Liver (Hepatocellular) Cancer Prevention (PDQ®)–Health Professional Version

Who Is at Risk?

The critical etiologic agent in at least 80% of hepatocellular cancer (HCC) cases worldwide is chronic hepatitis B virus (HBV) infection or chronic hepatitis C virus (HCV) infection.[1] Both viruses, either alone or when present with other risk factors, are responsible for staggering increases in the risk of HCC, relative to the absence of these hepatitis viruses. Men with chronic HBV or HCV infection are more likely to develop HCC than are women with the same chronic infection, with some, but not the entire difference explained by varying prevalence of other risk factors.[2] Cirrhosis, regardless of its etiology, predisposes patients to HCC [3] and is present in 70% to 90% of HCC patients at the time of diagnosis.[4] Heavy alcohol use is a strong etiologic agent for HCC because it can cause cirrhosis and the presence of HBV or HCV increases risk even more.[5] Exposure to aflatoxin B1 strongly increases HCC risk in individuals with chronic HBV infection and may do so, but to a much lesser extent, in individuals without chronic HBV infection.[1] Nonalcoholic steatohepatitis (NASH) increases risk of HCC among patients who have accompanying cirrhosis [6] and may modestly increase risk in patients without cirrhosis.[7,8] Cigarette smoking modestly increases the risk.[9] Untreated hereditary hemochromatosis and certain other rare medical and genetic conditions are responsible for large increases in HCC risk but are responsible for only a small percentage of cases.[1] The future HCC incidence among patients newly diagnosed with nonalcoholic fatty liver (NAFL) is not known, and because NAFL can progress to NASH, and NAFL patients can develop cirrhosis, there is reason to believe that NAFL patients are at elevated risk.[10] A diagnosis of metabolic syndrome (MetS) is associated with an increased risk of HCC,[11] as are obesity and type 2 diabetes, which are common component conditions of MetS.[11] Those three conditions also can occur concurrently with NAFL.[12] The frequent coexistence of these four conditions makes the interpretation of condition-specific risk measures difficult. Decreases in HCC incidence rates have occurred after implementation of HBV vaccination programs,[13] and treatment with nucleos(t)ide analog therapy reduces but does not eliminate the risk of HCC in patients with chronic HBV infection.[14] Replacement of a food supply that was heavily contaminated with aflatoxin B1 with one that contained much lower levels resulted in a more than 50% reduction in primary liver cancer.[15] HCV treatment with direct-acting antivirals that results in sustained virologic response may reduce HCC risk.[16]

Factors With Adequate Evidence of Increased Risk of Hepatocellular Cancer (HCC)

Factors With Inadequate Evidence of Increased Risk of HCC

Interventions With Adequate Evidence of Decreased Risk of HCC

Interventions With Inadequate Evidence of Decreased Risk of HCC

Chronic HBV Infection

Chronic hepatitis B virus (HBV) infection is the leading cause of hepatocellular cancer (HCC) in Asia and Africa.[1] Hepatitis B is transmitted through contact with infected blood, semen, or other body fluids. In areas with high incidence of chronic HBV infection and HCC, about 70% of infections are acquired in the perinatal period or in early childhood.[2] In addition to maternal-to-child transmission, HBV can be spread through sexual contact and contact with infected blood.[3] In the United States, the most common route of transmission is sharing drug-injecting needles.[4] It is estimated that 850,000 to 2.2 million people in the United States have chronic HBV infection [3] and that the infection is responsible for 10% to 15% of HCC cases.[5] The World Health Organization (WHO) estimates that 240 million people are infected worldwide.[4]

Evidence for a causal relationship between chronic HBV infection and HCC comes from etiologic studies, case series, case-control studies, and prospective epidemiological studies.[2] Ecological studies demonstrate a strong positive correlation between the prevalence of chronic HBV and HCC incidence and mortality. HBV is present in liver tissue in nearly all patients who are seropositive for the virus and have HCC,[2] and HBV DNA has been found in 10% to 20% of HCC tumors in patients who are seronegative but are positive for HBV antibodies.[2] Case-control studies and prospective studies have observed odds ratios or relative risks (RRs) of at least 5 for chronic HBV infection.[2] Some prospective studies have observed RRs exceeding 50.[2] The lifetime risk of HCC in individuals chronically infected with HBV is estimated to be between 10% and 25%.[2] Clinical factors that have been reported to increase risk in individuals with chronic HBV infection include higher levels of HBV replication; certain HBV genotypes; longer duration of infection; and coinfection with hepatitis C virus (HCV), HIV, or hepatitis D virus.[6] The presence of cirrhosis increases risk, although HBV can cause HCC in the absence of cirrhosis.[7]

Coinfection with HCV appears to have an additive effect on risk.[8] In addition, degree of increased risk of chronic HBV varies with the presence of other factors and is discussed in sections of this summary that cover those specific factors.

Chronic HCV Infection

Chronic HCV infection is the leading cause of HCC in North America, Europe, and Japan.[1] Chronic HCV infection accounts for about one-third of HCC cases in the United States.[4] HCV is a blood-borne pathogen; before screening of the blood supply or donated human organs (1992), HCV infection often was acquired during blood transfusions or organ transplants. Today, most new infections are caused by the sharing of drug-injecting needles. HCV can be transmitted during sexual contact, although this occurs infrequently. An estimated 2.7 to 3.9 million people in the United States have chronic hepatitis C.[9] In the United States, more cases are attributable to chronic HCV infection than to any other risk factor.[10]

Even though the mechanisms through which HCV increases HCC risk are unclear, chronic HCV infection is accepted as playing a causal role in the development of HCC. Evidence of a strong association comes primarily from cross-sectional and case-control studies, which suggest that individuals with HCV infection have at least a 15-fold increase in HCC risk, relative to individuals without HCV infection.[6] A prospective study of more than 23,000 residents of Taiwan observed a cumulative lifetime HCC incidence of 24% in men and 17% in women;[11] other prospective studies, including cases series of individuals accidently infected with HCV through blood transfusion, have produced a wide range of incidence estimates.[2] The reason for such variability is likely the variation in prevalence of advanced fibrosis and cirrhosis in the groups being studied. Chronic HCV infection typically leads to liver fibrosis, but HCC is rare in HCV-positive individuals with minimal or no fibrosis.[6] Once HCV-related cirrhosis develops, HCC develops annually in 1% to 8% of patients.[6] Other clinical factors that have been reported to increase risk in individuals with chronic HCV infection include coinfection with HBV or HIV, HCV genotype 1b, and steatosis.[6]

Coinfection with HBV appears to have an additive effect on risk.[8] In addition, degree of increased risk of chronic HCV varies with the presence of other factors and is discussed in sections of this summary that cover those specific factors.

Cirrhosis

The prevalence of cirrhosis in the United States is estimated to be 0.3%, which corresponds to more than 600,000 adults.[12] Because cirrhosis is present in 70% to 90% of HCC patients at the time of diagnosis,[13] cirrhosis is considered a predisposing factor for HCC.[14] In autopsy studies, 80% to 90% of individuals who die of HCC have cirrhotic livers.[14] A standardized incidence ratio of 60 was observed in a prospective 16-year study of 11,065 Danish individuals with cirrhosis (more than one-half of cases caused by alcohol consumption).[2] The 5-year cumulative risk of developing HCC for patients with cirrhosis is 5% to 30%, with risk dependent on cause of cirrhosis and stage of cirrhosis.[6]

With perhaps the exception of aflatoxin B1, all HCC risk factors are also risk factors for cirrhosis.[1] In patients with established cirrhosis, HCC risk may be modifiable with elimination of the factor responsible for cirrhosis.[15] However, evidence to support that possibility is limited, and reduction in risk is likely to occur only in patients with precirrhotic changes or very early-stage cirrhosis.[15]

Patients with HCV-related cirrhosis are at greater risk of developing HCC than are those with cirrhosis related to HBV and alcohol-related cirrhosis.[14] Using data from several prospective studies, 5-year cumulative HCC incidence rates for individuals with cirrhosis and specific risk factors were estimated as follows: HCV, 30% in Japan and 17% in Western countries; HBV, 15% in endemic areas and 10% in Western countries; and alcohol, 8%.[14]

Heavy Alcohol Use

Heavy alcohol use causes cirrhosis; between 8% and 20% of chronic alcoholics develop the condition.[1] HCC also occurs in heavy alcohol users who do not have cirrhosis. Some data exist to suggest a synergistic effect on HCC risk by heavy alcohol use and tobacco use, fatty liver disease, and metabolic syndrome (MetS) components.[16]

Many epidemiological studies have examined the association of alcohol use and HCC; those that could examine the impact of increasing exposure typically have seen a positive correlation between consumption and risk. The following RRs (95% confidence intervals [CIs]) were generated by using models derived from a meta-analysis: 1.19 (1.12–1.27) for 25 g of alcohol per day; 1.40 (1.25–1.56) for 50 g/d; and 1.81 (1.50–2.19) for 100 g/d.[1] While there is agreement that alcohol consumption, especially heavy consumption, is an important HCC risk factor, the magnitude of the increase in risk varies across studies.[16] Some studies report a twofold increase in risk with heavy consumption, while others observe a greater increase, at least fivefold. Variability is likely caused by many factors, including choice of control subjects, choice of referent categories, definition of heavy alcohol use, and presence of cofactors.

Alcoholics with cirrhosis appear to have a roughly tenfold risk of developing HCC, relative to alcoholics without cirrhosis.[14,16] In a cohort study of alcoholics, the summary incidence rate was 0.2 per 100 person-years in people with cirrhosis, and 0.01 per 100 person-years in those without cirrhosis.[14] The evidence for a twofold to threefold increase in risk with heavy alcohol use is more consistent for individuals with chronic HCV infection than for individuals with chronic HBV infection.[16] An Italian case-control study observed synergistic effects of heavy alcohol use and HBV or HCV infection: heavy alcohol use and HBV infection led to a 50-fold increase in risk, and heavy alcohol use and HCV infection led to a 100-fold increase in risk, relative to absence of heavy alcohol use and HBV or HCV infection.[17]

Aflatoxin B1

Aflatoxin B1 is a mycotoxin that can contaminate corn and peanuts stored in warm, humid environments.[2] The highest levels of aflatoxin B1 exposure are found in sub-Saharan Africa, Southeast Asia, and China.[18]

Aflatoxin B1 was deemed a carcinogen by the International Agency for Research on Cancer (IARC) in 1987.[2] The population-attributable risk of aflatoxin B1 to HCC is estimated to be 20% in the Western Pacific (including China), 27% in southeast Asia, and 40% in Africa.[19] Exposure may be responsible for up to 155,000 HCC cases worldwide.[19]

Prospective cohort studies established aflatoxin B1 as an etiologic agent for HCC, and demonstrated that magnitude of risk varies by presence or absence of chronic HBV infection. A nested case-control study comprising about 18,000 men who resided in Shanghai in the 1980s indicated that aflatoxin exposure increases risk 4-fold among individuals without chronic HBV infection, but exposure increases risk 60-fold among individuals with chronic HBV infection.[20] A subsequent cohort study in Taiwan observed a similar multiplicative or more-than-multiplicative increase in risk with the presence of both factors, relative to the presence of neither factor.[20]

NASH

Nonalcoholic steatohepatitis (NASH) is an aggressive yet dynamic condition; it can regress, persist at a relatively constant level of activity, or cause progressive fibrosis that leads to cirrhosis. It is estimated that 6% of the U.S. adult population has NASH and that 2% of U.S. adults will develop NASH-related cirrhosis at some time in their lives.[21]

At least 17 prospective cohort studies have examined HCC risk in patients with either NASH or nonalcoholic fatty liver disease (NAFLD), but few have examined NASH patients alone.[22] The most frequently referenced study of NASH patients is a prospective study conducted in the United States that examined HCC experience in 195 patients with NASH-related cirrhosis. After a median follow-up of 3.2 years, 13% of the patients had been diagnosed with HCC.[23] Yearly cumulative incidence in this case series was 2.6%. A case series of HCV patients was conducted concurrently; that group experienced higher rates (20% had an HCC diagnosis, and yearly cumulative incidence was 4%).

HCC has been observed in patients with NASH who do not have cirrhosis. Reliable risk estimates are not available, but most researchers believe that these individuals are at elevated risk, albeit lower than in those with cirrhosis.[22]

MetS, obesity, type 2 diabetes, insulin resistance, hypertension, and hyperlipidemia or dyslipidemia, are suspected risk factors for HCC and are associated with NASH. A study of 8.5 million people from 22 countries reported prevalence estimates for NASH patients with the following diagnoses: overweight or obesity, 80%; hyperlipidemia or dyslipidemia, 72%; type 2 diabetes, 44%; and MetS, 71%.[24]

Cigarette Smoking

The relationship between tobacco use and liver cancer has been studied extensively for many years.[25] Early epidemiological studies produced positive associations, but doubt regarding the legitimacy of tobacco use as an independent risk factor existed because of the possibility of residual confounding by HBV status, HCV status, and alcohol consumption. In addition, some studies also suggested that the increase in risk might exist only in subgroups, particularly in patients with chronic HBV infection. In 2004, the IARC reported that tobacco use was causally associated with HCC; that conclusion was on the basis of studies that had consistently shown increased risk with increased duration or intensity of tobacco use after careful consideration of potential confounders.[25] In 2014, the U.S. Surgeon General concluded a causal relationship on the basis of study results published after 2004.[26]

An extensive meta-analysis published in 2009 examined 38 cohort and 58 case-control studies that evaluated the relationship between cigarette smoking and liver cancer.[25] Studies varied in their degree of adjustment for possible confounders, though most adjusted for age and about one-third adjusted for alcohol consumption. Relative to never-smokers, the summary RR (SRR) for current smokers was 1.51 (95% CI, 1.37–1.67) and for former smokers, 1.12 (95% CI, 0.78–1.60). The point estimate was similar when restricted to five high-quality studies that adjusted for alcohol use (RR, 1.45; 95% CI, 1.14–1.80); the point estimates were similar but not significant when restricted to three studies that adjusted for chronic HBV infection and three studies that adjusted for chronic HCV infection. A dose-response relationship for the number of cigarettes smoked per day was observed, even though there was substantial statistical heterogeneity in the eight studies that were analyzed together for that analysis. A prospective cohort study published after the meta-analysis observed significant linear increases in risk with increasing number of cigarettes smoked per day, years smoked, and pack-years; analyses were adjusted for grams of alcohol consumed per day, and significant linear increases also were observed when daily drinkers were excluded.[27]

A meta-analysis that examined the relationship of cigarette smoking in the presence and absence of chronic HBV or HCV infection observed the following:[28] in the absence of viral infection, cigarette smoking was associated with an RR of about 1.5 to 2; in the presence of HBV, the increase in risk appeared additive; and in the presence of HCV, the increase in risk appeared to be more than multiplicative. Relative to persons who were negative for HBV and did not smoke cigarettes, the adjusted random effects estimate was 21.7 (11.8–40) for those with HBV who smoked cigarettes. Relative to individuals who were negative for HCV and did not smoke cigarettes, the adjusted random effects estimate was 19.6 (1.55–247) for those with HCV who smoked cigarettes.[28]

Certain Rare Medical and Genetic Conditions (Untreated HH, Alpha-1-Antitrypsin Deficiency, Glycogen Storage Disease, Porphyria Cutanea Tarda, and Wilson Disease)

Untreated hereditary hemochromatosis (HH), alpha-1-antitrypsin (AAT) deficiency, glycogen storage disease, porphyria cutanea tarda (PCT), and Wilson disease are known to increase the risk of developing HCC. While increases in risk are known or believed to be large, these conditions contribute little to the burden of HCC.

Hemochromatosis is an autosomal recessive disorder that leads to excessive absorption of dietary iron and subsequent iron loading in certain organs, including the liver.[2] Between 1 in 200 and 1 in 400 individuals of northern European descent carry the most common genetic mutation, although many of these individuals do not develop progressive iron overload.[29] Patients with untreated hemochromatosis may develop cirrhosis. The annual incidence of HCC in patients with hemochromatosis is 4% once cirrhosis has been established.[30] In cohorts of patients with untreated hemochromatosis and cirrhosis, the observed number of HCC cases is at least 20-fold higher than expected.[29] HCC is seen, albeit rarely, in hemochromatosis patients who do not have cirrhosis.[29] Between 25% and 45% of premature deaths in hemochromatosis patients are caused by HCC.[29] Hemochromatosis can be treated successfully through phlebotomy, repeated at necessary intervals.[30] Treatment before the development of cirrhosis appears to greatly reduce the risk of HCC.[30] It is hypothesized that the presence of other HCC risk factors, particularly chronic HBV infection, chronic HCV infection, and heavy alcohol use, could increase risk among patients with untreated hemochromatosis in a more-than-additive manner,[29] but appropriate data in which to explore this possibility are not available.

AAT deficiency is an inherited disorder affecting the lungs, liver, and rarely, the skin. It is estimated that about 100,000 individuals in the United States have AAT deficiency.[31] Liver disease results from the accumulation within hepatocytes of unsecreted variant AAT proteins.[32] Individuals with certain AAT deficiency genotypes are at high risk of developing HCC.[33]

Glucose-6-phosphatase deficiency (G6PD) is an autosomal-recessive disorder. It also is known as von Gierke disease and is more commonly known as glycogen storage disease, or GSD1. The defective enzymes involved are mainly active in the liver and kidneys. The incidence of GSD1 is 1 per 100,000 live births. HCC is recognized as a late complication of GSD1.[34] No estimates of increase in HCC risk are available.

PCT is the result of deficient activity of hepatic uroporphyrinogen; acute intermittent porphyria (AIP, also known as Swedish porphyria) is characterized by deficient activity of porphobilinogen. The prevalence of PCT in the United States is 1 in 25,000.[35] PCT and AIP are associated with increases in HCC risk.[2] A prospective study in Sweden of individuals with porphyria observed a standardized incidence ratio of 21 for PCT and 70 for AIP.[36]

Wilson disease (hepatolenticular degeneration) is caused by a genetic abnormality inherited in an autosomal recessive manner that leads to impairment of cellular copper transport. Worldwide prevalence is approximately 1 in 30,000 live births.[37] Wilson disease causes progressive liver damage, including cirrhosis. The association between Wilson disease and HCC is uncertain but suspected given that tumors of the liver, including HCC, are observed in Wilson disease patients.[38]

NAFL

Nonalcoholic fatty liver (NAFL) is diagnosed when hepatic steatosis cannot be explained by alcohol use or viral infection.[1] It generally is an asymptomatic, benign condition and is often detected incidentally.[2] NAFL can progress to cirrhosis or nonalcoholic steatohepatitis (NASH). Up to 4% of NAFL patients may develop cirrhosis,[3] and a small clinical study suggested that between 20% and 50% of NAFL patients may develop NASH.[4] The observation that NAFL patients have developed these conditions, which are known to increase hepatocellular cancer (HCC) risk, leads to the conclusion that NAFL increases HCC risk.

Even though NAFL and NASH have different clinical relevance, they often are combined into one clinical entity known as NAFLD (nonalcoholic fatty liver disease). While prevalence estimates and measures of relative risk (RR) are available for NAFLD and NASH, they are unavailable for NAFL. NAFLD estimates can provide an upper bound for NAFL, however.

In the United States, NAFLD prevalence is estimated at 25%.[5] NAFLD prevalence has more than doubled in the last 30 years [1] and is now the most common liver disorder in the United States.[1] NAFLD is sometimes referred to as the hepatic presentation of metabolic syndrome (MetS);[5] increases in NAFLD rates parallel those of MetS, including obesity and type 2 diabetes.[1] MetS, obesity, and type 2 diabetes are frequent NAFLD comorbidities. Estimates of global prevalence of MetS, obesity, and type 2 diabetes in individuals with NAFLD are as follows: MetS, 43%; obesity, 51%; and type 2 diabetes, 23%.[1] A meta-analysis that considered data from countries around the world reported that the HCC incidence rate ratio for NAFLD versus non-NAFLD patients was 1.94 (95% confidence interval [CI], 1.28–2.92).[1] HCC has been diagnosed in patients with both cirrhotic and noncirrhotic NAFLD.[6] A study of 1,500 U.S. Veterans' Administration patients with NAFLD, 107 patients developed HCC. Of the 107 patients, 6 patients had level 1 evidence (histological) of no cirrhosis, and 31 patients had level 2 evidence (imaging or biospecimen) of no cirrhosis.[7] Furthermore, the percentage of noncirrhotic HCC patients among those with NAFLD was greater than was observed for other known HCC risk factors.[7]

MetS

MetS is diagnosed when at least three of five metabolic risk factors (central adiposity, high triglyceride levels, low levels of high-density lipoprotein, high fasting glucose levels, and hypertension) are present.[8] The prevalence of MetS has been rising for at least the last 30 years, and by 2012, more than one-third of U.S. adults met the criteria for MetS.[9]

A meta-analysis of more than 7,000 HCC cases from five studies produced a risk ratio of 1.8 (95% CI, 1.37–2.40) for a diagnosis of MetS.[10] The combined risk ratios were varied (range, 1.2 [95% CI, 0.55–2.53] to 3.7 [96% CI, 1.78–7.58]).

MetS and NAFLD are frequently comorbid conditions. The prevalence of MetS among patients with NAFLD was estimated to be 42.5% in a meta-analysis that included studies from around the world.[1] Given that obesity and type 2 diabetes, two suspected HCC risk factors, are component causes of MetS and also prevalent in patients with NAFLD, attempts to disentangle the independent impact on HCC risk of MetS using epidemiological data is not warranted. Observed associations should not be interpreted as causal relationships.

Only a few studies have examined insulin resistance, hypertension, and dyslipidemia, yet there is a suggestion that the first two are associated with an increase in HCC risk.[11] These factors will not be discussed further.

Obesity

Obesity has been considered extensively as a risk factor for HCC, and in most instances, a positive association has been observed. A European multicenter prospective cohort study with 177 HCC cases examined central obesity, as measured by waste-to-hip ratio, and observed a more-than-threefold increase in HCC risk for the highest tertile (males, ≥ 27.81; females, ≥ 26.65), relative to the lowest (RR, 3.51; 95% CI, 2.09–5.87), after adjustment for several potential confounders, including alcohol consumption.[12] A meta-analysis of 26 prospective studies (25,337 HCC cases) reported that obesity (BMI ≥ 30 kg/m2) was associated with an increased risk of primary liver cancer (SRR, 1.83; 95% CI, 1.59–2.11). Of note is that the included studies varied in their control for confounding, with 11 not controlling for alcohol consumption and 15 not controlling for history of diabetes; furthermore, not all studies were population based. Nevertheless, point estimates were somewhat consistently suggestive of a modest increase in risk, and associations of a similar magnitude have been seen in Japanese and U.S. populations.[13,14]

NAFLD is estimated to be present in up to 90% of individuals with obesity.[15] Obesity is a component cause of MetS, another suspected HCC risk factor; obesity also is a frequent comorbidity to type 2 diabetes, yet another suspected HCC risk factor. Attempts to disentangle the independent impact on HCC risk of obesity using epidemiological data is not warranted. Observed associations should not be interpreted as causal relationships.

Type 2 Diabetes

Type 2 diabetes has been considered extensively as a risk factor for HCC, and in most instances, positive associations have been observed. The most recent meta-analysis of diabetes and HCC was published in 2012.[16] Seventeen case-control studies and 32 cohort studies were included, and a summary RR of 2.31 (95% CI, 1.87–2.84) for either type 1 or type 2 diabetes was observed. Of the 49 studies used to produce the summary RR, only 19 adjusted for alcohol use and 13 for obesity, and not all were population based. The summary risk estimate for type 2 diabetes alone, based on data from 13 studies, was 2.18 (95% CI, 1.58–3.01). Studies published since the meta-analysis produced estimates similar to those of the summary measure.[17]

NAFLD is estimated to be present in up to 70% of type 2 diabetics.[15] Type 2 diabetes is a component cause of MetS, another suspected HCC risk factor; type 2 diabetes is a frequent comorbidity to obesity, yet another suspected HCC risk factor. An additional complexity is that diabetes can be caused by cirrhosis.[18] With the exception of cirrhosis, attempts to disentangle the independent impact on HCC risk of type 2 diabetes using epidemiological data is not warranted. Observed associations should not be interpreted as causal relationships.

HBV Vaccination

Hepatitis B virus (HBV) vaccines became available for the prevention of HBV infection in the early 1980s.[1] The World Health Organization recommends that all infants receive the hepatitis B vaccine as soon as possible after birth, preferably within 24 hours.[2] By 2011, 180 countries had introduced infant HBV vaccination, and the global HBV vaccination coverage rate for the final dose was estimated to be about 78%.[1] It is estimated that in 2015, the worldwide prevalence of HBV infection in children younger than 5 years was about 1.3%, compared with about 4.7% in the prevaccination era.[2]

Epidemiological evidence regarding the ability of hepatitis B vaccination to reduce hepatocellular cancer (HCC) comes from follow-up studies of children and risk of childhood liver cancer. In a cluster randomized controlled trial of HBV immunization of 75,000 newborns in Qidong, China (an area where HBV is endemic), the incidence ratio of primary liver cancer in the vaccination-at-birth group compared with the control group (68% of whom received catch-up vaccinations at ages 10–14 years) was 0.16 (95% confidence interval [CI], 0.03–0.77).[3] A registry study conducted in Taiwan identified 1,509 patients aged 6 to 26 years with HCC, and observed that HCC incidence per 100,000 person-years was 0.92 in the unvaccinated cohort and 0.23 in the vaccinated birth cohorts.[4]

It is too soon to know if neonate vaccination also will reduce HCC risk in later adulthood, and no data have been published on the impact of vaccination in adulthood. Nevertheless, vaccination at any age before infection should reduce HCC risk. Mathematical modeling suggests that neonatal HBV vaccination ultimately will lead to the elimination of 70% to 85% of HBV-related HCC cases worldwide.[5] Booster immunizations currently are not recommended for those who are not immunocompromised.[6]

Treatment for Chronic HBV Infection

The presence of hepatitis B surface antigen for more than 6 months identifies patients with chronic HBV infection. Expanded and sustained HBV vaccination ultimately will decrease the prevalence of individuals with chronic HBV infection, but the need to minimize downstream consequences of chronic infection, including the risk of HCC, exists for the foreseeable future. Anti-HBV treatment options for chronic HBV carriers are interferon and nucleos(t)ide analogues (NAs). Interferon is used in young patients who want a short course of therapy and have well-compensated liver disease,[7] although it is not consistently associated with a reduction in HCC incidence. There are several NAs that are preferred because of their low risk of viral resistance (e.g., entecavir, tenofovir disoproxil fumarate, and tenofovir alafenamide). Other NAs (e.g., lamivudine, adefovir, and telbivudine) are available, although they are less preferred because of the emergence of viral resistance, which may lead to hepatic decompensation.[8] Reductions in HCC risk, when observed for interferon therapy, have typically been among treatment responders with preexisting liver cirrhosis.[9] A reduction in HCC risk has been consistently observed for patients treated with NA therapy, regardless of cirrhosis status.[9]

The decision to initiate anti-HBV therapy depends on several factors, including the presence or absence of hepatitis B e antigen (HBeAg), a relative increase of alanine transaminase (ALT) compared with the upper limit of normal (ULN), HBV DNA level, degree of fibrosis, and age. It has been recommended that patients in the immune-active phase of chronic HBV be treated with anti-HBV therapy. Patients are considered to be in the immune-active phase if they have evidence of liver inflammation and are either: (1) HBeAg-positive with an HBV DNA level of more than 20,000 IU/mL and an ALT level more than two times the ULN, or (2) HBeAg-negative with an HBV DNA level of more than 2,000 IU/mL and an ALT level more than two times the ULN.[8] Patients with inactive HBV, in general, have normal ALT levels and HBV DNA levels of more than 2,000 IU/mL.[8]

Antiviral therapy has not been routinely recommended for patients who are not in the immune-active phase. Patients who are neither in the immune-active phase nor in one of the other standard phases of chronic HBV (immune-tolerant phase or inactive phase) are considered to be in an indeterminate phase, representing approximately 40% of patients with chronic HBV.[10] The 10-year cumulative incidence of HCC was higher among patients in the indeterminate phase of chronic HBV (4.6%; 95% CI, 3.0%–7.2%) compared with patients in the inactive phase (0.5%; 95% CI, 0.2%–1.3%).[10] However, their risk may be reduced if anti-HBV therapy is initiated.

In a multicenter, international, retrospective cohort study of 819 patients with chronic HBV who had no fibrosis or liver cirrhosis in the indeterminate phase, anti-HBV therapy was associated with a 70% reduction in HCC risk (hazard ratio [HR], 0.30; 95% CI, 0.10–0.60).[10] The cumulative incidence of HCC was significantly lower in those treated with anti-HBV therapy compared with those who were not, with proportions as follows:

While these findings suggest a significant benefit of anti-HBV therapy in reducing HCC incidence, several limitations should be noted. Firstly, the study did not specify details on HCC surveillance or the HCC diagnostic criteria used, although it was reported that diagnoses were made according to the American Association for the Study of Liver Diseases (AASLD) guidelines, using either pathology or noninvasive imaging. Additionally, the study did not provide information about the specific types or doses of anti-HBV therapy administered, although it was noted that patients in the treatment group remained on therapy throughout follow-up.[11]

The degree of HCC risk reduction with NA therapy has been nearly consistent across studies, with treated patients experiencing about half the risk of those who are not treated with NA therapy.[9,12] Most studies have been conducted in countries outside North America, yet the two studies conducted in North America observed similarly-sized, statistically significant reductions. A Canadian cohort of 322 patients with chronic HBV infection experienced lower than expected rates of HCC with a standardized incidence ratio of 0.46 (95% CI, 0.23–0.82) for patients treated with NA therapy, relative to those who were not.[13] A U.S. cohort of more than 2,000 patients with chronic HBV infection observed an HR of 0.39 (95% CI, 0.27–0.56) with treatment, although the cohort included patients treated with interferon.[14]

Availability of Food Not Contaminated With Aflatoxin B1

Qidong, China, historically has had exceptionally high rates of primary liver cancer, due to endemic chronic HBV infection and a food supply (predominately corn) with high levels of aflatoxin B1 contamination. Agricultural reforms in the 1980s led to greater availability of rice, which typically harbors much lower levels of aflatoxin B1. A population-based cancer registry was used to examine primary liver cancer mortality in Qidong in residents born before 2002, the year that universal HBV vaccination of newborns was achieved. For that group, a higher-than-50% reduction in mortality from primary liver cancer was observed following the availability of rice. About 80% of the benefit was estimated to be among those infected with HBV.[15]

HCV Treatment With DAAs

Treatment with direct-acting antivirals (DAAs) leads to elimination of hepatitis C virus (HCV) infection in almost all patients.[1] The goal of therapy is to eradicate HCV RNA and attain a sustained virologic response (SVR), which is defined as an undetectable RNA level 12 weeks after the completion of therapy. Attainment of an SVR is associated with a 97% to 100% chance of being HCV RNA negative during 5-year follow-up, and patients can therefore be considered cured of the HCV infection.[1]

Results from studies of hepatocellular cancer (HCC) risk after attaining SVR have produced conflicting results; some have observed increases in risk after treatment.[2] Most studies have included small numbers of patients, and some had insufficient follow-up time.[2] Some studies did not consider that the presence or absence of cirrhosis could affect the impact of DAAs on HCC risk.[3]

The strongest evidence to date regarding DAA treatment and HCC risk comes from a cohort study of more than 22,000 U.S. veterans receiving DAA treatment for HCV infection.[2] In that cohort, 271 HCC diagnoses occurred. Patients treated with DAAs who attained an SVR had an approximately 75% reduction in the HCC risk, relative to those who did not attain an SVR. Reduction relative risk with SVR was similar in patients with cirrhosis (hazard ratio [HR], 0.31; 95% CI, 0.23–0.44) and patients without cirrhosis (HR, 0.18; 95% CI, 0.11–0.30). Nevertheless, among patients who achieved an SVR, those with cirrhosis had an almost fivefold increase in HCC risk, relative to those without cirrhosis (HR, 4.73; 95% CI, 3.34–6.68).

Statin Use Among Adults With HBV or HCV

Statins, also known as 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase inhibitors, are cholesterol-lowering medications. Statins have been implicated in the regulation of cell proliferation, apoptosis, and tumor progression in cancer patients, and statin use at the time of cancer diagnosis has been reported to be associated with reduced cancer risk and improved survival. A systematic review and meta-analysis noted that statin use was associated with lower cancer mortality and progression overall and in patients who initiated statin use after cancer diagnosis.[4] Another meta-analysis indicated that statin use may be associated with a 37% reduced risk of HCC (odds ratio [OR], 0.63; 95% CI, 0.52– 0.76).[5] However, this meta-analysis included a patient population with and without HBV/HCV infection, making the results difficult to interpret for HBV- or HCV-infected individuals.[6] In a U.K. study of 3,719 liver cancer cases and 14,876 controls, the authors observed a 35% lower risk (OR, 0.65; 95% CI, 0.58–0.74) of liver cancer among patients who received one or more statin prescriptions before a liver cancer diagnosis date for cases and corresponding date for matched controls after adjusting for factors including HBV infection, HCV infection, alcohol-related disorders, and diabetes mellitus.[7]

Nonstatin Cholesterol-Lowering Medication Use Among Adults

Although several studies have shown that statin use lowers liver cancer risk, many patients are not able to tolerate statin therapy because of its side effects. It is unclear whether other cholesterol-lowering medications reduce the risk of liver cancer. Cholesterol-absorption inhibitors work in the small intestine to prevent cholesterol reabsorption and reduce the level of circulating cholesterol, which may regulate key signaling factors for angiogenesis and liver tumor growth. In the U.K.-based, nested case-control study, receiving one or more prescriptions for cholesterol-absorption inhibitors was associated with a lower risk of liver cancer overall (OR, 0.69; 95% CI, 0.50–0.95) and among patients with liver disease (OR, 0.53; 95% CI, 0.30–0.96).[7]

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about liver (hepatocellular) cancer prevention. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

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The preferred citation for this PDQ summary is:

PDQ® Screening and Prevention Editorial Board. PDQ Liver (Hepatocellular) Cancer Prevention. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/liver/hp/liver-prevention-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389403]

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