Hepatocellular carcinoma (HCC) is a leading cause of global cancer death. Major etiologies of HCC relate to chronic viral infections as well as metabolic conditions. The survival rate of people with HCC is very low and has been attributed to late diagnosis with limited treatment options. Combining ultrasound and the biomarker alpha-fetoprotein (AFP) is currently one of the most widely used screening combinations for HCC. However, the clinical utility of AFP is controversial, and the frequency and operator-dependence of ultrasound lead to a variable degree of sensitivity and specificity across the globe. In this review, we summarize recent developments in the search for non-invasive serum biomarkers for early detection of HCC to improve prognosis and outcome for patients. We focus on tumor-associated protein markers, immune mediators (cytokines and chemokines), and micro-RNAs in serum or circulating extracellular vesicles and examine their potential for clinical application.

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.

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. 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. 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). 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.

With the introduction of antiretroviral therapy (ART), a dramatic reduction in HIV-related morbidity and mortality has been observed. However, it is now becoming increasingly clear that liver-related complications, particularly rapid fibrosis development from ART as well as from the chronic HIV infection itself, are of serious concern to HIV patients. The pathophysiology of liver fibrosis in patients with HIV is a multifactorial process whereby persistent viral replication, and bacterial translocation lead to chronic immune activation and inflammation, which ART is unable to fully suppress, promoting production of fibrinogenic mediators and fibrosis. In addition, mitochondrial toxicity, triggered by both ART and HIV, contributes to intrahepatic damage, which is even more severe in patients co-infected with viral hepatitis. In recent years, new insights into the mechanisms of accelerated fibrosis and liver disease progression in HIV has been obtained, and these are detailed and discussed in this review.