Burden of mortality from hepatocellular carcinoma and biliary tract cancers by race and ethnicity and sex in US, 2018–2023

Article information

Clin Mol Hepatol. 2024;30(4):756-770

Publication date (electronic) : 2024 June 24

doi : https://doi.org/10.3350/cmh.2024.0318

Donghee Kim^,1, Richie Manikat¹, Karn Wijarnpreecha^2,3, George Cholankeril^4,5, Aijaz Ahmed¹

¹Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA

²Department of Medicine, Division of Gastroenterology and Hepatology, University of Arizona College of Medicine, Phoenix, AZ, USA

³Department of Internal Medicine, Division of Gastroenterology and Hepatology, Banner University Medical Center, Phoenix, AZ, USA

⁴Liver Center, Division of Abdominal Transplantation, Michael E DeBakey Department of General Surgery, Baylor College of Medicine, Houston, TX, USA

⁵Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA

Corresponding author : Donghee Kim Division of Gastroenterology and Hepatology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94304, USA Tel: +1-650-497-9261, Fax: +1-650-498-5692, E-mail: dhkimmd@stanford.edu

Editor: Ju Dong Yang, Cedars-Sinai Medical Center, USA

Received 2024 April 29; Revised 2024 June 20; Accepted 2024 June 20.

Abstract

INTRODUCTION

Hepatobiliary cancers, which include hepatocellular carcinoma (HCC) and biliary tract cancers, are associated with significant morbidity and mortality worldwide. Based on data published in the Global Cancer Statistics 2020 report, liver cancer is the sixth most prevalent cancer, with the third highest mortality rate [1]. While liver and intrahepatic bile duct cancers are not among the top 10 leading causes of new cancer cases in the United States (US) in 2024, it made the cut-off for the top 5 leading estimated cancer-related deaths in males and the top 7 estimated cancer-related deaths in females [2]. The incidence of liver and intrahepatic bile duct cancer has stabilized in males, while rates continue to increase in females by about 2% annually [2]. Age-standardized mortality from HCC increased from 4.14 per 100,000 individuals in 2009 to 4.90 per 100,000 individuals in 2018, with an average increase of annual percent change (APC) of 1.9% in the US [3]. Biliary tract cancers, which include intrahepatic cholangiocarcinoma (ICC), extrahepatic cholangiocarcinoma (ECC), gallbladder cancer, and ampulla of Vater cancer (AVC), as a group, have a significantly lower prevalence than HCC, but have a much higher fatality, presumably associated with late diagnosis at an advanced stage [4,5]. A recent study showed that there was a linear increase in mortality from ICC, but gallbladder cancer-related mortality steadily decreased during the same period between 2009 and 2017 in the US [6]. However, there was a lack of up-to-date trends in mortality from HCC and biliary tract cancers before and during the coronavirus disease 2019 (COVID-19) pandemic (2018–2023). In addition, recent reports up to 2018 have demonstrated a concerning higher mortality and steeper increasing trend in the mortality of HCC and biliary tract cancers among racial and ethnic minority individuals in the US [6,7]. Furthermore, the impact of the COVID-19 pandemic on HCC and biliary tract cancers-related mortality stratified by race and ethnicity and sex remains unknown. Therefore, there was an unmet need to investigate whether the change in mortality rates and trends in mortality due to HCC and biliary tract cancers among racial and ethnic minority individuals was noted before and during the COVID-19 pandemic.

The deleterious effects of COVID-19 pandemic-related resource reallocation may have been more pronounced in vulnerable racial and ethnic minority patients with cancer, resulting in an increase in all-cause mortality [8]. During the early phase of the COVID-19 pandemic, the management of COVID-19 was prioritized, which might have undermined the care of patients with HCC and biliary tract cancers. The inability to visit outpatient clinics for evaluation of early symptoms, diagnosis, and treatment as a result of social isolation or lockdowns may have negatively impacted the mortality trends in HCC and biliary tract cancers during the COVID-19 pandemic. Healthcare disruptions during the COVID-19 pandemic may have amplified the widening gaps in healthcare inequalities [9]. A recent study showed that non-COVID-19 excess deaths in the US during the COVID-19 pandemic were 2 to 4 times higher in non-Hispanic Black, non-Hispanic Asian, and Hispanic males and females compared with non-Hispanic White males and females [10]. Therefore, the burden of the COVID-19 pandemic on healthcare resources may have been detrimental and contributed to increasing the mortality associated with HCC and biliary tract cancers and further compounding the disparities in medical care across races and ethnicities. This study used the national mortality data from the National Vital Statistics System (NVSS) to calculate contemporary trends in HCC and biliary tract cancer-related mortality from 2018 to 2023 in the US. The aims of this study were (1) to investigate contemporary trends in mortality for HCC and biliary tract cancers and (2) to determine race and ethnicity- and sex-specific trends in mortality for HCC and biliary tract cancers.

MATERIALS AND METHODS

RESULTS

Age-standardized mortality for hepatocellular carcinoma and biliary tract cancers

As indicated in Figure 1A and Table 1, the age-standardized mortality from HCC (defined as underlying cause of death) decreased from 7.95 per 100,000 persons in 2018 to 7.42 per 100,000 persons in 2023. Joinpoint analysis revealed a statistically significant average APC decrease of –1.4% (95% CI –2.0% to –0.7%) without any trend segment. When we defined HCC as multiple causes of death, the age-standardized mortality due to HCC slightly increased from 8.68 (2020) to 8.74 (2021) during the early phase of the COVID-19 pandemic and decreased to 8.50 (2022) during the late phase of the COVID-19 pandemic. The age-standardized HCC-related mortality, defined as multiple cause of death, decreased with an average APC of –0.8% (95% CI –1.4% to –0.1%), which was slightly lower than the average APC (–1.4%; 95% CI –2.0% to –0.7%) defined as underlying cause of death. When we assessed the mortality trends based on contributing cause of death due to HCC, we noted that the proportion of contributing cause of death from HCC among individuals with HCC listed on the multiple cause of death captured about 10.7% before the COVID-19 pandemic and 12.9% during the early phase of the COVID-19 pandemic. Contrary to decreasing trends in the underlying cause of death due to HCC (APC –1.4%; [95% CI –2.0% to –0.7%), age-standardized HCC-related mortality as the contributing cause of death sharply increased before and during the early phase of the COVID-19 pandemic with an increase of APC of 9.7% (95% CI 4.6% to 22.0% for 2018–2021; Fig. 2A) and remained stable during the late phase of COVID-19. As shown in Supplementary Figure 1A, COVID-19-related mortality among HCC as contributing cause of death peaked at 9.1% (COVID-19 listed as underlying cause of death) in 2020 and 17% (COVID-19 listed as multiple cause of death) in 2022. As shown in Figure 3, age-standardized HCC-related mortality due to HCV infection continuously decreased initially from 1.42 (2018) per 100,000 persons to 0.90 (2023) with an average APC of –8.5% (95% CI –8.5% to –8.5%) without any trend segment before and during the COVID-19 pandemic. In contrast, there was a linear increase in the age-standardized HCC-related mortality from MASLD (APC 9.7%; 95% CI 4.2% to 15.5%) without any trend segment before and during the COVID-19 pandemic. There were no significant trends in HCC-related mortality due to HBV and ALD.

Figure 1.

Annual age-standardized mortality for hepatocellular carcinoma and biliary tract cancers in the United States between 2018 and 2023. (A) Annual age-standardized mortality for hepatocellular carcinoma. (B) Annual age-standardized mortality for biliary tract cancers defined underlying cause of death. (C) Annual age-standardized mortality for biliary tract cancers defined multiple cause of death. AVC, ampulla of Vater cancer; ECC, extrahepatic cholangiocarcinoma; GBca, gallbladder cancer; ICC, intrahepatic cholangiocarcinoma; HCC, hepatocellular carcinoma; MCOD, multiple cause of death; UCOD, underlying cause of death. ^*P<0.05.

Table 1.

Age-standardized hepatocellular carcinoma and biliary tract cancer-related mortality rate and APC among US adults ≥25 years in 2018–2023

Figure 2.

Age-standardized mortality due to hepatocellular carcinoma and intrahepatic cholangiocarcinoma as underlying or contributing cause of death in the United States from 2018 to 2023. (A) Hepatocellular carcinoma. (B) Intrahepatic cholangiocarcinoma. APC, annual percentage change; CI, confidence interval. ^*P<0.05.

Figure 3.

Age-standardized mortality for hepatocellular carcinoma stratified according to etiology in the United States between 2018 and 2023. ALD, alcohol-related liver disease; CI, confidence interval; HBV, hepatitis B virus infection; HCV, hepatitis C virus infection; MASLD, metabolic dysfunction-associated steatotic liver disease. ^*P<0.05.

The number of deaths due to ICC steadily increased from 7,459 in 2018 to 9,370 in 2023. The age-standardized mortality due to ICC (defined as underlying cause of death) increased from 2.97 (2018) per 100,000 persons and 3.04 (2019) before the COVID-19 pandemic and from 3.04 in 2020, 3.31 in 2021, to 3.49 in 2023 during the COVID-19 pandemic (Fig. 1B). There was a linear increase in the age-standardized ICC-related mortality (APC 3.1%; 95% CI 1.2% to 4.9% as underlying cause of death; APC 4.0%; 2.4% to 5.7% for multiple cause of death) without any trend segment. As shown in Figure 2B, age-standardized ICC-related mortality, defined as contributing cause of death, more steeply increased with an average APC of 15.0% (95% CI 11.2% to 19.0%) without any trend segment than mortality defined as underlying cause of death (APC 3.1%; 95% CI 1.2% to 4.9%). COVID-19-related mortality among ICC listed as contributing cause of death peaked at 9.2% (COVID-19 listed as underlying cause of death) and 17.9% (COVID-19 listed as multiple cause of death) in 2021 (Supplementary Fig. 1B).

The age-standardized ECC-related mortality remained stable from 2018 to 2023 (APC 0.4%; 95% CI –1.5% to 2.4%). When we defined ECC as multiple causes of death (Fig. 1C), age-standardized mortality increased significantly from 0.43 (2020) to 0.53 (2022) during the COVID-19 pandemic (APC 4.8%; 95% CI 1.8% to 7.8%) without any trend segment. The age-standardized mortality from AVC steadily increased from 2018 to 2023 without any trend segment (APC 4.1%; 95% CI 0.5% to 7.9% as underlying cause of death; APC 4.9%; 95% CI 2.2% to 7.8% as multiple cause of death). In contrast, the age-standardized mortality due to gallbladder cancer (defined as underlying cause of death) decreased from 0.86 (2018) per 100,000 persons to 0.79 (2023). Mortality due to gallbladder cancer steadily decreased without any trend segment (APC –1.9%; 95% CI –3.8% to –0.0% as underlying cause of death; –1.3%; 95% CI –3.0% to 0.3% as multiple cause of death).

Age-standardized mortality for hepatocellular carcinoma and biliary tract cancers by sex

When we analyzed mortality by sex, HCC, ICC, and ECC-related mortality (defined as underlying cause of death) in males was higher than in females (Tables 2, 3 and Figs. 4, 5). Regarding HCC (Table 2 and Fig. 4), decreasing trends in mortality due to HCC were noted in males (APC –1.9%; 95% CI –2.7% to –1.2%) without any trend segment while these trends remained stable in females (APC 0.1%; 95% CI –0.7% to 0.9%). Increasing trends in ICC-related mortality were similar between males (APC 2.4%; 95% CI 0.7% to 4.1%) and females (APC 2.9%; 95% CI 0.2% to 5.7%, Table 3 and Fig. 5) without any trend segment. Regarding ECC (Table 3 and Fig. 5), trends in mortality remain stable in females and males. Gallbladder cancer-related mortality in females was higher compared to males, with decreasing trends in mortality that were steeper in men (APC –2.2%; 95% CI –4.2% to –0.2%) than in women (APC –1.6%; 95% CI –3.7% to 0.6%, Table 3 and Fig. 5) without any trend segment.

Table 2.

Age-standardized hepatocellular carcinoma-related mortality rate and APC among US adults ≥25 years in 2018–2023

Table 3.

Age-standardized biliary tract cancer-related mortality rate and APC among US adults ≥25 years in 2018–2023

Figure 4.

Annual age-standardized sex-based and race and ethnicity-based mortality for hepatocellular carcinoma in the United States between 2018 and 2023. (A) Sex-based mortality for hepatocellular carcinoma. (B) Race and ethnicity-based mortality for hepatocellular carcinoma. CI, confidence interval; NHA, non-Hispanic Asian; NHAIAN; non-Hispanic American Indian or Alaska Native; NHB, non-Hispanic Black; NHW, non-Hispanic White. ^*P<0.05.

Figure 5.

Annual age-standardized sex-based and race and ethnicity-based mortality for biliary tract cancers in the United States between 2018 and 2023. (A) Sex-based mortality for intrahepatic cholangiocarcinoma. (B) Race and ethnicity-based mortality for intrahepatic cholangiocarcinoma. (C) Sex-based mortality for extrahepatic cholangiocarcinoma. (D) Race and ethnicity-based mortality for extrahepatic cholangiocarcinoma. (E) Sex-based mortality for gallbladder cancer. (F) Race and ethnicity-based mortality for gallbladder cancer. CI, confidence interval; NHA, non-Hispanic Asian; NHB, non-Hispanic Black; NHW, non-Hispanic White. ^*P<0.05.

DISCUSSION

In this population-based national study, we estimated up-to-date mortality trends in HCC and biliary tract cancers in the US. Annual mortality due to HCC has decreased steadily before and during the COVID-19 pandemic. While the mortality associated with ICC and AVC increased linearly, ECC-related mortality remained stable during the study. In contrast, mortality due to gallbladder cancer decreased steadily before and during the COVID-19 pandemic.

Contrary to decreasing trends in the underlying cause of death due to HCC, HCC-related mortality as the contributing cause of death sharply increased before and during the early phase of the COVID-19 pandemic. Contributing cause of death due to ICC increased more steeply than the underlying cause of death due to ICC during the COVID-19 pandemic. COVID-19-related mortality among patients with HCC consisted of up to 9% as the underlying cause of death and 17% as the multiple cause of death. During the COVID-19 pandemic, the inability to visit healthcare providers for the care of other diseases (cardiovascular disease, extrahepatic cancer, etc.) and the increase in COVID-19-related deaths may provide a plausible explanation for the discrepancy between underlying cause of death and multiple cause of death, which consisted of the underlying cause of death or contributing causes. Although these data suggested the impact of COVID-19 on mortality among individuals with HCC and ICC, further studies are needed to determine the impact of COVID-19 on mortality in HCC and biliary tract cancers.

Recent reports from the Surveillance, Epidemiology, and End Results (SEER) dataset 1992–2018 and 2000–2019 showed that the incidence of HCC in the US began to decline to start in 2015 [18,19]. These data from the SEER database were limited due to the unavailability of the etiology of liver disease in patients with HCC [18,19]. In comparison to the previous study that reported plateauing trends in mortality due to HCC from 2009 to 2018 [3], this study showed a decrease in HCC-related mortality from 2018 to 2023. A previous study reported an increase in HCC-related mortality due to HCV infection at an annual rate of 5.4% (95% CI 3.6% to 7.3%) from 2009 to 2014, followed by a decrease from 2014 to 2018 in the annual rate of –3.5% (95% CI –5.9% to –1.1%) [3]. We found that HCC-related mortality from HCV infection continuously decreased with an average APC of –8.5% before and during the COVID-19 pandemic. While HCV infection remains the leading etiology of HCC in the US, the improvement in sustained virological response due to direct-acting antiviral agents against HCV infection has resulted in about 50–80% risk reduction of HCC in this subset [20,21]. However, although the continued decline in HCC-related mortality due to HCV infection may offset rising rates of HCC-related mortality due to MASLD, we noted that HCC-related mortality due to MASLD accelerated during the COVID-19 pandemic. In another study using the SEER dataset, while the proportion of HCC diagnosed at stage 1 increased from 1992 to 2019, the proportion of HCC diagnosed at stage 4 decreased [22]. Therefore, an overall improvement in the efficacy of HCV treatment and early diagnosis may partly explain our results that showed a decrease in age-standardized mortality from HCC with an average APC decrease of –1.4% (95% CI –2.0% to –0.7%).

The mortality rate due to HCC among males was over 3-fold higher than in females. Instead, we found decreasing trends in mortality due to HCC in males, while these trends remained stable in females. A recent study reported increasing HCC incidence among females between 2014 and 2019 (APC 2.0%) compared to stable trends in incidence among males (APC 0.0%) during the same period [2], which potentially mirrors the lack of decline in recent mortality rates in females. A recent US multicenter study showed that females had a significantly higher frequency of MASLD as an etiology of HCC and noncirrhotic HCC than males [23]. Stable trends in mortality in females may be explained by a steady increase in HCC-related mortality due to MASLD. Although cautious interpretation is needed due to underestimation of MASLD, we noted a clue of a steady increase in HCC-related mortality due to MASLD in females (Supplementary Fig. 2). Further studies are needed to provide further evidence.

We found that the racial and ethnic minority groups in the US have a disproportionately higher burden of HCC-related mortality. In comparison to the previously reported trends in the incidence rates from five years ago [19], our study showed a markedly steeper decline in racial and ethnic minority groups-specific mortality trends associated with HCC among non-Hispanic Black individuals, non-Hispanic Asian individuals, and Hispanic individuals versus non-Hispanic White individuals. The continuing decrease in mortality associated with HCC was driven mainly by decreasing trends among racial and ethnic minority individuals and males.

Early diagnosis of cholangiocarcinoma may be challenging due to multiple reasons, including hard-to-access/image anatomical location, the silent clinical presentation with late onset of symptoms, paucicellular nature, and lack of consensus on surveillance strategies [24]. Consistent with the increasing incidence rate [6], the increasing trends in mortality due to ICC may be associated with late diagnosis and limited treatment options following the diagnosis. In this study, the racial and ethnic minority groups in the US were noted to have a disproportionately higher burden of ICC-and gallbladder cancer-related mortality. Additionally, we observed a higher increasing trend in ICC-related mortality in non-Hispanic Black individuals. Contrary to HCC or other biliary tract cancers, approximately two-thirds of deaths due to gallbladder cancer occurred among females. We noted a faster decrease in mortality due to gallbladder cancer in males than in females. Consistent with our study, there were race and ethnicity-specific and sex-specific differences in the incidence and survival of biliary tract cancers in the US [25,26]. Future studies are needed to improve our understanding of the specific root cause(s) associated with race- and ethnicity-based differences in the mortality of patients with HCC and biliary tract cancers.

The decreasing incidence of gallbladder cancer may be associated with the concomitant increase in cholecystectomy for gallstone and gallbladder polyps, which are known risk factors for gallbladder cancer [27,28]. Our study showed a slight increase in gallbladder cancer-related mortality in 2020. Because most elective and emergency surgeries, including cholecystectomy, were halted and delayed during the COVID-19 pandemic [29], gallbladder cancer-related incidence and mortality may be affected during and after the pandemic. Future studies are needed to confirm this hypothesis.

The main strength of our study is that it includes an up-to-date report of the national longitudinal mortality trends in HCC and biliary tract cancers by sex or race and ethnicity. This allowed us to evaluate population-based data and gain a unique insight into mortality due to HCC or biliary tract cancers based on sex and race/ethnicity. Because we utilized the recent NVSS 2018–2023 dataset, we were able to investigate the contemporary burdens of HCC- and biliary tract cancer-related mortality before and during the COVID-19 pandemic. However, the present study had several limitations. First, the underlying or multiple cause of death may be subject to underestimation and misclassification. Such problems can be mitigated when analyzing trends in which underestimation has been assumed to be relatively constant over the study period. Second, regarding low mortality from ECC, the current ICD-10 system did not have any codes for specific perihilar and hilar cholangiocarcinoma [30]. Future ICD-11 should have clear codes for perihilar and distal cholangiocarcinoma. Third, data for the non-Hispanic American Indian or Alaska Native were unreliable due to a small number of events due to biliary tract cancers and, therefore, were excluded from the final analysis for biliary tract cancer-related mortality stratified by race and ethnicity. We were also unable to investigate race and ethnicity-specific or sex-specific trends in mortality due to AVC because of a small number of events. In addition, COVID-19-related mortality in ECC, gallbladder cancer, and AVC could not be estimated due to a small number of events. Fourth, the provisional dataset for 2023 national mortality may be incomplete and likely not include all deaths that occurred during a given period (accessed in May 2024). This 2023 NVSS mortality provisional dataset may be posed to reporting lag. Therefore, this result using the 2023 NVSS mortality provisional dataset should be interpreted cautiously. Fifth, the low mortality rates from MASLD are consistent with significant underreporting of this etiology on death certificates, leading to underestimation of the true prevalence of MASLD by utilizing ICD codes. In addition, we were unable to capture all etiologies of chronic liver disease among individuals with HCC due to the inherent limitation of this database based on death certificates. These limitations may be alleviated because these underestimations were supposed to be constant during the study period. Therefore, these results need to be interpreted cautiously.

In conclusion, while overall HCC-related mortality tended to decline after the introduction of potent antiviral agents, ICC- and AVC-related mortality have increased steadily. Recent declines in HCC may be primarily due to declines among racial and ethnic minority individuals and males. Mortality for ECC remained stable, while gallbladder cancer-related mortality constantly decreased before and during the COVID-19 pandemic. In addition, racial and ethnic minority individuals in the US have a disproportionately high burden of HCC and biliary tract cancer-related mortality. In the future, an attempt to formally study and more clearly understand the reason(s) for the differences in mortality among racial and ethnic minority individuals with HCC and biliary tract cancers may help gain further insight into crucial mechanistic pathways and/or gaps in linkage-to-care.

SUPPLEMENTAL MATERIAL

Article information Continued

Notes