Epidemiology Of Hepatocellular Carcinoma Research Articles

Changing etiology and epidemiology of hepatocellular carcinoma: Asia and worldwide.

Approximately 80% of hepatocellular carcinoma (HCC) cases arise in sub-Saharan Africa and Eastern Asia, following a similarly high prevalence of chronic hepatitis B virus (HBV) carriers in these regions. The etiology and epidemiology of HCC have recently changed worldwide. Although HBV infection is the main contributor to HCC development, a slow but continuous decline in HBV infection rates has been reported since 1990. Owing to the widespread use of direct-acting antivirals, the incidence of hepatitis C virus-related HCC has remarkably decreased in Japan and European countries. In Korea, Taiwan, and Singapore, the incidence of HBV-related HCC has significantly decreased owing to vaccination against HBV. Globally, while HBV accounted for more than half of HCCs in 1990, this had decreased to 42% in 2019. In contrast, the proportion of patients with alcoholic- and nonalcoholic steatohepatitis (NASH) increased from 13% to 18% and from 5% to 6%, respectively. NASH-related HCC has characteristics that differ from those of virus-associated HCC. Compared with other etiologies, patients with NASHassociated HCC are older, have a higher body mass index, and have higher rates of type 2 diabetes mellitus, hypertension, hyperlipidemia, and cardiovascular disease. Nonalcoholic fatty liver disease (NAFLD)-associated HCC is also known to develop in the absence of cirrhosis, unlike alcohol-related and autoimmune liver diseases. Because patients with NAFLD usually have diabetes or obesity, surveying this population is challenging. Optimal selection of the target population and surveillance tools among patients with NAFLD needs to be determined.

Hepatocellular Carcinoma in Ceará: Epidemiology and Treatment in a Reference Liver Transplant Center in Northeast Brazil

Hepatocellular carcinoma remains a significant worldwide malignancy and an important cause of cancer-related death. The incidence is increasing globally. In Latin America, there is no consistent data on the epidemiology of hepatocellular carcinoma. However, Brazil is considered a country with an intermediate incidence of this liver neoplasm. In the state of Ceará, situated in the northeast region of Brazil, there are no consistent clinical and epidemiologic data on the actual incidence and the treatment of hepatocellular carcinoma. The purpose of this article is to describe epidemiologic characteristics and treatment forms of patients with hepatocellular carcinoma who were treated in a Liver Transplant Center. A retrospective observational study was conducted using the database from the register of 299 patients with hepatocellular carcinoma between June 2004 and February 2022. Only patients born in Ceará were included. Therefore, most patients were eligible, based on the Milan Criteria, to undergo liver transplantation with a Model End Stage Liver Disease score of 12.48 ± 4.66 points, and the waiting list time was approximately 7 months with 8.7% hepatocellular carcinoma recurrence after liver transplant. A total of 38.5 % of cases were outside the Milan criteria at the time of cancer diagnosis, and transarterial chemoembolization was the main treatment choice. In conclusion, the diagnosis of hepatocellular carcinoma in Ceará mainly occurs in male patients with hepatitis C or alcoholism, with a mean age of 61.55 years and a previous diagnosis of liver disease. Liver transplantation was the best curative therapeutic form in patients with cirrhosis and hepatocellular carcinoma in Ceará, where a significant number of patients were diagnosed with intermediate and advanced-stage hepatocellular carcinoma, so public health policies are important for the screening and monitoring of liver disease.

Management of Hepatocellular Carcinoma: The East-West Difference

Abstract: Hepatocellular carcinoma (HCC) is highly prevalent, which contributes to the high disease burden worldwide. It was recognized as the sixth most common cancer and the fourth leading cause of mortality in cancer patients in the Global Cancer Statistics 2018. The management of HCC between eastern and western countries varies from region to region due to the different epidemiology of HCC and the approach of clinicians. Over the past decades, the multidisciplinary team approach has taken a leading role in the therapeutic paradigm of HCC, and the main treatment options include, but are not limited to 1) surgical resection; 2) transarterial chemoembolization (TACE); and 3) systemic therapies. Among these, surgical resection and TACE are applicable in earlyintermediate stage HCC with curative intent, while systemic therapies are mostly applied to advanced unresectable HCC. An individualized approach should be encouraged and tailored for each patient, taking into account the different patient population, staging, and treatment responses to achieve the best efficacy. This review discusses current advances and compares the eastern and western treatment options in the management of HCC.

Changes in the Epidemiology of Hepatocellular Carcinoma in Carinthia, Austria, 2012-2023.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths and remains a major burden on healthcare systems worldwide. The incidence of HCC continues to rise globally, despite preventative efforts being made. This study aimed to investigate epidemiological changes observed in the etiology and survival outcomes of HCC patients at Klinikum Klagenfurt am Wörthersee between 2012 and 2023. This was a retrospective, single-center cohort study. Two time-periods (2012-2017 and 2018-2023) were created to enable comparison between the respective intervals. IBM SPSS was used to analyze statistical data. More patients were diagnosed with HCC during the second time period (n = 128, n = 148). The median age of diagnosis was 72.5 years (SD 8.6). Patients were on average 2 years younger in the second time period compared to the first (p = 0.042). Alcohol remained the leading underlying etiology of HCC and no statistically significant change was seen over time (p = 0.353). Nevertheless, a clear upward trend in the number of NASH cases was evident over time (n = 15, n = 28, respectively). Nearly half of the patient population had a normal AFP (<7 µg/L) level at the time of diagnosis (n = 116, 42.6%). The survival time for HCC patients remained similar between time periods, with a median overall survival time of 20.5 months (95% CI 16.8-24.2, p = 0.841), despite improvements in management strategies and the availability of new systemic treatments. More advanced-stage HCC cases were documented in the second period (BCLC-C, n = 23 to n = 46, p = 0.051). An increased number of HCC patients without liver cirrhosis were identified during the second time period (n = 22, n= 47, respectively, p = 0.005). NASH was the most common underlying etiology in patients without liver cirrhosis (50%) compared to alcohol use in being the primary cause in cirrhotic patients (65%, p < 0.001). HCC continues to be an important health concern in our society. The number of HCC patients without liver cirrhosis is steadily increasing, with NAFLD/NASH, due to underlying lifestyle diseases playing an important etiological role. Continued efforts should be made to prevent HCC and to screen at-risk population groups. Preventative strategies and screening techniques should be adjusted in light of the changing epidemiological landscape of HCC, where more focus will have to be placed on detecting HCC in patients without underlying cirrhosis.

Global trends in hepatocellular carcinoma epidemiology: implications for screening, prevention and therapy.

Hepatocellular carcinoma (HCC) mortality rates are increasing globally, and particularly in the Western world. Cirrhosis remains the predominant risk factor for HCC. However, epidemiological shifts in the incidence of HCC from patients with virus-related liver disease to those with non-viral aetiologies, including alcohol-associated and metabolic dysfunction-associated steatotic liver disease, have important implications for prevention, surveillance and treatment. Hepatitis B vaccination and antiviral therapy for hepatitis B and C are effective for primary prevention of virus-related HCCs, but chemoprevention strategies for non-viral liver disease remain an unmet need. Emerging data suggest associations between aspirin, statins, metformin and coffee and reduced HCC incidence, although none has been proved to be causally related. Secondary prevention of HCC via semi-annual surveillance is associated with improvements in early detection and thus reduced mortality; however, current tools, including abdominal ultrasonography, have suboptimal sensitivity for thedetection of earlystage HCC, particularly in patients with obesity and/or non-viral liver disease. Promising blood-based or imaging-based surveillance strategies are emerging, although these approaches require further validation before adoption in clinical practice. In the interim, efforts should be focused on maximizing use of the existing surveillance tools given their prevalent underuse globally. Remarkable advances have been made in the treatment of HCC, including expanded eligibility for surgical therapies, improved patient selection for locoregional treatments and increased systemic treatment options, including immune-checkpoint inhibitors. In this Review, we discuss trends in the epidemiology of HCC and their implications for screening, prevention and therapy.

Clinical characteristics of hepatocellular carcinoma in patients with cirrhosis: a comparative cohort study.

The epidemiology of cirrhosis has changed over the last two decades. We aimed to assess whether the epidemiology and clinical presentation of hepatocellular carcinoma (HCC) occurring in cirrhosis has changed. The patients were recruited from the Cirrhosis Registry. This database included patients with cirrhosis who had attended the outpatient' liver clinic at the Centre Hospitalier Jolimont in La Louvière, Belgium, since January 1995. We extracted data on two cohorts of patients with cirrhosis collected over an identical time period and followed up for the same duration. Cohort 1 included 504 patients enrolled from 1995 to 2005; among them, 89 patients developed HCC during the defined follow-up period (group 1). Cohort 2 included 566 patients enrolled from 2006 to 2016, among whom 73 patients developed HCC during the defined follow-up period (group 2). When patients with HCC in both groups were compared, no differences were found in the age at HCC diagnosis, the test that alerted on the presence of HCC, the extension, and the stage of the lesion at diagnosis. In the group 1, hepatitis C virus-related HCC occurred in 53% of the cases compared with 18% in the group 2 (P<0.001). Alcohol-related HCC occurred in 27% in the group 1 compared with 60% in the group 2 (P<0.001). The prevalence of metabolic dysfunction-associated steatotic liver disease-related HCC accounted for 10% in all groups. The general epidemiology of HCC has not changed; however the etiology of underlying cirrhosis has changed.

The Emerging Role of Metformin in the Treatment of Hepatocellular Carcinoma: Is There Any Value in Repurposing Metformin for HCC Immunotherapy?

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. There has been significant progress in understanding the risk factors and epidemiology of HCC during the last few decades, resulting in efficient preventative, diagnostic and treatment strategies. Type 2 diabetes mellitus (T2DM) has been demonstrated to be a major risk factor for developing HCC. Metformin is a widely used hypoglycemic agent for patients with T2DM and has been shown to play a potentially beneficial role in improving the survival of patients with HCC. Experimental and clinical studies evaluating the outcomes of metformin as an antineoplastic drug in the setting of HCC were reviewed. Pre-clinical evidence suggests that metformin may enhance the antitumor effects of immune checkpoint inhibitors (ICIs) and reverse the effector T cells' exhaustion. However, there is still limited clinical evidence regarding the efficacy of metformin in combination with ICIs for the treatment of HCC. We appraised and analyzed in vitro and animal studies that aimed to elucidate the mechanisms of action of metformin, as well as clinical studies that assessed its impact on the survival of HCC patients.

Hepatocellular Carcinoma Surveillance among Individuals with Cirrhosis: Trends by Payer, Etiology, and Calendar Year, from a Statewide, Multi-Payer Dataset, 2010-2018.

Hepatocellular carcinoma (HCC) surveillance is underutilized, with <25% of individuals with cirrhosis receiving surveillance exams as recommended. The epidemiology of cirrhosis and HCC in the United States has also shifted in recent years, but little is known about recent trends in surveillance utilization. We characterized patterns of HCC surveillance by payer, cirrhosis etiology, and calendar year in insured individuals with cirrhosis. We conducted a retrospective cohort study of individuals with cirrhosis using claims data from Medicare, Medicaid, and private insurance plans in North Carolina. We included individuals ≥ 18 years with a first occurrence of an ICD-9/10 code for cirrhosis between January 1, 2010, and June 30, 2018. The outcome was HCC surveillance by abdominal ultrasound, CT, or MRI. We estimated 1- and 2-year cumulative incidences for HCC surveillance and assessed longitudinal adherence to surveillance by computing the proportion of time covered (PTC). Among 46,052 individuals, 71% were enrolled through Medicare, 15% through Medicaid, and 14% through private insurance. The overall 1-year cumulative incidence of HCC surveillance was 49% and the 2-year cumulative incidence was 55%. For those with an initial screen in the first 6 months of their cirrhosis diagnosis, the median 2-year PTC was 67% (Q1, 38%; Q3, 100%). HCC surveillance initiation after cirrhosis diagnosis remains low, though it has improved slightly over time, particularly among individuals with Medicaid. This study provides insight into recent trends in HCC surveillance and highlights areas to target for future interventions, particularly among patients with nonviral etiologies.

A244 SIMILAR RISK OF INCIDENT HEPATOCELLULAR CARCINOMA IN IMMIGRANTS/REFUGEES WITH HEPATITIS B CIRRHOSIS REGARDLESS OF THEIR REGION OF ORIGIN

Abstract Background In Canada, over 75% of new immigrants/refugees come from HBV-endemic areas. Whether the risk of hepatocellular carcinoma (HCC) in immigrants/refugees with HBV cirrhosis is associated with their region of origin has not been reported. Purpose The aim of our study was to describe the epidemiology of HCC in foreign-born individuals with HBV cirrhosis stratified by region of origin. Method Population-based retrospective cohort study using administrative healthcare data in Ontario, Canada. Recent immigrants/refugees with HBV (sAg+ or DNA+) and cirrhosis from 2000–2017 were identified and stratified by World Bank region of origin by linkage to the Immigration, Refugees and Citizenship Canada Permanent Resident Database. Individuals were followed until HCC, death, liver transplant, or end of study (2020). The 1-, 5-, and 10-year cumulative incidences (CI) of HCC were calculated. Using adjusted competing risks regression, the subdistribution hazard ratios (sHR) for HCC were calculated with region of origin as the main exposure where death/LT were competing events. Result(s) 4,438 immigrants/refugees were included (64% male, median age 47 years [IQR 37–56], 72% Asia/Pacific, 9% South Asia, 6% Sub-Saharan Africa, 3% Latin America/Caribbean, 7% Europe/Central Asia, 3% Middle East/North Africa) with 430 (10%) developing incident HCC over a median of 7.9 years (IQR 4.5-11.7). Age at HCC diagnosis was lowest in those from Sub-Saharan Africa (53 years IQR [44-58]). Overall, the annual incidence of HCC was 1.14/100 person-years. The CI of HCC at 1-, 5-, and 10 years was highest in those from Latin American/Caribbean (6.8%, 10.3%, and 13.1%), East Asia/Pacific (4.5%, 7.7%, 10.3%) and South Asia (4.0%, 7.2%, 10.3%). After adjusted competing risk regression (Table), decompensated cirrhosis (sHR 2.5; 95% CI 1.7–3.5), male sex (sHR 2.2; 95% CI 1.7–2.7), and age (sHR 1.05, 95% CI 1.04–1.06) were independently associated with HCC, while region of origin was not. Conclusion(s) Among immigrants/refugees with HBV cirrhosis, HCC is associated with male sex, older age, and decompensated cirrhosis but not with their region of origin. Efforts ensuring timely detection and evaluation of HBV in immigrants/refugees with a goal to prevent development of decompensated cirrhosis and provide early detection of HCC should be aggressively pursued regardless of their region of origin. Please acknowledge all funding agencies by checking the applicable boxes below None Disclosure of Interest None Declared

Serum Protein Kinase C Delta: New Kid on the Block for Early Detection of Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related deaths in the world.1 Age-standardized incidence rates of HCC are highest in Asia and Africa; however, both incidence and mortality are rapidly rising in the United States and Europe due to a shift in epidemiology of HCC from viral hepatitis to nonalcoholic fatty liver disease–related cancer.2 Given the dual clinical challenges of detection at late stages and the high incidence-to-mortality ratio of HCC,3 major hepatology societies have recommended abdominal ultrasound with or without alpha fetoprotein (AFP) as the primary HCC surveillance strategy for at-risk patients.

Interplay Between Fatty Acids, Stearoyl-Co-A Desaturase, Mechanistic Target of Rapamycin, and Yes-Associated Protein/Transcriptional Coactivator With PDZ-Binding Motif in Promoting Hepatocellular Carcinoma

Nonalcoholic fatty liver disease has reached pandemic proportions with one of its most consequential complications being hepatocellular carcinoma (HCC). Nonalcoholic fatty liver disease-related HCC is becoming the leading indication for liver transplantation in the United States. Given the scarcity of available organs, early detection and prevention remain key in prevention and management of the disease. Over the years, the yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) pathway emerged as a key signal transduction pathway in the pathogenesis of HCC. In this review, we explore the interplay between the YAP/TAZ pathway as a point of convergence in HCC pathogenesis. We review the evidence of how lipid reprogramming and key lipid pathways, saturated and monounsaturated fatty acids (through the rate-limiting enzyme stearoyl Co-A desaturase), the mevalonic acid pathway (the role of statins), and mechanistic target of rapamycin all play critical roles in intricate and complex networks that tightly regulate the YAP/TAZ pro-oncogenic pathway. Nonalcoholic fatty liver disease has reached pandemic proportions with one of its most consequential complications being hepatocellular carcinoma (HCC). Nonalcoholic fatty liver disease-related HCC is becoming the leading indication for liver transplantation in the United States. Given the scarcity of available organs, early detection and prevention remain key in prevention and management of the disease. Over the years, the yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) pathway emerged as a key signal transduction pathway in the pathogenesis of HCC. In this review, we explore the interplay between the YAP/TAZ pathway as a point of convergence in HCC pathogenesis. We review the evidence of how lipid reprogramming and key lipid pathways, saturated and monounsaturated fatty acids (through the rate-limiting enzyme stearoyl Co-A desaturase), the mevalonic acid pathway (the role of statins), and mechanistic target of rapamycin all play critical roles in intricate and complex networks that tightly regulate the YAP/TAZ pro-oncogenic pathway. Primary liver cancer is the second leading cause of cancer death worldwide.1Sung H. Ferlay J. Siegel R.L. et al.Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J Clin. 2021; 71: 209-249Crossref PubMed Scopus (24505) Google Scholar Hepatocellular carcinoma (HCC), which comprises 90% of the cases, commonly presents in patients with hepatic fibrosis associated with chronic hepatitis B virus or hepatitis C virus, excessive alcohol consumption, or the metabolic syndrome (MetS). As described below, the genetic landscape of HCC is complex and includes mutations in the Wnt/β-catenin (CTNNB1) pathway, chromatin remodeling, telomere maintenance, and inactivation of p53. In the USA, liver cancer incidence rates have more than tripled since 1980, while the cancer-associated death rates have more than doubled during this time. In parallel, nonalcoholic fatty liver disease (NAFLD), a common condition in patients with obesity and type 2 diabetes, has reached pandemic proportions and continues to rise.2Estes C. Razavi H. Loomba R. et al.Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease.Hepatology. 2018; 67: 123-133Crossref PubMed Scopus (960) Google Scholar In the era of direct-acting antiviral therapy for hepatitis C virus and improved hepatitis B virus treatment, NAFLD-HCC is predicted to become the leading indication for liver transplantation.3Younossi Z.M. Stepanova M. Ong J. et al.Nonalcoholic steatohepatitis is the most rapidly increasing indication for liver transplantation in the United States.Clin Gastroenterol Hepatol. 2021; 19: 580-589.e5Abstract Full Text Full Text PDF PubMed Google Scholar As liver transplantation remains a scarce resource with recent evidence suggesting that HCCs are transplanted less often following changes in United States Organ Procurement Network policy,4Kwong A.J. Ghaziani T.T. Mehta N. Decreased urgency among liver transplantation candidates with hepatocellular carcinoma in the United States.Liver Transpl. 2022; 28: 725-727Crossref PubMed Scopus (2) Google Scholar understanding its underlying mechanisms is of upmost importance to develop and implement chemoprevention and early detection programs, as well as tailor treatment approaches. NAFLD and HCC are complex diseases that result from genetic and environmental interactions.5Eslam M. Valenti L. Romeo S. Genetics and epigenetics of NAFLD and NASH: clinical impact.J Hepatol. 2018; 68: 268-279Abstract Full Text Full Text PDF PubMed Scopus (462) Google Scholar Many clinical potentially modifiable risk factors have been associated with NAFLD-HCC development, including features of the MetS, as defined by the clustering of type 2 diabetes, hypertension, dyslipidemia, and obesity, where each condition plays an additive or synergistic role in the pathogenesis of NAFLD-HCC.6Simon T.G. King L.Y. Chong D.Q. et al.Diabetes, metabolic comorbidities, and risk of hepatocellular carcinoma: results from two prospective cohort studies.Hepatology. 2018; 67: 1797-1806Crossref PubMed Scopus (68) Google Scholar,7Kanwal F. Kramer J.R. Mapakshi S. et al.Risk of hepatocellular cancer in patients with non-alcoholic fatty liver disease.Gastroenterology. 2018; 155: 1828-1837.e2Abstract Full Text Full Text PDF PubMed Google Scholar Although statins are commonly prescribed for the treatment of dyslipidemia and the MetS, their use has been shown to be protective in all etiologies of HCC,8Singh S. Singh P.P. Singh A.G. et al.Statins are associated with a reduced risk of hepatocellular cancer: a systematic review and meta-analysis.Gastroenterology. 2013; 144: 323-332Abstract Full Text Full Text PDF PubMed Google Scholar,9Simon T.G. Duberg A.S. Aleman S. et al.Lipophilic statins and risk for hepatocellular carcinoma and death in patients with chronic viral hepatitis: results from a nationwide Swedish population.Ann Intern Med. 2019; 171: 318-327Crossref PubMed Scopus (61) Google Scholar including in nonalcoholic steatohepatitis (NASH), the more severe form in the NAFLD spectrum.10Kaplan D.E. Serper M.A. Mehta R. et al.Effects of hypercholesterolemia and statin exposure on survival in a large national cohort of patients with cirrhosis.Gastroenterology. 2019; 156: 1693-1706.e12Abstract Full Text Full Text PDF PubMed Google Scholar,11Pinyopornpanish K. Al-Yaman W. Butler R.S. et al.Chemopreventive effect of statin on hepatocellular carcinoma in patients with nonalcoholic steatohepatitis cirrhosis.Am J Gastroenterol. 2021; 116: 2258-2269Crossref PubMed Scopus (7) Google Scholar The mechanisms involved in NAFLD-related HCC pathogenesis are therefore of major fundamental and translational importance but remain incompletely understood. In a large veteran population, the estimated incidence of HCC in the patients with NAFLD is 0.21/1000 person-years (PY), with the highest incidence occurring in the subpopulation of patients with cirrhosis (10.6/1000 PY).7Kanwal F. Kramer J.R. Mapakshi S. et al.Risk of hepatocellular cancer in patients with non-alcoholic fatty liver disease.Gastroenterology. 2018; 155: 1828-1837.e2Abstract Full Text Full Text PDF PubMed Google Scholar Simon et al6Simon T.G. King L.Y. Chong D.Q. et al.Diabetes, metabolic comorbidities, and risk of hepatocellular carcinoma: results from two prospective cohort studies.Hepatology. 2018; 67: 1797-1806Crossref PubMed Scopus (68) Google Scholar demonstrated similar findings in a European population-based cohort of biopsy-proven NAFLD and NASH, where HCC occurred at an incidence of 6.2/1000 PY for patients with underlying cirrhosis (95% confidence interval 4.2–8.8/1000 PY). The incidence of HCC was lower for patients with biopsy-proven simple steatosis (n = 5939) at 0.8/1000 PY and NASH without fibrosis (n = 1050) at 1.2/1000 PY.6Simon T.G. King L.Y. Chong D.Q. et al.Diabetes, metabolic comorbidities, and risk of hepatocellular carcinoma: results from two prospective cohort studies.Hepatology. 2018; 67: 1797-1806Crossref PubMed Scopus (68) Google Scholar The differences in incidence and disease progression likely reflect the heterogeneity in the NAFLD population, potentially nonmodifiable genetic differences, and their gene-environment interactions. There is evidence from previous genome-wide association studies demonstrating a predominance of NAFLD in Hispanic patients, followed by Caucasians and African Americans,12Romeo S. Kozlitina J. Xing C. et al.Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease.Nat Genet. 2008; 40: 1461-1465Crossref PubMed Scopus (2215) Google Scholar which have been further substantiated in the HCC population.13Trepo E. Caruso S. Yang J. et al.Common genetic variation in alcohol-related hepatocellular carcinoma: a case-control genome-wide association study.Lancet Oncol. 2022; 23: 161-171Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar Unlike viral and ethanol-associated causes of HCC, NAFLD patients represent a distinct high-risk population where 20%–30% of all HCCs occur in the absence of cirrhosis.14Kanwal F. Kramer J.R. Li L. et al.Effect of metabolic traits on the risk of cirrhosis and hepatocellular cancer in nonalcoholic fatty liver disease.Hepatology. 2020; 71: 808-819Crossref PubMed Scopus (105) Google Scholar,15Benhammou J.N. Aby E.S. Shirvanian G. et al.Improved survival after treatments of patients with nonalcoholic fatty liver disease associated hepatocellular carcinoma.Sci Rep. 2020; 10: 9902Crossref PubMed Scopus (8) Google Scholar Although current guidance does not recommend HCC screening in patients without cirrhosis, the estimated disease burden globally16Huang D.Q. El-Serag H.B. Loomba R. Global epidemiology of NAFLD-related HCC: trends, predictions, risk factors and prevention.Nat Rev Gastroenterol Hepatol. 2021; 18: 223-238Crossref PubMed Scopus (437) Google Scholar and health-care-associated costs17Allen A.M. Van Houten H.K. Sangaralingham L.R. et al.Healthcare cost and utilization in nonalcoholic fatty liver disease: real-world data from a large U.S. Claims Database.Hepatology. 2018; 68: 2230-2238Crossref PubMed Scopus (70) Google Scholar prompt the need for further research in this population, as outlined by recent professional society recommendations.18Kanwal F. Shubrook J.H. Younossi Z. et al.Preparing for the NASH epidemic: a call to action.Metabolism. 2021; 122: 154822Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar Heritability of NAFLD and NASH has been suggested based on early observations of the clustering of disease in families and twins.19Schwimmer J.B. Celedon M.A. Lavine J.E. et al.Heritability of nonalcoholic fatty liver disease.Gastroenterology. 2009; 136: 1585-1592Abstract Full Text Full Text PDF PubMed Scopus (338) Google Scholar,20Loomba R. Schork N. Chen C.H. et al.Heritability of hepatic fibrosis and steatosis based on a prospective twin study.Gastroenterology. 2015; 149: 1784-1793Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar In NAFLD-related HCC, teasing out inherited genetic contributions from chronic fibrosis/cirrhosis vs NAFLD-specific causes using genome-wide association studies remains a challenge and is still being investigated. Independent of its genetic predisposing factors, HCC often results from an accumulation of somatic mutations that lead to tumor initiation and progression. Studies have demonstrated that each HCC has about 40–60 somatic mutations, several of which converge on key molecular pathways.21Llovet J.M. Zucman-Rossi J. Pikarsky E. et al.Hepatocellular carcinoma.Nat Rev Dis Primers. 2016; 2: 16018Crossref PubMed Google Scholar Many mutations affect telomere maintenance (telomere reverse transcriptase activation); Wnt activation (mutation in CTNNB1 which encodes β-catenin, APC, and AXIN1); the tumor suppressor p53 gene (TP53); chromatin remodeling (including in the adenine-thymine-rich interactions-rich interaction domain 1A or ARID1A); activation of the PI3K/mechanistic target of rapamycin (mTORC1); and activation of receptor tyrosine kinases.21Llovet J.M. Zucman-Rossi J. Pikarsky E. et al.Hepatocellular carcinoma.Nat Rev Dis Primers. 2016; 2: 16018Crossref PubMed Google Scholar, 22Llovet J.M. Kelley R.K. Villanueva A. et al.Hepatocellular carcinoma.Nat Rev Dis Primers. 2021; 7: 6Crossref PubMed Scopus (1262) Google Scholar, 23Chiang D.Y. Villanueva A. Hoshida Y. et al.Focal gains of VEGFA and molecular classification of hepatocellular carcinoma.Cancer Res. 2008; 68: 6779-6788Crossref PubMed Scopus (480) Google Scholar, 24Guegan J.P. Lapouge M. Voisin L. et al.Signaling by the tyrosine kinase Yes promotes liver cancer development.Sci Signal. 2022; 15eabj4743Crossref PubMed Scopus (1) Google Scholar, 25Takeda H. Takai A. Eso Y. et al.Genetic landscape of multistep hepatocarcinogenesis.Cancers (Basel). 2022; 14: 568Crossref PubMed Scopus (3) Google Scholar The majority of mutations identified have been shown not to be actionable therapeutically.22Llovet J.M. Kelley R.K. Villanueva A. et al.Hepatocellular carcinoma.Nat Rev Dis Primers. 2021; 7: 6Crossref PubMed Scopus (1262) Google Scholar,26Hyman D.M. Taylor B.S. Baselga J. Implementing genome-driven oncology.Cell. 2017; 168: 584-599Abstract Full Text Full Text PDF PubMed Scopus (297) Google Scholar Of the multiple pathways identified, certain ones deserve special attention because of their common occurrence. For instance, β-catenin activation through point mutations of CTNNB1 and mutation of TP53 occurs in up to 50% of HCC cases.25Takeda H. Takai A. Eso Y. et al.Genetic landscape of multistep hepatocarcinogenesis.Cancers (Basel). 2022; 14: 568Crossref PubMed Scopus (3) Google Scholar,27de La Coste A. Romagnolo B. Billuart P. et al.Somatic mutations of the beta-catenin gene are frequent in mouse and human hepatocellular carcinomas.Proc Natl Acad Sci U S A. 1998; 95: 8847-8851Crossref PubMed Scopus (979) Google Scholar,28Khalaf A.M. Fuentes D. Morshid A.I. et al.Role of Wnt/beta-catenin signaling in hepatocellular carcinoma, pathogenesis, and clinical significance.J Hepatocell Carcinoma. 2018; 5: 61-73Crossref PubMed Google Scholar HCCs can be subclassified into proliferation and nonproliferation classes with some overlaps in the mutational landscape, including in β-catenin activation.22Llovet J.M. Kelley R.K. Villanueva A. et al.Hepatocellular carcinoma.Nat Rev Dis Primers. 2021; 7: 6Crossref PubMed Scopus (1262) Google Scholar,29Zucman-Rossi J. Villanueva A. Nault J.C. et al.Genetic landscape and biomarkers of hepatocellular carcinoma.Gastroenterology. 2015; 149: 1226-1239.e4Abstract Full Text Full Text PDF PubMed Scopus (760) Google Scholar An emerging area of interest is the interplay among lipid metabolism, mTORC1, and the Hippo pathway in HCC. These represent major foci of this article, which are discussed in subsequent sections. It is widely accepted that growing cells require unsaturated fatty acids and cholesterol as essential building blocks for biogenesis of cellular membranes. Early on, investigators observed that cancer cells also synthesize lipids.30Medes G. Thomas A. Weinhouse S. Metabolism of neoplastic tissue. IV. A study of lipid synthesis in neoplastic tissue slices in vitro.Cancer Res. 1953; 13: 27-29PubMed Google Scholar Lipids, and specifically fatty acids, have been shown to have an integral role in changing the tumor environment (TME) to meet the demands of rapid cell proliferation observed in cancer cells, where oxygen and nutrients are scarce.31Currie E. Schulze A. Zechner R. et al.Cellular fatty acid metabolism and cancer.Cell Metab. 2013; 18: 153-161Abstract Full Text Full Text PDF PubMed Scopus (1206) Google Scholar This hallmark of cancer cells has been termed “metabolic reprogramming,”32Beloribi-Djefaflia S. Vasseur S. Guillaumond F. Lipid metabolic reprogramming in cancer cells.Oncogenesis. 2016; 5e189Crossref PubMed Google Scholar and has been linked to clinical aggressiveness of many tumors.33de Gonzalo-Calvo D. Lopez-Vilaro L. Nasarre L. et al.Intratumor cholesteryl ester accumulation is associated with human breast cancer proliferation and aggressive potential: a molecular and clinicopathological study.BMC Cancer. 2015; 15: 460Crossref PubMed Scopus (127) Google Scholar This is supported by a large body of evidence that suppression of lipogenic pathways decreases cell growth in both in vitro and in vivo models.34Guillaumond F. Bidaut G. Ouaissi M. et al.Cholesterol uptake disruption, in association with chemotherapy, is a promising combined metabolic therapy for pancreatic adenocarcinoma.Proc Natl Acad Sci U S A. 2015; 112: 2473-2478Crossref PubMed Scopus (241) Google Scholar,35Svensson R.U. Parker S.J. Eichner L.J. et al.Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small-cell lung cancer in preclinical models.Nat Med. 2016; 22: 1108-1119Crossref PubMed Scopus (280) Google Scholar Understanding tumor lipid metabolism and the crosstalk between the lipidome and the pathways that drive HCC has therefore advanced the targeting of lipid pathways in cancer treatments and includes the use of fatty acid synthase (FASN) TVB-2640 for non-small-cell carcinoma (NCT03808558), high-grade sarcoma (NCT03032484), and triple-negative breast cancer (NCT03179904), which are all currently investigated in clinical trials. The study of the lipidome has only recently been extended to understanding the role of lipids in the pathogenesis of HCC. Most human studies have been conducted in viral etiologies of HCC and have focused on urine and serum lipid analyses with the aim to understand tumor biology and develop clinical biomarkers.36Xue R. Lin Z. 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Triba M.N. et al.Identification of serum proton NMR metabolomic fingerprints associated with hepatocellular carcinoma in patients with alcoholic cirrhosis.Clin Cancer Res. 2012; 18: 6714-6722Crossref PubMed Scopus (61) Google Scholar, 41Chen T. Xie G. Wang X. et al.Serum and urine metabolite profiling reveals potential biomarkers of human hepatocellular carcinoma.Mol Cell Proteomics. 2011; 10M110.004945Google Scholar, 42Passos-Castilho A.M. Carvalho V.M. Cardozo K.H. et al.Serum lipidomic profiling as a useful tool for screening potential biomarkers of hepatitis B-related hepatocellular carcinoma by ultraperformance liquid chromatography-mass spectrometry.BMC Cancer. 2015; 15: 985Crossref PubMed Scopus (16) Google Scholar Given that serum and tissue lipids measurements are not always concordant,43Parker B.L. Calkin A.C. Seldin M.M. et al.An integrative systems genetic analysis of mammalian lipid metabolism.Nature. 2019; 567: 187-193Crossref PubMed Scopus (62) Google Scholar other studies have focused on understanding the lipid profile of the HCCs and adjacent nontumor tissue controls.44Lu Y. Li N. Gao L. et al.Acetylcarnitine is a candidate diagnostic and prognostic biomarker of hepatocellular carcinoma.Cancer Res. 2016; 76: 2912-2920Crossref PubMed Scopus (58) Google Scholar,45Li Z. Guan M. Lin Y. et al.Aberrant lipid metabolism in hepatocellular carcinoma revealed by liver lipidomics.Int J Mol Sci. 2017; 18: 2550Crossref PubMed Scopus (57) Google Scholar Few lipidomic studies have been conducted in NAFLD-HCC patients. Lewinska et al46Lewinska M. Santos-Laso A. Arretxe E. et al.The altered serum lipidome and its diagnostic potential for non-alcoholic fatty liver (NAFL)-associated hepatocellular carcinoma.EBioMedicine. 2021; 73103661Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar recently studied the serum lipidome profile of patients with NAFLD-HCC (n = 27) and compared it to that of patients with ethanol and viral etiologies of HCC (n = 32), morbidly obese patients (n = 102), and healthy controls (n = 35). Compared to patients with ethanol and viral etiologies of HCC and obsese patients with NAFLD, NAFLD-HCC patients had higher triglycerides (47:0 and 45:1) and phosphatidylcholine (16:0/17:0, 18:2/0:0, 0:0/18:2) levels but lower monounsaturated fatty acids (MUFAs), polyunsaturated fatty acids, and linoleic acid, after adjusting for age, sex, and body mass index.46Lewinska M. Santos-Laso A. Arretxe E. et al.The altered serum lipidome and its diagnostic potential for non-alcoholic fatty liver (NAFL)-associated hepatocellular carcinoma.EBioMedicine. 2021; 73103661Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar The authors propose that the lower MUFA and polyunsaturated fatty acids pool may be related to an increase in the uptake of these lipid species by the HCCs from the serum to sustain their growth and proliferation. Consistent with these findings, Muir et al,47Muir K. Hazim A. He Y. et al.Proteomic and lipidomic signatures of lipid metabolism in NASH-associated hepatocellular carcinoma.Cancer Res. 2013; 73: 4722-4731Crossref PubMed Scopus (110) Google Scholar identified that stearoyl-Co-A desaturase (SCD), the rate-limiting enzyme in the conversion of saturated fatty acids (SFAs) to MUFAs, which is preferentially found on the endoplasmic reticulum, was upregulated in human NAFLD-related HCC samples and Pten-null NASH-HCC murine models. While unsaturated fatty acids are required for cellular proliferation and membrane biogenesis, fatty acids also play important signaling functions that remain much less understood. As indicated above, SCD plays a critical role in regulating the ratio of unsaturated fatty acids/SFAs. MUFAs represent the precursors of the main components of cellular membranes and are crucially important in the pathogenesis of the MetS, NAFLD, NASH, and HCC pathogenesis.48Chiappini F. Coilly A. Kadar H. et al.Metabolism dysregulation induces a specific lipid signature of nonalcoholic steatohepatitis in patients.Sci Rep. 2017; 746658Crossref Scopus (110) Google Scholar, 49Walle P. Takkunen M. Mannisto V. et al.Fatty acid metabolism is altered in non-alcoholic steatohepatitis independent of obesity.Metabolism. 2016; 65: 655-666Abstract Full Text Full Text PDF PubMed Google Scholar, 50Lai K.K.Y. Kweon S.M. Chi F. et al.Stearoyl-CoA desaturase promotes liver fibrosis and tumor development in mice via a Wnt positive-signaling loop by stabilization of low-density lipoprotein-receptor-related proteins 5 and 6.Gastroenterology. 2017; 152: 1477-1491Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar This is supported by clinical studies demonstrating worse overall survival of patients with HCCs who demonstrate a high SCD expression, compared to HCCs with low SCD expression. Consistent with SCD playing a critical role in HCC tumor growth, Bansal et al51Bansal S. Berk M. Alkhouri N. et al.Stearoyl-CoA desaturase plays an important role in proliferation and chemoresistance in human hepatocellular carcinoma.J Surg Res. 2014; 186: 29-38Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar demonstrated the inverse relationship between SCD gene expression patterns and HCC tumor differentiation. Similarly, the role of SCD in HCC is further supported by an elevated serum saturated to unsaturated phosphatidylcholine (16:0/16:1) level in patients with cirrhosis and HCC.50Lai K.K.Y. Kweon S.M. Chi F. et al.Stearoyl-CoA desaturase promotes liver fibrosis and tumor development in mice via a Wnt positive-signaling loop by stabilization of low-density lipoprotein-receptor-related proteins 5 and 6.Gastroenterology. 2017; 152: 1477-1491Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar,52Cotte A.K. Cottet V. Aires V. et al.Phospholipid profiles and hepatocellular carcinoma risk and prognosis in cirrhotic patients.Oncotarget. 2019; 10: 2161-2172Crossref PubMed Scopus (4) Google Scholar Mechanistic studies of SCD and MUFAs in chronic liver disease point to selective effects of SCD on different resident liver cell types including M1 macrophage, hepatic stellate cells, and hepatocytes.53Kikuchi K. Tsukamoto H. Stearoyl-CoA desaturase and tumorigenesis.Chem Biol Interact. 2020; 316: 108917Crossref PubMed Scopus (0) Google Scholar These data suggest that the TME, supported by these other cell types, may play an integral role in HCC growth and aggressiveness. However, detailed human cell-type studies are lacking and have only recently been able to be identified with the advent of single-cell and single-nucleus RNA sequencing.54Slyper M. Porter C.B.M. Ashenberg O. et al.A single-cell and single-nucleus RNA-Seq toolbox for fresh and frozen human tumors.Nat Med. 2020; 26: 792-802Crossref PubMed Scopus (1) Google Scholar, 55Alvarez M. Benhammou J.N. Darci-Maher N. et al.Human liver single nucleus and single cell RNA sequencing identify a hepatocellular carcinoma-associated cell-type affecting survival.Genome Med. 2022; 14: 50Crossref PubMed Scopus (2) Google Scholar As shown in Figure 1, SCD expression is regulated at multiple levels,56Benhammou J.N. Ko A. Alvarez M. et al.Novel lipid long intervening noncoding RNA, oligodendrocyte maturation-associated long intergenic noncoding RNA, regulates the liver steatosis gene stearoyl-coenzyme A desaturase as an enhancer RNA.Hepatol Commun. 2019; 3: 1356-1372Crossref PubMed Google Scholar including by the sterol regulatory element-binding protein 1 (SREBP1), the master transcription regulator of lipid biosynthesis, which has higher expression in HCC through mammalian target of rapamycin (mTOR) signaling. mTOR Functions as a catalytic subunit in 2 distinct multiprotein complexes, the mTORC1, characterized by the subunit Raptor (regulatory-associated protein of mTORC1), and mTORC2, characterized by the subunit Rictor (Raptor-independent companion of mTORC2). The heterodimer of the tumor suppressor TSC1 and TSC2 represses mTORC1 activity by acting as the GTPase-activating protein for Rheb, a potent activator of mTORC1 in its guanosine triphosphate-bound state (Figure 1). Using an interactive open-access database (www.proteinatlas.org/pathology), we found that higher expression of Rheb is significantly associated with poor survival in HCC cases (Figure 2A). In the presence of amino acids, activated Akt and/or an extracellular signal-regulated kinasesK/p90RSK phosphorylate and uncouple TSC1/TSC2 from Rheb, leading to Rheb-GTP accumulation and mTORC1 activation at lysosomal membranes, which then promotes cell growth.57Porstmann T. Santos C.R. Griffiths B. et al.SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth.Cell Metab. 2008; 8: 224-236Abstract Full Text Full Text PDF PubMed Scopus (950) Google Scholar Ragulator complex proteins LAMTOR 1, 3, and 5, which are involved in amino acid sensing and mTORC1 activation, are also significantly associated with unfavorable prognosis (survival) in HCC (Figure 2B–D). The association of Rheb and LAMTORS 1, 3, and 5 with unfavorable prognosis emphasizes the importance of mTORC1 function in HCC development. In turn, mTORC1 increases lipogenesis through regulation of SREBP1 at several levels, including trafficking, processing, and transcription58Han J. Wang Y. mTORC1 signaling in hepatic lipid metabolism.Protein Cell. 2018; 9: 145-151Crossref PubMed Scopus (73) Google Scholar that culminate in its nuclear localization and transcriptional activation. In turn, nuclear SREBP1 induces the expression of lipogenesis genes, including SCD.Figure 2Kaplan-Meier plots for gene expression of the signaling network in HCC. Images were reproduced from the Human Protein Atlas (version 17) available from www.proteinatlas.org.59Uhlén M. Fagerberg L. Hallström B.M. et al.Proteomics. Tissue-based map of the human proteome.Science. 2015; 347: 1260419Crossref PubMed Google Scholar Transcriptomics data were available from 365 patients in total with 119 female and 246 male patients. A majority of patients (n = 235) were still alive at the time of data collection. The stage distribution was (i) 170 patients, stage (ii) 84 patients, stage (iii) 83 patients, stage (iv) 4 patients, and 24 patients with missing data information. The links to the specific genes shown are as follows:Show full caption(A) Rheb: https://www.proteinatlas.org/ENSG00000106615-RHEB/pathology/liver+cancer/(B) LAMTOR1: https://www.proteinatlas.org/ENSG00000149357-LAMTOR1/pathology/liver+cancer(C) LAMTOR3: https://www.proteinatlas.org/ENSG00000109270-LAMTOR3/pathology/liver+cancer(D) LAMBOR5: https://www.proteinatlas.org/ENSG00000134248-LAMTOR5/pathology/liver+cancer(E) SAV1: https://www.proteinatlas.org/ENSG00000151748-SAV1/pathology/liver+cancer(F) BIRC5: https://www.proteinatlas.org/ENSG00000089685-BIRC5/pathology/liver+cancer(G) TEAD2: https://www.proteinatlas.org/ENSG00000074219-TEAD2/pathology/liver+cancer(H) Mob4: https://www.proteinatlas.org/ENSG00000115540-MOB4/pathology/liver+cancer.View Large

Epidemiologic, Genetic, Pathogenic, Metabolic, Epigenetic Aspects Involved in NASH-HCC: Current Therapeutic Strategies

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and is the sixth most frequent cancer in the world, being the third cause of cancer-related deaths. Nonalcoholic steatohepatitis (NASH) is characterized by fatty infiltration, oxidative stress and necroinflammation of the liver, with or without fibrosis, which can progress to advanced liver fibrosis, cirrhosis and HCC. Obesity, metabolic syndrome, insulin resistance, and diabetes exacerbates the course of NASH, which elevate the risk of HCC. The growing prevalence of obesity are related with increasing incidence of NASH, which may play a growing role in HCC epidemiology worldwide. In addition, HCC initiation and progression is driven by reprogramming of metabolism, which indicates growing appreciation of metabolism in the pathogenesis of this disease. Although no specific preventive pharmacological treatments have recommended for NASH, dietary restriction and exercise are recommended. This review focuses on the molecular connections between HCC and NASH, including genetic and risk factors, highlighting the metabolic reprogramming and aberrant epigenetic alterations in the development of HCC in NASH. Current therapeutic aspects of NASH/HCC are also reviewed.

Changing epidemiology of hepatocellular carcinoma in South America: A report from the South American liver research network

Introduction and ObjectivesMost epidemiological data on hepatocellular carcinoma (HCC) originate from resource-rich countries. We have previously described the epidemiology of HCC in South America through the South American Liver Research Network. Here, we provide an update on the changing epidemiology of HCC in the continent seven years since that report. Materials and MethodsWe evaluated all cases of HCC diagnosed between 2019 to 2021 in centers from six countries in South America. A templated, retrospective chart review of patient characteristics at the time of HCC diagnosis, including basic demographic, clinical and laboratory data, was completed. Diagnosis of HCC was made radiologically or histologically for all cases via institutional standards. ResultsCenters contributed to a total of 339 HCC cases. Peru accounted for 37% (n=125) of patients; Brazil 16% (n=57); Chile 15% (n=51); Colombia 14% (n=48); Argentina 9% (n=29); and Ecuador 9% (n=29). The median age at HCC diagnosis was 67 years (IQR 59-73) and 61% were male. The most common risk factor was nonalcoholic fatty liver disease (NAFLD, 37%), followed by hepatitis C (17%), alcohol use disorder (11%) and hepatitis B (12%). The majority of HCCs occurred in the setting of cirrhosis (80%). HBV-related HCC occurred at a younger age compared to other causes, with a median age of 46 years (IQR 36-64). ConclusionsWe report dramatic changes in the epidemiology of HCC in South America over the last decade, with a substantial increase in NAFLD-related HCC. HBV-related HCC still occurs at a much younger age when compared to other causes.

Global epidemiology of alcohol-associated cirrhosis and HCC: trends, projections and risk factors.

Heavy alcohol consumption is a major cause of morbidity and mortality. Globally, alcohol per-capita consumption rose from 5.5 litres in 2005 to 6.4 litres in 2016 and is projected to increase further to 7.6 litres in 2030. In 2019, an estimated 25% of global cirrhosis deaths were associated with alcohol. The global estimated age-standardized death rate (ASDR) of alcohol-associated cirrhosis was 4.5 per 100,000 population, with the highest and lowest ASDR in Africa and the Western Pacific, respectively. The annual incidence of hepatocellular carcinoma (HCC) among patients with alcohol-associated cirrhosis ranged from 0.9% to 5.6%. Alcohol was associated with approximately one-fifth of global HCC-related deaths in 2019. Between 2012 and 2017, the global estimated ASDR for alcohol-associated cirrhosis declined, but the ASDR for alcohol-associated liver cancer increased. Measures are required to curb heavy alcohol consumption to reduce the burden of alcohol-associated cirrhosis and HCC. Degree of alcohol intake, sex, older age, obesity, type 2 diabetes mellitus, gut microbial dysbiosis and genetic variants are key factors in the development of alcohol-associated cirrhosis and HCC. In this Review, we discuss the global epidemiology, projections and risk factors for alcohol-associated cirrhosis and HCC.

Comprehensive Review of Hepatocellular Carcinoma in India: Current Challenges and Future Directions.

There is not much information on hepatocellular carcinoma (HCC) in India. Here, we review the existing data, available treatment choices, and future directions in HCC management. An extensive search was conducted through PubMed and MEDLINE for studies published between January 2000 and June 2022 on the epidemiology of HCC in India using the following key words: atezolizumab, BCLC staging, hepatocellular carcinoma, immune checkpoint inhibitors, immunotherapy, and programmed cell death ligand-1, with the filters humans and English language. The most frequent risk factors for the development of HCC in India include nonalcoholic fatty liver disease, hepatitis B virus and hepatitis C virus infection, liver cirrhosis, and alcohol intake. On the basis of new findings, the Barcelona Clinic Liver Cancer (BCLC) Staging Criteria need to be revised. As most cases in India are discovered at a later stage, curative treatments such as surgical resection, ablation, or liver transplantation may not be an option. Clinical trials are underway for a number of immune checkpoint drugs that target cytotoxic T-cell lymphocyte-4 and programmed cell death-1/programmed cell death-ligand 1. In India, phase III trials of atezolizumab in combination with other drugs are underway for the treatment of various malignancies. Renin angiotensin system inhibitors, antivirals, primary hepatocyte transplantation, and bioartificial liver devices are among the future options for the management of HCC. In developing countries like India, HCC is often diagnosed at an advanced stage because of a delay in routine testing or screening. Therefore, developing effective treatment regimens for such stages is critical. Immunotherapy is a promising treatment option that has the potential to increase overall response and survival rate.

Hepatocellular Carcinoma Due to Nonalcoholic Fatty Liver Disease: Current Concepts and Future Challenges.

Obesity has been labeled as the global pandemic of the 21st century, resulting from a sedentary lifestyle and caloric excess. Nonalcoholic fatty liver disease (NAFLD), characterized by excessive hepatic steatosis, is strongly associated with obesity and metabolic syndrome and is estimated to be present in one-quarter of the world population, making it the most common cause of the chronic liver disease (CLD). NAFLD spectrum varies from simple steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis. The burden of NAFLD has been predicted to increase in the coming decades resulting in increased rates of decompensated cirrhosis, hepatocellular carcinoma (HCC), and liver-related deaths. In the current review, we describe the pathophysiology of NAFLD and NASH, risk factors associated with disease progression, related complications, and mortality. Later, we have discussed the changing epidemiology of HCC, with NAFLD emerging as the most common cause of CLD and HCC. We have also addressed the risk factors of HCC development in the NAFLD population (including demographic, metabolic, genetic, dietary, and lifestyle factors), presentation of NAFLD-associated HCC, its prognosis, and the issue of HCC development in non-cirrhotic NAFLD. Lastly, the problems related to HCC screening in the NAFLD population, the remaining challenges, and future directions, especially the need to identify the high-risk individuals, will be discussed. We will conclude the review by summarizing the clinical evidence for treating fibrosis and preventing HCC in those at risk with NAFLD-associated HCC.

Changing epidemiology of hepatocellular carcinoma in Asia.

Liver cancer is the fifth most common cancer and the second leading cause of malignant death in Asia, and Asia reports 72.5% of the world's cases in 2020. As the most common histological type, hepatocellular carcinoma (HCC) accounts for the majority of incidence and mortality of liver cancer cases. This review presents the changing epidemiology of HCC in Asian countries in recent years. Globally, aged, male and Asian populations remain the group with the highest risk of HCC. Hepatitis B virus (HBV) and hepatitis C virus (HCV) are still the leading risk factors of HCC with a slight decline in most Asian countries, which is mainly attributed to HBV vaccination of newborns, prevention of HCV horizontal transmission and treatment of chronic hepatitis. However, the prevalence of HCC caused by metabolic factors, including metabolic syndrome, obesity and non-alcoholic fatty liver diseases, is increasing rapidly in Asian countries, which may eventually become the major cause of HCC. Excessive alcohol consumption continues to be an important risk factor as the average consumption of alcohol is still growing. Hopefully, great effort has been made to better prevention and treatment of HCC in most Asian regions, which significantly prolongs the survival of HCC patients. Asian countries tend to use more aggressive intervention than European and American countries, but it remains unclear whether this preference is related to a better prognosis. In conclusion, HCC remains a major disease burden in Asia, and the management of HCC should be adjusted dynamically based on the changing epidemiology.

Epidemiology of Hepatocellular Carcinoma in Latvia from 1997 to 2017

Abstract We analysed the age- and sex-specific incidence, disease-stage distribution, treatment modalities, and survival of patients with hepatocellular carcinoma (HCC) in Latvia from 1997 to 2017. Retrospective data from the Cancer Registry of Latvia identified 692 men and 427 women aged &gt;19 years who were diagnosed with HCC, confirmed by autopsy, morphological, radiological, or clinical examinations. The total incidence of HCC increased from 2.63 to 3.75 cases per 100 000 person-years in 1997–2007 and 2008–2017, respectively. It was higher in men and increased with age. Two-thirds (65.9%) of patients were diagnosed with stage IV HCC. Overall, 935 patients died during follow-up. The survival rate was low: 32.5% and 22.2% of patients survived for 6 months and 1 year after diagnosis, respectively. Male sex, older age, and advanced stage at diagnosis were associated with poor prognosis. The proportion of radically treated patients was higher, and survival was better, in the period 2008–2017. Our epidemiological analysis of HCC over 20 years shows that the overall incidence of HCC has been increasing in Latvia since 1997; however, it is similar to that of other European countries. Advanced stage at diagnosis results in a low proportion of radically treated patients and poor overall survival.

Non-alcoholic fatty liver disease and hepatocellular carcinoma: Clinical challenges of an intriguing link.

Non-alcoholic fatty liver disease (NAFLD) has emerged as the most common liver disorder worldwide mainly attributed to the epidemic spread of obesity and type 2 diabetes mellitus. Although it is considered a benign disease, NAFLD can progress to non-alcoholic steatohepatitis, liver cirrhosis and hepatocellular carcinoma (HCC). Most data regarding the epidemiology of NAFLD-related HCC are derived from cohort and population studies and show that its incidence is increasing as well as it is likely to emerge as the leading indication for liver transplantation, especially in the Western World. Although cirrhosis constitutes the main risk factor for HCC development, in patients with NAFLD, HCC can arise in the absence of cirrhosis, indicating specific carcinogenic molecular pathways. Since NAFLD as an underlying liver disease for HCC is often underdiagnosed due to lack of sufficient surveillance in this population, NAFLD-HCC patients are at advanced HCC stage at the time of diagnosis making the management of those patients clinically challenging and affecting their prognostic outcomes. In this current review, we summarize the latest literature on the epidemiology, other than liver cirrhosis-pathogenesis, risk factors and prognosis of NAFLD-HCC patients. Finally, we emphasize the prevention of the development of NAFLD-associated HCC and we provide some insight into the open questions and issues regarding the appropriate surveillance policies for those patients.

Hepatocellular carcinoma on the background of nonalcoholic fatty liver disease: epidemiological update

The epidemiological features of hepatocellular carcinoma have changed significantly in the last decades. While for a long-time viral hepatitis and alcohol consumption have been the leading risk factors, the current spread of obesity and type 2 diabetes has contributed to the emergence of non-alcoholic fatty liver disease (NAFLD) worldwide, which has become the leading chronic liver disease as well as one of the main etiologies of hepatocellular carcinoma (HCC), especially in western countries. In this review, we resume the latest data about the epidemiology of metabolic liver disease and HCC arising from NAFLD and discuss the main clinical and molecular features leading to the progression of liver disease and the development of HCC in NAFLD. The emerging concept of metabolic associated fatty liver disease and its association with the development of HCC are also introduced.