In this population-based study in California, we found that foreign-born Asians had significantly and consistently higher incidence rates of liver cancer than US-born Asians—as high as a five-fold difference among Japanese women. By contrast, foreign-born Hispanic men had significantly lower liver cancer incidence rates than their US-born counterparts, a disparity that widened as the incidence rate increased more among US-born than foreign-born Hispanic men in recent years. A similar increase among US-born Hispanic women, meanwhile, closed an earlier gap with foreign-born Hispanic women. We also found that liver cancer incidence rates varied by neighborhood ethnic enclave status and SES, with increased rates among Hispanics and Asians living in neighborhoods with both higher enclave status and lower SES. In all subgroups, the markedly stronger IRRs by nativity than by neighborhood ethnic enclave status, SES, or both suggest that individual-level nativity is a more important determinant of liver cancer risk than these residential neighborhood characteristics.
The observed disparities in liver cancer incidence by nativity and residential characteristics are likely explained in large part by differences in known and unknown environmental and behavioral (as opposed to genetic) risk factors for liver cancer. The rising prevalence of such risk factors, such as obesity and chronic HCV infection, in past decades may explain the increasing trend in liver cancer incidence among US-born and, to a lesser extent, foreign-born Hispanics observed here and elsewhere (3
). The consistency of our results when the analysis was limited to regional and distant-stage disease argues against patterns of liver cancer screening as an explanation for the observed incidence rate patterns. Instead, perhaps the most prominent cause of the rising incidence rates of liver cancer in the US, especially among Hispanics, is chronic HCV infection. The prevalence of HCV infection escalated from the 1960s through the 1980s, mostly as a result of intravenous drug use and contaminated blood transfusion, and is expected to drive a continued increase in liver cancer rates for several years to come following a latency period of two to four decades (41
). HCV is likely a leading cause of liver cancer among Hispanics; at a New York City medical center between 1994 and 2001, 60% of Hispanic liver cancer patients were infected with HCV, compared with 43% of non-Hispanic patients (43
). However, further population-based studies are needed to determine the percentage of liver cancer due to HCV in Hispanics. The incidence rate patterns in our study may point to a higher prevalence of HCV infection among US-born than foreign-born Hispanic males, and possibly a higher prevalence among less acculturated and lower-SES males and females, although data to support this conjecture are lacking. While separate studies suggest that the prevalence of HCV infection is higher among Mexicans in the US than those in Mexico (44
), to our knowledge, no studies have directly compared the prevalence of HCV infection among Hispanics by nativity, acculturation, or SES. Alcohol abuse, another behavioral risk factor for liver cancer (46
), may also help to explain some of the observed incidence patterns by nativity and neighborhood characteristics. In support of this hypothesis, population-based data from the 2001 California Health Interview Survey (CHIS) (47
)showed that US-born Hispanic males had a higher prevalence of binge drinking in the past month (31.8%; 95% CI: 29.0–34.5%) than foreign-born Hispanic men (26.4%; 95% CI: 24.2–28.6%), whereas there was no difference in the prevalence of binge drinking between US-born and foreign-born Asian men (14.0% and 14.5%, respectively). Of note, a study based in SEER-Medicare found the proportion of liver cancer attributable to alcoholic liver disease did not increase during the 1990s (42
), and there is no consistent evidence of an increase in the prevalence of alcohol abuse in the US over the last several decades (48
), indicating that alcohol abuse is unlikely to be responsible for the rising incidence of liver cancer. Instead, the more likely causes are HCV and nonalcoholic fatty liver disease or steatohepatitis; the latter is an underlying cause of cirrhosis that has become increasingly common in concert with the epidemics of type 2 diabetes and obesity (50
), and appears to be more common in Mexican Americans than in other racial/ethnic groups in the US (52
). According to 2001 CHIS data, the prevalence of obesity among Hispanic adults generally coincided with liver cancer incidence patterns, with higher rates among US-born Hispanic men (27.7%; 95% CI: 25.0–30.3%) than foreign-born Hispanic men (21.1%; 95% CI: 19.1–23.1%), and higher rates among foreign-born Hispanic women (29.0%; 95% CI: 26.9–31.0%) than US-born Hispanic women (25.3%; 95% CI: 23.0–27.5%) (47
). A higher prevalence of obesity among women and a lower prevalence among men in Mexico compared with those in California (54
) may also contribute to international liver cancer incidence patterns in Hispanics. Among Asians, however, CHIS data on the prevalence of obesity did not correspond with liver cancer incidence patterns, with higher rates in US-born (12.9%; 95% CI: 7.5–18.3%) than foreign-born Asian men (4.9%; 3.3–6.5%), and slightly higher rates in US-born (5.4%; 2.9–8.0%) than foreign-born Asian women (3.7%; 2.6–4.8%) (47
). These patterns, along with the fact that liver cancer incidence rates among Asians have not risen in concert with the rising prevalence of obesity and chronic HCV infection, suggest that nonalcoholic fatty liver disease and HCV may not be major contributing factors to liver cancer risk among US Asians.
Instead, 60–80% of liver cancer among Asians in Asia, as well as foreign-born Asians in US, is caused by chronic HBV infection (55
) (except in Japan, where up to 50–70% of liver cancer is attributable to HCV (59
)). The predominant etiologic role of HBV in most of Asia likely explains why Asians, despite having markedly lower prevalences of binge drinking and obesity than Hispanics, nevertheless have higher incidence rates of liver cancer. HBV is endemic in most of East and Southeast Asia, where approximately 10% of the population is chronically infected (61
). (Japan is an exception, with a 2–7% prevalence of chronic HBV infection (61
).) By comparison, the prevalence of chronic HBV infection in the US non-Asian population is less than 0.5% (61
). Most chronic HBV infection in Asia is acquired at birth from infected mothers and during early childhood from close contact with infected adults or children (62
). Due in part to the lower population-wide prevalence of chronic HBV infection in the US, and perhaps to the widespread availability of an HBV vaccine since 1982, the prevalence of chronic HBV infection is substantially lower in US-born than foreign-born Asians (61
). The prevalence of HCV infection is also likely lower in US-born than foreign-born Asians, given the higher population-wide prevalence of HCV infection in several Asian countries than in the US (60
), although direct evidence is unavailable. In addition, aflatoxin B1
, a hepatocarcinogenic metabolite produced by Aspergillus
fungi, is more prevalent and more commonly consumed with contaminated staple foods in Asia than in the US (65
). These differences most likely offer the primary explanation for the lower incidence rates of liver cancer among US-born than foreign-born Asians in our study, as well as the lower rates among Asians in the US than in Asia.
The nativity patterns we observed among Hispanics are consistent with those of El-Serag et al.
, who found that liver cancer mortality rates among US-born Hispanic men in California and Texas in 1999–2001 were double those among foreign-born Hispanic men, whereas rates did not differ appreciably between US-born and foreign-born Hispanic women (40
). El-Serag et al
. also found that liver cancer mortality rates increased substantially more among US-born than foreign-born Hispanic men and women between 1979–1981 and 1999–2001. By using incidence instead of mortality data, we showed that these patterns were most likely due to differences in disease risk, rather than liver cancer treatment. Although they lacked the ability to compare US- with foreign-born Hispanics, Pinheiro et al.
found that liver cancer incidence rates among (predominantly foreign-born) Mexican, Puerto Rican, and Cuban males in Florida in 1999–2001 were consistently higher than the GLOBOCAN 2002 incidence rates in their countries of origin, whereas rates were lower among Mexican, Puerto Rican, and Cuban females in Florida than in Central America (66
). Similarly, Ho et al.
reported higher liver cancer incidence rates in US mainland than island Puerto Rican males, but not females (67
). Taken together, these results reinforce the notion that behavioral or environmental risk factors related to migration or acculturation act rapidly to influence liver cancer incidence among Hispanic males within a single generation. In particular, Pinheiro et al.
suggested that the diverging patterns by sex might be due to a tendency of male immigrants to adopt less healthy lifestyles, including increased alcohol consumption and intravenous drug use leading to viral hepatitis infection, compared with females (66
Previous studies of liver cancer patterns by nativity among US Asians also found results similar to ours, although our data enhance prior findings in several ways. El-Serag et al.
reported that liver cancer mortality rates among Asian men and women in California and Texas were nearly three times higher in the foreign-born than the US-born, and increased modestly among foreign-born but not US-born Asian men and women between 1979–1981 and 1999–2001 (40
). Again, by analyzing incidence data, we ruled out the possibility that these patterns could have been due to differences in liver cancer treatment. Like us, Rosenblatt et al.
found using SEER data that liver cancer incidence rates were highest among Asians in Asia, intermediate among foreign-born Asians in the US, and lowest among US-born Asians. However, they did not compute rate ratios to compare incidence rates directly between foreign-born and US-born Asians, and they randomly imputed birthplace for all cases with unknown birthplace. Because birthplace is non-randomly missing in cancer registry data (15
), we strengthened these prior findings through imputation of missing birthplace using a validated SSN-based method. Lee et al.
found similar results comparing liver cancer incidence rates between native South Koreans and Korean Americans, but they did not classify Korean Americans by nativity.
To our knowledge, no other study in the US has examined differences in liver cancer incidence rates by neighborhood ethnic enclave status and SES. A Canadian study found that liver cancer incidence rates were geographically clustered according to the proportion of immigrants within provincial health regions (68
). In that study, the regional prevalence of smoking, alcohol use, obesity, and diabetes, as well as the distribution of physical activity, fruit and vegetable consumption, education, and income, did not contribute significantly to geographic variation in liver cancer incidence, although the large geographic scale may have obscured true etiologic effects.
An important consideration in interpreting our results is the impact of misclassification of undocumented/unlawful immigrants as US-born instead of foreign-born. In 2006, approximately 2.8 million undocumented immigrants lived in California, comprising about 8% of the state’s inhabitants and 30% of all immigrants (69
). Approximately 90% of undocumented immigrants in California are estimated to be from Latin America, including 65% from Mexico alone; most of the remaining 10% are from Asia (69
). Undocumented immigrants may be more likely than documented immigrants to falsely report themselves as US-born, as well as to provide false SSNs. A recent study by the Social Security Administration found that only 4% of US employees overall had SSNs that did not match the name and number in the administration’s records, although this figure is almost certainly an underestimate of the proportion of mismatched SSNs specifically among undocumented immigrants (70
However, we believe that the bias due to misclassification of nativity among undocumented immigrants was limited in our study. False reporting of a US birthplace would likely have affected both the numerators and denominators of incidence rates, producing little net change. Bias due to the use of false SSNs to impute nativity for patients with missing birthplace information, resulting in an overestimate of US-born cases and a corresponding underestimate of foreign-born cases, was also limited, as nativity was imputed for only 9% of cases. Furthermore, even an individual using a false SSN would have been correctly classified as foreign-born if the SSN was issued after the individual reached age 25 years (if Asian) or 20 years (if Hispanic). For legally documented immigrants who had a true SSN issued early in life and missing birthplace in the CCR, the bias due to being misclassified by our algorithm as US-born was tempered by the fact that those individuals would have spent the majority of their lives in the US, like the US-born population with whom they were grouped.
Other limitations of our study include the lack of cancer registry data on individual-level risk factors that may contribute to the observed incidence rate differences, as well as our inability to examine joint combinations of nativity and neighborhood enclave status or SES, due to the unavailability of nativity-and race/ethnicity-specific population data at the census-tract level. Counterbalancing these limitations are the notable strengths of this study, including its setting in the state with the nation’s largest Hispanic and Asian populations; the generalizability of our results, due to the population-based design; and our use of high-quality cancer registry data. For the 91% of cases with known birthplace, we have previously demonstrated that cancer registry birthplace information is highly valid in comparison with self-reported birthplace (29
). Likewise, prior studies have shown excellent agreement between cancer registry data and self-reported data on race, and good agreement on Hispanic ethnicity and Asian subgroup (71
In summary, we found that liver cancer incidence rates among California Hispanics and Asians varied significantly by nativity, residential enclave status, and neighborhood SES, with US-born Hispanic males, possibly foreign-born Hispanic females, foreign-born Asian males and females, and those living in lower-SES, higher-enclave-status neighborhoods having higher rates than their respective comparison groups. These geographic and environmental differences highlight the importance of behavioral and environmental risk factors in liver cancer development, and provide valuable new information to guide the prioritization of future liver cancer control strategies. In particular, our results indicate that cultural, linguistic, and socioeconomic considerations are likely critical in the design of programs to prevent, detect, and treat hepatitis B and C infection and reduce the prevalence of alcohol abuse, obesity, and diabetes in the high-risk Hispanic and Asian populations. For example, to be accessible to those at greatest risk, such programs may need to be located in dense ethnic enclaves and to offer hepatitis testing, antiviral and substance abuse treatment, liver cancer screening, and other preventive care for free or at a low cost. Better understanding of how behavioral risk factors for liver cancer vary by nativity, acculturation, and SES can enhance such programs to maximize their effectiveness and impact.