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Asian perspective on NAFLD-associated HCC

  • Terry Cheuk-Fung Yip
    Affiliations
    Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong

    Medical Data Analytics Centre, The Chinese University of Hong Kong, Hong Kong

    State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong
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  • Hye Won Lee
    Affiliations
    Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
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  • Wah Kheong Chan
    Affiliations
    Gastroenterology and Hepatology Unit, Department of Medicine, University of Malaya, Kuala Lumpur, Malaysia
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  • Grace Lai-Hung Wong
    Affiliations
    Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong

    Medical Data Analytics Centre, The Chinese University of Hong Kong, Hong Kong

    State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong
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  • Vincent Wai-Sun Wong
    Correspondence
    Corresponding author. Address: Department of Medicine and Therapeutics, 9/F, Prince of Wales Hospital, 30-32 Ngan Shing Street, Shatin, Hong Kong; Tel.: +852 35051205, fax: +852 26373852.
    Affiliations
    Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong

    Medical Data Analytics Centre, The Chinese University of Hong Kong, Hong Kong

    State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong
    Search for articles by this author
Published:October 03, 2021DOI:https://doi.org/10.1016/j.jhep.2021.09.024

      Summary

      Recent data suggest that non-alcoholic fatty liver disease (NAFLD) has become a major public health problem in Asia, with an updated population prevalence of 34%. In parallel, NAFLD-associated hepatocellular carcinoma (HCC) is also on the rise. In this review, we describe the changing epidemiology of HCC in Asia over the past 30 years. While traditional risk factors for HCC (older age, male sex and metabolic factors) are also important in Asia, the PNPLA3 gene polymorphism is particularly prevalent in East Asia and may increase the risk of HCC. NAFLD among non-obese individuals is also commonly described in Asia. Because NAFLD is often undiagnosed, few patients receive HCC surveillance, and the target surveillance population beyond patients with cirrhosis remains poorly defined. As a result, NAFLD-associated HCC is often diagnosed at an advanced stage, rendering curative treatment impossible. Finally, despite around 20-30 years of universal vaccination, chronic HBV infection remains prevalent in Asia, and emerging evidence highlights the importance of metabolic factors and concomitant hepatic steatosis on HCC development in infected patients. Future studies should explore the role of metabolic treatments in HCC prevention among patients with hepatic steatosis and concomitant liver diseases.

      Keywords

      Introduction

      Asia is a vast continent with much variability in economic development, lifestyle habits and genetic background. According to Worldometer data from 2021, Asia is home to 48 countries and 4.67 billion people. Recent data suggest that the prevalence of non-alcoholic fatty liver disease (NAFLD) in Asia has increased to 34%, which is as high as figures in Europe and North America.
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      Prevalence, incidence, and outcome of non-alcoholic fatty liver disease in Asia, 1999-2019: a systematic review and meta-analysis.
      Although Asians appear to have less severe liver histology and better clinical outcomes, the epidemiology is rapidly changing with NAFLD-associated hepatocellular carcinoma (HCC) on the rise.
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      • Wong V.W.
      New trends on obesity and NAFLD in Asia.
      With such a huge population, a small increase in HCC incidence would still translate into a high number of affected patients. Furthermore, chronic viral hepatitis, particularly chronic HBV infection, remains endemic in Asia. In this article, we review the changing epidemiology, risk factors and management of NAFLD-associated HCC in Asia. We also discuss the current understanding on the impact of hepatic steatosis in patients with chronic hepatitis B (CHB).

      Epidemiology and aetiologies of HCC in Asia

      Primary liver cancer, of which 75–85% of cases are HCC, is the sixth most common cancer and the third leading cause of cancer death globally.
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      Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
      In 2020, there were approximately 906,000 incident cases and 830,000 deaths due to primary liver cancer, which represented an incidence-to-mortality ratio that approaches 1. The disease burden of HCC varies across Asia. Eastern Asia has the highest age-standardised incidence rate (ASIR) of primary liver cancer in the world at 27.4/100,000 person-years.
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      Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
      Of note, Mongolia has a particularly high ASIR of primary liver cancer of 85.6/100,000 person-years, mainly due to viral hepatitis and alcohol consumption. South-Eastern Asia has a relatively high ASIR of primary liver cancer of 14.4/100,000 person-years (Fig. 1A). Central Asia, Southern Asia, and Western Asia have a lower ASIR of primary liver cancer compared to Eastern and South-Eastern Asia. The major risk factor for HCC in Asia remains chronic HBV/HCV infection. Although age is generally an important risk factor for HCC, the association is influenced by the aetiology of liver disease. For HBV, the average age at HCC diagnosis is about 50 years. In contrast, the mean age at which NAFLD-associated HCC develops is about 70 years.
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      Association of nonalcoholic fatty liver disease (NAFLD) with hepatocellular carcinoma (HCC) in the United States from 2004 to 2009.
      This may reflect the fact that NAFLD in general progresses more slowly than chronic viral hepatitis. HCC is male-predominant, with a male-to-female ratio of about 2 to 3 in Asia.
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      Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
      The aetiologies of HCC in Asia are transitioning from viral to non-viral risk factors including NAFLD. The prevalence of NAFLD is already as high in Asia as in the West.
      Figure thumbnail gr1
      Fig. 1Map of primary liver cancer and NAFLD in Asia.
      (A) ASIR of primary liver cancer, and (B) prevalence of NAFLD. Hepatocellular carcinoma accounts for 75-85% of primary liver cancer. Data were obtained from GLOBOCAN 2020 (https://gco.iarc.fr/today/home). The prevalence of NAFLD by any diagnostic modality was based on the study by Li et al.
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      Prevalence, incidence, and outcome of non-alcoholic fatty liver disease in Asia, 1999-2019: a systematic review and meta-analysis.
      ASIR, age-standardised incidence rate; NAFLD, non-alcoholic fatty liver disease.
      The prevalence of chronic HBV and HCV infection has been declining over time in Asia. Consequently, the incidence and mortality rates of HCC in Asia have been decreasing.
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      Global burden of 5 major types of gastrointestinal cancer.
      Of note, a study from Korea suggested that while the age-standardised incidence of HCC is decreasing, the absolute number of HCC-related deaths is still on the rise, likely reflecting the effect of population aging.
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      • Han S.
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      Increasing burden of liver cancer despite extensive use of antiviral agents in a hepatitis B virus-endemic population.
      In contrast, the prevalence of NAFLD in Asia has increased significantly, from 25% in early 2000 to 34% in recent years (Fig. 1B).
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      • Zou B.
      • Yeo Y.H.
      • Feng Y.
      • Xie X.
      • Lee D.H.
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      Prevalence, incidence, and outcome of non-alcoholic fatty liver disease in Asia, 1999-2019: a systematic review and meta-analysis.
      Together with the pandemic of obesity and diabetes, it is expected that the prevalence of NAFLD will continue to increase. While the majority of patients with NAFLD have simple steatosis without advanced liver disease, some can develop non-alcoholic steatohepatitis (NASH), which can result in cirrhosis and HCC. From 2016 to 2030, the prevalence of NASH in China and Japan is projected to increase by 48% and 14%, respectively.
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      Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016-2030.
      In addition, in the context of NAFLD, a significant proportion of HCCs develop in patients without cirrhosis.
      The aetiologies of HCC in Asia are undergoing a transition from viral to non-viral factors including NAFLD (Fig. 2).
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      A nationwide survey on non-B, non-C hepatocellular carcinoma in Japan: 2011-2015 update.
      In Korea, the proportion of HCC attributable to NAFLD increased from 3.8% in 2001-2005 to 12.2% in 2006-2010.
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      • Lee J.H.
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      Relative etiological role of prior hepatitis B virus infection and nonalcoholic fatty liver disease in the development of non-B non-C hepatocellular carcinoma in a hepatitis B-endemic area.
      In Japan, the proportion of HCC attributable to non-HBV and non-HCV aetiologies increased from 10.0% in 1991 to 32.5% in 2015.
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      • Fujiwara N.
      • Takehara T.
      • Okanoue T.
      • Seike M.
      • et al.
      A nationwide survey on non-B, non-C hepatocellular carcinoma in Japan: 2011-2015 update.
      It is estimated that from 2016 to 2030, there will be an 82% increase in incident HCC cases in China. Likewise, the number of incident HCC cases are predicted to increase by 44%, 65%, 80%, 80%, and 85% in Japan, Hong Kong, Singapore, South Korea, and Taiwan during the same period, respectively.
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      • Anstee Q.M.
      • Arias-Loste M.T.
      • Bantel H.
      • Bellentani S.
      • Caballeria J.
      • et al.
      Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016-2030.
      ,
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      • Chien R.N.
      • Chuang W.L.
      • Fung J.
      • Goh G.B.
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      Modelling NAFLD disease burden in four Asian regions-2019-2030.
      Figure thumbnail gr2
      Fig. 2Secular trend of the aetiologies of HCC in Japan.
      BC, HBV and HCV co-infection; HCC, hepatocellular carcinoma; NBNC, neither HBV nor HCV infection. The figure was reproduced with permission from Tateishi et al.
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      • Uchino K.
      • Fujiwara N.
      • Takehara T.
      • Okanoue T.
      • Seike M.
      • et al.
      A nationwide survey on non-B, non-C hepatocellular carcinoma in Japan: 2011-2015 update.

      Risk factors for NAFLD-associated HCC

      Advanced age, male sex, and presence of NASH-related cirrhosis are important risk factors for HCC among patients with NAFLD (Fig. 3). Moreover, lifestyle, genetics, metabolic risk factors, as well as the severity of NAFLD play an important role in the risk of HCC in patients with NAFLD. Herein, we describe the risk factors for NAFLD-associated HCC with emphasis on data from Asia.
      Figure thumbnail gr3
      Fig. 3Risk factors for NAFLD-associated HCC in Asia.
      HCC, hepatocellular carcinoma; NAFLD, non-alcoholic fatty liver disease.

      Lifestyle factors

      NAFLD is the result of an energy imbalance caused by overnutrition and a sedentary lifestyle, potentiated by genetic susceptibility. Traditionally, there has been an emphasis on the urban-rural divide in metabolic diseases in low-income countries. Nonetheless, although NAFLD and obesity remain less prevalent in rural areas, recent data clearly indicated that the gap is closing fast. In fact, rising BMI in rural areas is the main driver of the obesity epidemic in Asia.
      Collaboration NCDRF
      Rising rural body-mass index is the main driver of the global obesity epidemic in adults.
      In a multicentre prospective study of patients with NAFLD from 5 Asian regions, unhealthy lifestyle habits such as smoking (3.8-22.6%) and soft drink consumption (22.6-62.2%) were common.
      • Zhang X.
      • Goh G.B.
      • Chan W.K.
      • Wong G.L.
      • Fan J.G.
      • Seto W.K.
      • et al.
      Unhealthy lifestyle habits and physical inactivity among Asian patients with non-alcoholic fatty liver disease.
      Less than 30% of patients met the recommendations of Physical Activity Guidelines, and less than 50% reported any vigorous or moderate-intensity physical activity at all. Meanwhile, Asian patients with NAFLD spent a median of 42 hours a week sitting. In another population study from Hong Kong, people with NAFLD had lower Dietary Quality Index-International scores, and consumed less vegetables, fruits and vitamin C.
      • Chan R.
      • Wong V.W.
      • Chu W.C.
      • Wong G.L.
      • Li L.S.
      • Leung J.
      • et al.
      Diet-quality scores and prevalence of nonalcoholic fatty liver disease: a population study using proton-magnetic resonance spectroscopy.
      Although lifestyle factors have a strong association with NAFLD and some of them have been mechanistically linked to HCC in animal studies, human data on a causal relationship with HCC are scarce. A systematic review and meta-analysis of 14 prospective studies (including 4 from Japan, Korea and Taiwan) demonstrated an inverse association between physical activity and the risk of liver cancer (hazard ratio 0.75 comparing high vs. low physical activity).
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      • Schlesinger S.
      Physical activity and the risk of liver cancer: a systematic review and meta-analysis of prospective studies and a bias analysis.
      Nonetheless, it is difficult to dissect the effects of individual lifestyle factors because of their complex interrelation (e.g. people who exercise less are more likely to have a less healthy diet) and the inherent limitation of the tools to quantify these factors, not to mention the difficulty in taking all potential confounders into account.
      At the same body mass index, Asians are more likely to have central obesity than Caucasians. Central obesity is a good indicator of metabolic health and NAFLD-associated HCC risk in the Asian population.

      Genetic factors

      Genomic studies in the past 15 years have identified a number of gene polymorphisms that promote (e.g. PNPLA3 and TM6SF2) and prevent (e.g. HSD17B13) the development of NAFLD.
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      • Valenti L.
      • Romeo S.
      Genetics and epigenetics of NAFLD and NASH: clinical impact.
      Among these factors, the PNPLA3 rs738409 I148M variant has been most consistently replicated in the Asian population.
      • Shen J.
      • Wong G.L.
      • Chan H.L.
      • Chan H.Y.
      • Yeung D.K.
      • Chan R.S.
      • et al.
      PNPLA3 gene polymorphism accounts for fatty liver in community subjects without metabolic syndrome.
      Importantly, the PNPLA3 variant is more common among East Asian patients than Caucasian and Black patients. This may partly explain the relatively high prevalence of NAFLD in Asia despite less severe metabolic conditions.
      In some cohort studies, these gene polymorphisms were associated with not only NAFLD but also its histological severity. This in turn translates into an increased risk of HCC. Recently, a multicentre European study combined PNPLA3, TM6SF2, GCKR, MBOAT7 and HSD17B13 to derive polygenic risk scores for HCC prediction in patients with NAFLD and the general population.
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      • Zanoni I.
      • et al.
      Non-invasive stratification of hepatocellular carcinoma risk in non-alcoholic fatty liver using polygenic risk scores.
      Although most of these genetic markers have been explored in the Asian population, data on NAFLD-associated HCC are largely lacking. In addition, the prevalence and functional significance of the genetic markers may differ in the Asian population. For example, the TM6SF2 rs58542926 E167K variant is of low frequency across all populations, but the prevalence is similar in Chinese and Caucasian patients, and lower in Hispanic and Black patients.
      • Wong V.W.
      • Wong G.L.
      • Tse C.H.
      • Chan H.L.
      Prevalence of the TM6SF2 variant and non-alcoholic fatty liver disease in Chinese.
      The rs641738 variant adjacent to the MBOAT7 gene is less common in Chinese than Caucasian patients, and correlates less with hepatic inflammation among patients with CHB.
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      • Chan H.L.Y.
      • Petta S.
      • Mangia A.
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      • et al.
      The membrane-bound O-acyltransferase domain-containing 7 variant rs641738 increases inflammation and fibrosis in chronic hepatitis B.
      However, a study from Hong Kong showed that both histological hepatic steatosis and the APOC3 rs2854116 variant were associated with the incidence of HCC in patients with CHB.
      • Chan A.W.
      • Wong G.L.
      • Chan H.Y.
      • Tong J.H.
      • Yu Y.H.
      • Choi P.C.
      • et al.
      Concurrent fatty liver increases risk of hepatocellular carcinoma among patients with chronic hepatitis B.
      The APOC3 gene polymorphism was originally shown to be associated with NAFLD in Asian Indians.
      The role of epigenetics, e.g. DNA methylation, histone modification and non-coding RNAs, has been studied extensively in the field of HCC. Emerging data suggest that these processes are also involved in the pathogenesis of NAFLD.
      • Eslam M.
      • Valenti L.
      • Romeo S.
      Genetics and epigenetics of NAFLD and NASH: clinical impact.
      Aging, in particular, is conducive to DNA methylation and contributes to the development of both NAFLD and HCC. Future studies should determine the role of epigenetics in NAFLD-associated HCC.

      Metabolic risk factors

      NAFLD shares risk factors with metabolic conditions, including type 2 diabetes, dyslipidaemia, obesity, and hypertension. The prevalence of diabetes in Asia is rising, with a steeper rising trend in developing countries than developed countries. Some countries in South Asia including India and Pakistan have a particularly high prevalence of diabetes.
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      • Ma R.C.
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      • Chan J.C.
      • Chia K.S.
      • et al.
      Diabetes in Asia and the pacific: implications for the global epidemic.
      Diabetes increases the risk of HCC development. In a Taiwanese study, the incidence of HCC was 21.0 vs. 10.4 per 10,000 person-years in those with and without diabetes, respectively, with an adjusted hazard ratio (HR) of 1.73 (95% CI 1.47-2.03).
      • Lai S.W.
      • Chen P.C.
      • Liao K.F.
      • Muo C.H.
      • Lin C.C.
      • Sung F.C.
      Risk of hepatocellular carcinoma in diabetic patients and risk reduction associated with anti-diabetic therapy: a population-based cohort study.
      Compared to patients with a diabetes duration of 2 to 5 years, adjusted odds ratios of HCC for those with a diabetes duration of 6 to 10 years and those with a diabetes duration >10 years were 1.8 (95% CI 0.8-4.1) and 2.2 (95% CI 1.2-4.8), respectively. With respect to diabetes treatment, the adjusted odds ratios of HCC were 0.3 (95% CI 0.2-0.6), 0.3 (95% CI 0.1-0.7), 7.1 (95% CI 2.9-16.9), 1.9 (95% CI 0.8-4.6), and 7.8 (95% CI 1.5-40.0) for those treated with biguanides, thiazolidinediones, sulfonylureas, insulin, and dietary control, respectively.
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      • Curley S.A.
      • Li D.
      • Kaseb A.
      • Davila M.
      • Abdalla E.K.
      • et al.
      Association of diabetes duration and diabetes treatment with the risk of hepatocellular carcinoma.
      Obesity promotes inflammation and hepatocarcinogenesis by increasing levels of pro-inflammatory cytokines such as tumour necrosis factor-alpha and interleukin-6. In a meta-analysis of studies in the general population and among patients with chronic liver disease, overweight (BMI ≥25 kg/m2) and obesity (BMI ≥30 kg/m2) are associated with an increased risk of primary liver cancer (relative risks = 1.48 and 1.83, respectively).
      • 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.
      Body fat composition differs between Asian and Caucasian populations.
      • Fan J.G.
      • Kim S.U.
      • Wong V.W.
      New trends on obesity and NAFLD in Asia.
      Asians tend to have a higher percentage of body fat and more central fat deposition than Caucasians at the same BMI (Fig. 4). Particularly in Asians, central obesity is more physiologically informative regarding metabolic health and the risk of NAFLD-associated HCC than in Caucasians. In many Asian populations, the risk of HCC begins at a BMI of 23 kg/m2. The following body weight classifications have been suggested for Asians: <18.5 kg/m2, underweight; 18.5–22.9 kg/m2, normal; 23–24.9 kg/m2, overweight; and ≥25 kg/m2, obesity.
      • Fan J.G.
      • Kim S.U.
      • Wong V.W.
      New trends on obesity and NAFLD in Asia.
      Moreover, the excessive accumulation of visceral adipose tissue has shown to be a risk factor for non-B non-C HCC recurrence.
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      • Takai K.
      • Miwa T.
      • Maeda T.
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      • Shiraki M.
      • et al.
      Increased visceral adipose tissue and hyperinsulinemia raise the risk for recurrence of non-B non-C hepatocellular carcinoma after curative treatment.
      Accumulation of visceral adipose tissue results in the recruitment of macrophages and may play a critical role in HCC development. Thus, more attention should be given to body fat distribution when screening patients who are at high risk of HCC development.
      Lifestyle and metabolic factors, genetic and epigenetic factors, as well as gut microbiota are potential risk factors for HCC development in the Asian NAFLD population.
      Figure thumbnail gr4
      Fig. 4Different body fat distribution in Asians and Caucasians.
      At the same body mass index, Asians tend to have more central fat deposition and visceral adiposity than Caucasians. As a result, Asians start to develop metabolic complications such as diabetes and NAFLD at a lower body mass index. NAFLD, non-alcoholic fatty liver disease.
      Cytokines with autocrine, paracrine, and endocrine functions, including hepatokines (angiopoietin-like proteins, fetuins A and B, fibroblast growth factors, hepassocin, and retinol-binding protein 4) and adipokines (adiponectin, apelin, chemerin, leptin, resistin, visfatin), play an important role in the pathophysiology of NAFLD-associated HCC, regardless of cirrhosis status.
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      • Syn W.K.
      • Canbay A.
      Hepatokines and adipokines in NASH-related hepatocellular carcinoma.
      The gut microbiota also play a role in NAFLD-associated HCC. In a mouse model, dietary cholesterol promoted the development of NAFLD-associated HCC by altering the gut microbiota and metabolites.
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      • Lau H.C.H.
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      • et al.
      Dietary cholesterol drives fatty liver-associated liver cancer by modulating gut microbiota and metabolites.
      The levels of Akkermansia and Bifidobactrium species were lower in patients with NAFLD-associated HCC than in those with NASH cirrhosis. However, more data are needed to determine the role played by microbiota in hepatocarcinogenesis in Asian populations.

      Aflatoxin, herbs and alcohol

      Aflatoxins are a class of toxins produced by the Aspergillus fungi.
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      • Selim M.I.
      Aflatoxin B1: a review on metabolism, toxicity, occurrence in food, occupational exposure, and detoxification methods.
      Contamination of crops by the fungi is particularly common in Sub-Saharan Africa and some parts of Southeast Asia because of the hot and humid climate. Aflatoxin B1 is the most potent form of aflatoxin; it acts synergistically with HBV to induce HCC.
      Complementary and herbal medicine is often used among Asian patients with chronic liver disease. Some such medicines are claimed to have hepatoprotective effects, but a few components have been shown to be potentially harmful. In particular, aristolochic acid is found in Chinese wild ginger and has been widely used in traditional Chinese medicine. Aristolochic acid is highly mutagenic and has been implicated in the development of urothelial cancers and renal failure. Recently, a study using whole exome sequencing showed that 78% of the HCC tissues from Taiwan (47% in China and 29% in Southeast Asia) showed the distinctive mutational signature of aristolochic acid exposure.
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      Aristolochic acids and their derivatives are widely implicated in liver cancers in Taiwan and throughout Asia.
      Alcohol-related liver disease is one of the leading causes of cirrhosis and HCC in Asia. Although the diagnosis of NAFLD requires the exclusion of excessive alcohol consumption, many patients in real life have both metabolic risk factors and alcohol use, and patients with both risk factors have higher mortality than those with either alone.
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      • et al.
      Effects of alcohol consumption and metabolic syndrome on mortality in patients with nonalcoholic and alcohol-related fatty liver disease.
      At present, per capita alcohol consumption remains lower in Asian countries than in Western countries, but the gap is narrowing. According to the Chinese Longitudinal Health Longevity Survey, 20% of the respondents reported alcohol use, and 1.1% had alcohol dependence.
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      • Chang Y.C.
      • Liu C.T.
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      Correlates of alcohol consumption and alcohol dependence among older adults in contemporary China: results from the Chinese Longitudinal Healthy Longevity Survey.

      Severity of liver disease

      Fibrosis and cancer-associated fibroblasts influence the risk of HCC development by modulating the tumour microenvironment. Fibrosis is the main risk factor for HCC in patients with chronic liver disease. However, NAFLD-associated HCC can develop without cirrhosis. In Asia, almost half of patients with NAFLD-associated HCC were non-cirrhotic at the time of HCC diagnosis.
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      • Wong G.L.
      • Chan A.W.
      • Nik Mustapha N.R.
      • Chan S.L.
      • et al.
      Positive hepatitis B core antibody is associated with cirrhosis and hepatocellular carcinoma in nonalcoholic fatty liver disease.
      One hypothesis is that the mechanisms underlying HCC development differ between cirrhotic and non-cirrhotic patients with NAFLD. Obesity promotes NASH pathogenesis by activating signal transducer and activator of transcription 1 (STAT1), while NASH-associated HCC is driven principally by sSTAT3. HCC in patients with NAFLD without advanced fibrosis is more frequently seen in males, and is characterised by large tumours.
      • Kodama K.
      • Kawaguchi T.
      • Hyogo H.
      • Nakajima T.
      • Ono M.
      • Seike M.
      • et al.
      Clinical features of hepatocellular carcinoma in nonalcoholic fatty liver disease patients without advanced fibrosis.
      Non-invasive tests, such as the NAFLD fibrosis score, aspartate aminotransferase-to-platelet ratio index (APRI), fibrosis-4 score, BARD score, and liver stiffness measurement (LSM) can be used to predict the fibrosis stage and long-term outcomes of patients with NAFLD. For example, the cumulative incidence of HCC was higher in Japanese patients with NAFLD and significant fibrosis (APRI >1.5) compared to those without fibrosis (HR 25.03, 95% CI 9.02-69.52).
      • Kawamura Y.
      • Arase Y.
      • Ikeda K.
      • Seko Y.
      • Imai N.
      • Hosaka T.
      • et al.
      Large-scale long-term follow-up study of Japanese patients with non-alcoholic Fatty liver disease for the onset of hepatocellular carcinoma.
      LSM by transient elastography also correlated with overall survival, cardiovascular- and liver-related events in patients with NAFLD.
      • Shili-Masmoudi S.
      • Wong G.L.
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      • Liu K.
      • Chermak F.
      • Shu S.S.
      • et al.
      Liver stiffness measurement predicts long-term survival and complications in non-alcoholic fatty liver disease.
      The limited ability of ultrasound to detect small lesions, low sensitivity of serum alpha-fetoprotein, and undiagnosed cirrhosis contribute to ineffective surveillance and delayed diagnosis of NAFLD-associated HCC.

      Management of NAFLD-associated HCC

      HCC screening

      Although HCC can develop in patients with NAFLD without cirrhosis, the absolute risk is low at <0.1% per year.
      • Fan J.G.
      • Kim S.U.
      • Wong V.W.
      New trends on obesity and NAFLD in Asia.
      This, together with the high prevalence of NAFLD, does not support HCC surveillance in this population. A recent systematic review and meta-analysis estimated the incidence rate of HCC to be 0.03 per 100 person-years among patients with NAFLD and a lesser degree of fibrosis, while the rate was found to be much higher at 3.78 per 100 person-years among those with cirrhosis.
      • Orci L.A.
      • 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.
      Therefore, HCC surveillance using ultrasound with or without serum alpha-fetoprotein level every 6 months, per current guidelines, should be considered in patients with NASH-related cirrhosis. However, the diagnosis of cirrhosis may not be apparent in patients with NAFLD based on regular blood and imaging tests, resulting in a lack of HCC surveillance in this population compared to patients with cirrhosis caused by chronic viral hepatitis. The use of fibrosis scores, which are simple and based on readily available parameters, can help detect patients with advanced liver fibrosis or cirrhosis, who are at increased risk of developing HCC. For example, in a large retrospective cohort study, APRI was found to be useful for identifying patients with NAFLD and a significantly greater incidence of HCC.
      • Kawamura Y.
      • Arase Y.
      • Ikeda K.
      • Seko Y.
      • Imai N.
      • Hosaka T.
      • et al.
      Large-scale long-term follow-up study of Japanese patients with non-alcoholic Fatty liver disease for the onset of hepatocellular carcinoma.
      A clear assessment and referral pathway for primary care providers to follow will enable patients with more severe NAFLD to be identified and linked to specialist care and subsequently enrolled into a HCC surveillance programme, when indicated.
      A liver biopsy can confirm suspected cirrhosis in patients with NAFLD, but it is invasive, associated with a small risk of serious complications, and limited by sampling and observer variability. LSM can be used for the diagnosis of cirrhosis, but there is no standardised cut-off that is universally accepted. LSM >15 kPa, which is considered highly suggestive of compensated advanced chronic liver disease,
      • de Franchis R.
      • Baveno V.I.F.
      Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension.
      has been proposed by The Baveno working group as a threshold at which HCC surveillance should be considered in patients with NAFLD,
      • Wong V.W.
      • Irles M.
      • Wong G.L.
      • Shili S.
      • Chan A.W.
      • Merrouche W.
      • et al.
      Unified interpretation of liver stiffness measurement by M and XL probes in non-alcoholic fatty liver disease.
      but further studies and consensus are needed. Other HCC surveillance issues unique to patients with NAFLD include ultrasound’s limited ability to detect small lesions in overweight/obese individuals, the low sensitivity of serum alpha-fetoprotein, and the significantly higher cardiovascular disease risk that may limit certain potentially curative treatments.
      • Foog D.H.
      • Kwok D.
      • Yu B.C.
      • Wong V.W.
      Managing HCC in NAFLD.

      HCC treatment

      Patients with NAFLD-associated HCC are less likely to receive curative management than patients with HCC of other aetiologies, primarily because of patient factors (e.g. older age, more comorbidities, and poorer cardiopulmonary function) and tumour factors (larger and multifocal tumours) (Fig. 5).
      • Chin K.M.
      • Prieto M.
      • Cheong C.K.
      • Di Martino M.
      • Ielpo B.
      • Goh B.K.P.
      • 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.
      Western centres reported higher rates of blood loss, need for blood transfusion, post-operative liver derangement and complications in patients with NAFLD-associated HCC undergoing liver resection.
      • McCormack L.
      • Petrowsky H.
      • Jochum W.
      • Furrer K.
      • Clavien P.A.
      Hepatic steatosis is a risk factor for postoperative complications after major hepatectomy: a matched case-control study.
      Asian centres are generally more aggressive in treating HCC, with a higher proportion of patients receiving treatments with curative intent, namely liver resection, liver transplantation and curative ablation.
      • Chin K.M.
      • Prieto M.
      • Cheong C.K.
      • Di Martino M.
      • Ielpo B.
      • Goh B.K.P.
      • 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.
      Generally, Asian centres do not report differences between NAFLD-associated and non-NAFLD HCC in terms of operative time (possibly because of less obese Asian NAFLD patients), perioperative blood loss and transfusion requirements. Post-operative complications (e.g. post-hepatectomy liver failure and prolonged stay in intensive care units) are more commonly seen in some but not all Asian centres.
      • Chin K.M.
      • Prieto M.
      • Cheong C.K.
      • Di Martino M.
      • Ielpo B.
      • Goh B.K.P.
      • 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.
      Concomitant fatty liver is common among Asian patients with current or past HBV infection and increases the risk of fibrosis progression and HCC development.
      Figure thumbnail gr5
      Fig. 5Special considerations regarding treatment of NAFLD-associated HCC in Asia.
      Asian centres are generally more aggressive in treating HCC, with a higher proportion of patients receiving treatments with curative intent. Asian patients’ smaller average body size may make liver resection, liver transplantation and local ablative therapy more feasible. In contrast, the underdiagnosis of NAFLD and inconsistent HCC surveillance (compared with other liver diseases) often result in delayed diagnosis of HCC, rendering curative treatment impossible. HCC, hepatocellular carcinoma; NAFLD, non-alcoholic fatty liver disease.
      Systemic therapies (e.g. tyrosine kinases inhibitors, immunotherapies) are often offered to patients with advanced or recurrent HCC as well as those with progressive disease. Lenvatinib (an oral multikinase inhibitor) was used in 334 Asian patients with unresectable HCC (21% non-viral non-alcoholic aetiologies) in the REFLECT study; it was non-inferior to sorafenib in terms of overall survival in patients with untreated advanced HCC.
      • Kudo M.
      • Finn R.S.
      • Qin S.
      • Han K.H.
      • 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.
      Atezolizumab (a programmed death-ligand 1 inhibitor) and bevacizumab (a vascular endothelial growth factor inhibitor) were used in 133 Asians with unresectable HCC (30% non-viral aetiologies) in the IMbrave150 trial; this combination therapy resulted in better overall and progression-free survival outcomes compared to sorafenib.
      • Finn R.S.
      • Qin S.
      • Ikeda M.
      • Galle P.R.
      • Ducreux M.
      • Kim T.Y.
      • et al.
      Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma.
      Regrettably, patients with NAFLD-associated HCC have not been well represented in these studies. Furthermore, sorafenib works better for HCV-related HCC than for other aetiologies.
      • Bruix J.
      • Cheng A.L.
      • Meinhardt G.
      • Nakajima K.
      • De Sanctis Y.
      • Llovet J.
      Prognostic factors and predictors of sorafenib benefit in patients with hepatocellular carcinoma: analysis of two phase III studies.
      Cardiac (e.g. ventricular failure, atrial fibrillation) and thyroid toxicities (e.g. subclinical hypothyroidism) from immunotherapies may also be more common in patients with NAFLD-associated HCC.
      • Sangro B.
      • Chan S.L.
      • Meyer T.
      • Reig M.
      • El-Khoueiry A.
      • Galle P.R.
      Diagnosis and management of toxicities of immune checkpoint inhibitors in hepatocellular carcinoma.
      There are insufficient data to determine whether the safety and efficacy of immunotherapies differ in Asian and Western patients.

      Impact of hepatic steatosis on chronic hepatitis B

      Due to the increasing prevalence of obesity and NAFLD and the endemicity of chronic HBV infection in many parts of Asia, it is increasingly common to see patients with concomitant fatty liver disease and chronic HBV infection. The presence of hepatic steatosis is associated with severe fibrosis and HCC in patients with chronic HBV infection.
      • Chan A.W.
      • Wong G.L.
      • Chan H.Y.
      • Tong J.H.
      • Yu Y.H.
      • Choi P.C.
      • et al.
      Concurrent fatty liver increases risk of hepatocellular carcinoma among patients with chronic hepatitis B.
      Furthermore, the presence of fatty liver increases the risk of HCC in patients with CHB in whom HBV has been effectively suppressed by antiviral therapy.
      • Cho H.
      • Chang Y.
      • Lee J.H.
      • Cho Y.Y.
      • Nam J.Y.
      • Lee Y.B.
      • et al.
      Radiologic nonalcoholic fatty liver disease increases the risk of hepatocellular carcinoma in patients with suppressed chronic hepatitis B.
      Patients with CHB, obesity and diabetes are less likely to have fibrosis improvement on antiviral therapy.
      • Marcellin P.
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      • Buti M.
      • Afdhal N.
      • Sievert W.
      • Jacobson I.M.
      • et al.
      Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study.
      ,
      • Lee H.W.
      • Yip T.C.
      • Tse Y.K.
      • Wong G.L.
      • Kim B.K.
      • Kim S.U.
      • et al.
      Hepatic decompensation in cirrhotic patients receiving antiviral therapy for chronic hepatitis B.
      In a large cohort of patients with chronic HBV infection from 2 centres in North America and Europe, the presence of steatohepatitis was significantly associated with HCC and death.
      • Choi H.S.J.
      • Brouwer W.P.
      • Zanjir W.M.R.
      • de Man R.A.
      • Feld J.J.
      • Hansen B.E.
      • et al.
      Nonalcoholic steatohepatitis is associated with liver-related outcomes and all-cause mortality in chronic hepatitis B.
      Diabetes mellitus, which is closely associated with fatty liver disease, has also been shown to be independently associated with the development of HCC in patients with CHB.
      • Hsu Y.C.
      • Yip T.C.
      • Ho H.J.
      • Wong V.W.
      • Huang Y.T.
      • El-Serag H.B.
      • et al.
      Development of a scoring system to predict hepatocellular carcinoma in Asians on antivirals for chronic hepatitis B.
      In all, current evidence points towards a deleterious effect of fatty liver disease on patients with CHB despite the bidirectional inverse association of fatty liver disease and CHB. This highlights the importance of actively managing concomitant fatty liver disease to further reduce the risk of liver-related complications, including HCC, in patients with chronic HBV infection. Conversely, previous HBV infection has been found to be associated with more severe fibrosis and an increased risk of HCC in patients with fatty liver disease (Fig. 6).
      • Chan T.T.
      • Chan W.K.
      • Wong G.L.
      • Chan A.W.
      • Nik Mustapha N.R.
      • Chan S.L.
      • et al.
      Positive hepatitis B core antibody is associated with cirrhosis and hepatocellular carcinoma in nonalcoholic fatty liver disease.
      Therefore, the endemicity of chronic HBV infection and the prevalence of previous HBV infection may partly explain the higher risk of NAFLD-related HCC in Asia. Currently, the role of testing for and treatment of occult HBV infection in patients with NAFLD remains unclear.
      Figure thumbnail gr6
      Fig. 6Increased risk of liver-related events in Asian patients with NAFLD and positive hepatitis B core antibody.
      Hepatitis B core antibody is a marker of prior or occult HBV infection. In a study of 489 patients with NAFLD from Hong Kong and Malaysia, 6.5% of those with positive hepatitis B core antibody and 2.2% of those without developed liver-related events (i.e., HCC and cirrhotic complications). All 4 patients who developed HCC had positive hepatitis B core antibody. The figure was reproduced with permission from Chan et al.
      • Chan T.T.
      • Chan W.K.
      • Wong G.L.
      • Chan A.W.
      • Nik Mustapha N.R.
      • Chan S.L.
      • et al.
      Positive hepatitis B core antibody is associated with cirrhosis and hepatocellular carcinoma in nonalcoholic fatty liver disease.
      HCC, hepatocellular carcinoma; NAFLD, non-alcoholic fatty liver disease.

      Conclusions

      With the rising incidence of NAFLD-associated HCC in Asia, the absolute number of NAFLD-associated HCC cases is going to surpass that in the West in the coming years. This is particularly challenging because of the concurrent endemic of chronic viral hepatitis in the region, together with the pandemic of obesity and diabetes. It is simply impossible to screen billions of Asian patients with NAFLD for HCC. Precise HCC risk prediction based on well-established clinical, metabolic and/or genetic risk factors, together with other patient characteristics, will guide the selection of patients for HCC surveillance. Nonetheless, patients with NAFLD were underrepresented in previous studies on the impact of HCC surveillance on cancer-related death. Managing NAFLD-associated HCC is challenging in Asia as tumours are often diagnosed at an advanced stage when curative treatment is no longer possible. Clinicians should recognise that CHB may coexist with fatty liver and metabolic factors (especially diabetes and obesity) and that hepatic steatosis may increase the risk of disease progression in patients with CHB, even among patients with complete viral suppression with antiviral therapy and those with previous HBV infection. With NASH treatments currently in various phases of clinical development, future phase III and IV studies will be crucial to determine whether these new treatments can prevent NAFLD-associated HCC.

      Abbreviations

      ASIR, age-standardised incidence rate; APRI, aspartate aminotransferase/platelet ratio index; CHB, chronic hepatitis B; HCC, hepatocellular carcinoma; HR, hazard ratio; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; STAT1/3, signal transducer and activator of transcription 1/3.

      Financial support

      This work is supported in part by a direct grant from The Chinese University of Hong Kong (2019.043).

      Authors’ contributions

      Vincent Wong outlined the writing plan of the review article. All authors contributed to literature research and the drafting of the manuscript. All authors read and approved the final version of the manuscript.

      Conflicts of interests

      Grace Wong has served as an advisory committee member for Gilead Sciences and Janssen, and as a speaker for Abbott, Abbvie, Bristol-Myers Squibb, Echosens, Gilead Sciences, Janssen and Roche. Vincent Wong has served as a consultant or advisory board member for 3V-BIO, AbbVie, Allergan, Boehringer Ingelheim, Echosens, Gilead Sciences, Inventiva, Merck, Novartis, Novo Nordisk, Pfizer, ProSciento, Sagimet Biosciences, TARGET PharmaSolutions, and Terns; and a speaker for Abbott, AbbVie, Echosens, Gilead Sciences, and Novo Nordisk. He has received a grant from Gilead Sciences for fatty liver research.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Supplementary data

      The following is the supplementary data to this article:

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