An Overview of Hepatocellular Carcinoma Surveillance Focusing on Non-Cirrhotic NAFLD Patients: A Challenge for Physicians

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver disease worldwide and it ranges from simple steatosis to hepatocellular carcinoma (HCC). HCC represents the first liver tumor and the third source of cancer death. In the next few years, the prevalence of NAFLD and consequently of HCC is estimated to increase, becoming a major public health problem. The NAFLD-HCC shows several differences compared to other causes of chronic liver disease (CLD), including the higher percentage of patients that develop HCC in the absence of liver cirrhosis. In HCC surveillance, the international guidelines suggest a six months abdominal ultrasound (US), with or without alpha-fetoprotein (AFP) evaluation, in patients with cirrhosis and in a subgroup of patients with chronic hepatitis B infection. However, this screening program reveals several limitations, especially in NAFLD patients. Thus, new biomarkers and scores have been proposed to overcome the limits of HCC surveillance. In this narrative review we aimed to explore the differences in the HCC features between NAFLD and non-NAFLD patients, and those between NAFLD-HCC developed in the cirrhotic and non-cirrhotic liver. Finally, we focused on the limits of tumor surveillance in NAFLD patients, and we explored the new biomarkers for the early diagnosis of HCC.

HCC in patients without cirrhosis: A review

“…Other proposed mechanisms of oncogenesis include lipid peroxidation (resulting in oxidative stress and free radical formation), and elevated levels of insulin + IGF-1 resulting in cellular proliferation. [10,11] Patients with MASLD and metabolic syndrome have been shown to possess a higher risk for HCC development in patients without cirrhosis than when compared to patients without cirrhosis with hepatotropic viral infection or alcohol use disorder. In fact, a 2014 study demonstrated that the leading etiology of noncirrhotic HCC was related to metabolic syndrome.…”

“…In fact, a 2014 study demonstrated that the leading etiology of noncirrhotic HCC was related to metabolic syndrome. [3,11] In addition, a study from 2018 revealed that the annual incidence of HCC in patients with MASLD without cirrhosis was about 0.08 per 1000 patients. Among MASLD-related HCC, the percentage of cases without underlying cirrhosis has ranged from 10% to 75%.…”

“…This process and overall chronic level of inflammation is a risk factor for the development of HCC. Other proposed mechanisms of oncogenesis include lipid peroxidation (resulting in oxidative stress and free radical formation), and elevated levels of insulin + IGF-1 resulting in cellular proliferation 10,11 …”

Cardiometabolic risk factors in MASLD patients with HCC: the other side of the coin

“…A total of 10–20% of HCC cases is attributable to MASLD ( 2 ), thus projecting the proportion of the annual incidence of the liver cancer worldwide and requiring a growing attention in surveillance programs ( 3 , 4 ). With the advances in antiviral therapies, MASLD-related HCC is becoming also the sixth most common tumor globally and the second indication for liver transplantation in the United States ( 5 ).…”

A Machine Learning-Based Method for Detecting Liver Fibrosis

“…In addition to cardiovascular risk and the progression of liver fibrosis, the importance of MASLD diagnosis lies in the possibility of developing hepatocellular carcinoma without cirrhosis. These mechanisms are still unknown [ 10 , 11 , 12 ].…”