• HCC risk factors
• cancer screening
• hepatocellular carcinoma
• liver disease without cirrhosis
• metabolic dysfunction-associated steatotic liver disease

• hyperinsulinemia
• hyperuricemia
• liver biopsy
• low-density lipoprotein
• metabolic dysfunction associated steatotic liver disease
• metabolic syndrome

• Alanine aminotransferase
• Alanine aminotransferase to high-density lipoprotein cholesterol ratio
• High-density lipoprotein cholesterol
• NAFLD
• Non-linear

• Humans
• Female
• Adult
• Middle Aged
• Male
• Non-alcoholic Fatty Liver Disease/diagnosis
• Cholesterol, HDL
• Alanine Transaminase
• Retrospective Studies
• Prospective Studies
• China/epidemiology

• 82272598 Natural Science Funding of China
• 2020A1515011203 Natural Science Foundation of Guangdong Province, China
• JCYJ20210324135804012 Science, Technology, and Innovation Commission of Shenzhen
• JCYJ20220530150407015 the Science, Technology, and Innovation Commission of Shenzhen

• Hepatocellular carcinoma
• Nonalcoholic fatty liver disease
• Screening

• MAFLD-HCC
• MHR
• lipid metabolism
• nomogram
• prognostic prediction

• Key Research and Development Program of Hebei Province

• Hepatocellular carcinoma
• Immune checkpoint inhibitors
• Nonalcoholic fatty liver disease
• Nonalcoholic steatohepatitis
• Tyrosine kinase inhibitors

• Humans
• Carcinoma, Hepatocellular/diagnosis
• Carcinoma, Hepatocellular/epidemiology
• Carcinoma, Hepatocellular/etiology
• Non-alcoholic Fatty Liver Disease/complications
• Non-alcoholic Fatty Liver Disease/diagnostic imaging
• Non-alcoholic Fatty Liver Disease/epidemiology
• Liver Neoplasms/diagnosis
• Liver Neoplasms/epidemiology
• Liver Neoplasms/etiology
• Disease Progression
• Liver Cirrhosis/complications
• Liver Cirrhosis/pathology

• Humans
• Carcinoma, Hepatocellular/epidemiology
• Carcinoma, Hepatocellular/etiology
• Non-alcoholic Fatty Liver Disease/complications
• Non-alcoholic Fatty Liver Disease/epidemiology
• Liver Neoplasms/epidemiology
• Liver Neoplasms/etiology
• Risk Factors
• Liver Cirrhosis/complications
• Liver Cirrhosis/epidemiology

• Longitudinal study
• Non-alcoholic fatty liver disease
• Non-obese
• Serum uric acid to HDL-cholesterol ratio

• cirrhosis
• liver cancer
• liver fibrosis
• non-alcoholic fatty liver disease
• non-alcoholic steatohepatitis

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.

• Non-alcoholic fatty liver disease
• Hepatocellular carcinoma
• Epidemiology
• Risk factors
• Surveillance
• Risk stratification

• Carcinoma, Hepatocellular/epidemiology
• Carcinoma, Hepatocellular/therapy
• Diabetes Mellitus, Type 2
• Humans
• Liver Cirrhosis/epidemiology
• Liver Neoplasms/epidemiology
• Liver Neoplasms/therapy
• Non-alcoholic Fatty Liver Disease/diagnosis
• Non-alcoholic Fatty Liver Disease/epidemiology
• Non-alcoholic Fatty Liver Disease/therapy

There are limited data regarding the factors associated with hepatocellular carcinoma (HCC) in non-alcoholic fatty liver disease (NAFLD) patients without cirrhosis. We sought to determine the prevalence and factors associated with HCC in NAFLD patients with or without cirrhosis.

Adults with NAFLD (June 2015 to May 2020) were identified using the electronic health record database (Explorys Inc, Cleveland, OH) from 26 major integrated US healthcare systems. The prevalence of HCC was calculated. Multivariable analyses adjusting for covariates were performed to evaluate the associated risk factors and the presence of HCC.

A total of 392,800 NAFLD patients were identified. Among 1110 patients with HCC, 170 (15.3%) had no cirrhosis. The prevalence of HCC in non-cirrhotic and cirrhotic NAFLD patients was 4.6/10,000 persons (95% CI 3.9–5.3), and 374.4/10,000 persons (95% CI 350.9–398.8), respectively. Age > 65 years (adjusted OR; 3.37, 95% CI 2.47–4.59), ever had elevated alanine aminotransferase (2.69; 2.14–3.37), male gender (2.57; 1.88–3.49), smoker (1.75; 1.23–2.49), and diabetes (1.56; 1.15–2.11) were associated with HCC in non-cirrhotic NAFLD (all P < 0.05). The prevalence of HCC in the non-cirrhotic with all five risk factors was 45.5/10,000 persons (95% CI 17.4–73.6). The factors associated with HCC in cirrhotic NAFLD included clinical decompensation, age > 65 years, male gender, Hispanic race, elevated alanine aminotransferase, diabetes and smoker (all P < 0.05).

These data identified the major risk factors for the development of HCC in NAFLD patients. In the non-cirrhotics, older male patients with smoking history, diabetes and an elevated alanine aminotransferase had highest risk and may need increased judicious monitoring.

• Fatty liver
• Liver cirrhosis
• Liver neoplasms

Background. Hepatocellular carcinoma (HCC) is most commonly considered as a complication of cirrhosis. However, an increasing number of HCC in subjects with non-alcoholic fatty liver disease (NAFLD) without cirrhosis is being reported. We conducted a meta-analysis to assess the prevalence of the absence of cirrhosis in NAFLD-associated HCC. Methods. Four databases were searched until March 2021 (CRD42021242969). The original articles included were those reporting data on the presence or absence of cirrhosis among at least 50 subjects with NAFLD-associated HCC. The number of subjects with absent cirrhosis in each study was extracted. For statistical pooling of data, a random-effects model was used. Subgroup analyses according to the continent, target condition and reference standard for the diagnosis of cirrhosis were conducted. Results. Thirty studies were included, evaluating 13,371 subjects with NAFLD-associated HCC. The overall prevalence of cases without cirrhosis was 37% (95%CI 28 to 46). A higher prevalence was reported in Asia versus Europe, North America and South America (45, 36, 37 and 22%, respectively) as well as in studies adopting histology only as the reference standard for the diagnosis of cirrhosis versus histology and other modalities (e.g., radiology, endoscopy, biochemistry or overt clinical findings) (53 and 27%, respectively). No difference was found between studies including subjects with non-alcoholic steatohepatitis (NASH) only, versus NAFLD with or without NASH (p = 0.385). One in three subjects with NAFLD-associated HCC presented without cirrhosis. This should be reflected in future guidelines and surveillance programs adapted to allow for the early detection of these cancers too.

• cirrhosis
• hepatocellular carcinoma
• meta-analysis
• non-alcoholic fatty liver disease
• non-alcoholic steatohepatitis

• Aged
• Carcinoma, Hepatocellular/physiopathology
• Databases, Factual
• Female
• Hepatitis B/physiopathology
• Humans
• Liver Neoplasms/physiopathology
• Male
• Middle Aged
• Non-alcoholic Fatty Liver Disease/physiopathology
• Proportional Hazards Models
• Survival Analysis
• Taiwan

• Diabetes
• HCC
• NAFLD
• NASH
• Non-cirrhotic HCC
• Type 2 diabetes mellitus

• Carcinoma, Hepatocellular/etiology
• Diabetes Mellitus, Type 2/complications
• Humans
• Liver Cirrhosis/complications
• Liver Neoplasms/etiology
• Matched-Pair Analysis
• Neoplasm Recurrence, Local/epidemiology
• Non-alcoholic Fatty Liver Disease/complications

• Ruprecht-Karls-Universität Heidelberg (1026)

The incidence of nonalcoholic fatty liver disease (NAFLD)-related hepatocellular carcinoma (HCC) is increasing. However, an effective screening or surveillance method is not established. Recently, the NAFLD/nonalcoholic steatohepatitis (NASH) guidelines of Japan were revised to incorporate new strategies and evidence for the management and surveillance of NAFLD/NASH. Advanced fibrosis and lifestyle-related and metabolic comorbidities, especially obesity and diabetes mellitus, are associated with HCC development. At the first screening, serum markers of hepatic fibrosis (hyaluronic acid, type IV collagen 7S, and mac-2 binding protein), or the fibrosis (FIB)-4 index or the nonalcoholic fatty liver disease fibrosis score (NFS), or a platelet count should be evaluated. When liver fibrosis is indicated, consultation with a gastroenterology specialist should be considered for the second screening. The risk of HCC should be stratified using the FIB-4 index or the NFS. Liver stiffness should be measured using vibration-controlled transient elastography in those at intermediate or high risk. Blood tests and imaging should be performed every 6–12 months in patients with advanced fibrosis for HCC surveillance. We review here what is known about NAFLD-HCC and provide perspectives for future research.

Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and can develop into hepatocellular carcinoma (HCC). The incidence of NAFLD-related HCC, which is accompanied by life-threatening complications, is increasing. Advanced fibrosis and lifestyle-related and metabolic comorbidities, especially obesity and diabetes mellitus, are associated with HCC development. However, HCC is also observed in the non-cirrhotic liver. Often, diagnosis is delayed until the tumor is relatively large and the disease is advanced; an effective screening or surveillance method is urgently required. Recently, the NAFLD/nonalcoholic steatohepatitis (NASH) guidelines of Japan were revised to incorporate new strategies and evidence for the management and surveillance of NAFLD/NASH. Fibrosis must be tested for noninvasively, and the risk of carcinogenesis must be stratified. The treatment of lifestyle-related diseases is expected to reduce the incidence of NAFLD and prevent liver carcinogenesis.

• hepatocellular carcinoma
• nonalcoholic fatty liver disease
• prevalence
• prognosis
• surveillance

• Liver steatosis
• NAFLD
• cirrhosis
• hepatocellular carcinoma
• metabolic syndrome
• survival

Hepatocellular carcinoma (HCC) is a common and deadly malignancy. The disease usually develops on a background of chronic liver disease. Until recently, the most common etiology was infection with the hepatitis C virus (HCV). The advent of direct-acting antiviral (DAA) therapies has been a major breakthrough in HCV treatment. Sustained virologic response can now be achieved in almost all treated patients, even in patients with a high risk for the development of HCC, such as the elderly or those with significant fibrosis. Early reports raised concerns of a high risk for HCC occurrence after DAA therapy both in patients with previous resection of tumors and those without previous tumors. As the World Health Organization’s goals for eradication of HCV are being endorsed worldwide, the elimination of HCV seems feasible. Simultaneous to the decrease in the burden of cirrhosis from HCV, non-alcoholic fatty liver disease (NAFLD) incidence has been increasing dramatically including significant increased incidence of cirrhosis and HCC in these patients. Surprisingly, a substantial proportion of patients with NAFLD were shown to develop HCC even in the absence of cirrhosis. Furthermore, HCC treatment and potential complications are known to be influenced by liver steatosis. These changes in etiology and epidemiology of HCC suggest the beginning of a new era: The post–HCV era. Changes may eventually undermine current practices of early detection, surveillance and management of HCC. We focused on the risk of HCC occurrence and recurrence in the post–HCV era, the surveillance needed after DAA therapy and current studies in HCC patients with NAFLD.

• Hepatocellular carcinoma
• Hepatitis C virus
• Direct-acting antivirals
• Non-alcoholic fatty liver disease
• Non-alcoholic steatohepatitis

• Antiviral Agents/adverse effects
• Carcinoma, Hepatocellular/diagnosis
• Carcinoma, Hepatocellular/etiology
• Carcinoma, Hepatocellular/therapy
• Disease Progression
• Early Detection of Cancer/methods
• Hepacivirus/drug effects
• Hepacivirus/isolation & purification
• Hepacivirus/pathogenicity
• Hepatitis C, Chronic/drug therapy
• Hepatitis C, Chronic/pathology
• Hepatitis C, Chronic/virology
• Humans
• Incidence
• Liver/drug effects
• Liver/pathology
• Liver/virology
• Liver Cirrhosis/epidemiology
• Liver Cirrhosis/pathology
• Liver Cirrhosis/virology
• Liver Neoplasms/diagnosis
• Liver Neoplasms/etiology
• Liver Neoplasms/therapy
• Liver Transplantation/statistics & numerical data
• Non-alcoholic Fatty Liver Disease/epidemiology
• Non-alcoholic Fatty Liver Disease/pathology
• Non-alcoholic Fatty Liver Disease/surgery
• Sustained Virologic Response