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1
Hammitt, Laura, Dean Quinn, Ewa Janczewska, Francisco J. Pasquel, Richard Tytus, K. Rajender Reddy, Katia Abarca, et al. "1050. Phase 3 Trial to Evaluate the Safety, Tolerability, and Immunogenicity of V114 Followed by 23valent Pneumococcal Polysaccharide Vaccine 6 Months Later in At-risk Adults Aged 18–49 Years (PNEU-DAY): A Subgroup Analysis by Baseline Risk Factors." Open Forum Infectious Diseases 8, Supplement_1 (November 1, 2021): S616—S617. http://dx.doi.org/10.1093/ofid/ofab466.1244.
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Abstract Background Risk factors (RFs) for pneumococcal disease (PD) in immunocompetent individuals include comorbidities, behavioral habits, or living in a community with increased risk of PD transmission. RF stacking of comorbidities is associated with a higher incidence of PD, approaching that of immunocompromised individuals. Pneumococcal vaccination of certain adults is recommended with the 23-valent pneumococcal polysaccharide vaccine (PPSV23) alone/sequentially with pneumococcal conjugate vaccine (PCV). V114, an investigational 15-valent PCV, contains 2 epidemiologically important serotypes (STs), 22F and 33F, in addition to the 13 STs in 13-valent PCV (PCV13). Methods PNEU-DAY was a Phase 3 study evaluating V114 or PCV13 administered on Day 1, and PPSV23 given 6 months later, in adults aged 18–49 years with or without RFs. This subgroup analysis assessed safety, tolerability, and immunogenicity of V114 and PCV13 based on the number of baseline PD RFs, which included chronic liver, lung, and heart disease, diabetes mellitus, tobacco use, and alcohol consumption. Adverse events (AEs; overall and solicited) were collected after each vaccination. Immunogenicity assessment was based on ST-specific opsonophagocytic activity (OPA) at 30 days after each vaccination. Subgroup analyses were conducted by RF group (0, 1, or ≥2 RFs for PD). Results Among the 1515 participants randomized to V114 (n=1135) or PCV13 (n=380), 25.2% had no RFs, 54.7% had 1 RF and 20.1% had ≥2 RFs for PD at baseline. The proportions of participants with solicited AEs following V114/PCV13 and PPSV23 were comparable across the 3 subgroups, with injection-site pain, myalgia, and fatigue being the most common. V114 and PCV13 were immunogenic in all subgroups based on OPA geometric mean titers (GMTs) at 30 days post-vaccination for the 13 shared STs (Figure); in addition, V114 induced a robust immune response to the 2 unique STs (22F, 33F) in all subgroups. PPSV23 following PCV was immunogenic for all 15 STs contained in V114 across all subgroups. Figure. Serotype-specific OPA GMTs at baseline and 30 days post-vaccination with V114 and PCV13 by number of baseline risk factors (per-protocol population) Conclusion V114 administered alone/sequentially with PPSV23 is well tolerated and immunogenic for all 15 vaccine STs, including those not contained in PCV13, in immunocompetent adults aged 18–49 years, regardless of the number of baseline RFs. Disclosures Laura Hammitt, MD, MedImmune (Grant/Research Support, Scientific Research Study Investigator, Research Grant or Support)Merck & Co., Inc. (Grant/Research Support, Scientific Research Study Investigator, Research Grant or Support)Novavax (Grant/Research Support, Scientific Research Study Investigator, Research Grant or Support)Pfizer (Grant/Research Support, Scientific Research Study Investigator, Research Grant or Support) Francisco J. Pasquel, MD, MPH, Boehringer Ingelheim (Consultant)Dexcom (Grant/Research Support)Eli Lilly & Company (Consultant)Insulet (Grant/Research Support)Merck & Co., Inc. (Consultant, Grant/Research Support) K. Rajender Reddy, MD, BMS (Grant/Research Support)Deciphera (Advisor or Review Panel member)Gilead (Grant/Research Support)Grifols (Grant/Research Support)HCC-TARGET (Grant/Research Support)Intercept (Grant/Research Support)Mallinckrodt (Grant/Research Support, Advisor or Review Panel member)NASH-TARGET (Grant/Research Support)Pfizer (Advisor or Review Panel member)Sequana (Grant/Research Support) Ron Dagan, MD, Medimmune/AstraZeneca (Grant/Research Support, Scientific Research Study Investigator, Research Grant or Support)MSD (Consultant, Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member, Research Grant or Support, Speaker’s Bureau)Pfizer (Consultant, Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member, Research Grant or Support, Speaker’s Bureau) Rachel Dawson, D.O. MPH, Merck & Co., Inc. (Employee, Shareholder) Jennifer McCauley, BSc, Merck & Co., Inc. (Employee) Kyeongmi Cheon, Ph.D., Merck & Co., Inc. (Employee, Shareholder) Alison Pedley, PhD, Merck & Co., Inc. (Employee) Tina Sterling, BS, Merck & Co., Inc. (Employee, Shareholder) Gretchen Tamms, B.S., Merck Sharp and Dohme (Employee, Shareholder) Luwy Musey, MD, Merck & Co., Inc. (Employee) Ulrike K. Buchwald, MD, MS, Merck & Co., Inc. (Employee)TB Alliance (Employee)
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Lleo, Ana, Ynto S. de Boer, Rodrigo Liberal, and Massimo Colombo. "The risk of liver cancer in autoimmune liver diseases." Therapeutic Advances in Medical Oncology 11 (January 2019): 175883591986191. http://dx.doi.org/10.1177/1758835919861914.
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Hepatocellular carcinoma (HCC), the dominant primary malignancy of the liver, has almost invariably a fatal outcome that can be averted only by early diagnosis and treatment. While the close association of HCC with chronic viral hepatitis and alcohol abuse has impacted favourably on screening and treatment of this deadly tumour, at the same time it has long obscured the etiologic role of autoimmune liver diseases. Recently, a systematic analysis of 25 published cohorts disclosed a 3.1 × 1000 patients/year incidence of HCC in autoimmune hepatitis patients that tripled in those with cirrhosis. HCC is also a sequela of primary biliary cholangitis, where the incidence is more relevant in males, those with advanced liver disease and nonresponders to ursodeoxycholic acid therapy. Cholangiocarcinoma (CCA), the second ranking primary cancer of the liver, is also on the rise with its intrahepatic pattern, in part reflecting an association with chronic liver diseases of diverse aetiology. In the USA and northern Europe, perihilar CCA is a frequent complication of primary sclerosing cholangitis, a cholestatic disorder thought to be immune mediated. International Guidelines clearly recommend HCC screening with abdominal ultrasonography every 6 months in autoimmune cirrhotic patients. While surveillance of patients with autoimmune liver disorders who are at risk of HCC affects both early diagnosis and radical therapy of this tumour, this is not the case for CCA, where early diagnosis is challenged by the lack of sensitive and accurate tests for screening.
3
Hedrich, Viola, Kristina Breitenecker, Leila Djerlek, Gregor Ortmayr, and Wolfgang Mikulits. "Intrinsic and Extrinsic Control of Hepatocellular Carcinoma by TAM Receptors." Cancers 13, no. 21 (October 29, 2021): 5448. http://dx.doi.org/10.3390/cancers13215448.
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Hepatocellular carcinoma (HCC) is the major subtype of liver cancer, showing high mortality of patients due to limited therapeutic options at advanced stages of disease. The receptor tyrosine kinases Tyro3, Axl and MerTK—belonging to the TAM family—exert a large impact on various aspects of cancer biology. Binding of the ligands Gas6 or Protein S activates TAM receptors causing homophilic dimerization and heterophilic interactions with other receptors to modulate effector functions. In this context, TAM receptors are major regulators of anti-inflammatory responses and vessel integrity, including platelet aggregation as well as resistance to chemotherapy. In this review, we discuss the relevance of TAM receptors in the intrinsic control of HCC progression by modulating epithelial cell plasticity and by promoting metastatic traits of neoplastic hepatocytes. Depending on different etiologies of HCC, we further describe the overt role of TAM receptors in the extrinsic control of HCC progression by focusing on immune cell infiltration and fibrogenesis. Additionally, we assess TAM receptor functions in the chemoresistance against clinically used tyrosine kinase inhibitors and immune checkpoint blockade in HCC progression. We finally address the question of whether inhibition of TAM receptors can be envisaged for novel therapeutic strategies in HCC.
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Junior, Yin-Siew Lai, Huyen Thi Nguyen, Farrah P. Salmanida, and Ko-Tung Chang. "MERTK+/hi M2c Macrophages Induced by Baicalin Alleviate Non-Alcoholic Fatty Liver Disease." International Journal of Molecular Sciences 22, no. 19 (September 30, 2021): 10604. http://dx.doi.org/10.3390/ijms221910604.
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Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases worldwide. An accumulation of fat, followed by inflammation, is the major cause of NAFLD progression. During inflammation, macrophages are the most abundant immune cells recruited to the site of injury. Macrophages are classified into “proinflammatory” M1 macrophages, and “anti-inflammatory” M2 macrophages. In NAFLD, M1 macrophages are the most prominent macrophages that lead to an excessive inflammatory response. Previously, we found that baicalin could polarize macrophages into anti-inflammatory M2c subtype macrophages with an increased level of MERTK expression. Several studies have also shown a strong correlation between MERTK expression and cholesterol efflux, efferocytosis, as well as phagocytosis capability. Therefore, in this study, we aim to elucidate the potential and efficacy of mononuclear-cell (MNC)-derived MERTK+/hi M2c macrophages induced by baicalin as a cell-based therapy for NAFLD treatment. In our results, we have demonstrated that a MERTK+/hi M2c macrophage injection to NAFLD mice contributes to an increased level of serum HDL secretion in the liver, a decline in the circulating CD4+CD25− and CD8+CD25− T cells and lowers the total NAFLD pathological score by lessening the inflammation, necrosis, and fibrosis. In the liver, profibrotic COL1A1 and FN, proinflammation TNFα, as well as the regulator of lipid metabolism PPARɣ expression, were also downregulated after injection. In parallel, the transcriptomic profiles of the injected MERTK+/hi M2c macrophages showed that the various genes directly or indirectly involved in NAFLD progression (e.g., SERPINE1, FADS2) were also suppressed. Downregulation of cytokines and inflammation-associated genes, such as CCR5, may promote a pro-resolving milieu in the NAFLD liver. Altogether, cell-based therapy using MERTK+/hi M2c macrophages is promising, as it ameliorates NAFLD in mice.
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Jiang, Kun, and Barbara A. Centeno. "Primary Liver Cancers, Part 2." Cancer Control 25, no. 1 (January 1, 2018): 107327481774465. http://dx.doi.org/10.1177/1073274817744658.
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Hepatocellular carcinoma (HCC) and primary intrahepatic cholangiocarcinoma (ICC) have been increasing in incidence worldwide and are leading causes of cancer death. Studies of the molecular alterations leading to these carcinomas provide insights into the key mechanisms involved. A literature review was conducted to identify articles with information relevant to current understanding of the etiologies and molecular pathogenesis of HCC and ICC. Chronic inflammatory diseases are the key etiological risk factors for both HCC and ICC, although other diseases play a role, and for many ICCs, an underlying risk factor is not identified. Mutations in catenin beta 1 ( CTNBB1) and tumor protein 53 (P53) are the main genetic alterations in HCC. Isocitrate dehydrogenases 1 and 2 (IDH1/2), KRAS protooncogene GTPase (KRAS), a RAS Viral Oncogene Homolog in neoroblastoma (NRAS) and P53 are primary genetic alterations in ICC. In both diseases, the mutational landscape is dependent on the underlying etiology. The most significant etiologies and genetic processes involved in the carcinogenesis of HCC and ICC are reviewed.
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Nguyen, Xuan-vinh Kevin, Jason Zhang, Ken Lee Chin, Stephen Bloom, and Amanda J. Nicoll. "Is Hepatocellular Carcinoma in Fatty Liver Different to Non-Fatty Liver?" Nutrients 14, no. 18 (September 19, 2022): 3875. http://dx.doi.org/10.3390/nu14183875.
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Background: Non-alcoholic fatty liver disease (NAFLD) has become the most prevalent liver disease in Australia and is recognised to play a role in the development of hepatocellular carcinoma (HCC). There are no clear guidelines regarding screening for HCC in NAFLD. The aim of this retrospective study was to compare the characteristics and survival rates of NAFLD-HCC to patients with non-NAFLD-HCC to help guide future research in this area. Methods: A total of 152 HCC patients with either NAFLD (n = 36) or non-NAFLD (n = 116) were retrospectively analysed from the HCC database and medical records. Chi-square and independent t-test were used to compare baseline characteristics and Kaplan–Meier curves and Cox models were used for survival analysis. Results: Patients with NAFLD-HCC were more likely to be diagnosed due to symptoms rather than through screening, and at an older age, compared with non-NAFLD HCC. The median survival rates were lower in NAFLD-HCC (17.2 months) than in those with non-NAFLD-HCC (23.5 months). Conclusion: There is a rise in the number of HCC cases in patients with NAFLD, and this has significant implications for hepatologists as they are presented with more advanced diseases and have poorer outcomes. Future studies on HCC will need to identify this group earlier in order to have an impact on the HCC survival rate.
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Rizzo, Giacomo Emanuele Maria, Giuseppe Cabibbo, and Antonio Craxì. "Hepatitis B Virus-Associated Hepatocellular Carcinoma." Viruses 14, no. 5 (May 7, 2022): 986. http://dx.doi.org/10.3390/v14050986.
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Hepatitis B virus (HBV) is DNA-based virus, member of the Hepadnaviridae family, which can cause liver disease and increased risk of hepatocellular carcinoma (HCC) in infected individuals, replicating within the hepatocytes and interacting with several cellular proteins. Chronic hepatitis B can progressively lead to liver cirrhosis, which is an independent risk factor for HCC. Complications as liver decompensation or HCC impact the survival of HBV patients and concurrent HDV infection worsens the disease. The available data provide evidence that HBV infection is associated with the risk of developing HCC with or without an underlying liver cirrhosis, due to various direct and indirect mechanisms promoting hepatocarcinogenesis. The molecular profile of HBV-HCC is extensively and continuously under study, and it is the result of altered molecular pathways, which modify the microenvironment and lead to DNA damage. HBV produces the protein HBx, which has a central role in the oncogenetic process. Furthermore, the molecular profile of HBV-HCC was recently discerned from that of HDV-HCC, despite the obligatory dependence of HDV on HBV. Proper management of the underlying HBV-related liver disease is fundamental, including HCC surveillance, viral suppression, and application of adequate predictive models. When HBV-HCC occurs, liver function and HCC characteristics guide the physician among treatment strategies but always considering the viral etiology in the treatment choice.
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Chen, Shen, Yi Tang, Wanjun Fang, Taiping He, Xu Chen, and Peiwen Zhang. "CoQ10 Promotes Resolution of Necrosis and Liver Regeneration After Acetaminophen-Induced Liver Injury." Toxicological Sciences 185, no. 1 (October 20, 2021): 19–27. http://dx.doi.org/10.1093/toxsci/kfab123.
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Abstract Coenzyme Q10 (CoQ10) which acts as an electron transporter in the mitochondrial respiratory chain has many beneficial effects on liver diseases. In our previous research, CoQ10 has been found to attenuate acetaminophen (APAP)-induced acute liver injury (ALI). However, whether CoQ10 administration is still effective at the late stage of APAP overdose is still unknown. In this study, we aimed to test CoQ10 efficacy at the late stage of APAP overdose. C57BL/6J mice were intraperitoneally treated with APAP to induce liver injury. CoQ10 (5 mg/kg) was given to mice at 16 h after APAP treatment. The results showed that while CoQ10 treatment at 16 h post-APAP overdose had no effects on the expression of ROS generated genes or scavenged genes, it still significantly decreased necrosis of hepatocytes following APAP-induced ALI. Moreover, CoQ10 increased MerTK+ macrophages accumulation in the APAP-overdose liver and inhibition of MerTK signaling partly abrogated the protective role of CoQ10 treatment on the hepatic necrosis. CoQ10 treatment also significantly enhanced hepatocytes proliferation as shown in the increased 5-bromodeoxyuridine incorporation in the APAP-intoxicated mice liver section. In addition, CoQ10 treatment increased hepatic Proliferating Cell Nuclear Antigen (PCNA) and Cyclin D1 expression and promoted activation of the β-catenin signaling in APAP-overdose mice. To conclude, these data provide evidence that CoQ10 treatment is still effective at the late stage of APAP-induced ALI and promotes resolution of necrosis and liver regeneration following ALI.
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Kim, Young-Ah, Kwan-Kyu Park, and Sun-Jae Lee. "LncRNAs Act as a Link between Chronic Liver Disease and Hepatocellular Carcinoma." International Journal of Molecular Sciences 21, no. 8 (April 20, 2020): 2883. http://dx.doi.org/10.3390/ijms21082883.
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Long non-coding RNAs (lncRNAs) are emerging as important contributors to the biological processes underlying the pathophysiology of various human diseases, including hepatocellular carcinoma (HCC). However, the involvement of these molecules in chronic liver diseases, such as nonalcoholic fatty liver disease (NAFLD) and viral hepatitis, has only recently been considered in scientific research. While extensive studies on the pathogenesis of the development of HCC from hepatic fibrosis have been conducted, their regulatory molecular mechanisms are still only partially understood. The underlying mechanisms related to lncRNAs leading to HCC from chronic liver diseases and cirrhosis have not yet been entirely elucidated. Therefore, elucidating the functional roles of lncRNAs in chronic liver disease and HCC can contribute to a better understanding of the molecular mechanisms, and may help in developing novel diagnostic biomarkers and therapeutic targets for HCC, as well as in preventing the progression of chronic liver disease to HCC. Here, we comprehensively review and briefly summarize some lncRNAs that participate in both hepatic fibrosis and HCC.
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Rajapaksha, Indu. "Liver Fibrosis, Liver Cancer, and Advances in Therapeutic Approaches." Livers 2, no. 4 (November 2, 2022): 372–86. http://dx.doi.org/10.3390/livers2040028.
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Chronic liver diseases (CLDs) that lead to hepatic fibrosis, cirrhosis, and/or hepatocellular carcinoma (HCC) have become a major cause of illness and death worldwide. The main causative factors for CLDs are chronic viral infections, excessive alcohol consumption, non-alcoholic fatty liver disease (NAFLD), and cholestatic diseases. The primary approach to managing cirrhosis should be removing the causative agent, and the secondary approach should address fibrogenesis. Liver cancer is also a leading cause of death worldwide, and many therapeutic approaches exist to treat the disease. However, liver transplantation remains the last treatment option for cirrhosis and liver cancer. Thus, this review discusses the pathophysiology of liver fibrosis, its progression to cirrhosis and HCC, and current therapeutic options available to treat the diseases with potential therapeutic options that will be available in the near future.
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Crespo, María, Magdalena Leiva, and Guadalupe Sabio. "Circadian Clock and Liver Cancer." Cancers 13, no. 14 (July 20, 2021): 3631. http://dx.doi.org/10.3390/cancers13143631.
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Circadian clocks control several homeostatic processes in mammals through internal molecular mechanisms. Chronic perturbation of circadian rhythms is associated with metabolic diseases and increased cancer risk, including liver cancer. The hepatic physiology follows a daily rhythm, driven by clock genes that control the expression of several proteins involved in distinct metabolic pathways. Alteration of the liver clock results in metabolic disorders, such as non-alcoholic fatty liver diseases (NAFLD) and impaired glucose metabolism, that can trigger the activation of oncogenic pathways, inducing spontaneous hepatocarcinoma (HCC). In this review, we provide an overview of the role of the liver clock in the metabolic and oncogenic changes that lead to HCC and discuss new potentially useful targets for prevention and management of HCC.
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Rigopoulou, Eirini I., and George N. Dalekos. "Current Trends and Characteristics of Hepatocellular Carcinoma in Patients with Autoimmune Liver Diseases." Cancers 13, no. 5 (March 1, 2021): 1023. http://dx.doi.org/10.3390/cancers13051023.
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Hepatocellular carcinoma (HCC), the commonest among liver cancers, is one of the leading causes of mortality among malignancies worldwide. Several reports demonstrate autoimmune liver diseases (AILDs), including autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC) to confer increased risk of hepatobiliary malignancies, albeit at lower frequencies compared to other liver diseases. Several parameters have been recognized as risk factors for HCC development in AIH and PBC, including demographics such as older age and male sex, clinical features, the most decisive being cirrhosis and other co-existing factors, such as alcohol consumption. Moreover, biochemical activity and treatment response have been increasingly recognized as prognostic factors for HCC development in AIH and PBC. As available treatment modalities are effective only when HCC diagnosis is established early, surveillance has been proven essential for HCC prognosis. Considering that the risk for HCC is not uniform between and within disease groups, refinement of screening strategies according to prevailing demographic, clinical, and molecular risk factors is mandated in AILDs patients, as personalized HCC risk prediction will offer significant advantage in patients at high and/or medium risk. Furthermore, future investigations should draw attention to whether modification of immunosuppression could benefit AIH patients after HCC diagnosis.
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Liepelt, Anke, and Frank Tacke. "Stromal cell-derived factor-1 (SDF-1) as a target in liver diseases." American Journal of Physiology-Gastrointestinal and Liver Physiology 311, no. 2 (August 1, 2016): G203—G209. http://dx.doi.org/10.1152/ajpgi.00193.2016.
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The chemokine stromal cell-derived factor-1 (SDF-1) or CXCL12 is constitutively expressed in healthy liver. However, its expression increases following acute or chronic liver injury. Liver sinusoidal endothelial cells (LSEC), hepatic stellate cells (HSC), and malignant hepatocytes are important sources of SDF-1/CXCL12 in liver diseases. CXCL12 is able to activate two chemokine receptors with different downstream signaling pathways, CXCR4 and CXCR7. CXCR7 expression is relevant on LSEC, while HSC, mesenchymal stem cells, and tumor cells mainly respond via CXCR4. Here, we summarize recent developments in the field of liver diseases involving this chemokine and its receptors. SDF-1-dependent signaling contributes to modulating acute liver injury and subsequent tissue regeneration. By activating HSC and recruiting mesenchymal cells from bone marrow, CXCL12 can promote liver fibrosis progression, while CXCL12-CXCR7 interactions endorse proregenerative responses in chronic injury. Moreover, the SDF-1 pathway is linked to development of hepatocellular carcinoma (HCC) by promoting tumor growth, angiogenesis, and HCC metastasis. High hepatic CXCR4 expression has been suggested as a biomarker indicating poor prognosis of HCC patients. Tumor-infiltrating myeloid-derived suppressor cells (MDSC) also express CXCR4 and migrate toward CXCL12. Thus CXCL12 inhibition might not only directly block HCC growth but also modulate the tumor microenvironment (angiogenesis, MDSC), thereby sensitizing HCC patients to conventional or emerging novel cancer therapies (e.g., sorafenib, regorafenib, nivolumab, pembrolizumab). We herein summarize the current knowledge on the complex interplay between CXCL12 and CXCR4/CXCR7 in liver diseases and discuss approaches on the therapeutic targeting of these axes in hepatitis, fibrosis, and liver cancer.
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Force, Madison, Grace Park, Divya Chalikonda, Christopher Roth, Micah Cohen, Dina Halegoua-DeMarzio, and Hie-Won Hann. "Alpha-Fetoprotein (AFP) and AFP-L3 Is Most Useful in Detection of Recurrence of Hepatocellular Carcinoma in Patients after Tumor Ablation and with Low AFP Level." Viruses 14, no. 4 (April 8, 2022): 775. http://dx.doi.org/10.3390/v14040775.
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Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and is a leading cause of mortality worldwide. While there are many risk factors for HCC including alcohol, obesity, and diabetes, hepatitis B virus (HBV) and hepatitis C virus (HCV) infection still account for the majority of HCC worldwide. Globally, HBV is the leading risk factor for HCC. Patients with chronic hepatitis B (CHB) and advanced liver disease are at high risk for HCC. Screening for HCC is done routinely with ultrasound with or without alpha-fetoprotein (AFP) at six-month intervals. The combination of ultrasound and AFP has been shown to provide some additional detection of 6–8% of cases compared to ultrasound alone; however, this also increases false-positive results. This is because AFP can be elevated not only in the setting of HCC, but also in chronic hepatitis, liver cirrhosis, or ALT flare in CHB, which limits the specificity of AFP. AFP-L3 is a subfraction of AFP that is produced by malignant hepatocytes. The ratio of AFP-L3 to total AFP is reported as a percentage, and over 10% AFP-L3 is consistent with a diagnosis of HCC. Here, we review five cases of patients with CHB, cirrhosis, and HCC, and their levels of AFP and the AFP-L3% at various stages of disease including ALT flare, cirrhosis, initial diagnosis of HCC, and recurrence of HCC. These cases emphasize the utility of AFP-L3% in identifying early, new or recurrent HCC prior to the presence of imaging findings.
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Giraud, Julie, and Maya Saleh. "Host–Microbiota Interactions in Liver Inflammation and Cancer." Cancers 13, no. 17 (August 27, 2021): 4342. http://dx.doi.org/10.3390/cancers13174342.
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Hepatocellular carcinoma (HCC) is a classical inflammation-promoted cancer that occurs in a setting of liver diseases, including nonalcoholic fatty liver disease (NAFLD) or alcoholic liver disease (ALD). These pathologies share key characteristics, notably intestinal dysbiosis, increased intestinal permeability and an imbalance in bile acids, choline, fatty acids and ethanol metabolites. Translocation of microbial- and danger-associated molecular patterns (MAMPs and DAMPs) from the gut to the liver elicits profound chronic inflammation, leading to severe hepatic injury and eventually HCC progression. In this review, we first describe how the gut and the liver communicate and discuss mechanisms by which the intestinal microbiota elicit hepatic inflammation and HCC. We focus on the role of microbial products, e.g., MAMPs, host inflammatory effectors and host–microbiome-derived metabolites in tumor-promoting mechanisms, including cell death and senescence. Last, we explore the potential of harnessing the microbiota to treat liver diseases and HCC.
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Mohr, Raphael, Burcin Özdirik, Joeri Lambrecht, Münevver Demir, Johannes Eschrich, Lukas Geisler, Teresa Hellberg, et al. "From Liver Cirrhosis to Cancer: The Role of Micro-RNAs in Hepatocarcinogenesis." International Journal of Molecular Sciences 22, no. 3 (February 2, 2021): 1492. http://dx.doi.org/10.3390/ijms22031492.
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In almost all cases, hepatocellular carcinoma (HCC) develops as the endpoint of a sequence that starts with chronic liver injury, progresses to liver cirrhosis, and finally, over years and decades, results in liver cancer. Recently, the role of non-coding RNA such as microRNA (miRNA) has been demonstrated in the context of chronic liver diseases and HCC. Moreover, data from a phase II trial suggested a potential role of microRNAs as therapeutics in hepatitis-C-virus infection, representing a significant risk factor for development of liver cirrhosis and HCC. Despite progress in the clinical management of chronic liver diseases, pharmacological treatment options for patients with liver cirrhosis and/or advanced HCC are still limited. With their potential to regulate whole networks of genes, miRNA might be used as novel therapeutics in these patients but could also serve as biomarkers for improved patient stratification. In this review, we discuss available data on the role of miRNA in the transition from liver cirrhosis to HCC. We highlight opportunities for clinical translation and discuss open issues applicable to future developments.
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Chaopathomkul, Bundit, Ornalin Boonsirisak, and Krit Pongpirul. "Correlation of the Stiffness of Hepatocellular Carcinoma and Surrounding Liver Parenchyma by Point Shear Wave Elastography." Journal of Diagnostic Medical Sonography 35, no. 1 (October 2, 2018): 10–15. http://dx.doi.org/10.1177/8756479318801587.
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The purpose of this study was to assess the correlation between hepatocellular carcinoma (HCC) and surrounding liver parenchyma stiffness using point shear wave elastography (pSWE). HCC was diagnosed using the criteria of the American Association for the Study of Liver Diseases. Liver fibrosis was classified into three groups (nonsignificant fibrosis, significant fibrosis, and cirrhosis). pSWE was performed on the HCC and the adjacent hepatic parenchyma and was expressed as kilopascal (kPa). A total of 59 HCC patients with 64 tumors were included in the study. The mean stiffnesses of HCC and liver background were 9.25 ± 3.76 and 10.84 ± 4.81 kPa, respectively. There was no statistical significance in HCC stiffness in any stage of liver fibrosis. Low HCC/liver background stiffness ratio was noted in the cirrhotic group and statistically significant in two comparison groups (cirrhosis vs significant fibrosis and cirrhosis vs nonsignificant fibrosis), with P < .001. In this cohort, HCC stiffness alone demonstrated no statistically significant difference in various stages of liver fibrosis.
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Mohamed, Salem Youssef. "Management of hepatocellular carcinoma." african journal of gastroenterology and hepatology 4, no. 1 (October 8, 2021): 19–25. http://dx.doi.org/10.52378/mhae1978.
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Hepatocellular carcinoma (HCC) is a heterogeneous disease that develops most of the time on diseases liver. Early diagnosis and management are the best options for the patients, so screening programs are mandatory for those who are at risk of the development of HCC. Despite the challenge of management of HCC, there is hopeful management for HCC as the field of primary liver cancer has moved quickly
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Cerrito, Lucia, Irene Mignini, Maria Elena Ainora, Carolina Mosoni, Antonio Gasbarrini, and Maria Assunta Zocco. "Hepatocellular Carcinoma in Patients with Nonalcoholic Fatty Liver Disease: The Prognostic Role of Liver Stiffness Measurement." Cancers 15, no. 3 (January 19, 2023): 637. http://dx.doi.org/10.3390/cancers15030637.
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Nonalcoholic fatty liver disease (NAFLD), which is nowadays the most common etiology of chronic liver disease, is associated with an increased risk of hepatocellular carcinoma (HCC), with or without cirrhosis. Owing to the high prevalence of NAFLD worldwide, it becomes crucial to develop adequate strategies for surveillance of HCC and new prediction models aiming at stratifying NAFLD population for HCC risk. To this purpose, several noninvasive tests (NITs) have been proposed in the several last years, including clinical parameters, serum biomarkers, and imaging techniques. Most of these tools are focused on the assessment of liver fibrosis. Both ultrasound (US) elastography (especially transient elastography) and magnetic resonance (MR) elastography have been evaluated to estimate HCC risk in NAFLD patients. Recently, the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) include these techniques among the recommended NITs for the assessment of liver fibrosis. The aim of this review is to summarize the most recent data on the role of US and MR elastography in HCC risk stratification in patients with NAFLD.
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Machida, Keigo. "TLRs, Alcohol, HCV, and Tumorigenesis." Gastroenterology Research and Practice 2010 (2010): 1–8. http://dx.doi.org/10.1155/2010/518674.
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Chronic liver damage caused by viral infection, alcohol, or obesity can result in increased risk for hepatocellular carcinoma (HCC). Ample epidemiological evidence suggests that there is a strong synergism between hepatitis C virus (HCV) and alcoholic liver diseases (ALD). The Toll-like receptor (TLR) signaling pathway is upregulated in chronic liver diseases. Alcoholism is associated with endotoxemia that stimulates expression of proinflammatory cytokine expression and inflammation in the liver and fat tissues. Recent studies of HCC have centered on cancer-initiating stem cell (CSC), including detection of CSC in cancer, identification of CSC markers, and isolation of CSC from human HCC cell lines. Synergism between alcohol and HCV may lead to liver tumorigenesis through TLR signaling.
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Hsu, Po-Yao, Po-Cheng Liang, Ching-I. Huang, Meng-Hsuan Hsieh, Yi-Shan Tsai, Tzu-Chun Lin, Ming-Lun Yeh, et al. "Effects of Achieving SVR on Clinical Characteristics and Surgical Outcomes in Patients Who Developed Early-Stage HCV-Related Hepatocellular Carcinoma and Received Curative Resection: Preoperative versus Postoperative SVR." Viruses 14, no. 11 (October 31, 2022): 2412. http://dx.doi.org/10.3390/v14112412.
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The high accessibility to healthcare and increasing awareness of hepatocellular carcinoma (HCC) surveillance after sustained virologic response (SVR) to HCV treatment allow early detection of operable HCC in Taiwan. However, the effects of achieving SVR on patient characteristics and surgical outcomes after curative resection remain elusive. We aimed to compare the clinical presentation and postoperative prognosis among patients with early-stage HCV-related HCC and different viral status. We retrospectively analyzed 208 patients with BCLC stage 0 or A-HCC, including 44 patients who remained HCV viremic, 90 patients who developed HCC after achieving SVR (post-SVR HCC), and 74 patients who subsequently achieved SVR after resection. Patients with post-SVR HCC had a lower degree of hepatitis and better liver function than those who achieved SVR or remained viremic after resection. Notably, 75.6% of patients with post-SVR HCC did not have cirrhosis. Patients with post-SVR HCC and those achieving SVR after resection exhibited comparable recurrence rates and recurrence-free survival, while patients with persistent viremia had the worst surgical outcomes. We concluded that patients with post-SVR HCC had a better liver function but similar surgical outcomes compared with patients who achieved SVR after resection. The low prevalence of cirrhosis in patients with post-SVR HCC highlights the importance of regular surveillance after SVR.
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Chen, Yi-Hsun, Wei-Kai Wu, and Ming-Shiang Wu. "Microbiota-Associated Therapy for Non-Alcoholic Steatohepatitis-Induced Liver Cancer: A Review." International Journal of Molecular Sciences 21, no. 17 (August 20, 2020): 5999. http://dx.doi.org/10.3390/ijms21175999.
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Even though advancement in medicine has contributed to the control of many diseases to date, cancer therapy continues to pose several challenges. Hepatocellular carcinoma (HCC) etiology is multifactorial. Recently, non-alcoholic fatty liver disease (NAFLD) has been considered as an important risk factor of HCC. NAFLD can be divided into non-alcoholic simple fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH) based on histopathological features. Recently, studies have indicated that the gut microbiota is associated with NAFLD and HCC. Therefore, in this review, we have discussed the effects of gut microbiota-related mechanisms, including dysbiosis and gut barrier function, and gut microbiota-derived metabolites on NAFLD and HCC pathogenesis and the potential therapeutic strategies for NAFLD and HCC. With a better understanding of the gut microbiota composition and function, new and improved diagnostic, prognostic, and therapeutic strategies for common liver diseases can be developed.
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Fujiwara, Naoto, and Yujin Hoshida. "Hepatocellular Carcinoma Risk Stratification by Genetic Profiling in Patients with Cirrhosis." Seminars in Liver Disease 39, no. 02 (March 25, 2019): 153–62. http://dx.doi.org/10.1055/s-0039-1681031.
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AbstractPrediction of future hepatocellular carcinoma (HCC) risk in the sizable chronic liver disease population is an urgent unmet need to enable regular HCC screening for early detection. Germline deoxyribonucleic acid polymorphisms likely represent etiology-specific host factors that determine HCC susceptibility, including single nucleotide polymorphisms in EGF, IFNL3, MICA, and TLL1 in hepatitis C with or without active viral infection, and PNPLA3, TM6SF2, and MBOAT7 in metabolic liver diseases. Transcriptome-based prognostic liver signature in diseased liver tissue has been associated with long-term HCC risk in viral and metabolic etiologies. Transcriptomic signatures of hepatic injury and specific cell type such as aggregated lymphocytes also predict HCC development. Circulating factors such as proteins and their chemical modification, nucleotides, and metabolites may serve for less-invasive assessment of short- or long-term HCC risk. These biomarkers will enable individual HCC risk-based personalized clinical management for cost-effective early HCC detection and improvement of patient survival.
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Mochizuki, Susumu, Hisashi Nakayama, Tokio Higaki, Takao Okubo, Yutaka Midorikawa, Masamichi Moriguchi, Osamu Aramaki, Shintaro Yamazaki, Masahiko Sugitani, and Tadatoshi Takayama. "Repeat Liver Resection for Hepatocellular Carcinoma Complicating Primary Biliary Cirrhosis." International Surgery 98, no. 4 (October 1, 2013): 424–27. http://dx.doi.org/10.9738/intsurg-d-13-00082.1.
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Abstract The incidence of hepatocellular carcinoma (HCC) complicating primary biliary cirrhosis (PBC) is between 0.7% and 16%. Repeat liver resection for recurrent HCC complicating PBC is not usually performed and not published because this approach is not generally applicable due to liver dysfunction. We applied repeat liver resection for these diseases. Three patients were diagnosed with PBC. The first HCC was noted at a mean of 6 years (4–17 years) after diagnosis of PBC. The second HCC occurred at a mean of 2.5 years (0.4–3 years) after the first surgery. All patients were treated with curative resection on first and second surgery. The mean overall survival time after the first liver resection was 46 months. Repeat liver resection for recurrent HCC complicating PBC is an option and may improve the outcome.
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Kawagishi, Naoki, Goki Suda, Yoshiya Yamamoto, Masaru Baba, Ken Furuya, Osamu Maehara, Shunsuke Ohnishi, et al. "Serum Angiopoietin-2 Predicts the Occurrence and Recurrence of Hepatocellular Carcinoma after Direct-Acting Antiviral Therapy for Hepatitis C." Viruses 15, no. 1 (January 7, 2023): 181. http://dx.doi.org/10.3390/v15010181.
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Progressive liver fibrosis after anti-HCV treatment is a risk factor for HCC. Angiopoietin-2 (Ang2) is associated with non-regression of liver fibrosis after direct-acting antiviral (DAA). This study evaluated the predictive value of serum Ang2 levels for HCC occurrence or recurrence after DAA administration. In this retrospective study, 310 HCV-infected patients treated with DAAs in 2014–2020 were screened and evaluated for HCC occurrence or recurrence every three–six months. Multivariate Cox regression analysis revealed that age ≥ 75 years (HR: 2.92, 95% CI: 1.34–6.33; p = 0.007) and baseline Ang2 level ≥ 464 pg/mL (HR: 2.75, 95% CI: 1.18–6.37; p = 0.019) were significantly associated with HCC occurrence after DAA therapy. A high or low risk of HCC after DAA therapy could be distinguished by the combination of age and baseline Ang2 level. The cumulative incidences of de-novo HCC at two and four years were 0.8% and 3.8% in the low-risk group and 22.6% and 27.1% in the high-risk group, respectively. Baseline Ang2 level ≥ 402 pg/mL was significantly associated with HCC recurrence in patients who achieved sustained virological response with DAAs (HR: 3.68). In conclusion, serum Ang2 levels can predict HCC occurrence and recurrence after successful HCV eradication by DAAs.
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Léveillé, Mélissa, and Jennifer L. Estall. "Mitochondrial Dysfunction in the Transition from NASH to HCC." Metabolites 9, no. 10 (October 16, 2019): 233. http://dx.doi.org/10.3390/metabo9100233.
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The liver constantly adapts to meet energy requirements of the whole body. Despite its remarkable adaptative capacity, prolonged exposure of liver cells to harmful environmental cues (such as diets rich in fat, sugar, and cholesterol) results in the development of chronic liver diseases (including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH)) that can progress to hepatocellular carcinoma (HCC). The pathogenesis of these diseases is extremely complex, multifactorial, and poorly understood. Emerging evidence suggests that mitochondrial dysfunction or maladaptation contributes to detrimental effects on hepatocyte bioenergetics, reactive oxygen species (ROS) homeostasis, endoplasmic reticulum (ER) stress, inflammation, and cell death leading to NASH and HCC. The present review highlights the potential contribution of altered mitochondria function to NASH-related HCC and discusses how agents targeting this organelle could provide interesting treatment strategies for these diseases.
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Yang, Yoon, So Kim, and Ekihiro Seki. "Inflammation and Liver Cancer: Molecular Mechanisms and Therapeutic Targets." Seminars in Liver Disease 39, no. 01 (January 17, 2019): 026–42. http://dx.doi.org/10.1055/s-0038-1676806.
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AbstractHepatocellular carcinoma (HCC) is associated with chronic inflammation and fibrosis arising from different etiologies, including hepatitis B and C and alcoholic and nonalcoholic fatty liver diseases. The inflammatory cytokines tumor necrosis factor-α and interleukin-6 and their downstream targets nuclear factor kappa B (NF-κB), c-Jun N-terminal kinase (JNK), and signal transducer and activator of transcription 3 drive inflammation-associated HCC. Further, while adaptive immunity promotes immune surveillance to eradicate early HCC, adaptive immune cells, such as CD8+ T cells, Th17 cells, and B cells, can also stimulate HCC development. Thus, the role of the hepatic immune system in HCC development is a highly complex topic. This review highlights the role of cytokine signals, NF-κB, JNK, innate and adaptive immunity, and hepatic stellate cells in HCC and discusses whether these pathways could be therapeutic targets. The authors will also discuss cholangiocarcinoma and liver metastasis because biliary inflammation and tumor-associated stroma are essential for cholangiocarcinoma development and because primary tumor-derived inflammatory mediators promote the formation of a “premetastasis niche” in the liver.
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Orcutt, Sonia T., and Daniel A. Anaya. "Liver Resection and Surgical Strategies for Management of Primary Liver Cancer." Cancer Control 25, no. 1 (January 1, 2018): 107327481774462. http://dx.doi.org/10.1177/1073274817744621.
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Primary liver cancer—including hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC)—incidence is increasing and is an important source of cancer-related mortality worldwide. Management of these cancers, even when localized, is challenging due to the association with underlying liver disease and the complex anatomy of the liver. Although for ICC, surgical resection provides the only potential cure, for HCC, the risks and benefits of the multiple curative intent options must be considered to individualize treatment based upon tumor factors, baseline liver function, and the functional status of the patient. The principles of surgical resection for both HCC and ICC include margin-negative resections with preservation of adequate function of the residual liver. As the safety of surgical resection has improved in recent years, the role of liver resection for HCC has expanded to include selected patients with preserved liver function and small tumors (ablation as an alternative), tumors within Milan criteria (transplant as an alternative), and patients with large (>5 cm) and giant (>10 cm) HCC or with poor prognostic features (for whom surgery is infrequently offered) due to a survival benefit with resection for selected patients. An important surgical consideration specifically for ICC includes the high risk of nodal metastasis, for which portal lymphadenectomy is recommended at the time of hepatectomy for staging. For both diseases, onco-surgical strategies including portal vein embolization and parenchymal-sparing resections have increased the number of patients eligible for curative liver resection by improving patient outcomes. Multidisciplinary evaluation is critical in the management of patients with primary liver cancer to provide and coordinate the best treatments possible for these patients.
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Rossetto, Anna, Valli De Re, Agostino Steffan, Matteo Ravaioli, Gianmaria Miolo, Patrizia Leone, Vito Racanelli, Alessandro Uzzau, Umberto Baccarani, and Matteo Cescon. "Carcinogenesis and Metastasis in Liver: Cell Physiological Basis." Cancers 11, no. 11 (November 5, 2019): 1731. http://dx.doi.org/10.3390/cancers11111731.
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Hepatocellular carcinoma (HCC) incidence is rising. This paper summarises the current state of knowledge and recent discoveries in the cellular and physiological mechanisms leading to the development of liver cancer, especially HCC, and liver metastases. After reviewing normal hepatic cytoarchitecture and immunological characteristics, the paper addresses the pathophysiological factors that cause liver damage and predispose to neoplasia. Particular attention is given to chronic liver diseases, metabolic syndrome and the impact of altered gut microbiota, disrupted circadian rhythm and psychological stress. Improved knowledge of the multifactorial aetiology of HCC has important implications for the prevention and treatment of this cancer and of liver metastases in general.
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Khan, Majid, Sanaullah Khan, Mehrunnisa Fatima Gondal, Safia Bibi, Bakht Tarin Khan, Abdul Majid, Ayesha Khattak, et al. "Genetic diversity in enhancer II region of HBV genotype D and its association with advanced liver diseases." PLOS ONE 17, no. 1 (January 4, 2022): e0261721. http://dx.doi.org/10.1371/journal.pone.0261721.
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Background Hepatitis B Virus (HBV) is one of the most common human infectious agents, and the mutations in its genome may cause chronic hepatitis (CH), liver cirrhosis (LC), and hepatocellular carcinoma (HCC). This study was designed to characterize the enhancer-II (Enh-II) region of X gene in HBV positive patients to assess the association of such mutations with CH, LC, and HCC. Methods HBV positive samples (N = 200) with patients’ demographic and clinical data were collected from different regions of Khyber Pakhtunkhwa (KP), Pakistan. The Enh-II region of the HBx gene was sequenced and zanalyzed for polymorphism associated with advanced liver disease. Univariate and logistic regression analyses were performed to evaluate potent mutations associated with a risk for LC and HCC. Results HBV Enh-II region sequences analysis revealed 25 different mutations. The highest frequency of mutations S101F (62.2%), A102V/R/G/I (56.25%), M103L/A (68.75%)were found in HCC, followed in LC and CH patients as 57.1%, 42.8%, 28.52% 16%, 15.2% and 18.4% respectively. H94 deletion in the α-box of the Enh-II region, associated with a high risk of HCC was found in half of the HCC patients. This deletion was present in 28.5% of LC and 6.5% of CH patients. Importantly, the high frequency of some notable mutations such as E109A/Y, A110S/K, Y111D/E, and F112L was first time reported in the entire study population. The frequencies of these mutations were high in HCC (43.75%, 37.5%, 50% and 43.75% respectively) as compared to LC (14.28%, 14.28%, 28.2% and 42.8%) and CH patients (12.8%, 15.2%, 16.8% and 16% respectively). Conclusion Mutations associated with LC and HCC are prevalent in the Enh-II region in Pakistani HBV isolates. The mutations found are alarming in CH patients as these may progress to LC and HCC in a large number of patients.
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Plissonnier, Marie-Laure, Katharina Herzog, Massimo Levrero, and Mirjam Zeisel. "Non-Coding RNAs and Hepatitis C Virus-Induced Hepatocellular Carcinoma." Viruses 10, no. 11 (October 30, 2018): 591. http://dx.doi.org/10.3390/v10110591.
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Hepatitis C virus (HCV) infection is a worldwide health problem and is one of the main causes of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). Despite recent improvements, effective treatments for HCC are still missing and new tools for early detection are needed. Non-coding RNAs (ncRNAs) have emerged as important regulators of gene expression and key players in human carcinogenesis, including HCC. Aberrant expression of ncRNAs is associated with HCC metastasis, invasion, dissemination, and recurrence. This review will focus on the recent advances in ncRNA expression profiles, their dysregulation in HCV-related HCC, and the clinical perspective of ncRNA signatures for the early detection of HCC.
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Radmanić, Leona, and Snježana Zidovec-Lepej. "The Role of Stem Cell Factor, Epidermal Growth Factor and Angiopoietin-2 in HBV, HCV, HCC and NAFLD." Life 12, no. 12 (December 9, 2022): 2072. http://dx.doi.org/10.3390/life12122072.
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Growth factors play a significant role in the immunopathogenesis of liver diseases, especially in liver fibrosis and cirrhosis. They can also play a role in liver regeneration and tissue repair. The regenerative capacity of the liver has been well established. Molecular mechanisms leading to regeneration involve a complex network of diverse molecules. Chronic liver injury leads to the dysregulation of regenerative mechanisms in the liver that, in addition to molecular oncogenesis, lead to uncontrolled cell proliferation and development of hepatocellular carcinoma (HCC). Stem cell factor (SCF), epidermal growth factor (EGF) and Angiopietin-2 (Ang-2) have been shown to be extremely important in the pathogenesis of liver diseases, and given their role in hepatitis B (HBV) or C virus (HCV), HCC and nonalcoholic fatty liver disease (NAFLD), they seem to be potential targets for future research into antifibrotic drugs. The role of SCF receptor c-kit in the liver is debatable, as it has impact on both liver regeneration and liver disease. EGF is a potential indicator of the survival of patients with HCC and can be a biomarker and therapeutic target structure in HCC. Further research is needed to investigate the potential role of Ang-2 for NAFLD associated with liver damage as a non-invasive circulating biomarker.
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Wang, Yijun, Shigang Shan, Yingtang Gao, Qin Zhang, Fengmei Wang, Xiang Jing, and Zhi Du. "Correlation of prognosis with the gradually increased Golgi protein 73 expression in the progression of benign liver diseases to precancerous lesions and hepatocellular carcinoma." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): e15050-e15050. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e15050.
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e15050 Background: Serum golgi protein73 (sGP73) is a novel biomarker for hepatocellular carcinoma (HCC). However, there are few reports on the pattern of GP73 expression in the progression of benign liver diseases to precancerous lesions and HCC. This study aimed to investigate GP73 expression and it correlation with clinicopathologic parameters. Methods: Tissue GP73 (tGP73) levels were detected in specimens of group A (n=186) including HCC (n=62), peritumoral tissue (PTL) (n=43), high/low-grade hepatic atypical hyperplasia (AH) (n=32/2), chronic hepatitis B (CHB) (n=42) and normal controls (NC) (n=5) by immunohistochemistry, and GP73 expression in group B (n=159) and group C (n=16) were detected by RT-PCR and Western blot respectively. sGP73 levels were detected in subjects of group D (n=287) by ELISA. Results: GP73 expression increased gradually from NC, CHB, PTL to high-grade AH and HCC at both protein and mRNA levels (P<0.05), while sGP73 in HCC group was lower than in liver cirrhosis (LC) group (P<0.001). Both tGP73 and sGP73 levels were negatively associated with tumor size and TNM stage, and tGP73 levels were positively associated with tumor differentiation. The high-tGP73 group showed significantly better overall and disease-free survival than low-tGP73 group (P=0.008, P=0.018). Multivariate analysis revealed that the tGP73 level was an independent prognostic factor for HCC, but not sGP73. Conclusions: GP73 increases gradually in the progression ofbenign liver diseases to precancerous lesions and HCC. This expression pattern suggests the regulatory mechanism of GP73 is related to the progression of chronic liver diseases. Furthermore, a high level of tGP73 is a favorable prognostic factor for HCC.
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Smirne, Carlo, Cristina Rigamonti, Carla De Benedittis, Pier Paolo Sainaghi, Mattia Bellan, Michela Emma Burlone, Luigi Mario Castello, and Gian Carlo Avanzi. "Gas6/TAM Signaling Components as Novel Biomarkers of Liver Fibrosis." Disease Markers 2019 (September 8, 2019): 1–15. http://dx.doi.org/10.1155/2019/2304931.
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Liver fibrosis consists in the accumulation of extracellular matrix components mainly derived from activated hepatic stellate cells. This is commonly the result of chronic liver injury repair and represents an important health concern. As liver biopsy is burdened with many drawbacks, not surprisingly there is great interest to find new reliable noninvasive methods. Among the many are new potential fibrosis biomarkers under study, some of the most promising represented by the growth arrest-specific gene 6 (Gas6) serum protein and its family of tyrosine kinase receptors, namely, Tyro3, Axl, and MERTK (TAM). Gas6/TAM system (mainly, Axl and MERTK) has in fact recently emerged as an important player in the progression of liver fibrosis. This review is aimed at giving an overall perspective of the roles played by these molecules in major chronic liver diseases. The most promising findings up to date acknowledge that both Gas6 and its receptor serum levels (such as sAxl and, probably, sMERTK) have been shown to potentially allow for easy and accurate measurement of hepatic fibrosis progression, also providing indicative parameters of hepatic dysfunction. Although most of the current scientific evidence is still preliminary and there are no in vivo validation studies on large patient series, it still looks very promising to imagine a possible future prognostic role for these biomarkers in the multidimensional assessment of a liver patient. One may also speculate on a potential role for this system targeting (e.g., with small molecule inhibitors against Axl) as a therapeutic strategy for liver fibrosis management, always bearing in mind that any such therapeutic approach might face toxicity.
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Micali, Cristina, Ylenia Russotto, Grazia Caci, Manuela Ceccarelli, Andrea Marino, Benedetto Maurizio Celesia, Giovanni Francesco Pellicanò, Giuseppe Nunnari, and Emmanuele Venanzi Rullo. "Loco-Regional Treatments for Hepatocellular Carcinoma in People Living with HIV." Infectious Disease Reports 14, no. 1 (January 7, 2022): 43–55. http://dx.doi.org/10.3390/idr14010006.
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Hepatocellular carcinoma (HCC) accounts for approximately 75–90% of primary liver cancers and is the sixth most common cancer and the third leading cause of cancer-related deaths worldwide. In the HIV-positive population, the risk of HCC is approximately four times higher than in the general population, with higher cancer-specific mortality than in HIV-negative patients. In most cases, HCC diagnosis is made in patients younger than the HIV-negative population and in the intermediate-advanced stage, thus limiting the therapeutic possibilities. Treatment choice in HIV-positive patients with HCC is subject to cancer staging, liver function and health status, as for HIV-negative and non-HIV-negative HCC patients. There are relatively few studies on the efficacy and safety in HIV-positive patients to date in loco-regional treatments for HCC. So far, literature shows that curative treatments such as radiofrequency ablation (RFA) have no significant differences in overall survival between HIV-positive and HIV-negative patients, as opposed to palliative treatments such as TACE, where there is a significant difference in overall survival. Although it can be assumed that the most recently discovered loco-regional therapies are applicable to HIV-positive patients with HCC in the same way as HIV-negative patients, further studies are needed to confirm this hypothesis. The purpose of our review is to evaluate these treatments, their efficacy, effectiveness, safety and their applicability to HIV-positive patients.
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Liang, Zenghui, Yingtang Gao, Wenxia Shi, Daokuan Zhai, Shilei Li, Li Jing, Hua Guo, Tong Liu, Yajie Wang, and Zhi Du. "Expression and Significance of MicroRNA-183 in Hepatocellular Carcinoma." Scientific World Journal 2013 (2013): 1–6. http://dx.doi.org/10.1155/2013/381874.
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Objective. In our previous study, we found that some miRNAs were deregulated in hepatocellular carcinoma (HCC), including miR-183. However, the expression of miR-183 in the progression of benign liver diseases to HCC and its correlation with clinicopathologic factors remain undefined.Methods. MiR-183 expression was measured in normal controls (NC) (n=21), chronic viral hepatitis B or C (CH) tissues (n=10), liver cirrhosis (LC) tissues (n=18), HCC tissues (n=92), and adjacent nontumor tissues (NT) (n=92) by quantitative real-time reverse-transcription polymerase chain reaction (qRT-PCR).Results. The expression levels of miR-183 were significantly higher in HCC than in NT, LC, CH, and NL (P=0.001,P<0.001,P=0.011,P<0.001, resp.). The upregulated miR-183 in HCC was correlated with TNM stage (P=0.042) and cirrhosis (P=0.025). The Kaplan-Meier survival analysis showed that miR-183 expression was not associated with the survival of HCC patients. However, miR-183 yielded an area under the curve (AUC) of 0.808 with 59.8% sensitivity and 91.8% specificity in discriminating HCC from benign liver diseases (CH and LC) or NC.Conclusions. The upregulated miR-183 may associate with onset and progression of HCC, but not with the patient survival. A further research is needed to determine the potential of miR-183 as biomarker for HCC.
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Kano, Noora, Elizabeth J. Want, and Mark J. W. McPhail. "Metabolomics in Advanced Liver Disease." Current Treatment Options in Gastroenterology 19, no. 2 (April 25, 2021): 380–97. http://dx.doi.org/10.1007/s11938-021-00347-w.
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Abstract Purpose of review Cirrhosis is one of the most important global public health problems. Patients with cirrhosis risk progression to acute-on-chronic liver failure (ACLF), associated with high mortality rates, and development of hepatocellular carcinoma (HCC). Metabolomics could identify urgently required novel biomarkers to improve disease diagnosis, monitor progression, and identify therapies. Recent findings In this review, current metabolic studies in decompensated cirrhosis, ACLF, and HCC over the past 3 years are summarised. Over numerous metabolomics studies, in cirrhosis, common alterations in proteins, carbohydrates, lipids, bile acids, and microbial metabolites were identified. In ACLF, changes in metabolites related to energy metabolism, amino acids, lipids, bile acids, and microbial metabolites were reported. Amino acids, bile acids, free fatty acids, and phospholipids were identified as important metabolite classes for discrimination between cirrhosis and HCC. Summary Metabolomics can improve our understanding of advanced liver diseases and provide the basis of the future studies and therapeutic advancements.
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Lu, Shelly C., and José M. Mato. "S-adenosylmethionine in Liver Health, Injury, and Cancer." Physiological Reviews 92, no. 4 (October 2012): 1515–42. http://dx.doi.org/10.1152/physrev.00047.2011.
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S-adenosylmethionine (AdoMet, also known as SAM and SAMe) is the principal biological methyl donor synthesized in all mammalian cells but most abundantly in the liver. Biosynthesis of AdoMet requires the enzyme methionine adenosyltransferase (MAT). In mammals, two genes, MAT1A that is largely expressed by normal liver and MAT2A that is expressed by all extrahepatic tissues, encode MAT. Patients with chronic liver disease have reduced MAT activity and AdoMet levels. Mice lacking Mat1a have reduced hepatic AdoMet levels and develop oxidative stress, steatohepatitis, and hepatocellular carcinoma (HCC). In these mice, several signaling pathways are abnormal that can contribute to HCC formation. However, injury and HCC also occur if hepatic AdoMet level is excessive chronically. This can result from inactive mutation of the enzyme glycine N-methyltransferase (GNMT). Children with GNMT mutation have elevated liver transaminases, and Gnmt knockout mice develop liver injury, fibrosis, and HCC. Thus a normal hepatic AdoMet level is necessary to maintain liver health and prevent injury and HCC. AdoMet is effective in cholestasis of pregnancy, and its role in other human liver diseases remains to be better defined. In experimental models, it is effective as a chemopreventive agent in HCC and perhaps other forms of cancer as well.
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Chang, Kuo-Chin, Ming-Tsung Lin, Jing-Houng Wang, Chao-Hung Hung, Chien-Hung Chen, Sherry Yueh-Hsia Chiu, and Tsung-Hui Hu. "HBcrAg Predicts Hepatocellular Carcinoma Development in Chronic B Hepatitis Related Liver Cirrhosis Patients Undergoing Long-Term Effective Anti-Viral." Viruses 14, no. 12 (November 29, 2022): 2671. http://dx.doi.org/10.3390/v14122671.
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Hepatitis B core-related antigen (HBcrAg) is a predictor of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients. Studies on anti-viral therapy have shown that the use of NUC therapy in HBV patients could reduce the incidence of HCC. However, the incidence of HCC continues to increase after long-term anti-viral therapy. The relationship between HBcrAg and HCC development in CHB-related liver cirrhosis (LC) patients undergoing long-term anti-viral therapy is still unclear. This study enrolled 1108 treatment-naïve CHB patients diagnosed with HBV-related LC receiving NUC therapy from April 1999 to February 2015. The baseline biomarkers, disease history, and following results were collected by the hospital. Among the 1108 patients, 219 developed HCC within a median follow-up period of 6.85 years. A multivariable Cox regression model was used, with adjustment for age, gender, FIB-4, DM, and HBsAg-HQ. The adjusted hazard ratios for the HBcrAg tertile levels were 1.70 (95%CI: 1.21, 2.39) and 2.14 (95%CI: 1.50, 3.05) for levels 3.4–4.9 and >4.9 logU/mL, respectively, compared with levels ≤3.4. The effect of the HBcrAg level on HCC incidence was found to be significantly modified by HBsAg-HQ, where lower HBsAg-HQ (≤ 3) values were associated with a significantly higher risk, but HBsAg-HQ levels >3 were not. Our results highlight that, after adjustment for potential confounding factors, patients with CHB-related LC and higher HBcrAg levels are at significant risk for HCC development, even while undergoing long-term effective anti-viral therapy. The HBcrAg level is therefore an independent risk factor for HCC development, especially for patients with HBsAg-HQ levels <3.
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Yao, Xue-Qing, Ling Li, Long-Zhen Piao, Guang-Jian Zhang, Xue-Zhu Huang, Ying Wang, and Zhe-Long Liang. "Overexpression of Ubiquitin-Specific Protease15 (USP15) Promotes Tumor Growth and Inhibits Apoptosis and Correlated With Poor Disease-Free Survival in Hepatocellular Carcinoma." Technology in Cancer Research & Treatment 19 (January 1, 2020): 153303382096745. http://dx.doi.org/10.1177/1533033820967455.
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USP15 is a member of ubiquitin-specific proteases (USPs, the largest subfamily of deubiquitinases) and functions as a stabilize factor of target proteins in reversible ubiquitiantion progression. Dysregulated expression of USP15 has been observed in various cancers. However the expression profile and regulatory mechanism of USP15 in hepatocellular carcinoma (HCC) remains largely elusive. To exam the USP15 expression changes in the progression of HCC, we performed IHC analysis to test USP15 expression in a series of cancer-prone diseases including 2 normal liver tissues, 6 liver cirrhosis, 16 primary liver lesions and 15 metastases of hepatocellular carcinoma. The expression of USP15 was upregulated in various liver diseases in compared with normal tissue significantly (p < 0.05). Although no significant different of USP15 expression were discovered between cirrhotic tissue and primary tissue, its expression in HCC metastatic tissue was upregulated. Subsequently, we test the USP15 expression profile in a cohort of 66 HCC patients. USP15 expression was positively correlated with the recurrence of HCC significantly (p = 0.004). HCC patients with high USP15 expression had shorter disease free survival time in compare with those with low USP15 expression (56.9% VS 26.7%, P = 0.012). Subsequently, Cox multivariate analyses of clinical factors associated with disease free survival were performed and USP15 expression (p = 0.008) together with tumor size (p = 0.034) were proved to be independent predict factors in HCC. Then, we silenced USP15 expression in HCC cells and the results showed that downregulated USP15 expression resulting proliferation inhibition and apoptosis induction. In conclusion, our results suppose USP15 to be a potential target in HCC.
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Mello, Tommaso, Maria Materozzi, and Andrea Galli. "PPARs and Mitochondrial Metabolism: From NAFLD to HCC." PPAR Research 2016 (2016): 1–18. http://dx.doi.org/10.1155/2016/7403230.
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Metabolic related diseases, such as type 2 diabetes, metabolic syndrome, and nonalcoholic fatty liver disease (NAFLD), are widespread threats which bring about a significant burden of deaths worldwide, mainly due to cardiovascular events and cancer. The pathogenesis of these diseases is extremely complex, multifactorial, and only partially understood. As the main metabolic organ, the liver is central to maintain whole body energetic homeostasis. At the cellular level, mitochondria are the metabolic hub connecting and integrating all the main biochemical, hormonal, and inflammatory signaling pathways to fulfill the energetic and biosynthetic demand of the cell. In the liver, mitochondria metabolism needs to cope with the energetic regulation of the whole body. The nuclear receptors PPARs orchestrate lipid and glucose metabolism and are involved in a variety of diseases, from metabolic disorders to cancer. In this review, focus is placed on the roles of PPARs in the regulation of liver mitochondrial metabolism in physiology and pathology, from NAFLD to HCC.
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Tu, Thomas, Sandra Bühler, and Ralf Bartenschlager. "Chronic viral hepatitis and its association with liver cancer." Biological Chemistry 398, no. 8 (July 26, 2017): 817–37. http://dx.doi.org/10.1515/hsz-2017-0118.
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AbstractChronic infection with hepatitis viruses represents the major causative factor for end-stage liver diseases, including liver cirrhosis and primary liver cancer (hepatocellular carcinoma, HCC). In this review, we highlight the current understanding of the molecular mechanisms that drive the hepatocarcinogenesis associated with chronic hepatitis virus infections. While chronic inflammation (associated with a persistent, but impaired anti-viral immune response) plays a major role in HCC initiation and progression, hepatitis viruses can also directly drive liver cancer. The mechanisms by which hepatitis viruses induce HCC include: hepatitis B virus DNA integration into the host cell genome; metabolic reprogramming by virus infection; induction of the cellular stress response pathway by viral gene products; and interference with tumour suppressors. Finally, we summarise the limitations of hepatitis virus-associated HCC model systems and the development of new techniques to circumvent these shortcomings.
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Wei, Q., Y. Jiang, M. Yang, J. Xie, M. Xiao, and J. Gu. "AB1104 ANALYSIS OF ANTINUCLEAR ANTIBODY TITERS AND PATTERNS USING HEP 2 INDIRECT IMMUNOFLUORESCENCE IN VARIOUS LIVER DISEASES." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 1841–42. http://dx.doi.org/10.1136/annrheumdis-2020-eular.726.
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Background:Abnormal liver function can be seen in not only hepatitis B virus infection (HBV), hepatitis C virus infection (HCV), hepatic carcinoma (HCC), but also in primary biliary cirrhosis (PBC), autoimmune hepatitis (AIH), and systemic autoimmune rheumatic diseases (SARD). Antinuclear antibody (ANA) testing using indirect immunofluorescence assay (IIFA) is a common and economical method which contributes to detect SARD and autoimmune liver diseases [1].Objectives:Our objective was to investigate ANA positivity, titers and their patterns in multiple liver diseases, including PBC, AIH, HBV, HCV, and HCC, compared to healthy controls (HC).Methods:2537 patients with SARD, 137 PBC cases, 57 AIH cases, 3420 HBV cases, 769 HCV cases, 268 HCC cases, and 1073 HC were retrospectively assessed. The titers and patterns of ANA were detected with the IIFA method.Results:ANA positivity rate was considerably discernible between these diseases, which is 90.1% in SARD, 93.4% in PBC, 49.1% in AIH, 19.1% in HBV, 13.9% in HCV and 23.5% in HCC. Moreover, only 4.9% of HCC cases, 2.5% of HBV patients and 1.6% of HCV patients had an ANA titer ≥ 1:320. The mixed pattern which composed of at least two patterns majorly lied in PBC. AC-15 and AC-21 was frequently related to liver diseases; the former pattern was more frequently found in AIH (84.2%) and PBC (8.8%), and the latter pattern was easily seen in PBC (62.2%) and HCC (22.6%). The positive rate of ANA in HC was 12.2% and its major pattern was AC-2.Conclusion:There are differences in ANA positivity among patients with SARD and various liver diseases. Some mixed patterns may provide important evidence for the diagnosis of PBC. Clinicians should pay attention to ANA patterns and titer during the interpretation of this test.References:[1]Damoiseaux J, Andrade L, Carballo OG, Conrad K, Francescantonio P, Fritzler MJ, Garcia DLTI, Herold M, Klotz W, Cruvinel WM, Mimori T, von Muhlen C, Satoh M, Chan EK, (2019) Clinical relevance of HEp-2 indirect immunofluorescent patterns: the International Consensus on ANA patterns (ICAP) perspective. ANN RHEUM DIS 78: 879-889Figure 1.The Proportion of Each ANA Pattern Exhibited in Different Diseases and HCANA: antinuclear antibodies; HC: healthy controls; PBC: primary biliary cirrhosis; AIH: autoimmune hepatitis; SARD: systemic autoimmune rheumatic diseases; HBV: hepatitis B virus infection: HCV: hepatitis C virus infection: HCC: hepatic carcinoma.Acknowledgments:None.Disclosure of Interests:None declared
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Lo, Emily Kwun Kwan, Felicianna, Jing-Hang Xu, Qiao Zhan, Zheng Zeng, and Hani El-Nezami. "The Emerging Role of Branched-Chain Amino Acids in Liver Diseases." Biomedicines 10, no. 6 (June 18, 2022): 1444. http://dx.doi.org/10.3390/biomedicines10061444.
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Chronic liver diseases pose a substantial health burden worldwide, with approximately two million deaths each year. Branched-chain amino acids (BCAAs)—valine, leucine, and isoleucine—are a group of essential amino acids that are essential for human health. Despite the necessity of a dietary intake of BCAA, emerging data indicate the undeniable correlation between elevated circulating BCAA levels and chronic liver diseases, including non-alcoholic fatty liver diseases (NAFLD), cirrhosis, and hepatocellular carcinoma (HCC). Moreover, circulatory BCAAs were positively associated with a higher cholesterol level, liver fat content, and insulin resistance (IR). However, BCAA supplementation was found to provide positive outcomes in cirrhosis and HCC patients. This review will attempt to address the contradictory claims found in the literature, with a special focus on BCAAs’ distribution, key signaling pathways, and the modulation of gut microbiota. This should provide a better understanding of BCAAs’ possible contribution to liver health.
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Manzia, Tommaso Maria, Alessandro Parente, Roberta Angelico, Carlo Gazia, and Giuseppe Tisone. "The Revolution in Indication for Liver Transplantation: Will Liver Metastatic Disease Overcome the End-Stage Liver Disease in the Next Future?" Transplantology 1, no. 2 (December 2, 2020): 111–22. http://dx.doi.org/10.3390/transplantology1020011.
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Indications for liver transplantation (LT) have constantly been evolving during the last few decades due to a better understanding of liver diseases and innovative therapies. Likewise, also the underlying causes of liver disease have changed. In the setting of transplant oncology, recent developments have pushed the boundaries of oncological indications for LT outside hepatocellular carcinoma (HCC), especially for secondary liver tumors, such as neuroendocrine and colorectal cancer. In the next years, as more evidence emerges, LT could become the standard treatment for well-selected metastatic liver tumors. In this manuscript, we review and summarize the available evidence for LT in liver tumors beyond HCC with a focus on metastatic liver malignancies, highlighting the importance of these new concepts for future implications.
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Sasaki, Reina, Tatsuo Kanda, Osamu Yokosuka, Naoya Kato, Shunichi Matsuoka, and Mitsuhiko Moriyama. "Exosomes and Hepatocellular Carcinoma: From Bench to Bedside." International Journal of Molecular Sciences 20, no. 6 (March 20, 2019): 1406. http://dx.doi.org/10.3390/ijms20061406.
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As hepatocellular carcinoma (HCC) usually occurs in the background of cirrhosis, which is an end-stage form of liver diseases, treatment options for advanced HCC are limited, due to poor liver function. The exosome is a nanometer-sized membrane vesicle structure that originates from the endosome. Exosome-mediated transfer of proteins, DNAs and various forms of RNA, such as microRNA (miRNA), long noncoding RNA (lncRNA) and messenger RNA (mRNA), contributes to the development of HCC. Exosomes mediate communication between both HCC and non-HCC cells involved in tumor-associated cells, and several molecules are implicated in exosome biogenesis. Exosomes may be potential diagnostic biomarkers for early-stage HCC. Exosomal proteins, miRNAs and lncRNAs could provide new biomarker information for HCC. Exosomes are also potential targets for the treatment of HCC. Notably, further efforts are required in this field. We reviewed recent literature and demonstrated how useful exosomes are for diagnosing patients with HCC, treating patients with HCC and predicting the prognosis of HCC patients.
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Agha, Adnan, Manuele Furnari, Rafaat Morched Chakik, Mamdouh M. Abdulhadi Ali, Dib Alsaudi, Mohammed Bazeed, Vincenzo Savarino, and Edoardo G. Giannini. "Hepatocellular Carcinoma Is the Most Frequent Final Diagnosis of Focal Liver Lesions Identified in a Cross-Sectional Evaluation of Patients with Chronic Liver Disease in Saudi Arabia." Journal of Cancer Research 2015 (January 6, 2015): 1–4. http://dx.doi.org/10.1155/2015/492782.
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Background. Hepatocellular carcinoma (HCC) is a frequent diagnosis in patients with chronic liver disease (CLD) and a newly identified liver lesion, although benign diseases may also be responsible for this finding. Objective. To evaluate the characteristics of focal liver lesions in a population of patients with CLD not under surveillance for HCC in the Middle East. Methods. We performed a cross-sectional study evaluating 77 patients with CLD and a focal liver lesion identified during ultrasonography. Patients’ characteristics were analyzed on the basis of the final diagnosis (HCC versus benign lesions). Results. The most frequent diagnosis was HCC (64.9%). These patients were older (median age 64 versus 55 years, P=0.003) and cirrhotics (80.0% versus 51.9%, P=0.018), with multinodular lesions (58.0% versus 29.6%, P=0.031) and portal vein thrombosis (24.0% versus 0%, P=0.001) compared to patients with benign lesions. Prevalence of elevated alpha-fetoprotein (>10 ng/mL) was similar in both groups (80.0% versus 88.9%, P=0.198). Cirrhosis (odds ratio: 3.283) and multinodularity (odds ratio: 2.898) were independently associated with HCC. Conclusions. HCC is the most common diagnosis in Middle-Eastern patients with CLD and a liver lesion identified outside HCC surveillance programs, especially in cirrhotic patients. In these patients, elevated alpha-fetoprotein does not differentiate HCC from benign lesions.
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Chang, Chiung-Fang, Ssu-Jung Lu, Chih-Hsuan Wang, and Kuo-Shyang Jeng. "MAPK regulates the immune responses in liver cirrhosis and hepatocellular carcinoma." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 64.03. http://dx.doi.org/10.4049/jimmunol.206.supp.64.03.
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Abstract Liver diseases causes approximately 2 million death per year worldwide. Aberrant apoptosis is associated with the progression of liver fibrosis and cirrhosis, even for hepatocellular carcinoma (HCC). HCC is one of major causes of cancer death worldwide due to high heterogeneity and recurrence. Immune scores could be used to link HCC disease-free survival and to identify several microenvironment-related genes. MAPK signaling plays an important role in liver fibrogenesis and HCC. ERK activation is associated with aggressive HCC, resulting in short overall survival. In this study, the immune responses of liver fibrosis and HCC mediated by ERK signaling were investigated. Both WT and Erk2 deficient mice were fed with choline-deficient diet to induce liver cirrhosis. Erk2 deficient livers have less degree of liver cirrhosis than WT livers. Our preliminary data suggested there was a significant increasement in the percentages of regulatory T cells in Erk2 deficient splenocytes. The percentages of follicular T cells were similar in WT and Erk2 deficient splenocytes. However, there was no significant differences in Erk2 deficient hepatic CD4 T cells for regulatory T cells and follicular T cells. In addition, Egr1 is one of ERK signaling downstream transcription factors. In HCC, there were about 10-fold differences in gene expression in the Egr1high and Egr1low group and the differential gene expression was identified. In hepatotoxicity, there was about more than 100 genes involved in HCC, 50~70 genes in liver cirrhosis, liver inflammation and liver necrosis/cell death. Therefore, MAPK signaling plays an important role in regulating the immune responses in the liver cirrhosis and HCC progression.
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Cai, Chao, Jing Lin, Ji Li, Xiao-Dong Wang, Lan-Man Xu, Da-Zhi Chen, and Yong-Ping Chen. "miRNA-432 and SLC38A1 as Predictors of Hepatocellular Carcinoma Complicated with Alcoholic Steatohepatitis." Oxidative Medicine and Cellular Longevity 2022 (May 25, 2022): 1–18. http://dx.doi.org/10.1155/2022/4832611.
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Alcoholic steatohepatitis (ASH) is asymptomatic in the early stages and is typically advanced at the time of diagnosis. With the global rise in alcohol abuse, ASH is currently among the most detrimental diseases around the world. Hepatocellular carcinoma (HCC) is one of the final outcomes of numerous liver diseases. However, at present, HCC screening is mostly focused on liver cancer development. Moreover, there is no effective biomarker to predict the prognosis and recurrence of liver cancer. Meanwhile, there are limited studies on the prognosis and recurrence of HCC patients complicated with ASH. In this study, using bioinformatic analysis as well as cellular and animal models, we screened the differentially expressed (DE) miRNA-432 and SLC38A1 gene in ASH. Based on our analysis, miRNA-432 targeted SLC38A1, and the levels of miRNA-432 and SLC38A1 could accurately predict the overall survival (OS) and relapse free survival (RFS) in patients with liver cancer. Hence, these two genetic elements have the potential to synergistically predict the prognosis and recurrence of HCC complicated with ASH.
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Nguyen-Dinh, Song-Huy, Wei-Feng Li, Yueh-Wei Liu, Chih-Chi Wang, Yen-Hao Chen, Jing-Houng Wang, and Chao-Hung Hung. "Comparisons of Viral Etiology and Outcomes of Hepatocellular Carcinoma Undergoing Liver Resection between Taiwan and Vietnam." Viruses 14, no. 11 (November 20, 2022): 2571. http://dx.doi.org/10.3390/v14112571.
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Epidemiologic data have suggested that etiologic variations of hepatocellular carcinoma (HCC) exist in different geographic areas, and might be associated with different outcomes. We compared the viral etiology, clinicopathological characteristics and surgical outcomes between 706 Taiwanese and 1704 Vietnamese patients with HCC undergoing liver resection. Vietnamese patients had a significantly higher ratio of hepatitis B virus (HBV) (p < 0.001) and a lower ratio of hepatitis C virus (HCV) (p < 0.001) and non-B non-C than Taiwanese patients. Among patients with HBV or non-B non-C, the mean age was younger in Vietnam than in Taiwan (p < 0.001, p = 0.001, respectively). The HCC patients in Vietnam had significantly higher serum alpha-fetoprotein (AFP) levels (p < 0.001), larger tumors (p < 0.001), and a higher ratio of macrovascular invasion (p < 0.001) and extrahepatic metastasis (p < 0.001), compared to those in Taiwan. Patients treated in Vietnam had a higher tumor recurrent rate (p < 0.001), but no difference in overall survival was found between both groups. In subgroup analysis, the recurrent rate of HCC was the highest in patients with dual HBV/HCV, followed by HCV or HBV, and non-B non-C (p < 0.001). In conclusion, although the viral etiology and clinicopathological characteristics of HCC differed, postoperative overall survival was comparable between patients in Taiwan and Vietnam.