What’s Behind the Rise in Rates of Hepatocellular Carcinoma?by Caroline Helwick
San Francisco—Although rates of hepatocellular carcinoma (HCC) and HCC-related mortality have been declining in areas of high incidence, including China and Japan, the rates are increasing in traditionally low-incidence areas, including the United States, Canada and parts of Europe.
In the United States, for example, the incidence of HCC has nearly tripled over the past 30 years, with the most rapid increase observed since the 1990s and the highest rates seen in Texas, Mississippi and Alabama (El-Serag HB. N Engl J Med 2011;365:1118-1127).
“The southern part of Texas has a [liver-related mortality] rate that is close to some parts of China,” noted Hashem El-Serag, MD, MPH, the Dan L. Duncan Professor of Medicine and chief of gastroenterology and hepatology, Baylor College of Medicine, Houston. Dr. El-Serag discussed possible causes of the increased incidence of HCC at the 2014 American Society of Clinical Oncology Gastrointestinal Cancers Symposium.
Survival ‘Dismal’
“At a time when the incidence is rapidly increasing, the five-year survival rate is dismally low—about 10% to 15%,” Dr. El-Serag noted.
Globally, more than half of all cases of HCC result from hepatitis B virus (HBV) infection, while 30% of cases are related to hepatitis C virus (HCV) infection; in the United States, those rates are 15% and 47%, respectively. In regions where HBV is the primary etiology of HCC, HCC incidence is highest in the third or fourth decade of life; where HCV predominates, HCC incidence peaks in the fifth or sixth decade of life.
“Interestingly, in countries where HCC rates are increasing, incidence is shifting from the old to the young. In the United States, we are shifting from HCC occurring at 70 to 80 years of age to mostly 60 years of age,” he said.
Tracing the Worldwide HCV Epidemic
There are three regions of the world with a similar prevalence of HCV, yet considerable differences in the incidence of HCC: Japan, southern Europe and the United States. The annual mortality rate per 100,000 persons due to HCC is approximately 30 in Japan, 15 in Europe and 5 in the United States.
“This puzzles epidemiologists,” Dr. El-Serag said. “It may have to do with the time at which HCV was introduced into the region: in the 1920s in Japan, in the 1940s in Europe and in the 1960s in the United States. The implication of this is that it’s only a matter of time for regions of low incidence to catch up with those of higher incidence, although this may or may not be true, especially in lieu of recent developments in the treatment of HCV.”
This pattern reflects a “cohort phenomenon,” Dr. El-Serag explained, in which HCV infection occurs in young adulthood and HCC emerges a few decades later.
“As the cohort of young men with HCV-related HCC dies, we begin to see HCC in age groups and gender groups that are not typical for HCC,” he said. “The last wave to present in the HCC epidemic will be older women.”
Risk Factors for Progression To HCC
The relative risk for developing HCC is 25 times higher among HCV-infected persons compared with individuals who are not infected. The absolute risk is one per 100 after 30 years of HCV infection, rising to 3.5 per 100 in the setting of HCV-related cirrhosis
Several factors render HCV-infected persons more likely to develop HCC: older age, longer duration of HCV infection, male gender and race. Potentially modifiable risk factors include alcohol consumption (40-50 g/day), obesity, type 2 diabetes and coinfection with HBV or HIV. Testing positive for HCV RNA, and possibly HCV genotypes 1 and 3, are related to increased risk as well. The REACH-B (Risk estimation for hepatocellular carcinoma in chronic hepatitis B) model incorporates these risk factors to calculate a score that is prognostic for the development of HCC at three, five and 10 years of infection (Yang HI et al. Lancet Oncol 2011;12:568-574).
The risk for progression of HBV to HCC also can be estimated: Risk factors include male gender; alcohol consumption; and coinfection with HCV, hepatitis D virus or HIV. In patients who are hepatitis B e antigen (HBeAg)-positive, the risk for HCC is increased by a prolonged interval before seroconversion, age older than 40 years, mildly and persistently abnormal alanine aminotransferase (ALT) levels and viral genotype C (more so than B). For HBeAg-negative patients, persistent viral replication, high level of HBV DNA, abnormal ALT levels and presence of HBV precore and basal core promoter mutations are risk factors.
An understanding of the HCV–HCC connection led to the recent recommendation by the Centers for Disease Control and Prevention that individuals born between 1945 and 1965 be screened for HCV, thus potentially providing protection from progression to HCC. But although eradication of HCV reduces a person’s risk for HCC, if cirrhosis has developed, the risk does not fall back to baseline. Age is also important: Older individuals with cirrhosis who are cured of HCV have a higher risk for HCC than younger people.“This information has important implications for what will happen after the HCC epidemic is over,” Dr. El-Serag noted. “The risk for HCC is unlikely to return to baseline.”
Similarly, adequate suppression of HBV DNA by antiviral medications is believed to reduce the risk for HCC, but this theory is based largely on observational studies only.
Dr. El-Serag cautioned that even the newest agents targeting HBV and HCV may not completely eliminate liver cancer.
“There is great discrepancy between the extremely high efficacy of these medications and their effectiveness in community practice,” he said.
Also, there are other risk factors that are especially potent when they occur in combination.
“Alcohol can cause alcoholic cirrhosis, which may lead to HCC on its own, but it is a virulent player in the presence of HCV or HBV,” he said.
Data regarding tobacco use are inconsistent. Smoking is not likely to be a risk factor on its own, but in the presence of HBV infection the effect is “more than additive,” and in the presence of HCV infection the interaction is “multiplicative,” Dr. El-Serag noted.
Of increasing importance in the risk for development of HCC are obesity and insulin resistance. A body mass index of 35 kg/m2 or greater is associated with a 4.5-fold increased risk for liver cancer. Insulin resistance can lead to diabetes, which doubles the risk for HCC. Insulin resistance also predisposes individuals to nonalcoholic fatty liver disease (NAFLD), which in 20% of patients may progress to nonalcoholic steatohepatitis; this, in turn, leads to cirrhosis in 10% to 15% of patients.
“Hepatologists believe that NAFLD increases the risk for HCC, but as a relatively new entity, there are no population-based studies,” Dr. El-Serag noted. “We don’t know the magnitude of risk, but what’s clear is that cirrhosis-related NAFLD is associated with increased risk for HCC, although the risk is less than that associated with HCV. The risk factors that compound that risk are obesity and cirrhosis [White D et al. Clin Gastroenterol Hepatol 2012;10:1342-1359],” he said.
Is Prevention Possible?
Conversely, coffee consumption and metformin use (in diabetic patients) appear protective against HCC. Meta-analyses suggest that each cup of coffee is associated with an approximately 25% reduction in risk, whereas metformin use reduces risk by 76% (Zhang H et al. Scand J Gastroenterol 2013;48:78-87). Additionally, observational studies suggest that statins are associated with a 47% risk reduction; however, this association has not been supported by clinical trials.
In summary, Dr. El-Serag concluded: “HCC is a global problem that continues to increase. Prevention is largely through HBV vaccination and antiviral treatments, but there are major gaps in effectiveness for all our prevention measures. Although there is a possibility that coffee, statins and metformin are protective, we need trials before we implement these strategies.”
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