• FIB‐3 index
• FIB‐4 index
• general health checkup
• liver fibrosis
• metabolic dysfunction‐associated liver disease

• Carcinogenic risk estimation
• DNA methylation
• Hepatocellular carcinoma
• High-performance liquid chromatography
• Infinium assay
• Non-alcoholic steatohepatitis

In patients with hepatitis C virus-related liver disease, direct-acting antivirals (DAAs) suppress the development of hepatocellular carcinoma (HCC). However, it is unclear whether their use after curative HCC treatment suppresses its recurrence in patients with hepatitis C virus-related liver disease. We retrospectively evaluated the inhibitory effect of DAAs on HCC recurrence using propensity score matching. Both the first and second HCC recurrence rates in the DAA-treated group were lower than those in the non-DAA-treated group, suggesting that the inhibitory effect of DAA therapy on HCC recurrence is sustained.

It remains unclear whether hepatocellular carcinoma (HCC) recurrence in hepatitis C virus (HCV)-infected patients can be suppressed by the elimination of the virus using direct-acting antivirals (DAAs) after radical HCC treatment. We evaluated the sustained inhibitory effect of DAAs on HCC recurrence after curative treatment. This multicenter retrospective study included 190 HCV-positive patients after radical treatment for early-stage HCC. Patients were classified into the DAA treatment group (n = 70) and the non-DAA treatment group (n = 120) after HCC treatment. After propensity score matching (PSM), 112 patients were assessed for first and second recurrences using the Kaplan–Meier method and analyzed using a log-rank test. The first recurrence rates at 1 and 3 years were 3.6% and 42.1% in the DAA treatment group and 21.7% and 61.9% in the non-DAA treatment group, respectively (p = 0.0026). Among 85 patients who received radical treatment, the second recurrence rate at 3 years was 2.2% in the DAA treatment group and 33.9% in the non-DAA treatment group (p = 0.0128). In HCV-positive patients with early-stage HCC, the first and second recurrences were suppressed by DAA therapy after radical treatment, suggesting that the inhibitory effect of DAA therapy on HCC recurrence was sustained.

• disease-free survival
• hepatocellular carcinoma
• hepatectomy
• overall survival
• steatosis

• Alcoholism
• Carcinoma, Hepatocellular/surgery
• Disease-Free Survival
• Fatty Liver/complications
• Fatty Liver/epidemiology
• Hepatectomy
• Humans
• Liver Neoplasms/surgery
• Prognosis
• Retrospective Studies
• Virus Diseases

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

• Cardiovascular disease
• Fibrosis
• HCC
• NAFLD/NASH guidelines
• Treatment

• Disease Progression
• Evidence-Based Practice/methods
• Evidence-Based Practice/trends
• Guidelines as Topic
• Humans
• Japan
• Non-alcoholic Fatty Liver Disease/diagnosis
• Non-alcoholic Fatty Liver Disease/physiopathology
• Non-alcoholic Fatty Liver Disease/therapy

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

• HCC
• NAFLD/NASH guidelines
• cardiovascular disease
• fibrosis
• treatment

• Cost
• Database analysis
• Japan
• Nonalcoholic fatty liver disease
• Nonalcoholic steatohepatitis

• Adolescent
• Adult
• Aged
• Comorbidity
• Cross-Sectional Studies
• Female
• Health Care Costs/statistics & numerical data
• Humans
• Japan/epidemiology
• Liver/physiopathology
• Male
• Middle Aged
• Non-alcoholic Fatty Liver Disease/economics
• Non-alcoholic Fatty Liver Disease/epidemiology
• Prevalence
• Resource Allocation/methods
• Retrospective Studies

• Gilead Sciences

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

• HCC
• NAFLD
• NASH
• liver fibrosis
• macrophage

• HCC
• Japan
• NAFLD
• NASH
• cirrhosis
• mortality

• NAFLD
• alpha-fetoprotein
• liver cancer
• risk factors
• steatohepatitis
• steatosis
• ultrasound

• UL1 TR001863 NCATS NIH HHS
• DK034989 Yale Liver Center

Non‐alcoholic fatty liver disease (NAFLD) and non‐alcoholic steatohepatitis (NASH) represent a growing unmet medical need and an increasingly prevalent cause of cirrhosis, hepatocellular carcinoma (HCC), and death in Japan. The aim of this review was to characterize the epidemiology of NAFLD and NASH in Japan. An English and Japanese literature search was conducted in PubMed, Embase, and ICHUSHI Web, identifying 6553 studies, 67 of which were included. Prevalence of NAFLD in the Japanese population rose from the early 1990s (12.6–12.9%) to the early 2000s (24.6–34.7% of the population). Japanese NASH prevalence is estimated to be 1.9–2.7%. NAFLD and NASH are more common among males than females; however, females experience more severe disease than males. While obese patients had higher prevalence of NAFLD/NASH, nonobese individuals (body mass index [BMI] <25 kg/m²) consistently comprised 20% to >35% of NAFLD and NASH patients. The evidence shows that, despite obesity being linked with worse disease stages, “lean‐NASH” also plays an important role in NASH epidemiology. Besides obesity, diabetes and metabolic syndrome appeared to be reliably associated with disease severity. The prevalence of advanced fibrosis or cirrhotic disease was the highest in patients with NASH‐HCC (44–80% with stage F3/F4 disease), while 21–50% of patients with NASH had F3/F4 disease. NAFLD/NASH is common in the Japanese population, and the prevalence of these conditions has tripled in the last two decades. Furthermore, these NAFLD/NASH patients have a high comorbidity burden. Early and efficient identification of safe and effective treatments for NAFLD/NASH patients is urgently needed.

• cirrhosis
• epidemiology
• morbidity
• non‐alcoholic fatty liver disease
• non‐alcoholic steatohepatitis

• Hepatocellular carcinoma
• liver cirrhosis
• non-alcohol steatohepatitis
• non-alcoholic fatty liver disease

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

• acetaminophen toxicity
• acute liver failure
• acute‐on‐chronic liver failure
• drug‐induced liver injury
• epidemiology
• hepatocellular carcinoma
• non‐alcoholic fatty liver disease

• carcinoma, hepatocellular
• epidemiologic factors
• liver cirrhosis
• prognosis

• Biomarkers, Tumor/metabolism
• Carcinoma, Hepatocellular/complications
• Carcinoma, Hepatocellular/epidemiology
• Carcinoma, Hepatocellular/prevention & control
• Carcinoma, Hepatocellular/therapy
• Humans
• Liver Cirrhosis/complications
• Liver Cirrhosis/epidemiology
• Liver Cirrhosis/prevention & control
• Liver Cirrhosis/therapy
• Liver Neoplasms/complications
• Liver Neoplasms/epidemiology
• Liver Neoplasms/prevention & control
• Liver Neoplasms/therapy
• Prognosis

• NAFLD
• attenuation measurement
• liver steatosis

• Apoptosis
• Endoplasmic reticulum stress
• Free fatty acids
• Non-alcoholic fatty liver disease
• Nonalcoholic steatohepatitis

• Animals
• Apoptosis
• Autophagy
• Caspases/metabolism
• Disease Progression
• Endoplasmic Reticulum Stress
• Epigenesis, Genetic
• Fatty Acids, Nonesterified/metabolism
• Hepatocytes
• Humans
• Ligands
• Mitogen-Activated Protein Kinase 8/metabolism
• Non-alcoholic Fatty Liver Disease/genetics
• Non-alcoholic Fatty Liver Disease/metabolism
• Reactive Oxygen Species/metabolism
• Receptors, Death Domain/metabolism
• Signal Transduction

The increased prevalence of hepatocellular carcinoma (HCC) without viral infection, namely, NHCC, is a major public health issue worldwide. NHCC is frequently derived from non‐alcoholic fatty liver (NAFL) and non‐alcoholic steatohepatitis, which exhibit dysregulated fatty acid (FA) metabolism. This raises the possibility that NHCC evolves intracellular machineries to adapt to dysregulated FA metabolism. We herein aim to identify NHCC‐specifically altered FA and key molecules to achieve the adaptation. To analyze FA, imaging mass spectrometry (IMS) was performed on 15 HCC specimens. The composition of saturated FA (SFA) in NHCC was altered from that in typical HCC. The stearate‐to‐palmitate ratio (SPR) was significantly increased in NHCC. Associated with the SPR increase, the ELOVL6 protein level was upregulated in NHCC. The knockdown of ELOVL6 reduced SPR, and enhanced endoplasmic reticulum stress, inducing apoptosis of Huh7 and HepG2 cells. In conclusion, NHCC appears to adapt to an FA‐rich environment by modulating SPR through ELOVL6.

• ELOVL6
• endoplasmic reticulum stress
• hepatocellular carcinoma
• non-alcoholic steatohepatitis
• saturated fatty acid

• Elastography
• Liver biopsy
• MR elastography
• Nonalcoholic fatty liver disease
• Scoring system

• Biomarkers/blood
• Biopsy
• Elasticity Imaging Techniques/methods
• Genetic Predisposition to Disease
• Humans
• Liver/pathology
• Magnetic Resonance Imaging/methods
• Non-alcoholic Fatty Liver Disease/diagnosis
• Non-alcoholic Fatty Liver Disease/genetics
• Non-alcoholic Fatty Liver Disease/pathology
• Severity of Illness Index

• NAFLD
• NASH
• metabolic syndrome
• non-alcoholic steatohepatitis
• obesity
• obeticholic acid
• pioglitazone
• vitamin E

• Adolescent
• Asia
• Bariatric Surgery
• Carcinoma, Hepatocellular/etiology
• Chenodeoxycholic Acid/administration & dosage
• Chenodeoxycholic Acid/analogs & derivatives
• Child
• Diet
• Exercise
• Fatty Acids, Omega-3/administration & dosage
• Gastroenterology/organization & administration
• Humans
• Liver Neoplasms/etiology
• Liver Transplantation
• Non-alcoholic Fatty Liver Disease/diagnosis
• Non-alcoholic Fatty Liver Disease/etiology
• Non-alcoholic Fatty Liver Disease/therapy
• Obesity/complications
• Obesity/surgery
• Pacific Islands
• Practice Guidelines as Topic
• Risk
• Systematic Reviews as Topic
• Thiazolidinediones/administration & dosage
• Vitamin E/administration & dosage

• NAFLD
• NASH
• hepatocellular carcinoma
• liver biopsy
• liver stiffness measurement
• metabolic syndrome
• non-alcoholic steatohepatitis
• obesity
• transient elastography

• Adolescent
• Asia/epidemiology
• Child
• Gastroenterology/organization & administration
• Hepatitis, Viral, Human/epidemiology
• Humans
• Non-alcoholic Fatty Liver Disease/diagnosis
• Non-alcoholic Fatty Liver Disease/epidemiology
• Non-alcoholic Fatty Liver Disease/etiology
• Non-alcoholic Fatty Liver Disease/therapy
• Pacific Islands/epidemiology
• Practice Guidelines as Topic
• Prevalence
• Risk Assessment
• Risk Factors
• Systematic Reviews as Topic

• Asia
• Hepatitis
• liver neoplasms
• non-alcoholic fatty liver disease
• risk factors

The epidemic of insulin resistance, obesity, and metabolic syndrome has led to the emergence of nonalcoholic steatohepatitis (NASH) as the most common cause of liver disease in the US. Patients with NASH are at an increased risk for hepatic disease-related morbidity and death, and chronic inflammation in NASH patients can lead to hepatocellular carcinoma (HCC). The prevalence of HCC is higher in males than in females, and genetic studies have identified androgen and androgen receptors (ARs) as partially responsible for the gender disparity in the development of liver disease and HCC. Although many factors are known to play important roles in the progression of inflammation in NASH patients, the role of androgen and AR in the progression of NASH to HCC has been understudied. This review summarizes the evidence for a potential role of androgen and the AR pathway in the development of NASH-related HCC and in the treatment of HCC. It has been proposed that AR plays a role in the progression of HCC: inhibitory roles in early stages of hepatocarcinogenesis and tumor-promoting roles in advanced stages. AR can be activated by several pathways, even in the absence of androgen. While AR has been explored as a potential therapeutic target in HCC, several clinical trials have failed to demonstrate a clinical benefit of antiandrogen drugs in HCC. This review discusses the potential reason for these observations and discuss the potential future trials design in this important setting.

• androgen receptor
• flutamide
• hepatocellular carcinoma
• nonalcoholic steatohepatitis
• sorafenib

• Amino acids
• branched chain
• carcinoma
• hepatocellular
• liver cirrhosis
• medication adherence

• Adults
• Children
• Nonalcoholic Fatty Liver Disease
• Nonalcoholic Steatohepatitis

• Aflatoxin
• Epidemiology
• Hepatitis B
• Hepatitis C
• Hepatocellular carcinoma
• Non-alcoholic steatohepatitis NASH

• Aflatoxins/toxicity
• Asia/epidemiology
• Carcinoma, Hepatocellular/epidemiology
• Carcinoma, Hepatocellular/etiology
• Hepatitis B/complications
• Hepatitis B/epidemiology
• Hepatitis C/complications
• Hepatitis C/epidemiology
• Hepatitis C, Chronic/complications
• Hepatitis C, Chronic/epidemiology
• Humans
• Liver Neoplasms/epidemiology
• Liver Neoplasms/etiology
• Non-alcoholic Fatty Liver Disease/epidemiology
• Obesity/complications
• Risk Factors

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. The main etiologies of HCC are hepatitis B virus and hepatitis C virus (HCV), and non-hepatitis B/non-hepatitis C HCC (NBNC-HCC) has also been identified as an etiological factor. Although the incidence of HCV-related HCC in Japan has decreased slightly in recent years, that of NBNC-HCC has increased. The onset mechanism of NBNC-HCC, which has various etiologies, remains unclear; however, nonalcoholic steatohepatitis (NASH), a severe form of nonalcoholic fatty liver disease, is known to be an important risk factor for NBNC-HCC. Among the different advanced glycation end-products (AGEs) formed by the Maillard reaction, glyceraldehyde-derived AGEs, the predominant components of toxic AGEs (TAGE), have been associated with NASH and NBNC-HCC, including NASH-related HCC. Furthermore, the expression of the receptor for AGEs (RAGE) has been correlated with the malignant progression of HCC. Therefore, TAGE induce oxidative stress by binding with RAGE may, in turn, lead to adverse effects, such as fibrosis and malignant transformation, in hepatic stellate cells and tumor cells during NASH or NASH-related HCC progression. The aim of this review was to examine the contribution of the TAGE-RAGE axis in NASH-related HCC.

• Hepatocellular carcinoma
• Nonalcoholic steatohepatitis
• Advanced glycation end-products
• Toxic advanced glycation end-products
• Receptor for advanced glycation end-products
• Hepatic stellate cells

• Alpha-fetoprotein
• Association
• Fatty liver
• Obesity
• Risk factor

• Adult
• Biomarkers/blood
• Chi-Square Distribution
• China/epidemiology
• Cross-Sectional Studies
• Fatty Liver/blood
• Fatty Liver/diagnostic imaging
• Fatty Liver/epidemiology
• Female
• Humans
• Logistic Models
• Male
• Metabolic Syndrome/epidemiology
• Middle Aged
• Multivariate Analysis
• Prevalence
• Risk Factors
• Ultrasonography
• Up-Regulation
• alpha-Fetoproteins/analysis

• Diet, Mediterranean
• Humans
• Non-alcoholic Fatty Liver Disease/diet therapy