Home
JournalsCollections
For Authors For Reviewers For Editorial Board Members
Article Processing Charges Open Access
Ethics Advertising Policy
Editorial Policy Resource Center
Company Information Contact Us
Publications > Journals > Journal of Clinical and Translational Hepatology> Article Full Text
Review Article
OPEN ACCESS

Download PDF

Hepatocellular Carcinoma in Non-alcoholic Fatty Liver Disease: Current Progresses and Challenges

  • Yu-Xian Teng1,#,
  • Si Xie1,#,
  • Ping-Ping Guo1,
  • Zhu-Jian Deng1,
  • Zi-Yi Zhang1,
  • Wei Gao1,
  • Wan-Guang Zhang3,*  and
  • Jian-Hong Zhong1,2,* 
Journal of Clinical and Translational Hepatology   2022;10(5):955-964

doi: 10.14218/JCTH.2021.00586

Received:

Revised:

Accepted:

Published online:

 Author information

Citation: Teng YX, Xie S, Guo PP, Deng ZJ, Zhang ZY, Gao W, et al. Hepatocellular Carcinoma in Non-alcoholic Fatty Liver Disease: Current Progresses and Challenges. J Clin Transl Hepatol. 2022;10(5):955-964. doi: 10.14218/JCTH.2021.00586.

Abstract

The rising global prevalence of metabolic diseases has increased the prevalence of non-alcoholic fatty liver disease (NAFLD), leading to an increase in cases of NAFLD-related hepatocellular carcinoma (HCC). To provide an updated literature review detailing epidemiology, risk factors, pathogenic pathways, and treatment strategies linked to NAFLD-related HCC, we conducted a literature search on PubMed from its inception to December 31, 2021. About 25% of the global population suffers from NAFLD. The annual incidence of HCC among NAFLD patients is approximately 1.8 per 1,000 person-years. Older age, male sex, metabolic comorbidities, unhealthy lifestyle habits (such as smoking and alcohol consumption), physical inactivity, genetic susceptibility, liver fibrosis, and degree of cirrhosis in NAFLD patients are important risk factors for NAFLD-related HCC. Therefore, low-calorie diet, moderate-intensity exercise, treatment of metabolic comorbidities, and cessation of smoking and alcohol are the main measures to prevent NAFLD-related HCC. In addition, all patients with advanced NAFLD-related fibrosis or cirrhosis should be screened for HCC. Immune suppression disorders and changes in the liver microenvironment may be the main pathogenesis of NAFLD-related HCC. Hepatic resection, liver transplantation, ablation, transarterial chemoembolization, radiotherapy, targeted drugs, and immune checkpoint inhibitors are used to treat NAFLD-related HCC. Lenvatinib treatment may lead to better overall survival, while immune checkpoint inhibitors may lead to worse overall survival. Given the specific risk factors for NAFLD-related HCC, primary prevention is key. Moreover, the same treatment may differ substantially in efficacy against NAFLD-related HCC than against HCC of other etiologies.

Keywords

Epidemiology, Hepatocellular carcinoma, Non-alcoholic fatty liver disease, Risk factor, Treatment strategy

Introduction

Hepatocellular carcinoma (HCC), the most common type of primary liver cancer, is prevalent worldwide, especially in Southeast Asia.1 The main causes of HCC include infection with hepatitis B virus (HBV) or hepatitis C virus (HCV) and chronic alcohol abuse. In the past decade, non-alcoholic fatty liver disease (NAFLD) has emerged in the USA and some European countries as a risk factor for HCC, the incidence of which is increasing.2,3 Although the prevalence of HCC among patients with NAFLD remains lower than its incidence among patients with chronic HBV or HCV infection, around 25% of the global population has NAFLD, and the prevalence is even higher in high-income areas.4,5 Thus, the prevalence of NAFLD-related HCC is predicted to increase.5 This highlights the need to clearly understand the epidemiology, risk factors, pathogenic mechanisms, and effective strategies for preventing and treating NAFLD-related HCC.

Search strategy

PubMed database (https://pubmed.ncbi.nlm.nih.gov/ ) was systematically searched for publications related to the prevention, screening, and treatment of NAFLD-related HCC, in the presence or absence of non-alcoholic steatohepatitis (NASH). The database was searched from its inception until December 31, 2021. The search terms included “NAFLD” OR “NASH” OR “steatosis” AND “hepatocellular carcinoma”. Only research articles and reviews published in English were considered. Studies were screened initially based on titles and abstracts, then retained studies were read in full to determine eligibility. Case reports were excluded. Reference lists in relevant literature were searched manually to identify additional studies.

Epidemiology

Several meta-analyses and cohort studies with large samples have shown that 25-30% of the global population suffers from NAFLD, with the highest prevalence in the Middle East and South America, and the lowest in Africa.6–8 Prevalence of NAFLD has been increasing annually, leading to more frequent NAFLD-related adverse events, including HCC and death. Indeed, the prevalence of NASH, an advanced form of NAFLD, is projected to double by 2030 worldwide.5

NAFLD is already the fastest-growing cause of HCC in some developed countries. In 2016, the annual incidence of HCC among NAFLD patients was 1.8 per 1,000 person-years, and the overall mortality was 5.3 per 1,000 person-years.6,7 The incidence of NAFLD-related HCC varies greatly among NAFLD patients, depending on whether they also have NASH or cirrhosis. Patients with severe fibrosis or cirrhosis are at the highest risk of HCC. For example, the incidence rate of HCC was 0.03 per 100 person-years in patients with NAFLD at a stage earlier than cirrhosis and 3.78 per 100 person-years in patients with cirrhosis.9 The latter group of patients accounts for 20-50% of HCC cases. Moreover, the incidence of NAFLD-related HCC in patients with non-cirrhotic NAFLD also varies among regions. HCC incidence ranges from 0.1 to 1.3 per 1,000 person-years in patients from the USA and Europe. However, studies from Asia found annual HCC incidences ranges from 0.04% to 0.6%. Interestingly, studies in Asia, USA, and Europe have found that the presence of NASH and fibrosis were associated with a higher HCC incidence in patients with non-cirrhotic NAFLD. In patients with cirrhotic NAFLD, the annual incidence of HCC ranges from 0.7% to 2.6%. Moreover, this data from Asia is consistent with the data from the USA and Europe.5

Risk factors for NAFLD-related HCC

Metabolic comorbidities associated with NAFLD include obesity, hyperlipidemia, hypertension, type 2 diabetes, and metabolic syndrome. A relationship between HCC and metabolic diseases such as obesity and type 2 diabetes is well established,10–14 with diabetes contributing the most to risk of HCC.14 Metformin treatment and glycemic control significantly reduce the risk of HCC in NAFLD patients with type 2 diabetes.15 Thus, patients with NAFLD should be screened regularly for diabetes or prediabetes. In addition, the degree of fibrosis is significantly associated with liver-related events and mortality in NAFLD patients,16 and HCC is more frequent among NAFLD patients with cirrhosis.17

Metabolic comorbidities have been strongly associated with older age, lifestyle, and genetic predisposition.18 For example, the higher body mass index in rural populations is a major cause of the global adult obesity epidemic and a risk factor for NAFLD.19 Unhealthy lifestyle habits and lack of exercise are common among NAFLD patients.20 A relationship between lack of exercise and the occurrence of HCC has also been demonstrated.21 Alcohol consumption is associated with increased mortality in patients with fatty liver disease and metabolic syndrome.22 Tobacco smoking also increases the risk of NAFLD23 and the incidence of HCC24 in the general population. However, we are unaware of studies exploring the relationship between smoking and HCC in NAFLD patients. In addition, there are sex and ethnic differences in the occurrence of NAFLD. Women are at lower risk of NAFLD than men but, once NAFLD is established, women are at a higher risk of severe fibrosis than men, especially after age 50.25 A meta-analysis found that NAFLD prevalence was highest among Hispanics, but lowest among Blacks in the USA.26 Occurrence of NAFLD may depend on genetic susceptibility, and appropriate genetic tools may be useful for predicting risk of HCC in patients with NAFLD.27

Therefore, older age, male sex, metabolic comorbidities, unhealthy lifestyle habits (such as smoking and alcohol consumption), physical inactivity, genetic susceptibility, liver fibrosis, and degree of cirrhosis in NAFLD patients are important risk factors for NAFLD-related HCC (Fig. 1). Focusing on risk factors that contribute to tumor development will help clarify the mechanisms of HCC and design new prevention and treatment strategies.

Epidemiology, risk factors, prevention, pathogenic pathways, and treatment strategies of non-alcoholic fatty liver disease-related HCC.
Fig. 1  Epidemiology, risk factors, prevention, pathogenic pathways, and treatment strategies of non-alcoholic fatty liver disease-related HCC.

HAIC, hepatic arterial infusion chemotherapy; HCC, hepatocellular carcinoma; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; TACE, transarterial chemoembolization.

Pathogenesis

NAFLD is a metabolic liver disease caused by excessive accumulation of fat in the liver due to diet, metabolism, and other causes. Several metabolic pathways identified by metabolomics and lipidomics have been implicated in NAFLD.28 Lipotoxicity mediated by free fatty acids and diglycerol can cause insulin resistance and endoplasmic reticulum stress in liver cells, which leads to a chronically inflammatory environment in the liver, resulting in NASH and liver fibrosis which can eventually progress to liver cirrhosis or even HCC.28 NAFLD is a complex, multifactorial disease, and NASH is a critical first step toward cancer. Although NASH occurs in the context of metabolic alterations, large networks of immune cells are also involved in the evolution of NASH into cirrhosis and HCC.29 In this way, the intrahepatic microenvironment has a significant impact on the occurrence, development, and prognosis of HCC, and the immune microenvironment of the tumor is closely related to the survival outcome of patients.30,31 Several groups have investigated the pathogenesis of NAFLD-related HCC, and the mainstream view is that it is related to immune suppression disorders and changes in the liver microenvironment.30–36 In a mouse model of NASH, CD8+ T cells and natural killer T cells co-promoted the development of HCC.32 In addition, CD8+ PD1+ T cells in NASH mice can induce hepatocyte cancer transformation by disrupting immune surveillance.33 Conversely, CD4+ T cells can prevent malignant hepatocyte transformation by restoring immune surveillance.34 However, the chronic inflammatory environment caused by NAFLD in the liver can inhibit the activation of CD8+ T cells, thus disrupting immune surveillance and promoting the formation of HCC.35

The pathogenesis and progression of NAFLD and NAFLD-related HCC are very complex, involving many factors. In addition to disorders of the immune microenvironment and dysregulation of immune surveillance, there are also more and more studies on the pathogenesis of NAFLD-related HCC from the perspectives of gut inflammation and gut dysbiosis, fibrosis caused by chronic inflammation and genetics.5,12,36–40 Metagenomic and metabolomic studies found that dysregulation is characteristic of the microbiota of patients with NAFLD-related cirrhosis, and the composition and function of the microbiota change with the development of HCC. Moreover, the gut microbiota of NAFLD-related HCC patients has unique microbiome/metabolomic characteristics and modulates peripheral immune responses.36 In addition, animal experiments have found that dietary cholesterol promotes the formation of NAFLD-related HCC by inducing alteration of gut microbiota and metabolites. Therefore, cholesterol inhibition and gut microbiota regulation may be effective strategies to prevent NAFLD-related HCC.12 In the field of inflammation, dietary and genetic obesity has been shown to promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression.38 Moreover, IL-6 leads to activation of signal transducer and activator of transcription 3, which stimulates hepatocyte proliferation and malignant transformation.39 In the field of genetics, many studies found the single nucleotide polymorphism of the patatin-like phospholipase domain-containing 3 (PNPLA3) is associated with an increased risk of advanced fibrosis among patients with a variety of liver diseases and is an independent risk factor for HCC among patients with NASH or alcohol-related cirrhosis.40 However, further studies are needed to elucidate the mechanisms by which the PNPLA3 mutation contributes to hepatocarcinogenesis. To evaluate the molecular processes underlying hepatocarcinogenesis in this cohort, Pinyol et al.37 collected 80 NASH-related HCC and 125 NASH samples and analyzed the data from expression array and whole exome sequencing. They found NASH-related HCCs display unique molecular features, including higher rates of ACVR2A mutations and the presence of a newly identified mutational signature.

Prevention and surveillance

Due to the popularization of HBV vaccines and growing use of oral antiviral drugs, hepatitis caused by HBV and HCV can be effectively controlled.41 As a consequence, the prevalence of HBV- or HCV-related HCC is expected to decrease substantially in the future. In contrast, the lack of effective treatments for NAFLD means that the most effective approach is prevention, through alterations in lifestyle and diet. For example, a large multicenter cohort study in Europe suggested a negative association between manual labor and the occurrence of HCC.42 Another European cohort study found that closer adherence to the Mediterranean diet appears to protect against HCC.43 Official guidelines about NAFLD recommend the combination of a low-calorie diet and moderate-intensity exercise to keep body weight low.44–50

Several cohort studies have suggested that metformin and statins reduce the risk of HCC in patients with type 2 diabetes.51,52 Aspirin can slow the progression of liver fibrosis in NAFLD patients.53 Long-term, low-dose aspirin treatment can reduce the risk of HCC in patients with chronic viral hepatitis,54 and this decrease correlates positively with duration of aspirin use.55 In principle, medications for NAFLD or NASH, such as liraglutide56 and namodenoson,57 should reduce the risk of NAFLD-related HCC, but this remains to be demonstrated in large, multicenter studies with long follow-up.

In terms of HCC surveillance, almost all diagnosis and treatment guidelines recommend that high-risk patients undergo liver ultrasound examination and serum alpha fetoprotein monitoring at least once every six months.58–62 The onset of HCC is insidious. By the time the disease is discovered, 70% of patients have already reached an intermediate or advanced stage of disease.63 Therefore, effective monitoring strategies are particularly important, and early diagnosis and treatment can significantly improve prognosis. However, effective monitoring of patients with NAFLD or NASH faces many difficulties. While the prevalence of NAFLD-related HCC is much lower than that of HBV- or HCV-related HCC, the high prevalence of NAFLD translates to greater costs and effort for generalized screening. In addition, nearly half of patients with NAFLD-related HCC do not develop cirrhosis during disease progression, making monitoring even more challenging.17 Therefore, effective methods to monitor for NAFLD-related HCC are still lacking.

No NAFLD official guidelines reported the diagnosis criteria of NAFLD-related HCC (Table 1).44–50 Diagnosis of NAFLD-related HCC is often performed based on clinical symptoms, which explains why the disease is often at an advanced stage when it is diagnosed. Patients with cirrhosis due to NAFLD or NASH are well recognized as high-risk subgroups of HCC in Western and Eastern official guidelines.44–50 Moreover, patients with advanced liver fibrosis due to NAFLD are also candidates for HCC screening in American Gastroenterological Association guideline.50 Ultrasound is the primary surveillance test. In overweight or obese patients, either computed tomography or magnetic resonance imaging scan can be used instead.49,50 Non-enhanced magnetic resonance imaging is a useful diagnostic tool because it is fast, does not require enhanced contrast agent, and offers better specificity and sensitivity than ultrasound.64 In order to reduce risk of HCC, NAFLD patients should lose weight, control diabetes and dyslipidemia, as well as cease tobacco smoking and drinking alcohol (Table 1).47,49,50

Table 1

Current NAFLD guidelines for the screening, prevention, and diagnosis for HCC among patients with NAFLD

Asia-Pacific 201745China 201846Korean 202149Japan 202048EASL 201647AASLD 201844AGA 202050
Screening of high-risk subgroupsNASH patients with cirrhosis.NASH patients with cirrhosisPatients with cirrhosis due to NAFLD.Patients with cirrhosis due to NAFLD.n.d.Patients with cirrhosis due to NAFLD.Patients with cirrhosis or advanced liver fibrosis due to NAFLD.
Recommended screening methodsUltrasound every 6 months.n.d.Ultrasound is the primary surveillance test; In overweight or obese patients, CT or MRI can be used instead.Ultrasound and tumor markers every 6 months.No recommendation can be currently made on the timing of surveillance and its cost-effectiveness.Not stated.Ultrasound; When the quality of ultrasound is suboptimal for screening of HCC (e.g., due to obesity), either CT or MRI should be performed, with or without a-fetoprotein, every 6 months.
Methods to prevent HCCn.d.n.d.Cessation of alcohol drinking and tobacco smoking; Weight loss.n.d.Cessation of alcohol drinking in NASH-cirrhosis.n.d.Cessation of alcohol drinking and tobacco smoking; Control diabetes, dyslipidemia, and obesity.
Diagnosis criteria of HCCn.d.n.d.Not stated.n.d.n.d.n.d.Not stated.

AASLD, the American Association for the Study of Liver Diseases; AGA, American Gastroenterological Association; CT, computed tomography; EASL, the European Association for the Study of the Liver; HCC, hepatocellular carcinoma; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; n.d., not described; MRI, magnetic resonance imaging.

Together, these guidelines highlight the need to screen for HCC in all patients with advanced NAFLD-related fibrosis or cirrhosis. They also recommend abstaining from alcohol and smoking, altering one’s lifestyle and using appropriate medications in order to optimize the management of diabetes, lipids, and obesity (Fig. 1). Although over 30% of NAFLD-related HCC cases occur in non-cirrhotic NASH patients, the overall risk of HCC occurrence in these patients is relatively low, HCC surveillance is not recommended for non-cirrhotic patients with NAFLD.44–50

Treatment

At present, HCC diagnosis and treatment guidelines in various countries and regions recommend different treatment methods depending on tumor stage but not etiology.58–62 NAFLD-related HCC differs from HCC related to HBV, HCV, or alcohol in terms of pathogenic factors, epidemiology, histological characteristics, tumor stages, and complications. For example, patients with NAFLD-related HCC frequently present some characteristics typical of metabolic syndrome, such as old age, obesity, type 2 diabetes, or cardiovascular complications.65 These factors are likely to affect the choice of treatment and prognosis of patients. With the increasing prevalence of NAFLD-related HCC, several studies have compared how patients with that or other types of HCC fare after various treatments. These studies, described below, examined outcomes after hepatic resection, local ablation, liver transplantation, transarterial chemoembolization (TACE), radiotherapy, targeted drugs, immunotherapy, and/or postoperative adjuvant therapy (Table 2, Fig. 1). 66–78

Table 2

Comparison of treatment strategies and outcomes in patients with HCC related to NAFLD or other etiologies

Treatment strategyStudies and patients includedTreatment outcomesTreatment safety in patients with NAFLD-related HCC
Hepatic resectionOne meta-analysis included 15 cohort studies with 7,226 patients;66 another included 9 cohort studies with 5,579 patients67Better DFS and OS66,67Higher rates of peri- and postoperative complications67
Radiofrequency ablationTwo retrospective study with 52868 or 520 patients69Similar OSSimilar postoperative morbidity69
Liver transplantationOne meta-analysis included 9 cohort studies with 717 patients with NASH and 3,520 without70Similar OSLower risk of graft failure, but more likely to die from cardiovascular complications or sepsis
Transarterial chemoembolizationOne retrospective study with 30 patients with NASH and 190 without71Similar OSSimilar number of complications
Radiotherapyn.d.n.d.n.d.
Radioembolization with yttrium-90One retrospective study with 87 patients with NAFLD and 67 with HBV72Similar OSSimilar treatment-related toxicity
Tyrosine kinase inhibitors
SorafenibTwo retrospective studies with 5,20173 or 180 patients74Similar OS73,74Similar rate of adverse events73
LenvatinibTwo retrospective studies with 1,23276 and 530 patients75Better PFS75,76 and OS76Similar rate of grade 3/4 adverse events;76 more frequent hypothyroidism and urine protein conditions75
Immune checkpoint inhibitorsOne meta-analysis included 3 randomized trials with 1,657 patients and three independent cohorts of 358 patients77,78Worse OS77n.d.
Adjuvant therapyn.d.n.d.n.d.

DFS, disease-free survival; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; n.d., not described; NAFLD, non-alcoholic fatty liver disease; OS, overall survival; PFS, progression-free survival.

Hepatic resection and local ablation

Hepatic resection is the most important curative treatment for early-stage HCC, and even some patients with intermediate, advanced or recurrent disease can benefit from it.79–82 Several recent retrospective studies have compared outcomes after hepatic resection to treat NAFLD-related HCC or HCC of other etiologies. Some studies suggested that patients with NAFLD-related HCC had longer survival,83,84 while others found similar overall survival among patients with HCC of different etiologies.85,86 Two recently published meta-analyses concluded that patients with NAFLD-related HCC had better overall and disease-free survival after hepatic resection than patients with HCC of other etiologies.66,67 However, serious perioperative complications were significantly more common among patients with NAFLD-related HCC (33.3%) than among those with HBV-related HCC (15.7%).87 Two studies also suggested higher perioperative complications and mortality among patients with NAFLD-related HCC than among those with HCC of other etiologies.88,89 Therefore, although hepatic resection may be associated with good overall and disease-free survival of patients with NAFLD-related HCC in the long term, such patients should be carefully evaluated preoperatively to check for cardiovascular complications or metabolic diseases and to reduce perioperative complications and mortality.

The indications for local ablation of HCC are stricter than those for hepatic resection, but the requirements for liver function are relatively low (Child-Pugh A or B). A retrospective analysis based on the USA’s Surveillance, Epidemiology, and End Results database showed that the overall survival rate after radiofrequency ablation was similar for patients with NAFLD-related HCC as for patients with HCC of other etiologies.68 Another multicenter retrospective cohort in France found patients with NAFLD-related HCC were significantly older, more obese and had more components of metabolic syndrome. However, there were no differences in morbidity, tumor recurrence and overall survival among patients with NAFLD-related HCC vs other aetiologies.69 Therefore, radiofrequency ablation has achieved similar long-term oncological outcomes in NAFLD-related HCC compared to other etiologies. However, more studies are needed to confirm these findings.

Liver transplantation

In 2013, NASH was the second main cause of inclusion in the liver transplant waiting list, after HCV infection.90,91 Compared to the USA’s situation,90,92 HCC prevalence may be higher among European patients who receive liver transplants because of NASH, and the overall survival and transplant survival among these patients are similar to those among patients who receive liver transplants for other reasons.91 NASH has been identified as an independent risk factor for early death after liver transplantation.93

Diabetes compromises the prognosis of liver transplantation patients, and diabetes combined with obesity further degrades it, especially in the presence of HCC.91,94 Therefore, obese HCC patients are at significantly higher risk of perioperative life-threatening complications related to liver transplantation. Patients with NAFLD-related HCC are generally older and obese, and they have cardiovascular and cerebrovascular problems, which complicate liver transplantation and make such patients less likely to receive the transplant. In one study of 1,208 liver transplant recipients, the overall survival rate was lower for patients with NAFLD-related HCC than for those with HCC of other etiologies.68 Three retrospective studies found that overall survival after liver transplantation was similar between patients with NAFLD-related HCC and patients with HCC of other etiologies.90,91,95 A meta-analysis of nine studies involving 717 patients with NASH and 3,520 patients without NASH found no differences in their overall survival at 1, 3, or 5 years after liver transplantation.70 That meta-analysis concluded that NASH patients are at lower risk of transplant failure than non-NASH patients but at higher risk of post-transplant death from cardiovascular complications or septicemia. The higher incidence of postoperative complications in NASH patients may reflect erythrocyte hyperaggregation and hyperfibrinogen due to metabolic syndrome, which may create a prethrombotic state and predispose the patient to thromboembolism and atherosclerotic thrombotic events.96

In conclusion, the most frequent causes of death after liver transplantation in patients with NAFLD-related HCC are tumor recurrence, extrahepatic metastasis, infection, as well as cardiovascular and cerebrovascular complications. Nevertheless, these patients show similar long-term post-transplant survival as patients with HCC of other etiologies. Improving our understanding and management of metabolic risk factors may reduce perioperative risks associated with liver transplantation in patients with NAFLD-related HCC. As NAFLD prevalence increases worldwide, so too does the number of steatosis allografts. Such grafts show worse function and shorter time to failure,97 and effective tools to quantify the extent of steatosis are needed.

TACE and radiotherapy

TACE is the standard treatment for intermediate stage HCC according to European and USA guidelines.58,59,62 In the Chinese HCC guidelines, TACE can be used for patients in stages Ib to IIIb.60 A retrospective study found no difference in time to disease progression, overall survival, or complications after TACE between 30 patients with NASH-related HCC and 190 patients with HCC without NASH.71 A small retrospective study found that body mass index >25 kg/m2 was associated with lower rate of tumor control and greater risk of progression after TACE.98

Although European and USA guidelines on HCC mention radiotherapy, they do not explicitly recommend it at any stage of the disease.58,59,62 The Chinese guidelines, in contrast, recommend radiotherapy for stages IIIa and IIIb.60 Although evidence seems to be growing that external radiation therapy can benefit patients with HCC,99,100 data are lacking on NAFLD-related HCC. A retrospective study found no difference in overall survival or radiation injury between 87 patients with NAFLD-related HCC or 62 with HBV-related HCC after yttrium-90 radioembolization.72 Larger studies are needed in order to draw reliable conclusions about the efficacy and safety of TACE or radiotherapy for NAFLD-related HCC.

Systemic therapy

Systemic treatments for HCC include mainly molecularly targeted drugs and immune checkpoint inhibitors (ICIs).41,101,102 HCC guidelines recommend these therapies for patients with advanced HCC whose Eastern Cooperative Oncology Group (ECOG) score is 0-1 and whose liver function is Child-Pugh grade A or B.58–62

Many phase III clinical trials of molecularly targeted agents as first- or second-line therapies against advanced HCC have been reported,102,103 but patients in these trials have not been stratified by NAFLD or NASH status. An international multicenter cohort study showed that sorafenib treatment was associated with similar overall survival (p=0.57) and adverse events between 183 patients with NAFLD-related HCC and 5,018 patients with HCC of other etiologies.73 Another retrospective study also found that sorafenib was associated with similar median overall survival between 37 patients with NAFLD-related HCC (23.4 months) and 143 patients with other types of HCC (27.0 months) (p=0.17).74

Lenvatinib is a standard targeted therapy for advanced HCC.104 A multicenter retrospective study from Japan found that median progression-free survival was longer among 103 patients with NAFLD- or NASH-related HCC than among 427 patients with viral- or alcohol-related HCC (9.3 vs. 7.5 months, p=0.012).75 Nevertheless, median overall survival was similar between the two groups (20.5 vs. 16.9 months, p=0.057), which was confirmed in multivariate analysis. Another retrospective study from Japan found better outcomes for patients with alcohol- or NASH-related HCC (n=22) than for patients with HBV- or HCV-related HCC (n=45) in terms of objective response rate (59.1% vs. 46.7%), median progression-free survival (13.7 vs. 6.6 months, p<0.01), and median overall survival (“not reached” vs. 15.9 months, p<0.01).105 In an international multicenter retrospective study of 1,232 patients with advanced HCC, those who also had NASH showed significantly higher overall and progression-free survival than patients with HCV or HBV infection or other etiologies after first-line treatment with lenvatinib.76 A retrospective study in the USA showed 12-month progression-free survival rates of 64.9% for 233 patients with total advanced HCC after first-line lenvatinib therapy, compared to 43.0% for the subset of 32 patients who also had NASH.106,107 The corresponding 12-month overall survival rates were 72.6% and 66.0%. More studies are needed to confirm the efficacy of molecularly targeted drugs against NAFLD- or NASH-related HCC.

A number of recent prospective and retrospective studies have reported the safety and efficacy of ICIs alone or in combination with such molecularly targeted agents as first- or second-line treatments against advanced HCC.102,103,108 However, these studies did not perform subgroup analyses based on NAFLD or NASH status. Recently, a meta-analysis105 of the randomized controlled trials CheckMate 459,109 IMbrave150,110 and KEYNOTE-240111 found that ICI treatment was effective against virus-related HCC but ineffective against HCC unrelated to viral infection. Consistently, three studies found significantly better overall survival after ICI therapy among patients with HCC unrelated to NAFLD than among those with NAFLD-related HCC.77,78 In animal studies, ICI treatment failed to slow tumor progression in a mouse model of NAFLD-related HCC,77 while it did slow the progression of HCC in non-NASH mice.112 Therefore, current ICI therapies may not benefit patients with NAFLD-related HCC, which should be explored in future studies.

The combination of molecularly targeted drugs and ICI is associated with higher objective response rate and longer overall survival for patients with advanced HCC than either treatment alone.103,108,110 Compared to patients with HCC of other etiologies, those with NAFLD-related HCC may have better overall survival after lenvatinib treatment but worse overall survival after ICI treatment (Table 2). Future studies should investigate the efficacy of lenvatinib plus ICI against NAFLD-related HCC.

Adjuvant therapy

Hepatic resection, liver transplantation, and ablation are the curative treatment options for HCC, but the postoperative recurrence rate can exceed 50%.58–62 European and USA HCC guidelines do not recommend any adjuvant therapy,58,59,62 whereas Chinese and South Korean HCC guidelines recommend TACE and adoptive immunotherapy.60,61 Given the growing evidence for ICI efficacy against advanced HCC, several ongoing phase III clinical trials are exploring the efficacy of adjuvant ICI monotherapy or combination therapy in patients at high risk of recurrence. For example, the Imbrave-050 trial will compare recurrence-free survival after adjuvant atezolizumab plus bevacizumab or rigorous monitoring.113 The CHECKMATE-9DX trial will compare recurrence-free survival after adjuvant nivolumab or placebo.114 The EMERALD-2 trial will compare recurrence-free survival after adjuvant treatment with durvalumab alone, devarumab combined with bevacizumab, or placebo.115 Patients at high risk of recurrence will be included in all three trials. We look forward to the results of these trials to provide guidance about treatment options after surgery. In addition, these trials should allow subgroup analysis based on HCC etiology, providing options for the adjuvant treatment of NAFLD-related HCC.

Future prospects

With the spread of metabolic syndrome around the world, NAFLD has become the main cause of chronic liver disease worldwide, and it will soon become the main cause of HCC. Clinical characteristics typical of metabolic syndrome, such as old age, obesity, type 2 diabetes, or cardiovascular complications may increase the risk of NAFLD-related HCC. NAFLD can directly progress to HCC without fibrosis or cirrhosis, and since patients are not routinely screened for NAFLD, HCC is frequently diagnosed at an advanced stage, resulting in worse long-term survival. Third, metabolic syndrome concomitant with HCC may limit therapeutic options, such as eliminating the possibility of liver transplantation or increasing risk of cardiovascular complications after surgery. Finally, although many studies have examined the metabolomics and lipidomics of NAFLD and NASH,28 specific molecular characteristics and diagnostic markers remain elusive.

Principles behind the diagnosis and treatment of NAFLD-related HCC are similar to those for HCC of other etiologies. Primary prevention is key. Lifestyle changes and drugs such as metformin, statins, and aspirin have been suggested as primary preventive strategies.116 Secondary prevention will become more effective as drugs to treat NAFLD become available.117 Attention should also be paid to tertiary prevention in the form of NAFLD prevention as well as early detection and timely, individualized treatment of NAFLD-related HCC.

If NAFLD-related HCC can be detected at an early stage, more patients will have the opportunity to receive curative treatment that improves long-term outcomes. Screening for HCC is the most important step to improve secondary prevention, but only if patients at high risk are identified. At present, HCC guidelines58–62 include patients with cirrhosis as the focus group for monitoring. NAFLD guidelines recommend routine screening only for NAFLD or NASH patients with advanced liver fibrosis or cirrhosis.48–50 However, in the absence of cirrhosis, NAFLD or NASH is the primary cause of HCC, so even NAFLD or NASH patients without cirrhosis should be monitored as well. One of the greatest clinical challenges in NAFLD screening is determining whether patients with pre-cirrhotic NAFLD are at sufficiently high risk of developing HCC to justify screening for it. Establishing a model to predict risk of HCC in the presence of NAFLD may allow differentiated patient management that could greatly reduce medical costs.118–121 For example, a scoring system developed in Taiwan can stratify the general population, identifying patients at high risk of HCC and thereby reducing healthcare costs.122 Other risk prediction models based on non-invasive clinical characteristics can accurately predict the risk of HCC in HBV-infected patients.123,124

Individualized treatment is also important. Not all treatments are suitable for all patients with NAFLD-related HCC, so comorbidities of NAFLD patients should be taken into account. Certain biological markers may help guide the choice of treatment for patients with NAFLD-related HCC. For example, markers could identify which patients would benefit most from molecularly targeted drugs and ICI therapy, reducing ineffective treatment costs and unnecessary risk of complications. For example, a multicenter retrospective study found that levels of C-reactive protein and alpha-fetoprotein could accurately predict overall survival and tumor response to ICI therapy in patients with advanced HCC.125

The above problems and challenges in the prevention, screening, diagnosis, and treatment of NAFLD/NASH provide a direction for basic and clinical research. Continuous research and clinical efforts can help improve diagnosis, treatment, and management of NAFLD-related HCC in the near future.

Conclusions

As the prevalence of NAFLD/NASH and NAFLD-related HCC increases worldwide, more attention and research need to focus on these patients. Currently, there is no treatment strategy specific for NAFLD-related HCC. Thus, prevention is a top priority, which can involve public health measures and efforts to improve NAFLD screening tools, establish models for predicting HCC among patients with NAFLD, and induce lifestyle changes that reduce metabolic risk factors. Advanced tumor stage, old age, obesity, and comorbidities limit the use of some HCC therapies, such as hepatectomy and transplantation. Because NAFLD patients are at greater risk of perioperative complications, careful preoperative evaluation is required. The use of local ablation, radiotherapy, and TACE in NAFLD-related HCC has not been well investigated, and more studies are needed to evaluate these strategies. The efficacy of different therapies can depend on HCC etiology; for example, ICI appears to work better against HBV- or HCV-related HCC than against NAFLD-related HCC. However, this and related findings need to be verified carefully in light of the substantial number of cases of NAFLD and NASH that go undiagnosed, such that the HCC in such patients is misattributed to other etiologies. Finally, etiological stratification and/or efficacy prediction using biomarkers may significantly improve patient outcomes. Raising awareness of the burden of NAFLD and implementing screening programs are the main goals pursued by health authorities around the world, with the common objective of improving the prognosis of patients with NAFLD-related HCC.

Abbreviations

DFS: 

disease-free survival

HBV: 

hepatitis B virus

HCV: 

hepatitis C virus

HCC: 

hepatocellular carcinoma

NAFLD: 

non-alcoholic fatty liver disease

NASH: 

non-alcoholic steatohepatitis

OS: 

overall survival

PFS: 

progression-free survival

TACE: 

transarterial chemoembolization

Declarations

Data sharing statement

All data used in this study can be obtained from the cited literature.

Funding

This work was supported by the Specific Research Project of Guangxi for Research Bases and Talents (GuiKe AD22035057), the Natural Science Foundation of Guangxi Province (2020GXNSFAA159022), Bagui Scholars Programs of Guangxi Zhuang Autonomous Region (2019AQ20), the National Natural Science Foundation of China (82060510), and Guangxi Undergraduate Training Program for Innovation and Entrepreneurship (202110598178 and 202110598073).

Conflict of interest

JHZ has been an editorial board member of Journal of Clinical and Translational Hepatology since 2020. The other authors have no conflict of interests related to this publication.

Authors’ contributions

Conception of the study (JHZ), acquirement and analyzation of the data, drafting and revision of the manuscript, and approving the final version to be published (All Authors).

References

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021;71(3):209-249 View Article PubMed/NCBI
  2. Pais R, Fartoux L, Goumard C, Scatton O, Wendum D, Rosmorduc O, et al. Temporal trends, clinical patterns and outcomes of NAFLD-related HCC in patients undergoing liver resection over a 20-year period. Aliment Pharmacol Ther 2017;46(9):856-863 View Article PubMed/NCBI
  3. Younossi ZM, Otgonsuren M, Henry L, Venkatesan C, Mishra A, Erario M, et al. Association of nonalcoholic fatty liver disease (NAFLD) with hepatocellular carcinoma (HCC) in the United States from 2004 to 2009. Hepatology 2015;62(6):1723-1730 View Article PubMed/NCBI
  4. Eguchi Y, Wong G, Lee IH, Akhtar O, Lopes R, Sumida Y. Hepatocellular carcinoma and other complications of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in Japan: A structured review of published works. Hepatol Res 2021;51(1):19-30 View Article PubMed/NCBI
  5. Huang DQ, El-Serag HB, Loomba R. Global epidemiology of NAFLD-related HCC: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol 2021;18(4):223-238 View Article PubMed/NCBI
  6. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016;64(1):73-84 View Article PubMed/NCBI
  7. Li J, Zou B, Yeo YH, Feng Y, Xie X, Lee DH, et al. Prevalence, incidence, and outcome of non-alcoholic fatty liver disease in Asia, 1999-2019: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol 2019;4(5):389-398 View Article PubMed/NCBI
  8. Golabi P, Paik JM, AlQahtani S, Younossi Y, Tuncer G, Younossi ZM. Burden of non-alcoholic fatty liver disease in Asia, the Middle East and North Africa: Data from Global Burden of Disease 2009-2019. J Hepatol 2021;75(4):795-809 View Article PubMed/NCBI
  9. Orci LA, Sanduzzi-Zamparelli M, Caballol B, Sapena V, Colucci N, Torres F, et al. Incidence of Hepatocellular Carcinoma in Patients With Nonalcoholic Fatty Liver Disease: A Systematic Review, Meta-analysis, and Meta-regression. Clin Gastroenterol Hepatol 2022;20(2):283-292.e10 View Article PubMed/NCBI
  10. Lai SW, Chen PC, Liao KF, Muo CH, Lin CC, Sung FC. Risk of hepatocellular carcinoma in diabetic patients and risk reduction associated with anti-diabetic therapy: a population-based cohort study. Am J Gastroenterol 2012;107(1):46-52 View Article PubMed/NCBI
  11. Chen Y, Wang X, Wang J, Yan Z, Luo J. Excess body weight and the risk of primary liver cancer: an updated meta-analysis of prospective studies. Eur J Cancer 2012;48(14):2137-2145 View Article PubMed/NCBI
  12. Zhang X, Coker OO, Chu ES, Fu K, Lau HCH, Wang YX, et al. Dietary cholesterol drives fatty liver-associated liver cancer by modulating gut microbiota and metabolites. Gut 2021;70(4):761-774 View Article PubMed/NCBI
  13. Yang JD, Ahmed F, Mara KC, Addissie BD, Allen AM, Gores GJ, et al. Diabetes Is Associated With Increased Risk of Hepatocellular Carcinoma in Patients With Cirrhosis From Nonalcoholic Fatty Liver Disease. Hepatology 2020;71(3):907-916 View Article PubMed/NCBI
  14. Kanwal F, Kramer JR, Li L, Dai J, Natarajan Y, Yu X, et al. Effect of Metabolic Traits on the Risk of Cirrhosis and Hepatocellular Cancer in Nonalcoholic Fatty Liver Disease. Hepatology 2020;71(3):808-819 View Article PubMed/NCBI
  15. Kramer JR, Natarajan Y, Dai J, Yu X, Li L, El-Serag HB, et al. Effect of diabetes medications and glycemic control on risk of hepatocellular cancer in patients with nonalcoholic fatty liver disease. Hepatology 2021 View Article PubMed/NCBI
  16. Taylor RS, Taylor RJ, Bayliss S, Hagström H, Nasr P, Schattenberg JM, et al. Association Between Fibrosis Stage and Outcomes of Patients With Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis. Gastroenterology 2020;158(6):1611-1625.e12 View Article PubMed/NCBI
  17. Kanwal F, Kramer JR, Mapakshi S, Natarajan Y, Chayanupatkul M, Richardson PA, et al. Risk of Hepatocellular Cancer in Patients With Non-Alcoholic Fatty Liver Disease. Gastroenterology 2018;155(6):1828-1837.e2 View Article PubMed/NCBI
  18. Yip TC, Lee HW, Chan WK, Wong GL, Wong VW. Asian perspective on NAFLD-associated HCC. J Hepatol 2022;76(3):726-734 View Article PubMed/NCBI
  19. NCD Risk Factor Collaboration (NCD-RisC). Rising rural body-mass index is the main driver of the global obesity epidemic in adults. Nature 2019;569(7755):260-264 View Article PubMed/NCBI
  20. Zhang X, Goh GB, Chan WK, Wong GL, Fan JG, Seto WK, et al. Unhealthy lifestyle habits and physical inactivity among Asian patients with non-alcoholic fatty liver disease. Liver Int 2020;40(11):2719-2731 View Article PubMed/NCBI
  21. Baumeister SE, Leitzmann MF, Linseisen J, Schlesinger S. Physical Activity and the Risk of Liver Cancer: A Systematic Review and Meta-Analysis of Prospective Studies and a Bias Analysis. J Natl Cancer Inst 2019;111(11):1142-1151 View Article PubMed/NCBI
  22. Younossi ZM, Stepanova M, Ong J, Yilmaz Y, Duseja A, Eguchi Y, et al. Effects of Alcohol Consumption and Metabolic Syndrome on Mortality in Patients With Nonalcoholic and Alcohol-Related Fatty Liver Disease. Clin Gastroenterol Hepatol 2019;17(8):1625-1633.e1 View Article PubMed/NCBI
  23. Jung HS, Chang Y, Kwon MJ, Sung E, Yun KE, Cho YK, et al. Smoking and the Risk of Non-Alcoholic Fatty Liver Disease: A Cohort Study. Am J Gastroenterol 2019;114(3):453-463 View Article PubMed/NCBI
  24. Abdel-Rahman O, Helbling D, Schöb O, Eltobgy M, Mohamed H, Schmidt J, et al. Cigarette smoking as a risk factor for the development of and mortality from hepatocellular carcinoma: An updated systematic review of 81 epidemiological studies. J Evid Based Med 2017;10(4):245-254 View Article PubMed/NCBI
  25. Balakrishnan M, Patel P, Dunn-Valadez S, Dao C, Khan V, Ali H, et al. Women Have a Lower Risk of Nonalcoholic Fatty Liver Disease but a Higher Risk of Progression vs Men: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol 2021;19(1):61-71.e15 View Article PubMed/NCBI
  26. Rich NE, Oji S, Mufti AR, Browning JD, Parikh ND, Odewole M, et al. Racial and Ethnic Disparities in Nonalcoholic Fatty Liver Disease Prevalence, Severity, and Outcomes in the United States: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol 2018;16(2):198-210.e2 View Article PubMed/NCBI
  27. Bianco C, Jamialahmadi O, Pelusi S, Baselli G, Dongiovanni P, Zanoni I, et al. Non-invasive stratification of hepatocellular carcinoma risk in non-alcoholic fatty liver using polygenic risk scores. J Hepatol 2021;74(4):775-782 View Article PubMed/NCBI
  28. Masoodi M, Gastaldelli A, Hyötyläinen T, Arretxe E, Alonso C, Gaggini M, et al. Metabolomics and lipidomics in NAFLD: biomarkers and non-invasive diagnostic tests. Nat Rev Gastroenterol Hepatol 2021;18(12):835-856 View Article PubMed/NCBI
  29. Huby T, Gautier EL. Immune cell-mediated features of non-alcoholic steatohepatitis. Nat Rev Immunol 2021:1-15 View Article PubMed/NCBI
  30. Fridman WH, Zitvogel L, Sautès-Fridman C, Kroemer G. The immune contexture in cancer prognosis and treatment. Nat Rev Clin Oncol 2017;14(12):717-734 View Article PubMed/NCBI
  31. Sia D, Jiao Y, Martinez-Quetglas I, Kuchuk O, Villacorta-Martin C, Castro de Moura M, et al. Identification of an Immune-specific Class of Hepatocellular Carcinoma, Based on Molecular Features. Gastroenterology 2017;153(3):812-826 View Article PubMed/NCBI
  32. Wolf MJ, Adili A, Piotrowitz K, Abdullah Z, Boege Y, Stemmer K, et al. Metabolic activation of intrahepatic CD8+ T cells and NKT cells causes nonalcoholic steatohepatitis and liver cancer via cross-talk with hepatocytes. Cancer Cell 2014;26(4):549-564 View Article PubMed/NCBI
  33. Kang TW, Yevsa T, Woller N, Hoenicke L, Wuestefeld T, Dauch D, et al. Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 2011;479(7374):547-551 View Article PubMed/NCBI
  34. Ma C, Kesarwala AH, Eggert T, Medina-Echeverz J, Kleiner DE, Jin P, et al. NAFLD causes selective CD4(+) T lymphocyte loss and promotes hepatocarcinogenesis. Nature 2016;531(7593):253-257 View Article PubMed/NCBI
  35. Shalapour S, Lin XJ, Bastian IN, Brain J, Burt AD, Aksenov AA, et al. Inflammation-induced IgA+ cells dismantle anti-liver cancer immunity. Nature 2017;551(7680):340-345 View Article PubMed/NCBI
  36. Behary J, Amorim N, Jiang XT, Raposo A, Gong L, McGovern E, et al. Gut microbiota impact on the peripheral immune response in non-alcoholic fatty liver disease related hepatocellular carcinoma. Nat Commun 2021;12(1):187 View Article PubMed/NCBI
  37. Pinyol R, Torrecilla S, Wang H, Montironi C, Piqué-Gili M, Torres-Martin M, et al. Molecular characterisation of hepatocellular carcinoma in patients with non-alcoholic steatohepatitis. J Hepatol 2021;75(4):865-878 View Article PubMed/NCBI
  38. Park EJ, Lee JH, Yu GY, He G, Ali SR, Holzer RG, et al. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell 2010;140(2):197-208 View Article PubMed/NCBI
  39. Naugler WE, Sakurai T, Kim S, Maeda S, Kim K, Elsharkawy AM, et al. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 2007;317(5834):121-124 View Article PubMed/NCBI
  40. Singal AG, Manjunath H, Yopp AC, Beg MS, Marrero JA, Gopal P, et al. The effect of PNPLA3 on fibrosis progression and development of hepatocellular carcinoma: a meta-analysis. Am J Gastroenterol 2014;109(3):325-334 View Article PubMed/NCBI
  41. Llovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, et al. Hepatocellular carcinoma. Nat Rev Dis Primers 2021;7(1):6 View Article PubMed/NCBI
  42. Baumeister SE, Schlesinger S, Aleksandrova K, Jochem C, Jenab M, Gunter MJ, et al. Association between physical activity and risk of hepatobiliary cancers: A multinational cohort study. J Hepatol 2019;70(5):885-892 View Article PubMed/NCBI
  43. Turati F, Trichopoulos D, Polesel J, Bravi F, Rossi M, Talamini R, et al. Mediterranean diet and hepatocellular carcinoma. J Hepatol 2014;60(3):606-611 View Article PubMed/NCBI
  44. Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, et al. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology 2018;67(1):328-357 View Article PubMed/NCBI
  45. Chitturi S, Wong VW, Chan WK, Wong GL, Wong SK, Sollano J, et al. The Asia-Pacific Working Party on Non-alcoholic Fatty Liver Disease guidelines 2017-Part 2: Management and special groups. J Gastroenterol Hepatol 2018;33(1):86-98 View Article PubMed/NCBI
  46. Fan JG, Wei L, Zhuang H, National Workshop on Fatty Liver and Alcoholic Liver Disease, Chinese Society of Hepatology, Chinese Medical Association; Fatty Liver Disease Expert Committee, Chinese Medical Doctor Association. Guidelines of prevention and treatment of nonalcoholic fatty liver disease (2018, China). J Dig Dis 2019;20(4):163-173 View Article PubMed/NCBI
  47. European Association for the Study of the Liver (EASL)., European Association for the Study of Diabetes (EASD)., European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol 2016;64(6):1388-1402 View Article PubMed/NCBI
  48. Tokushige K, Ikejima K, Ono M, Eguchi Y, Kamada Y, Itoh Y, et al. Evidence-based clinical practice guidelines for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis 2020. Hepatol Res 2021;51(10):1013-1025 View Article PubMed/NCBI
  49. Kang SH, Lee HW, Yoo JJ, Cho Y, Kim SU, Lee TH, et al. KASL clinical practice guidelines: Management of nonalcoholic fatty liver disease. Clin Mol Hepatol 2021;27(3):363-401 View Article PubMed/NCBI
  50. Loomba R, Lim JK, Patton H, El-Serag HB. AGA Clinical Practice Update on Screening and Surveillance for Hepatocellular Carcinoma in Patients With Nonalcoholic Fatty Liver Disease: Expert Review. Gastroenterology 2020;158(6):1822-1830 View Article PubMed/NCBI
  51. Islam MM, Poly TN, Walther BA, Yang HC, Jack Li YC. Statin Use and the Risk of Hepatocellular Carcinoma: A Meta-Analysis of Observational Studies. Cancers (Basel) 2020;12(3):E671 View Article PubMed/NCBI
  52. Zhang ZJ, Zheng ZJ, Shi R, Su Q, Jiang Q, Kip KE. Metformin for liver cancer prevention in patients with type 2 diabetes: a systematic review and meta-analysis. J Clin Endocrinol Metab 2012;97(7):2347-2353 View Article PubMed/NCBI
  53. Simon TG, Henson J, Osganian S, Masia R, Chan AT, Chung RT, et al. Daily Aspirin Use Associated With Reduced Risk For Fibrosis Progression In Patients With Nonalcoholic Fatty Liver Disease. Clin Gastroenterol Hepatol 2019;17(13):2776-2784.e4 View Article PubMed/NCBI
  54. Simon TG, Duberg AS, Aleman S, Chung RT, Chan AT, Ludvigsson JF. Association of Aspirin with Hepatocellular Carcinoma and Liver-Related Mortality. N Engl J Med 2020;382(11):1018-1028 View Article PubMed/NCBI
  55. Memel ZN, Arvind A, Moninuola O, Philpotts L, Chung RT, Corey KE, et al. Aspirin Use Is Associated with a Reduced Incidence of Hepatocellular Carcinoma: A Systematic Review and Meta-analysis. Hepatol Commun 2021;5(1):133-143 View Article PubMed/NCBI
  56. Armstrong MJ, Gaunt P, Aithal GP, Barton D, Hull D, Parker R, et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet 2016;387(10019):679-690 View Article PubMed/NCBI
  57. Safadi R, Braun M, Francis A, Milgrom Y, Massarwa M, Hakimian D, et al. Randomised clinical trial: A phase 2 double-blind study of namodenoson in non-alcoholic fatty liver disease and steatohepatitis. Aliment Pharmacol Ther 2021;54(11-12):1405-1415 View Article PubMed/NCBI
  58. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol 2018;69(1):182-236 View Article PubMed/NCBI
  59. Marrero JA, Kulik LM, Sirlin CB, Zhu AX, Finn RS, Abecassis MM, et al. Diagnosis, Staging, and Management of Hepatocellular Carcinoma: 2018 Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology 2018;68(2):723-750 View Article PubMed/NCBI
  60. Zhou J, Sun H, Wang Z, Cong W, Wang J, Zeng M, et al. Guidelines for the Diagnosis and Treatment of Hepatocellular Carcinoma (2019 Edition). Liver Cancer 2020;9(6):682-720 View Article PubMed/NCBI
  61. Korean Liver Cancer Association (KLCA)., National Cancer Center (NCC), Goyang, Korea. 2018 Korean Liver Cancer Association-National Cancer Center Korea Practice Guidelines for the Management of Hepatocellular Carcinoma. Korean J Radiol 2019;20(7):1042-1113 View Article PubMed/NCBI
  62. Reig M, Forner A, Rimola J, Ferrer-Fàbrega J, Burrel M, Garcia-Criado Á, et al. BCLC strategy for prognosis prediction and treatment recommendation: The 2022 update. J Hepatol 2022;76(3):681-693 View Article PubMed/NCBI
  63. Zhong JH, Peng NF, You XM, Ma L, Xiang X, Wang YY, et al. Tumor stage and primary treatment of hepatocellular carcinoma at a large tertiary hospital in China: A real-world study. Oncotarget 2017;8(11):18296-18302 View Article PubMed/NCBI
  64. Park HJ, Jang HY, Kim SY, Lee SJ, Won HJ, Byun JH, et al. Non-enhanced magnetic resonance imaging as a surveillance tool for hepatocellular carcinoma: Comparison with ultrasound. J Hepatol 2020;72(4):718-724 View Article PubMed/NCBI
  65. Foerster F, Gairing SJ, Müller L, Galle PR. NAFLD-driven HCC: Safety and efficacy of current and emerging treatment options. J Hepatol 2022;76(2):446-457 View Article PubMed/NCBI
  66. Molinari M, Kaltenmeier C, Samra PB, Liu H, Wessel C, Lou Klem M, et al. Hepatic Resection for Hepatocellular Carcinoma in Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis of 7226 Patients. Ann Surg Open 2021;2(2):e065 View Article PubMed/NCBI
  67. Chin KM, Prieto M, Cheong CK, Di Martino M, Ielpo B, Goh BKP, et al. Outcomes after curative therapy for hepatocellular carcinoma in patients with non-alcoholic fatty liver disease: a meta-analysis and review of current literature. HPB (Oxford) 2021;23(8):1164-1174 View Article PubMed/NCBI
  68. Wong CR, Njei B, Nguyen MH, Nguyen A, Lim JK. Survival after treatment with curative intent for hepatocellular carcinoma among patients with vs without non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2017;46(11-12):1061-1069 View Article PubMed/NCBI
  69. Nguyen N, Rode A, Trillaud H, Aubé C, Manichon AF, Hocquelet A, et al. Percutaneous radiofrequency ablation for hepatocellular carcinoma developed on non-alcoholic fatty liver disease. Liver Int 2022;42(4):905-917 View Article PubMed/NCBI
  70. Wang X, Li J, Riaz DR, Shi G, Liu C, Dai Y. Outcomes of liver transplantation for nonalcoholic steatohepatitis: a systematic review and meta-analysis. Clin Gastroenterol Hepatol 2014;12(3):394-402.e1 View Article PubMed/NCBI
  71. Young S, Sanghvi T, Rubin N, Hall D, Roller L, Charaf Y, et al. Transarterial Chemoembolization of Hepatocellular Carcinoma: Propensity Score Matching Study Comparing Survival and Complications in Patients with Nonalcoholic Steatohepatitis Versus Other Causes Cirrhosis. Cardiovasc Intervent Radiol 2020;43(1):65-75 View Article PubMed/NCBI
  72. Schotten C, Bechmann LP, Manka P, Theysohn J, Dechêne A, El Fouly A, et al. NAFLD-Associated Comorbidities in Advanced Stage HCC Do Not Alter the Safety and Efficacy of Yttrium-90 Radioembolization. Liver Cancer 2019;8(6):491-504 View Article PubMed/NCBI
  73. Howell J, Samani A, Mannan B, Hajiev S, Aval LM, Abdelmalak R, et al. Impact of NAFLD on clinical outcomes in hepatocellular carcinoma treated with sorafenib: an international cohort study. J Clin Oncol 2021;39(3_suppl):289 View Article PubMed/NCBI
  74. Shimose S, Hiraoka A, Nakano M, Iwamoto H, Tanaka M, Tanaka T, et al. First-line sorafenib sequential therapy and liver disease etiology for unresectable hepatocellular carcinoma using inverse probability weighting: A multicenter retrospective study. Cancer Med 2021;10(23):8530-8541 View Article PubMed/NCBI
  75. Hiraoka A, Kumada T, Tada T, Tani J, Kariyama K, Fukunishi S, et al. Efficacy of lenvatinib for unresectable hepatocellular carcinoma based on background liver disease etiology: multi-center retrospective study. Sci Rep 2021;11(1):16663 View Article PubMed/NCBI
  76. Rimini M, Kudo M, Tada T, Shigeo S, Kang W, Suda G, et al. Nonalcoholic steatohepatitis in hepatocarcinoma: new insights about its prognostic role in patients treated with lenvatinib. ESMO Open 2021;6(6):100330 View Article PubMed/NCBI
  77. Pfister D, Núñez NG, Pinyol R, Govaere O, Pinter M, Szydlowska M, et al. NASH limits anti-tumour surveillance in immunotherapy-treated HCC. Nature 2021;592(7854):450-456 View Article PubMed/NCBI
  78. Teng YX, Guo PP, Qin KZ, Chen K, Papatheodoridis G, Xiang BD, et al. Lenvatinib With or Without Immune Checkpoint Inhibitors in Subsets of Advanced Hepatocellular Carcinoma. EJMO 2022;6(1):25-29 View Article PubMed/NCBI
  79. Zhong JH, Ke Y, Gong WF, Xiang BD, Ma L, Ye XP, et al. Hepatic resection associated with good survival for selected patients with intermediate and advanced-stage hepatocellular carcinoma. Ann Surg 2014;260(2):329-340 View Article PubMed/NCBI
  80. Wang YY, Xiang BD, Ma L, Zhong JH, Ye JZ, Wang K, et al. Development and Validation of a Nomogram to Preoperatively Estimate Post-hepatectomy Liver Dysfunction Risk and Long-term Survival in Patients With Hepatocellular Carcinoma. Ann Surg 2021;274(6):e1209-e1217 View Article PubMed/NCBI
  81. Zhong JH, Xing BC, Zhang WG, Chan AW, Chong CCN, Serenari M, et al. Repeat hepatic resection versus radiofrequency ablation for recurrent hepatocellular carcinoma: retrospective multicentre study. Br J Surg 2021;109(1):71-78 View Article PubMed/NCBI
  82. Yuan BH, Zhu YK, Zou XM, Zhou HD, Li RH, Zhong JH. Repeat hepatic resection versus percutaneous ablation for the treatment of recurrent hepatocellular carcinoma: meta-analysis. BJS Open 2022;6(2):zrac036 View Article PubMed/NCBI
  83. Liu L, Xie S, Teng YX, Deng ZJ, Chen K, Liu HT, et al. Outcomes of Liver Resection for Metabolic Dysfunction-Associated Fatty Liver Disease or Chronic Hepatitis B-Related HCC. Front Oncol 2022;11:783339 View Article PubMed/NCBI
  84. Viganò L, Conci S, Cescon M, Fava C, Capelli P, D’Errico A, et al. Liver resection for hepatocellular carcinoma in patients with metabolic syndrome: A multicenter matched analysis with HCV-related HCC. J Hepatol 2015;63(1):93-101 View Article PubMed/NCBI
  85. Lin BZ, Lin TJ, Lin CL, Liao LY, Chang TA, Lu BJ, et al. Differentiation of clinical patterns and survival outcomes of hepatocellular carcinoma on hepatitis B and nonalcoholic fatty liver disease. J Chin Med Assoc 2021;84(6):606-613 View Article PubMed/NCBI
  86. Yang T, Hu LY, Li ZL, Liu K, Wu H, Xing H, et al. Liver Resection for Hepatocellular Carcinoma in Non-alcoholic Fatty Liver Disease: a Multicenter Propensity Matching Analysis with HBV-HCC. J Gastrointest Surg 2020;24(2):320-329 View Article PubMed/NCBI
  87. Tian Y, Lyu H, He Y, Xia Y, Li J, Shen F. Comparison of Hepatectomy for Patients with Metabolic Syndrome-Related HCC and HBV-Related HCC. J Gastrointest Surg 2018;22(4):615-623 View Article PubMed/NCBI
  88. Billeter AT, Müller PC, Albrecht T, Roessler S, Löffler M, Lemekhova A, et al. Impact of Type 2 Diabetes on Oncologic Outcomes of Hepatocellular Carcinomas in Non-Cirrhotic, Non-alcoholic Steatohepatitis: a Matched-Pair Analysis. J Gastrointest Surg 2021;25(5):1193-1202 View Article PubMed/NCBI
  89. Kaufmann B, Reca A, Wang B, Friess H, Feldstein AE, Hartmann D. Mechanisms of nonalcoholic fatty liver disease and implications for surgery. Langenbecks Arch Surg 2021;406(1):1-17 View Article PubMed/NCBI
  90. Wong RJ, Aguilar M, Cheung R, Perumpail RB, Harrison SA, Younossi ZM, et al. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterology 2015;148(3):547-555 View Article PubMed/NCBI
  91. Haldar D, Kern B, Hodson J, Armstrong MJ, Adam R, Berlakovich G, et al. Outcomes of liver transplantation for non-alcoholic steatohepatitis: A European Liver Transplant Registry study. J Hepatol 2019;71(2):313-322 View Article PubMed/NCBI
  92. Cholankeril G, Wong RJ, Hu M, Perumpail RB, Yoo ER, Puri P, et al. Liver Transplantation for Nonalcoholic Steatohepatitis in the US: Temporal Trends and Outcomes. Dig Dis Sci 2017;62(10):2915-2922 View Article PubMed/NCBI
  93. Barritt AS4th, Dellon ES, Kozlowski T, Gerber DA, Hayashi PH. The influence of nonalcoholic fatty liver disease and its associated comorbidities on liver transplant outcomes. J Clin Gastroenterol 2011;45(4):372-378 View Article PubMed/NCBI
  94. Adams LA, Arauz O, Angus PW, Sinclair M, MacDonald GA, Chelvaratnam U, et al. Additive impact of pre-liver transplant metabolic factors on survival post-liver transplant. J Gastroenterol Hepatol 2016;31(5):1016-1024 View Article PubMed/NCBI
  95. Reddy SK, Steel JL, Chen HW, DeMateo DJ, Cardinal J, Behari J, et al. Outcomes of curative treatment for hepatocellular cancer in nonalcoholic steatohepatitis versus hepatitis C and alcoholic liver disease. Hepatology 2012;55(6):1809-1819 View Article PubMed/NCBI
  96. Vayá A, Hernández-Mijares A, Bonet E, Sendra R, Solá E, Pérez R, et al. Association between hemorheological alterations and metabolic syndrome. Clin Hemorheol Microcirc 2011;49(1-4):493-503 View Article PubMed/NCBI
  97. Chu MJ, Dare AJ, Phillips AR, Bartlett AS. Donor Hepatic Steatosis and Outcome After Liver Transplantation: a Systematic Review. J Gastrointest Surg 2015;19(9):1713-1724 View Article PubMed/NCBI
  98. Wu SE, Charles HW, Park JS, Goldenberg AS, Deipolyi AR. Obesity conveys poor outcome in patients with hepatocellular carcinoma treated by transarterial chemoembolization. Diagn Interv Imaging 2017;98(1):37-42 View Article PubMed/NCBI
  99. Feng M, Suresh K, Schipper MJ, Bazzi L, Ben-Josef E, Matuszak MM, et al. Individualized Adaptive Stereotactic Body Radiotherapy for Liver Tumors in Patients at High Risk for Liver Damage: A Phase 2 Clinical Trial. JAMA Oncol 2018;4(1):40-47 View Article PubMed/NCBI
  100. Hong J, Cao L, Xie H, Liu Y, Yu J, Zheng S. Stereotactic body radiation therapy versus radiofrequency ablation in patients with small hepatocellular carcinoma: a systematic review and meta-analysis. Hepatobiliary Surg Nutr 2021;10(5):623-630 View Article PubMed/NCBI
  101. Lan XB, Papatheodoridis G, Teng YX, Zhong JH. The upward trend in the immunotherapy utilization for hepatobiliary cancers. Hepatobiliary Surg Nutr 2021;10(5):692-695 View Article PubMed/NCBI
  102. Liu HT, Jiang MJ, Deng ZJ, Li L, Huang JL, Liu ZX, et al. Immune Checkpoint Inhibitors in Hepatocellular Carcinoma: Current Progresses and Challenges. Front Oncol 2021;11:737497 View Article PubMed/NCBI
  103. Deng ZJ, Li L, Teng YX, Zhang YQ, Zhang YX, Liu HT, et al. Treatments of Hepatocellular Carcinoma with Portal Vein Tumor Thrombus: Current Status and Controversy. J Clin Transl Hepatol 2022;10(1):147-158 View Article PubMed/NCBI
  104. Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet 2018;391(10126):1163-1173 View Article PubMed/NCBI
  105. Tomonari T, Sato Y, Tanaka H, Mitsuhashi T, Hirao A, Tanaka T, et al. Therapeutic efficacy of lenvatinib in nonviral unresectable hepatocellular carcinoma. JGH Open 2021;5(11):1275-1283 View Article PubMed/NCBI
  106. Singal AG, Nagar SP, Hitchens A, Davis KL, Iyer S. Real-world effectiveness of lenvatinib monotherapy among unresectable hepatocellular carcinoma patients in the USA. Future Oncol 2021;17(21):2759-2768 View Article PubMed/NCBI
  107. Singal AG, Nagar SP, Hitchens A, Davis KL, Iyer S. Real-World Effectiveness of Lenvatinib in Hepatocellular Carcinoma Patients with Nonalcoholic Steatohepatitis. Clin Gastroenterol Hepatol 2021:S1542-3565(21)01258-1 View Article PubMed/NCBI
  108. Chen K, Wei W, Liu L, Deng ZJ, Li L, Liang XM, et al. Lenvatinib with or without immune checkpoint inhibitors for patients with unresectable hepatocellular carcinoma in real-world clinical practice. Cancer Immunol Immunother 2022;71(5):1063-1074 View Article PubMed/NCBI
  109. Yau T, Park JW, Finn RS, Cheng AL, Mathurin P, Edeline J, et al. CheckMate 459: A randomized, multi-center phase III study of nivolumab (NIVO) vs sorafenib (SOR) as first-line (1L) treatment in patients (pts) with advanced hepatocellular carcinoma (aHCC). Ann Oncol 2019;30:v874 View Article PubMed/NCBI
  110. Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, et al. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med 2020;382(20):1894-1905 View Article PubMed/NCBI
  111. Finn RS, Ryoo BY, Merle P, Kudo M, Bouattour M, Lim HY, et al. Pembrolizumab As Second-Line Therapy in Patients With Advanced Hepatocellular Carcinoma in KEYNOTE-240: A Randomized, Double-Blind, Phase III Trial. J Clin Oncol 2020;38(3):193-202 View Article PubMed/NCBI
  112. Chung AS, Mettlen M, Ganguly D, Lu T, Wang T, Brekken RA, et al. Immune Checkpoint Inhibition is Safe and Effective for Liver Cancer Prevention in a Mouse Model of Hepatocellular Carcinoma. Cancer Prev Res (Phila) 2020;13(11):911-922 View Article PubMed/NCBI
  113. Hack SP, Spahn J, Chen M, Cheng AL, Kaseb A, Kudo M, et al. IMbrave 050: a Phase III trial of atezolizumab plus bevacizumab in high-risk hepatocellular carcinoma after curative resection or ablation. Future Oncol 2020;16(15):975-989 View Article PubMed/NCBI
  114. Jimenez Exposito MJ, Akce M, Montero Alvarez JL, Assenat E, Balart LA, Baron AD, et al. CA209-9DX: phase III, randomized, double-blind study of adjuvant nivolumab vs placebo for patients with hepatocellular carcinoma (HCC) at high risk of recurrence after curative resection or ablation. Ann Oncol 2018;29(Suppl 8):VIII267-VIII268 View Article PubMed/NCBI
  115. Knox J, Cheng AL, Cleary PG, Kokudo N, Lencioni R, Park J, et al. A phase 3 study of durvalumab with or without bevacizumab as adjuvant therapy in patients with hepa-tocellular carcinoma at high risk of recurrence after curative hepatic resection or ablation: EMERALD-2. Ann Oncol 2019;30(Suppl 4):IV59-IV60 View Article PubMed/NCBI
  116. Geh D, Manas DM, Reeves HL. Hepatocellular carcinoma in non-alcoholic fatty liver disease-a review of an emerging challenge facing clinicians. Hepatobiliary Surg Nutr 2021;10(1):59-75 View Article PubMed/NCBI
  117. Stojsavljevic-Shapeski S, Duvnjak M, Virovic-Jukic L, Hrabar D, Smircic Duvnjak L. New Drugs on the Block-Emerging Treatments for Nonalcoholic Steatohepatitis. J Clin Transl Hepatol 2021;9(1):51-59 View Article PubMed/NCBI
  118. Ioannou GN. Epidemiology and risk-stratification of NAFLD-associated HCC. J Hepatol 2021;75(6):1476-1484 View Article PubMed/NCBI
  119. Younossi ZM, Noureddin M, Bernstein D, Kwo P, Russo M, Shiffman ML, et al. Role of Noninvasive Tests in Clinical Gastroenterology Practices to Identify Patients With Nonalcoholic Steatohepatitis at High Risk of Adverse Outcomes: Expert Panel Recommendations. Am J Gastroenterol 2021;116(2):254-262 View Article PubMed/NCBI
  120. Kanwal F, Shubrook JH, Adams LA, Pfotenhauer K, Wai-Sun Wong V, Wright E, et al. Clinical Care Pathway for the Risk Stratification and Management of Patients With Nonalcoholic Fatty Liver Disease. Gastroenterology 2021;161(5):1657-1669 View Article PubMed/NCBI
  121. Ioannou GN, Green P, Kerr KF, Berry K. Models estimating risk of hepatocellular carcinoma in patients with alcohol or NAFLD-related cirrhosis for risk stratification. J Hepatol 2019;71(3):523-533 View Article PubMed/NCBI
  122. Wen CP, Lin J, Yang YC, Tsai MK, Tsao CK, Etzel C, et al. Hepatocellular carcinoma risk prediction model for the general population: the predictive power of transaminases. J Natl Cancer Inst 2012;104(20):1599-1611 View Article PubMed/NCBI
  123. Lee MH, Yang HI, Liu J, Batrla-Utermann R, Jen CL, Iloeje UH, et al. E.V.E.A.L.-HBV Study Group. Prediction models of long-term cirrhosis and hepatocellular carcinoma risk in chronic hepatitis B patients: risk scores integrating host and virus profiles. Hepatology 2013;58(2):546-554 View Article PubMed/NCBI
  124. Yang HI, Sherman M, Su J, Chen PJ, Liaw YF, Iloeje UH, et al. Nomograms for risk of hepatocellular carcinoma in patients with chronic hepatitis B virus infection. J Clin Oncol 2010;28(14):2437-2444 View Article PubMed/NCBI
  125. Scheiner B, Pomej K, Kirstein MM, Hucke F, Finkelmeier F, Waidmann O, et al. Prognosis of patients with hepatocellular carcinoma treated with immunotherapy - development and validation of the CRAFITY score. J Hepatol 2022;76(2):353-363 View Article PubMed/NCBI

Copyright © 2022 Authors. This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial 4.0 License (CC BY-NC 4.0), permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

  • © 2024 Xia & He Publishing Inc.
  • Total visits : 2610277
  • Visits today : 752