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Hepatocellular carcinoma in non-alcoholic fatty liver disease: An emerging menace

Open AccessPublished:February 13, 2012DOI:https://doi.org/10.1016/j.jhep.2011.10.027

      Summary

      Hepatocellular carcinoma (HCC) is a common cancer worldwide that primarily develops in cirrhosis resulting from chronic infection by hepatitis B virus and hepatitis C virus, alcoholic injury, and to a lesser extent from genetically determined disorders such as hemochromatosis. HCC has recently been linked to non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of obesity and related metabolic disorders such as diabetes. This association is alarming due to the globally high prevalence of these conditions and may contribute to the rising incidence of HCC witnessed in many industrialized countries. There is also evidence that NAFLD acts synergistically with other risk factors of HCC such as chronic hepatitis C and alcoholic liver injury. Moreover, HCC may complicate non-cirrhotic NAFLD with mild or absent fibrosis, greatly expanding the population potentially at higher risk. Major systemic and liver-specific molecular mechanisms involved include insulin resistance and hyperinsulinemia, increased TNF signaling pathways, and alterations in cellular lipid metabolism. These provide new targets for prevention, early recognition, and effective treatment of HCC associated with NAFLD. Indeed, both metformin and PPAR gamma agonists have been associated with lower risk and improved prognosis of HCC. This review summarizes current evidence as it pertains to the epidemiology, pathogenesis, and prevention of NAFLD-associated HCC.

      Abbreviations:

      HCC (hepatocellular carcinoma), NAFLD (non-alcoholic fatty liver disease)

      Keywords

      Introduction

      Liver cancer is the fifth most frequently diagnosed cancer worldwide and the third leading cause of cancer death. In 2008, an estimated 748,300 new liver cancer cases and 695,900 liver cancer deaths occurred, reflecting the poor prognosis of this disease [
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      HCC is increasingly common in the United States, with an age-adjusted incidence rising from 1.5 to 4.9 per 100,000 individuals in the past 30 years [
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      ]. This worrisome trend has been primarily attributed to the high prevalence of chronic hepatitis C in this population and it is predicted to plateau by 2020 [
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      Epidemiology of HCC associated with NAFLD

      HCC in obesity and diabetes

      Several large-scale epidemiological studies have associated the increasingly prevalent overweight and obesity with a higher risk of HCC [
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      ]. In a cohort of 900,000 American adults, the risk of dying from liver cancer was 4.5 times higher in men with a body mass index of 35 kg/m2 or above compared to the reference group with a normal body mass index (18.5 to 24.9 kg/m2) [
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      Type 2 diabetes is an increasingly common metabolic disorder strongly linked to obesity and characterized by hyperglycemia, insulin resistance, and hyperinsulinemia. It has been associated with increased risk of several cancers [
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      ]. A population-based study from 14% of the United States population found that diabetes conferred a three-fold risk of HCC [
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      ]. The association between diabetes and HCC has been further demonstrated by studies published from different geographical locations [
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      Risk factors for hepatocellular carcinoma: synergism of alcohol with viral hepatitis and diabetes mellitus.
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      Increased risk of hepatocellular carcinoma among patients with hepatitis C cirrhosis and diabetes mellitus.
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      • Wang C.S.
      • Yao W.J.
      • Chang T.T.
      • Wang S.T.
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      • Liao K.F.
      • Muo C.H.
      • Lin C.C.
      • Sung F.C.
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      ] and ascertained by repeated meta-analyses [
      • El-Serag H.B.
      • Hampel H.
      • Javadi F.
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      ,
      • Wang P.
      • Kang D.
      • Cao W.
      • Wang Y.
      • Liu Z.
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      ]. The findings indicate that diabetes in most individuals may exist for long time before the diagnosis of HCC and there are synergistic interactions between diabetes and other HCC risk factors [
      • Chen C.L.
      • Yang H.I.
      • Yang W.S.
      • Liu C.J.
      • Chen P.J.
      • You S.L.
      • et al.
      Metabolic factors and risk of hepatocellular carcinoma by chronic hepatitis B/C infection: a follow-up study in Taiwan.
      ,
      • 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.
      ,
      • Veldt B.J.
      • Chen W.
      • Heathcote E.J.
      • Wedemeyer H.
      • Reichen J.
      • Hofmann W.P.
      • et al.
      Increased risk of hepatocellular carcinoma among patients with hepatitis C cirrhosis and diabetes mellitus.
      ,
      • Wang C.S.
      • Yao W.J.
      • Chang T.T.
      • Wang S.T.
      • Chou P.
      The impact of type 2 diabetes on the development of hepatocellular carcinoma in different viral hepatitis statuses.
      ,
      • 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.
      ].
      HCC has been linked to NAFLD, the major hepatic manifestation of obesity and associated metabolic conditions [
      • Abdelmalek M.F.
      • Diehl A.M.
      Nonalcoholic fatty liver disease as a complication of insulin resistance.
      ]. The epidemiology of NAFLD mirrors recent changes in the prevalence of obesity and diabetes. NAFLD has become the most common liver disorder in the United States and other industrialized countries, affecting up to 30% of the general adult population and 90% of those with morbid obesity (body mass index greater than or equal to 40 kg/m2) [
      • Browning J.D.
      • Szczepaniak L.S.
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      • Horton J.D.
      • Cohen J.C.
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      Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity.
      ,
      • Lazo M.
      • Clark J.M.
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      ]. The overlap between the prevalence of NAFLD and diabetes is equally substantial. The rate of biopsy-proven NAFLD among diabetics may reach 74% [
      • Byrne C.D.
      • Olufadi R.
      • Bruce K.D.
      • Cagampang F.R.
      • Ahmed M.H.
      Metabolic disturbances in non-alcoholic fatty liver disease.
      ,
      • Williams C.D.
      • Stengel J.
      • Asike M.I.
      • Torres D.M.
      • Shaw J.
      • Contreras M.
      • et al.
      Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study.
      ], and NAFLD is commonly associated with insulin resistance and hyperinsulinemia even in the non-obese [
      • Marchesini G.
      • Brizi M.
      • Morselli-Labate A.M.
      • Bianchi G.
      • Bugianesi E.
      • McCullough A.J.
      • et al.
      Association of nonalcoholic fatty liver disease with insulin resistance.
      ].

      HCC in advanced NAFLD

      While most individuals with NAFLD have isolated steatosis, approximately 20% of all cases present as steatohepatitis, which is microscopically defined and consists of steatosis and a specific form of hepatocellular injury, parenchymal and portal inflammation, and variable degrees of fibrosis with the potential to progress to cirrhosis [
      • Rafiq N.
      • Bai C.
      • Fang Y.
      • Srishord M.
      • McCullough A.
      • Gramlich T.
      • et al.
      Long-term follow-up of patients with nonalcoholic fatty liver.
      ,
      • Ekstedt M.
      • Franzen L.E.
      • Mathiesen U.L.
      • Thorelius L.
      • Holmqvist M.
      • Bodemar G.
      • et al.
      Long-term follow-up of patients with NAFLD and elevated liver enzymes.
      ]. The first report on HCC complicating NAFLD with cirrhosis was published in 1990 [
      • Powell E.E.
      • Cooksley W.G.
      • Hanson R.
      • Searle J.
      • Halliday J.W.
      • Powell L.W.
      The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years.
      ]. Subsequent studies of natural history in NAFLD indicated that while steatosis has an almost negligible effect on liver-related mortality [
      • Rafiq N.
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      • Fang Y.
      • Srishord M.
      • McCullough A.
      • Gramlich T.
      • et al.
      Long-term follow-up of patients with nonalcoholic fatty liver.
      ,
      • Ekstedt M.
      • Franzen L.E.
      • Mathiesen U.L.
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      • Holmqvist M.
      • Bodemar G.
      • et al.
      Long-term follow-up of patients with NAFLD and elevated liver enzymes.
      ], steatohepatitis is a risk for the development of cirrhosis and HCC [
      • 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 exact prevalence of HCC in cirrhotic NAFLD remains unknown. Two groups from Sweden described three and five cases of HCC in cohorts of 129 and 256 subjects with NAFLD followed for 13.7 and 21 years, respectively [
      • Ekstedt M.
      • Franzen L.E.
      • Mathiesen U.L.
      • Thorelius L.
      • Holmqvist M.
      • Bodemar G.
      • et al.
      Long-term follow-up of patients with NAFLD and elevated liver enzymes.
      ,
      • Soderberg C.
      • Stal P.
      • Askling J.
      • Glaumann H.
      • Lindberg G.
      • Marmur J.
      • et al.
      Decreased survival of subjects with elevated liver function tests during a 28-year follow-up.
      ]. In the past 10 years, approximately 300 cases of NAFLD-associated HCC have been reported [
      • Takuma Y.
      • Nouso K.
      Nonalcoholic steatohepatitis-associated hepatocellular carcinoma: our case series and literature review.
      ,
      • Ertle J.
      • Dechene A.
      • Sowa J.P.
      • Penndorf V.
      • Herzer K.
      • Kaiser G.
      • et al.
      Non-alcoholic fatty liver disease progresses to hepatocellular carcinoma in the absence of apparent cirrhosis.
      ,
      • Yasui K.
      • Hashimoto E.
      • Komorizono Y.
      • Koike K.
      • Arii S.
      • Imai Y.
      • et al.
      Characteristics of patients with nonalcoholic steatohepatitis who develop hepatocellular carcinoma.
      ]. The majority of affected patients have been men of a median age over 70 years with diabetes and hypertension as common co-morbidities [
      • Takuma Y.
      • Nouso K.
      Nonalcoholic steatohepatitis-associated hepatocellular carcinoma: our case series and literature review.
      ,
      • Ertle J.
      • Dechene A.
      • Sowa J.P.
      • Penndorf V.
      • Herzer K.
      • Kaiser G.
      • et al.
      Non-alcoholic fatty liver disease progresses to hepatocellular carcinoma in the absence of apparent cirrhosis.
      ,
      • Yasui K.
      • Hashimoto E.
      • Komorizono Y.
      • Koike K.
      • Arii S.
      • Imai Y.
      • et al.
      Characteristics of patients with nonalcoholic steatohepatitis who develop hepatocellular carcinoma.
      ].
      Reports indicate that the risk of HCC due to NAFLD is less than that of chronic hepatitis C. In a ten-year prospective study, ten out of 149 American patients with NAFLD-associated cirrhosis developed HCC compared to 25 out of 147 patients with hepatitis C virus-associated cirrhosis [
      • Sanyal A.J.
      • Banas C.
      • Sargeant C.
      • Luketic V.A.
      • Sterling R.K.
      • Stravitz R.T.
      • et al.
      Similarities and differences in outcomes of cirrhosis due to nonalcoholic steatohepatitis and hepatitis C.
      ]. Another study from the United States found a 2.6% yearly cumulative incidence of HCC in patients with NAFLD-associated cirrhosis compared with a 4.0% incidence in those with hepatitis C virus-associated cirrhosis over a median follow-up of 3.2 years [
      • Ascha M.S.
      • Hanouneh I.A.
      • Lopez R.
      • Tamimi T.A.
      • Feldstein A.F.
      • Zein N.N.
      The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis.
      ]. A prospective five-year study in Japan for the development of HCC found a rate of 11.3% among 68 patients with NAFLD-associated cirrhosis compared to 30.5% among 69 patients with hepatitis C virus-associated cirrhosis [
      • Yatsuji S.
      • Hashimoto E.
      • Tobari M.
      • Taniai M.
      • Tokushige K.
      • Shiratori K.
      Clinical features and outcomes of cirrhosis due to non-alcoholic steatohepatitis compared with cirrhosis caused by chronic hepatitis C.
      ].
      Nonetheless, based on its prevalence and natural history, NAFLD in the United States and other developed countries may become the primary source of HCC and offset the impact of successful measures on reducing the incidence of hepatitis C virus-related liver cancer [
      • El-Serag H.B.
      • Rudolph K.L.
      Hepatocellular carcinoma: epidemiology and molecular carcinogenesis.
      ]. This concern was substantiated by a recent study from Germany analyzing 162 cases of HCC that identified steatohepatitis as the underlying etiology in 24% of patients, surpassing chronic hepatitis C (23.3%), chronic hepatitis B (19.3%), and alcoholic liver disease (12.7%) [
      • Ertle J.
      • Dechene A.
      • Sowa J.P.
      • Penndorf V.
      • Herzer K.
      • Kaiser G.
      • et al.
      Non-alcoholic fatty liver disease progresses to hepatocellular carcinoma in the absence of apparent cirrhosis.
      ].

      HCC in cryptogenic cirrhosis

      Current figures probably underestimate the role of NAFLD in HCC development. NAFLD and related metabolic factors may act synergistically with other conditions to promote hepatocarcinogenesis. This has been suggested to occur in cirrhosis associated with both chronic hepatitis C infection and alcoholic liver disease [
      • Ascha M.S.
      • Hanouneh I.A.
      • Lopez R.
      • Tamimi T.A.
      • Feldstein A.F.
      • Zein N.N.
      The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis.
      ,
      • Pekow J.R.
      • Bhan A.K.
      • Zheng H.
      • Chung R.T.
      Hepatic steatosis is associated with increased frequency of hepatocellular carcinoma in patients with hepatitis C-related cirrhosis.
      ]. In addition, NAFLD may remain unrecognized as the etiology in cases of HCC arising in cryptogenic cirrhosis, a condition for which no underlying etiology has been clinically identified [
      • Caldwell S.H.
      • Oelsner D.H.
      • Iezzoni J.C.
      • Hespenheide E.E.
      • Battle E.H.
      • Driscoll C.J.
      Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease.
      ]. It is estimated that 30% to 40% of all HCCs in industrialized countries occur in patients with cryptogenic cirrhosis [
      • El-Serag H.B.
      • Rudolph K.L.
      Hepatocellular carcinoma: epidemiology and molecular carcinogenesis.
      ]. Studies suggest that the majority of these cases are associated with either prior NAFLD or other features of the metabolic syndrome [
      • Nair S.
      • Mason A.
      • Eason J.
      • Loss G.
      • Perrillo R.P.
      Is obesity an independent risk factor for hepatocellular carcinoma in cirrhosis?.
      ,
      • Regimbeau J.M.
      • Colombat M.
      • Mognol P.
      • Durand F.
      • Abdalla E.
      • Degott C.
      • et al.
      Obesity and diabetes as a risk factor for hepatocellular carcinoma.
      ]. Sequential biopsy studies have, in fact, documented that active steatohepatitis may eventually result in bland cirrhosis. Since key elements of steatohepatitis such as hepatocellular lipid accumulation, ballooning injury and necroinflammation are often absent in cirrhosis, the diagnosis of NAFLD may be missed unless detailed medical history reveals its prior existence [
      • Poonawala A.
      • Nair S.P.
      • Thuluvath P.J.
      Prevalence of obesity and diabetes in patients with cryptogenic cirrhosis: a case-control study.
      ]. Excluding a role of alcohol in these and other forms of chronic liver disease remains challenging.

      HCC in non-cirrhotic NAFLD

      HCC has been documented to occur in livers without underlying cirrhosis or even liver disease. In fact, up to 54% of all cases of HCC develop in non-cirrhotic livers according to various etiologies and geographic areas [
      • Nzeako U.C.
      • Goodman Z.D.
      • Ishak K.G.
      Hepatocellular carcinoma in cirrhotic and noncirrhotic livers. A clinico-histopathologic study of 804 North American patients.
      ,
      • Brancatelli G.
      • Federle M.P.
      • Grazioli L.
      • Carr B.I.
      Hepatocellular carcinoma in noncirrhotic liver: CT, clinical, and pathologic findings in 39 U.S. residents.
      ]. An uncertain fraction of these likely arise through transformation of hepatic adenomas. A literature review of over 1600 adenomas has shown that up to 4.2% of hepatocellular adenomas harbor HCC at the time of resection [
      • Stoot J.H.
      • Coelen R.J.
      • De Jong M.C.
      • Dejong C.H.
      Malignant transformation of hepatocellular adenomas into hepatocellular carcinomas: a systematic review including more than 1600 adenoma cases.
      ]. Most reported cases of non-cirrhotic HCC occur in chronic hepatitis B attributed to the direct oncogenic properties of hepatitis B virus through genomic integration and the transactivation effects of HBx protein. In Sub-Saharan Africa, dietary exposure to aflatoxin may synergize with the carcinogenic effects of chronic hepatitis B infection [
      • Hussain S.P.
      • Schwank J.
      • Staib F.
      • Wang X.W.
      • Harris C.C.
      TP53 mutations and hepatocellular carcinoma: insights into the etiology and pathogenesis of liver cancer.
      ]. HCC may also arise without established cirrhosis in 14% to 19% of patients with chronic hepatitis C infection and alcoholic liver disease, although the mechanisms of carcinogenesis remain unclear [
      • Nzeako U.C.
      • Goodman Z.D.
      • Ishak K.G.
      Hepatocellular carcinoma in cirrhotic and noncirrhotic livers. A clinico-histopathologic study of 804 North American patients.
      ,
      • Yeh M.M.
      • Daniel H.D.
      • Torbenson M.
      Hepatitis C-associated hepatocellular carcinomas in non-cirrhotic livers.
      ].
      A rapidly growing literature indicates that NAFLD contributes to non-cirrhotic HCC. Since 2004, at least 116 cases of HCC have been reported in histologically-confirmed NAFLD without cirrhosis (Table 1). This number represents more than one-third of all NAFLD-associated HCC cases reported, suggesting either that non-cirrhotic HCC may occur more commonly in NAFLD than in liver diseases of other etiologies, or a reporting bias. Indeed, some of these reports include cases with F3 (bridging) fibrosis that may represent sampling error or incomplete cirrhosis. Nonetheless, a retrospective French study showed that the etiology of liver disease in 80 cases of HCC remained unknown in 50 (62%) without portal fibrosis in the background livers as opposed to only 15 out of 250 (6%) in which extensive fibrosis or cirrhosis was present [
      • Bralet M.P.
      • Regimbeau J.M.
      • Pineau P.
      • Dubois S.
      • Loas G.
      • Degos F.
      • et al.
      Hepatocellular carcinoma occurring in nonfibrotic liver: epidemiologic and histopathologic analysis of 80 French cases.
      ]. Since most cases without advanced fibrosis had steatosis (52%) and portal inflammation (79%), the majority of patients with HCC of unknown etiology in this series possibly had NAFLD. More recently, the same group analyzed a subsequent cohort of HCC patients (30 men and one woman) with the metabolic syndrome as the only risk factor for liver disease and found mild or no fibrosis in most cases compared to those harboring HCC associated with an overt cause of liver disease (65% vs. 26%, p <0.0001) [
      • 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.
      ]. Of note, five of the hepatocellular carcinomas in this series definitely arose from pre-existing inflammatory (telangiectatic) adenoma [
      • 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.
      ].
      Table 1Case reports and case series of HCC diagnosed in non-cirrhotic NAFLD.
      M, male; F, female; S, solitary; M, multifocal; n.r., not reported.
      • Bencheqroun R.
      • Duvoux C.
      • Luciani A.
      • Zafrani E.S.
      • Dhumeaux D.
      Hepatocellular carcinoma without cirrhosis in a patient with nonalcoholic steatohepatitis.
      ,
      • Bullock R.E.
      • Zaitoun A.M.
      • Aithal G.P.
      • Ryder S.D.
      • Beckingham I.J.
      • Lobo D.N.
      Association of non-alcoholic steatohepatitis without significant fibrosis with hepatocellular carcinoma.
      ,
      • Gonzalez L.
      • Blanc J.F.
      • Sa Cunha A.
      • Rullier A.
      • Saric J.
      • Le Bail B.
      • et al.
      Obesity as a risk factor for hepatocellular carcinoma in a noncirrhotic patient.
      ,
      • Cuadrado A.
      • Orive A.
      • Garcia-Suarez C.
      • Dominguez A.
      • Fernandez-Escalante J.C.
      • Crespo J.
      • et al.
      Non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma.
      ,
      • Hai S.
      • Kubo S.
      • Shuto T.
      • Tanaka H.
      • Takemura S.
      • Yamamoto T.
      • et al.
      Hepatocellular carcinoma arising from nonalcoholic steatohepatitis: report of two cases.
      ,
      • Ichikawa T.
      • Yanagi K.
      • Motoyoshi Y.
      • Hamasaki K.
      • Nakao K.
      • Toriyama K.
      • et al.
      Two cases of non-alcoholic steatohepatitis with development of hepatocellular carcinoma without cirrhosis.
      ,
      • Hashizume H.
      • Sato K.
      • Takagi H.
      • Hirokawa T.
      • Kojima A.
      • Sohara N.
      • et al.
      Primary liver cancers with nonalcoholic steatohepatitis.
      ,
      • Chagas A.L.
      • Kikuchi L.O.
      • Oliveira C.P.
      • Vezozzo D.C.
      • Mello E.S.
      • Oliveira A.C.
      • et al.
      Does hepatocellular carcinoma in non-alcoholic steatohepatitis exist in cirrhotic and non-cirrhotic patients?.
      ,
      • Ikura Y.
      • Mita E.
      • Nakamori S.
      Hepatocellular carcinomas can develop in simple fatty livers in the setting of oxidative stress.
      One case was a combination of HCC/cholangiocarcinoma.
      ∗∗Distribution of four cases with steatosis <5% among non-cirrhotic and cirrhotic HCC could not be determined from the published data and only 16 out of 20 reported cases with F0–F2 fibrosis are included here.
      ∗∗∗One out of 30 patients in the entire cohort was a female, but gender-specific data for the stage of fibrosis were not reported.
      The largest group of NAFLD-associated non-cirrhotic HCC to date was recently described in a cross-sectional study from Japan. The authors analyzed 87 cases of HCC occurring in patients with histologically confirmed steatohepatitis and found no established cirrhosis in 43 cases [
      • Yasui K.
      • Hashimoto E.
      • Komorizono Y.
      • Koike K.
      • Arii S.
      • Imai Y.
      • et al.
      Characteristics of patients with nonalcoholic steatohepatitis who develop hepatocellular carcinoma.
      ]. Men developed HCC at a less advanced stage of fibrosis than women, and the prevalence of cirrhosis was significantly lower in men than in women (39% vs. 70%, p = 0.008) [
      • Yasui K.
      • Hashimoto E.
      • Komorizono Y.
      • Koike K.
      • Arii S.
      • Imai Y.
      • et al.
      Characteristics of patients with nonalcoholic steatohepatitis who develop hepatocellular carcinoma.
      ].
      HCC has also been reported to develop in patients who have features of the metabolic syndrome and histological evidence of NAFLD, but have neither steatohepatitis nor fibrosis [
      • Guzman G.
      • Brunt E.M.
      • Petrovic L.M.
      • Chejfec G.
      • Layden T.J.
      • Cotler S.J.
      Does nonalcoholic fatty liver disease predispose patients to hepatocellular carcinoma in the absence of cirrhosis?.
      ]. This observation is particularly alarming as it indicates that hepatic steatosis alone may be complicated by the development of HCC. Relationships between steatosis, steatohepatitis, cirrhosis, and HCC are not necessarily linear and this pattern possibly applies to HCC arising in non-alcoholic, non-cirrhotic fatty liver disease (Fig. 1). Recent analysis of a US health care claim database covering 18 million lives yearly from 2002 to 2008 found that NAFLD was the leading condition with no other risk factor claimed for 38.2% of patients with HCC and cirrhosis was reported in only 46% of these cases [
      • Sanyal A.
      • Poklepovic A.
      • Moyneur E.
      • Barghout V.
      Population-based risk factors and resource utilization for HCC: US perspective.
      ]. Accordingly, the number of individuals with NAFLD potentially at risk for developing HCC may be much larger than previously thought. This presents a compelling need to understand the pathogenesis and natural history of malignant transformation in NAFLD and review potential strategies for HCC prevention and surveillance in the affected population.
      Figure thumbnail gr1
      Fig. 1Development of HCC in NAFLD. NAFLD is closely linked to obesity and related adverse health effects such as the metabolic syndrome and type 2 diabetes. Key components of the pathogenesis known to promote this process are listed. NAFLD may primarily manifest as steatosis, steatohepatitis, or (cryptogenic) cirrhosis due to obesity-associated metabolic derangements or it may progress through these stages over several decades. HCC may complicate any stage of NAFLD with potential differences in the pathobiology of non-fibrotic and non-cirrhotic hepatocarcinogenesis to be fully determined. Arrows illustrate relative probabilities of disease transitions based on current evidence.

      Pathogenesis of HCC associated with NAFLD

      General molecular mechanisms

      Similar to other cancers, development of HCC in cirrhosis is a stepwise process following a dysplasia–carcinoma sequence that may take several decades to evolve in chronic liver disease [
      • Thorgeirsson S.S.
      • Grisham J.W.
      Molecular pathogenesis of human hepatocellular carcinoma.
      ,
      • Farazi P.A.
      • DePinho R.A.
      Hepatocellular carcinoma pathogenesis: from genes to environment.
      ]. In this setting, sustained cycles of hepatocellular destruction and compensatory proliferation in response to metabolic and oxidative toxicity, inflammation, innate and adaptive immunity, and fibrosis create an environment conducive to carcinogenesis. Genomic aberrations accumulate as chronic hepatitis evolves through cirrhosis into HCC. Initially, epigenetic mechanisms may lead to aberrant hypo- or hypermethylation of DNA on CpG groups in the promoter regions and other chromosomal segments in addition to inducing cis- and transactivation and chromatin acetylation [
      • Lee S.
      • Lee H.J.
      • Kim J.H.
      • Lee H.S.
      • Jang J.J.
      • Kang G.H.
      Aberrant CpG island hypermethylation along multistep hepatocarcinogenesis.
      ,
      • Kondo Y.
      • Kanai Y.
      • Sakamoto M.
      • Mizokami M.
      • Ueda R.
      • Hirohashi S.
      Genetic instability and aberrant DNA methylation in chronic hepatitis and cirrhosis-A comprehensive study of loss of heterozygosity and microsatellite instability at 39 loci and DNA hypermethylation on 8 CpG islands in microdissected specimens from patients with hepatocellular carcinoma.
      ]. Subsequently, these epigenetic changes lead to structural genomic lesions such as point mutations, multiple allelic deletions, chromosomal gains, telomere erosion, and telomerase reactivation [
      • Thorgeirsson S.S.
      • Grisham J.W.
      Molecular pathogenesis of human hepatocellular carcinoma.
      ]. A critical step in these processes is the selection of monoclonal populations of pre-malignant hepatocytes or progenitor cells from which HCC will emerge [
      • Paradis V.
      • Laurendeau I.
      • Vidaud M.
      • Bedossa P.
      Clonal analysis of macronodules in cirrhosis.
      ].
      The extraordinary heterogeneity of genomic aberrations in HCC suggests that multiple regulatory pathways may be compromised [
      • Breuhahn K.
      • Longerich T.
      • Schirmacher P.
      Dysregulation of growth factor signaling in human hepatocellular carcinoma.
      ]. Indeed, hepatocarcinogenesis has been associated with reactivation of the developmental pathways (e.g., Wnt/β-catenin, hedgehog, and c-Met/hepatocyte growth factor), upregulation of multiple growth factors (e.g., platelet-derived growth factor, vascular endothelial growth factor, fibroblast growth factor, and transforming growth factor), and stimulation of proliferative cell signaling cascades (e.g., mitogen-activated protein kinases, the Janus kinase/signal transducers and activators of transcription [STAT] kinase system, and the phosphoinositide-3-kinase/Akt pathway) [
      • Thorgeirsson S.S.
      • Grisham J.W.
      Molecular pathogenesis of human hepatocellular carcinoma.
      ,
      • Farazi P.A.
      • DePinho R.A.
      Hepatocellular carcinoma pathogenesis: from genes to environment.
      ]. The process may be augmented through inhibition of cell cycle regulators (e.g., the retinoblastoma-1 protein) and disruption of pivotal tumor suppressors (e.g., the phosphatase and tensin homolog and the pleiotropic p53) that would normally antagonize uncontrolled and erroneous cell proliferation [
      • Thorgeirsson S.S.
      • Grisham J.W.
      Molecular pathogenesis of human hepatocellular carcinoma.
      ,
      • Farazi P.A.
      • DePinho R.A.
      Hepatocellular carcinoma pathogenesis: from genes to environment.
      ].
      Complexity of hepatocarcinogenesis results in functional redundancy and robustness that may account for the poor overall prognosis [
      • Kitano H.
      Cancer as a robust system: implications for anticancer therapy.
      ]. Moreover, heterogeneous phenotypes of malignant hepatocytes may reflect disease mechanisms that correspond to different etiologies and exhibit different growth characteristics and clinical course [
      • Farazi P.A.
      • DePinho R.A.
      Hepatocellular carcinoma pathogenesis: from genes to environment.
      ]. Specific patterns of molecular alterations defined by genomic, microRNA, and protein-based analyses may be linked to the emergence of HCC in liver diseases of various origins [
      • Thorgeirsson S.S.
      • Grisham J.W.
      Molecular pathogenesis of human hepatocellular carcinoma.
      ,
      • Breuhahn K.
      • Gores G.
      • Schirmacher P.
      Strategies for hepatocellular carcinoma therapy and diagnostics: lessons learned from high throughput and profiling approaches.
      ]. Accordingly, the molecular signature of HCC developing in NAFLD may allow identification of specific targets for the prevention, recognition, and treatment of HCC associated with obesity and diabetes.

      Mechanisms of hepatocarcinogenesis in NAFLD

      Several mechanisms may account for a tumor-promoting environment in obesity and diabetes, distinguishing the pathogenesis of HCC linked to NAFLD from that of viral and other etiologies [
      • Stickel F.
      • Hellerbrand C.
      Non-alcoholic fatty liver disease as a risk factor for hepatocellular carcinoma: mechanisms and implications.
      ,
      • Starley B.Q.
      • Calcagno C.J.
      • Harrison S.A.
      Nonalcoholic fatty liver disease and hepatocellular carcinoma: a weighty connection.
      ]. Obesity is characterized by a low-grade, chronic inflammatory response implicated in increased cancer risk in general [
      • Shoelson S.E.
      • Herrero L.
      • Naaz A.
      Obesity, inflammation, and insulin resistance.
      ,
      • Hotamisligil G.S.
      Inflammation and metabolic disorders.
      ]. Adipose tissue expansion promotes the release of pro-inflammatory cytokines providing a key element to this process [
      • Hotamisligil G.S.
      Inflammation and metabolic disorders.
      ,
      • Unger R.H.
      • Clark G.O.
      • Scherer P.E.
      • Orci L.
      Lipid homeostasis, lipotoxicity and the metabolic syndrome.
      ]. Tumor necrosis factor (TNF) is a major adipose-derived cytokine and a potent activator of pro-oncogenic pathways involving NF-κB, JNK, the mammalian target of rapamycin (mTOR), and extracellular signal-regulated kinases [
      • Stickel F.
      • Hellerbrand C.
      Non-alcoholic fatty liver disease as a risk factor for hepatocellular carcinoma: mechanisms and implications.
      ,
      • Marra F.
      • Bertolani C.
      Adipokines in liver diseases.
      ]. In addition, interleukin-6 (IL-6) has a key role in the obesity-associated inflammatory response and exerts cell proliferative and anti-apoptotic effects through activation of its major transcriptional target, STAT3 [
      • Stickel F.
      • Hellerbrand C.
      Non-alcoholic fatty liver disease as a risk factor for hepatocellular carcinoma: mechanisms and implications.
      ,
      • Marra F.
      • Bertolani C.
      Adipokines in liver diseases.
      ]. The role of adipose-derived TNF and IL-6 in the development of HCC has recently been demonstrated in an experimental model where either dietary or genetic obesity strongly promoted malignant liver tumor growth induced by diethyl nitrosamine in mice if production of these cytokines and their key oncogenic signaling pathways were intact [
      • Park E.J.
      • Lee J.H.
      • Yu G.Y.
      • He G.
      • Ali S.R.
      • Holzer R.G.
      • et al.
      Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression.
      ].
      Adipose tissue expansion promotes an adverse secretory profile of adipose-derived hormones or adipokines. Adiponectin, an abundant adipokine with potent anti-inflammatory effects, is expressed at reduced levels in obesity, diabetes, and NAFLD [
      • Kaser S.
      • Moschen A.
      • Cayon A.
      • Kaser A.
      • Crespo J.
      • Pons-Romero F.
      • et al.
      Adiponectin and its receptors in non-alcoholic steatohepatitis.
      ,
      • Kadowaki T.
      • Yamauchi T.
      • Kubota N.
      • Hara K.
      • Ueki K.
      • Tobe K.
      Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome.
      ]. Low adiponectin levels may be insufficient to suppress endotoxin-mediated inflammatory signaling in Kupffer cells and other macrophages [
      • Thakur V.
      • Pritchard M.T.
      • McMullen M.R.
      • Nagy L.E.
      Adiponectin normalizes LPS-stimulated TNF-alpha production by rat Kupffer cells after chronic ethanol feeding.
      ], to activate adenosine monophosphate kinase, an inhibitor of the mTOR oncogenic pathway [
      • Awazawa M.
      • Ueki K.
      • Inabe K.
      • Yamauchi T.
      • Kaneko K.
      • Okazaki Y.
      • et al.
      Adiponectin suppresses hepatic SREBP1c expression in an AdipoR1/LKB1/AMPK dependent pathway.
      ], and to control angiogenesis, a pivotal mechanism of tumor growth [
      • Brakenhielm E.
      • Veitonmaki N.
      • Cao R.
      • Kihara S.
      • Matsuzawa Y.
      • Zhivotovsky B.
      • et al.
      Adiponectin-induced antiangiogenesis and antitumor activity involve caspase-mediated endothelial cell apoptosis.
      ]. In contrast, circulating levels of leptin, another major adipokine, are high in NAFLD [
      • Angulo P.
      • Alba L.M.
      • Petrovic L.M.
      • Adams L.A.
      • Lindor K.D.
      • Jensen M.D.
      Leptin, insulin resistance, and liver fibrosis in human nonalcoholic fatty liver disease.
      ]. Since leptin exerts pro-inflammatory and pro-fibrogenic effects by activating Kupffer cells and stellate cells, it has been connected to disease progression in fibrotic NAFLD [
      • Shen J.
      • Sakaida I.
      • Uchida K.
      • Terai S.
      • Okita K.
      Leptin enhances TNF-alpha production via p38 and JNK MAPK in LPS-stimulated Kupffer cells.
      ,
      • Aleffi S.
      • Petrai I.
      • Bertolani C.
      • Parola M.
      • Colombatto S.
      • Novo E.
      • et al.
      Upregulation of proinflammatory and proangiogenic cytokines by leptin in human hepatic stellate cells.
      ,
      • Ikejima K.
      • Okumura K.
      • Kon K.
      • Takei Y.
      • Sato N.
      Role of adipocytokines in hepatic fibrogenesis.
      ].
      Cancer cells often exhibit increased rates of fatty acid synthesis and accumulation of lipid droplets [
      • Menendez J.A.
      • Lupu R.
      Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis.
      ,
      • Straub B.K.
      • Herpel E.
      • Singer S.
      • Zimbelmann R.
      • Breuhahn K.
      • Macher-Goeppinger S.
      • et al.
      Lipid droplet-associated PAT-proteins show frequent and differential expression in neoplastic steatogenesis.
      ], suggesting that increased availability of lipids in hepatocytes may provide bioenergetic and structural support to the rapidly proliferating cells of HCC. Increased expression of key genes regulating lipogenesis correlates with cell proliferation rates and poor prognosis in HCC [
      • Yamashita T.
      • Honda M.
      • Takatori H.
      • Nishino R.
      • Minato H.
      • Takamura H.
      • et al.
      Activation of lipogenic pathway correlates with cell proliferation and poor prognosis in hepatocellular carcinoma.
      ], and lipid accumulation in hepatocytes is accompanied by distinct patterns of expression and distribution of perilipins, a family of lipid droplet-associated proteins [
      • Straub B.K.
      • Herpel E.
      • Singer S.
      • Zimbelmann R.
      • Breuhahn K.
      • Macher-Goeppinger S.
      • et al.
      Lipid droplet-associated PAT-proteins show frequent and differential expression in neoplastic steatogenesis.
      ,
      • Kimmel A.R.
      • Brasaemle D.L.
      • McAndrews-Hill M.
      • Sztalryd C.
      • Londos C.
      Adoption of PERILIPIN as a unifying nomenclature for the mammalian PAT-family of intracellular lipid storage droplet proteins.
      ]. The precise mechanisms of altered formation and utilization of lipid droplets in the development of HCC in NAFLD remain to be elucidated.
      Lipotoxicity is defined as the cellular dysfunction caused by ectopic deposition of fat in non-adipose tissues such as the liver [
      • Unger R.H.
      • Clark G.O.
      • Scherer P.E.
      • Orci L.
      Lipid homeostasis, lipotoxicity and the metabolic syndrome.
      ] and may contribute to the development of HCC in NAFLD. Accumulation of fatty acids may interfere with cellular signaling pathways and promote oncogenic mechanisms through altered regulation of gene transcription [
      • Vinciguerra M.
      • Carrozzino F.
      • Peyrou M.
      • Carlone S.
      • Montesano R.
      • Benelli R.
      • et al.
      Unsaturated fatty acids promote hepatoma proliferation and progression through downregulation of the tumor suppressor PTEN.
      ,
      • Joshi-Barve S.
      • Barve S.S.
      • Amancherla K.
      • Gobejishvili L.
      • Hill D.
      • Cave M.
      • et al.
      Palmitic acid induces production of proinflammatory cytokine interleukin-8 from hepatocytes.
      ]. Enhanced rates of fatty acid oxidation yield lipid peroxides and free radicals that may cause macromolecular oxidative injury, mitochondrial dysfunction, endoplasmic reticulum stress, and apoptosis [
      • Wei Y.
      • Wang D.
      • Topczewski F.
      • Pagliassotti M.J.
      Saturated fatty acids induce endoplasmic reticulum stress and apoptosis independently of ceramide in liver cells.
      ,
      • Malhi H.
      • Bronk S.F.
      • Werneburg N.W.
      • Gores G.J.
      Free fatty acids induce JNK-dependent hepatocyte lipoapoptosis.
      ]. These molecular events may promote the liver inflammatory response and thus increase the risk for hepatocarcinogenesis.
      Adipose tissue expansion, release of pro-inflammatory cytokines, and lipotoxicity collectively promote systemic and hepatic insulin resistance, which result in hyperinsulinemia. Both are common features of NAFLD and have been linked to tumor development [
      • Biddinger S.B.
      • Kahn C.R.
      From mice to men: insights into the insulin resistance syndromes.
      ,
      • Gallagher E.J.
      • LeRoith D.
      Minireview: IGF, Insulin, and Cancer.
      ]. Deregulated metabolic effects of insulin result in excessive activation of proliferative cell signaling cascades that remain responsive to insulin action and have been implicated in the development of HCC [
      • Bugianesi E.
      Non-alcoholic steatohepatitis and cancer.
      ]. Moreover, hyperinsulinemia results in reduced hepatic synthesis of insulin-like growth factor (IGF)-binding protein-1 and increased bioavailability of IGF-1, which further promotes cellular proliferation and inhibits apoptosis [
      • Ohlsson C.
      • Mohan S.
      • Sjogren K.
      • Tivesten A.
      • Isgaard J.
      • Isaksson O.
      • et al.
      The role of liver-derived insulin-like growth factor-I.
      ]. The relative contribution of systemic insulin resistance and liver tissue-specific molecular events to the development of HCC in NAFLD remains incompletely understood.

      HCC growth in non-cirrhotic livers

      When discussing the emergence of HCC in the absence of cirrhosis, it is important to acknowledge that in the literature the term ‘non-cirrhotic’ pertains to a variety of histopathologic features in the background livers ranging from the normal to the diseased liver but with no detectable fibrosis, to stages of non-cirrhotic fibrosis to incomplete cirrhosis [
      • Regimbeau J.M.
      • Colombat M.
      • Mognol P.
      • Durand F.
      • Abdalla E.
      • Degott C.
      • et al.
      Obesity and diabetes as a risk factor for hepatocellular carcinoma.
      ]. The distinctions are likely significant, since the pathogenesis may differ according to the presence or absence of underlying liver disease, and the extent thereof. A few groups have investigated biomarkers that may distinguish the molecular pathogenesis of HCC in cirrhotic vs. non-cirrhotic livers. For example, Paradis and colleagues found that deregulation of the Wnt/β-catenin pathway had little role in the development of HCC associated with the metabolic syndrome in the absence of significant liver fibrosis [
      • 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.
      ].
      HCC diagnosed in cirrhotic and non-cirrhotic livers may display different imaging and pathological attributes such as size, differentiation, and encapsulation [
      • Brancatelli G.
      • Federle M.P.
      • Grazioli L.
      • Carr B.I.
      Hepatocellular carcinoma in noncirrhotic liver: CT, clinical, and pathologic findings in 39 U.S. residents.
      ,
      • 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.
      ]. When associated with NAFLD, HCC is often moderately or well differentiated and occurs as solitary large mass [
      • Regimbeau J.M.
      • Colombat M.
      • Mognol P.
      • Durand F.
      • Abdalla E.
      • Degott C.
      • et al.
      Obesity and diabetes as a risk factor for hepatocellular carcinoma.
      ,
      • Bugianesi E.
      • Leone N.
      • Vanni E.
      • Marchesini G.
      • Brunello F.
      • Carucci P.
      • et al.
      Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma.
      ]. HCCs that develop in livers with mild or no fibrosis may share these characteristics [
      • Yasui K.
      • Hashimoto E.
      • Komorizono Y.
      • Koike K.
      • Arii S.
      • Imai Y.
      • et al.
      Characteristics of patients with nonalcoholic steatohepatitis who develop hepatocellular carcinoma.
      ,
      • Kawada N.
      • Imanaka K.
      • Kawaguchi T.
      • Tamai C.
      • Ishihara R.
      • Matsunaga T.
      • et al.
      Hepatocellular carcinoma arising from non-cirrhotic nonalcoholic steatohepatitis.
      ,
      • Iannaccone R.
      • Piacentini F.
      • Murakami T.
      • Paradis V.
      • Belghiti J.
      • Hori M.
      • et al.
      Hepatocellular carcinoma in patients with nonalcoholic fatty liver disease: helical CT and MR imaging findings with clinical-pathologic comparison.
      ]. Similarly, HCC complicating the metabolic syndrome and arising in non-fibrotic livers often remains well differentiated despite a larger size [
      • 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.
      ]. These imaging attributes are not necessarily specific to NAFLD and may rather reflect the development of HCC in the absence of cirrhosis, for which NAFLD seems to have preponderance [
      • Iannaccone R.
      • Piacentini F.
      • Murakami T.
      • Paradis V.
      • Belghiti J.
      • Hori M.
      • et al.
      Hepatocellular carcinoma in patients with nonalcoholic fatty liver disease: helical CT and MR imaging findings with clinical-pathologic comparison.
      ].
      A major step in the development of cirrhotic HCC is activation of hepatic stellate cells. Stimulated by various forms of chronic liver injury, these cells are primarily responsible for secreting collagen that results in liver fibrosis [
      • Bataller R.
      • Brenner D.A.
      Liver fibrosis.
      ]. In addition, activated stellate cells produce various growth factors and may stimulate oncogenic pathways that contribute to the expansion and selection of neoplastic clones of liver cells [
      • Friedman S.L.
      Mechanisms of hepatic fibrogenesis.
      ]. The pathogenic role of stellate cells may be limited in non-cirrhotic HCC characterized by different growth pattern and appearance on imaging studies such as lack of encapsulation. Accordingly, diminished activation of stellate cells with delayed formation of fibrotic septa may result in larger liver nodules that are not obscured by extensive scarring [
      • Hytiroglou P.
      • Park Y.N.
      • Krinsky G.
      • Theise N.D.
      Hepatic precancerous lesions and small hepatocellular carcinoma.
      ].

      Prevention of HCC associated with NAFLD

      Role of diabetes control by insulin-sensitizing therapy

      Based on the overwhelming epidemiologic evidence that diabetes overlapping with NAFLD is an independent risk factor of HCC [
      • El-Serag H.B.
      • Hampel H.
      • Javadi F.
      The association between diabetes and hepatocellular carcinoma: a systematic review of epidemiologic evidence.
      ,
      • Davila J.A.
      • Morgan R.O.
      • Shaib Y.
      • McGlynn K.A.
      • El-Serag H.B.
      Diabetes increases the risk of hepatocellular carcinoma in the United States: a population based case control study.
      ,
      • El-Serag H.B.
      • Tran T.
      • Everhart J.E.
      Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma.
      ,
      • Chen C.L.
      • Yang H.I.
      • Yang W.S.
      • Liu C.J.
      • Chen P.J.
      • You S.L.
      • et al.
      Metabolic factors and risk of hepatocellular carcinoma by chronic hepatitis B/C infection: a follow-up study in Taiwan.
      ,
      • 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.
      ,
      • Veldt B.J.
      • Chen W.
      • Heathcote E.J.
      • Wedemeyer H.
      • Reichen J.
      • Hofmann W.P.
      • et al.
      Increased risk of hepatocellular carcinoma among patients with hepatitis C cirrhosis and diabetes mellitus.
      ,
      • Wang C.S.
      • Yao W.J.
      • Chang T.T.
      • Wang S.T.
      • Chou P.
      The impact of type 2 diabetes on the development of hepatocellular carcinoma in different viral hepatitis statuses.
      ,
      • Wang P.
      • Kang D.
      • Cao W.
      • Wang Y.
      • Liu Z.
      Diabetes mellitus and risk of hepatocellular carcinoma: a systematic review and meta-analysis.
      ], effective treatment of insulin resistance and hyperinsulinemia may be critical to prevent hepatocarcinogenesis in the affected population. Several reports indicate that the use of insulin-sensitizing agents in diabetes may reduce the risk of HCC [
      • 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.
      ,
      • 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.
      ,
      • 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.
      ,
      • 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.
      ]. Metformin improves insulin resistance through the activation of AMPK, which blocks glucose output from the liver and boosts glucose uptake in the skeletal muscle. In addition, metformin has direct antiproliferative effects primarily by inhibiting the mTOR oncogenic pathway [
      • Mousa S.A.
      • Aljada A.
      Metformin and neoplasia: implications and indications.
      ]. A case control study from Italy involving 610 patients with HCC of mixed etiology found an odds ratio of 0.15 for HCC in metformin-treated diabetic patients with cirrhosis when compared to those treated with sulphonylureas or insulin [
      • 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.
      ]. In a French observational cohort of 100 consecutive diabetic patients with ongoing HCV cirrhosis, the hazard ratio for developing HCC was found to be 0.19 during a median follow-up of 5.7 years among those treated with metformin [
      • 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.
      ]. Moreover, a case control study from a large US cancer center reported that treatment with metformin or the insulin-sensitizing peroxisome proliferators activated receptor-γ (PPARγ) agonist thiazolidinediones resulted in an adjusted risk ratio of 0.3 for HCC among diabetics while the use of insulin secretagogue sulfonylurea drugs was associated with a 7.1-fold increase in HCC risk compared to non-users [
      • 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.
      ].
      Insulin-sensitizing therapy may also improve the prognosis of HCC. A recent study showed that metformin therapy is associated with lower mortality in diabetic patients with early stage HCC after radiofrequency ablation [
      • Chen T.M.
      • Lin C.C.
      • Huang P.T.
      • Wen C.F.
      Metformin associated with lower mortality in diabetic patients with early stage hepatocellular carcinoma after radiofrequency ablation.
      ]. While current guidelines for the management of HCC have no specific recommendations for cases associated with NAFLD, obesity, and diabetes [
      • Bruix J.
      • Sherman M.
      Management of hepatocellular carcinoma: an update.
      ], the use of insulin-sensitizing drugs and avoidance of treatments contributing to hyperinsulinemia is likely to enhance prevention and improve disease outcomes of HCC.

      Surveillance of HCC in NAFLD

      The prognosis of HCC is generally poor with dismal overall survival rates for all stages combined [
      • El-Serag H.B.
      Hepatocellular carcinoma.
      ,
      • Bruix J.
      • Sherman M.
      Management of hepatocellular carcinoma: an update.
      ]. However, it is encouraging that long-term survival after treatment with curative intent at early stages of the disease may now reach 50% to 70% over 5 years [
      • Forner A.
      • Reig M.E.
      • de Lope C.R.
      • Bruix J.
      Current strategy for staging and treatment: the BCLC update and future prospects.
      ]. Further improvement in these figures is critically linked to effective surveillance and early recognition. For now, cirrhosis remains the primary indication for implementing HCC surveillance with chronic hepatitis B as a major exception [
      • Bruix J.
      • Sherman M.
      Management of hepatocellular carcinoma: an update.
      ]. New findings on HCC in liver disease associated with obesity and diabetes prompt some reconsideration of cancer surveillance strategies, although current evidence is insufficient to allow firm recommendations. It is important to emphasize that HCC may have a distinct pathogenesis in NAFLD, but the presence of cirrhosis results in a substantially higher HCC incidence, as seen in all other forms of chronic liver disease [
      • Braga C.
      • La Vecchia C.
      • Negri E.
      • Franceschi S.
      Attributable risks for hepatocellular carcinoma in northern Italy.
      ,
      • Hashimoto E.
      • Yatsuji S.
      • Tobari M.
      • Taniai M.
      • Torii N.
      • Tokushige K.
      • et al.
      Hepatocellular carcinoma in patients with nonalcoholic steatohepatitis.
      ].
      Cryptogenic cirrhosis certainly complicates the approach to liver cancer surveillance [
      • Caldwell S.H.
      • Oelsner D.H.
      • Iezzoni J.C.
      • Hespenheide E.E.
      • Battle E.H.
      • Driscoll C.J.
      Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease.
      ]. Since cryptogenic cirrhosis develops insidiously, patients and caregivers may not be aware of its presence and thus may not benefit from surveillance programs established for those diagnosed with chronic viral hepatitis or alcoholic liver disease. This problem was well documented in a single-center study of 105 patients with HCC, where prior histological diagnosis of steatohepatitis or clinically suspected NAFLD was present in 47% of those with cryptogenic cirrhosis [
      • Marrero J.A.
      • Fontana R.J.
      • Su G.L.
      • Conjeevaram H.S.
      • Emick D.M.
      • Lok A.S.
      NAFLD may be a common underlying liver disease in patients with hepatocellular carcinoma in the United States.
      ]. Patients with cryptogenic liver disease were less likely to be enrolled in liver cancer surveillance (23% vs. 61%, p = 0.01), resulting in delayed diagnosis, larger tumor size, and diminished likelihood for successful therapy [
      • Marrero J.A.
      • Fontana R.J.
      • Su G.L.
      • Conjeevaram H.S.
      • Emick D.M.
      • Lok A.S.
      NAFLD may be a common underlying liver disease in patients with hepatocellular carcinoma in the United States.
      ].
      Figure thumbnail fx2

      Conclusions

      NAFLD, by itself and in synergy with other risk factors, is becoming the most common cause of HCC in developed countries. As the global prevalence of obesity and diabetes is increasing, other parts of the world are likely to follow suit. To make things more difficult, a considerable number of NAFLD-associated HCC cases develop in non-cirrhotic livers. Thus, we may need to contemplate a paradigm shift in liver cancer surveillance. Fortunately, there is still some good news. For now at least, HCC appears to be a rare complication of NAFLD in the complete absence of fibrosis. In addition, the prognosis of HCC is significantly better without cirrhosis [
      • Bruix J.
      • Sherman M.
      Management of hepatocellular carcinoma: an update.
      ]. Since fibrosis in NAFLD is linked to steatohepatitis, reliable distinction from steatosis alone by liver biopsy or, preferably, emerging non-invasive biomarkers will identify those at risk of disease progression and in need of cancer surveillance. Better understanding of molecular pathways that accelerate hepatocarcinogenesis in obesity and diabetes as well as mapping of the molecular carcinoma sequence in a non-cirrhotic background will facilitate these efforts and provide new diagnostic and therapeutic targets. Nonetheless, prevention of obesity, diabetes, and NAFLD remain the best long-term strategy.

      Conflict of interest

      The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

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