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Nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver disease worldwide, and its prevalence increases continuously. As it predisposes to hepatocellular carcinoma both in the presence and in the absence of cirrhosis, it is not surprising that the incidence of NAFLD-related hepatocellular carcinoma would also rise. Some of the mechanisms involved in hepatocarcinogenesis are particular to individuals with fatty liver, and they help explain why liver cancer develops even in patients without cirrhosis. Genetic and immune-mediated mechanisms seem to play an important role in the development of hepatocellular carcinoma in this population. Currently, it is consensual that patients with NAFLD-related cirrhosis should be surveilled with ultrasonography every 6 mo (with or without alpha-fetoprotein), but it is known that they are less likely to follow this recommendation than individuals with other kinds of liver disease. Moreover, the performance of the methods of surveillance are lower in NAFLD than they are in other liver diseases. Furthermore, it is not clear which subgroups of patients without cirrhosis should undergo surveillance. Understanding the mechanisms of hepatocarcinogenesis in NAFLD could hopefully lead to the identification of biomarkers to be used in the surveillance for liver cancer in these individuals. By improving surveillance, tumors could be detected in earlier stages, amenable to curative treatments.

Introduction and Objectives: Tolloid like protein 1 (TLL1) rs17047200 has been reported to be associated with HCC development and liver fibrosis. However, to our knowledge, no studies have been performed on Latin Americans and comparative differences between TLL1 rs17047200 in HCC patients from Latin America and Europe are undefined. Materials and Methods: Cross-sectional analysis was performed on Latin American and European individuals. We analyzed TLL1 rs17047200 on DNA from 1194 individuals, including 420 patients with HCC (86.0 % cirrhotics) and 774 without HCC (65.9 % cirrhotics). Results: TLL1 rs17047200 genotype AT/TT was not associated with HCC development in Latin Americans (OR: 0.699, 95 %CI 0.456-1.072, p = 0.101) or Europeans (OR: 0.736, 95 %CI 0.447-1.211, p = 0.228). TLL1 AT/TT was not correlated with fibrosis stages among metabolic dysfunction-associated steatotic liver disease (MASLD) patients from Latin America (OR: 0.975, 95 %CI 0.496-1.918, p = 0.941). Among Europeans, alcohol-related HCC had lower TLL1 AT/TT frequencies than cirrhosis (18.3 % versus 42.3 %, OR: 0.273, 95 %CI 0.096-0.773, p = 0.015). Conclusions: We found no evidence that the TLL1 rs17047200 AT/TT genotype is a risk factor for HCC development in Latin Americans or Europeans. A larger study integrating ethnic and etiology backgrounds is needed to determine the importance of the TLL1 SNP in HCC development. [ABSTRACT FROM AUTHOR]

Simple Summary: Hepatocellular carcinoma (HCC) is a prevalent and fatal type of liver cancer with various risk factors. This study examines the connection between a specific genetic variant, STAT4 rs7574865, and HCC risk in Latin American and European populations. The results reveal no general association between this genetic variant and HCC in the studied groups. This study underscores the significance of researching diverse populations to gain a better understanding of the broader influence of genetic factors on HCC risk, which may aid in developing more effective strategies for identifying and managing high-risk individuals. Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. The STAT4 rs7574865 genetic variant has been associated with an increased risk of developing HCC in Asian populations. However, this association has not been studied in Latin America and is poorly assessed in European populations. This case-control study investigated the association between STAT4 rs7574865 and HCC risk in these populations. We evaluated DNA samples from seven medical institutions across six Latin American countries and one Dutch institution in 1060 individuals (344 HCC and 716 controls). STAT4 rs7574865 SNP was genotyped using TaqMan-genotyping assay and analyzed using logistic regression. We found no significant association between the homozygous risk allele (G) of STAT4 and HCC development in either population, with odds ratios (OR) for GG versus TT of 0.85 (CI: 0.48–1.52, p = 0.58) and 0.81 (CI: 0.34–1.93, p = 0.67) for Latin Americans and Europeans respectively. No correlation was found between the risk allele and HCC based on underlying liver disease. However, we found that Latin Americans of European ancestry were more likely to carry the risk allele. Our results suggest that the STAT4 SNP rs7574865 does not influence the risk of developing HCC in Latin American or European populations, highlighting the importance of evaluating genetic risk factors in various ethnic groups and understanding the possible influence of ancestry on the genetic basis of disease. [ABSTRACT FROM AUTHOR]

Introduction and Objectives: Most 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 Methods: We 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. Results: Centers 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). Conclusions: We 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. [ABSTRACT FROM AUTHOR]

The article offers information on the global impact of Hepatitis C virus (HCV) as a major cause of morbidity and mortality. Topics include the prevalence of HCV worldwide, particularly in Latin America where millions of individuals live with HCV, with a significant proportion experiencing advanced fibrosis or cirrhosis.

Simple Summary: Chronic liver diseases commonly cause severe scarring of the liver (cirrhosis) and liver cancer. The eventual progression of this scarring process to liver cancer is influenced by a variety of factors, including inflammatory cytokines (soluble mediators of cell communication). In order to increase our understanding of these mediators we studied them in the blood of patients with hepatitis B (HBV), hepatitis C (HCV), alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) patients with liver cirrhosis. We studied more than a 100 cytokines in up to 400 patients. We discovered that patients with cirrhosis had a vast upregulation of a wide variety of immune mediators, which stimulated inflammation and were linked with tumor-promoting roles. In contrast to prevailing assumptions, each type of underlying liver disease exhibited a unique immune mediator profile in blood, which is likely to impact how we will study these markers in the future. Patients with HBV cirrhosis had the largest number of upregulated inflammation-inducing mediators, compared to HCV, ALD and NAFLD. Next, we related blood immune mediator levels with liver cancer. To do so, we studied cytokine profiles in patients with small tumors, thus, those qualified for surgical curative strategies. We observed unique sets of cytokines in serum in each liver cancer group, indicating a role for these mediators in detecting liver cancer. In conclusion, our findings underscore the impact of different liver diseases on circulating immune mediators. Future studies that aim to study them as diagnostic tools will need to correct for this important effect accordingly. Background and Aims: Chronic liver disease—from any etiology—can progress to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). The progression of liver cirrhosis to the end stages of disease is influenced by a variety of factors, including inflammatory cytokines. We pursued a study of cytokine-mediated inflammatory responses in hepatitis B (HBV), hepatitis C (HCV), alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) patients with liver cirrhosis. Methods: Immune profiles were determined through the serum multiplex profiling of >100 cytokines in a 188 cirrhotic patients, 35 healthy controls and 196 early-stage HCC patients. Results: Patients with liver cirrhosis exhibited a vast upregulation of proinflammatory cytokines (p < 0.0001), including those with pro-oncogenic features, when compared to healthy individuals. In contrast to prevailing assumptions, each etiological cause of cirrhosis exhibited a unique cytokine profile in blood. Regardless of antiviral therapy, HBV cirrhosis patients had the largest number of upregulated proinflammatory mediators, compared to HCV, ALD and NAFLD (p < 0.0001). To further evaluate the etiology-dependent modulation of cytokine response in relation to liver cancer, we studied cytokine profiles in early-stage HCC patients strictly stratified by underlying liver disease. We observed unique sets of differentially expressed cytokines in each cohort of early-stage HCC patients of different cirrhosis etiologies. Conclusions: Our findings, therefore, underscore the importance of stratification by the etiological cause of liver cirrhosis in immune-based studies. [ABSTRACT FROM AUTHOR]

To evaluate the characteristics and response to therapy for HCC in sub-Saharan Africa. We retrospectively evaluated demographic, clinical and outcome variables of HCC in a referral clinic in Ethiopia from 2016 to 2018. Survival assessment was performed using the Mann-Whitney test. Associations between categorical variables was assessed using Pearson Chi-square test. We report 46 HCC cases with a median age of 54 years (IQR 45–62) and 50% female. Viral hepatitis was the most common underlying etiology, with 41% of subjects infected with hepatitis B virus (HBV) and 45% with hepatitis C. The median MELD was 12 (IQR 8–17), we found no association between survival and a MELD score 15, regardless of underlying disease (pr=0.61, p>0.05). 31% of individuals underwent supportive treatment with a median survival of 27 days (IQR 19–181), 18% used Sorafenib (median survival of 94 days, IQR 24–121), and trans-arterial chemoembolization (TACE) was utilized in 16% (median survival of 352 days, IQR 30–436). HBV cases were diagnosed younger (31% before the age of 40) and those on Tenofovir had a longer median survival than those off Tenofovir (121 vs 34 days). Our study found that antiviral treatment of HBV infection was associated with longer survival in HCC. Furthermore, Sorafenib seemed beneficial in patients that used this modality and NLR was a good prognostic factor. [ABSTRACT FROM AUTHOR]

Background & Aims: Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide. Most studies addressing the epidemiology of HCC originate from developed countries. This study reports the preliminary findings of a multinational approach to characterize HCC in South America. Methods: We evaluated 1336 HCC patients seen at 14 centres in six South American countries using a retrospective study design with participating centres completing a template chart of patient characteristics. The diagnosis of HCC was made radiographically or histologically for all cases according to institutional standards. Methodology of surveillance for each centre was following AASLD or EASL recommendations. Results: Sixty-eight percent of individuals were male with a median age of 64 years at time of diagnosis. The most common risk factor for HCC was hepatitis C infection (HCV, 48%), followed by alcoholic cirrhosis (22%), Hepatitis B infection (HBV, 14%) and NAFLD (9%). We found that among individuals with HBV-related HCC, 38% were diagnosed before age 50. The most commonly provided therapy was transarterial chemoembolization (35% of HCCs) with few individuals being considered for liver transplant (<20%). Only 47% of HCCs were diagnosed during surveillance, and there was no difference in age of diagnosis between those diagnosed incidentally vs by surveillance. Nonetheless, being diagnosed during surveillance was associated with improved overall survival (P = .01). Conclusions: Our study represents the largest cohort to date reporting characteristics and outcomes of HCC across South America. We found an important number of HCCs diagnosed outside of surveillance programmes, with associated increased mortality in those patients. [ABSTRACT FROM AUTHOR]

The article offers information about the epidemiology of hepatocellular carcinoma (HCC) in South America, based on a multicenter study across six countries, and highlights the impact of non-alcoholic fatty liver disease (NAFLD) as a rising risk factor for HCC. It discusses the potential biases of single-center studies and the impact of the COVID-19 pandemic on healthcare access and utilization.

Simple Summary: Non-homeostatic cytokine expression during hepatocellular carcinogenesis, together with simple and inexpensive cytokine detection techniques, has opened up its use as potential biomarkers, from cancer detection to prognosis. However, carcinogenic programs during cancer progression are not linear. Therefore, cytokines with prognostic potential in one stage may not be relevant in another. Here, we reviewed cytokines with clinical potential in different settings during hepatocellular carcinoma progression. Hepatocellular carcinoma (HCC) is the primary form of liver cancer and a leading cause of cancer-related death worldwide. Early detection remains the most effective strategy in HCC management. However, the spectrum of underlying liver diseases preceding HCC, its genetic complexity, and the lack of symptomatology in early stages challenge early detection. Regardless of underlying etiology, unresolved chronic inflammation is a common denominator in HCC. Hence, many inflammatory molecules, including cytokines, have been investigated as potential biomarkers to predict different stages of HCC. Soluble cytokines carry cell-signaling functions and are easy to detect in the bloodstream. However, its biomarkers' role remains limited due to the dysregulation of immune parameters related to the primary liver process and their ability to differentiate carcinogenesis from the underlying disease. In this review, we discuss and provide insight on cytokines with clinical relevance for HCC differentiating those implicated in tumor formation, early detection, advanced disease, and response to therapy. [ABSTRACT FROM AUTHOR]