Abstract
Background & Aims:
The main causes of hepatocellular carcinoma (HCC) include chronic hepatitis C and B viral infections (HCV, HBV), NAFLD, alcohol-related disease (ALD). Etiology-specific HCC incidence rates and temporal trends on a population-basis are needed to improve HCC control and prevention.
Methods:
All 14,420 HCC cases from the Florida statewide cancer registry were individually linked to data from the hospital discharge agency and the viral hepatitis department to determine the predominant etiology of each case diagnosed during 2010–2018. Age-adjusted incidence rates (AAIR) were used to assess the intersection between etiology and detailed race-ethnicity. Etiology-specific temporal trends based on diagnosis year were assessed using Joinpoint regression.
Results:
HCV remains the leading cause of HCC among men, but since 2017 NAFLD-HCC is the leading cause among women. HCV-HCC AAIRs are particularly high among US-born minority men, including Puerto Rican (10.9 per 100,000), African American (8.0 per 100,000), and US-born Mexican American men (7.6 per 100,000). NAFLD is more common among all Hispanics and Filipinos, HBV-HCC among Asian and Haitian Black men. HCV-HCC surpasses HBV-HCC in Asian women. ALD-HCC is high among specific Hispanic male groups. Population-based HCV-HCC rates experienced a rapid decline since 2015 (−9.6% annually), while ALD-HCC (+6.0%) and NAFLD-HCC (+4.3%) are rising (p<0.05).
Conclusions:
New directly acting anti-viral drugs have impacted rates of HCV-HCC, offsetting important increases in both ALD- and NAFLD-HCC. Hispanics may be a group of concern due to higher rates for ALD- and NAFLD-HCC. HCC etiology varies remarkably and may warrant specific interventions by detailed race-ethnicity.
Keywords: etiology, liver cancer, race, ethnicity, trends
Graphical Abstract
Introduction
Hepatocellular carcinoma (HCC), representing 78% of liver cancers in the United States (US), is highly fatal with only 18% of patients surviving 5 years [1]. Approximately 25,000 new HCC cases are diagnosed annually and incidence rates have increased 48% since 2000 [2]. Clinician reports have shown that over 90% of HCC cases can be attributed to a particular etiology, with the most prevalent causes being chronic hepatitis C infection (HCV), chronic hepatitis B infection (HBV), alcohol-related liver disease (ALD), and non-alcoholic fatty liver disease (NAFLD) [3,4]. Yet, the respective burden of each distinct cause of HCC in the diverse US population is poorly understood, a knowledge gap that hinders our ability to develop effective prevention and control efforts, especially for the non-infectious causes of HCC.
To date, studies describing the relative burden of HCC causal factors have primarily been hospital-based series [3]. Often, these studies utilize only proportions without considering the size of the underlying population at risk, limiting resultant epidemiological information. Moreover, hospital-based series are subject to selection biases, rooted in referral and health insurance coverage patterns, which can perpetuate data limitations for marginalized subpopulations. HCC is a cancer that disproportionately affects those of low socioeconomic status, as well as immigrant, Veteran, and incarcerated populations [4], all of whom are difficult to capture in clinical research studies because they often diverge from typical healthcare pathways. Establishing etiology-specific HCC patterns and trends based on truly inclusive (population-based) data is critical to develop effective prevention and control efforts, especially for those most vulnerable.
In this study, we use individual-level data from three independent population-based data sources in novel statewide linkages to estimate incidence rates and trends by etiology. Moreover, we leverage the remarkable diversity of Florida’s population to examine these patterns in detailed race-ethnicity groups: Central Americans, Cubans, Dominicans, Mexican—including US-born Mexican and Foreign-born Mexican—Puerto Ricans, and South Americans instead of Hispanic/Latino(x) only, and African American, Haitian and West Indian instead of Non-Hispanic (NH) Black only. We expand and deepen the findings of our previous study [5] by including more years of data (2010–2018) instead of 2014–2015 only, computing population-based rates accounting for all HCC cases, adding data from a new linkage with chronic viral hepatitis biomarkers, performing trend analyses, and including a more refined subgroup analysis for Black, Hispanic, and Asian populations.
Materials and Methods
All liver cancer cases reported to the statewide cancer registry, the Florida Cancer Data System (FCDS), diagnosed during 2010–2018, were studied. The FCDS has been recognized for its quality/completeness and has maintained Gold Certification status from the North American Association of Central Cancer Registries for 20 years [6]. Eligible cases for this report included all ICD-O-3 HCC morphologies 8170–8180 (n=12,992). In addition, and because American clinical practice guidelines allow for HCC diagnosis without biopsy, based on imaging alone, cancer cases coded C22.0 (liver) with morphologies 8000–8010 (n=1,428) were also included unless any other primary cancer (e.g., breast, colon, etc.) had occurred prior to the corresponding HCC diagnosis which could cause misclassification of the liver as the primary cancer site.
All HCC cases were individually linked with two data sources: firstly, with the statewide hospital and discharge data provided by Florida’s Agency for Healthcare Administration (AHCA), a database including diagnosis codes for every medical episode in any hospital setting in Florida and secondly the viral hepatitis data from the Florida Department of Health’s Department of Sexually Transmitted Diseases and Viral Hepatitis surveillance. Linkages were deterministic based on first and last name, sex, birth date, social security number, when available, and county of residence. For the viral hepatitis data, all HCV-RNA positive and/or anti-HCV positive cases and HBV-DNA positive and/or HBs Ag positive cases were considered chronic HCV and chronic HBV cases respectively. For discharge data, relevant diagnosis codes for the etiology of HCC were extracted using established ICD-9-CM and ICD-10-CM codes [7,8] (Table S1).
Based on these two linkages, we assessed seven types of causes including HCV, HBV, ALD, NAFLD, and rarer causes such as autoimmune diseases, genetic causes (e.g., hemochromatosis), and cryptogenic (defined as cases matched with discharge data, but without any code of the remaining six causes, and non-matched to viral hepatitis). To select a predominant-cause category in cases with multiple causes, we used Beste’s hierarchical approach [9], largely based on decreasing strength of association (from past research) for each HCC etiology. Because this is a population-based study, to avoid underestimating etiology-specific counts which would distort rates and trends we performed multiple imputations (MI) with 20 iterations based on sex, racial/ethnicity group, age group, region of residence, and year of diagnosis for cases that did not initially match with any of the data sources (n=1,795 or 12.4%) and placed each into the mentioned 7 cause groups.
We computed proportions of cases by etiology for each racial/ethnic group, sex, and by age groups. We also analyzed etiology of HCC by stage at diagnosis, level of poverty defined by the prevalence of poverty in the respective census tract of residence (0% to < 5%, very low; 5% to < 10%, low; 10% to < 20%, intermediate; 20% to < 100%, high), and US or foreign birth, in addition to race-ethnicity level I (broad racial-ethnic groups comprising non-Hispanic (NH) White (White), NH-Black (Black), and NH-Asian/Pacific Islander (API), as well as Hispanic of all races) and level II (detailed groups including those among the Hispanic population: Central Americans, Cubans, Dominicans, Mexican—including US-born Mexican and Foreign-born Mexican—Puerto Ricans, and South Americans, and among the Black population: African American/US-born Black, Haiti-born Black and West Indies-born Black). We compared prevalence proportions for each of these characteristics using Chi-square tests. Technical aspects of the definition of race-ethnicity Levels I and II can be found in supplemental Annex 1. Level II group identification was possible for 87.5% of Hispanic and 91.2% of NH-Black persons. For the missing cases we used the combined MI procedure with imputation of etiology into a specific group based on age, sex, county of residence, and HCC etiology (when available).
To demonstrate population-level differences, we calculated annualized, sex-stratified, etiology-specific age-adjusted incidence rates (AAIR) for HCC for each Level I and II race and ethnicity groups using the 2000 US population standard and 18 age group bands. Population denominators corresponding to each age group, race-ethnicity, and sex came from the American Community Survey (ACS) 2010–2018 [10]. Finally, we used Joinpoint regression to assess annual rate trends of the predominant cause by sex, race, and race-ethnicity level I [11]. For Asian level II groups such as Chinese or Filipino, we were unable to calculate detailed rates because of their relatively low numbers and the imprecision of their denominator ACS data available for Florida. However, to depict unstudied heterogeneity among Asian persons regarding HCC, we collected and linked data as far back as 2005 to attain informative proportions for this important population. In this study, we only report on cases and rates for the four most common HCC causes: HCV, HBV, ALD, and NAFLD. All numbers presented in tables are post-imputation.
Data were analyzed using SAS 9.4 and SPSS V22.0.
Results
All 14,420 cases of HCC diagnosed during 2010–2018 and identified through the population-based cancer registry constituted our analytical dataset. Table 1 shows the distribution of general demographics and predominant HCC etiologies. The most prevalent etiology was HCV (n=6,714; 46.6%), followed by 3,927 NAFLD-HCC (27.2%), 1,879 ALD-HCC (13.0%), and 633 HBV-HCC (4.4%). The remaining were cryptogenic (7.3%) and other causes (1.5%) including hemochromatosis, auto-immune hepatitis, among others. When considering all overlapping causes rather than only the predominant cause, two important combinations were HCV with NAFLD (24.6% of all cases) and HCV with ALD (13.9% of all cases) (Table S2).
Table 1.
Sociodemographic and clinical characteristics by predominant cause of HCC cases. Florida 2010–2018.
| Totala N (%) | HCV-HCC N (%) | HBV-HCC N (%) | ALD-HCC N (%) | NAFLD-HCC N (%) | p-valueb | |
|---|---|---|---|---|---|---|
| Total Cases | 14,420 | 6714 | 632 | 1879 | 3927 | |
| Median Age | 64 | 60 | 59 | 66 | 71 | |
| Sex | <0.0001 | |||||
| Male | 11,082 (76.9%) | 5,348 (79.7%) | 530 (83.9%) | 1,568 (83.4%) | 2,723 (69.3%) | |
| Female | 3,338 (23.1%) | 1,365 (20.3%) | 102 (16.1%) | 312 (16.6%) | 1,204 (30.7%) | |
| Race/Ethnicity | <0.0001 | |||||
| Whites | 9,412 (65.3%) | 4,367 (65.0%) | 153 (24.2%) | 1,337 (71.2%) | 2,691 (68.5%) | |
| Blacks | 1,878 (13.0%) | 1,076 (16.0%) | 215 (34.0%) | 148 (7.9%) | 294 (7.5%) | |
| Asians | 427 (3.0%) | 130 (1.9%) | 172 (27.2%) | 19 (1.0%) | 69 (1.8%) | |
| Hispanics | 2,703 (18.7%) | 1,141 (17.0%) | 93 (14.7%) | 375 (20.0%) | 873 (22.2%) | |
| Age Group | <0.0001 | |||||
| <49 | 609 (4.2%) | 225 (3.4%) | 146 (23.1%) | 73 (3.9%) | 80 (2.0%) | |
| 50–69 | 9,106 (63.1%) | 5,612 (83.6%) | 345 (54.6%) | 1,053 (56.0%) | 1,463 (37.3%) | |
| 70+ | 4,705 (32.6%) | 877 (13.1%) | 141 (22.3%) | 753 (40.1%) | 2,383 (60.7%) | |
| Stage at Diagnosis | <0.0001 | |||||
| Localized | 6,441 (44.7%) | 3,075 (45.8%) | 284 (44.9%) | 836 (44.5%) | 1,815 (46.2%) | |
| Regional | 3,702 (25.7%) | 1749 (26.1%) | 152 (24.1%) | 483 (25.7%) | 898 (22.9%) | |
| Distant | 2,156 (15.0%) | 912 (13.6%) | 109 (17.2%) | 237 (12.6%) | 615 (15.7%) | |
| Unknown | 2,121 (14.7%) | 978 (14.6%) | 87 (13.8%) | 323 (17.2%) | 599 (15.3%) | |
| Poverty Level | <0.0001 | |||||
| Very low poverty | 1,189 (8.2%) | 450 (6.7%) | 58 (9.2%) | 156 (8.3%) | 401 (10.2%) | |
| Low poverty | 3,269 (22.7%) | 1,354 (20.2%) | 141 (22.3%) | 471 (25.1%) | 995 (25.3%) | |
| Medium poverty | 5,438 (37.7%) | 2,498 (37.2%) | 225 (35.6%) | 714 (38.0%) | 1,530 (39.0%) | |
| High poverty | 4,386 (30.4%) | 2,353 (35.0%) | 203 (32.1%) | 514 (27.4%) | 958 (24.4%) | |
| Unknown | 138 (1.0%) | 59 (0.9%) | 4 (0.6%) | 23 (1.2%) | 42 (1.1%) | |
| Nativity Status | <0.0001 | |||||
| US birth | 10,211 (70.8%) | 5,014 (74.7%) | 249 (39.4%) | 1,346 (71.6%) | 2,662 (67.8%) | |
| Foreign birth | 2,331 (16.2%) | 756 (11.3%) | 310 (49.1%) | 286 (15.2%) | 731 (18.6%) | |
| Unknown birth | 1,878 (13.0%) | 945 (14.1%) | 72 (11.4%) | 248 (13.2%) | 534 (13.6%) | |
| Detailed Black Subgroups | <0.0001 | |||||
| African American/US-born Blackc | 1,600 (11.1%) | 1,003 (14.9%) | 112 (17.7%) | 13 (7.1%) | 238 (6.1%) | |
| Haiti-born Black | 165 (1.1%) | 37 (0.6%) | 84 (13.3%) | -- | 23 (0.6%) | |
| West Indies-born Black | 84 (0.6%) | 30 (0.4%) | 12 (1.9%) | 10 (0.5%) | 27 (0.7%) | |
| Detailed Hispanic Subgroups | <0.0001 | |||||
| Central American | 231 (1.6%) | -- | 14 (2.2%) | 46 (2.4%) | 89 (2.3%) | |
| Cuban | 809 (5.6%) | 309 (4.6%) | 27 (4.3%) | 90 (4.8%) | 324 (8.3%) | |
| Dominican | 81 (0.6%) | 33 (0.5%) | 12 (1.9%) | 8 (0.4%) | 23 (0.6%) | |
| Mexican | 226 (1.6%) | 82 (1.2%) | -- | 61 (3.2%) | 56 (1.4%) | |
| Foreign-born Mexican | 113 (0.8%) | 24 (0.4%) | -- | 37 (2.0%) | 36 (0.9%) | |
| US-born Mexican | 113 (0.8%) | 58 (0.9%) | -- | 24 (1.3%) | 20 (0.5%) | |
| Puerto Rican | 982 (6.8%) | 558 (8.3%) | 20 (3.2%) | 108 (5.7%) | 228 (5.8%) | |
| South American | 346 (2.4%) | 87 (1.3%) | 15 (2.4%) | 60 (3.2%) | 144 (3.7%) | |
-- Note: Not reported; observations fewer than 10.
Includes all listed as well as Cryptogenic and Others (e.g. genetic, auto-immune);
p-value from chi-square test of independence, computed on 4 categories of etiology-specific HCC;
African American is exclusively reserved to US-born Black persons in this report.
Abbreviations: ALD, alcoholic liver disease; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HBV, hepatitis B virus; NAFLD, non-alcoholic fatty liver disease.
Demographic and clinical characteristics by cause of HCC
HCV-HCC proportions were significantly higher among males, US-born, and residents of high poverty areas. The median age at diagnosis for HCV-HCC was 60 years; however, among those with NAFLD-HCC, the median age was 71. The proportion of those residing in high poverty areas for NAFLD-HCC was lower than for HCV-HCC (p<0.05). HBV-HCC was more prevalent among persons not born in the US and had the lowest median age (59 years). There were no marked differences in stage at diagnosis by etiology. However, Black populations showed a poorer distribution of stage at diagnosis, with the lowest percentage of localized HCC (38.9%) of all racial-ethnic groups (Table S3).
Leading causes of HCC by race and ethnicity
Puerto Rican men had the highest HCC rates at 19.6 per 100,000, largely due to a high rate of HCV-HCC (Table 2, Figure S1). In contrast, West-Indies born Black men had the lowest HCC rates of all groups (3.0). Among women, foreign-born Mexican women showed the highest rates (5.9), principally attributable to high rates of NAFLD-HCV, and West-Indies born Black women had the lowest rate (1.6). Overall, while HCV-HCC was the main cause of HCC in most populations, HBV-HCC was the leading cause among Haitian-born Black men and Asian men. NAFLD-HCC was the leading cause among foreign-born Mexican (men and women), Central American (men and women), South American (men and women), and Cuban women (Table S4). NH-White, Cuban, and West Indian Black groups were the three with significantly lower HCC rates than the all-races combined rate. NH-White and Cuban persons account for 62% of the Florida population and their relatively lower rates bring the Florida HCC overall rates below the US average masking the high risk detected for some Florida populations [5,10].
Table 2.
Age-adjusteda incidence rates (AAIR) per 100,000 by detailed race/ethnicity. Florida 2010–2018.
| Level I Race/ethnicity | Level II Race/ethnicity | n | Totalb | HCV-HCC | HBV-HCC | ALD-HCC | NAFLD-HCC |
|---|---|---|---|---|---|---|---|
| Rate (95% CI) | Rate (95% CI) | Rate (95% CI) | Rate (95% CI) | Rate (95% CI) | |||
| MALES COMBINED d | 11,082 | 9.3 (9.2–9.5) | 4.4 (4.3–4.6) | 0.5 (0.5–0.5) | 1.3 (1.3–1.4) | 2.3 (2.2–2.4) | |
| White | 7,419 | 8.8 (8.6–9.1) | 4.4 (4.3–4.6) | 0.2 (0.1–0.2) | 1.3 (1.2–1.4) | 2.2 (2.1–2.3) | |
| Black c | 1,387 | 10.7 (10.1–11.3) | 5.9 (5.5–6.3) | 1.5 (1.3–1.7) | 0.9 (0.7–1.1) | 1.5 (1.3–1.8) | |
| African American/US-born Blacke | 1,188 | 13.1 (12.3–13.8) | 8.0 (7.5–8.6) | 1.1 (0.9–1.3) | 1.2 (0.9–1.4) | 1.8 (1.5–2.2) | |
| Haiti-born Black | 129 | 8.0 (6.6–9.7) | 1.6 (1.0–2.6) | 4.6 (3.6–5.9) | -- | 0.8 (0.4–1.7) | |
| West Indies-born Black | 50 | 3.0 (2.2–4.4) | 0.9 (0.5–2.1) | -- | -- | 0.9 (0.5–2.1) | |
| Asian | 290 | 11.0 (9.7–12.4) | 3.1 (2.5–3.9) | 4.9 (4.0–5.8) | 0.6 (0.4–1.0) | 1.6 (1.1–2.2) | |
| Hispanic c | 1,986 | 10.4 (10.0–10.9) | 4.3 (4.0–4.6) | 0.4 (0.3–0.5) | 1.7 (1.5–1.9) | 3.2 (2.9–3.5) | |
| Central American | 147 | 10.8 (8.9–12.9) | 2.6 (1.8–3.5) | 0.6 (0.3–1.1) | 2.8 (1.9–4.0) | 4.1 (2.8–5.6) | |
| Cuban | 596 | 7.4 (6.8–8.1) | 2.8 (2.5–3.2) | 0.3 (0.2–0.5) | 1.0 (0.8–1.3) | 2.8 (2.4–3.2) | |
| Dominican | 60 | 9.4 (7.0–12.4) | 3.5 (2.1–5.3) | -- | -- | 2.7 (1.5–4.5) | |
| Mexican | 168 | 11.8 (9.8–14.1) | 3.6 (2.7–4.7) | -- | 3.9 (2.8–5.2) | 2.8 (1.8–4.3) | |
| Foreign-born Mexican | 80 | 9.2 (6.9–12.2) | 1.6 (0.9–3.1) | -- | 3.5 (2.2–5.4) | 3.0 (1.6–5.3) | |
| US-born Mexican | 88 | 17.1 (13.5–21.4) | 7.6 (5.4–10.2) | -- | 4.5 (2.7–6.9) | 2.6 (1.2–4.9) | |
| Puerto Rican | 762 | 19.4 (18.0–20.8) | 10.9 (10.0–12.0) | 0.4 (0.3–0.7) | 2.4 (1.9–2.9) | 4.1 (3.4–4.9) | |
| South American | 233 | 8.1 (7.1–9.3) | 1.8 (1.3–2.3) | 0.4 (0.2–0.7) | 1.5 (1.1–2.1) | 3.6 (2.8–4.4) | |
| FEMALES COMBINED d | 3,338 | 2.4 (2.4–2.5) | 1.0 (1.0–1.1) | 0.1 (0.1–0.1) | 0.2 (0.2–0.3) | 0.8 (0.8–0.9) | |
| White | 1,993 | 2.2 (2.1–2.3) | 0.9 (0.8–1.0) | 0.03 (0.02–0.05) | 0.3 (0.2–0.3) | 0.7 (0.7–0.8) | |
| Black c | 491 | 3.2 (2.9–3.5) | 1.7 (1.5–2.0) | 0.2 (0.1–0.3) | 0.3 (0.2–0.3) | 0.8 (0.7–1.0) | |
| African American/US-born Blacke | 412 | 3.9 (3.5–4.3) | 2.2 (1.9–2.5) | 0.2 (0.1–0.3) | 0.3 (0.2–0.5) | 0.9 (0.7–1.1) | |
| Haiti-born Black | 37 | 2.2 (1.5–3.2) | 0.9 (0.5–1.7) | -- | -- | 0.7 (0.3–1.4) | |
| West Indies-born Black | 34 | 1.6 (1.1–2.6) | 0.7 (0.4–1.6) | -- | -- | 0.5 (0.3–1.5) | |
| Asian | 137 | 4.3 (3.6–5.1) | 1.4 (1.0–1.8) | 1.2 (0.9–1.7) | 0.1 (0.0–0.2) | 1.1 (0.7–1.5) | |
| Hispanic c | 717 | 3.1 (2.8–3.3) | 1.1 (0.9–1.2) | 0.1 (0.0–0.1) | 0.2 (0.2–0.3) | 1.4 (1.2–1.5) | |
| Central American | 84 | 4.4 (3.5–5.5) | 0.7 (0.4–1.2) | -- | -- | 2.7 (2.0–3.6) | |
| Cuban | 213 | 2.1 (1.8–2.4) | 0.8 (0.7–1.0) | -- | -- | 1.0 (0.8–1.2) | |
| Dominican | 21 | 2.2 (1.3–3.4) | -- | -- | -- | -- | |
| Mexican | 58 | 5.4 (4.0–7.0) | 1.7 (1.0–2.7) | -- | -- | 2.5 (1.6–3.7) | |
| Foreign-born Mexican | 33 | 5.9 (3.9–8.6) | -- | -- | -- | 3.2 (1.8–5.4) | |
| US-born Mexican | 25 | 5.0 (3.1–7.4) | 2.6 (1.3–4.4) | -- | -- | -- | |
| Puerto Rican | 220 | 4.8 (4.2–5.5) | 2.1 (1.7–2.5) | -- | 0.4 (0.2–0.6) | 1.9 (1.5–2.4) | |
| South American | 113 | 2.9 (2.4–3.5) | 0.6 (0.4–0.9) | -- | 0.4 (0.2–0.6) | 1.4 (1.1–1.9) | |
--Note: Rates based on fewer than 10 observations are not reported because of possibility of identification.
Age-adjusted to the 2000 US standard population;
Includes all listed as well as Cryptogenic and Others (e.g. genetic, auto-immune);
Includes all cases of this race and/or ethnicity; not just listed groups;
All race-ethnicities combined only includes those listed here (excludes multiracial, other, and unknown race);
African American is exclusively reserved to US-born Black persons in this report.
Abbreviations: ALD, alcoholic liver disease; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HBV, hepatitis B virus; NAFLD, non-alcoholic fatty liver disease.
Cause-specific incidence rates by sex
The overall HCC AAIR for Florida was 9.3 per 100,000 (95%CI:9.2–9.5) for men which is 3.8-fold higher than the AAIR in women at 2.4 (95%CI:2.4–2.5) (Table 2). By etiology, male-to-female sex ratios for HBV-HCC and ALD-HCC were 5.6 (4.5–7.1) and 5.6 (4.9–6.4), respectively. For HCV-HCC the ratio was 4.4 (4.2–4.7) while for NAFLD-HCC the ratio was 2.7 (2.5–2.9).
HCV-HCC rates
Among men HCC rates were dominated by HCV-HCC rates, which were highest among US-born populations other than NH-White persons. AAIRs for Puerto Rican, African American, and US-born Mexican American males were 10.9, 8.0, and 7.6, respectively, all significantly above 4.4 seen among NH-White men. For women, HCV-HCC rates were high among the same ethnic groups with rates of 2.2, 2.1, and 2.6, respectively, all significantly higher than the rate among NH-White women (1.0). The lowest rates of HCV-HCC were found among foreign-born Hispanic and foreign-born NH-Black populations.
NAFLD-, ALD-, and HBV-HCC rates
NAFLD-HCC incidence rates were significantly higher among Hispanic persons compared to NH-White persons (50% higher in males and double for females) (Figure S1). When sexes were combined, NAFLD-HCC incidence rate ratios using NH-White persons as reference were 1.53 (1.41–1.65) for Hispanic, 0.90 (0.69–1.15) for Asian, and 0.81 (0.71–1.91) for NH-Black persons. AAIRs of NAFLD-HCC among NH-Black men and women and NH-White women were the lowest of all groups. ALD-HCC rates were low among women of all ethnicities but high among Puerto Rican, Central American, and Mexican males. HBV-HCC AAIRs were high among Asian (4.9/100,000) and Haitian Black males (4.6/100,000), which were four-fold higher than among the next ranked group, African American males (1.1/100,000). Among women, HBV-HCC rates were low (<0.2/100,000) in all groups, apart from Asian women (1.2/100,000).
Cause-specific incidence trends 2010–2018
Trends for all racial-ethnic groups presented by etiology and sex can be seen in Figures 1 and 2 and Table S5. Overall HCC rates were stable for males over the 2010–2018 period but increased in women, 2.7% annually. However, there were substantial differences by cause. After a continuous increase, there was a sharp reduction in HCV-HCC trends (all races combined) during 2015–2018 (−8.7% annually in men and −11.9% in women). In 2010–2018, ALD-HCC increased for both sexes (6.0% annually), although, among women, the increase is based on very low baseline rates (0.2/100,000). Overall, the NAFLD-HCC AAIR increased 4.3% annually. While HCV-HCC continued to have the highest rates in all male populations, in women, NAFLD-HCC surpassed HCV-HCC rates in 2017. In 2018, the NAFLD-HCC AAIR for all women combined was 1.2 per 100,000 compared to HCV-HCC, 0.8 per 100,000 in women. In 2018 alone, for men and women combined, HCV and NAFLD accounted for 36% and 35% of all HCC cases respectively.
Figure 1 (Males) and Figure 2 (Females).
Trends in HCC age-adjusted incidence rates for all race/ethnicities combined. Florida 2010–2018. Rates are shown by select HCC etiologies: Total, HCV, NAFLD, ALD, HBV. Annual percentage change (AAPC) estimates shown next to each respective curve. *Trend significantly different than zero at P < .05.
Leading causes of HCC among Asian Americans
Lastly, proportions dating back to 2005 were pooled for Asian Populations (Table 3) and significant differences were observed by sex, with HBV-HCC being the most common etiology in Asian men and HCV-HCC, the most common among Asian women.
Table 3.
Distribution of HCC cases by etiology among Non-Hispanic Asian Americans. Florida, 2005–2018.
| Totala N (%) | HCV-HCC n (%) | HBV-HCC n (%) | ALD-HCC n (%) | NAFLD-HCC n (%) | p-valuec | |
|---|---|---|---|---|---|---|
| Detailed Subgroup | <0.0001 | |||||
| All Asians Combinedb | 600 | (31.7%) | (38.0%) | (5.0%) | (16.3%) | |
| Chinese | 99 | (21.2%) | (53.5%) | -- | (17.2%) | |
| Filipino | 80 | (20.0%) | (21.3%) | -- | (36.3%) | |
| Japanese | 32 | (43.8%) | -- | -- | -- | |
| Korean | 48 | (27.1%) | (45.8%) | -- | -- | |
| South Asian | 89 | (32.6%) | (32.6%) | -- | (18.0%) | |
| Southeast Asian | 34 | -- | (47.1%) | -- | -- | |
| Vietnamese | 184 | (42.9%) | (38.6%) | -- | (8.7%) | |
| Sex | 0.004 | |||||
| Men | 411 | (30.2%) | (41.8%) | (6.3%) | (14.4%) | |
| Women | 189 | (34.9%) | (30.2%) | -- | (20.6%) | |
-- Note: Not reported; observations fewer than 10.
Includes all listed as well as Cryptogenic category, Other causes category (e.g. genetic, auto-immune);
Includes all cases of this race-ethnicity; not just listed groups;
p-value from chi-square test.
Abbreviations: ALD, alcoholic liver disease; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HBV, hepatitis B virus; NAFLD, non-alcoholic fatty liver disease.
Discussion
In this population-based analysis we document, for the first time, etiology-specific HCC trends based on one state’s entire population. We observed a recent but substantial decline in HCV-HCC rates (−9.6% annually since 2014 in all groups combined) and substantial increasing trends for ALD-HCC (+6.0%) and NAFLD-HCC (+4.3%) during 2010–2018.
HCV-HCC was the most common etiology, with the highest rates among persons aged 50–69 years. The primary cause of chronic HCV infection is historical use of HCV-infected blood transfusions, while additional suggested potential causes include risky practices in tattoo parlors and/or IV drug use during 1960–1990 [12].
HCV-HCC rates were higher among specific US-born populations including Puerto Ricans, African Americans, and Mexicans, compared to NH-Whites. Higher rates in the Puerto Rican population are supported by the higher HCV prevalence reported by the Latino SOL study [13]. Moreover, US-born non-White people such as Puerto Ricans, African Americans, and Mexicans, exhibit higher rates of incarceration [14], a group among whom the HCV prevalence is as high as 23% [15,16]. High rates in these populations, approximately double those of other populations residing in the US during the same period (i.e., NH-White and Cuban persons), may be related to complex social environments of specific Hispanic groups and African American persons, especially among males.
The second most common form of HCC was NAFLD-HCC. NAFLD is the most common chronic liver disease in the US affecting up to 100 million Americans [17] and particularly Hispanic persons, among whom a genetic predisposition among other risk factors has been suggested [18]. In this study, rates of NAFLD-HCC among Hispanic persons were at least 40% higher than among NH-White and NH-Black populations. Unlike HCV-HCC, the difference between US-born and foreign-born populations was not marked. NAFLD is typically associated with obesity and diabetes, both of which are more prevalent among African Americans than Hispanics [19]. However, among Black persons the association between obesity and NAFLD is not so evident [20], and, in agreement, we found lower rates of NAFLD-HCC among NH-Black persons than would otherwise be expected.
ALD-HCC rates were higher among males, particularly among Puerto Rican, Central American, and Mexican persons. While it is known that consumption of alcohol and binge drinking is more prevalent in these groups [21,22], the pathways for these behaviors may be different according to each group’s distinct historical trajectory and/or recency of immigration to the US.
HBV-HCC rates were high among male Asian and Haitian Black persons. While the high prevalence of HBV is known among Asian groups, HBV characterization among Haitian persons, particularly in Florida, is less well reported. Previous work has shown Haiti to be a high prevalence HBV country with ongoing vertical transmission [23]. Haiti was the last country in the Americas to introduce hepatitis B vaccination in 2012, and as of 2019, the birth dose of hepatitis B vaccine had yet to be included in their vaccination schedule [23].
Except for the Japanese population, it is generally assumed that HBV is the cause of most HCCs among Asian persons [4]. However, our study suggests a more nuanced etiologic distribution in this heterogeneous population. For instance, among Asian women (all groups combined) HCV superseded HBV as the first cause of HCC. While HBV-HCC was the most prevalent cause among Chinese, Korean, and Southeast Asian Americans, an important proportion of cases among Asian persons were due to HCV. HCV was the leading cause among Japanese persons, while among those South Asian and Vietnamese, the proportions of cases due to HBV-HCC and HCV-HCC were nearly equivalent. Lastly, and similarly to Hispanic populations, NAFLD-HCC was the leading cause among Filipino persons, which could be a result of socio-environmental factors such as diet and cooking habits.
Our study shows that on a population-basis HCV-HCC started to decline after 2014, coinciding with the discovery of DAAs. This decline contrasts with increases in both NAFLD-HCC and ALD-HCC in both sexes. The increase in ALD-HCC aligns with increasing mortality rates from alcoholic cirrhosis observed in the US [24]. Overall, given the higher incidence of HCV-HCC in men and the favorable recent trends in HCV-HCC, it is logical that more favorable HCC trends of all causes combined are also recorded in men. Future HCC trends will depend on the success and speed of HCV treatment and the prevention and control of the rising trend in NAFLD-HCC and ALD-HCC.
The major strengths of our study are first, the unique presentation of etiology-specific HCC rates on a population basis (i.e., all HCC cases for an entire state) with no restriction on ages by leveraging existing individual-level surveillance data, and second, the novel characterization of HCC profiles specific for each detailed race-ethnicity. Because population-based incidence rates measure risk, they facilitate accurate comparisons for each etiology-specific HCC, which is advantageous when compared to hospital-based series or simple proportions. For instance, while NAFLD-HCC accounts for as many as 36% of all HCC cases among females and 25% in males, the actual AAIR is higher in males 2.3/100,000 compared to 0.8/100,000 in females (IRR 2.7; 95%CI:2.5–2.9).
Importantly, the incidence rates presented here result not only from variation in the prevalence of each risk factor for each population, but also, from differences in treatment for underlying liver diseases that can progress to HCC. Therefore, HCC disparities are a consequence of risk factors, but also, the result of access to quality healthcare, which aggravates existing disparities. For example, differential rates of antiviral therapy and/or transplantation directly impact the development of HCC.
There are several limitations to the current study. Aflatoxin exposure, an established risk factor for HCC, common in Africa, Asia, and parts of Central Americans, could not be studied; however, existing data suggests low prevalence of aflatoxin in the US. Another limitation is that up to 50% of people with an anti-HCV positive result do not have detectable HCV RNA [25]. However, we were unable to distinguish the two scenarios and all patients with positive HCV antibody were considered to have HCV-related HCC. However, of all HCV-HCC cases in our analysis, only 0.4% were identified based on this test alone. A third limitation, similar to other population-based studies [7,8], is the reliance upon NAFLD-related condition codes [7–9] such as diabetes, obesity, and metabolic syndrome; NAFLD historically has not been captured by discharge data and it was impossible to distinguish between NAFLD and NASH. The hierarchical classification of HCC causes may, to a limited degree, result in an underestimation of etiologies ranked lower than HCV, such as ALD and NAFLD. Lastly, the Florida Department of Health does not release individual-level data on Viral Hepatitis matches from VA institutions because of existing legal agreements. This limitation is not extended to veterans who received care at any given point in non-VA institutions and its overall impact was small (see sensitivity analysis for Multiple Imputation procedure in Annex S2 and Table S6).
Our study shows disparate HCC incidence in specific groups and provides important data about which groups could benefit from enhanced HCC screening, treatment, and surveillance of underlying liver disease. Knowledge of etiology-specific HCC is also important to anticipate the future HCC burden and develop targeted outreach and intervention programs. Further, these causes are not specific to HCC, and primary and secondary prevention efforts will impact chronic liver disease outcomes in general. The current challenges are to ensure that populations at risk are tested for viral hepatitis infection, that all persons with chronic HCV and/or HBV infection receive appropriate medication. In this respect, we are developing a continuing medical education effort to highlight the need for following the current screening recommendations, which will be preferentially targeting medical practitioners in areas serving the most affected racial-ethnic groups in Florida. Other options could include targeted mailings, radio show announcements, educational programs, or health fairs in specific ethnic enclaves. Even more challenging will be to find ways to target the rising incidence of ALD-HCC and NAFLD-HCC, as well as clarifying the origins or causes of the Hispanic population’s vulnerability to these two exposures. In this regard, while ALD-HCC patterns are sex-specific, which does not suggest genetic susceptibility among Hispanic persons, NAFLD-HCC rates are significantly higher in both Hispanic men and women compared to both NH-Whites and NH-Blacks. In conclusion, HCC patterns and trends are highly complex and their surveillance by etiology is fundamental to better control and prevent this challenging disease.
Data Availability:
The Florida cancer incidence data used in this report were collected by the Florida Cancer Data System (FCDS), the statewide cancer registry funded by the Florida Department of Health (FDOH) and the Centers for Disease Control and Prevention’s National Program of Cancer Registries (CDC-NPCR). The views expressed herein are solely those of the author(s) and not necessarily reflect those of the FDOH or CDC-NPC. This study was approved by the University of Miami and the Florida Department of Health Institutional Review Boards. The datasets are available by request with required approvals from the Florida Department of Health Cancer Registry Program and Florida Department of Health Institutional Review Board. Applications for data request are available from the FCDS Webpage (http://fcds.med.miami.edu/inc/datarequest.shtml).
Supplementary Material
What You Need to Know:
BACKGROUND:
Incidence rates and trends of hepatocellular carcinoma (HCC) by etiology, including alcohol-related disease, NAFLD, HCV, HBV, are unknown in the US. Heterogeneity by detailed racial-ethnic groups has been largely ignored.
FINDINGS:
HCV-HCC is declining while alcohol and NAFLD-HCC are increasing. HCV-HCC is the leading etiology among Puerto Rican, African American, and US-born Mexican men. NAFLD-HCC leads among women, Hispanics and Filipinos.
IMPLICATIONS FOR PATIENT CARE:
Remarkable variation in HCC etiology warrants tailored awareness and interventions by detailed race-ethnicity. Of concern are Hispanics, due to higher rates for alcohol- and NAFLD-HCC, two rising disease entities.
Acknowledgements
We would like to acknowledge and thank Drs. Karen Callahan, David Goldberg, and Jared Jashinsky for their help and/or contributions to this work.
Financial Support Statement: This work was supported by the Bankhead Coley Research Program of the State of Florida, Grant Number 20B16. Supplemental funding was provided by the Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine.
Footnotes
Conflict of Interest: The authors declare no conflicts of interest.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The Florida cancer incidence data used in this report were collected by the Florida Cancer Data System (FCDS), the statewide cancer registry funded by the Florida Department of Health (FDOH) and the Centers for Disease Control and Prevention’s National Program of Cancer Registries (CDC-NPCR). The views expressed herein are solely those of the author(s) and not necessarily reflect those of the FDOH or CDC-NPC. This study was approved by the University of Miami and the Florida Department of Health Institutional Review Boards. The datasets are available by request with required approvals from the Florida Department of Health Cancer Registry Program and Florida Department of Health Institutional Review Board. Applications for data request are available from the FCDS Webpage (http://fcds.med.miami.edu/inc/datarequest.shtml).