Conference Presentation

A progressive increase in HCC-related mortality has been observed over the last 3 decades. According to the United States vital statistics, the overall age-adjusted mortality rate for HCC (ICD-9 155.0, which excludes cholangiocarcinoma and metastatic liver cancer) has risen significantly from 1.7 per 100,000 (95 percent CI, 1.7 to 1.8) during 1981–1995 to 2.4 per 100,000 (2.4 to 2.5) during 1991–1995. The recent rise in HCC mortality in the United States is a result of the rising incidence rate of HCC observed during the same time period coupled with a dismal survival rate (5 percent at 5 years). Data from the population-based SEER registries indicate that the age-adjusted incidence rate of HCC (ICD-O 8170) has increased from 1.4 per 100,000 during 1976–1980 to 3.0 per 100,000 during 1996–1998, more than a twofold increase.

The latter rates probably underestimate the true incidence by approximately 30 percent as they represent only histologically confirmed HCC. During the same time, the temporal trends for hospitalizations with primary liver cancer have mirrored those of incidence and mortality. For example, data from the national VA computerized database show that the overall number of hospitalizations as well as the age-adjusted proportional hospitalization rate for HCC have increased by 42 percent from 1981–1997, reaching a hospitalization rate of 4.1 per 10,000 (3.7 to 4.5) during 1993–1997.

Demographic Risk Factors for HCC

There are significant gender, ethnicity, and geographic variations in the incidence of HCC in the United States. Caucasians are two to three times less affected than African Americans, who in turn are two to three times less affected than Asians, Pacific Islanders, or Native Americans. For all ethnic groups, men are two to three time more affected than women.

Asians men have the highest age-adjusted incidence rates (up to 23 per 100,000). However, men and women of all ethnic groups have been affected by the recent increase in incidence. The reasons for these ethnic and gender variations probably relate to the prevalence and time of acquisition of the major HCC risk factors. It is known that the prevalence of HCV, HBV, and alcoholic cirrhosis is two- to threefold higher in African-Americans and Hispanics than in whites. Native American Eskimos and recent immigrants from China, Taiwan, Korea, and Vietnam have high prevalence rates of HBV similar to those in their original countries. There are significant geographic variations within the United States in HCC (irrespective of the demographic differences between these regions): Hawaii had the highest age-adjusted incidence rate (4.6/100,000), followed by San Francisco-Oakland (3.2/100,000) and New Mexico (2.0/100,000), whereas Iowa and Utah have the lowest rates of approximately 1.0/100,000.

We used hierarchical linear multivariate analysis to examine the temporal trends in HCC incidence while controlling for age, gender, and ethnicity as well as adjusting for potential clustering of persons with similar demographic characteristics within geographic regions.

This analysis has confirmed a twofold increase in HCC over a time period between 1975and 1998 while adjusting for all the variables described above.

Concomitant with the rising rates of HCC, there has been a shift of incidence from typically elderly patients to relatively younger patients between ages 40 to 60. This shift reflects a cohort/period effect, affecting those who were born after 1920 and who seem to have been exposed to environmental agent(s) that have caused a cumulative increase in the HCC risk in all age groups of these cohorts. One plausible hypothesis is that these cohorts were infected with HCV during the 1950s–1970s, when they were in their twenties to forties, and are now presenting with HCV-related HCC. The full extent of this cohort/period effect has not been realized yet (the incidence rates have not leveled off yet).

Underlying Etiology for the Rising Incidence of HCC in the United States

Due to the essential role of cirrhosis in the development of HCC in the majority of cases, an increase in the number of persons living with cirrhosis is the likely explanation of the rising incidence of HCC. Declines in the mortality rates due to cirrhosis (partly related to improved management of esophageal varices and peritonitis) have been observed in the United States over the last 25 years. In addition, the incidence of cirrhosis related to HCV infection is rising. We carried out a population-based study in which the computerized records of hospitalized HCC patients during 1993 and 1998 (n=1,605) in all VA hospitals were searched for specific risk factors. There was a threefold increase in the age-adjusted rates for HCC associated with HCV from 2.3 per 100,000 (1.8 to 3.0) between 1993 and 1995 to 7.0 per 100,000 (5.9 to 8.1) between 1996 and 1998. HCV infection accounted for at least half of the increase in the number of HCCcases among United States veterans. During the same time periods, age-adjusted rates for HCC with either HBV (2.2 vs. 3.1 per 100,000) or alcoholic cirrhosis (8.4 vs. 9.1 per 100,000) remained stable. The rates for HCC without risk factors have also remained without a statistically significant change from 17.5 (15.8 to 19.1) between 1993 and 1995 to 19.0 per 100,000 (17.3 to 20.7) between 1996 and 1998. Thirty-eight percent of patients without specific risk factors had a diagnosis of nonspecific cirrhosis, many of whom were not tested for HCV. Similar trends have been observed from the large referral setting of M.D. Anderson Medical Center, where we recently reviewed the medical records of all patients residing in the United States who received a pathological diagnosis of HCC during 1993–1998; all patients were tested for HCV and HBV. The number of patients referred with HCC steadily increased from 143 in 1993–1995 to 216 in 1996–1998; of those, 26 patients (18 percent) and 66 patients (31 percent) were HCV positive during 1993–1995 and 1996–1998, respectively (P = 0.01). These data and a summary of all published HCC studies in the United States indicate that HCV is present in approximately 25–30 percent of cases, with more recent series reporting a greater proportion of HCV-related cirrhosis.

The risk of HCC in HCV: Cirrhosis is present in virtually all cases of HCV-related HCC. Once cirrhosis is established, HCC develops at an annual rate of 1 percent to 5 percent. The more important figure, the incidence of cirrhosis in HCV-infected patients, is more difficult to determine. We have examined the natural history of HCV (i.e., non-treated) in a systematic review of the literature among all subjects at risk for chronic HCV infection (excluding studies in  which cohorts were selected from patients with chronic liver disease and those where the onset time of infection could not be identified). The incidence rates of cirrhosis and HCC were determined in 21 studies. Even within this selected groups of studies, large variations were found in the estimates of cirrhosis (0–33 percent) and HCC (0–2.8 percent), time to cirrhosis (13–23 yrs), and time to HCC (17–31 yrs). Short duration of followup, small sample size, incomplete documentation of risk factors (e.g., alcohol), and incomplete screening for cirrhosis/HCC explain some of these variations. Due to the significant heterogeneity in these results, pooled estimates from studies are unlikely to be valid. Nevertheless, in studies with the best-documented onset of infection, there is an average incidence of cirrhosis of 1 percent per year and of HCC of 0.05 percent per year (20 percent and 1 percent at 20 years, respectively) in patients with chronic HCV infection. The mode of HCV acquisition appears to affect the progression of HCV; studies of community-acquired or Anti-D IgG related HCV infection had more benign course than that associated with transfusion or hemophilia. A graphic presentation of the incidence rates of cirrhosis or HCC vs. the sample size/duration of followup suggests the presence of publication bias and that the true estimates could be significantly higher or lower than those described above.

Host related factors seem to be more important than viral factors in determining the progression of HCV infection to cirrhosis and HCC. These factors include older age of HCV acquisition, male gender (x2–3), heavy alcohol intake > 50 gm/day (x5–50), HBV (x 5–15) or HIV co-infection, and possibly increased hepatic iron. Most important of all seems to be time elapsed since acquiring HCV infection with a median time of 30 years being the time frame when most HCC starts appearing. All HCV genotypes have been implicated in HCV-related HCC. Diabetes and obesity are also emerging risk factors; in a large case-control study among veterans (823 patients with HCC and 3,459 controls), we found diabetes to be associated with a 1.5-fold increase in the risk of HCC in the presence of other major HCC risk factors such as HCV, HBV, and alcoholic cirrhosis. Obesity has been shown to increase the risk of hepatic steatosis and fibrosis in HCV-infected patients, and diabetes is a known risk for NASH, which could progress to cirrhosis.

Due to the large pool of HCV-infected persons, it is likely that the rising incidence of HCC will continue over the next several years. Despite having a current HCV prevalence similar to that of Japan 20–30 years earlier, extrapolating the current Japanese HCC trends (10 times that of the current United States rates) to future trends in the United States may be inappropriate. (For example, <40 percent in the United States is HCV-related vs. 90 percent of HCC in Japan; also, most patients with end-stage liver disease in the United States die from non-HCC cirrhosis related complications, whereas in Japan, decompensated liver disease is unusual.)

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5. El-Serag HB, Everhart JE. Improved survival following variceal hemorrhage over an 11-year period in the Department of Veteran Affairs. Am J Gastroenterol 2000;95:3566–73.

6. El-Serag HB, Richardson P, Everhart JE. The role of diabetes in hepatocellular carcinoma among veterans: A case-control study. Am J Gastroenterol 2001;96:2462–7.

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Hepatocellular Carcinoma (HCC) and HCV in the United States
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