significantly correlated with disease-free and progression-free survival, which may be associated with aberrant expression of progesterone receptor. Moreover, we found a significantly positive correlation between CDK1 and CDK4 expression and tumor-infiltrating activated CD4+ T cell and exhausted T cell-related signature. Finally, we identified drugs with good potential prognostic value predicted by CDK1 and CDK4 levels. CDK1 and CDK4 may be potential prognostic biomarkers for HCC. Moreover, targeting four transcription factors (E2F1, PTTG1, RELA, and SP1) combined with immunotherapy may be a new therapeutic strategy for treating HCC patients with high CDK1 and CDK4 expression, especially hepatitis-related HCC.

Utility of combining PIVKA-II and AFP in the surveillance and monitoring of hepatocellular carcinoma in the Asia-Pacific region.

Even though the combined use of ultrasound (US) and alpha-fetoprotein (AFP) is recommended for the surveillance of hepatocellular carcinoma (HCC), the utilization of AFP has its challenges, including accuracy dependent on its cut-off levels, degree of liver necroinflammation, and etiology of liver disease. Though various studies have demonstrated the utility of protein induced by vitamin K absence II (PIVKA-II) in surveillance, treatment monitoring, and predicting recurrence, it is still not recommended as a routine biomarker test. A panel of 17 experts from Asia-Pacific, gathered to discuss and reach a consensus on the clinical usefulness and value of PIVKA-II for the surveillance and treatment monitoring of HCC, based on six predetermined statements. The experts agreed that PIVKA-II was valuable in the detection of HCC in AFP-negative patients, and could potentially benefit detection of early HCC in combination with AFP. PIVKA-II is clinically useful for monitoring curative and intra-arterial locoregional treatments, outcomes, and recurrence, and could potentially predict microvascular invasion risk and facilitate patient selection for liver transplant. However, combining PIVKA-II with US and AFP for HCC surveillance, including small HCC, still requires more evidence, whilst its role in detecting AFP-negative HCC will potentially increase as more patients are treated for hepatitis-related HCC. PIVKA-II in combination with AFP and US has a clinical role in the Asia-Pacific region for surveillance. However, implementation of PIVKA-II in the region will have some challenges, such as requiring standardization of cut-off values, its cost-effectiveness and improving awareness among healthcare providers.

Concept of HBV and HCV as a risk factor and prevention of viral hepatitis-related hepatocellular carcinoma

Abstract Hepatocellular carcinoma (HCC) represents one of the most common cancers worldwide, and it is a very important reason for cancer-related death. Infection with hepatitis B virus (HBV) and hepatitis C virus (HCV) is considered the major leading cause of HCC. The pathophysiology of HB and HC viral-related HCC includes chronic inflammation, deorganization of cell signaling pathways, and oxidative stress. Contrary to HCV, HBV is oncogenic by itself, due to its integration into the DNA of cell. Six months of ultrasound monitoring is recommended for high-risk patients. Using antiviral drugs to manage viral hepatitis decreases the risk of evolution and reoccurrence of HCC. Also, effective preventive measures are very important in decreasing the risk of HCC. The prevention involves primary prevention which is based on HBV vaccination, treatment of acute infection, and eliminating the route of transmission, while secondary prevention is based on using antiviral drugs against HBV and HCV infection to prevent the progress of disease into carcinoma. However, tertiary prevention involves treating the carcinoma to prevent the reoccurrence of the cancer.

Viral Hepatitis Among African Immigrants with Hepatocellular Carcinoma in Minnesota: High Prevalence Yet Low Awareness.

We aimed to study the virologic profile of immigrants from Africa with viral hepatitis-related hepatocellular carcinoma (HCC) who received care at our institution. We conducted a descriptive study among African-born patients with HCC who received care at University of Minnesota Medical Center from 2011 to 2018. We analyzed the prevalence, virologic profiles and treatment of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections prior to HCC diagnosis. 74 African-born patients with HCC were eligible for analysis. 54 had HCV and 20 had HBV infection. 80% of HBV patients were treated but remained with inadequate viral suppression at the time of HCC diagnosis while only 39% of HCV patients were treated prior to HCC diagnosis. Lost to follow up was common in both groups. Our findings suggest thatthere is a significant gap in appropriate viral hepatitis care in an African immigrant population in Minnesota. Culturally-appropriate strategies are needed to bridge this gap.

Molecular pathogenesis: Connections between viral hepatitis-induced and non-alcoholic steatohepatitis-induced hepatocellular carcinoma.

Hepatocellular carcinoma(HCC) is the sixth most common cancer in the world and is usually caused by viral hepatitis (HBV and HCV), alcoholic, and non-alcoholic fatty liver disease(NAFLD). Viral hepatitis accounts for 80% of HCC cases worldwide. In addition, With the increasing incidence of metabolic diseases, NAFLD is now the most common liver disease and a major risk factor for HCC in most developed countries. This review mainly described the specificity and similarity between the pathogenesis of viral hepatitis(HBV and HCV)-induced HCC and NAFLD-induced HCC. In general, viral hepatitis promotes HCC development mainly through specific encoded viral proteins. HBV can also exert its tumor-promoting mechanism by integrating into the host chromosome, while HCV cannot. Viral hepatitis-related HCC and NASH-related HCC differ in terms of genetic factors, and epigenetic modifications (DNA methylation, histone modifications, and microRNA effects). In addition, both of them can lead to HCC progression through abnormal lipid metabolism, persistent inflammatory response, immune and intestinal microbiome dysregulation.

Role of Rab GTPases in Hepatocellular Carcinoma.

The Rab GTPase family contains almost 70 genes in the human genome and acts as the key regulator of intracellular membrane trafficking in human cells. The dysregulation of Rab GTPase has been shown to be associated with multiple human diseases, ranging from neurodegeneration, and infection to cancer. Rab GTPases not only play important roles in genome replication, morphogenesis and the release of hepatitis B virus (HBV) or hepatitis C virus (HCV), but also contribute to hepatitis-related hepatocarcinogenesis and hepatocellular carcinoma (HCC) progression. The alteration of Rab GTPase expression in HCC plays an important role in tumour cell proliferation, invasion and migration. Notably, the expression of Rab genes can be regulated by some noncoding RNAs, such as miRNAs and circRNAs. Thus, Rab GTPases can serve as promising rational and therapeutic targets for HCC treatments. In this review, we summarized recent advancements in this field focusing on Rab GTPases in HCC.

Study of abnormal lipid metabolism analysis and significance of fatty acid binding protein expression in patients with hepatocellular carcinoma

Objective: Hepatocellular carcinoma (HCC) is the fourth most dominant cancer in the world and the second leading cause of cancer-related deaths in the China. With the increase in the incidence of metabolic syndrome (MS) in the population, the correlation between MS and HCC has gradually been recognized. MS manifests as non-alcoholic fatty liver disease (shortly known as NAFLD) in the liver. A large number of research results has shown that the development of fatty liver is closely related to the occurrence of HCC, in which lipid metabolism plays a key regulatory role, and lipid metabolism is regulated by fatty acid binding protein (FABP). This study signifies the lipid metabolism analysis and the key FABP expression conditions in HCC. Methods: Data of patients who were first diagnosed with primary HCC between January 2016 to July 2019 were collected, and were divided into two groups according to the etiology, namely the viral and non-viral hepatitis-related HCC group. The relationship between MS-related factors and HCC was analyzed by t-test and chi square test. The expressions of FABP1, FABP4 and FABP5 were detected in cancer and adjacent tissues by immunohistochemistry, and the expressions of FABP1, FABP4 and FABP5 in HCC with fatty liver were detected by immunofluorescence. Finally, the expressional characteristics of the above-mentioned FABPs in HCC patients were analyzed with different clinicopathological features. Results: There were statistically significant differences in the rate of abnormal lipid metabolism and the number of abnormalities in MS-related factors between the viral and non-viral hepatitis-related HCC group. FABP1, FABP4, and FABP5 expression in HCC tissues were lower than the corresponding adjacent tumor tissues. Compared with simple HCC, FABP1, FABP4, FABP5 expression were increased in HCC tissues with steatosis, and the expression of FABP was closely related to the clinical characteristics of patients. Conclusion: Abnormal lipid metabolism is closely related to non-viral hepatitis-related HCC. The expression of lipid metabolism regulatory proteins FABP1, FABP4, and FABP5 are down-regulated in HCC tissues, but up-regulated in HCC with fatty liver, suggesting that the relationship between MS, especially dyslipidemia, and HCC should be paid attention to in clinical practice for early intervention. FABP1, FABP4, FABP5 may regulate HCC occurrence and development.

Current impact of viral hepatitis on liver cancer development: The challenge remains.

Chronic infections due to hepatitis B and hepatitis C viruses are responsible for most cases of hepatocellular carcinoma (HCC) worldwide, and this association is likely to remain during the next decade. Moreover, viral hepatitis-related HCC imposes an important burden on public health in terms of disability-adjusted life years. In order to reduce such a burden, some major challenges must be faced. Universal vaccination against hepatitis B virus, especially in the neonatal period, is probably the most relevant primary preventive measure against the development of HCC. Moreover, considering the large adult population already infected with hepatitis B and C viruses, it is also imperative to identify these individuals to ensure their access to treatment. Both hepatitis B and C currently have highly effective therapies, which are able to diminish the risk of development of liver cancer. Finally, it is essential for individuals at high-risk of HCC to be included in surveillance programs, so that tumors are detected at an early stage. Patients with hepatitis B or C and advanced liver fibrosis or cirrhosis benefit from being followed in a surveillance program. As hepatitis B virus is oncogenic and capable of leading to liver cancer even in individuals with early stages of liver fibrosis, other high-risk groups of patients with hepatitis B are also candidates for surveillance. Considerable effort is required concerning these strategies in order to decrease the incidence and the mortality of viral hepatitis-related HCC.

Tertiary Prevention of HCC in Chronic Hepatitis B or C Infected Patients.

Simple SummaryHepatocellular carcinoma (HCC) recurrence is the major obstacle concerning patients’ survival. Tertiary prevention by antiviral therapies could reduce HCC recurrence rate in both chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infected patients. In chronic hepatitis B (CHB) patients, nucleos(t)ide analogues (Nuc) provide a more effective HCC tertiary prevention effect than an interferon (IFN)-based regimen. In chronic hepatitis C (CHC) patients, the tertiary prevention effect by direct acting antiviral agents (DAAs) was reported non-inferior to that by IFN-based therapy. Chronic hepatitis C patients left untreated had the worst survival benefit as well as shorted recurrence-free interval than those treated by either type of antiviral regimen. Although the risk of HCC recurrence could only be decreased but not diminished by antiviral therapies due to host and microenvironmental factors beyond virus infection, antiviral therapy helps to preserve and improve liver function which makes multi-modality anticancer treatment feasible to improve survival.Hepatocellular carcinoma (HCC) ranks as a leading cause of common cancer and cancer-related death. The major etiology of HCC is due to chronic hepatitis virus including HBV and HCV infections. Scheduled HCC surveillance in high risk populations improves the early detection rate and the feasibility of curative treatment. However, high HCC recurrence rate still accounts for the poor prognosis of HCC patients. In this article, we critically review the pathogenesis of viral hepatitis-related hepatocellular carcinoma and the evidence of tertiary prevention efficacy by current available antiviral treatment, and discuss the knowledge gap in viral hepatitis-related HCC tertiary prevention.

Adjuvant treatment strategy after curative resection for hepatocellular carcinoma.

Hepatic resection represents the first-line treatment for patients with resectable hepatocellular carcinoma (HCC). However, the 5-year recurrence rates of HCC after surgery have been reported to range from 50% to 70%. In this review, we evaluated the available evidence for the efficiency of adjuvant treatments to prevent HCC recurrence after curative liver resection. Antiviral therapy has potential advantages in terms of reducing the recurrence rate and improving the overall survival (OS) and/or disease-free survival of patients with hepatitis-related HCC. Postoperative adjuvant transarterial chemoembolization can significantly reduce the intrahepatic recurrence rate and improve OS, especially for patients with a high risk of recurrence. The efficacy of molecular targeted drugs as an adjuvant therapy deserves further study. Adjuvant adoptive immunotherapy can significantly improve the clinical prognosis in the early stage. Randomized controlled trial (RCT) studies evaluating adjuvant immune checkpoint inhibitors are ongoing, and the results are highly expected. Adjuvant hepatic artery infusion chemotherapy might be beneficial in patients with vascular invasion. Huaier granule, a traditional Chinese medicine, has been proved to be effective in prolonging the recurrence-free survival and reducing extrahepatic recurrence. The efficiency of other adjuvant treatments needs to be further confirmed by large RCT studies.

Long-term effectiveness of population-wide multifaceted interventions for hepatocellular carcinoma in Taiwan

Taiwan has launched a series of population-wide interventions to prevent hepatocellular carcinoma (HCC) related to hepatitis B and C virus infection since 1984. We took this opportunity to investigate the impact of each intervention on the incidence and case-fatality rate of HCC, and assessed their relative contributions to the overall reduction in mortality during this period. Population-based registry data on HCC mortality and incidence from individuals aged 0 to 84 years between 1979 and 2016 were collected before (Period 1) and after universal hepatitis B vaccination from 1984 (Period 2), universal health care from 1995 (Period 3), and viral hepatitis therapy from 2003 (Period 4). A Bayesian Poisson regression model was used for mortality decomposition analysis to estimate the respective contributions of these interventions to the reduction in age-specific incidence and case-fatality rates. Mortality declined substantially in children, young- and middle-aged groups, but only slightly decreased in the elderly group. The declining trends in mortality were in part explained by incidence reduction and in part by a remarkable decline in case-fatality rate attributed to universal health care. Hepatitis B vaccination led to a 35.9% (26.8% to 44.4%) reduction in incidence for individuals aged 30 years or below, whereas antiviral therapy reduced the incidence of HCC by 14.9% (11.8% to 17.9%) and 15.4% (14.1% to 16.6%) for individuals aged 30-49 years and 50-69 years, respectively. Vaccination and antiviral therapy were effective in reducing HCC incidence and mortality for the young and middle-aged groups, while the case-fatality rate was improved by universal health care for all age groups. Since 1984, a series of population-wide interventions have been launched in Taiwan to prevent viral hepatitis-related hepatocellular carcinoma, including a universal hepatitis B vaccination program (from 1984), universal health care (from 1995), and a national viral hepatitis therapy program (from 2004). Vaccination and antiviral therapy were effective in reducing HCC incidence and mortality for the young and middle-aged groups, while the case-fatality rate was improved by universal health care for all age groups.

ALPPS versus PVE in Hepatitis-related Hepatocellular Carcinoma- Comparison of Oncological Outcomes

Introduction: ALPPS has been popularised for future liver remnant (FLR) augmentation in liver metastasis or noncirrhotic liver tumors in recent years. Data on the oncological outcomes of ALPPS in chronic hepatitis or cirrhosis related HCC remained limited.

Diagnostic value of 5 serum biomarkers for hepatocellular carcinoma with different epidemiological backgrounds: A large-scale, retrospective study

Objective:Hepatocellular carcinoma (HCC) is a lethal global disease that requires an accurate diagnosis. We assessed the potential of 5 serum biomarkers (AFP, AFU, GGT-II, GPC3, and HGF) in the diagnosis of HCC.Methods:In this retrospective study, we measured the serum levels of each biomarker using ELISAs in 921 participants, including 298 patients with HCC, 154 patients with chronic hepatitis (CH), 122 patients with liver cirrhosis (LC), and 347 healthy controls from 3 hospitals. Patients negative for hepatitis B surface antigen and hepatitis C antibody (called “NBNC-HCC”) and patients positive for the above indices (called “HBV-HCC and HCV-HCC”) were enrolled. The selected diagnostic model was constructed using a training cohort (n = 468), and a validation cohort (n = 453) was used to validate our results. Receiver operating characteristic analysis was used to evaluate the diagnostic accuracy.Results:The α-L-fucosidase (AFU)/α-fetoprotein (AFP) combination was best able to distinguish NBNC-HCC [area under the curve: 0.986 (95% confidence interval: 0.958–0.997), sensitivity: 92.6%, specificity: 98.9%] from healthy controls in the test cohort. For screening populations at risk of developing HCC (CH and LC), the AFP/AFU combination improved the diagnostic specificity for early-stage HCC [area under the curve: 0.776 (0.712–0.831), sensitivity: 52.5%, specificity: 91.6% in the test group]. In all-stage HBV-HCC and HCV-HCC, AFU was also the best candidate biomarker combined with AFP [area under the curve: 0.835 (0.784–0.877), sensitivity 69.1%, specificity: 87.4% in the test group]. All results were verified in the validation group.Conclusions:The AFP/AFU combination could be used to identify NBNC-HCC from healthy controls and hepatitis-related HCC from at-risk patients.

The transition in the etiologies of hepatocellular carcinoma-complicated liver cirrhosis in a nationwide survey of Japan

BackgroundWe recently reported the real-world changes in the etiologies of liver cirrhosis (LC) based on nationwide survey data and assessed the etiologies of LC with hepatocellular carcinoma (HCC).MethodsFifty-five participants from 68 institutions provided data on 23,637 patients with HCC-complicated LC. The changing trends in etiologies were assessed. We further analyzed the data from 29 hospitals that provided the annual number of newly identified HCC-complicated LC patients from 2008 to 2016 (N = 9362) without any missing years and assessed the transition in the real number of newly identified HCC-complicated LC cases.ResultsIn the overall cohort, hepatitis C virus (HCV) infection (60.3%) and hepatitis B virus (HBV) infection (12.9%) were the leading and third-most common causes of HCC-complicated LC in Japan, respectively. HCV infection was found to be the leading cause throughout Japan. The rate of viral hepatitis-related HCC decreased from 85.3 to 64.4%. Among non-viral etiologies, notable increases were observed in nonalcoholic steatohepatitis (NASH)-related HCC (from 1.5 to 7.2%) and alcoholic liver disease (ALD)-related HCC (from 8.5 to 18.6%). Regarding the real number of newly diagnosed patients, the number of patients with viral hepatitis-related HCC decreased, while the number of patients with non-viral HCC, particularly NASH-related HCC, increased.ConclusionsViral hepatitis has remained the main cause of HCC in Japan. However, the decrease in viral hepatitis-related HCC, particularly HCV-related HCC highly contributed to the etiological changes. In addition, the increased incidence of non-viral HCC, particularly NASH-related HCC, was involved in the changing etiologies of HCC-complicated LC in Japan.