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Prevention of NAFLD-associated HCC: Role of lifestyle and chemoprevention

Open AccessPublished:August 02, 2021DOI:https://doi.org/10.1016/j.jhep.2021.07.025

      Summary

      In many countries worldwide, the burden of hepatocellular carcinoma (HCC) associated with non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) is increasing. Preventive strategies are needed to counteract this trend. In this review, we provide an overview of the evidence on preventive strategies in NAFLD-associated HCC. We consider the impact of lifestyle factors such as weight loss, physical activity, smoking, dietary patterns and food items, including coffee and alcohol, on both HCC and NAFLD/NASH. Furthermore, evidence on chemopreventive treatments, including aspirin, antidiabetic treatments and statins is summarised. The role of adjuvant therapies for tertiary prevention of HCC is briefly reviewed.

      Keywords

      Prevention of NAFLD-associated HCC

      Carcinogenic processes and pathways leading to the development of hepatocellular carcinoma (HCC) in patients with non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are complex and incompletely understood. While the progression to cirrhosis precedes the development of HCC in most aetiologies of chronic liver disease, this is not necessarily the case with NAFLD-associated HCC, which may occur in the absence of cirrhosis.
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      Systematic review with meta-analysis: risk of hepatocellular carcinoma in non-alcoholic steatohepatitis without cirrhosis compared to other liver diseases.
      Several risk factors that are associated with HCC in the NAFLD population may be modified by lifestyle intervention or chemoprevention, although a beneficial effect of these measures likely extends beyond the modulation of risk factors (Fig. 1). In the following review, we provide an overview of proposed preventive measures in the context of NAFLD-HCC.
      Figure thumbnail gr1
      Fig. 1Modifiable and non-modifiable risk factors for HCC development in NAFLD have been identified.
      Lifestyle and chemoprevention strategies may target modifiable risk factors. HCC, hepatocellular carcinoma; NAFLD, non-alcoholic fatty liver disease.

      Lifestyle factors

      Metabolic diseases, most notably diabetes and obesity along with other dysmetabolic traits such as hypertension and dyslipidaemia, are associated with an increased risk of HCC.
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      Effect of metabolic traits on the risk of cirrhosis and hepatocellular cancer in nonalcoholic fatty liver disease.
      To some extent, this risk may be mediated by a higher rate of progression to NAFLD/NASH cirrhosis, a precancerous condition, in the presence of these factors, although NAFLD-associated HCC may arise in non-cirrhotic livers.
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      • et al.
      Systematic review with meta-analysis: risk of hepatocellular carcinoma in non-alcoholic steatohepatitis without cirrhosis compared to other liver diseases.
      ,
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      Risk of hepatocellular cancer in patients with non-alcoholic fatty liver disease.
      Lifestyle-related modifiable factors such as certain food items, dietary patterns, and physical activity are associated with a reduced risk of HCC, while alcohol consumption and smoking are associated with carcinogenesis in various tissues including the liver.
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      Meta-analysis of epidemiologic studies on cigarette smoking and liver cancer.
      A study conducted in the prospective, population-based Singapore Chinese Health Study cohort, which included a population with high prevalence of viral hepatitis B, found the highest composite score of healthy lifestyle factors, including normal body mass index, low alcohol consumption, abstaining from cigarette smoking, adherence to the Mediterranean diet, and sufficient sleep duration, to be associated with a markedly lower risk of HCC (hazard ratio [HR] 0.13; 95% CI 0.06–0.30).
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      Composite score of healthy lifestyle factors and risk of hepatocellular carcinoma: findings from a prospective cohort study.
      This suggests that HCC risk may be reduced by the combined modification of these risk factors. Lifestyle interventions, which may be employed for this purpose, thus present an essential tool in HCC prevention and should be utilised in patients with NAFLD.

      Weight loss

      Weight loss has not been directly proven to reduce NAFLD-associated HCC. Previous clinical studies, however, have shown beneficial effects of weight loss on NAFLD activity, with some findings indicating the possibility of fibrosis regression.
      Combined lifestyle interventions in patients with metabolic comorbidities and NAFLD demonstrated significant histological improvements in steatosis, inflammation, ballooning injury, and overall NAFLD activity score, but not in fibrosis stage, in patients who achieved weight loss of at least 7% of body weight.
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      Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis (NASH).
      ,
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      Effect of a 12-month intensive lifestyle intervention on hepatic steatosis in adults with type 2 diabetes.
      Conversely, in a more recent Cuban study with paired liver biopsies from 261 patients with NAFLD, a 10% reduction in body weight led to NASH resolution in 90% and fibrosis regression in 45% of patients after 52 weeks.
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      • et al.
      Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis.
      Dietary factors, such as implementation of the Mediterranean diet and regular physical activity may reduce the risk of NAFLD-associated HCC beyond the potential effect of weight loss and should be recommended to all patients with NAFLD/NASH.
      The effect of weight loss after bariatric surgery rather than lifestyle adjustments in patients with NAFLD and obesity was evaluated in a large meta-analysis.
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      • Yu J.
      • Brar K.
      • Banfield L.
      • Gmora S.
      • et al.
      Complete resolution of nonalcoholic fatty liver disease after bariatric surgery: a systematic review and meta-analysis.
      Histological resolution of steatosis, inflammation, and fibrosis was observed in 66%, 50%, and 40% of patients, respectively. However, 12% of patients showed postoperative worsening of histological disease activity. It has been suggested that some cases of hepatic decompensation after bariatric surgery occur in the setting of malnutrition and in patients with previously unrecognised significant alcohol intake,
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      • Wan T.
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      • Rodrigues S.G.
      • Dufour J.-F.
      • et al.
      Malnutrition and alcohol in patients presenting with severe complications of cirrhosis after laparoscopic bariatric surgery.
      highlighting the importance of lifestyle monitoring and counselling beyond weight loss.
      It should also be noted that the effects of bariatric surgery on disease severity in NAFLD/NASH may be mediated in part by post-interventional endocrine changes, particularly changes in levels of digestive peptide hormones and reproductive hormones.
      • Casimiro I.
      • Sam S.
      • Brady M.J.
      Endocrine implications of bariatric surgery: a review on the intersection between incretins, bone, and sex hormones.
      For example, concentrations of the incretin glucagon-like peptide-1 (GLP-1) rise shortly after bariatric surgery, preceding weight loss.
      • Hutch C.R.
      • Sandoval D.
      The role of GLP-1 in the metabolic success of bariatric surgery.
      GLP-1 agonists have been shown to improve steatohepatitis in NASH in clinical trials,
      • Armstrong M.J.
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      • et al.
      Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study.
      ,
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      • Okanoue T.
      • Ratziu V.
      • et al.
      A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis.
      suggesting that increased GLP-1 levels may contribute to the beneficial effect of bariatric surgery.

      Diet

      Various dietary patterns, nutrients, and food groups have been examined in the context of NAFLD and HCC,
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      Dietary factors can protect against liver cancer development.
      • George E.S.
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      The association between diet and hepatocellular carcinoma: a systematic review.
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      Dietary interventions in liver diseases: focus on MAFLD and cirrhosis.
      although few studies have looked at HCC risk specifically in patients with NAFLD. Recently, a systematic review identified 30 observational studies (17 cohort, 7 case-control, 6 cohort with nested case-control subset) that focus on the association of food groups and dietary patterns with primary liver cancer, with 23 studies specifying HCC as the main outcome.
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      The association between diet and hepatocellular carcinoma: a systematic review.
      A summary of important findings regarding the impact of diet on the risk of HCC and NAFLD/NASH is provided in Table 1.
      Table 1Dietary patterns, food groups and nutrients, and association with risk of primary liver cancer, suggested mechanism of action in liver cancer and findings in NAFLD/NASH populations.
      Nutritional item, group or dietary patternPrimary liver cancer riskPotential influences on other risk factors for liver cancer and suggested pathophysiological linksFindings regarding NAFLD/NASH
      Dietary patterns
      Mediterranean diet (MED)Reduced
      • Beneficial: Diet mainly containing food groups associated with reduced risk; favouring a high ratio of unsaturated to saturated fats; improvement of dysmetabolic traits and systemic inflammation.
      • Adverse: Unclear role of SSBs (excluded from index scores); encourages light alcohol consumption; associated with higher levels of SHBG in women.
      • Beneficial effects beyond weight loss, including improvement of glycaemic indices, anthropometric variables, lipid profile, IHF (including NAFLD resolution) and markers of severity of liver injury.
        • Meir A.Y.
        • Rinott E.
        • Tsaban G.
        • Zelicha H.
        • Kaplan A.
        • Rosen P.
        • et al.
        Effect of green-Mediterranean diet on intrahepatic fat: the DIRECT PLUS randomised controlled trial.
        • Akhlaghi M.
        • Ghasemi-Nasab M.
        • Riasatian M.
        Mediterranean diet for patients with non-alcoholic fatty liver disease, a systematic review and meta-analysis of observational and clinical investigations.
        • Moosavian S.P.
        • Arab A.
        • Paknahad Z.
        The effect of a Mediterranean diet on metabolic parameters in patients with non-alcoholic fatty liver disease: a systematic review of randomized controlled trials.
      • Associated with reduced odds of developing advanced NAFLD.
        • Ma J.
        • Hennein R.
        • Liu C.
        • Long M.T.
        • Hoffmann U.
        • Jacques P.F.
        • et al.
        Improved diet quality associates with reduction in liver fat, particularly in individuals with high genetic risk scores for nonalcoholic fatty liver disease.
      • Advantageous effect on cardiovascular markers.
        • Asbaghi O.
        • Choghakhori R.
        • Ashtary-Larky D.
        • Abbasnezhad A.
        Effects of the Mediterranean diet on cardiovascular risk factors in non-alcoholic fatty liver disease patients: a systematic review and meta-analysis.
      • Recommended by European guidelines on NAFLD.
        EASL–EASD–EASO
        Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease.
      Dietary approaches to stop hypertensionNeutral
      • Beneficial: Low intake of SSBs, alcohol and sodium; containing several food groups associated with reduced risk; low glycaemic index; improvement of hypertension and other dysmetabolic traits.
      • No robust data exist (improvement of several markers, but likely confounded by weight loss
        • Razavi Zade M.
        • Telkabadi M.H.
        • Bahmani F.
        • Salehi B.
        • Farshbaf S.
        • Asemi Z.
        The effects of DASH diet on weight loss and metabolic status in adults with non-alcoholic fatty liver disease: a randomized clinical trial.
        ).
      Food groups
      VegetablesReduced
      • Beneficial: Source of vitamins, minerals, dietary fibres, and other bioactive compounds with anti-carcinogenic properties (e.g. flavonoid polyphenols).
      • Studied mostly in the context of unrefined carbohydrates, plant-based protein and fibre content, and in MED.
      • Severe steatosis (FLI) was inversely associated with plant-based protein intake.
        • Rietman A.
        • Sluik D.
        • Feskens E.J.M.
        • Kok F.J.
        • Mensink M.
        Associations between dietary factors and markers of NAFLD in a general Dutch adult population.
      • High insoluble fibre and fibre from fruit were associated with improvements in non-invasive scores and liver enzymes.
        • Cantero I.
        • Abete I.
        • Monreal J.I.
        • Martinez J.A.
        • Zulet M.A.
        Fruit fiber consumption specifically improves liver Health status in obese subjects under energy restriction.
      • No benefit demonstrated for purely vegetarian diet.
        • Markova M.
        • Pivovarova O.
        • Hornemann S.
        • Sucher S.
        • Frahnow T.
        • Wegner K.
        • et al.
        Isocaloric diets high in animal or plant protein reduce liver fat and inflammation in individuals with type 2 diabetes.
      • ”Green” MED (additional Mankai, nuts and tea as source of green plant-based proteins and polyphenols) doubled IHF loss compared to MED alone.
        • Meir A.Y.
        • Rinott E.
        • Tsaban G.
        • Zelicha H.
        • Kaplan A.
        • Rosen P.
        • et al.
        Effect of green-Mediterranean diet on intrahepatic fat: the DIRECT PLUS randomised controlled trial.
      WholegrainsReduced
      • Beneficial: Source of dietary fibres; lower glycaemic index.
      FruitsNeutral
      • Beneficial: Source of vitamins, minerals, dietary fibres, and other bioactive compounds with anti-carcinogenic properties (e.g. flavonoid polyphenols).
      • Adverse: High glycaemic index of certain foods.
      NutsNeutral
      • Beneficial: Source of unsaturated fats, vegetable protein, vitamins, folate, fibre, and minerals.
      FishReduced
      • Beneficial: High content of n3 PUFAs.
      • Studied mostly in the context of MED and PUFAs (e.g. fish oil supplement).
      White meat (poultry)Reduced
      • Beneficial: Source of PUFAs.
      • Adverse: Contains BCAAs (mTORC1 activation).
      • Largely studied in the context of dietary protein (animal vs. plant-based).
      • Data not consistent: steatosis (presence and severity, latter by FLI) associated with protein intake from animal sources,
        • Rietman A.
        • Sluik D.
        • Feskens E.J.M.
        • Kok F.J.
        • Mensink M.
        Associations between dietary factors and markers of NAFLD in a general Dutch adult population.
        ,
        • Alferink L.J.
        • Kiefte-de Jong J.C.
        • Erler N.S.
        • Veldt B.J.
        • Schoufour J.D.
        • de Knegt R.J.
        • et al.
        Association of dietary macronutrient composition and non-alcoholic fatty liver disease in an ageing population: the Rotterdam Study.
        while other data suggest improvement of steatosis with high protein diet irrespective of source.
        • Xu C.
        • Markova M.
        • Seebeck N.
        • Loft A.
        • Hornemann S.
        • Gantert T.
        • et al.
        High-protein diet more effectively reduces hepatic fat than low-protein diet despite lower autophagy and FGF21 levels.
      DairyNeutral
      • Beneficial: Certain foods may contain probiotics (e.g. yogurt).
      • Adverse: Contains SFAs; high glycaemic index of certain foods (e.g. milk, yogurt); increase of IGF-1 levels (low-fat dairy).
      (Processed) red meatIncreased
      • Adverse: Contains carcinogens (e.g. heme iron, N-nitrous compounds, heterocyclic amines); increased generation of ROS (during iron reduction); contains high levels of cholesterol, SFAs, and BCAAs (mTORC1 activation).
      • Often studied in context of dietary pattern (“Western” diet).
      • Processed meat consumption positively associated with liver iron content.
        • Recaredo G.
        • Marin-Alejandre B.A.
        • Cantero I.
        • Monreal J.I.
        • Herrero J.I.
        • Benito-Boillos A.
        • et al.
        Association between different animal protein sources and liver status in obese subjects with non-alcoholic fatty liver disease: fatty liver in obesity (FLiO) study.
      TeaNeutral
      • Beneficial: Contains bioactive compounds with anti-carcinogenic properties (e.g. flavonoids, caffeine).
      • Reduction of liver enzymes in NAFLD for green tea.
        • Mahmoodi M.
        • Hosseini R.
        • Kazemi A.
        • Ofori-Asenso R.
        • Mazidi M.
        • Mazloomi S.M.
        Effects of green tea or green tea catechin on liver enzymes in healthy individuals and people with nonalcoholic fatty liver disease: a systematic review and meta-analysis of randomized clinical trials.
      CoffeeReduced
      • Beneficial: Contains antioxidants and phenolic compounds; caffeine inhibits the PI3K/Akt pathway.
      • Regular coffee consumption significantly associated with decreased risk of fibrosis development in NAFLD.
        • Hayat U.
        • Siddiqui A.A.
        • Okut H.
        • Afroz S.
        • Tasleem S.
        • Haris A.
        The effect of coffee consumption on the non-alcoholic fatty liver disease and liver fibrosis: a meta-analysis of 11 epidemiological studies.
      Sugar-sweetened beverages (SSBs)Increased
      • Adverse: High glycaemic index, gut dysbiosis, generation of reactive oxygen species, activation of pro-inflammatory pathways (fructose).
      • No deleterious effect of fructose in isocaloric trials; increase in liver enzymes and IHF in hypercaloric diet.
        • Chiu S.
        • Sievenpiper J.L.
        • de Souza R.J.
        • Cozma A.I.
        • Mirrahimi A.
        • Carleton A.J.
        • et al.
        Effect of fructose on markers of non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of controlled feeding trials.
      • Reduction of IHF with SSBs and free sugar reduction.
        • Schwimmer J.B.
        • Ugalde-Nicalo P.
        • Welsh J.A.
        • Angeles J.E.
        • Cordero M.
        • Harlow K.E.
        • et al.
        Effect of a low free sugar diet vs usual diet on nonalcoholic fatty liver disease in adolescent boys: a randomized clinical trial.
      • SSBs containing fructose and sucrose, but not glucose, increased hepatic lipogenesis.
        • Geidl-Flueck B.
        • Hochuli M.
        • Németh Á.
        • Eberl A.
        • Derron N.
        • Köfeler H.C.
        • et al.
        Fructose- and sucrose- but not glucose-sweetened beverages promote hepatic de novo lipogenesis: a randomized controlled trial.
      Nutrients
      Monounsaturated fatty acids (MUFAs)Reduced
      • Beneficial: Effects of MED if primary source of MUFAs is plant-based (e.g. olive oil, nuts, fish).
      • Adverse: Effects of red meat if primary source of MUFAs.
      • Significant reduction in IHF, improvement in hepatic and overall insulin sensitivity with MUFAs from olive oil.
        • Errazuriz I.
        • Dube S.
        • Slama M.
        • Visentin R.
        • Nayar S.
        • O’Connor H.
        • et al.
        Randomized controlled trial of a MUFA or fiber-rich diet on hepatic fat in prediabetes.
      Saturated fatty acids (SFAs)Neutral
      • Adverse: Promotion of adipose tissue inflammation, activation of hepatic lipogenesis, NF-κB activation, and JNK/AP-1 signalling.
      • SFA-rich hypercaloric diet leads to marked increases in IHF and visceral adipose tissue.
        • Rosqvist F.
        • Iggman D.
        • Kullberg J.
        • Cedernaes J.
        • Johansson H.-E.
        • Larsson A.
        • et al.
        Overfeeding polyunsaturated and saturated fat causes distinct effects on liver and visceral fat accumulation in humans.
      Polyunsaturated fatty acids (PUFAs)Neutral
      • Beneficial: Anti-inflammatory properties (decreased IL-6, IL-1β, TNF); blocking of β-catenin and COX-2 by n3 PUFAs; improved insulin sensitivity and induction of adiponectin.
      • Adverse: Pro-inflammatory metabolites of n6 PUFAs.
      • Reduction of IHF and liver enzymes with n3 PUFAs.
        • Parker H.M.
        • Johnson N.A.
        • Burdon C.A.
        • Cohn J.S.
        • O’Connor H.T.
        • George J.
        Omega-3 supplementation and non-alcoholic fatty liver disease: a systematic review and meta-analysis.
      BCAAs, branched chain amino acids; COX, cyclooxygenase; FLI, Fatty Liver Index; HOMA-IR, homeostatic model assessment of insulin resistance; IGF-1, insulin-like growth factor 1; IHF, intrahepatic fat; IL, interleukin; JNK/AP-1, c-Jun N-terminal kinase/activator protein 1; MED, Mediterranean diet; mTORC1, mammalian target of rapamycin complex 1; MUFAs, monounsaturated fatty acids; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; PUFAs, polyunsaturated fatty acids; RCT, randomised controlled trial; ROS, reactive oxygen species; SFAs, saturated fatty acids; SHBG, sex-hormone binding globulin; SSBs, sugar-sweetened beverages; TNF, tumour necrosis factor.
      Among dietary patterns, higher index scores of adherence to the Mediterranean diet were significantly associated with a decreased risk of HCC (odds ratio [OR] 0.51; 95% CI 0.34–0.75
      • Turati F.
      • Trichopoulos D.
      • Polesel J.
      • Bravi F.
      • Rossi M.
      • Talamini R.
      • et al.
      Mediterranean diet and hepatocellular carcinoma.
      ; HRs 0.62; 95% CI 0.47–0.84
      • Li W.-Q.
      • Park Y.
      • McGlynn K.A.
      • Hollenbeck A.R.
      • Taylor P.R.
      • Goldstein A.M.
      • et al.
      Index-based dietary patterns and risk of incident hepatocellular carcinoma and mortality from chronic liver disease in a prospective study.
      and 0.68; 95% CI 0.51–0.90
      • Bogumil D.
      • Park S.-Y.
      • Le Marchand L.
      • Haiman C.A.
      • Wilkens L.R.
      • Boushey C.J.
      • et al.
      High-quality diets are associated with reduced risk of hepatocellular carcinoma and chronic liver disease: the multiethnic cohort.
      ) in several studies,
      • Turati F.
      • Trichopoulos D.
      • Polesel J.
      • Bravi F.
      • Rossi M.
      • Talamini R.
      • et al.
      Mediterranean diet and hepatocellular carcinoma.
      • Li W.-Q.
      • Park Y.
      • McGlynn K.A.
      • Hollenbeck A.R.
      • Taylor P.R.
      • Goldstein A.M.
      • et al.
      Index-based dietary patterns and risk of incident hepatocellular carcinoma and mortality from chronic liver disease in a prospective study.
      • Bogumil D.
      • Park S.-Y.
      • Le Marchand L.
      • Haiman C.A.
      • Wilkens L.R.
      • Boushey C.J.
      • et al.
      High-quality diets are associated with reduced risk of hepatocellular carcinoma and chronic liver disease: the multiethnic cohort.
      while no significant association was reported from a large American prospective cohort study (HR 0.75; 95% CI 0.49–1.15).
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      • Yang W.
      • Simon T.G.
      • Smith-Warner S.A.
      • Fung T.T.
      • Sui J.
      • et al.
      Dietary patterns and risk of hepatocellular carcinoma among U.S. men and women.
      In NAFLD, additional beneficial effects of the Mediterranean diet beyond weight loss have been identified on glycaemic indices, cardiovascular risk markers, anthropometric variables, lipid profile, intrahepatic fat content, and markers of severity of liver injury.
      • Meir A.Y.
      • Rinott E.
      • Tsaban G.
      • Zelicha H.
      • Kaplan A.
      • Rosen P.
      • et al.
      Effect of green-Mediterranean diet on intrahepatic fat: the DIRECT PLUS randomised controlled trial.
      • Akhlaghi M.
      • Ghasemi-Nasab M.
      • Riasatian M.
      Mediterranean diet for patients with non-alcoholic fatty liver disease, a systematic review and meta-analysis of observational and clinical investigations.
      • Moosavian S.P.
      • Arab A.
      • Paknahad Z.
      The effect of a Mediterranean diet on metabolic parameters in patients with non-alcoholic fatty liver disease: a systematic review of randomized controlled trials.
      • Asbaghi O.
      • Choghakhori R.
      • Ashtary-Larky D.
      • Abbasnezhad A.
      Effects of the Mediterranean diet on cardiovascular risk factors in non-alcoholic fatty liver disease patients: a systematic review and meta-analysis.
      The Mediterranean diet is recommended by European guidelines on NAFLD.
      EASL–EASD–EASO
      Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease.

      Physical activity

      Evidence suggests that physical activity reduces HCC risk beyond the confounding effects of weight loss. Potential mechanisms include improvement of mitochondrial functions, such as mitochondrial biogenesis and autophagy, attenuation of NAFLD/NASH activity, and modulation of carcinogenic signalling pathways.
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      Mitochondrial dynamics and nonalcoholic fatty liver disease (NAFLD): new perspectives for a fairy-tale ending?.
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      • Humar B.
      • et al.
      Exercise attenuates the transition from fatty liver to steatohepatitis and reduces tumor formation in mice.
      • Saran U.
      • Guarino M.
      • Rodríguez S.
      • Simillion C.
      • Montani M.
      • Foti M.
      • et al.
      Anti-tumoral effects of exercise on hepatocellular carcinoma growth.
      HCC risk reduction in active individuals and those performing at least 2 hours of vigorous activity per week was recently demonstrated in the pan-European EPIC (European Prospective Investigation into Cancer and Nutrition cohort) study (HR 0.55; 95% CI 0.38–0.80 and HR 0.50; 0.33–0.76, respectively), independently of body weight and other common risk factors for HCC.
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      • Jenab M.
      • Gunter M.J.
      • et al.
      Association between physical activity and risk of hepatobiliary cancers: a multinational cohort study.
      These findings were further corroborated in a meta-analysis of 14 prospective studies, which found a significantly lower risk in individuals with high physical activity compared to low physical activity (HR 0.75; 95% CI 0.63–0.89).
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      • Leitzmann M.F.
      • 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.
      Physical activity might to some extent also attenuate the increased risk of alcohol-related cancers, including liver cancer, in individuals who consume alcohol regularly.
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      • Vassallo A.J.
      • Hamer M.
      • Stamatakis E.
      Does adequate physical activity attenuate the associations of alcohol and alcohol-related cancer mortality? A pooled study of 54 686 British adults.

      Coffee

      One dietary item that has shown promising effects in both NAFLD/NASH and HCC is coffee. Individuals that drank coffee at least twice per day had a significantly lower risk of liver cancer compared to non-drinkers (HR 0.40; 95% CI 0.20–0.79).
      • Tamura T.
      • Wada K.
      • Konishi K.
      • Goto Y.
      • Mizuta F.
      • Koda S.
      • et al.
      Coffee, green tea, and caffeine intake and liver cancer risk: a prospective cohort study.
      Findings from a meta-analysis of 6 Japanese cohort studies confirmed this observation, showing a pooled relative risk estimate of 0.50 (95% CI 0.38–0.66) for regular coffee consumption compared with no coffee consumption.
      • Tamura T.
      • Hishida A.
      • Wakai K.
      Coffee consumption and liver cancer risk in Japan: a meta-analysis of six prospective cohort studies.
      This is in line with findings from a large meta-analysis of international case-control and prospective cohort studies, which found a pooled relative risk of 0.52 (95% CI 0.42–0.63).
      • Godos J.
      • Micek A.
      • Marranzano M.
      • Salomone F.
      • Rio D.D.
      • Ray S.
      Coffee consumption and risk of biliary tract cancers and liver cancer: a dose-response meta-analysis of prospective cohort studies.
      In the context of NAFLD/NASH, this might be mediated by a reduced risk of fibrosis development, as a meta-analysis of observational studies demonstrated a pooled relative risk of 0.68 (95% CI 0.68–0.79) for fibrosis in patients with NAFLD who consumed coffee regularly.
      • Hayat U.
      • Siddiqui A.A.
      • Okut H.
      • Afroz S.
      • Tasleem S.
      • Haris A.
      The effect of coffee consumption on the non-alcoholic fatty liver disease and liver fibrosis: a meta-analysis of 11 epidemiological studies.
      No conclusive data exist regarding the optimal type and dosage of coffee intake. Whether consumption of decaffeinated coffee is associated with similarly beneficial effects is not entirely clear, as conflicting results exist and several studies fail to further specify the type of coffee consumed.
      • Tamura T.
      • Hishida A.
      • Wakai K.
      Coffee consumption and liver cancer risk in Japan: a meta-analysis of six prospective cohort studies.
      ,
      • Hayat U.
      • Siddiqui A.A.
      • Okut H.
      • Afroz S.
      • Tasleem S.
      • Haris A.
      The effect of coffee consumption on the non-alcoholic fatty liver disease and liver fibrosis: a meta-analysis of 11 epidemiological studies.
      A large meta-analysis, including over 2 million participants from 18 cohort and 8 case-control studies, reported a non-significant risk reduction of 14% (relative risk [RR] 0.86; 95% CI 0.74–1.00) for intake of 2 cups of decaffeinated coffee daily.
      • Kennedy O.J.
      • Roderick P.
      • Buchanan R.
      • Fallowfield J.A.
      • Hayes P.C.
      • Parkes J.
      Coffee, including caffeinated and decaffeinated coffee, and the risk of hepatocellular carcinoma: a systematic review and dose-response meta-analysis.
      In this meta-analysis, the authors further examined the dose-response relationship between coffee consumption and HCC risk. Consumption of 2 cups per day was associated with a 35% risk reduction (RR 0.65; 95% CI 0.59–0.72) and the risk was halved with consumption of 5 cups per day.
      • Kennedy O.J.
      • Roderick P.
      • Buchanan R.
      • Fallowfield J.A.
      • Hayes P.C.
      • Parkes J.
      Coffee, including caffeinated and decaffeinated coffee, and the risk of hepatocellular carcinoma: a systematic review and dose-response meta-analysis.
      This is in line with findings from an updated meta-analysis, reporting a 15% liver cancer risk reduction (RR 0.85; 95% CI 0.82–0.88) for each cup of coffee consumed.
      • Godos J.
      • Micek A.
      • Marranzano M.
      • Salomone F.
      • Rio D.D.
      • Ray S.
      Coffee consumption and risk of biliary tract cancers and liver cancer: a dose-response meta-analysis of prospective cohort studies.
      Several epidemiological studies found that coffee consumption is associated with a reduced risk of HCC.
      While an increase in cholesterol levels has been observed with consumption of unfiltered coffee, evidence from observational studies suggests that this does not increase the risk of cardiovascular disease and has overall beneficial effects on metabolism and the cardiovascular system.
      • Dam RM van
      • Hu F.B.
      • Willett W.C.
      Coffee, caffeine, and Health.
      Therefore, encouraging coffee consumption, as currently recommended by EASL guidelines in individuals with chronic liver disease,
      EASL Clinical Practice Guidelines
      Management of hepatocellular carcinoma.
      should also be applied in NAFLD.

      Alcohol

      Alcohol shares several pathophysiological mechanisms with NAFLD/NASH, shows synergies with metabolic risk factors for NAFLD-HCC, especially diabetes and obesity, and drives specific carcinogenic mechanisms.
      • Ganne-Carrié N.
      • Nahon P.
      Hepatocellular carcinoma in the setting of alcohol-related liver disease.
      While a threshold for non-harmful consumption has been debated in the context of NAFLD, mounting evidence suggests that moderate alcohol consumption has detrimental effects,
      • Petroni M.L.
      • Brodosi L.
      • Marchignoli F.
      • Musio A.
      • Marchesini G.
      Moderate alcohol intake in non-alcoholic fatty liver disease: to drink or not to drink?.
      especially in the presence of metabolic risk factors. Recently, a large study of well-characterised patients with NAFLD, in whom alcohol consumption was prospectively assessed, found that at low levels of alcohol consumption (0–9 g/day) there was no benefit in terms of development of advanced liver disease and an increased risk of incident cancer.
      • Åberg F.
      • Puukka P.
      • Salomaa V.
      • Männistö S.
      • Lundqvist A.
      • Valsta L.
      • et al.
      Risks of light and moderate alcohol use in fatty liver disease: follow-up of population cohorts.
      One case-control study
      • Marrero J.A.
      • Fontana R.J.
      • Fu S.
      • Conjeevaram H.S.
      • Su G.L.
      • Lok A.S.
      Alcohol, tobacco and obesity are synergistic risk factors for hepatocellular carcinoma.
      and 2 longitudinal studies
      • Loomba R.
      • Yang H.-I.
      • Su J.
      • Brenner D.
      • Iloeje U.
      • Chen C.-J.
      Obesity and alcohol synergize to increase the risk of incident hepatocellular carcinoma in men.
      ,
      • Loomba R.
      • Yang H.-I.
      • Su J.
      • Brenner D.
      • Barrett-Connor E.
      • Iloeje U.
      • et al.
      Synergism between obesity and alcohol in increasing the risk of hepatocellular carcinoma: a prospective cohort study.
      from the USA and Taiwan have demonstrated a supra-additive interaction of alcohol consumption and obesity on HCC development (OR 5.5, HRs 3.40 and 3.82, respectively), meaning that the synergistic risk of both factors exceeded the sum of the separate factors (OR 1.2, HRs 0.64 and 1.17 for isolated obesity; OR 2.6, HRs 1.64 and 1.46 for isolated alcohol consumption; reviewed in
      • Åberg F.
      • Färkkilä M.
      • Männistö V.
      Interaction between alcohol use and metabolic risk factors for liver disease: a critical review of epidemiological studies.
      ). Similar findings were reported by 2 case-control studies that assessed the risk associated with diabetes and heavy alcohol consumption (defined as either ≥80 g/day or >4 drinks/day) in patients with HCC compared to matched controls with other malignancies and healthy controls (ORs 9.9 and 17.3 for concomitant diabetes and alcohol consumption; ORs 2.4 and 2.5 for isolated diabetes; ORs 2.6 and 3.4 for isolated alcohol consumption,
      • Hassan M.M.
      • Hwang L.-Y.
      • Hatten C.J.
      • Swaim M.
      • Li D.
      • Abbruzzese J.L.
      • et al.
      Risk factors for hepatocellular carcinoma: synergism of alcohol with viral hepatitis and diabetes mellitus.
      ,
      • Yuan J.-M.
      • Govindarajan S.
      • Arakawa K.
      • Yu M.C.
      Synergism of alcohol, diabetes, and viral hepatitis on the risk of hepatocellular carcinoma in blacks and whites in the U.S.
      reviewed in
      • Åberg F.
      • Färkkilä M.
      • Männistö V.
      Interaction between alcohol use and metabolic risk factors for liver disease: a critical review of epidemiological studies.
      ). Given the high prevalence of metabolic conditions among individuals living with NAFLD, these findings are especially relevant in this context.
      Conclusive data regarding the effect of specific drinking patterns on liver cancer risk is lacking. In a cohort of patients undergoing liver biopsy for suspected NAFLD, moderate alcohol consumption was associated with a lower risk of advanced fibrosis compared to alcohol abstinence, but this pattern was not confirmed in patients who reported binge drinking.
      • Mitchell T.
      • Jeffrey G.P.
      • de Boer B.
      • MacQuillan G.
      • Garas G.
      • Ching H.
      • et al.
      Type and pattern of alcohol consumption is associated with liver fibrosis in patients with non-alcoholic fatty liver disease.
      Another study found daily drinking to be associated with an increased risk of cirrhosis,
      • Askgaard G.
      • Grønbæk M.
      • Kjær M.S.
      • Tjønneland A.
      • Tolstrup J.S.
      Alcohol drinking pattern and risk of alcoholic liver cirrhosis: a prospective cohort study.
      thus indirectly increasing the risk of liver cancer. Among Japanese men who consumed alcohol at levels consistent with NAFLD diagnostic criteria, there was no difference in overall cancer-related mortality when stratified by drinking days per week.
      • Marugame T.
      • Yamamoto S.
      • Yoshimi I.
      • Sobue T.
      • Inoue M.
      • Tsugane S.
      • et al.
      Patterns of alcohol drinking and all-cause mortality: results from a large-scale population-based cohort study in Japan.
      However, whether this is also the case in patients with underlying NAFLD is unknown.
      Smoking and alcohol cessation should be considered important goals in the prevention of NAFLD-HCC.

      Smoking

      Smoking is associated with an increased risk of HCC in general, while data specifically on NAFLD is lacking. A meta-analysis of 81 studies reported pooled ORs for HCC development of 1.55 (95% CI 1.46–1.65) in current and 1.39 (95% CI 1.26–1.52) in former smokers compared to non-smokers.
      • 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.
      Data from the Liver Cancer Pooling Project demonstrated that the risk of HCC in patients who quit smoking >30 years ago was similar to that in never smokers (HR 1.09; 95% CI 0.74–1.61),
      • Petrick J.L.
      • Campbell P.T.
      • Koshiol J.
      • Thistle J.E.
      • Andreotti G.
      • Beane-Freeman L.E.
      • et al.
      Tobacco, alcohol use and risk of hepatocellular carcinoma and intrahepatic cholangiocarcinoma: the Liver Cancer Pooling Project.
      suggesting a beneficial effect of smoking cessation on HCC risk.
      Regarding the synergistic effect of smoking and metabolic comorbidities, few data exist. No synergistic effect of diabetes on HCC occurrence among smokers was observed in an American case-control study.
      • Yuan J.-M.
      • Govindarajan S.
      • Arakawa K.
      • Yu M.C.
      Synergism of alcohol, diabetes, and viral hepatitis on the risk of hepatocellular carcinoma in blacks and whites in the U.S.
      However, another case-control study reported a synergistic effect among individuals with obesity.
      • Marrero J.A.
      • Fontana R.J.
      • Fu S.
      • Conjeevaram H.S.
      • Su G.L.
      • Lok A.S.
      Alcohol, tobacco and obesity are synergistic risk factors for hepatocellular carcinoma.
      Thus, it is not entirely clear whether the risk of HCC among NAFLD/NASH patients with metabolic conditions exposed to smoking may exceed the risk of patients with other aetiologies of liver disease.

      Chemoprevention

      Several drugs have been shown to modulate risk factors and carcinogenic pathways in NAFLD/NASH-associated HCC, thereby suggesting potential for use in the development and implementation of prevention strategies. In this section, we review drugs that have demonstrated a preventive effect on HCC.

      Aspirin

      In a pooled analysis of 2 prospective cohort studies in the USA (N = 133,371), Simon et al. (2018) showed that regular use of at least 650 mg aspirin per week was associated with a 50% reduction in HCC risk (HR 0.51; 95% CI 0.34–0.77).
      • Simon T.G.
      • Ma Y.
      • Ludvigsson J.F.
      • Chong D.Q.
      • Giovannucci E.L.
      • Fuchs C.S.
      • et al.
      Association between aspirin use and risk of hepatocellular carcinoma.
      A Swedish, nationwide registry-based study confirmed that regular intake of less than 160 mg/d aspirin for at least 5 years, lowered the risk of HCC (HR 0.69; 95% CI 0.62–0.76), without increasing the risk of gastrointestinal bleeding.
      • Simon T.G.
      • Duberg A.-S.
      • Aleman S.
      • Chung R.T.
      • Chan A.T.
      • Ludvigsson J.F.
      Association of aspirin with hepatocellular carcinoma and liver-related mortality.
      In a study of 361 patients with biopsy-confirmed NAFLD, daily aspirin use was shown to significantly lower the OR of NASH and fibrosis.
      • Simon T.G.
      • Henson J.
      • Osganian S.
      • Masia R.
      • Chan A.T.
      • Chung R.T.
      • et al.
      Daily aspirin use associated with reduced risk for fibrosis progression in patients with nonalcoholic fatty liver disease.
      Potential chemoprophylactic treatments that may be warranted in patients with associated comorbidities or in certain circumstances include aspirin, metformin, and statins.
      Selective cyclooxygenase-2 inhibition was suggested as being responsible for aspirin’s inhibitory effect on fibrosis, portal hypertension, and proliferation of liver cancer cells. In addition, in animal models, aspirin inhibited platelet-derived growth factor, known as an important factor in the activation of hepatic stellate cells and promotion of fibrosis.
      • Yoshida S.
      • Ikenaga N.
      • Liu S.B.
      • Peng Z.-W.
      • Chung J.
      • Sverdlov D.Y.
      • et al.
      Extrahepatic platelet-derived growth factor-β, delivered by platelets, promotes activation of hepatic stellate cells and biliary fibrosis in mice.
      Aspirin has also been shown to inhibit P4HA2, which is involved not only in collagen synthesis but also in HCC development.
      • Wang T.
      • Fu X.
      • Jin T.
      • Zhang L.
      • Liu B.
      • Wu Y.
      • et al.
      Aspirin targets P4HA2 through inhibiting NF-κB and LMCD1-AS1/let-7g to inhibit tumour growth and collagen deposition in hepatocellular carcinoma.
      Moreover, recent evidence suggests that platelet recruitment and activation in the liver contribute to HCC development in mice, specifically via platelet glycoprotein Ibα signalling.
      • Malehmir M.
      • Pfister D.
      • Gallage S.
      • Szydlowska M.
      • Inverso D.
      • Kotsiliti E.
      • et al.
      Platelet GPIbα is a mediator and potential interventional target for NASH and subsequent liver cancer.
      Given the growing body of evidence regarding the association of NAFLD and cardiovascular disease, the use of aspirin in patients with NAFLD may be an appropriate option for select patients.

      Antidiabetic drugs

      Metformin

      Several large population-based cohort studies reported that metformin, a first-line drug to treat type 2 diabetes, has a chemoprophylactic effect on HCC (Table 2).
      Table 2Chemopreventive effect of metformin on HCC.
      YearStudyDesignSample size, nHCC cases, nMetformin users in HCC group (%)Results, HR (95% Cl)
      2010Hassan et al.
      • Hassan M.M.
      • 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.
      Hospital-based cohort1,52442047.10.3 (0.2–0.6)
      2010Donadon et al.
      • Donadon V.
      • Balbi M.
      • Mas M.D.
      • Casarin P.
      • Zanette G.
      Metformin and reduced risk of hepatocellular carcinoma in diabetic patients with chronic liver disease.
      Hospital-based cohort54919023.50.2 (0.1–0.4)
      2010Kawaguchi et al.
      • Kawaguchi T.
      • Taniguchi E.
      • Morita Y.
      • Shirachi M.
      • Tateishi I.
      • Nagata E.
      • et al.
      Association of exogenous insulin or sulphonylurea treatment with an increased incidence of hepatoma in patients with hepatitis C virus infection.
      Hospital-based cohort2411383.70.6 (0.2–2.2)
      2011Nkontchou et al.
      • Nkontchou G.
      • Cosson E.
      • Aout M.
      • Mahmoudi A.
      • Bourcier V.
      • Charif I.
      • et al.
      Impact of metformin on the prognosis of cirrhosis induced by viral hepatitis C in diabetic patients.
      Hospital-based cohort1003926.00.2 (0.04–0.8)
      2012Lai et al.
      • 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.
      Retrospective cohort study96,7451’120840.49 (0.37–0.66)
      2012Ruiter et al.
      • Ruiter R.
      • Visser L.E.
      • van Herk-Sukel M.P.P.
      • Coebergh J.-W.W.
      • Haak H.R.
      • Geelhoed-Duijvestijn P.H.
      • et al.
      Lower risk of cancer in patients on metformin in comparison with those on sulfonylurea derivatives: results from a large population-based follow-up study.
      Population-based cohort85,289
      with antidiabetic drug prescription. HCC, hepatocellular carcinoma; HR, hazard ratio; NASH, non-alcoholic steatohepatitis; NAFLD, non-alcoholic fatty liver disease; n.a., not applicable.
      1’59061.80.7 (0.5–0.9)
      2011Chen et al.
      • 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.
      Population- based cohort16216239.60.24 (0.07–0.80)
      2019Vilar-Gomez et al.
      • Vilar-Gomez E.
      • Vuppalanchi R.
      • Desai A.P.
      • Gawrieh S.
      • Ghabril M.
      • Saxena R.
      • et al.
      Long-term metformin use may improve clinical outcomes in diabetic patients with non-alcoholic steatohepatitis and bridging fibrosis or compensated cirrhosis.
      Cohort30757.60.25 (0.11–0.58)
      2021Cho et al.
      • Cho W.-R.
      • Wang C.-C.
      • Tsai M.-Y.
      • Chou C.-K.
      • Liu Y.-W.
      • Wu Y.-J.
      • et al.
      Impact of metformin use on the recurrence of hepatocellular carcinoma after initial liver resection in diabetic patients.
      Retrospective cohort study85785761.3No protective effect
      with antidiabetic drug prescription. HCC, hepatocellular carcinoma; HR, hazard ratio; NASH, non-alcoholic steatohepatitis; NAFLD, non-alcoholic fatty liver disease; n.a., not applicable.
      In a sub-analysis of a meta-analysis evaluating 37 trials, the authors found a significant HCC risk reduction in metformin users regarding both HCC incidence (78%) and mortality (77%).
      • Zhang H.-L.
      • Yu L.-X.
      • Yang W.
      • Tang L.
      • Lin Y.
      • Wu H.
      • et al.
      Profound impact of gut homeostasis on chemically-induced pro-tumorigenic inflammation and hepatocarcinogenesis in rats.
      Another meta-analysis of 10 studies, with 22,650 HCC cases among 334,307 diabetic patients, showed that the use of metformin was associated with a 41% reduction in HCC incidence.
      • Singh S.
      • Singh P.P.
      • Singh A.G.
      • Murad M.H.
      • Sanchez W.
      Anti-diabetic medications and the risk of hepatocellular cancer: a systematic review and meta-analysis.
      Currently, no adjuvant treatment is approved for tertiary prevention of HCC recurrence.
      Metformin seems to exert anti-tumoral effects through multiple mechanisms, e.g. by decreasing the level of insulin-like growth factor-1; downregulating JNK (c-Jun N-terminal kinase)/p38 MAPK (mitogen-activated protein kinase), human epidermal growth factor receptor-2, and NF-κB pathways; activating AMP-activated protein kinase; inhibiting mTOR (mammalian target of rapamycin); and reducing endogenous production of reactive oxygen species.
      • Vilar-Gomez E.
      • Vuppalanchi R.
      • Desai A.P.
      • Gawrieh S.
      • Ghabril M.
      • Saxena R.
      • et al.
      Long-term metformin use may improve clinical outcomes in diabetic patients with non-alcoholic steatohepatitis and bridging fibrosis or compensated cirrhosis.
      The only trial that aimed to evaluate the chemoprophylactic effect of metformin in patients with viral hepatitis C (NCT02319200) was terminated early due to slow recruitment. Currently no further randomised controlled trials to examine the effects of metformin on the development of HCC are planned.

      Pioglitazone

      Pioglitazone, an activator of peroxisome proliferator-activated receptor-γ (PPAR-γ) known for its insulin-sensitising effects, reduced the incidence of HCC in a hospital-based case-control study and a population-based cohort study.
      • Hassan M.M.
      • 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.
      • 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.
      • Chang C.-H.
      • Lin J.-W.
      • Wu L.-C.
      • Lai M.-S.
      • Chuang L.-M.
      • Arnold Chan K.
      Association of thiazolidinediones with liver cancer and colorectal cancer in type 2 diabetes mellitus.
      In contrast with these findings, an Italian nested case-control study using healthcare databases failed to show a significant effect of pioglitazone on HCC risk.
      • Bosetti C.
      • Franchi M.
      • Nicotra F.
      • Asciutto R.
      • Merlino L.
      • La Vecchia C.
      • et al.
      Insulin and other antidiabetic drugs and hepatocellular carcinoma risk: a nested case-control study based on Italian healthcare utilization databases.
      The fact that the antitumor effect of PPAR-γ ligands is dose-dependent might explain the conflicting findings.
      • Fröhlich E.
      • Wahl R.
      In vitro studies suggested that the anti-carcinogenic properties of pioglitazone could be the result of suppression of hepatic stellate cell activation.
      • Yang Y.
      • Zhao L.-H.
      • Huang B.
      • Wang R.-Y.
      • Yuan S.-X.
      • Tao Q.-F.
      • et al.
      Pioglitazone, a PPARγ agonist, inhibits growth and invasion of human hepatocellular carcinoma via blockade of the rage signaling: pioglitazone inhibits growth & invation of HCC.
      ,
      • Galli A.
      • Crabb D.W.
      • Ceni E.
      • Salzano R.
      • Mello T.
      • Svegliati–Baroni G.
      • et al.
      Antidiabetic thiazolidinediones inhibit collagen synthesis and hepatic stellate cell activation in vivo and in vitro.
      This anti-fibrotic and anti-carcinogenic effect of low dose pioglitazone was confirmed in 2 rodent models.
      • Li S.
      • Ghoshal S.
      • Sojoodi M.
      • Arora G.
      • Masia R.
      • Erstad D.J.
      • et al.
      Pioglitazone reduces hepatocellular carcinoma development in two rodent models of cirrhosis.
      In addition, pioglitazone demonstrated a positive effect on adiponectin levels, which was associated with protection from carcinogenesis.
      • Sumie S.
      • Kawaguchi T.
      • Kawaguchi A.
      • Kuromatsu R.
      • Nakano M.
      • Satani M.
      • et al.
      Effect of pioglitazone on outcome following curative treatment for hepatocellular carcinoma in patients with hepatitis C virus infection: a prospective study.
      However, serious side effects such as weight gain, bone loss, and fracture risk, increased risk of myocardial infarction (rosiglitazone) and increased risk of bladder cancer (pioglitazone) limit the use of this drug class.
      • Tang H.
      • Shi W.
      • Fu S.
      • Wang T.
      • Zhai S.
      • Song Y.
      • et al.
      Pioglitazone and bladder cancer risk: a systematic review and meta-analysis.
      • Grey A.
      Skeletal consequences of thiazolidinedione therapy.
      • Lincoff A.M.
      • Wolski K.
      • Nicholls S.J.
      • Nissen S.E.
      Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials.

      Statins

      Several clinical trials have reported that statins are effective in reducing HCC risk (Table 3). The results of a recent meta-analysis of 24 studies showed a 46% decrease in HCC risk among statin users, suggesting that statins may be an option in chemoprophylaxis.
      • Islam MdM.
      • Poly T.N.
      • Walther B.A.
      • Yang H.-C.
      • Li Y-C (Jack)
      Statin use and the risk of hepatocellular carcinoma: a meta-analysis of observational studies.
      According to a sub-analysis of another meta-analysis, the use of lipophilic statins was associated with a significantly reduced risk of HCC compared with hydrophilic statins (51% vs. 27%).
      • Facciorusso A.
      • Abd El Aziz M.A.
      • Singh S.
      • Pusceddu S.
      • Milione M.
      • Giacomelli L.
      • et al.
      Statin use decreases the incidence of hepatocellular carcinoma: an updated meta-analysis.
      This finding could be explained by the greater lipid solubility and membrane permeability of lipophilic substances, enabling them to exert their cholesterol-dependent effects on HCC development.
      • Hamelin B.
      Hydrophilicity/ lipophilicity: relevance for the pharmacology and clinical effects of HMG-CoA reductase inhibitors.
      HCC prevention in patients with NAFLD/NASH should embrace a multifactorial approach that includes optimisation of lifestyle habits, management of metabolic comorbidities, and chemoprevention when appropriate.
      Table 3Summary of studies on the chemopreventive effect of statins on HCC.
      Completed trials
      YearStudyStudy designSample size, nHCC cases, nStatin users in HCC group, %Results

      AHR (95%Cl)
      2009El-Serag HB et al.
      • El–Serag H.B.
      • Johnson M.L.
      • Hachem C.
      • Morgana R.O.
      Statins are associated with a reduced risk of hepatocellular carcinoma in a large cohort of patients with diabetes.
      Cohort6,5151,303260.7 (0.6–0.9)
      2011Chiu HF et al.
      • Chiu H.-F.
      • Ho S.-C.
      • Chen C.-C.
      • Yang C.-Y.
      Statin use and the risk of liver cancer: a population-based case–control study.
      Case-control2,3321,166n.a.0.6 (0.4–0.9)
      2012Tsan H et al.
      • Tsan Y.-T.
      • Lee C.-H.
      • Wang J.-D.
      • Chen P.-C.
      Statins and the risk of hepatocellular carcinoma in patients with hepatitis B virus infection.
      Cohort33,4131,0215.60.5 (0.4–0.6)
      2013Tsan H et al.
      • Tsan Y.-T.
      • Lee C.-H.
      • Ho W.-C.
      • Lin M.-H.
      • Wang J.-D.
      • Chen P.-C.
      Statins and the risk of hepatocellular carcinoma in patients with hepatitis C virus infection.
      Cohort260,86427,8835.20.5 (0.5–0.6)
      2015McGlynn et al.
      • McGlynn K.A.
      • Divine G.W.
      • Sahasrabuddhe V.V.
      • Engel L.S.
      • VanSlooten A.
      • Wells K.
      • et al.
      Statin use and risk of hepatocellular carcinoma in a U.S. population.
      Case-control5,8351,54419.50.55 (0.45–0.69)
      2016Simon TG et al.
      • Simon T.G.
      • King L.Y.
      • Zheng H.
      • Chung R.T.
      Statin use is associated with a reduced risk of fibrosis progression in chronic hepatitis C.
      Cohort9,13523331.30.51 (0.36–0.72)
      2017Kim G et al.
      • Kim G.
      • Jang S.-Y.
      • Han E.
      • Lee Y.
      • Park S.
      • Nam C.M.
      • et al.
      Effect of statin on hepatocellular carcinoma in patients with type 2 diabetes: a nationwide nested case-control study: statin use and the risk of HCC in DM patients.
      Case-control1,37424710.90.36 (0.22–0.60)
      2018Kim G et al.
      • Kim G.
      • Kang E.S.
      Prevention of hepatocellular carcinoma by statins: clinical evidence and plausible mechanisms.
      Case-control9,8521,6426.70.44 (0.33–0.58)
      Ongoing trials
      NCT02968810, USARandomised controlled trial, Phase IIOngoingArm 1: simvastatin QD

      Arm 2: placebo QD
      NCT03024684, TaiwanRandomised controlled trial, Phase IVOngoingArm 1: atorvastatin 10 mg QD

      Arm 2: placebo QD
      AHR, adjusted hazard ratio; HCC, hepatocellular carcinoma; QD, once daily.
      Potential mechanisms include inhibition of MYC, protein kinase B (AKT), and NF-κB pathways, as well as decreased production of interleukin-6, tumour necrosis factor-α, and transforming growth factor-β1.
      • Li S.
      • Saviano A.
      • Erstad D.J.
      • Hoshida Y.
      • Fuchs B.C.
      • Baumert T.
      • et al.
      Risk factors, pathogenesis, and strategies for hepatocellular carcinoma prevention: emphasis on secondary prevention and its translational challenges.
      In addition, simvastatin has been shown to reduce tumour cell growth and impair tumour cell adhesion to endothelial cell monolayers, resulting in reduced tumour cell invasion.
      • Relja
      Simvastatin modulates the adhesion and growth of hepatocellular carcinoma cells via decrease of integrin expression and ROCK.
      Given that many patients with NAFLD/NASH are prescribed statins, more data will likely become available in the future.

      Antifibrotic therapies

      Several drugs specifically targeting the pathogenesis of NASH are being tested, but obeticholic acid (OCA), a farnesoid X receptor agonist, is the only drug that has been shown to improve fibrosis without worsening NASH – based on an interim analysis of a phase III trial (REGENERATE; NCT02548351).
      • Ratziu V.
      • Sanyal A.J.
      • Loomba R.
      • Rinella M.
      • Harrison S.
      • Anstee Q.M.
      • et al.
      REGENERATE: design of a pivotal, randomised, phase 3 study evaluating the safety and efficacy of obeticholic acid in patients with fibrosis due to nonalcoholic steatohepatitis.
      Whether this translates into a reduced risk of HCC is not yet known. Moreover, OCA has several side effects, including pruritus and elevated LDL cholesterol levels. The latter is of particular importance in the NAFLD population because it is associated with cardiovascular disease, which is the leading cause of death in this population.
      • Eslam M.
      • Alvani R.
      • Shiha G.
      Obeticholic acid: towards first approval for NASH.
      However, it has been reported that the increase in LDL cholesterol was transient and could be managed with statins. Thus, LDL cholesterol levels should be followed up regularly and treated as necessary. Long-term safety and efficacy need to be evaluated in real-world populations, particularly with regard to tolerability and cardiovascular risk.

      Pre- and probiotics

      A growing body of evidence suggests that intestinal dysbiosis increases the permeability of the intestinal barrier, which allows substances such as short-chain fatty acids, bile acids, bacterial components, choline, and endogenous ethanol to reach the liver, prompting the development of NAFLD and progression to NASH.
      • Aragonès G.
      • González-García S.
      • Aguilar C.
      • Richart C.
      • Auguet T.
      Gut microbiota-derived mediators as potential markers in nonalcoholic fatty liver disease.
      Dietary factors interact with the gut-liver axis, but this ecosystem may also be targeted more specifically using pre- and probiotics.
      • Schwabe R.F.
      • Greten T.F.
      Gut microbiome in HCC - mechanisms, diagnosis and therapy.
      In a diethylnitrosamine (DEN) model of rat hepatocarcinogenesis, probiotic-treated rats were protected from acute hepatic injury, had a significantly lower rate of cell proliferation and less extensive intrahepatic leukocyte infiltration.
      • Zhang H.-L.
      • Yu L.-X.
      • Yang W.
      • Tang L.
      • Lin Y.
      • Wu H.
      • et al.
      Profound impact of gut homeostasis on chemically-induced pro-tumorigenic inflammation and hepatocarcinogenesis in rats.
      Yoshimoto et al. showed that obesity-induced alterations in the gut microbiota of mice promote the development of HCC and that this effect may be mitigated by antibiotic therapy.
      • Yoshimoto S.
      • Loo T.M.
      • Atarashi K.
      • Kanda H.
      • Sato S.
      • Oyadomari S.
      • et al.
      Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome.
      Possible mechanisms by which probiotics exert their antitumorigenic effects include their ability to bind carcinogens (e.g. aflatoxin B1), modulate gut microbiota and immune response, improve intestinal barrier function and reduce the absorption of lipopolysaccharides (carcinogen-induced hepatocarcinogenesis).
      • Wan M.L.Y.
      • El-Nezami H.
      Targeting gut microbiota in hepatocellular carcinoma: probiotics as a novel therapy.
      All studies reviewed reported no adverse effects or safety issues with the clinical use of probiotics in patients with NAFLD.
      • Perumpail B.
      • Li A.
      • John N.
      • Sallam S.
      • Shah N.
      • Kwong W.
      • et al.
      The therapeutic implications of the gut microbiome and probiotics in patients with NAFLD.
      Theoretically, probiotics can be used alone or in conjunction with other NAFLD-targeted therapies. However, the identification of appropriate bacterial strains, potential interactions with other agents, and the risk of "relapse" after cessation of therapeutic intervention require further investigation.

      Tertiary chemoprophylaxis - adjuvant therapies

      A high rate of recurrence after curative therapies for HCC indicates the need for adjuvant treatment in selected cases.

      Tyrosine kinases inhibitors

      One drug class that has been investigated in this setting is tyrosine kinase inhibitors, which are currently being used for the systematic treatment of advanced HCC. However, the phase III STORM study failed to show a benefit of sorafenib compared to placebo in terms of recurrence-free survival (33.3 vs. 33.7 months, p = 0.26), indicating that sorafenib is not an effective option in the adjuvant setting for HCC.
      • Bruix J.
      • Takayama T.
      • Mazzaferro V.
      • Chau G.-Y.
      • Yang J.
      • Kudo M.
      • et al.
      Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial.

      Immunotherapy

      The encouraging results of immunotherapy, 15–20% rate of durable objective remissions (including complete response in 1–5%) in patients with HCC, have raised hopes for effective adjuvant treatment of HCC. Currently, several studies on the use of immunotherapy as adjuvant therapy are ongoing (Table 4). However, a recent meta-analysis of 3 large randomised controlled phase III trials of immunotherapies in advanced HCC (CheckMate-45911, IMbrave1505, and KEYNOTE-24010) showed that non-viral HCC might be less responsive to these treatments than viral HCC (HR 0.92; 95% CI 0.77–1.1 and HR 0.64; 95% CI 0.48–0.94, respectively).
      • Pfister D.
      • Núñez N.G.
      • Pinyol R.
      • Govaere O.
      • Pinter M.
      • Szydlowska M.
      • et al.
      NASH limits anti-tumour surveillance in immunotherapy-treated HCC.
      Moreover, Pfister et al. observed that prophylactic anti-programmed cell death 1 (PD1) treatment led to an increase in the incidence of NASH-HCC. These findings call for a critical evaluation of ongoing trials of anti-PD1 drugs in NASH populations.
      Table 4Ongoing clinical trials evaluating possible adjuvant agents in HCC.
      TrialTarget populationArmsClinical trial identifier
      EMERALD-2HCC at high risk of recurrence after curative hepatic resection or ablationArm 1: durvalumab (Q3W) + bevacizumab (Q3W)

      Arm 2: durvalumab (Q3W) + bevacizumab placebo (Q3W)

      Arm 3: durvalumab placebo (Q3W) + bevacizumab placebo (Q3W)
      NCT03847428
      JUPITER 0Locally advanced HCC after curative hepatic resectionArm 1: toripalimab

      arm 2: placebo
      NCT03859128
      IMbrave050HCC at high risk of recurrence after surgical resection or ablationArm 1: atezolizumab plus bevacizumab

      Arm 2: active surveillance of participants
      NCT04102098
      CheckMate 9DXHCC at high risk of recurrence after curative hepatic resection or ablationArm 1: nivolumab

      Arm 2: placebo
      NCT03383458
      KEYNOTE-937HCC with complete radiological response after surgical resection or local ablationArm 1: pembrolizumab

      Arm 2: placebo
      NCT03867084
      HCC, hepatocellular carcinoma; Q3W, once every 3 weeks.

      Conclusion

      Weight loss, dietary modifications, and increased physical activity remain the mainstays of HCC prevention in the NAFLD/NASH population. However, patients with diabetes, obesity and cardiovascular comorbidities may benefit from chemoprevention in addition to lifestyle modification.
      Evidence for tertiary prevention of HCC is still inconclusive, and moreover, emerging data on the potentially deleterious effect of anti-PD1 drugs on HCC warrant caution in the NAFLD/NASH population.
      Overall, these findings need to be interpreted with caution as few data exist on HCC in the context of NAFLD specifically. Response of NAFLD-associated HCC to lifestyle factors and chemopreventive agents may differ from other aetiologies and – considering the heterogeneity of the NAFLD/NASH population – within clinical phenotypes of NAFLD/NASH. An increasing understanding of underlying pathophysiological mechanisms and disease phenotypes may in the future allow for targeted preventive strategies for NAFLD-associated HCC.

      Abbreviations

      GLP-1, glucagon-like peptide-1; HCC, hepatocellular carcinoma; HR, hazard ratio; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; OCA, obeticholic acid; OR, odds ratio; PPAR-γ, peroxisome proliferator-activated receptor-γ; RR, relative risk

      Financial support

      NL receives financial support through a scholarship from the Swiss Liver Foundation , and a scholarship from the Gottfried and Julia Bangerter-Rhyner Foundation and Swiss Academy of Medical Sciences (SAMS) . The authors have received no other financial support pertaining to this project.

      Authors’ contributions

      All authors contributed substantially to the conception and design of the work. NL and PR performed the literature review and drafted the manuscript. JFD reviewed the manuscript critically for important intellectual content. All authors approved of the final version.

      Conflict of Interest

      The authors have no potential conflicts (financial, professional, or personal) that are relevant to the manuscript to disclose.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Acknowledgements

      NL would like to thank the Swiss Liver Foundation, and the Gottfried and Julia Bangerter-Rhyner Foundation and Swiss Academy of Medical Sciences (SAMS) for supporting her work.

      Supplementary data

      The following is the supplementary data to this article:

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