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Hepatocellular Carcinoma Screening and Nonalcoholic Fatty Liver Disease: How is it Different?

      Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are major contributors to the burden of liver disease today. Effective therapeutic strategies for prevention of progression of NASH to cirrhosis are still elusive. As with other diseases causing cirrhosis, NASH also increases risk of hepatocellular carcinoma (HCC). NAFLD without cirrhosis also, has been shown to be a risk factor for HCC but pathogenesis of HCC in these patients, is not clear. Several risk factors for HCC in patients with NAFLD-/NASH-related cirrhosis have been identified. Surveillance strategies for HCC in NASH-related cirrhosis is similar to other patients with cirrhosis. No guidelines are currently available for surveillance in patients with NAFLD exclusively, owing to considerable gaps in knowledge. Prevention of NAFLD and lifestyle changes addressing the risk factors for HCC remain the backbone of managing patients with NAFLD- and NAFLD-related complications such as HCC.

      Keywords

      Nonalcoholic fatty liver disease (NAFLD) and associated nonalcoholic steatohepatitis (NASH) have been increasing at epidemic proportions owing to the increasing prevalence of obesity and metabolic syndrome (MetS). It has rapidly become the most common cause for end-stage liver disease requiring liver transplantation. With an increasing burden of NASH-related end-stage liver disease, complications such as hepatocellular carcinoma (HCC) will more frequently be encountered by hepatologists managing these patients. The incidence of HCC in patients with NAFLD-/NASH-related liver disease is steadily rising and is contributing to a major disease burden along with chronic viral hepatitis and alcoholic cirrhosis.

      Burden of HCC in patients with NASH

      Although chronic viral hepatitis (hepatitis B virus [HBV] in Asia and Africa and hepatitis C virus [HCV] in USA and Europe) are still the leading causes of HCC, NASH has been found to be the second leading risk factor for HCC.
      • 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.
      HCV-related liver disease is on the decline owing to the widespread use of directly acting antiviral agents, and therefore NASH-related disease is soon expected to surpass HCV as the leading cause of HCC in western world. With increasing immunization and effective viral suppressive agents against HBV in HBV endemic areas of South East Asia, Africa, China, and India, the burden due to HBV-HCC is likely to decline in these regions in the ensuing years. The prevalence of NASH is in these countries is substantial. The decline in viral hepatitis-related cirrhosis, liver diseases due to NAFLD is soon emerging as a major cause of chronic liver disease, as well as HCC
      • Khan F.
      • Perumpail R.
      • Wong R.
      • Ahmed A.
      Advances in hepatocellular carcinoma: nonalcoholic steatohepatitis- related hepatocellular carcinoma.
      In the recent years, a sharp increase in NASH-related HCC has been described. A retrospective cohort study amongst adult liver transplant recipients from 2002 to 2012 indicated that there was four fold increase in patients undergoing liver transplantation for NASH-related HCC compared with 2-fold increase in number of patients undergoing transplantation for HCV-related HCC. During this 10-year span, NASH also became the second leading cause of HCC-related liver transplantation in America, steadily increasing from 8.3% in 2002 to 10.3% in 2007 and to 13.5% in 2012.
      • 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.
      Most estimates of HCC in patients come from data from tertiary referral centers with very few population-based studies. Though this gives an estimate of the burden, such estimates have several pitfalls. First, noncirrhotic patients with HCC who develop HCC may be excluded in data arising from transplant centers. Second, one has to recognize that the histological diagnosis of NASH is difficult in cirrhotic livers because characteristic features of NASH may be absent with the onset of cirrhosis. The majority of cryptogenic cirrhosis is actually burned out NASH
      • 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.
      ,
      • Poonawala A.
      • Nair S.P.
      • Thuluvath P.J.
      Prevalence of obesity and diabetes in patients with cryptogenic cirrhosis: a case-control study.
      and when this fact is not considered, the true burden of disease may be underestimated.
      The prevalence of HCC in patients with NASH-related cirrhosis have been described in several studies. In a recent retrospective cohort study from a total of 130 facilities in the Veterans Health Administration, 296,707 patients with NAFLD were compared with 296,707 matched controls. During 2,382,289 person-years [PYs] of follow-up, 490 patients with NAFLD developed HCC (0.21/1000 PYs). HCC incidence was significantly higher among patients with NAFLD vs controls (0.02/1000 PYs; hazard ratio, 7.62; 95% confidence interval, 5.76–10.09). Among patients with NAFLD, those with cirrhosis had the highest annual incidence of HCC (10.6/1000 PYs). Among patients with NAFLD cirrhosis, HCC risk ranged from 1.6 to 23.7 per 1000 PYs based on other demographic characteristics. 20% of NAFLD patients with HCC had no evidence of cirrhosis.
      • Kanwal F.
      • Kramer J.R.
      • Mapakshi S.
      • et al.
      Risk of hepatocellular cancer in patients with non-alcoholic fatty liver disease.
      In another study, Surveillance, Epidemiology and End Results registries (2004–2009) was used to identify NAFLD, HCV, HBV, alcoholic liver disease (ALD), and other liver disease. NAFLD was also defined by clinical diagnosis (cryptogenic cirrhosis, obese-diabetics with cryptogenic liver disease). A total of 4929 HCC cases and 14,937 controls without HCC were included. Of the HCC cases, 54.9% were related to HCV, 16.4% to ALD, 14.1% to NAFLD, and 9.5% to HBV. Across the 6-year period (2004–2009), the number of NAFLD-HCC showed a 9% annual increase. NAFLD-HCC were older, had shorter survival time, more heart disease, and were more likely to die from their primary liver cancer (all P < 0.0001)
      • Younossi Z.M.
      • Otgonsuren M.
      • Henry L.
      • et al.
      Association of nonalcoholic fatty liver disease (NAFLD) with hepatocellular carcinoma (HCC) in the United States from 2004 to 2009.
      . Mittal et al
      • Mittal S.
      • Sada Y.H.
      • El-Serag H.B.
      • et al.
      Temporal trends of nonalcoholic fatty liver disease-related hepatocellular carcinoma in the veteran affairs population.
      evaluated a national cohort of 1500 patients who developed HCC from 2005 through 2010 from Veterans Administration (VA) hospitals. NAFLD was diagnosed based on histologic evidence for, or the presence of, the MetS in the absence of HCV infection, hepatitis B, or ALD. NAFLD was the underlying risk factor for HCC in 120 patients (8.0%); NAFLD was the third most common risk factor for HCC in the VA population. The proportion of NAFLD-related HCC was relatively stable from 2005 through 2010.
      The risk of HCC in NAFLD has also been described in several Asian studies. Data for HCC from 53 tertiary care centers in Japan from 1991 to 2010 were collected. Detailed data of 5326 patients with nonviral etiology were available. The etiologies were autoimmune hepatitis, primary biliary cirrhosis, ALD, non-alcoholic fatty liver disease (NAFLD), unclassified, and other. The proportion of patients with nonviral etiologies increased from 10.0% in 1991 to 24.1% in 2010. Of the patients, 92% were categorized as ALD, NAFLD, or unclassified. Diabetes was most prevalent in NAFLD (63%). Most cases of non-B, non-C HCC are related to lifestyle factors, including obesity and diabetes.
      • Tateishi R.
      • Okanoue T.
      • Fujiwara N.
      • et al.
      Clinical characteristics, treatment, and prognosis of non-B,non-C hepatocellular carcinoma: a large retrospective multicenter cohort study.
      Therefore risk for HCC in NASH-related cirrhosis varies between 1% and 22% in NAFLD-associated cirrhosis, depending on the cohort studied. Most studies available are retrospective studies, and these studies have been tabulated in Table 1.
      Table 1Studies Describing HCC in Cirrhosis of Liver due to NASH.
      Publication YearAuthorStudy DesignComments
      2018Kanwal et al
      • Kanwal F.
      • Kramer J.R.
      • Mapakshi S.
      • et al.
      Risk of hepatocellular cancer in patients with non-alcoholic fatty liver disease.
      Retrospective cohort study296707 NAFLD patients with 296707 matched controls.

      Incidence of HCC 0.21/1000 Person- Years. HCC risk ranged from 1.6 to 23.7 per 1000 Person-Years.
      2015Younossi et al
      • Younossi Z.M.
      • Otgonsuren M.
      • Henry L.
      • et al.
      Association of nonalcoholic fatty liver disease (NAFLD) with hepatocellular carcinoma (HCC) in the United States from 2004 to 2009.
      Retrospective studySEER database examined for cause of HCC – NAFLD HCC present in 14.1%
      2015Mittal et al
      • Mittal S.
      • Sada Y.H.
      • El-Serag H.B.
      • et al.
      Temporal trends of nonalcoholic fatty liver disease-related hepatocellular carcinoma in the veteran affairs population.
      Cohort of 1500 patients with HCC included and etiology describedThird most common factor for HCC was NAFLD and accounted for 8% of cases
      2015Tatesishi et al
      • Tateishi R.
      • Okanoue T.
      • Fujiwara N.
      • et al.
      Clinical characteristics, treatment, and prognosis of non-B,non-C hepatocellular carcinoma: a large retrospective multicenter cohort study.
      Retrospective multicenter cohort studyTrend of patients diagnosed with HCC assessed from 53 tertiary care centers in Japan.

      Non virus related HCC increased from 1991 to 2010 and most cases were related to lifestyle factors like obesity and T2 DM
      2014Wong et al
      • 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 US.
      Retrospective cohort studyLT recipients in US from 2002 to 2012.LT for NASH HCC increased four folds
      2013Gonclaves et al
      • Gonçalves P.L.
      • Zago-Gomes Mda P.
      • Marques C.C.
      • Mendonça A.T.
      • Gonçalves C.S.
      • Pereira F.E.
      Etiology of liver cirrhosis in Brazil: chronic alcoholism and hepatitis viruses in liver cirrhosis diagnosed in the state of Espírito Santo.
      Retrospective studyOf 1516 patients with HCC,4% were caused by NAFLD
      2012Yang et al
      • Yang J.D.
      • Kim B.
      • Sanderson S.O.
      • et al.
      Hepatocellular carcinoma in olmsted county,Minnesota, 1976-2008.
      Retrospective surveyOf 47 patients with HCC,11% were caused by NAFLD
      2011Tokushige et al
      • Tokushige K.
      • Hashimoto E.
      • Horie Y.
      • Taniai M.
      • Higuchi S.
      Hepatocellular carcinoma in Japanese patients with nonalcoholic fatty liver disease, alcoholic liver disease, and chronic liver disease of unknown etiology: report of the nationwide survey.
      Retrospective nationwide surveyOf 14530 patients with HCC,2% were caused by NAFLD
      2011Hucke et al
      • Hucke F.
      • Sieghart W.
      • Schöniger-Hekele M.
      • Peck-Radosavljevic M.
      • Müller C.
      Clinical characteristics of patients with hepatocellular carcinoma in Austria -is there a need for a structured screening program?.
      Retrospective nationwide surveyOf 850 patients with HCC, 5% caused by NAFLD
      2011Ertle et al
      • Kawada N.
      • Imanaka K.
      • Kawaguchi T.
      • et al.
      Hepatocellular carcinoma arising from non-cirrhotic nonalcoholic steatohepatitis.
      Retrospective nationwide surveyOf 162 patients with HCC,22% caused by NAFLD
      2009Kawada et al
      • Malik S.M.
      • Gupte P.A.
      • de Vera M.E.
      • Ahmad J.
      Liver transplantation in patients with nonalcoholic steatohepatitis-related hepatocellular carcinoma.
      Retrospective study of subjects submitted to hepatic resectionOf 1168 patients with HCC, 1% caused by NAFLD
      2009Malik et al
      • 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?.
      Prospective enrollment with HCC submitted to liver transplantationOf 447 patients with HCC,4% caused by NAFLD
      2008Guzman et al
      • 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.
      Retrospective studyOf 50 patients with HCC, 13% caused by NAFLD
      2002Marrero et al
      • Bugianesi E.
      • Leone N.
      • Vanni E.
      • et al.
      Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma.
      Consecutive patients with HCC included and etiology determined105 consecutive patients – 13% due to CC due to NAFLD
      2002Bugaianesi et al
      • Paradis V.
      • Zalinski S.
      • Chelbi E.
      • et al.
      Hepatocellular carcinomas in patients with metabolic syndrome often develop without significant liver fibrosis: a pathological analysis.
      Retrospective study641 patients with cirrhosis and HCC. 23 out of 44 CC had metabolic syndrome
      NAFLD, nonalcoholic fatty liver disease; HCC, hepatocellular carcinoma; SEER, Surveillance, Epidemiology and End Results.
      The burden of noncirrhotic HCC in NAFLD has been also reported to be substantial (Table 2). A single-center pathological study on 128 patients undergoing liver resection for HCC between 1995 and 2000 was the first to report this observation.
      • Paradis V.
      • Zalinski S.
      • Chelbi E.
      • et al.
      Hepatocellular carcinomas in patients with metabolic syndrome often develop without significant liver fibrosis: a pathological analysis.
      In a US VA cohort
      • Mittal S.
      • El-Serag H.B.
      • Sada Y.H.
      • et al.
      Hepatocellular carcinoma in the absence of cirrhosis in United States veterans is associated with nonalcoholic fatty liver disease.
      including 1500 patients with HCC from 2005 to 2010, 194 patients, (13%) had no evidence of cirrhosis but had a higher prevalence of MetS and NAFLD. The risk of HCC in the same cohort, in the absence of cirrhosis was five fold lesser in patients with chronic hepatitis C than in those with NAFLD. A significant number (41.7%; P < 0.005) of individuals with NAFLD/NASH-HCC in s study by Ertle et al
      • Ertle J.
      • Dechêne A.
      • Sowa J.P.
      • et al.
      Non-alcoholic fatty liver disease progresses to hepatocellular carcinoma in the absence of apparent cirrhosis.
      had no evidence of underlying cirrhosis. Thus, several studies have reported that the risk of HCC exists in NAFLD in both patients with cirrhosis and without cirrhosis. Reported literature suggests 32%–100% of NAFLD-HCC occurs in noncirrhotic livers (Table 2). With increasing number of patients with NAFLD, long-term complications of NAFLD-HCC will be a substantial cause of mortality and morbidity.
      Table 2Studies Describing HCC in Patients of NAFLD Without Cirrhosis.
      Publication YearAuthorStudy DesignComments
      2019Bengstsson et al
      • Bengtsson B.
      • Stål P.
      • Wahlin S.
      • Björkström N.K.
      • Hagström H.
      Characteristics and outcome of hepatocellular carcinoma in patients with NAFLD without cirrhosis.
      Retrospective studyAll cases from 2004 to 2017. Of 1562 cases,14.4% due to NAFLD.37%did not have cirrhosis
      2019Gawrieh et al
      • Gawrieh S.
      • Dakhoul L.
      • Miller E.
      • et al.
      Characteristics, aetiologies and trends of hepatocellular carcinoma in patients without cirrhosis: a United States multicentre study.
      Retrospective study5144 patients with HCC,11.7 had no underlying cirrhosis
      2016Mohammad et al
      • Mohamad B.
      • Shah V.
      • Onyshchenko M.
      • et al.
      Characterization of hepatocellular carcinoma (HCC) in non-alcoholic fatty liver disease (NAFLD) patients without cirrhosis.
      Cross-sectional study47 patients of cirrhotic HCC compared with 36 noncirrhotics.

      Older age and large tumor size in noncirrhotics
      2016Mittal et al
      • Mittal S.
      • El-Serag H.B.
      • Sada Y.H.
      • et al.
      Hepatocellular carcinoma in the absence of cirrhosis in United States veterans is associated with nonalcoholic fatty liver disease.
      Retrospective study1500 patients who developed HCC from 2005 through 2010.NAFLD accounted for 8% of cases
      2015Perumpali et al
      • Perumpail R.B.
      • Wong R.J.
      • Ahmed A.
      • Harrison S.A.
      Hepatocellular carcinoma in the setting of non-cirrhotic nonalcoholic fatty liver disease and the metabolic syndrome: US experience.
      Retrospective study6 cases of non cirrhotic HCC of 44 cases reviewed
      2014Dyson et al
      • Dyson J.
      • Jaques B.
      • Chattopadyhay D.
      • et al.
      Hepatocellular cancer: the impact of obesity, type 2 diabetes and a multidisciplinary team.
      Cross-sectional studyHCC arising without cirrhosis are linked to NAFLD
      2011Ertle et al
      • Ertle J.
      • Dechêne A.
      • Sowa J.P.
      • et al.
      Non-alcoholic fatty liver disease progresses to hepatocellular carcinoma in the absence of apparent cirrhosis.
      Retrospective study162 patients with HCC included.41.7% had no cirrhosis
      2011Yasui et al
      • Yasui K.
      • Hashimoto E.
      • Komorizono Y.
      • et al.
      Characteristics of patients with nonalcoholic steatohepatitis who develop hepatocellular carcinoma.
      Cross-sectional studyOf 87 patients with NASH developed HCC, 43 patients had no cirrhosis
      2009Paradis et al
      • Paradis V.
      • Zalinski S.
      • Chelbi E.
      • et al.
      Hepatocellular carcinomas in patients with metabolic syndrome often develop without significant liver fibrosis: a pathological analysis.
      Retrospective studyLiver resection data −31 HCC with MS and no cirrhosis
      NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; HCC, hepatocellular carcinoma.

      Screening and surveillance for HCC

      Screening refers to application of a diagnostic test in a population which has no signs or symptoms of the disease. Surveillance is the repeated application of the diagnostic tests in the same population at risk for disease, in the absence of any prior evidence that the disease in question is present. Screening and surveillance for HCC in a population should satisfy all the World Health Organization (WHO) criteria required for a disease to qualify for a surveillance program. A meta-analyses of 47 studies which included retrospective and prospective studies showed that surveillance detects HCC at a earlier stage, increases receipt of curative therapy and improves patient survival.
      • Singal A.G.
      • Pillai A.
      • Tiro J.
      Early detection, curative treatment, and survival rates for hepatocellular carcinoma surveillance in patients with cirrhosis: a meta-analysis.
      All guidelines on management of cirrhosis therefore, recommend screening of HCC.
      • Heimbach J.K.
      • Kulik L.M.
      • Finn R.S.
      • et al.
      AASLD guidelines for the treatment of hepatocellular carcinoma.
      ,
      • European Association for the Study of the Liver
      Electronic address:[email protected]; European association for the study of the liver. EASL clinical Practice guidelines: management of hepatocellular carcinoma.
      Screening for high-risk patients without cirrhosis in patients with chronic hepatitis B, chronic HCV infection with advanced fibrosis are also recommended by these guidelines. Six monthly ultrasound abdomen is the recommended modality of screening and surveillance for HCC. Assessment of serum alfa-fetoprotein should be added to ultrasonography (USG).
      • European Association for the Study of the Liver
      Electronic address:[email protected]; European association for the study of the liver. EASL clinical Practice guidelines: management of hepatocellular carcinoma.
      Screening guidelines specific for patients with cirrhotic and noncirrhotic NAFLD are not available. However, NAFLD patients with cirrhosis should follow similar strategy for early HCC detection as all other cirrhosis patients discussed previously, unless evidence against such strategy is available. Systemic diseases such as diabetes, which is common in patients with NASH, may confer a higher risk and may lead to a varied tumor behavior and biology in patients with NAFLD-HCC. Therefore specific guidelines in NAFLD need to be developed. More studies are needed on understanding of the pathogenesis and molecular drivers of these tumors before specific guidelines can be developed.
      A significant burden of HCC is present in noncirrhotic patients of NAFLD. Given the large number of patients with NAFLD, the burden on health care and economic resources will be huge and framing guidelines for this population will be difficult. Studies focusing on risk stratification using phenotypic, genetic, and molecular markers for NAFLD-HCC will be required so that high risk patients who require screening can be identified among the large number of patients with NAFLD.

      Phenotypic risk factors for HCC in patients with NAFLD

      Several risk factors for development of HCC have been identified in patients with NAFLD (Table 3).Phenotypic features confer a higher risk of HCC in patients with NAFLD and therefore may help identify a select subgroup of NAFLD patients who may require screening. Evidence for cost-effectiveness of such screening will be needed before any recommendations can be made for screening of HCC in patients with NAFLD.
      Table 3Risk Factors for Hepatocellular Carcinoma in NAFLD Patients.
      Advanced liver disease
      Concomitant alcohol abuse
      Iron overload in a cirrhotic liver
      Obesity
      Type 2 diabetes mellitus
      Genetic predisposition (mutations in PNPLA3,TM6SF2,MBOAT7)
      Malignant transformation of hepatocellular Adenoma
      NAFLD, nonalcoholic fatty liver disease.
      Obesity and Type 2 diabetes mellitus (DM) are known risk factors for progression of NAFLD and also for HCC. These conditions are closely related and increase the risk of HCC in NAFLD independently and also cumulatively. Data from 5.24 million individuals in the Clinical Practice Research Data link from UK were analyzed, and it was found that a higher BMI was positively associated with liver cancer (hazard ratio [HR]: 1.19, 99% confidence interval [CI]: 1.12–1.27).
      • Bhaskaran K.
      • Douglas I.
      • Forbes H.
      • dos-Santos-Silva I.
      • Leon D.A.
      • Smeeth L.
      Body-mass index and risk of 22 specific cancers: a population-based cohort study of 5_24 million UK adults.
      A meta-analysis of 11 cohort studies estimated that the risk of HCC is increased by 17% in overweight subjects and by 89% in obese subjects; with an average increase in risk of 24% for every 5 kg/m2 increase in BMI. The relationship between diabetes was reported in a large-scale population study from Japan. The risk of malignancy in Diabetic patients was 20% and most of it was accounted for by HCC. The HR was 2.24 in males and 1.94 in females.
      • Inoue M.
      • Iwasaki M.
      • Otani T.
      • Sasazuki S.
      • Noda M.
      • Tsugane S.
      Diabetes mellitus and the risk of cancer: results from a large-scale population based cohort study in Japan.
      A 2.5-fold increase in both HCC prevalence and incidence among patients with T2DM compared with nondiabetic controls in a meta-analysis has been documented.
      • El-Serag H.B.
      • Hampel H.
      • Javadi F.
      The association between diabetes and hepatocellular carcinoma: a systematic review of epidemiologic evidence.
      The distribution of visceral fat has been shown to be important risk factor in the development and progression of NASH. Ethnic differences in distribution of visceral fat are also well known to vary. Waist-to-hip ratio may be a better indicator of the visceral fat distribution and therefore may be a more important predicator of HCC. An increased waist-to-hip ratio conferred a three fold risk of HCC, and it was a better indicator than BMI over 8.6 year follow-up period in the European Prospective Investigation into Cancer (EPIC) study
      • Schlesinger S.
      • Aleksandrova K.
      • Pischon T.
      • et al.
      Abdominal obesity, weight gain during adulthood and risk of liver and biliary tract cancer in a European cohort.

      Metabolic syndrome

      MetS is a cluster of conditions – increased blood pressure, high blood sugar, excess body fat around the waist, and abnormal cholesterol or triglyceride levels. The presence of these conditions increases the risk of cardiovascular, stroke, and DM. It is closely related to insulin resistance which is an important cause for NAFLD and also an important determinant for progression to NASH. The risk for HCC has also been associated with MetS. In a study by Turati et al,
      • Turati F.
      • Talamini R.
      • Pelucchi C.
      • Polesel J.
      • Franceschi S.
      • Crispo A.
      Metabolic syndrome and hepatocellular carcinoma risk.
      the risk of HCC increased with the increasing components of MetS. In patients with obesity and T2DM the OR of developing HCC was 4.75 (95% CI 1.75–12.89).

      Genetic factors

      Certain predisposing genetic polymorphisms may increase the risk of HCC in patients with NAFLD. A single-nucleotide polymorphism in the patatin-like phospholipase domain containing (PNPLA3) gene, a C-to-G genotype in the rs738409 gene determines differences in hepatic fat accumulation. The association between rs738409 gene mutation and HCC has been well determined.
      • Sookoian S.
      • Pirola C.J.
      Meta-analysis of the influence of I148M variant of patatin-like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease.
      It has also been suggested a polymorphism in the transmembrane 6 superfamily member 2 gene (TM6SF2) increases the risk of HCC. The evidence in its role in NAFLD-HCC requires further studies. Loss-of-function TERT mutations is the hallmark of HCC in carriers of this gene.
      • Dongiovanni P.
      • Romeo S.
      • Valenti L.
      Hepatocellular carcinoma in nonalcoholic fatty liver: role of environmental and genetic factors.
      Donati et al
      • Donati B.
      • Pietrelli A.
      • Pingitore P.
      • et al.
      Telomerase reverse transcriptase germline mutations and hepatocellular carcinoma in patients with nonalcoholic fatty liver disease.
      found membrane-bound O-acyltransferase (MBOAT7) rs641738 variant has been associated with NAFLD-HCC. The association was more profound in patients with advanced fibrosis.

      Current status of screening for HCC in NAFLD/NASH – where do we stand?

      The rising prevalence of NAFLD and the epidemiological data suggesting an increasing burden of HCC, it is evident that screening for HCC will be needed. But guidelines for screening in HCC will have to take into account the burden that screening and surveillance will put on the health-care resources especially so, in resource scarce countries. Epidemiological trends from various studies indicate that NAFLD-HCC is rising parallel to the rising incidence of obesity and diabetes.
      • Yopp A.C.
      • Choti M.A.
      Non-alcoholic steatohepatitis-related hepatocellular carcinoma: a growing epidemic?.
      Therefore the population that would require screening would be very large and a systematic surveillance programme may be impractical. Poor rates of surveillance therefore will be a problem. A multicenter Italian study reported 52% of patients with NAFLD-related HCC were not diagnosed on regular surveillance compared with 37% of patients with HCV-related HCC (P < 0.0001).
      • Piscaglia F.
      • Svegliati-Baroni G.
      • Barchetti A.
      HCC-NAFLD Italian Study Group Clinical patterns of hepatocellular carcinoma in nonalcoholic fatty liver disease: a multicenter prospective study.
      A similar report from the US cohort from VA hospitals revealed surveillance was carried out in only in 40% of patients diagnosed to have NAFLD when compared with 80% in HCV-related HCC.
      • Mittal S.
      • Sada Y.
      • El-Serag H.B.
      • et al.
      Temporal trends of nonalcoholic fatty liver disease-related hepatocellular carcinoma in the Veteran Affairs Population.
      The problem is further compounded in noncirrhotic NAFLD patients with HCC. In the absence of cirrhosis screening, all patients with NAFLD is impractical, particularly when the population prevalence of NAFLD may be as high as 10–30%. Therefore more studies on identifying those patients with high risk of developing HCC will be required before guidelines for screening of noncirrhotic patients and framed.
      In accordance with the WHO,
      • Prorok P.C.
      Epidemiologic approach for cancer screening. Problems in design and analysis of trials.
      one of the important fundamental principles for recommending screening for any disease, is that effective treatment capable of reducing morbidity and mortality should be available. Though HCC in early stages can be effectively managed, patients with NAFLD-HCC have several comorbid illnesses such as cardiac and renal disease, which precludes their effective treatment even when detected at an early stage. Therefore, the patients with NAFLD may succumb from cardiovascular diseases, cerebrovascular accidents, or renal diseases while undergoing HCC screening. The whole process of screening such a patient may not be cost-effective and would be a hindrance for using as a process for using in population at large. Therefore the outcome of screening in terms of the survival benefit, needs to be carefully assessed.
      The technique of surveillance recommended for detection of HCC is USG. In patients with NAFLD, in whom obesity is common and USG abdomen has several pitfalls. In a study by only 47.7% of NAFLD-HCC were diagnosed during specific surveillance or periodic ultrasound compared with 63.3% of HCV-HCC (P < 0.0001).
      • Leung C.
      • Yeoh S.W.
      • Patrick D.
      • et al.
      Characteristics of hepatocellular carcinoma in cirrhotic and non-cirrhotic non-alcoholic fatty liver disease.
      USG may not be useful in patients with small nodules owing to attenuation of ultrasound beam in bright liver. Focal fatty infiltration and echo structural heterogeneity may lead to under recognition or misinterpretation of small nodules. Identification of small lesions during surveillance of HCC may therefore be technically difficult.
      Thus, when we consider HCC screening in NAFLD, there are several unanswered questions. Risk stratification based on, specific phenotypic traits, genetic polymorphisms or special molecular markers and effectiveness of such stratification will have to be studied before guidelines can be formulated. Further, the optimum technique, recall interval, and surveillance frequency needs to be defined but is difficult with currently available evidence.
      The costs of screening noncirrhotic patients with NAFLD and its cost-effectiveness are still unclear. Screening can be cost-effective only if the incidence exceeds a threshold of 1.5% per year.
      • Kawamura Y.
      • Arase Y.
      • Ikeda K.
      • et al.
      Largescale long-term follow-up study of Japanese patients with non-alcoholicFatty liver disease for the onset of hepatocellular carcinoma.
      Though a considerable number of NAFLD-HCC have been reported in noncirrhotic patients, the incidence of such cases in the general population is still low.

      Is effective screening the answer – what should we be doing?

      HCC develops slowly over several years in patients with NAFLD. Lack of longitudinal epidemiological data on NAFLD-related HCC in noncirrhotic patients, lack of cost-effectiveness studies, and technical pitfalls with USG make formal guidelines difficult to frame. Available guidelines for cirrhotic patients in general, which recommend 6 monthly USG coupled with Alpha Feto Protein (AFP) may be followed. In noncirrhotic patients, lifestyle changes and primary prevention seems to be the most cost-effective approach. Primary prevention includes dietary and effective lifestyle changes including exercise to prevent obesity, insulin resistance and therefore MetS. Weight loss strategies to reduce obesity including bariatric techniques may be recommended. Physical activity has been shown to reduce the risk of developing HCC regardless of the etiology
      • Wen C.P.
      • Lin J.
      • Yang C.Y.
      • et al.
      Hepatocellular carcinoma risk prediction model for the general population: the predictive power of transaminases.
      . Effective pharmacological treatment of NASH is a fast growing field of research with several trials ongoing for drugs which can reduce fat and reverse fibrosis. Commonly used drugs such as metformin and statins have also been shown to have an effect on the risk of HCC. Two different meta-analysis has shown that metformin use in patients with Type 2 DM was associated with reduction of risk of HCC.
      • Zhang Z.J.
      • Zheng Z.J.
      • Shi R.
      • Su Q.
      • Jiang Q.
      • Kip K.E.
      Metformin for liver cancer prevention in patients with type 2 diabetes: a systematic review and meta-analysis.
      ,
      • Zhang H.
      • Gao C.
      • Fang L.
      • Zhao H.C.
      • Yao S.K.
      Metformin and reduced risk of hepatocellular carcinoma in diabetic patients: a meta-analysis.
      A large meta-analysis of 4298 cases of HCC showed that statin use was associated with 37% reduction in HCC
      • Singh S.
      • Singh P.P.
      • Singh A.G.
      • Murad M.H.
      • Sanchez W.
      Statins are associated with a reduced risk of hepatocellular cancer: a systematic review and meta-analysis.
      . Routine use of these drugs as chemo-preventive agent for HCC cannot be recommended until more longitudinal data are available.

      Summary

      The burden of NAFLD is increasing with the rising epidemic of obesity, insulin resistance, and MetS. The risk of HCC in NAFLD is well documented, especially in patients with advanced fibrosis and cirrhosis. In addition, significant proportion of patients with NAFLD-HCC have no underlying cirrhosis. Patients with cirrhosis should be screened such as cirrhotic patients of other etiologies. Recommendations for HCC screening in patient in noncirrhotic patients with NAFLD cannot be made due to lack of robust longitudinal data and studies on cost-effectiveness. USG has its limitations in screening patients with NAFLD, more so in obese patients. Effective prevention of NAFLD and management of risk factors that contribute to progression of NAFLD is the key to management of NAFLD-HCC.

      Conflicts of interest

      The authors have none to declare.

      References

        • 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.
        Hepatology. 2014; 59 (PMID: 24375711): 2188-2195https://doi.org/10.1002/hep.26986
        • Khan F.
        • Perumpail R.
        • Wong R.
        • Ahmed A.
        Advances in hepatocellular carcinoma: nonalcoholic steatohepatitis- related hepatocellular carcinoma.
        World J Hepatol. 2015; 7: 2155-2216
        • 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.
        Hepatology. 1999; 29: 664-669
        • Poonawala A.
        • Nair S.P.
        • Thuluvath P.J.
        Prevalence of obesity and diabetes in patients with cryptogenic cirrhosis: a case-control study.
        Hepatology. 2000; 32: 689-692
        • Kanwal F.
        • Kramer J.R.
        • Mapakshi S.
        • et al.
        Risk of hepatocellular cancer in patients with non-alcoholic fatty liver disease.
        Gastroenterology. 2018 Dec; 155 (Epub 2018 Aug 23.PubMed PMID: 30144434; PubMed Central PMCID: PMC6279617): 1828-1837https://doi.org/10.1053/j.gastro.2018.08.024
        • Younossi Z.M.
        • Otgonsuren M.
        • Henry L.
        • et al.
        Association of nonalcoholic fatty liver disease (NAFLD) with hepatocellular carcinoma (HCC) in the United States from 2004 to 2009.
        Hepatology. 2015 Dec; 62 (Epub 2015 Oct 24. PubMed PMID:26274335): 1723-1730https://doi.org/10.1002/hep.28123
        • Mittal S.
        • Sada Y.H.
        • El-Serag H.B.
        • et al.
        Temporal trends of nonalcoholic fatty liver disease-related hepatocellular carcinoma in the veteran affairs population.
        Clin Gastroenterol Hepatol. 2015 Mar; 13 (Epub 2014 Aug 19. PubMed PMID: 25148760; PubMed Central PMCID: PMC4333060): 594-601https://doi.org/10.1016/j.cgh.2014.08.013
        • Tateishi R.
        • Okanoue T.
        • Fujiwara N.
        • et al.
        Clinical characteristics, treatment, and prognosis of non-B,non-C hepatocellular carcinoma: a large retrospective multicenter cohort study.
        J Gastroenterol. 2015 Mar; 50 (Epub 2014 Jun 15. PubMed PMID: 24929638; PubMed Central PMCID: PMC4352653): 350-360https://doi.org/10.1007/s00535-014-0973-8
        • 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 US.
        Hepatology. 2014; 59: 2188-2195
        • Gonçalves P.L.
        • Zago-Gomes Mda P.
        • Marques C.C.
        • Mendonça A.T.
        • Gonçalves C.S.
        • Pereira F.E.
        Etiology of liver cirrhosis in Brazil: chronic alcoholism and hepatitis viruses in liver cirrhosis diagnosed in the state of Espírito Santo.
        Clinics (Sao Paulo). 2013; 68 (PubMed PMID: 23644846; PubMed Central PMCID:PMC3611744): 291-295
        • Yang J.D.
        • Kim B.
        • Sanderson S.O.
        • et al.
        Hepatocellular carcinoma in olmsted county,Minnesota, 1976-2008.
        Mayo Clin Proc. 2012 Jan; 87 (PubMed PMID: 22212963; PubMed Central PMCID:PMC3538386): 9-16https://doi.org/10.1016/j.mayocp.2011.07.001
        • Tokushige K.
        • Hashimoto E.
        • Horie Y.
        • Taniai M.
        • Higuchi S.
        Hepatocellular carcinoma in Japanese patients with nonalcoholic fatty liver disease, alcoholic liver disease, and chronic liver disease of unknown etiology: report of the nationwide survey.
        J Gastroenterol. 2011; 46: 1230-1237
        • Hucke F.
        • Sieghart W.
        • Schöniger-Hekele M.
        • Peck-Radosavljevic M.
        • Müller C.
        Clinical characteristics of patients with hepatocellular carcinoma in Austria -is there a need for a structured screening program?.
        Wien Klin Wochenschr. 2011 Sep; 123 (Epub 2011 Jul 29. PubMed PMID: 21800047): 542-551https://doi.org/10.1007/s00508-011-0033-9
        • Kawada N.
        • Imanaka K.
        • Kawaguchi T.
        • et al.
        Hepatocellular carcinoma arising from non-cirrhotic nonalcoholic steatohepatitis.
        J Gastroenterol. 2009; 44 (PubMed PMID: 19672551): 1190-1194https://doi.org/10.1007/s00535-009-0112-0
        • Malik S.M.
        • Gupte P.A.
        • de Vera M.E.
        • Ahmad J.
        Liver transplantation in patients with nonalcoholic steatohepatitis-related hepatocellular carcinoma.
        Clin Gastroenterol Hepatol. 2009 Jul; 7 (Epub 2009 Mar 9. PubMed PMID: 19281869): 800-806https://doi.org/10.1016/j.cgh.2009.02.025
        • 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?.
        Arch Pathol Lab Med. 2008 Nov; 132 (PubMed PMID: 18976012): 1761-1766https://doi.org/10.1043/1543-2165-132.11.1761
        • 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.
        Hepatology. 2002 Dec; 36 (PubMed PMID: 12447858): 1349-1354
        • Bugianesi E.
        • Leone N.
        • Vanni E.
        • et al.
        Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma.
        Gastroenterology. 2002 Jul; 123 (PubMed PMID: 12105842): 134-140
        • Paradis V.
        • Zalinski S.
        • Chelbi E.
        • et al.
        Hepatocellular carcinomas in patients with metabolic syndrome often develop without significant liver fibrosis: a pathological analysis.
        Hepatology. 2009; 49: 851-859
        • Mittal S.
        • El-Serag H.B.
        • Sada Y.H.
        • et al.
        Hepatocellular carcinoma in the absence of cirrhosis in United States veterans is associated with nonalcoholic fatty liver disease.
        Clin Gastroenterol Hepatol. 2016; 14: 124-131
        • Ertle J.
        • Dechêne A.
        • Sowa J.P.
        • et al.
        Non-alcoholic fatty liver disease progresses to hepatocellular carcinoma in the absence of apparent cirrhosis.
        Int J Canc. 2011 May 15; 128 (Epub 2011 Mar 14. PubMed PMID: 21128245): 2436-2443https://doi.org/10.1002/ijc.25797
        • Bengtsson B.
        • Stål P.
        • Wahlin S.
        • Björkström N.K.
        • Hagström H.
        Characteristics and outcome of hepatocellular carcinoma in patients with NAFLD without cirrhosis.
        Liver Int. 2019 Jun; 39 (Epub 2019 Mar 29.PubMed PMID: 30829446): 1098-1108https://doi.org/10.1111/liv.14087
        • Gawrieh S.
        • Dakhoul L.
        • Miller E.
        • et al.
        Characteristics, aetiologies and trends of hepatocellular carcinoma in patients without cirrhosis: a United States multicentre study.
        Aliment Pharmacol Ther. 2019 Oct; 50 (Epub 2019 Sep 1. PubMed PMID: 31475372): 809-821https://doi.org/10.1111/apt.15464
        • Mohamad B.
        • Shah V.
        • Onyshchenko M.
        • et al.
        Characterization of hepatocellular carcinoma (HCC) in non-alcoholic fatty liver disease (NAFLD) patients without cirrhosis.
        Hepatol Int. 2016 Jul; 10 (Epub 2015 Nov 11.PubMed PMID: 26558795): 632-639https://doi.org/10.1007/s12072-015-9679-0
        • Perumpail R.B.
        • Wong R.J.
        • Ahmed A.
        • Harrison S.A.
        Hepatocellular carcinoma in the setting of non-cirrhotic nonalcoholic fatty liver disease and the metabolic syndrome: US experience.
        Dig Dis Sci. 2015 Oct; 60 (Epub 2015 Aug 7. PubMed PMID: 26250831): 3142-3148https://doi.org/10.1007/s10620-015-3821-7
        • Dyson J.
        • Jaques B.
        • Chattopadyhay D.
        • et al.
        Hepatocellular cancer: the impact of obesity, type 2 diabetes and a multidisciplinary team.
        J Hepatol. 2014 Jan; 60 (Epub 2013 Aug 23. PubMed PMID: 23978719): 110-117https://doi.org/10.1016/j.jhep.2013.08.011
        • Yasui K.
        • Hashimoto E.
        • Komorizono Y.
        • et al.
        Characteristics of patients with nonalcoholic steatohepatitis who develop hepatocellular carcinoma.
        Clin Gastroenterol Hepatol. 2011 May; 9 (Epub 2011 Feb 12. PubMed PMID: 21320639): 428-433https://doi.org/10.1016/j.cgh.2011.01.023
        • Singal A.G.
        • Pillai A.
        • Tiro J.
        Early detection, curative treatment, and survival rates for hepatocellular carcinoma surveillance in patients with cirrhosis: a meta-analysis.
        PLoS Med. 2014 Apr 1; 11e1001624
        • Heimbach J.K.
        • Kulik L.M.
        • Finn R.S.
        • et al.
        AASLD guidelines for the treatment of hepatocellular carcinoma.
        Hepatology. 2018 Jan; 67: 358-380https://doi.org/10.1002/hep.29086
        • European Association for the Study of the Liver
        Electronic address:[email protected]; European association for the study of the liver. EASL clinical Practice guidelines: management of hepatocellular carcinoma.
        J Hepatol. 2018 Jul; 69: 182-236https://doi.org/10.1016/j.jhep.2018.03.019
        • Bhaskaran K.
        • Douglas I.
        • Forbes H.
        • dos-Santos-Silva I.
        • Leon D.A.
        • Smeeth L.
        Body-mass index and risk of 22 specific cancers: a population-based cohort study of 5_24 million UK adults.
        Lancet. 2014; 384: 755-765
        • Inoue M.
        • Iwasaki M.
        • Otani T.
        • Sasazuki S.
        • Noda M.
        • Tsugane S.
        Diabetes mellitus and the risk of cancer: results from a large-scale population based cohort study in Japan.
        Arch Intern Med. 2006; 166: 1871-1877
        • El-Serag H.B.
        • Hampel H.
        • Javadi F.
        The association between diabetes and hepatocellular carcinoma: a systematic review of epidemiologic evidence.
        Clin Gastroenterol Hepatol. 2006; 4: 369-380
        • Schlesinger S.
        • Aleksandrova K.
        • Pischon T.
        • et al.
        Abdominal obesity, weight gain during adulthood and risk of liver and biliary tract cancer in a European cohort.
        Int J Canc. 2013; 132: 645-657
        • Turati F.
        • Talamini R.
        • Pelucchi C.
        • Polesel J.
        • Franceschi S.
        • Crispo A.
        Metabolic syndrome and hepatocellular carcinoma risk.
        Br J Canc. 2013; 108: 222-228
        • Sookoian S.
        • Pirola C.J.
        Meta-analysis of the influence of I148M variant of patatin-like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease.
        Hepatology. 2011; 53: 1883-1894
        • Dongiovanni P.
        • Romeo S.
        • Valenti L.
        Hepatocellular carcinoma in nonalcoholic fatty liver: role of environmental and genetic factors.
        World J Gastroenterol. 2014; 20: 12945-12955
        • Donati B.
        • Pietrelli A.
        • Pingitore P.
        • et al.
        Telomerase reverse transcriptase germline mutations and hepatocellular carcinoma in patients with nonalcoholic fatty liver disease.
        Canc Med. 2017; 6: 1930-1940
        • Yopp A.C.
        • Choti M.A.
        Non-alcoholic steatohepatitis-related hepatocellular carcinoma: a growing epidemic?.
        Dig Dis. 2015; 33: 642-647
        • Piscaglia F.
        • Svegliati-Baroni G.
        • Barchetti A.
        HCC-NAFLD Italian Study Group Clinical patterns of hepatocellular carcinoma in nonalcoholic fatty liver disease: a multicenter prospective study.
        Hepatology. 2016; 63: 827-838
        • Mittal S.
        • Sada Y.
        • El-Serag H.B.
        • et al.
        Temporal trends of nonalcoholic fatty liver disease-related hepatocellular carcinoma in the Veteran Affairs Population.
        Clin Gastroenterol Hepatol. 2015; 13: 594-601
        • Prorok P.C.
        Epidemiologic approach for cancer screening. Problems in design and analysis of trials.
        Am J Pediatr Hematol Oncol. 1992 May; 14 (Review.PubMed PMID: 1530116): 117-128
        • Leung C.
        • Yeoh S.W.
        • Patrick D.
        • et al.
        Characteristics of hepatocellular carcinoma in cirrhotic and non-cirrhotic non-alcoholic fatty liver disease.
        World J Gastroenterol. 2015; 21: 1189-1196https://doi.org/10.3748/wjg.v21.i4.1189
        • Kawamura Y.
        • Arase Y.
        • Ikeda K.
        • et al.
        Largescale long-term follow-up study of Japanese patients with non-alcoholicFatty liver disease for the onset of hepatocellular carcinoma.
        Am J Gastroenterol. 2012; 107: 253-261
        • Wen C.P.
        • Lin J.
        • Yang C.Y.
        • et al.
        Hepatocellular carcinoma risk prediction model for the general population: the predictive power of transaminases.
        J Natl Cancer Inst. 2012; 104: 1599-1611
        • Zhang Z.J.
        • Zheng Z.J.
        • Shi R.
        • Su Q.
        • Jiang Q.
        • Kip K.E.
        Metformin for liver cancer prevention in patients with type 2 diabetes: a systematic review and meta-analysis.
        J Clin Endocrinol Metab. 2012; 97: 2347-2353
        • Zhang H.
        • Gao C.
        • Fang L.
        • Zhao H.C.
        • Yao S.K.
        Metformin and reduced risk of hepatocellular carcinoma in diabetic patients: a meta-analysis.
        Scand J Gastroenterol. 2013; 48: 78-87
        • Singh S.
        • Singh P.P.
        • Singh A.G.
        • Murad M.H.
        • Sanchez W.
        Statins are associated with a reduced risk of hepatocellular cancer: a systematic review and meta-analysis.
        Gastroenterology. 2013; 144: 323-332