SEARCH

SEARCH BY CITATION

Keywords:

  • liver cancer;
  • trends;
  • epidemiology

Abstract

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. References

Hepatocellular carcinoma (HCC) incidence rates vary by gender, age, time and place. Geographic differences in gender-, age- and time-specific HCC incidence rates may improve the understanding of HCC risk factors. We computed annual standardized HCC incidence rates for the United States (U.S.) 1978–2004 and for Denmark 1978–2003. Among U.S. white men aged 45–59 the HCC incidence rates were comparable to the Danish rates until 1995, but more than tripled over the following 8 years to become over 2.5-fold higher than the Danish rate by 2003, with an additional small increase in 2004. HCC rates in black U.S. men aged 45–59 also increased sharply after 1995. Among women aged 45–59 the U.S. HCC rates were elevated in recent years, but did not show the sharp increase after 1995 observed among men; the Danish rates showed a decreasing trend throughout 1978–2003. U.S. rates in the 60–74 years age groups showed a protracted and gradual increase with no evidence of a sharp increase after 1995. In the 60–74 years age group, rates for Danish men were comparable to those for U.S. white men, but rates for Danish women decreased. The U.S. prevalence rates of hepatitis C virus (HCV) infection are 2.1 and 1.1% for men and women, respectively, the Danish 0.2%. The disparity in HCV prevalence is the most likely explanation for the differences between Danish and U.S. trends in HCC incidence. Intravenous drug use and blood transfusions are the major sources of HCV, and we suggest that increased HCV infection prevalence among Vietnam era military veterans may contribute to the earlier and steeper HCC incidence increase for U.S. men than for U.S. women. © 2007 Wiley-Liss, Inc.

Hepatocellular carcinoma (HCC) incidence rates vary by gender, age, time and place.1 The United States (U.S.) and Denmark are low-incidence areas, in part because hepatitis B virus (HBV) is not endemic in either country.1 Unlike Danish incidence rates,2, 3 U.S. incidence rates increased from 1975 through 1998.4 We examined time trends in HCC incidence in the U.S. through 2004 and Denmark through 2003 in greater detail, and the observed differences by gender, age, time and place may contribute to the understanding of risk factors for HCC.

Material and methods

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. References

U.S. HCC incidence rates for 1978 through 2004 were obtained from the Surveillance Epidemiology and End Results Program of the National Cancer Institute.5 HCC was defined by ICD-O-3 topography code C22.0 and histology codes 8170, 81713, 81723, 81733, 81743 and 81753. Danish HCC incidence rates for 1978 through 2003 were obtained from the nationwide population-based Cancer Registry6; HCC was defined by ICD-O-1 topography code 155.0 and histology codes 81703, 81713, 81723, 81733, 81743 and 81753.

We computed annual gender-specific incidence rates for the age categories 45–59 and 60–74 years for U.S. whites and blacks and Danes. All rates were age-standardized to the U.S. population in 2000.

We used linear regression to estimate the annual change in U.S. incidence rates per year from 1978 through 1995, and extrapolated from this estimate the predicted incidence rates expected for 1996–2004 in the absence of a change in trend.

Results

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. References

Among men aged 45–59 the HCC incidence rates for U.S. whites were comparable to the Danish rates until 1995, but more than tripled over the following 8 years and became over 2.5-fold higher than the Danish rate by 2003, and the increase continued through 2004 (Fig. 1). HCC rates in black U.S. men aged 45–59 also increased sharply after 1995. The HCC rates for U.S. white women aged 45–59 were initially comparable to the Danish rates, but the U.S. rates increased over time, while the Danish rates decreased. From 1998 to 2003 the HCC rates for U.S. white women aged 45–59 nearly doubled, but the 2004 rate was lower than the 2003 rate. The HCC rates for U.S. black women aged 45–59 exceeded the projected trend after 1995, but did not show the clearly steeper increase observed after 1995 in U.S. men of the same age. Among men aged 60–74 the HCC rates for U.S. white men and Danish men were similar in magnitude, but the Danish rates were higher in the 1980s, whereas the U.S. rates were higher in the 1990s. U.S. rates in the 60–74 year age groups showed protracted and gradual increases, with no evidence that rates after 1995 departed from the trend prior to 1995. The HCC rates for Danish women decreased during the study period for both age groups.

thumbnail image

Figure 1. Hepatocellular carcinoma incidence rates by age, gender, country, race and year. U.S. whites are represented by the solid line, Danes by the dashed line. The thin straight lines represent a linear regression fit to the U.S. rates through 1995, but extended through 2004. All incidence rates are age-standardized to the U.S. population in 2000.

Download figure to PowerPoint

Discussion

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. References

The U.S. and Danish HCC incidence rates showed different time trends. Most striking was the growing difference in rates between white men aged 45–59 after 1995; the U.S. rate more than tripled while the Danish rate increased only slightly. The decreasing HCC rates among Danish women are also intriguing, since the rates increased in all other groups.

HCV infection is believed to underlie the increasing U.S. HCC incidence rates.7, 8 The prevalence rate of HCV antibodies in the U.S. NHANES 1999–2002 population was 2.1% among men and 1.1% among women,9 with the highest prevalence observed for the 1945–64 birth cohorts.8, 10 These birth cohorts have been exposed to both intravenous drug use and contaminated blood transfusions, which were primarily responsible for the relatively high incidence rates of HCV infection before diagnostic tests became available.4, 8, 9, 10, 11 Assuming a latency period of 20–30 years between HCV infection and development of HCC,12, 13 the sharp increase in U.S. HCC incidence from 1995 among those aged 45–59 is consistent with a large spread of HCV infection through intravenous drug exposure in the birth cohorts who were in their twenties or thirties in the 1960s and 1970s. HCV and HBV infection through blood transfusions are more likely to be responsible for the protracted gradual increase in HCC incidence for U.S. men and women aged 60–74.14

The magnitude of the U.S. HCC incidence rate increases in middle-aged men after 1995 and middle-aged women after 1998 have not previously been shown,4 nor has a gender-difference in the timing of the increase been noted.4 It is possible that HCV acquired from intravenous drug use affects the HCC rate with a longer delay for women than for men, but we suggest that HCV acquired during military service in Vietnam may partly explain the steeper and earlier increase in HCC incidence among U.S. men. Although service in the armed forces was not associated with increased HCV prevalence in the NHANES population,9 Vietnam era veterans have markedly higher HCV infection rates than older veterans, likely resulting from a variety of factors such as direct contact in combat or via transfusion with infected blood, intravenous drug use, group vaccinations using jet injectors or gamma globulin prophylaxis for hepatitis A.15 The timing of the recent increase in HCC rates for middle-aged men is consistent with HCV infection in the Vietnam era.

Intravenous drug use and infected blood transfusions were not restricted to the U.S. Therefore, we expected a Danish HCC incidence pattern resembling that in the U.S., but they are strikingly different. The prevalence rate of HCV antibodies in Denmark has been estimated at 98% among intravenous drug users in Copenhagen in 1988–89,16 1.5% among patients admitted to a university hospital in the metropolitan area in 1994,17 0.14% among university hospital staff outside the metropolitan area in 1998,18 0.07% among blood donors, with a range from 0.01% in rural counties to 0.08% in the metropolitan area,19 and 0.2% among the 1997 population.20 The 2000–2005 population incidence rate of chronic HCV was 6.2 per 100,000 men per year and 2.6 per 100,000 women per year, based on mandatory notifications by Danish medical doctors.21, 22, 23, 24, 25 This indicates that, as is observed in the U.S., the HCV prevalence rate may be about twice as high among men than among women in Denmark. It seems likely that the HCV prevalence rate increased over time in Denmark as it did in the U.S. The lack of a marked increase in HCC rates in Danish men, given the virtually complete registration of cancers in the Cancer Registry,6 suggests that the HCV prevalence rate was too low to cause a notable increase in the number of HCC cases in Denmark.

Other known risk factors for HCC include HBV, alcoholism and diabetes.7 Alcoholism is more prevalent than HCV in U.S. HCC patients (21.2% vs. 16.3%),14 but the incidence rate of alcohol-related HCC did not change in the U.S. in 1993–99.14 The average annual consumption level of pure ethanol per U.S. adult increased from 9.5 L in 1970 to 10.4 L in 1980, and then decreased to 8.4 L in 2004.26 Per adult alcohol consumption in Denmark was 9 L in 1970, 12 L from 1975 through 2000 and 11 L in 2004.27 Thus it is likely that alcoholism has a higher prevalence among Danish than among U.S. HCC patients, which, together with the much lower HCV infection rate in Denmark, may explain why changes in HCV prevalence have a smaller impact on trends in HCC rates in Denmark than in the U.S.

The prevalence rate of diabetes is increasing in both U.S. and Denmark, but is notably higher in the U.S.28, 29 Diabetes may thus have contributed to the growing HCC incidence differences between the U.S. and Denmark, although its association with HCC is complex and has not been a consistent finding.30

The prognosis for U.S. and Swedish patients with decompensated cirrhosis has improved, so that more will live to develop HCC.7, 31, 32 It has presumably improved in Denmark, too, which makes it an unlikely explanation for the growing difference in HCC incidence rates between U.S. and Denmark.

In conclusion, our findings appear to confirm that HCV prevalence rates are a key to understanding HCC trends in countries where HBV is not endemic. None of the other proposed HCC risk factors would appear to explain the observation that the acceleration of the increase in U.S. HCC incidence rates after 1995 was restricted to middle-age. Heavy alcohol consumption is an important HCC risk factor, particularly in older ages, but alcohol consumption rates appear to have been relatively constant in both the U.S. and Denmark. We extend existing knowledge by presenting age- and gender-specific HCC incidence rates for Denmark and for the U.S. after 1998. Our findings are consistent with HCV infection via intravenous drug use and contaminated blood transfusions playing a central role in recent HCC trends, and we suggest that increased HCV infection prevalence associated with military service in Vietnam may partly explain why the HCC incidence in U.S. middle-aged men increased earlier and more markedly than in U.S. middle-aged women. Projections that the proportion of U.S. patients who have lived with HCV for 20 years or more will not decrease until 2015 forewarn continued increases in HCC.8, 10

References

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. References
  • 1
    McGlynn KA,Tsao L,Hsing AW,Devesa SS,Fraumeni JF,Jr. International trends and patterns of primary liver cancer. Int J Cancer 2001; 94: 2906.
  • 2
    Storm HH,Engholm G. Relative survival of Danish cancer patients diagnosed 1981 to 1997 and followed to 2001. A status report. Ugeskr Laeger 2002; 164: 285564. (in Danish).
  • 3
    Danish National Board of Health. Cancer incidence in Denmark 2001. Copenhagen: Danish National Board of Health, 2002.
  • 4
    El-Serag HB,Davila JA,Petersen NJ,McGlynn KA. The continuing increase in the incidence of hepatocellular carcinoma in the United States: an update. Ann Intern Med 2003; 139: 81723.
  • 5
    Surveillance Epidemiology and End Results (SEER). SEER*Stat database (software version 6.3.5): incidence – SEER 9 Registries. Bethesda, Maryland: National Cancer Institute, Division of Cancer Control and Population Sciences, Surveillance Research Program, Cancer Statistics Branch, 2007.
  • 6
    Storm HH,Michelsen EV,Clemmensen IH,Pihl J. The Danish Cancer Registry—history, content, quality and use. Dan Med Bull 1997; 44: 5359.
  • 7
    El-Serag HB. Hepatocellular carcinoma: recent trends in the United States. Gastroenterology 2004; 127: S27S34.
  • 8
    Armstrong GL,Alter MJ,McQuillan GM,Margolis HS. The past incidence of hepatitis C virus infection: implications for the future burden of chronic liver disease in the United States. Hepatology 2000; 31: 77782.
  • 9
    Armstrong GL,Wasley A,Simard EP,McQuillan GM,Kuhnert WL,Alter MJ. The prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Ann Intern Med 2006; 144: 70514.
  • 10
    Dienstag JL. Hepatitis C: a bitter harvest. Ann Intern Med 2006; 144: 7701.
  • 11
    McGlynn KA,Tarone RE,El-Serag HB. A comparison of trends in the incidence of hepatocellular carcinoma and intrahepatic cholangiocarcinoma in the United States. Cancer Epidemiol Biomarkers Prev 2006; 15: 1198203.
  • 12
    Fattovich G,Stroffolini T,Zagni I,Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology 2004; 127: S3550.
  • 13
    Goodgame B,Shaheen NJ,Galanko J,El-Serag HB. The risk of end stage liver disease and hepatocellular carcinoma among persons infected with hepatitis C virus: publication bias? Am J Gastroenterol 2003; 98: 253542.
    Direct Link:
  • 14
    Davila JA,Morgan RO,Shaib Y,McGlynn KA,El-Serag HB. Hepatitis C infection and the increasing incidence of hepatocellular carcinoma: a population-based study. Gastroenterology 2004; 127: 137280.
  • 15
    Dominitz JA,Boyko EJ,Koepsell TD,Heagerty PJ,Maynard C,Sporleder JL,Stenhouse A,Kling MA,Hrushesky W,Zeilman C,Sontag S,Shah N et al. Elevated prevalence of hepatitis C infection in users of United States veterans medical centers. Hepatology 2005; 41: 8896.
  • 16
    Westh H,Worm AM,Jensen BL,Kroon S,Kvinesdal B,Nielsen CM,Wantzin P. Hepatitis C virus antibodies in homosexual men and intravenous drug users in Denmark. Infection 1993; 21: 11517.
  • 17
    Nelsing S,Wantzin P,Skot J,Krarup E,Nielsen TL,Krarup HB,Nielsen JO. The seroprevalence of hepatitis B and C in hospitalized Danish patients. Scand J Infect Dis 1995; 27: 4458.
  • 18
    Fisker N,Mygind LH,Krarup HB,Licht D,Georgsen J,Christensen PB. Blood borne viral infections among Danish health care workers—frequent blood exposure but low prevalence of infection. Eur J Epidemiol 2004; 19: 617.
  • 19
    Christensen PB. Epidemiology of hepatitis C. Ugeskr Laeger 1998; 160: 352932. (in Danish).
  • 20
    World Health Organization. Hepatitis C—global prevalence (update). Wkly Epidemiol Rec 1999; 74: 4257.
  • 21
    Statens Serum Institut. Reporting of hepatitis B and C. Epi-News 2001; 6: 11. (in Danish).
  • 22
    Statens Serum Institut. Acute and chronic hepatitis C 2000–2001. Epi-News 2002; 43: 11. (in Danish).
  • 23
    Statens Serum Institut. Acute and chronic hepatitis C 2002–2003. Epi-News 2004; 8: 11. (in Danish).
  • 24
    Statens Serum Institut. Acute and chronic hepatitis C 2004. Epi-News 2005; 7: 11. (in Danish).
  • 25
    Statens Serum Institut. Acute and chronic hepatitis C 2005. Epi-News 2006; 7: 11. (in Danish).
  • 26
    National Institute on Alcohol Abuse and Alcoholism. Apparent per capita ethanol consumption for the United States, 1850-2004. http://www.niaaa.nih.gov/Resources/DatabaseResources/QuickFacts/AlcoholSales/consum01.htm (accessed March 5, 2007).
  • 27
    Statistics Denmark. Sales of alcohol and tobacco, subject to excises duties by type (1995–2005). http://www.statistikbanken.dk (accessed March 5, 2007).
  • 28
    Cowie CC,Rust KF,Byrd-Holt DD,Eberhardt MS,Flegal KM,Engelgau MM,Saydah SH,Williams DE,Geiss LS,Gregg EW. Prevalence of diabetes and impaired fasting glucose in adults in the U.S. population: National Health and Nutrition Examination Survey 1999–2002. Diabetes Care 2006; 29: 12638.
  • 29
    Støvring H,Andersen M,Beck-Nielsen H,Green A,Vach W. Rising prevalence of diabetes: evidence from a Danish pharmaco-epidemiological database. Lancet 2003; 362: 5378.
  • 30
    Shaib YH,Davila JA,McGlynn K,El-Serag HB. Rising incidence of intrahepatic cholangiocarcinoma in the United States: a true increase? J Hepatol 2004; 40: 4727.
  • 31
    El-Serag HB,Everhart JE. Improved survival after variceal hemorrhage over an 11-year period in the Department of Veterans Affairs. Am J Gastroenterol 2000; 95: 356673.
    Direct Link:
  • 32
    Stokkeland K,Brandt L,Ekbom A,Hultcrantz R. Improved prognosis for patients hospitalized with esophageal varices in Sweden 1969–2002. Hepatology 2006; 43: 5005.