Epidemiology and Management of Hepatocellular Carcinoma

The major risk factors for hepatocellular carcinoma (HCC) in contemporary clinical practice are becoming increasingly related to sustained virological response after hepatitis C, suppressed hepatitis B virus during treatment, and alcoholic and nonalcoholic fatty liver disease. We review the emerging data on the risk and determinants of HCC in these conditions and the implications of HCC surveillance. However, from a public health perspective, active hepatitis C and B continue to drive most of the global burden of HCC. In United States, the age-adjusted incidence rates of HCC in Hispanics have surpassed those of HCC in Asians. Prognosis in HCC is complex because of the competing risk imposed by underlying cirrhosis and presence of malignancy. In addition to tumor burden, liver function and performance status; additional parameters including tumor biopsy, serum markers, and subclassification of current staging systems; and taking into account patterns of tumor progression may improve patient selection for therapy. Advancements in the treatment of HCC have included identification of patients who are most likely to derive a clinically significant benefit from the available therapeutic options. Additionally, the combination strategies of locoregional therapies and/or systemic therapy are being investigated. The major risk factors for hepatocellular carcinoma (HCC) in contemporary clinical practice are becoming increasingly related to sustained virological response after hepatitis C, suppressed hepatitis B virus during treatment, and alcoholic and nonalcoholic fatty liver disease. We review the emerging data on the risk and determinants of HCC in these conditions and the implications of HCC surveillance. However, from a public health perspective, active hepatitis C and B continue to drive most of the global burden of HCC. In United States, the age-adjusted incidence rates of HCC in Hispanics have surpassed those of HCC in Asians. Prognosis in HCC is complex because of the competing risk imposed by underlying cirrhosis and presence of malignancy. In addition to tumor burden, liver function and performance status; additional parameters including tumor biopsy, serum markers, and subclassification of current staging systems; and taking into account patterns of tumor progression may improve patient selection for therapy. Advancements in the treatment of HCC have included identification of patients who are most likely to derive a clinically significant benefit from the available therapeutic options. Additionally, the combination strategies of locoregional therapies and/or systemic therapy are being investigated. Hashem B. El-SeragView Large Image Figure ViewerDownload Hi-res image Download (PPT) The incidence and mortality of hepatocellular carcinoma (HCC) have been increasing in North America and several European regions and declining in traditionally high-risk regions, including Japan and parts of China. The main risk factors for HCC are chronic hepatitis C virus (HCV) or hepatitis B virus (HBV), heavy alcohol drinking, diabetes, and, possibly, nonalcoholic fatty liver disease (NAFLD).1Singal A.G. El-Serag H.B. Hepatocellular carcinoma from epidemiology to prevention: translating knowledge into practice.Clin Gastroenterol Hepatol. 2015; 13: 2140-2151Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar HCC has been the fastest-rising cause of cancer-related deaths in the United States. In an analysis including all 50 US states, HCC age-adjusted incidence rates increased from 4.4/100,000 in 2000 to 6.7/100,000 in 2012, increasing by 4.5% annually between 2000 and 2009 (Figure 1)2White D.L. Thrift A.P. Kanwal F. et al.Incidence of hepatocellular carcinoma in all 50 United States, from 2000 through 2012.Gastroenterology. 2017; 152: 812-820Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar. There has been a recent slowing of the increase in incidence and mortality rates for HCC in the United States, with an annual increase of only 0.7% from 2010 through 2012. However, HCC incidence is disproportionately increasing in men ages 55 to 64 years—especially those born in the peak era of HCV infection and in certain ethnic/racial groups, including Hispanics, African Americans, and whites. Asian men had the highest age-adjusted incidence rates attributed to chronic HBV, especially among immigrants from HBV-endemic areas. Subsequent generations of US-born Asians have much lower rates of HBV infection, and recent immigrants from HBV-endemic areas may be benefitting from reduced aflatoxin exposure and an increase in HBV vaccinations. HCC age-adjusted incidence rates among Hispanics have surpassed those among Asians. The rates are higher in US-born Hispanics than in non–US-born Hispanics. The reasons are likely related to higher rates of HCV (particularly in Mexican Americans),3Armstrong G.L. Wasley A. Simard E.P. et al.The prevalence of hepatitis C virus infection in the United States, 1999 through 2002.Ann Intern Med. 2006; 144: 705-714Crossref PubMed Google Scholar alcoholic liver disease, NAFLD,4Kallwitz E.R. Daviglus M.L. Allison M.A. et al.Prevalence of suspected nonalcoholic fatty liver disease in Hispanic/Latino individuals differs by heritage.Clin Gastroenterol Hepatol. 2015; 13: 569-576Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 5Mittal 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; 13: 594-601Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar and metabolic syndrome, including diabetes, which increases the risk of developing HCC either independently or through potentiating the effect of viral hepatitis and alcoholic liver disease. Hispanics with chronic HCV or NAFLD have a higher risk of progression to cirrhosis and HCC, which may be partly a genetic (eg, PNPLA3) predisposition. The consistently high and increasing HCC incidence rates among individuals born in the peak-HCV cohort (1945–1965), irrespective of age or calendar year, support a potential birth-cohort effect related to HCV that has not yet decreased but that is anticipated to do so by 2020. Directly acting antivirals (DAAs) may affect overall HCC incidence rates over the next 1–2 decades,6Chhatwal J. Kanwal F. Roberts M.S. Dunn M.A. Cost-effectiveness and budget impact of hepatitis C virus treatment with sofosbuvir and ledipasvir in the United States.Ann Intern Med. 2015; 162: 397-406Crossref PubMed Scopus (228) Google Scholar but the magnitude and timing of anticipated decreases in HCC incidence rates depend on the availability and penetration of HCV treatment, as well as increased detection, diagnosis, and linkage to care for individuals with chronic HCV infection. Patients with HCV-induced cirrhosis are at particularly high risk for the development of HCC, with an annual incidence of HCC ranging from 0.5% to 10%. Sustained virologic response (SVR) with DAA has emerged as the most dominant modifier of HCC in patients with HCV. Other than cirrhosis, the residual role of most traditional risk factors among those with active untreated or uncured HCV is unclear; these factors include older age, male sex, Hispanic ethnicity,7El-Serag H.B. Kramer J. Duan Z. Kanwal F. Racial differences in the progression to cirrhosis and hepatocellular carcinoma in HCV-infected veterans.Am J Gastroenterol. 2014; 109: 1427Crossref PubMed Scopus (47) Google Scholar diabetes, obesity, smoking, HCV genotype 3,8Kanwal F. Kramer J.R. Ilyas J. et al.HCV genotype 3 is associated with an increased risk of cirrhosis and hepatocellular cancer in a national sample of US Veterans with HCV.Hepatology. 2014; 60: 98-105Crossref PubMed Scopus (0) Google Scholar heavy alcohol use, and HIV or HBV coinfection.9El-Serag H.B. Epidemiology of viral hepatitis and hepatocellular carcinoma.Gastroenterology. 2012; 142: 1264-1273Abstract Full Text Full Text PDF PubMed Scopus (1732) Google Scholar Although DAA is likely to change the epidemiology of HCV-related HCC in those who are treated, most HCV-infected populations remain untreated.10Thrift A.P. El-Serag H.B. Kanwal F. Global epidemiology and burden of HCV infection and HCV-related disease.Nat Rev Gastroenterol Hepatol. 2017; 14: 122Crossref PubMed Scopus (136) Google Scholar Although few studies report a possibly unexpected high incidence of de novo and recurrent HCC after DAA treatment,11Reig M. Mariño Z. Perelló C. et al.Unexpected high rate of early tumor recurrence in patients with HCV-related HCC undergoing interferon-free therapy.J Hepatol. 2016; 65: 719-726Abstract Full Text Full Text PDF PubMed Scopus (484) Google Scholar growing data consistently illustrate a considerable (50%–80%) and steady HCC risk reduction over time of de novo HCC among those achieving DAA-related SVR. DAAs offer a chance of cure for patients with advanced cirrhosis, older patients, and those with alcohol use—all characteristics independently associated with risk of HCC in HCV.12Huang A.C. Mehta N. Dodge J.L. et al.Direct-acting antivirals do not increase the risk of hepatocellular carcinoma recurrence after local-regional therapy or liver transplant waitlist dropout.Hepatology. 2018; 68: 393-794Crossref PubMed Scopus (9) Google Scholar, 13Ioannou G.N. Green P.K. Berry K. HCV eradication induced by direct-acting antiviral agents reduces the risk of hepatocellular carcinoma.J Hepatol. 2018; 68: 25-32Abstract Full Text Full Text PDF Scopus (104) Google Scholar, 14Pol S. Lack of evidence of an effect of direct acting antivirals on the recurrence of hepatocellular carcinoma.J Hepatol. 2016; 65: 734-740Abstract Full Text Full Text PDF PubMed Scopus (240) Google Scholar These patients were not treated or had poor response to interferon (IFN)-based treatment. Despite these historical differences, in a systematic review of 26 studies on de novo HCC occurrence (IFN, n = 17; DAA, n = 9), there was no evidence for differential HCC occurrence or recurrence risk after SVR from DAA and IFN-based therapy.15Waziry R. Hajarizadeh B. Grebely J. et al.Hepatocellular carcinoma risk following direct-acting antiviral HCV therapy: a systematic review, meta-analyses, and meta-regression.J Hepatol. 2017; 67: 1204-1212Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar The implications of SVR-related change in HCC risk on HCC surveillance are evolving. Kanwal et al.16Kanwal F. Kramer J. Asch S.M. et al.Risk of hepatocellular cancer in HCV patients treated with direct-acting antiviral agents.Gastroenterology. 2017; 153: 996-1005Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar found that patients who achieved SVR with DAAs had a 76% reduction in risk of HCC compared with patients who did not achieve SVR.16Kanwal F. Kramer J. Asch S.M. et al.Risk of hepatocellular cancer in HCV patients treated with direct-acting antiviral agents.Gastroenterology. 2017; 153: 996-1005Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar The HCC-preventive effect of SVR was evident early on and increased over time. However, despite the relative reduction in risk of HCC, the absolute risk of HCC persisted in patients with DAA-induced SVR. HCC developed in 183 patients during approximately 20,415 patient-years of follow-up, at an annual incidence of 0.90%. Risk of HCC was the highest among those with cirrhosis, ranging from 1.0% to 2.2% per year, based on other demographic and clinical characteristics (Figure 2). These estimates reached or exceeded the cutoffs (0.8%–1.5% per year) beyond which HCC surveillance may become cost effective.17Sarasin F.P. Giostra E. Hadengue A. Cost-effectiveness of screening for detection of small hepatocellular carcinoma in western patients with Child-Pugh class A cirrhosis.Am J Med. 1996; 101: 422-434Abstract Full Text PDF PubMed Scopus (240) Google Scholar, 18Arguedas M.R. Chen V.K. Eloubeidi M.A. Fallon M.B. Screening for hepatocellular carcinoma in patients with hepatitis C cirrhosis: a cost-utility analysis.Am J Gastroenterol. 2003; 98: 679-690Crossref PubMed Scopus (179) Google Scholar In contrast, the risk of HCC was low in almost all patients without cirrhosis, with the exception of patients with a high baseline Fibrosis-4, suggesting presence of advanced fibrosis. Based on these data, HCC surveillance is likely to continue to be needed for all patients with cirrhosis or advanced fibrosis at the time of SVR. The extent of reduction of HCV-related HCC is also dependent on screening and detection of HCV-infected cohorts and the dissemination of DAA treatments. Chronic hepatitis B (CHB) is the leading etiology of HCC worldwide. The indications for antiviral therapy using nucleoside/nucleotide analogues (NAs) has been expanded in the past 1–2 decades to cover considerably more CHB patient groups. HBV can cause HCC in the absence of cirrhosis, although most cases of HBV-related HCC (70%–90%) occur in patients with cirrhosis.19Chayanupatkul M. Omino R. Mittal S. et al.Hepatocellular carcinoma in the absence of cirrhosis in patients with chronic hepatitis B virus infection.J Hepatol. 2017; 66: 355-362Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar Risk factors for HCC in CHB include demographic (male sex, older age, Asian or African ancestry, family history of HCC), viral (higher levels of HBV replication; HBV genotype; longer duration of infection; coinfection with HCV, human immunodeficiency virus, or hepatitis delta virus), clinical (cirrhosis), and environmental (exposure to aflatoxin, heavy intake of alcohol or tobacco) factors. However, like HCV treatment, NA viral suppression has emerged as the dominant modifier of HCC risk among patients with CHB. NA has been associated with risk reduction, but not elimination, of HCC in patients with CHB.20Sung J. Tsoi K. Wong V. et al.Meta-analysis: treatment of hepatitis B infection reduces risk of hepatocellular carcinoma.Aliment Pharmacol Ther. 2008; 28: 1067-1077Crossref PubMed Scopus (0) Google Scholar, 21Wu C.-Y. Lin J.-T. Ho H.J. et al.Association of nucleos (t) ide analogue therapy with reduced risk of hepatocellular carcinoma in patients with chronic hepatitis B—a nationwide cohort study.Gastroenterology. 2014; 147: 143-151Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 22Wong G.L.H. Chan H.L.Y. Mak C.W.H. et al.Entecavir treatment reduces hepatic events and deaths in chronic hepatitis B patients with liver cirrhosis.Hepatology. 2013; 58: 1537-1547Crossref PubMed Scopus (258) Google Scholar Several scoring systems, such as CU-HCC, GAG-HCC, and REACH-B, were set up to predict the risk of HCC.23Wong V.W.-S. Chan S.L. Mo F. et al.Clinical scoring system to predict hepatocellular carcinoma in chronic hepatitis B carriers.J Clin Oncol. 2010; 28: 1660-1665Crossref PubMed Scopus (229) Google Scholar, 24Yuen M.-F. Tanaka Y. Fong D.Y.-T. et al.Independent risk factors and predictive score for the development of hepatocellular carcinoma in chronic hepatitis B.J Hepatol. 2009; 50: 80-88Abstract Full Text Full Text PDF PubMed Scopus (332) Google Scholar, 25Yang H.-I. Yuen M.-F. Chan H.L.-Y. et al.Risk estimation for hepatocellular carcinoma in chronic hepatitis B (REACH-B): development and validation of a predictive score.Lancet Oncol. 2011; 12: 568-574Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar Although these systems were externally validated and can attain high negative predictive values (above 95%) for HCC development over a 3- to 10-year period in untreated patients, they may not adequately predict HCC in patients receiving NAs.26Kim W.R. Loomba R. Berg T. et al.Impact of long-term tenofovir disoproxil fumarate on incidence of hepatocellular carcinoma in patients with chronic hepatitis B.Cancer. 2015; 121: 3631-3638Crossref PubMed Scopus (65) Google Scholar, 27Ahn J. Lim J.K. Lee H.M. et al.Lower observed hepatocellular carcinoma incidence in chronic hepatitis B patients treated sith entecavir: results of the ENUMERATE study.Am J Gastroenterol. 2016; 111: 1297-1304Crossref PubMed Scopus (0) Google Scholar Studies have shown that age, cirrhosis, male sex, platelet count, liver stiffness, and diabetes are risk factors for HCC in patients with CHB receiving NAs,28Hsu Y.-C. Wu C.-Y. Lane H.-Y. et al.Determinants of hepatocellular carcinoma in cirrhotic patients treated with nucleos (t) ide analogues for chronic hepatitis B.J Antimicrob Chemother. 2014; 69: 1920-1927Crossref PubMed Google Scholar, 29Papatheodoridis G.V. Dalekos G.N. Yurdaydin C. et al.Incidence and predictors of hepatocellular carcinoma in Caucasian chronic hepatitis B patients receiving entecavir or tenofovir.J Hepatol. 2015; 62: 363-370Abstract Full Text Full Text PDF PubMed Google Scholar, 30Raffetti E. Fattovich G. Donato F. Incidence of hepatocellular carcinoma in untreated subjects with chronic hepatitis B: a systematic review and meta-analysis.Liver Int. 2016; 36: 1239-1251Crossref PubMed Scopus (47) Google Scholar whereas pretreatment viral load, hepatitis B e antigen status, hepatitis B surface antigen quantity, and aminotransferase level are not predictive for treated patients.31Chen C.-J. Yang H.-I. Su J. et al.Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level.JAMA. 2006; 295: 65-73Crossref PubMed Scopus (2154) Google Scholar, 32Yang H.-I. Lu S.-N. Liaw Y.-F. et al.Hepatitis B e antigen and the risk of hepatocellular carcinoma.New Engl J Med. 2002; 347: 168-174Crossref PubMed Scopus (0) Google Scholar, 33Tseng T.C. Liu C.J. Yang H.C. et al.High levels of hepatitis B surface antigen increase risk of hepatocellular carcinoma in patients with low HBV load.Gastroenterology. 2012; 142: 1140-1149Abstract Full Text Full Text PDF PubMed Scopus (281) Google Scholar The Cirrhosis, Age, Male sex, Diabetes (ie, CAMD) score was developed to predict HCC risk during the first few years of NA treatment, using data from patients continuously receiving entecavir or tenofovir for CHB in the national health care database in Taiwan34Hsu Y.C. Ho H.J. Lee T.Y. et al.Temporal trend and risk determinants of hepatocellular carcinoma in chronic hepatitis B patients on entecavir or tenofovir.J Viral Hepatitis. 2018; 25: 543-551Crossref PubMed Scopus (5) Google Scholar and was externally validated using population-wide data extracted from the state-run health care database in Hong Kong (Figure 3).34Hsu Y.C. Ho H.J. Lee T.Y. et al.Temporal trend and risk determinants of hepatocellular carcinoma in chronic hepatitis B patients on entecavir or tenofovir.J Viral Hepatitis. 2018; 25: 543-551Crossref PubMed Scopus (5) Google Scholar This score appeared to be similarly accurate to the well-established PAGE-B score that was validated in white and Asian populations.35Kim M.N. Hwang S.G. Rim K.S. et al.Validation of PAGE-B model in Asian chronic hepatitis B patients receiving entecavir or tenofovir.Liver Int. 2017; 37: 1747-1919Crossref Scopus (5) Google Scholar Although HCC incidence seems to decrease with cumulative NA treatment, it is unclear whether prolonged therapy can eventually eliminate the risk. Papatheodoridis et al36Papatheodoridis G.V. Idilman R. Dalekos G.N. et al.The risk of hepatocellular carcinoma is decreasing after the first 5 years of entecavir or tenofovir in Caucasians with chronic hepatitis B.Hepatology. 2017; 66: 1444-1453Crossref PubMed Scopus (0) Google Scholar reported that a substantial risk of HCC remains after the first 5 years of entecavir or tenofovir treatment in patients with cirrhosis or older than 50 years. It is also unclear how the risk of HCC may change after NA cessation. Most knowledge about the risk of HCC in HBV is based on studies conducted in Southeast Asia and sub-Saharan Africa, where HBV infection is endemic and acquired at birth or early childhood.37Lok A.S. McMahon B.J. Chronic hepatitis B: update 2009.Hepatology. 2009; 50: 661-662Crossref PubMed Scopus (2220) Google Scholar However, a multicenter study from the United States reported an annual incidence of 0.42%, although more than 50% of the cohort was Asian Pacific Islander in origin.38Gordon S.C. Lamerato L.E. Rupp L.B. et al.Antiviral therapy for chronic hepatitis B virus infection and development of hepatocellular carcinoma in a US population.Clin Gastroenterol Hepatol. 2014; 12: 885-893Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar In addition, a recent cohort of 8329, mostly male, patients was identified in the national Veterans Health Administration (VHA) database with CHB infection from 2001 through 2013. The annual HCC incidence was highest in American Pacific Islanders (0.65%), followed by whites (0.57%) and African Americans (0.40%). There was no difference in HCC risk between African Americans and whites. HCC risk increased with age: adjusted hazard ratios (HRs) were 1.97 (95% confidence interval [CI], 0.99–3.87) for 40–49 years, 3.00 (95% CI, 1.55–5.81) for 50–59 years, and 4.02 (95% CI, 2.03–7.94) for >60 years vs <40 years. Patients with cirrhosis had higher risk of HCC than patients without cirrhosis (adjusted HR, 3.69; 95% CI, 2.82–4.83).39Mittal S. Kramer J.R. Omino R. et al.Role of age and race in the risk of hepatocellular carcinoma in veterans with hepatitis B virus infection.Clin Gastroenterol Hepatol. 2018; 16: 252-259Abstract Full Text Full Text PDF PubMed Google Scholar Even among patients without cirrhosis, the annual incidence of HCC was more than 0.2% for all patients older than 40 years with high levels of alanine aminotransferase, regardless of race and independent of HBV therapy. The American Association for the Study of Liver Disease (AASLD) guidelines recommend HCC surveillance among HBV patients, based on the HCC incidence-rate thresholds of 0.2% or greater per year among those without cirrhosis and between 0.2% and 1.5% per year among patients with underlying cirrhosis.17Sarasin F.P. Giostra E. Hadengue A. Cost-effectiveness of screening for detection of small hepatocellular carcinoma in western patients with Child-Pugh class A cirrhosis.Am J Med. 1996; 101: 422-434Abstract Full Text PDF PubMed Scopus (240) Google Scholar, 18Arguedas M.R. Chen V.K. Eloubeidi M.A. Fallon M.B. Screening for hepatocellular carcinoma in patients with hepatitis C cirrhosis: a cost-utility analysis.Am J Gastroenterol. 2003; 98: 679-690Crossref PubMed Scopus (179) Google Scholar The guidelines use family history of HCC, age, and race as additional criteria for HCC risk stratification in CHB. HCC surveillance is recommended for all patients with cirrhosis and, in the absence of cirrhosis, for Asian men older than 40 years and Asian women older than age 50 years. The guidelines also suggest that surveillance should start at a younger age for Africans and African Americans than for other races/ethnicities, without an exact specification of the age cutoff year, based on previous studies in South Africa, published in 1977 and 1988, which reported that African blacks with HBV might develop HCC at an age <40 years.40Kew E. Marcus R. Some characteristics of Mozambican Shangaans with primary hepatocellular cancer.South Afr Med J. 1977; 51: 306-309PubMed Google Scholar, 41Kew M.C. Macerollo P. Effect of age on the etiologic role of the hepatitis B virus in hepatocellular carcinoma in blacks.Gastroenterology. 1988; 94: 439-442Abstract Full Text PDF PubMed Google Scholar A recent study in multiple African countries confirmed the younger age of HBV-related HCC in these countries.42Yang J.D. Mohamed E.A. Aziz A.O.A. et al.Characteristics, management, and outcomes of patients with hepatocellular carcinoma in Africa: a multicountry observational study from the Africa Liver Cancer Consortium.Lancet Gastroenterol Hepatol. 2017; 2: 103-111Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar Recent US-based studies confirmed that the age effect observed in the studies conducted in East Asia, the risk of HCC increased with age, and the inflection point for markedly increased risk of HCC was among those older than 40 years;39Mittal S. Kramer J.R. Omino R. et al.Role of age and race in the risk of hepatocellular carcinoma in veterans with hepatitis B virus infection.Clin Gastroenterol Hepatol. 2018; 16: 252-259Abstract Full Text Full Text PDF PubMed Google Scholar, 40Kew E. Marcus R. Some characteristics of Mozambican Shangaans with primary hepatocellular cancer.South Afr Med J. 1977; 51: 306-309PubMed Google Scholar however, the VHA cohort data indicate an extremely low risk of HCC in all individuals younger than 40 years, including African American patients (annual incidence, 0.03%). Furthermore, irrespective of age, the risk of HCC among African Americans with chronic HBV was not significantly different from the risk among whites. These data show that, in the United States, African Americans with chronic HBV may not need surveillance at an earlier age than patients of other racial groups. This recommendation may still be relevant to Africans in whom aflatoxin exposure plays an additional role. NAFLD has become the leading cause of chronic liver disease in most regions of the world, including the United States,43Stepanova M. De Avila L. Afendy M. et al.Direct and indirect economic burden of chronic liver disease in the United States.Clin Gastroenterol Hepatol. 2017; 15: 759-766Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar with up to 30% prevalence in the general population.44Williams C.D. Stengel J. Asike M.I. 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.Gastroenterology. 2011; 140: 124-131Abstract Full Text Full Text PDF PubMed Scopus (1164) Google Scholar An estimated 20%–30% of patients with NAFLD develop progressive liver disease with necroinflammation and fibrosis that can result in cirrhosis in 10%–20% of cases.45Ahmed A. Wong R.J. Harrison S.A. Nonalcoholic fatty liver disease review: diagnosis, treatment, and outcomes.Clin Gastroenterol Hepatol. 2015; 13: 2062-2070Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar The prevalence of NAFLD and risk of progression is higher among Hispanics than other racial and ethnic groups.46Rich N.E. Oji S. Mufti A.R. et al.Racial and ethnic disparities in nonalcoholic fatty liver disease prevalence, severity, and outcomes in the United States: a systematic review and meta-analysis.Clin Gastroenterol Hepatol. 2018; 16: 198-210Abstract Full Text Full Text PDF PubMed Google Scholar NAFLD is the fastest-growing cause of HCC-related transplantation in the United States,47Wong 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: 2188-2195Crossref PubMed Scopus (240) Google Scholar although the exact magnitude, timing, and determinants of HCC in NAFLD patients are unclear. A systematic review of epidemiologic studies (published through 2011) examining the NAFLD-HCC link found mixed results, with HCC risk ranging from 0% to 38% over 5–10 years of follow-up48White D.L. Kanwal F. El–Serag H.B. Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review.Clin Gastroenterol Hepatol. 2012; 10: 1342-1359Abstract Full Text Full Text PDF PubMed Scopus (372) Google Scholar; subgroups with cirrhosis were at distinctly high HCC risk. Most published studies included small or modest-sized NAFLD cohorts and, thus, had few or no incident HCC cases. Furthermore, most studies evaluated patients in tertiary care settings. Thus, the generalizability of these findings to community-based clinical populations with NAFLD is unclear. HCC occurring in the absence of cirrhosis is unusual and mainly occurs in up to 15% of HBV- related cases. Among new HCC cases without advanced fibrosis or cirrhosis in the United States, NAFLD constitutes the largest etiological proportion of cases.49Mittal 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: 124-131Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar This entity poses a challenge to clinical practice paradigms based on HCC risk mediated through cirrhosis. A lower proportion of patients with NAFLD-related HCC receive HCC surveillance before their HCC diagnosis or HCC-specific treatment than of patients with HCV-related HCC.49Mittal 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: 124-131Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar The available data on HCC risk support screening among patients with NAFLD-related cirrhosis, but it may be cost effective for patients with advanced fibrosis, especially those with multiple components of metabolic syndrome and Hispanics. Irrespective of NAFLD, diabetes and obesity increase HCC risk. Type 2 diabetes was associated with a 2- to 3-fold increase in the risk of HCC,50El-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: 369-380Abstract Full Text Full Text PDF PubMed Scopus (557) Google Scholar including in cohort studies that reduce the likelihood of reverse association.51Chen J. Han Y. Xu C. et al.Effect of type 2 diabetes mellitus on th