GASTROENTEROLOGY 2004;127:S35S50

Hepatocellular Carcinoma in Cirrhosis: Incidence and Risk Factors

GIOVANNA FATTOVICH,* TOMMASO STROFFOLINI,, IRENE ZAGNI,* and FRANCESCO DONATO
*Department of Gastroenterology, University of Verona, Verona; Clinical Epidemiology Unit, Istituto Superiore Sanit, Roma; Department of Gastroenterology, S. Giacomo Hospital, Roma; and Chair of Hygiene, University of Brescia, Brescia, Italy

Emerging data indicate that the mortality rate of hepatocellular carcinoma (HCC) associated with cirrhosis is rising in some developed countries, whereas mortality from nonHCC complications of cirrhosis is decreasing or is stable. Cohort studies indicate that HCC is currently the major cause of liver-related death in patients with compensated cirrhosis. Hepatitis C virus (HCV) infection is associated with the highest HCC incidence in persons with cirrhosis, occurring twice as commonly in Japan than in the West (5-year cumulative incidence, 30% and 17%, respectively), followed by hereditary hemochromatosis (5-year cumulative incidence, 21%). In hepatitis B virus (HBV)-related cirrhosis, the 5-year cumulative HCC risk is 15% in high endemic areas and 10% in the West. In the absence of HCV and HBV infection, the HCC incidence is lower in alcoholic cirrhotics (5-year cumulative risk, 8%) and subjects with advanced biliary cirrhosis (5-year cumulative risk, 4%). There are limited data on HCC risk in cirrhosis of other causes. Older age, male sex, severity of compensated cirrhosis at presentation, and sustained activity of liver disease are important predictors of HCC, independent of etiology of cirrhosis. In viral-related cirrhosis, HBV/HCV and HBV/HDV coinfections increase the HCC risk (2- to 6-fold relative to each infection alone) as does alcohol abuse (2- to 4-fold relative to alcohol abstinence). Sustained reduction of HBV replication lowers the risk of HCC in HBV-related cirrhosis. Further studies are needed to investigate other viral factors (eg, HBV genotype/mutant, occult HBV, HIV coinfection) and preventable or treatable comorbidities (eg, obesity, diabetes) in the HCC risk in cirrhosis.

factors for HCC.3 6 The present article reviews the burden, incidence, and risk factors for HCC in persons with cirrhosis, with an emphasis on HCV- and HBV-related cirrhosis.

The Burden of HCC in Cirrhosis

HCC is a common cause of death among patients with compensated cirrhosis. European cohort studies have reported that, among persons who died of a liverrelated cause, HCC was the responsible cause in 54%6 to 70%7 of patients with compensated cirrhosis of different etiologies and in 50% of patients with HCV-related cirrhosis.8 Data from one of the longitudinal studies, which involved 112 cirrhotic patients with HCC detected during ultrasound surveillance, showed that tumor progression was the cause of death of 63% of patients with HCC who died during the rst 4 years of surveillance (19871991), of 69% who died during the second 4-year period (19921996), and of 83% who died during the third period (19972001).6 Recent epidemiologic data indicate that, in the United States as well as in some European countries, the mortality rate from HCC is increasing.9 11 Conversely, cirrhosis-related mortality not due to HCC declined into the early 1990s in the same areas,12,13 although, subsequently, remained stable in the United States between 1995 and 1998.14 A similar trend was noted in Italy, between 1969 and 2000, where the mortality rates of cirrhosis showed a clear decline while the mortality rates for HCC slowly increased15 (Figure 1). A possible explanation for these ndings is that medical management of
Abbreviations used in this paper: AFP, -fetoprotein; AIH; autoimmune hepatitis; 1-ATD, 1-antitrypsin deciency; anti-HCV, antibody to HCV; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HH, hereditary hemochromatosis; IR, irregular regeneration; LCC, large cell change; NASH, nonalcoholic steatohepatitis; PBC, primary biliary cirrhosis; PCNA, proliferating cell nuclear antigen; PSC, primary sclerosing cholangites; PCT, porphyria cutanea tarda. 2004 by the American Gastroenterological Association 0016-5085/04/$30.00 doi:10.1053/j.gast.2004.09.014

irrhosis from any cause predisposes to hepatocellular carcinoma (HCC) and hence can be considered a premalignant condition. Indeed, the majority of patients worldwide with HCC have underlying cirrhosis.1 With the exception of some areas of the world where hepatitis B virus (HBV) infection is endemic and the role of other oncogenic agents (ie, aatoxin) may be important,2 it is uncommon to nd HCC in the absence of cirrhosis. On a global basis, longitudinal studies indicate that cirrhosis related to either hepatitis C virus (HCV) or hepatitis B virus (HBV) infections represent the major known risk

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tions must take into account the fact that there is increasing immigration to the European Union from countries on the eastern and southern borders and from the Mediterranean basin, where there are high rates of HCV infection, as well as from countries with high rates of HBV infection. This clearly adds to the future burden of both HBV and HCV infection in Europe, with a consequent increase in the frequency of both cirrhosis and HCC in the area. Similarly, the prevalence of anti-HCV is very high in the youngest age groups in other countries such as Egypt,19 and, therefore, HCV-related cirrhosis and HCC will continue to be important health problems in these countries for the next decades.
Figure 1. Age-adjusted death rates for hepatocellular carcinoma and cirrhosis by year in Italy, 1969 through 2000 (data from the Ofce of National Statistics, Rome).

HCC With and Without Underlying Cirrhosis

Patients at risk for HCC include those with chronic HBV or HCV infection, certain metabolic liver disease, such as hereditary hemochromatosis and porphyria cutanea tarda, and those with cirrhosis, regardless of its etiology. The prevalence of cirrhosis in persons with HCC is about 80%90% in autopsied series worldwide, and, therefore, approximately 10% to 20% of cases of HCC develop in persons without cirrhosis.1 Differences of geographic area, method of recruitment of the HCC cases (medical or surgical), and the type of material studied (liver biopsy specimens, autopsy, or partial hepatectomies) may account for the variable prevalence of HCC without underlying cirrhosis (7% to 54%) quoted in a series of studies.2,20 26 Percutaneous liver biopsy specimens are subject to sampling error. However, only a small proportion of patients with HCC without cirrhosis have absolutely normal liver histology, the majority of them showing a range of brosis intensity from no brosis at all to septal and bridging brosis, necroinammation, steatosis, and liver cell dysplasia.2527 Cirrhosis of all etiologies may be complicated by HCC, but persistent HBV or HCV infection account for over 80% of HCC cases worldwide.28 Studies that have investigated the presumptive etiology of HCC according to the presence or absence of cirrhosis are shown in Table 1.21,2326 Among HCC cases with cirrhosis, HCV infection was identied in 27%73%, HBV infection in 12%55%, heavy alcohol intake in 4%38%, and hemochromatosis and other causes in 2% 6%, leaving 4% 6% of the total number of cases without an identied cause. Among persons with HCC but without underlying cirrhosis, HCV infection accounted for 3%54%, HBV infection for 4%29%, heavy alcohol intake for 0%28%, and less common conditions for 1%5% of the cases; in a variable proportion of HCC cases, the etiology was unknown. Overall, these data are in agreement

non-HCC complications of cirrhosis, such as prevention and treatment of variceal bleeding and management of ascites, has improved, as has the availability of alcoholism treatment, leading to longer survival of patients with cirrhosis, who in turn are at greater risk over time of developing HCC. A recent report of a decrease in the mortality rate of alcohol-related cirrhosis supports this hypothesis.14 From a worldwide perspective, the burden of chronic HBV infection should begin to decline because of the increasing utilization of HBV immunization, whereas HCV infection will continue to have a global impact on health in the immediate future. Indeed, HCV may be responsible, in part, for the upward trend in the incidence and mortality from HCC in some countries.10 Because markers of HCV infection are found in 27% 75% of HCC cases in Europe and the United States, the reservoir of HCV infection in the general population raises concerns that there is likely to be an increasing incidence of cirrhosis and HCC in the coming decades in these same areas. Future projections of the HCC incidence can be made based on the hepatitis C age-specic prevalence in the general population. In the United States, the highest prevalence of antibody to HCV (antiHCV) (3.9%) is observed in subjects 30 to 50 years of age,16 suggesting that, in future decades, as these cohorts age, there will be an increase in the frequency of chronic liver disease that will include cirrhosis and HCC. In Italy, in contrast, because the peak anti-HCV prevalence is found in persons over the age of 50 years with a relatively low prevalence seen among the younger generation,17,18 it is unlikely that there will be an increasing incidence of cirrhosis and HCC because of hepatitis C in the next decades. However, these epidemiologic projec-

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Table 1. Prevalence of Risk Factors for Hepatocellular Carcinoma Among Patients With and Without Cirrhosis
No. HCC cases 250 80 84 56 373d 102d 1039d 79d 142 21 Mean age (y) 57 51 62 50 62 58 65 64 64 64 % With HCV infection 27 3 31 6 65e 54e 73a 44e 39 28 % With HBV infection 32 21 55 13 12 3.6 12 12 26 29 % With % With concurrent heavy % With HCV and HBV alcohol other risk infection intake factors 0 0 n.a. n.a. 11 0 5 3 2 5 29 13 38c 14c 4e 0 6 n.a. 25 28 6 1 n.a. n.a. n.a. n.a. 4.9 n.a. 2 5 % Without known risk factors 6 62 n.a. n.a. n.a. n.a. 3.7 n.a. 6 5

Author (reference) Bralet (25)a

Geographic area France Belgium Italy Italy Italy

Presence of cirrhosis Yes No Yes No Yes No Yes No Yes No

% Males 84 66 82 61 79 61 77 72 82 91

Van Roey (24)b Trevisani (21)b Stroffolini (23)b Chiesa (26)f

NOTE. HCV and HBV infection dened as follows: seropositivity for anti-HCV and HBsAg, respectively; HBV DNA in the liver tumor investigated by Bralet et al25 and HCV RNA and HBV DNA investigated in the sera by Chiesa et al.26 Heavy alcohol intake dened as follows: 50 g/day of ethanol,24,25 80 g/day of ethanol, 21,26, and history of alcoholic cirrhosis.23 HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HBV, hepatitis B virus; n.a., not available. aSurgically resected series. bTertiary care hospital series. cOverlapping with HCV and HBV infection (data can not be disentangled). dHBV and HCV serologic markers available for a subgroup of patients. ePatients with past HBV infection excluded. fPopulation-based study.

with previous ndings showing persistence and replication of HCV genomes in cancerous and noncancerous liver tissue of case series without cirrhosis but with some degree of brosis and inammation.29 These studies have found that HCC almost always occurs in a histologically abnormal liver and that the mere existence of chronic liver disease represents a potential risk for the development of HCC. Indeed, besides specic virus mechanisms that may contribute to hepatocarcinogenesis, chronic necroinammation and generation of reactive oxygen species can induce chromosomal mutations and eventually malignant transformation of proliferating hepatocytes. HCC features may differ in relation to the presence or absence of underlying cirrhosis. The mean age is usually older and male prevalence is more pronounced in HCC patients with than in those without cirrhosis in most20 22,24 but not in all studies.23,26 Abdominal pain or discomfort localized to the right upper quadrant is the most common presenting symptom in noncirrhotic patients, whereas, in individuals with cirrhosis, the majority of cancers are asymptomatic and diagnosed incidentally by ultrasound examination.21,24 As expected, liver function tests (albumin, bilirubin) are more commonly and more markedly altered in cirrhotic than in noncirrhotic patients with HCC.21,24 The picture may be substantially different in areas where there is a high incidence of liver cancer. No differences were found in the mean age (36 vs. 35 years, respectively), prevalence of present or past HBV infection (89% vs. 76%, respectively), clinical features, and

hepatic function between HCC patients with and without cirrhosis in the southern African black population.2

Incidence and Risk Factors for HCC According to Etiology of Cirrhosis

Although there have been several published studies on the risk of developing HCC in patients with cirrhosis, a comprehensive analysis is hampered by the different study designs (case control, cross-sectional, longitudinal), the heterogeneity of the patient populations relative to the severity of the cirrhosis stage at enrollment, and the lack of a focused analysis of HCC based on etiology. Furthermore, in studies involving subjects with HCV or HBV infection treated with interferon-, separate evaluation of HCC occurrence in untreated patients has not always been provided. For this review, the incidence (absolute risk) of HCC according to etiology of cirrhosis was estimated from studies selected according to the following criteria: (1) longitudinal studies; (2) studies of patients with the diagnosis of cirrhosis based on a liver biopsy or on well-dened clinical criteria; (3) studies that included patients with compensated cirrhosis, Child-Pugh class A or B; and (4) patients untreated for HBV or HCV infection. We included only published studies for which the following data were available: number of subjects, number of HCC cases, and mean duration of follow-up according to etiology of the liver disease, to calculate incidence rates computed for 100 person years. For some studies, additional information was retrieved by the

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Table 2. Overall Hepatocellular Carcinoma Incidence Rates in Longitudinal Studies of Patients With Chronic Hepatitis C Infection According to Clinical Setting and Geographic Area
Clinical setting Chronic hepatitisd Geographic area Europe Japan Taiwan Europe and United States Japan No. studies 1 6 1 13 7 Referencesa,b 30 3136 37e,f 5, 8, 30, 3847 32, 34, 35, 4851 No. patients 329 1451 553 1284 626 Mean follow-up (y) 4.2 6.2 9.2 4.5 5.8 HCC incidencec 0 1.8 0.3 3.7 7.1 95% Condence interval 1.502.05 0.160.46 3.204.17 6.197.96

Compensated cirrhosisg

HCC, hepatocellular carcinoma. aReferences are listed in chronologic order within the same geographical area. bReferences 5, 30, 44, 46, and 47 were updated by the authors. cIncidence per 100 person-years. dPatients with cirrhosis at entry and patients treated with interferon were excluded from the analysis. ePopulation-based study. fHCC incidence rate among subjects with persistently normal ALT level: 0.012 per 100 person-years (3 cases of 259 subjects). gPatients treated with interferon were excluded.

authors of this review. We computed a summary measure of the incidence rates for each etiology and the 5-year cumulative incidence as an immediate assessment of the patients absolute risk. Cirrhosis Associated With HCV Infection
Incidence of hepatocellular carcinoma. Several studies have shown that the risk of HCC in persons with HCV infection is higher in those with cirrhosis than in those with chronic hepatitis and appears to vary geographically.5,8,30 51 In a detailed study from Japan involving 490 untreated patients with chronic hepatitis C, the HCC incidence per 100 person years increased with the stage of brosis at diagnosis, from 0.4 among patients with stage F0 or F1 to 1.5, 5.1, and 6.9 among those with brosis stages F2, F3, and F4 brosis, respectively.35 Summary measures of HCC incidence rates in persons with HCV infection according to clinical setting and geographic area are shown in Table 2. In Japanese studies, the summary HCC incidence rate was 1.8 per 100 person years in subjects with chronic hepatitis C without cirrhosis at diagnosis and 7.1 in those with compensated cirrhosis, establishing a 4-fold higher risk of HCC for persons with cirrhosis than for those with chronic hepatitis.3136,48 51 In Europe and the United States, the summary HCC incidence rate in patients with HCVrelated cirrhosis was 3.7 per 100 person years,5,8,30,38 47 whereas no estimate could be calculated for persons with chronic hepatitis C without cirrhosis because of the lack of HCC cases in the only study performed.30 The 5-year cumulative risk for HCC in patients with cirrhosis was 17% in Europe and the United States and 30% in Japan. These different ndings from Europe and the United States compared with Japan do not seem to be due to

differences in demographic variables. In fact, studies of the HCC incidence in persons with HCV-related compensated cirrhosis show only a moderate difference in age at the time of diagnosis (56 and 59 years, respectively) and no difference in male preponderance (58% in both) between the 2 areas.8,38,39,41 45,48,49,51 The natural history of compensated cirrhosis caused by hepatitis C was assessed in a subgroup of 136 of 384 patients followed untreated for a mean of 6.8 years in a European collaborative study, referred to as the EUROHEP study.52 Alcohol abuse, hepatitis B coinfection, and metabolic disorders were excluded at diagnosis. In this cohort of white patients, the 5-year cumulative risk for HCC was 10%, and the mean interval between the time of diagnosis of cirrhosis and the occurrence of HCC was 5 years, with a wide range of from 0.5 to 10 years; the median age at diagnosis of HCC was 63 years (range, 50 74 years).8 Approximately half of the patients who developed HCC did not experience hepatic decompensation before or at the time of diagnosis of liver cancer, indicating that HCC that arises in the clinical setting of compensated cirrhosis is generally clinically silent.53 Risk factors for the development of HCC. Risk factors for HCC development among patients with HCVrelated cirrhosis can be considered as host related, virus related, and of external origin (Table 3). Host-related factors. Independent factors associated with progression to HCC are older age at diagnosis (55 years: 2- to 4-fold increased risk) and male sex (2- to 3-fold increased risk).38,39,46,53 Mild elevations in serum bilirubin level and decreased platelet count and the presence of peripheral manifestations of liver disease (vascular spiders and/or palmar erythema) on physical examination are also signicantly associated with HCC

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Table 3. Factors Affecting Progression to Hepatocellular Carcinoma in Compensated Cirrhosis Because of Hepatitis C
Factors Host related Age at diagnosis Age at infection Male sex Severity of liver disease at presentation Comorbidity Porphyria cutanea tarda Iron overload Liver steatosis Diabetes mellitus Viral related HCV genotype HCV load Overt HBV coinfection Occult HBV coinfection HIV coinfection External Alcohol intake Smoking Important Important Important Important Comment

Important (Southern Europe and United States) Controversial Growing evidence Growing evidence Controversial Insufcient evidence Important Growing evidence Growing evidence Important Controversial

occurrence.46,53 By multivariate modelling, adjusting for these prognostic factors, patients of the EUROHEP cohort could be stratied into 4 categories according to the 5-year risk of HCC: The risk was relatively low (3%) for a 50-year-old man with cirrhosis presenting with normal serum levels of bilirubin and platelet counts and was slightly higher (7%) for a 60-year-old man with the same baseline features but increased to 15% for a 50-year-old and to 25% for a 60-year-old man with cirrhosis, mild elevation in serum bilirubin levels (17 to 51 mol/L: 1.0 to 3.0 mg/dL), a low platelet count (100 to 130 109/l:100,000 to 130,000/mm3), and presence of spiders and/or palmar erythema.54 These ndings suggest that differences in the incidence of HCC among persons with cirrhosis reported in different studies may be due to differences in the clinical features of patients at enrollment, reecting differing stages of compensated cirrhosis. In the EUROHEP cohort of patients who developed transfusion-related hepatitis C that advanced to cirrhosis, the 5-year cumulative incidence of HCC was higher in those transfused at or after the age of 50 years than in those who had received transfusions at an earlier age (14% vs 2%, respectively),54 suggesting that, independent of duration of disease, hepatitis C more rapidly leads to cirrhosis and HCC in older persons. Several comorbid conditions are thought to increase the risk of HCC among patients with HCV-related cirrhosis, including porphyria cutanea tarda (PCT), hepatic iron overload, liver steatosis, and diabetes mellitus. A

strong association between PCT and HCV infection has been shown in southern Europe and the United States. In a cohort study among patients with cirrhosis (90% antiHCV positive), the HCC incidence rate was approximately 2-fold higher in patients with than in patients without PCT (7.9 vs. 3.5 per 100 person years, respectively) (data recalculated from the original paper).55 Although 1 case-control study reported that iron deposits in the liver assessed in a semiquantitative fashion were more frequent and more extensive in patients with than in those without HCC among subjects with HCV-related cirrhosis (odds ratio, 4.94),56 2 other studies did not conrm this association in patients with alcoholic or HCV-related cirrhosis.57,58 With regard to hemochromatosis, in one study, the gene mutations C282Y and H63D were found in similar frequency in patients with and those without HCC among subjects with alcoholic or HCV-related cirrhosis, suggesting a lack of association between HFE mutations and HCC in patients with cirrhosis.58 Both in vitro and in vivo studies suggest that HCV structural and nonstructural proteins can cause oxidative stress and steatosis and increase the risk of genomic mutations contributing to carcinogenesis.59 In a study of 161 patients with chronic HCV infection, multivariate analysis identied hepatic steatosis (risk ratio 2.8), together with aging, cirrhosis, and no interferon treatment, as independent risk factors for HCC in patients with chronic hepatitis C.60 A recent study has shown that, among U.S. veterans with diabetes mellitus, the risk of HCC is doubled and that diabetes mellitus is a risk factor for HCC per se independent of the presence of HCV-, HBV-, or alcohol-related cirrhosis.61 Viral-related factors. Most longitudinal studies have found no association between HCV genotype and risk of HCC in patients with cirrhosis.30,39,44,62 In the EUROHEP cohort study of 255 white patients with HCV-related cirrhosis, the 5-year cumulative incidence of HCC for patients infected by genotypes 1b, 2, or other genotypes was 6%, 4%, and 4%, respectively.62 There is also no evidence that viral concentration has an impact on HCC risk.35 Dual infection with HCV and HBV in cirrhotic patients has been linked to an increased risk of HCC. A meta-analysis of case-control studies found a synergism between the 2 viruses with regard to carcinogenesis, the risk being more additive than multiplicative.63 In cohort studies among Italian41,64 or Chinese65 patients with cirrhosis, those with HCV/HBV coinfection had a 2- to 6-fold higher risk of developing HCC compared with those with 1 infection only. Occult HBV infection (absence of hepatitis B surface antigen [HBsAg] but the detection of HBV-DNA in

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Table 4. Overall Hepatocellular Carcinoma Incidence Rates in Longitudinal Studies of Patients With Chronic Hepatitis B Infection According to Clinical Setting and Geographic Area
Clinical setting Asymptomatic carrier Geographic area North America Taiwan and China Japan Europe Taiwan Europe Taiwan Japan Europe Taiwan and Singapore Japan No. studies 2d 4e 1f 3 1 6 2 2 6 3 2 Referencesa,b 74, 75 37, 7678 79 8082 83 8489 9091 31, 92 8, 38, 40, 41, 85, 89 76, 93, 94 48, 95 No. patients 1804 18,869 513 410 189 471 461 737 401 278 306 Mean follow-up (y) 16 8 7.3 16 8 5.9 4.0 5.1 5.8 4.3 5.8 HCC incidencec 0.1 0.7 0.2 0.02 0.2 0.1 1.0 0.8 2.2 3.2 4.3 95% Condence interval 0.070.14 0.610.70 0.080.39 00.04 00.42 00.27 0.361.56 0.461.06 1.622.80 1.944.55 3.405.25

Inactive carrierg Chronic hepatitish

Compensated cirrhosisi

HCC, hepatocellular carcinoma. aReferences are listed in chronologic order within the same geographic area. bReferences 82, 85, 87, 89, and 91 were updated by the authors. cIncidence per 100 person years. dOne population-based study. eThree population-based studies. fPopulation-based study. gRepeatedly normal alanine aminotransferase levels and absence of hepatitis B e antigen (HBeAg) with presence of anti-HBe. hPatients with cirrhosis at entry and patients treated with interferon were excluded from the analysis. iPatients treated with interferon were excluded.

serum and/or in liver tissue) can be identied in as many as 50% of anti-HCV-positive patients who develop HCC.66 In a recent study, both integrated and free viral DNA, associated with persistence of viral transcription and replication, was identied in the liver tissue (tumoral and nontumoral) of 62% of 73 anti-HCV-positive patients with HCC compared with 37% of 153 anti-HCVpositive patients with chronic hepatitis or cirrhosis (odds ratio, 2.9).67 This suggests that occult HBV, similarly to overt HBV infection, increases the risk of HCC among patients with HCV infection. Markers of prior HBV infection (anti-HBc and/or anti-HBs) are associated with a 2-fold excess risk for HCC in patients with HCVrelated cirrhosis.68 Indeed, occult HBV infection is found more frequently in subjects with HCC or chronic liver disease who are positive for anti-HBc and/or anti-HBs compared with those negative for these markers,66,67 suggesting that markers of past HBV infection may be a proxy for an occult HBV infection. HCC seems to occur at a younger age and after a shorter period of HCV infection in subjects coinfected with human immunodeciency virus (HIV) compared with patients with HCV-related HCC but without HIV infection.69 Because newer therapies are decreasing mortality from HIV infection, it is highly likely that there will be an increase in the incidence of HCC in the future among HCV/HIV coinfected persons. External factors. Three case-control studies have shown that, as a result of the synergy between alcohol

intake and HCV infection, the risk of liver cancer is increased approximately 2- to 4-fold among subjects drinking more than 60 80 g/day of alcohol.70 72 The presumed basis for this is that both alcohol and HCV infection independently promote the development of cirrhosis. In a longitudinal cohort study of patients with HCV-related cirrhosis, heavy alcohol intake (65 g/day) was an independent factor for the development of HCC, increasing the risk approximately 3-fold.73 This means that there is a more than additive interaction between alcohol and HCV infection in the development of HCC. There are, however, no studies that have examined the risk of HCC among persons who ingest light to moderate amounts of alcohol. Also, there are no conclusive data establishing a causal role for cigarette smoking as a promoter of HCC in persons with hepatitis C-related cirrhosis. Cirrhosis Associated With HBV Infection
Incidence of hepatocellular carcinoma. As with

hepatitis C, the risk of HBV-infected persons developing HCC is higher in persons with than in those without cirrhosis and appears to vary depending on geographic area (Table 4).8,31,37,38,40,41,48,74 95 In a study from Taiwan by Beasley,76 the HCC incidence rate was 4.5 times higher among HBV-infected persons with cirrhosis than among HBsAg-positive asymptomatic carriers. With regard to studies conducted in East Asian countries (Taiwan, Singapore), the summary HCC incidence rate was

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0.2 per 100 person-years among inactive carriers, 1.0 in persons with chronic hepatitis B but without cirrhosis, and 3.2 in subjects with compensated cirrhosis (Table 4); the 5-year HCC cumulative incidence was 15% among those with cirrhosis. In contrast, in studies performed in Europe, where there is a low or intermediate rate of HBV endemicity, the summary HCC incidence was found to be 0.02 per 100 person-years in inactive carriers, 0.1 in persons with chronic hepatitis B without cirrhosis, and 2.2 in persons with compensated cirrhosis (Table 4); the 5-year HCC cumulative incidence was 10% among the cirrhotic group. Thus, in areas of high HBV endemicity, persons with cirrhosis have an approximately 3-fold higher risk for HCC than those with chronic hepatitis but without cirrhosis and a 16-fold higher HCC risk than the inactive carrier; the corresponding gures in the West are approximately a 16- and 107-fold higher HCC risk, respectively. The mean age at diagnosis of compensated cirrhosis because of type B hepatitis was 47, 44, and 46 years in studies from Europe, East Asian areas (Taiwan, Singapore), and Japan, respectively; the corresponding gures for the proportion who were males were 82%, 94%, and 76%, respectively.8,38,41,48,76,9395 In the EUROHEP cohort study, an analysis of the natural history of 161 Western European white patients with HBV-related compensated cirrhosis who were negative for the delta hepatitis virus and who remained untreated during a mean follow-up of 6 years revealed a 5-year cumulative risk for HCC of 9%; the mean interval between the time of diagnosis and the development of HCC among these individuals was 3.7 years (range, 0.515 years) and the median age at the time of diagnosis of HCC was 63 years (range, 40 78 years).8,53 The majority of patients with HCC did not experience hepatic decompensation before or at the time of diagnosis of liver cancer, much like that observed in persons with HCV-related cirrhosis.
Risk factors for development of hepatocellular carcinoma. Like HCV, there are host-related, viral-re-

Table 5. Factors Affecting Progression to Hepatocellular Carcinoma in Compensated Cirrhosis Because of Hepatitis B
Factors Host related Age at diagnosis Male sex Severity of liver disease at presentation Viral related HBV replication status during follow-up HBV genotype/HBV mutant HDV coinfection HCV coinfection HIV coinfection External Alcohol intake Smoking Environmental contaminants (aatoxins) Comment Important Important Important

Important More research needed Important Important More research needed Important Controversial Important in HBV endemic regions

lated, and external factors that have an impact on the rate of HCC occurrence among patients with HBV-related cirrhosis (Table 5). Host-related factors. Older age at diagnosis (50 years: an approximately 4-fold increased risk) is an independent factor affecting progression to HCC.38,53,96 In the EUROHEP cohort of patients with compensated cirrhosis because of type B hepatitis, subjects who developed HCC were older at the time of diagnosis of cirrhosis and had a longer duration of cirrhosis when compared with patients subsequently undergoing decompensation, suggesting that increasing age is an important risk factor because it likely reects a longer duration of cirrhosis.96

Data on the inuence of gender as a risk for HCC development in persons with compensated cirrhosis because of type B hepatitis are conicting.38,96 Baseline biochemical characteristics indicative of advancing cirrhosis are also signicant predictors of HCC occurrence in HBV-related cirrhosis.96 Viral-related factors. The prognostic role of high levels of HBV replication (dened by the presence of detectable serum HBV-DNA using a non-PCR assay [105106 copies per mL] or hepatitis B e antigen [HBeAg]) at the time of diagnosis as a predictor of HCC is still controversial. A population-based study in 11,893 Taiwanese men found that the risk of HCC increased 10-fold among men positive for HBsAg alone and 60fold for those positive for both HBsAg and HBeAg at diagnosis compared with men who were HBsAg negative.97 In the EUROHEP cohort, the risk for liver cancer did not differ among HBeAg-positive, HBeAg-negative/ HBV-DNA-positive, or HBeAg-negative/HBV-DNAnegative patients at diagnosis (5-year cumulative HCC incidence: 9%, 14%, and 8%, respectively [P .4 by log-rank test]).8 However, these negative results may be a consequence, in part, of the small sample size in each group of cirrhotic patients and of the low overall incidence of HCC. On the other hand, persistence or suppression of HBV replication during follow-up has a major prognostic role on the risk of HCC. In fact, cirrhotic patients who clear HBeAg and undergo suppression of HBV-DNA, ALT normalization, and, eventually, HBsAg loss have a very low risk of developing HCC.98,99 In the EUROHEP cohort, 32 of 309 patients with HBV-related cirrhosis lost HBsAg and only 1 of them, who was HCV coinfected, subsequently developed

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HCC.99 On the other hand, some longitudinal studies have indicated that HCC may still occur, although infrequently, in patients who have already developed cirrhosis at the time of spontaneous HBsAg loss and have no other evident risk factor for HCC.100 These observations support the increasing awareness of the medical importance of occult HBV in HBsAg-negative patients as a carcinogenic factor, particularly in the absence of other risk factors such as HCV infection and alcohol intake. Clear evidence that occult HBV is a risk factor for HCC in HBsAg-negative patients derives from the above-mentioned study by Pollicino et al,67 showing a higher prevalence of both integrated and free HBVDNA associated with low levels of transcription and replication in liver specimens of anti-HCV-negative HCC patients compared with anti-HCV-negative subjects with cirrhosis or chronic hepatitis (odds ratio, 9.6). The role of HBV genotypes on the risk of liver cancer is still under investigation. Data of 1 study from Taiwan suggested that HBV genotype B is associated with an increased risk of HCC,101 but other studies from Japan and China have reported that the lifelong risk of HCC did not differ between those with HBV genotype B and genotype C.102,103 It has been recently suggested that HBV carriers with the T1762/A1764 basal core promoter mutant are at increased risk for HCC and that this mutant may play a role in HBV-related hepatocarcinogenesis of diverse HBV genotypes.104 An important factor in HCC development is coinfection with similarly transmitted viral infections. The impact of dual HBV and HCV infection as a determinant of HCC occurrence has already been noted above. Hepatitis delta virus (HDV) infection was associated with a 3-fold increased risk for HCC in the EUROHEP cohort study among 200 HBsAg-positive patients (20% infected by HDV), followed for a mean period of 6.6 years.105 To our knowledge, there are no available data on the risk of HCC in HBV/HIV coinfected persons. Because of the high prevalence of HCV and HDV coinfections in this population,106 it is difcult to dene the role of HBV alone as a risk factor for the development of HCC in HIV-infected subjects. External factors. As already noted, chronic alcoholism plays a major role in increasing the rate of progression to HCC. A case control study found a synergism between alcohol drinking and HBV infection on the risk of liver cancer, increasing the risk approximately 2-fold for HBsAg-positive subjects of both sexes who drink more than 60 g/day of ethanol compared with HBsAg positive nondrinkers.71 In a longitudinal study of patients with compensated HBV-related cirrhosis, heavy

alcohol intake was associated with a 3-fold increased risk for HCC.95 Additional external factors that may contribute to the risk of liver cancer include smoking and dietary carcinogens. The association of cigarette smoking with HCC has been debated, but most reports do not include this information when studying HBV infection. In the study of 11,893 men in Taiwan described above, multipleregression analysis showed that, after adjustment for other risk factors, including HBV markers, the relative risk of HCC was increased 1.5-fold among cigarette smokers.97 Aatoxin, which contaminates food stored in humid conditions, induces specic mutation at codon 249 of the tumor-suppressor gene p53, mainly in persons infected with HBV. It has been reported that even modest levels of aatoxin exposure triple the risk of HCC in HBVinfected men.107 Alcohol-Related Cirrhosis Although a higher prevalence of HBV and especially of HCV infection has been shown among alcoholics, contributing to disease progression, some recent case-control studies have shown an independent role of alcohol in the induction of both cirrhosis108 and HCC,71,72 with a dose-effect relationship, adjusting for the other agents. A recent metaanalysis that included 3 cohort and 17 case-control studies showed a clear trend of increased risk of liver cancer with increasing alcohol intake.109 Furthermore, as previously discussed, synergism between alcohol intake and each hepatitis virus infection has been found in case-control studies to increase signicantly the risk for liver cancer71; longitudinal studies have conrmed these ndings, showing that cirrhotic patients with both heavy alcohol intake and HCV infection are at a higher risk of developing HCC than those with only alcoholic cirrhosis.110 In cohort studies of alcoholics, the summary HCC incidence rates are lower among alcoholics without cirrhosis (0.01 per 100 person-years) than among those with cirrhosis (0.2 per 100 person-years in population-based series and 1.7 per 100 person-years in liver clinic series, including both European and Japanese studies; 5-year HCC cumulative incidence of 0.9% and 8%, respectively) (Table 6).5,111 117 The mean age at diagnosis of alcoholic cirrhosis was 50 and 52 years in population-based and liver clinic series, respectively; the corresponding gures for the proportion who were males was 75% and 84%, respectively. Population-based studies identied patients with alcoholism on the basis of hospital discharge data. The higher HCC incidence rates observed among patients with alcoholic cirrhosis in clinic series-based studies

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Table 6. Overall Hepatocellular Carcinoma Incidence Rates in Studies of Patients With Alcoholism According to Clinical Setting and Geographic Area
Clinical setting Alcoholism Cirrhosis Geographic area Europe Europe Europe Japan No. studies 3d,e 3d,e 3f,g 2f,g Referencesa,b 111113 111113 5, 114115 116, 117 No. patients 178,915 15,020 584 174 Mean follow-up (y) 8.1 7.4 5 4.5 HCC incidencec 0.01 0.2 1.7 1.8 95% Condence interval 0.00830.011 0.150.20 1.212.21 0.842.71

HCC, hepatocellular carcinoma. are listed in chronologic order within the same geographic area. bReferences 5 and 114 were updated by the authors. cIncidence per 100 person-years. dPopulation-based series. eHBsAg and anti-HCV not investigated. fLiver clinic series. gPatients negative for both HBsAg and anti-HCV.
aReferences

compared with population-based studies may be explained by the inclusion of patients with more severe liver disease in the former. Overall, the presence of cirrhosis seems to increase the risk of developing HCC among alcoholics approximately 10-fold, as shown in studies, including both noncirrhotic and cirrhotic alcoholics.111,112 These data support the hypothesis that alcohol rst causes cirrhosis, which predisposes to the development of HCC. A role for alcohol as a direct carcinogen has still to be unequivocally demonstrated; however, some studies found that heavy alcohol intake was the only obvious risk factor in some HCC patients without cirrhosis, as previously reported.24 26 Cirrhosis Associated With Other Etiologies: Metabolic Liver Disease: Hereditary Hemochromatosis, Wilsons Disease, 1-Antitrypsin Deciency
Hereditary hemochromatosis. Studies of patients diagnosed with hereditary hemochromatosis (HH) have reported a highly increased risk of HCC, with the relative risk, as compared with the general population, ranging from 20 in population-based cohort studies118 to 200 in clinic studies with a high prevalence (69%) of HH patients with cirrhosis.119 An association of HH with HBV, HCV infection, and/or alcohol abuse has been commonly observed.120 An analysis of a study by Fracanzani et al,120 evaluating the risk of HCC among cirrhotic patients with HH, showed that there was no substantial difference in the HCC incidence in cases with HCV infection, HBV infection, or alcohol abuse compared with those without these etiologic factors (5 and 4 per 100 person-years, respectively), suggesting that the presence of HH is, per se, the contributing risk for HCC in these patients. Overall, the 5-year cumulative HCC incidence was 21% among persons with HH and cirrhosis.120

Wilsons disease. In a series of 363 patients with Wilsons disease, HCC developed in 2 (0.5%) patients, 31 and 38 years after the initial diagnosis, respectively, and both cases had underlying cirrhosis.121 Thus progression to HCC seems to be rare in patients with Wilsons disease. 1-Antitrypsin deciency. 1-Antitrypsin deciency (1-ATD) is associated with cirrhosis and HCC in adults. A cross-sectional study showed no difference in the HCC prevalence between patients with 1-ATDassociated cirrhosis and subjects with cirrhosis of other causes.122 However, two thirds of the patients with 1ATD-related cirrhosis and HCC were positive for HBV and/or HCV markers, and none of 130 patients with 1-ATD, but without signs of chronic liver disease, was found to have HCC.122 Overall, these ndings suggest that, in patients with 1-ATD deciency, associated HBV or HCV chronic liver disease plays a more important role in the development of cirrhosis that progresses to HCC than does the metabolic disorder itself.

Primary Biliary Cirrhosis In primary biliary cirrhosis (PBC) without HBV or HCV infection, HCC develops almost exclusively in patients with advanced stage III-IV, with an incidence of 0.8 to 1.8 per 100 person-years and a 5-year cumulative incidence of 4 (Table 7).123125 HCC is a rare complication in women; male patients with cirrhotic PBC are at increased risk for HCC.123 Primary Sclerosing Cholangitis A review of 134 patients with end-stage primary sclerosing cholangitis (PSC) undergoing orthotopic liver transplantation showed that 3 (2%) patients had HCC and that all 3 patients had well-established cirrhosis.126 To our knowledge, no incidence data are available, but

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Table 7. Studies on the Incidence of Hepatocellular Carcinoma Among Patients With Primary Biliary Cirrhosis Negative for Both HBsAg and anti-HCV
Author (reference) Jones (123) Caballeria (124) Shibuya (125) Geographic area United Kingdom Spain Japan Stage of the disease I or II III or IV I or II III or IV I or II III or IV No. patients 394 273 95 45 262 134 Mean age at entry (y) n.a. n.a. n.a. 55 56 63 Male (%) n.a. 11 4 2 n.a. n.a. No HCC 0 16 0 5 n.a. n.a. HCC incidence ratea 0 0.8 0 1.8 0.3 1.5 Mean follow-up (y) 7.3 7.3 5.3b 6.2 3.3 3.9

HCC, hepatocellular carcinoma; n.a., not available. aIncidence per 100 person-years. bCalculated by the authors of this review.

the low prevalence of HCC in PSC suggests that HCC occurs infrequently in cirrhotic stage PSC. Autoimmune Hepatitis Available data indicate that HCC complicating cirrhosis because of autoimmune hepatitis (AIH) is rare, particularly in the absence of HBV or HCV infection. One study from England has reported that 8 (4%) cirrhotic patients developed HCC in a cohort of 217 patients with AIH, but 6 of these 8 patients had evidence of concomitant HCV infection.127 In another study from the United States, only 1 of 88 patients with cirrhosis because of AIH developed HCC in the absence of HBV or HCV infection, establishing an incidence of 0.1 per 100 person-years; none of the 124 patients with AIH without histologic evidence of cirrhosis developed HCC during follow-up.128 Cryptogenic Cirrhosis There is a paucity of data on the incidence of HCC in persons with cryptogenic cirrhosis. Although cryptogenic cirrhosis probably represents the end point of different occult disorders, a number of recent publications have linked nonalcoholic steatohepatitis (NASH), cryptogenic cirrhosis, and HCC. In a study from the United States, about half the patients with cryptogenic cirrhosis and HCC had histologic or clinical features associated with nonalcoholic fatty liver disease (NAFLD).129 A retrospective casecontrol study has found that features suggestive of NASH, including precirrhosis obesity, type 2 diabetes, dyslipidemia, and insulin resistance, are more frequently observed in HCC arising in patients with cryptogenic cirrhosis than in those with HCC of viral or alcohol etiology.130 Overall, these data suggest that HCC may represent a late complication of NASH-related cirrhosis. Limited retrospective data showed that none of 10 patients with cryptogenic cirrhosis in the absence of comorbidities (eg, NAFLD, NASH, obesity, and/or diabetes) developed HCC (mean

follow-up of 3.5 years), whereas 3 of 22 persons with obesity-related cryptogenic cirrhosis developed HCC (mean follow-up of 1.8 years) with an incidence of 0.8 per 100 person-years (data recalculated from the original paper).131 However, a recent prospective cohort study of NASHassociated cirrhosis, dened on the basis of strict clinicopathologic criteria, found that no patient developed HCC during a mean 5-year-follow-up, suggesting that the incidence of HCC may be low in persons with NASH-associated cirrhosis or that the duration to its development in these individuals is markedly prolonged.132

Predictors of HCC in Cirrhosis

Age and Gender Older age and male sex have been found in longitudinal studies to be associated with an increased risk of HCC among persons with cirrhosis of different etiologies.6,40,133,134 Older age may reect a longer duration of cirrhosis. The higher risk of HCC among male cirrhotic patients could be explained by either the higher prevalence of other risk factors, such as alcohol abuse, or by a tumorigenic effect of androgens. Stage of Cirrhosis In a surveillance program of a cohort of 313 Italian cirrhotic patients of different etiologies (ChildPugh class A, 58%: B, 34%; C, 8%) for early diagnosis of HCC based on ultrasonography and alfafetoprotein (AFP) determination at 6-month intervals, Child-Pugh class B/C cirrhosis at entry was found to be an independent prognostic factor for HCC, with a 3-fold increased risk.134 In another prospective study of 400 Chinese cirrhotic patients, Child-Pugh class B cirrhosis (3-fold increased risk) or Child-Pugh class C cirrhosis (8-fold increased risk) were independent prognostic factors for HCC.65 Thus, patients with more advanced Child-Pugh scores are at higher risk of liver cancer.

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Activity of the Liver Disease The activity of the liver disease, characterized by inammation, necrosis, and regeneration, plays an important role in promoting HCC development. In a prospective study of 290 Western patients with cirrhosis of different causes, HCC occurrence was observed more frequently in patients with persistent elevation of alanine aminotransferase (ALT) levels during a 4-year-follow-up (17%) than in those with persistently normal or near normal values (5.5%) or in those who had ALT normalization during follow-up (6%).64 Another prospective study of 69 Japanese patients with HCV-related cirrhosis demonstrated that the 5-year incidence of HCC was as high as 54% in patients with persistently high serum ALT levels (annual average 80 IU) compared with only 7% in those with low ALT values and that the median interval between the diagnosis of cirrhosis and the development of HCC was 6 years in the high ALT group and 13 years in the low ALT group.135 Thus, these data indicate that sustained high serum ALT levels are associated with a high risk and more rapid development of HCC. Histologic Assessment The presence of large cell change (LCC) (initially called large cell dysplasia),46,136,137 irregular regeneration (IR) of hepatocytes,138 and macroregenerative nodules139 have been evaluated as morphologic predictors of HCC in cirrhosis. Two studies conducted in a large series of Western patients with cirrhosis have shown that LCC was a strong predictor of incipient HCC development, particularly among HBsAg-positive subjects.136,137 On the other hand, a French study did not nd an association between LCC and risk of HCC in patients with HCVrelated cirrhosis.46 Further studies are needed to conrm the relationship of severe IR to the HCC risk that was found in a prospective study of Japanese patients with HCV-related cirrhosis.138 A recent prospective study from Italy has indicated that ultrasound-detected macronodules characterize a subgroup of cirrhotic patients with a high risk of HCC and that the risk is further increased in the presence of morphologic features of high-grade dysplastic nodules.139 Furthermore, tissue markers of hepatocyte proliferation have been analyzed as predictors of HCC.140,141 Among patients with compensated cirrhosis of different etiologies, those with high proliferating cell nuclear antigen (PCNA) values, assessed by immunoperoxidase staining and indicative of high liver cell proliferation activity, had a 5-fold increased risk of HCC compared

with patients with low PCNA values.140 Nucleolar hypertrophy, assessed by silver staining of nucleolar organizer region protein (AgNOR), represents a morphologic feature that characterizes both proliferating and dysplastic hepatocytes. A recent study found that nucleolar indices (percentage of hepatocytes showing large nucleoli) of 2.5 or greater were associated with a very high risk for HCC in patients with HBV-related cirrhosis (hazard ratio, 7.08) and cryptogenic cirrhosis (hazard ratio, 7.16), whereas this parameter did not have signicant predictive relevance in patients with HCV-related cirrhosis.141 Overall, these data seem to indicate that LCC and nucleolar hypertrophy (AgNOR staining) may be useful predictors of HCC risk in HBV-related cirrhosis. However, these markers are not routinely utilized in clinical practice and depend on availability of liver biopsy.

Summary
The following conclusions can be drawn: (1) Mortality from HCC is rising in some developed countries, whereas mortality from cirrhosis is either decreasing or is stable, possibly because of improved medical management of non-HCC complications of cirrhosis, leading to longer survival of cirrhotic patients. (2) Cohort studies indicate that HCC currently represents the major cause of liver-related death in patients with compensated cirrhosis. (3) Cirrhosis underlies HCC in approximately 80%90% of cases worldwide. Patients developing HCC in a noncirrhotic liver almost always have chronic hepatitis, indicating that chronic necroinammation is a key element of HCC occurrence. In Western countries, HCV infection, HBV infection, and heavy alcohol intake are found in almost all HCC cases in cirrhosis; the same factors can be found in a variable proportion of HCC cases without cirrhosis, although the etiology of a number of them is still unknown. HH and other causes account for only a small number of total liver cancers. (4) Irrespective of the geographic area and of the etiology, the cirrhotic patient has an increased risk of HCC compared with person without cirrhosis, demonstrating that cirrhosis per se is the major risk factor for HCC development. (5) Figure 2 illustrates the 5-year cumulative HCC incidence according to etiology of cirrhosis. The highest HCC incidence is associated with HCV infection and appears to be about 2-fold higher in Japan than in the West (5-year cumulative incidence of 30% and 17%, respectively), suggesting the inuence of yet unknown environmental and/or host-related factors that may contribute to HCC progression. Irrespective of the severity of the underlying liver disease, the risk of HCC in persons with HBV infection is higher in geographic areas

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Figure 2. Combined data from published studies of the cumulative incidence of hepatocellular carcinoma in patients with compensated cirrhosis according to etiology. The 5-year cumulative incidence was 30% in hepatitis C virus (HCV)-related cirrhosis in Japan, 17% in HCV-related cirrhosis in Europe and the United States, 15% in hepatitis B virus (HBV)-related cirrhosis in Taiwan and Singapore, 10% in HBV-related cirrhosis in Europe, 21% in hereditary hemochromatosis (HH), 8% in alcoholic cirrhosis in the absence of HCV and HBV infection, and 4% in primary biliary cirrhosis (PBC) without viral markers.

of high endemicity than in Western countries, possibly because of earlier acquisition of the virus infection, longer duration of disease, or exposure to environmental toxins; in HBV-related cirrhosis, the 5-year cumulative HCC risk is 15% in areas with high HBV prevalence and 10% in the West. In the absence of HCV and HBV infection, alcoholic cirrhosis is associated with a lower HCC incidence (5-year cumulative risk of 8%). Cirrhotic patients with HH have a high HCC risk (5-year HCC cumulative risk of 21%). Low incidence rates are seen in advanced-stage biliary cirrhosis without viral markers (5-year cumulative risk of 4%). Limited data on HCC risk are available for cirrhosis because of other causes. (6) Older age, male sex, severity of compensated cirrhosis at presentation, and sustained activity of liver disease are important predictors of HCC independent of the etiology of cirrhosis. Among patients with viral-related cirrhosis, the HCC risk is increased in the presence of HBV and HCV, or HBV and HDV coinfection (2- to 6-fold with respect to each infection alone), or alcohol abuse (2- to 4-fold with respect to alcohol abstinence). Viral load and genotype do not seem to inuence the progression to HCC in HCV-related cirrhosis. Sustained reduction of HBV replication is associated with a low risk of HCC in HBV-related cirrhosis. Further studies are needed to investigate the role of additional viral factors (eg, HBVgenotype/mutants, occult HBV, HIV coinfection) and preventable or treatable comorbidities (eg, obesity, diabetes) as risks for HCC in persons with cirrhosis. Better knowledge of individual risk factors for HCC in persons with cirrhosis is the basis for disease management and for designing preventive or treatment strategies.

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