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Epidemiology and risk-stratification of NAFLD-associated HCC

  • George N. Ioannou
    Correspondence
    Corresponding author. Address: Veterans Affairs Puget Sound Health Care System Gastroenterology, S-111-Gastro, 1660 S. Columbian Way, Seattle, WA 98108, USA; Tel.: 206-277-3136, fax: 206-764-2232.
    Affiliations
    Veterans Affairs Puget Sound Healthcare System, USA

    University of Washington, Seattle, WA, USA
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Published:August 25, 2021DOI:https://doi.org/10.1016/j.jhep.2021.08.012

      Summary

      Non-alcoholic fatty liver disease (NAFLD) is projected to become the leading cause of hepatocellular carcinoma (HCC) in many countries. Many risk factors for NAFLD are also independently associated with HCC, including obesity, diabetes, Hispanic ethnicity and genetic polymorphisms in PNPLA3, TM6SF2, GCKR, MBOAT7 and HSD17B13. Steatosis-related lipotoxicity and oxidative DNA damage can induce hepatocarcinogenesis. These factors may explain the association between NAFLD and HCC, especially in the absence of cirrhosis. In fact, NAFLD/NASH is a leading cause of HCC in the absence of cirrhosis. Identifying patients with pre-cirrhotic NAFLD who have a high enough HCC risk to justify HCC screening represents one of the greatest clinical challenges in NAFLD. Validated models that combine multiple risk factors and fibrosis stage into “HCC risk calculators” are not yet available for patients with NAFLD. Development of such tools would enable risk stratification, identification of high-risk patients even in the absence of cirrhosis, and individualised (risk-based) surveillance strategies.

      Keywords

      Introduction

      Non-alcoholic fatty liver disease (NAFLD) is the fastest-growing cause of hepatocellular carcinoma (HCC) in the world. Coupled with reductions expected to occur in HBV-related HCC (due to greater vaccination coverage or successful viral suppression with antiviral medications) and HCV-related HCC (due to successful eradication with direct-acting antivirals
      • Beste L.A.
      • Green P.
      • Berry K.
      • Belperio P.
      • Ioannou G.N.
      Hepatitis C-related hepatocellular carcinoma incidence in the Veterans health administration after introduction of direct-acting antivirals.
      ), non-alcoholic steatohepatitis (NASH) will inevitably become the most common aetiology of HCC in many countries in the near future. Notable features of NAFLD-related HCC that have clinical relevance will be highlighted in this review, including its rising incidence, the relative importance of certain risk factors, occurrence in pre-cirrhotic liver disease and presentation at more advanced stages.
      Effective screening of at-risk persons provides the best opportunity for early detection, when potentially curative treatments are available. However, screening for HCC in patients with NAFLD represents an even harder challenge than in other liver conditions, owing to the well-recognised occurrence of HCC in pre-cirrhotic NAFLD, the enormous number of individuals with NAFLD, and additional limitations in the performance characteristics of available screening modalities unique to NAFLD. Risk stratification and risk-based surveillance (also known as “precision HCC screening”) have the potential to overcome some of these challenges, improve HCC screening in patients with NAFLD, and potentially reduce HCC-related mortality.

      Incidence of HCC in patients with NAFLD and NAFLD-related cirrhosis

      Because NAFLD has such a broad spectrum of histological severity, analyses of HCC incidence in NAFLD need to be anchored around distinct histological stages in order to be meaningful (Fig. 1). HCC incidence is extremely rare in patients with non-alcoholic fatty liver (NAFL, or “simple steatosis”, i.e. hepatic steatosis without necroinflammation or fibrosis), while in patients with NAFLD-related cirrhosis the incidence of HCC is high, broadly similar to other aetiologies of cirrhosis, with the exception of active HCV-related cirrhosis, which is associated with an even higher risk. In patients with pre-cirrhotic NASH, i.e. hepatic steatosis with necroinflammation and varying stages of fibrosis F1–F3, the risk of HCC is in-between that of NAFL and NAFLD-cirrhosis, depending on the stage of fibrosis as well as many other factors (see section below). Because NASH is still considered a histological diagnosis, it is extremely difficult to get representative estimates of HCC risk in patients with NASH, since only small proportions of at-risk patients undergo liver biopsy. Studies limited to patients who underwent liver biopsy and, among them, those who had adequate follow-up for HCC, are mostly derived from tertiary referral centres; hence, these studies cannot be considered representative of all patients with NAFLD/NASH, and likely report higher HCC incidence than in unselected cohorts with NAFLD/NASH, both because patients within these studies have different characteristics associated with higher HCC risk and because they undergo more intensive surveillance.
      Figure thumbnail gr1
      Fig. 1HCC incidence in patients with NAFLD based on histological stage.
      HCC incidence is very low in patients with NAFL ranging from 0.08–0.63 per 1,000 person-years.
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      HCC incidence in NAFLD-cirhosis is reported to be around 10–15 per 1,000 person-years.
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      Models estimating risk of hepatocellular carcinoma in patients with alcohol or NAFLD-related cirrhosis for risk stratification.
      Robust estimates of HCC risk in patients with NASH are not readily available because NASH is a histological diagnosis and liver biopsies tend to be performed in highly selected patients. It is reasonable to assume that HCC risk in NASH would be slightly higher than in NAFL and depend on fibrosis stage. HCC, hepatocellular carcinoma; NAFL, non-alcoholic fatty liver; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis.
      With these limitations in mind, the incidence of HCC in patients with NAFLD-related cirrhosis appears to be around 10–15 per 1,000 person-years
      • Kanwal F.
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      • Mapakshi S.
      • Natarajan Y.
      • Chayanupatkul M.
      • Richardson P.A.
      • et al.
      Risk of hepatocellular cancer in patients with non-alcoholic fatty liver disease.
      • Ioannou G.N.
      • Green P.
      • Lowy E.
      • Mun E.J.
      • Berry K.
      Differences in hepatocellular carcinoma risk, predictors and trends over time according to etiology of cirrhosis.
      • White D.L.
      • Kanwal F.
      • El-Serag H.B.
      Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review.
      • Ioannou G.N.
      • Green P.
      • Kerr K.F.
      • Berry K.
      Models estimating risk of hepatocellular carcinoma in patients with alcohol or NAFLD-related cirrhosis for risk stratification.
      (or about 1–1.5 per 100 person-years), which is similar to that of alcohol-associated cirrhosis but lower than active HCV-related cirrhosis.
      • Ioannou G.N.
      • Green P.
      • Lowy E.
      • Mun E.J.
      • Berry K.
      Differences in hepatocellular carcinoma risk, predictors and trends over time according to etiology of cirrhosis.
      The incidence of HCC is much lower in NAFL or NASH cohorts that exclude patients with cirrhosis: as low as 0.08 per 1,000 patient-years in a population-based study of ∼250,000 US Veterans,
      • White D.L.
      • Kanwal F.
      • El-Serag H.B.
      Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review.
      0.36 per 1,000 patient-years in a Danish cohort of hospitalized patients with fatty liver,
      • Sorensen H.T.
      • Mellemkjaer L.
      • Jepsen P.
      • Thulstrup A.M.
      • Baron J.
      • Olsen J.H.
      • et al.
      Risk of cancer in patients hospitalized with fatty liver: a Danish cohort study.
      0.43 per 1,000 patient-years in a study of 6,506 Japanese patients with ultrasonographic steatosis,
      • 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.
      and 0.62 per 1,000 patient-years among Olmsted County residents diagnosed with NAFLD.
      • Adams L.A.
      • Lymp J.F.
      • St Sauver J.
      • Sanderson S.O.
      • Lindor K.D.
      • Feldstein A.
      • et al.
      The natural history of nonalcoholic fatty liver disease: a population-based cohort study.
      The extent to which patients in these studies had NAFL or NASH and the stage of fibrosis is unclear since liver biopsies or non-invasive fibrosis tests were not performed.
      NAFLD is projected to become the leading cause of HCC in many countries.

      NASH is a leading cause of HCC in the absence of cirrhosis

      The majority of HCCs occur in the setting of cirrhosis, but a sizeable minority develop in pre-cirrhotic liver disease, e.g. about 14% (194/1,395) of HCCs in the Veterans Affairs (VA) healthcare system between 2005-2010
      • Mittal S.
      • El-Serag H.B.
      • Sada Y.H.
      • Kanwal F.
      • Duan Z.
      • Temple S.
      • et al.
      Hepatocellular carcinoma in the absence of cirrhosis in United States Veterans is associated with nonalcoholic fatty liver disease.
      and 12% (605/5,144) of HCCs diagnosed from 2000-2014 at 5 US medical centers.
      • Gawrieh S.
      • Dakhoul L.
      • Miller E.
      • Scanga A.
      • deLemos A.
      • Kettler C.
      • et al.
      Characteristics, aetiologies and trends of hepatocellular carcinoma in patients without cirrhosis: a United States multicentre study.
      It is interesting that NAFLD appears to account for a larger proportion of cases of non-cirrhotic HCC than cirrhotic HCC, e.g. 26.3% (159/605) vs. 13.4% (608/4,539) in a study by Gawrieh et al.
      • Gawrieh S.
      • Dakhoul L.
      • Miller E.
      • Scanga A.
      • deLemos A.
      • Kettler C.
      • et al.
      Characteristics, aetiologies and trends of hepatocellular carcinoma in patients without cirrhosis: a United States multicentre study.
      and 19% (37/194) vs. 6% (70/1,201) in a study by Mittal et al.
      • Mittal S.
      • El-Serag H.B.
      • Sada Y.H.
      • Kanwal F.
      • Duan Z.
      • Temple S.
      • et al.
      Hepatocellular carcinoma in the absence of cirrhosis in United States Veterans is associated with nonalcoholic fatty liver disease.
      In fact, in the study by Gawrieh et al., NAFLD was the most common aetiology of non-cirrhotic HCC. Also, in patients with NASH, a larger proportion of HCCs arise in those who do not have cirrhosis, ranging from 20% to 50%,
      • Kanwal F.
      • Kramer J.R.
      • Mapakshi S.
      • Natarajan Y.
      • Chayanupatkul M.
      • Richardson P.A.
      • et al.
      Risk of hepatocellular cancer in patients with non-alcoholic fatty liver disease.
      ,
      • Mittal S.
      • El-Serag H.B.
      • Sada Y.H.
      • Kanwal F.
      • Duan Z.
      • Temple S.
      • et al.
      Hepatocellular carcinoma in the absence of cirrhosis in United States Veterans is associated with nonalcoholic fatty liver disease.
      ,
      • Dyson J.
      • Jaques B.
      • Chattopadyhay D.
      • Lochan R.
      • Graham J.
      • Das D.
      • et al.
      Hepatocellular cancer: the impact of obesity, type 2 diabetes and a multidisciplinary team.
      • Paradis V.
      • Zalinski S.
      • Chelbi E.
      • Guedj N.
      • Degos F.
      • Vilgrain V.
      • et al.
      Hepatocellular carcinomas in patients with metabolic syndrome often develop without significant liver fibrosis: a pathological analysis.
      • Piscaglia F.
      • Svegliati-Baroni G.
      • Barchetti A.
      • Pecorelli A.
      • Marinelli S.
      • Tiribelli C.
      • et al.
      Clinical patterns of hepatocellular carcinoma in nonalcoholic fatty liver disease: a multicenter prospective study.
      compared to <10% in other liver diseases such as HCV. This suggests that there are factors related to the pathogenesis of NAFLD that are also directly related to the pathogenesis of HCC independent of the progression to advanced fibrosis and cirrhosis (Fig. 2). Such factors likely include obesity, diabetes, metabolic syndrome, insulin resistance and genetic factors (e.g. single nucleotide polymorphisms in PNPLA3, TM6SF2, GCKR and MBOAT7) and will be discussed in subsequent sections.
      Figure thumbnail gr2
      Fig. 2Risk factors for NAFLD that are also independently associated with HCC.
      These common risk factors may explain the associations between NAFLD and HCC, especially the development of HCC in pre-cirrhotic NAFLD. HCC, hepatocellular carcinoma; NAFLD, non-alcoholic fatty liver disease.

      Rising incidence of NAFLD-related HCC and proportion of all HCCs attributed to NAFLD over time

      The incidence of HCC has been rising in most countries around the world over the last 20-30 years, irrespective of the underlying liver disease aetiology; in fact, in the US, HCC was the malignancy associated with the greatest increase in both incidence and mortality in men and women from 2012-2017.
      • Henley S.J.
      • Ward E.M.
      • Scott S.
      • Ma J.
      • Anderson R.N.
      • Firth A.U.
      • et al.
      Annual report to the nation on the status of cancer, part I: national cancer statistics.
      The incidence of NAFLD-related HCC has been rising alongside most other aetiology-specific HCCs.
      • Beste L.A.
      • Leipertz S.L.
      • Green P.K.
      • Dominitz J.A.
      • Ross D.
      • Ioannou G.N.
      Trends in burden of cirrhosis and hepatocellular carcinoma by underlying liver disease in US Veterans, 2001-2013.
      Many studies considered trends over time in the proportion of HCCs attributed to NAFLD as a way to gauge whether the incidence of NAFLD-related HCC is rising faster than HCC due to other liver diseases (Table 1). Interestingly, most of those studies based on US populations do not show a significant increase in the proportion of HCCs attributed to NAFLD in time periods extending to 2014, mainly due to the dramatic increase in HCV-related HCC during the same time period. However, studies based in the UK and France, where the contribution of HCV-related HCC is less prominent, did show a substantial increase.
      Table 1Representative studies of trends over time in the proportion of HCCs attributed to NAFLD.
      StudyStudy periodCountryStudy populationProportion of HCC attributed to NAFLD
      Beste
      • Beste L.A.
      • Leipertz S.L.
      • Green P.K.
      • Dominitz J.A.
      • Ross D.
      • Ioannou G.N.
      Trends in burden of cirrhosis and hepatocellular carcinoma by underlying liver disease in US Veterans, 2001-2013.
      2001-2013USAUS Veterans with HCC in the VA healthcare system (n = 21,326)2004: 19.1%

      2006: 16.1%

      2008: 14.7%

      2010: 13.1%

      2012: 13.6%
      Goldberg
      • Goldberg D.
      • Ditah I.C.
      • Saeian K.
      • Lalehzari M.
      • Aronsohn A.
      • Gorospe E.C.
      • et al.
      Changes in the prevalence of hepatitis C virus infection, nonalcoholic steatohepatitis, and alcoholic liver disease among patients with cirrhosis or liver failure on the waitlist for liver transplantation.
      2006-2014USAHIRD dataset, 1,853 patients with HCC2006: 6.9%

      2008: 8.4%

      2010: 10.4%

      2012: 11.0%

      2014: 18.5%
      Mittal
      • Mittal S.
      • Sada Y.H.
      • El-Serag H.B.
      • Kanwal F.
      • Duan Z.
      • Temple S.
      • et al.
      Temporal trends of nonalcoholic fatty liver disease-related hepatocellular carcinoma in the veteran affairs population.
      2005-2010USASubset of US Veterans with HCC in the VA healthcare system (n = 1,500)2005: 7.5%

      2010: 12%
      Younossi
      • Younossi Z.M.
      • Otgonsuren M.
      • Henry L.
      • Venkatesan C.
      • Mishra A.
      • Erario M.
      • et al.
      Association of nonalcoholic fatty liver disease (NAFLD) with hepatocellular carcinoma (HCC) in the United States from 2004 to 2009.
      2004-2009USA4,929 patients with HCC in the SEER database2004: 15%

      2005: 13%

      2006: 13%

      2007: 14%

      2008: 16%

      2009: 14%
      Dyson
      • Dyson J.
      • Jaques B.
      • Chattopadyhay D.
      • Lochan R.
      • Graham J.
      • Das D.
      • et al.
      Hepatocellular cancer: the impact of obesity, type 2 diabetes and a multidisciplinary team.
      2000-2010UK632 patients with HCC evaluated at a single multidisciplinary liver tumour board (Newcastle-upon-Tyne)2000: 10%

      2010: 35%
      Pais
      • Pais R.
      • Fartoux L.
      • Goumard C.
      • Scatton O.
      • Wendum D.
      • Rosmorduc O.
      • et al.
      Temporal trends, clinical patterns and outcomes of NAFLD-related HCC in patients undergoing liver resection over a 20-year period.
      1995-2014France323 patients with HCC who underwent liver resection1995-1999: 2.6%

      2010-2014: 19.5%
      HCC, hepatocellular carcinoma; HIRD, HealthCore Integrated Research Database, a nationally representative population of commercially insured patients; NAFLD, non-alcoholic fatty liver disease; SEER, Surveillance Epidemiology and End Results; VA, Veterans Affairs.
      The availability of large, comprehensive, national transplant registries, such as the United Network for Organ Sharing (UNOS) in the USA and the European Liver Transplant Registry (ELTR) in Europe, allows for longitudinal comparisons of the relative contribution of NALD-related HCC that reflect population-based national trends (Table 2). All such analyses have demonstrated that the proportion of HCCs among liver transplant registrants or recipients that are attributed to NAFLD has been steadily increasing over time in the last 20 years,
      • Younossi Z.
      • Stepanova M.
      • Ong J.P.
      • Jacobson I.M.
      • Bugianesi E.
      • Duseja A.
      • et al.
      Nonalcoholic steatohepatitis is the fastest growing cause of hepatocellular carcinoma in liver transplant candidates.
      • Wong R.J.
      • Cheung R.
      • Ahmed A.
      Nonalcoholic steatohepatitis is the most rapidly growing indication for liver transplantation in patients with hepatocellular carcinoma in the U.S.
      • Goldberg D.
      • Ditah I.C.
      • Saeian K.
      • Lalehzari M.
      • Aronsohn A.
      • Gorospe E.C.
      • et al.
      Changes in the prevalence of hepatitis C virus infection, nonalcoholic steatohepatitis, and alcoholic liver disease among patients with cirrhosis or liver failure on the waitlist for liver transplantation.
      • Belli L.S.
      • Perricone G.
      • Adam R.
      • Cortesi P.A.
      • Strazzabosco M.
      • Facchetti R.
      • et al.
      Impact of DAAs on liver transplantation: major effects on the evolution of indications and results. An ELITA study based on the ELTR registry.
      • Flemming J.A.
      • Kim W.R.
      • Brosgart C.L.
      • Terrault N.A.
      Reduction in liver transplant wait-listing in the era of direct-acting antiviral therapy.
      reaching ∼18% by 2017 in the US.
      • Younossi Z.
      • Stepanova M.
      • Ong J.P.
      • Jacobson I.M.
      • Bugianesi E.
      • Duseja A.
      • et al.
      Nonalcoholic steatohepatitis is the fastest growing cause of hepatocellular carcinoma in liver transplant candidates.
      This is even more notable when considering that the incidence of HCV-related HCC was also rapidly increasing during most of this period, which would tend to attenuate proportions of HCC attributed to other aetiologies. One study that reported the number of new patients with NAFLD-related HCC listed for liver transplantation each year as a proportion of the US population, demonstrated an even more dramatic increase from 0.05/100,000 US population in 2003 to 0.81/100,000 in 2015.
      • Flemming J.A.
      • Kim W.R.
      • Brosgart C.L.
      • Terrault N.A.
      Reduction in liver transplant wait-listing in the era of direct-acting antiviral therapy.
      Many risk factors for NAFLD are also independently associated with HCC.
      Table 2Representative studies of trends over time in the proportion of HCCs attributed to NAFLD among liver transplant registrants or recipients.
      StudyStudy periodCountry/RegionStudy populationProportion of HCC attributed to NAFLDAnnual standardised incidence rate of liver transplant wait-listing for NAFLD-related HCC per 100,000 US population
      Wong
      • Wong R.J.
      • Cheung R.
      • Ahmed A.
      Nonalcoholic steatohepatitis is the most rapidly growing indication for liver transplantation in patients with hepatocellular carcinoma in the U.S.
      2002-2012USA61,868 liver transplant recipients (10,061 with HCC) – UNOS registry2002: 8.3%

      2007: 10.3%

      2012: 13.5%
      Younossi
      • Younossi Z.
      • Stepanova M.
      • Ong J.P.
      • Jacobson I.M.
      • Bugianesi E.
      • Duseja A.
      • et al.
      Nonalcoholic steatohepatitis is the fastest growing cause of hepatocellular carcinoma in liver transplant candidates.
      2002-2017USA170,540 liver transplant registrants (21,121 with HCC) – UNOS registry2002: 2%

      2007: 8%

      2012: 12%

      2017: 18%
      Belli 2018
      • Belli L.S.
      • Perricone G.
      • Adam R.
      • Cortesi P.A.
      • Strazzabosco M.
      • Facchetti R.
      • et al.
      Impact of DAAs on liver transplantation: major effects on the evolution of indications and results. An ELITA study based on the ELTR registry.
      2007-2107Europe60,527 liver transplant recipients (17,130 with HCC) – ELTR registry2007-2010: 1.3%

      2011-2013: 2.5%

      2014-2017: 3.7%
      Flemming
      • Flemming J.A.
      • Kim W.R.
      • Brosgart C.L.
      • Terrault N.A.
      Reduction in liver transplant wait-listing in the era of direct-acting antiviral therapy.
      2003-2015USA47,591 liver transplant registrants in the UNOS registry2003: 0.05

      2005: 0.17

      2007: 0.30

      2009: 0.40

      2011: 0.50

      2013: 0.61

      2015: 0.81
      ELTR, European Liver Transplant Registry; HCC, hepatocellular carcinoma; NAFLD, non-alcoholic fatty liver disease; UNOS, United Network for Organ Sharing.

      NAFLD is projected to become the leading cause of HCC in many countries

      Using dynamic Markov modelling to account for trends in obesity and diabetes, Estes et al. projected that the annual incidence of NAFLD-related HCC in the USA would increase by 137% from 5,160 cases in 2015 to 12,240 cases in 2030.
      • Estes C.
      • Razavi H.
      • Loomba R.
      • Younossi Z.
      • Sanyal A.J.
      Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease.
      Prevalent cases of NAFLD-related HCC were projected to increase in all 8 countries studied (China, Japan, France, Germany, Italy, Spain, the UK and the USA) ranging from a 47% increase in Japan (2,200 cases in 2016 to 3,240 cases in 2030) to a 130% in the USA (10,820 to 24,860).
      • Estes C.
      • 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.
      With HCV-related HCC projected to decline (due to more widespread adoption of direct-acting antivirals and depletion of the baby boomer cohort) and HBV-related HCC also declining (due to widespread adoption of national vaccination programmes and the impact of antiviral therapy), it is almost inevitable that NAFLD-related HCC will be the predominant aetiology of HCC in many countries of the world by the year 2030.

      Differences in clinical presentation between NAFLD-related HCC and other aetiologies of HCC

      Almost all studies report that patients with NAFLD-related HCC are at least 5–10 years older at presentation than patients with HCC related to other liver diseases.
      • Pais R.
      • Fartoux L.
      • Goumard C.
      • Scatton O.
      • Wendum D.
      • Rosmorduc O.
      • et al.
      Temporal trends, clinical patterns and outcomes of NAFLD-related HCC in patients undergoing liver resection over a 20-year period.
      ,
      • Younossi Z.M.
      • Otgonsuren M.
      • Henry L.
      • Venkatesan C.
      • Mishra A.
      • Erario M.
      • et al.
      Association of nonalcoholic fatty liver disease (NAFLD) with hepatocellular carcinoma (HCC) in the United States from 2004 to 2009.
      As described above, metabolic risk factors and presentation at pre-cirrhotic stages are more common in NAFLD-related HCC. NAFLD-related HCC tends to be diagnosed at more advanced stages, which may be attributed partly to failure to diagnose underlying cirrhosis (resulting in a lack of screening) or absence of cirrhosis (hence no indication for screening), but may also be related to biological factors or even worse performance characteristics of current screening tests in patients with NAFLD (e.g. ultrasonography in the setting of obesity). Whether outcomes are worse in NAFLD-related HCC vs. other aetiologies after adjustment for HCC stage, fibrosis stage, age and underlying comorbid conditions remains to be determined.

      Risk factors and predictors of HCC in patients with NAFLD

      Most risk factors or predictors of HCC in patients with NAFLD are similar to those in other liver diseases. However, many risk factors for the development of NAFLD are also risk factors for HCC (Fig. 2), which may help explain why patients with NAFLD (especially non-cirrhotic NAFLD) may be at higher risk of HCC than patients with other liver diseases at a similar stage of fibrosis (with the exception of HBV and HCV, which directly increase HCC risk). Furthermore, some risk factors may be associated more strongly with HCC in patients with NAFLD than in other liver disease aetiologies.
      Some of the best characterised risk factors for NAFLD, considered integral components of the NAFLD “phenotype”, have also been independently and strongly associated with HCC, including obesity, diabetes, insulin resistance and the metabolic syndrome.
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      • et al.
      Diabetes, metabolic comorbidities, and risk of hepatocellular carcinoma: results from two prospective cohort studies.
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      • et al.
      The role of pre-existing diabetes mellitus on hepatocellular carcinoma occurrence and prognosis: a meta-analysis of prospective cohort studies.
      • Stefan N.
      • Haring H.U.
      • Cusi K.
      Non-alcoholic fatty liver disease: causes, diagnosis, cardiometabolic consequences, and treatment strategies.
      In fact, while obesity increases the risk of many cancers, it has a particularly strong association with liver cancer,
      • Bhaskaran K.
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      Body-mass index and risk of 22 specific cancers: a population-based cohort study of 5.24 million UK adults.
      ,
      • Calle E.E.
      • Rodriguez C.
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      NAFLD is a leading cause of HCC in patients without cirrhosis or HBV infection.
      Exposure to fine particulate matter air pollution <2.5 μm in diameter (PM2.5), a complex mixture of chemicals primarily originating from fossil fuel combustion sources,
      International Agency for Research on Cancer (IARC)
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      Studies are still inconclusive as to whether PM2.5 exposure is also associated with NAFLD/NASH development.
      Alcohol consumption is also independently associated with HCC risk in patients with NAFLD,
      • Ascha M.S.
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      • Lopez R.
      • Tamimi T.A.
      • Feldstein A.F.
      • Zein N.N.
      The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis.
      although some studies suggest that risk increases only with relatively heavy alcohol use (e.g. >50 g/day
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      • et al.
      Tobacco, alcohol use and risk of hepatocellular carcinoma and intrahepatic cholangiocarcinoma: the Liver Cancer Pooling Project.
      ), which would “exclude” NAFLD by some diagnostic criteria.
      Medications that have been associated with a decreased risk of HCC include metformin,
      • Singh S.
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      • Singh A.G.
      • Murad M.H.
      • Sanchez W.
      Anti-diabetic medications and the risk of hepatocellular cancer: a systematic review and meta-analysis.
      aspirin
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      • Arvind A.
      • Moninuola O.
      • Philpotts L.
      • Chung R.T.
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      • et al.
      Aspirin use is associated with a reduced incidence of hepatocellular carcinoma: a systematic review and meta-analysis.
      ,
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      Association of aspirin with hepatocellular carcinoma and liver-related mortality.
      and statins.
      • Simon T.G.
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      • Aleman S.
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      • Khalili H.
      • et al.
      Lipophilic statins and risk for hepatocellular carcinoma and death in patients with chronic viral hepatitis: results from a nationwide Swedish population.
      ,
      • Singh S.
      • Singh P.P.
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      • Sanchez W.
      Statins are associated with a reduced risk of hepatocellular cancer: a systematic review and meta-analysis.
      In contrast, the use of sulfonylureas and insulin has been associated with an increased risk of liver cancer.
      • Singh S.
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      Fibrosis stage is one of the strongest liver-related predictors of overall survival and HCC risk in patients with NAFLD.
      • Angulo P.
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      • et al.
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      ,
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      • et al.
      Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up.
      Beyond the distinction between cirrhosis vs. no cirrhosis highlighted earlier, progressive fibrosis stages (F0–F4) are associated with increased HCC risk, whether determined by biopsy/histology or non-invasive fibrosis tests (e.g. elastography or serum fibrosis biomarker panels). Many readily available laboratory tests are well-known “predictors” of HCC, including low platelet count, high aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio and low albumin, while serum alpha-fetoprotein (AFP) could potentially be used as a screening test for early detection of HCC or as a marker of future HCC risk.
      Finally, it is really important to recognise that hepatic lipid accumulation itself, the defining characteristic of NAFLD, can generate pathogenic drivers of carcinogenesis, in particular oxidative DNA damage
      • Loomba R.
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      and lipotoxicity, including cholesterol-related lipotoxicity.
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      Dietary cholesterol promotes steatohepatitis related hepatocellular carcinoma through dysregulated metabolism and calcium signaling.
      These important topics are beyond the scope of this review.

      Genetic polymorphisms associated with HCC and polygenic risk scores

      Genetic polymorphisms in a number of genes have been associated with an increased risk of HCC, including variants in PNPLA3, TM6SF2, GCKR and MBOAT or decreased risk of HCC such as HSD17B13 variants.
      • Yang J.
      • Trepo E.
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      • Cao Q.
      • Moreno C.
      • Letouze E.
      • et al.
      A 17-beta-hydroxysteroid dehydrogenase 13 variant protects from hepatocellular carcinoma development in alcoholic liver disease.
      • Bianco C.
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      • et al.
      Non-invasive stratification of hepatocellular carcinoma risk in non-alcoholic fatty liver using polygenic risk scores.
      • Gellert-Kristensen H.
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      • Stender S.
      Combined effect of PNPLA3, TM6SF2, and HSD17B13 variants on risk of cirrhosis and hepatocellular carcinoma in the general population.
      The fact that these genetic polymorphisms that are strongly associated with the development of steatosis/steatohepatitis are also associated with HCC is consistent with a causal relationship between the two. Genetic variants have recently been combined into “polygenic risk scores”
      • Lewis C.M.
      • Vassos E.
      Polygenic risk scores: from research tools to clinical instruments.
      that capture part of an individual’s susceptibility to HCC.
      • Bianco C.
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      • Pelusi S.
      • Baselli G.
      • Dongiovanni P.
      • Zanoni I.
      • et al.
      Non-invasive stratification of hepatocellular carcinoma risk in non-alcoholic fatty liver using polygenic risk scores.
      ,
      • Gellert-Kristensen H.
      • Richardson T.G.
      • Davey Smith G.
      • Nordestgaard B.G.
      • Tybjaerg-Hansen A.
      • Stender S.
      Combined effect of PNPLA3, TM6SF2, and HSD17B13 variants on risk of cirrhosis and hepatocellular carcinoma in the general population.
      These genetic variants are associated with HCC risk in individuals with multiple underlying liver diseases (e.g. NAFLD, alcohol-associated liver disease, HCV) and it is unclear if the excess risk conferred by these variants is higher in NAFLD than in other liver diseases or if there are other gene-environment interactions. Such genetic variants may provide useful predictive information not captured by other risk factors and identify otherwise unsuspected high-risk individuals (e.g. those without advanced fibrosis). Another attractive property is that they only need to be determined once since they do not change over time (i.e. they capture “lifetime” risk). However, currently known genetic polymorphisms only account for a small proportion of liver cancers and polygenic risk scores have relatively low sensitivity and consequently low area under the receiver operating characteristic curve (AUROC). For example, in a European NAFLD cohort (n = 2,566) the AUROC of a polygenic risk score for HCC prediction was only 0.65, with the “best” single cut-off having a sensitivity of only 43% and a specificity of 79%.
      • Bianco C.
      • Jamialahmadi O.
      • Pelusi S.
      • Baselli G.
      • Dongiovanni P.
      • Zanoni I.
      • et al.
      Non-invasive stratification of hepatocellular carcinoma risk in non-alcoholic fatty liver using polygenic risk scores.
      Combining genetic variants or polygenic risk scores with other traditional risk factors in risk prediction models would be expected to significantly improve their performance characteristics. In addition to high cost, low clinical availability and potential need for genetic counselling, the evidence base for genetic testing in patients of non-European ancestry is weaker The proliferation of direct-to-consumer genetic testing companies (e.g. ancestry.com, 23andMe, Impute.me, Allelica, MyHeritage) that also calculate polygenic risk scores may change how we use genetic variants for HCC prediction in the future.
      • Lewis C.M.
      • Vassos E.
      Polygenic risk scores: from research tools to clinical instruments.
      Identifying patients with pre-cirrhotic NAFLD who have a high enough HCC risk to justify HCC screening is a major clinical challenge.

      The conundrum of HCC screening in NAFLD: how to identify the patients with pre-cirrhotic NAFLD who have high enough HCC risk to justify surveillance?

      There is broad consensus that patients with NAFLD-cirrhosis should undergo HCC screening since they appear to have an average HCC risk of ∼1-1.5% per 100 person-years. It is also clear that a substantial proportion of cases of NAFLD-related HCC will arise in the setting of pre-cirrhotic liver disease. However, overall, patients with pre-cirrhotic NAFLD have a very low risk of HCC that would not justify HCC surveillance. Therefore, the fundamental problem is how to estimate HCC risk in patients with NAFLD with sufficient accuracy in order to identify those with high enough HCC risk to justify HCC surveillance.
      Current EASL guidelines recommend HCC surveillance in patients with NAFLD-cirrhosis and also suggest considering surveillance in patients with F3 fibrosis (including F3 fibrosis diagnosed by elastography).
      European Association for the Study of the Liver
      EASL clinical practice guidelines: management of hepatocellular carcinoma.
      A recently published AGA clinical practice update adopted similar recommendations in favour of screening patients with cirrhosis, as well as patients with NASH and evidence of advanced fibrosis, which can be based on non-invasive markers if 2 different non-invasive tests are concordant for advanced fibrosis or cirrhosis.
      • Loomba R.
      • Lim J.K.
      • Patton H.
      • El-Serag H.B.
      AGA clinical practice update on screening and surveillance for hepatocellular carcinoma in patients with nonalcoholic fatty liver disease: expert review.
      AASLD guidelines recommend HCC surveillance only in the setting of cirrhosis (not advanced fibrosis [F3]).
      • Marrero J.A.
      • Kulik L.M.
      • Sirlin C.B.
      • Zhu A.X.
      • Finn R.S.
      • Abecassis M.M.
      • et al.
      Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the American association for the study of liver diseases.
      Most guidelines currently recommend surveillance with abdominal ultrasonography with/without serum AFP every 6 months.

      Estimating HCC risk for risk stratification and risk-based surveillance: Precision HCC screening

      Current HCC surveillance strategies depend entirely on histological stage, with universal agreement among professional societies that patients with cirrhosis should undergo screening, but a lack of consensus about whether patients with F3 fibrosis (by histology or non-invasive criteria) should undergo screening. However, this strategy is problematic for multiple reasons. First, histological stage is not the only determinant of HCC risk in patients with NAFLD. Multiple risk factors and predictors have been described which could be combined to improve HCC risk prediction. Second, a large proportion of HCCs occur in patients with NAFLD and F0–F2 fibrosis, which would still be missed even if screening was extended to patients with F3 fibrosis. Third, patients with F3 fibrosis based on different non-invasive tests likely have different HCC risk, and all are probably well below the threshold at which HCC surveillance is considered cost-effective in unselected patients (e.g. HCC risk was estimated to be only 0.39 per 1,000 patient-years in patients without a cirrhosis diagnosis who had fibrosis-4 [FIB-4] ≥2.67, which is the cut-off associated with advanced fibrosis or cirrhosis
      • Kanwal F.
      • Kramer J.R.
      • Mapakshi S.
      • Natarajan Y.
      • Chayanupatkul M.
      • Richardson P.A.
      • et al.
      Risk of hepatocellular cancer in patients with non-alcoholic fatty liver disease.
      ). Fourth, there are great differences in HCC risk even among patients with cirrhosis, which are not captured if all patients are aggregated into a single category.
      Combining estimates of fibrosis stage with traditional HCC risk factors and predictors into prediction models (“HCC risk calculators”) may enable identification of high-risk patients and allow for individualized, risk-based surveillance.
      A more accurate approach would be to estimate HCC risk directly (rather than indirectly by extrapolating from fibrosis stage) and use this estimate of HCC risk to make decisions about HCC surveillance. It is important to emphasise that this strategy implies that we already have evidence that a particular screening strategy is effective, i.e. that it reduces HCC-related mortality. Assuming that a screening strategy is effective, then estimates of HCC risk can be used to determine the threshold risk at which it is cost-effective – HCC risk being one of the most important determinants of screening cost-effectiveness. At the heart of precision cancer screening is the notion that an individual’s risk of cancer is positively correlated with the expected benefit that individual will receive from screening.
      • Marcus P.M.
      • Pashayan N.
      • Church T.R.
      • Doria-Rose V.P.
      • Gould M.K.
      • Hubbard R.A.
      • et al.
      Population-based precision cancer screening: a symposium on evidence, Epidemiology, and next steps.
      Beyond simply informing the decision of whether to screen or not, estimates of HCC risk can also be used to recommend an appropriate surveillance strategy according to the patient’s risk. The underlying principle is that the cost effectiveness of a surveillance strategy depends on a patient’s HCC risk, such that strategies that are more effective but also more expensive can be comparatively more cost-effective if they are targeted to high-risk groups. Conversely, strategies that are less effective but also substantially less expensive may be targeted to low-risk groups, especially if they have sufficient sensitivity. This strategy of risk stratification and “precision screening” depends on the availability of multiple screening tests with relatively well-known performance characteristics. Currently, only the standard-of-care HCC screening tests of abdominal ultrasonography and serum AFP are recommended. However, CT and MRI scans appear to be used fairly frequently for screening despite not being recommended.
      • Kim N.J.
      • Rozenberg-Ben-Dror K.
      • Jacob D.A.
      • Rich N.
      • Singal A.G.
      • Aby E.S.
      • et al.
      Provider attitudes toward risk-based hepatocellular carcinoma surveillance in patients with cirrhosis in the U.S.
      ,
      • Kim N.J.
      • Jacob D.A.
      • Ioannou G.N.
      • John B.V.
      • Rogal S.
      • Rozenberg-Ben-Dror K.
      Rates and predictors of undergoing different hepatocellular carcinoma screening tests in patients with cirrhosis.
      Also, multiple biomarker panels (including multiprotein-based and circulating tumour-derived DNA-based [“liquid biopsy”] panels) as well as abbreviated MRI protocols and other imaging-based protocols are being actively investigated as screening tests, which may provide legitimate opportunities for true precision-based screening for HCC in the near future. Studies suggest that providers are receptive to risk-based HCC surveillance strategies that depend on patients’ estimated HCC risk, instead of the current “one-size-fits-all” strategy.
      • Kim N.J.
      • Rozenberg-Ben-Dror K.
      • Jacob D.A.
      • Rich N.
      • Singal A.G.
      • Aby E.S.
      • et al.
      Provider attitudes toward risk-based hepatocellular carcinoma surveillance in patients with cirrhosis in the U.S.
      The concept and even the practice of precision cancer screening is not new.
      • Marcus P.M.
      • Pashayan N.
      • Church T.R.
      • Doria-Rose V.P.
      • Gould M.K.
      • Hubbard R.A.
      • et al.
      Population-based precision cancer screening: a symposium on evidence, Epidemiology, and next steps.
      Screening recommendations for many other cancers are conditional on age, sex, risk factors (e.g. smoking history for lung cancer screening), past screening history (e.g. number and size of adenomatous polyps to recommend interval colonoscopy for colorectal cancer screening) and family history (e.g. colorectal cancer screening). Risk-stratified screening strategies for breast cancer have been examined based on absolute risk calculated using age and polygenic risk scores and incorporating breast density.
      • Shieh Y.
      • Eklund M.
      • Madlensky L.
      • Sawyer S.D.
      • Thompson C.K.
      • Stover Fiscalini A.
      • et al.
      Breast cancer screening in the precision medicine era: risk-based screening in a population-based trial.
      Modelling studies suggest that restriction of prostate cancer screening to men at higher-than-average risk based on polygenic information could reduce overdiagnosis.
      • Pashayan N.
      • Duffy S.W.
      • Neal D.E.
      • Hamdy F.C.
      • Donovan J.L.
      • Martin R.M.
      • et al.
      Implications of polygenic risk-stratified screening for prostate cancer on overdiagnosis.
      The availability of multiple known risk factors and predictors of HCC makes risk estimation of HCC a particularly attractive potential application of precision cancer screening.

      Methods for estimating HCC risk in patients with NAFLD for precision HCC screening: Future directions

      Ideally, different HCC risk factors and predictors in patients with NAFLD would be combined in validated “HCC risk calculators” that accurately estimate HCC risk in individual patients (Fig. 3). Such HCC risk calculators do not currently exist for NAFLD. An HCC risk calculator was developed in 7,068 patients with NAFLD-cirrhosis that combined 7 predictors (age, sex, diabetes, body mass index, platelet count, serum albumin and AST/√ALT ratio) using a Cox proportional hazards model to estimate HCC risk.
      • Ioannou G.N.
      • Green P.
      • Kerr K.F.
      • Berry K.
      Models estimating risk of hepatocellular carcinoma in patients with alcohol or NAFLD-related cirrhosis for risk stratification.
      Decision curves showed higher standardised net benefit of risk-based screening using this prediction model compared to the screen-all approach. This model could potentially be used to stratify patients with NAFLD-cirrhosis to identify those at very high risk who could be targeted for screening outreach interventions or, in the future, more intensive screening with modalities such as abbreviated MRI. However, this model was not developed in patients with pre-cirrhotic NAFLD and therefore does not help identify those patients with pre-cirrhotic HCC who have high enough risk to justify screening.
      Figure thumbnail gr3
      Fig. 3Schematic strategy for HCC risk stratification in NAFLD.
      Multiple predictors and risk factors for HCC, including fibrosis stage, shown in the blue boxes may be combined by “HCC risk calculators” to produce estimates of HCC risk in individual patients with NAFLD. These HCC risk estimates can be used to determine whether a patient should undergo HCC screening (especially for patients with pre-cirrhotic NAFLD). Additionally, HCC risk estimates can be used in the future to determine optimal screening strategies (such as abbreviated MRI protocols for high-risk patients). HCC, hepatocellular carcinoma; NAFLD, non-alcoholic fatty liver disease.
      Future HCC risk calculators in NAFLD could explore multiple directions. First, it is likely that by combining elastography-derived liver stiffness, together with simple scoring systems such as FIB-4, other readily available blood tests that correlate with HCC risk (e.g. serum albumin, alkaline phosphatase and AFP, which can be a marker of future HCC risk as well as a screening test), medications associated with HCC risk, and additional established risk factors (such as sex, diabetes, obesity, race/ethnicity, alcohol and tobacco use), HCC risk calculators could result in more accurate predictions.
      Second, using machine learning approaches to simultaneously model a large number of these predictors rather than traditional regression techniques may result in some modest improvement in prediction accuracy and be more robust to missing values in predictors, although overfitting can be a problem and difficulties with interpretability and explainability of machine learning models may limit their adoption.
      Third, HCC risk calculators should be developed specifically in patients with pre-cirrhotic NAFLD, who represent the most challenging group for HCC screening. Such tools could help us determine who, among the millions of patients with NAFLD, to focus our screening efforts on.
      Fourth, incorporating genetic polymorphisms together with the aforementioned predictors into HCC risk calculators would likely improve prediction accuracy, but testing for such polymorphisms would need to become cheaper and more readily available in clinical point-of-care settings.
      Finally, it is important to point out that although estimating HCC risk is the central concept of precision screening, it is a necessary but not sufficient step to establish risk-based HCC surveillance strategies. Additional studies, including both randomised controlled trials and simulation/modelling studies are needed to determine particular risk thresholds at which screening should be offered or at which different screening strategies are more cost-effective, minimise harms and maximise benefits to the patient.

      Conclusion

      With NAFLD emerging as the most common aetiology of HCC, it is critical to optimise strategies for HCC screening in NAFLD. Estimating HCC risk in patients with NAFLD, with or without cirrhosis, using NAFLD-specific HCC risk factors and predictors will allow us to risk stratify patients and develop rational, cost-effective strategies for different HCC risk categories.

      Abbreviations

      AFP, alpha-fetoprotein; ALT, alanine aminotransferase; AST, aspartate aminotransferase; AUROC, area under the receiver operating characteristic curve; ELTR, European Liver Transplant Registry; FIB-4, fibrosis-4; HCC, hepatocellular carcinoma; NAFL, non-alcoholic fatty liver; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; UNOS, United Network for Organ Sharing; VA, Veterans Affairs.

      Financial support

      The author received no financial support to produce this manuscript.

      Authors’ contributions

      George Ioannou: Study concept, writing original draft, editing in response to reviewers’ comments, literature review and synthesis of data.

      Conflict of interest

      The author declares no conflicts of interest that pertain to this work.
      Please refer to the accompanying ICMJE disclosure form for further details.

      Supplementary data

      The following are the supplementary data to this article:

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