Liver cell carcinoma (LCC), predominantly represented by hepatocellular carcinoma (HCC), along with hepatic failure (HF), continues to significantly impact global morbidity and mortality, presenting substantial challenges to healthcare systems worldwide. HCC remains among the most prevalent malignancies, ranking sixth globally in cancer incidence and fourth in cancer-related mortality, reflecting its aggressive nature, late-stage detection, and limited curative treatments [¹]. Additionally, unspecified hepatic failure (ICD-10: K72.9) – a condition of severe hepatic decompensation reflecting diverse etiologies – places substantial demands on healthcare systems through high hospitalization rates, intensive care needs, and considerable patient morbidity [²]. This analysis uses K72.9 as the hepatic failure component of the combined endpoint; the acute (K72.0) and chronic (K72.1) subtypes were not captured separately, which is acknowledged as a limitation.

Despite considerable progress in diagnostics, including advanced imaging modalities, biomarker development, and improved screening strategies, as well as therapeutic innovations such as targeted molecular therapies, immunotherapy, and liver transplantation, marked disparities in mortality persist among various populations [³,⁴]. These disparities frequently reflect complex interactions of socioeconomic status, racial and ethnic differences, gender-related risk factors, geographic variability, and differential access to healthcare services [⁵]. Identifying and characterizing these disparities are thus imperative for tailoring interventions, reducing inequities, and improving overall patient outcomes.

To address these knowledge gaps, we leveraged the CDC WONDER (Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research) platform to conduct a 24-year national analysis of LCC- and HF-related mortality spanning 1999 to 2023. CDC WONDER offers a uniquely comprehensive, continuously updated repository of U.S. vital statistics data derived from death certificates filed across all 50 states and the District of Columbia, making it well-suited for longitudinal epidemiological surveillance of rare and chronic conditions [⁶].

We characterize mortality patterns through AAMRs and APCs stratified by sex, race/ethnicity, urban-rural status, U.S. census region, and state. This multidimensional approach allows identification of periods of accelerated change and of demographic or geographic subgroups bearing a disproportionate share of liver-related mortality, thereby highlighting priority areas for clinical and public health action.

Insights generated from this research not only augment existing knowledge but also serve as a critical evidence base for clinicians, public health authorities, and policymakers. By understanding nuanced patterns in liver disease-related mortality and recognizing high-risk populations and geographic disparities, stakeholders can develop targeted screening programs, refine clinical guidelines, enhance healthcare delivery, and implement policy initiatives to reduce the overall burden of liver-related diseases in the United States.

Between 1999 and 2023, the database recorded 22,963 adult deaths (ages 25 – 85+) in which LCC or HF was recorded as an underlying or contributing cause of death, of whom 17,822 (77.6%) were men and 5,141 (22.4%) were women (Supplemental Table 1). Race/ethnicity data (1999 – 2020) identified 2,803 deaths among NH Black individuals, 12,257 among NH Whites, 1,694 among NH Asian or Pacific Islanders, and 2,698 among Hispanic or Latino individuals (Supplemental Table 2). The aggregate AAMR followed a non-linear trajectory: a decline from 1999 to 2007 (APC: -2.4) was succeeded by near-stability from 2007 to 2017 (APC: +0.2), before a renewed and steeper fall from 2017 to 2023 (APC: -3.5) (Supplemental Table 3) and .

Drawing on 24 years of CDC WONDER mortality surveillance (1999 – 2023), this study characterizes shifting patterns of LCC- and HF-related mortality among U.S. adults aged 25 and older. The overall AAMR trajectory was non-linear: an initial reduction from 1999 to 2007 (APC: -2.4) transitioned to near-stability from 2007 to 2017 (APC: +0.2), before a more rapid decline resumed through 2023 (APC: -3.5). These patterns are consistent with, though cannot be causally attributed to, cumulative improvements in viral hepatitis detection and treatment, broader implementation of liver cancer (including HCC) surveillance protocols, expanded access to systemic therapies including targeted molecular agents and immunotherapy, and growth in liver transplantation programs, all of which have been associated in the literature with reduced liver disease progression [¹²]. Notably, the final Joinpoint segment (2017 – 2023 overall; 2017 – 2023 for men) represents a relatively short, terminal interval; such segments can be sensitive to end-point effects in Joinpoint regression and should be interpreted with appropriate caution. It must be noted that, as a death certificate – based ecological analysis, this study is descriptive and cannot establish that any specific clinical or public health intervention caused the observed change in trend.

These national trends differ from those reported in earlier U.S. regional analyses, which found rising LCC-attributable AAMR across the general population from 1999 to 2020 [¹³]. In contrast, contemporaneous analyses from China documented declines in HCC mortality between 2008 and 2017 and between 1999 and 2011 in separate regional cohorts [¹⁴,¹⁵], with findings attributed to improvements in early detection infrastructure and antiviral treatment uptake. These divergent international patterns underscore the dependence of mortality trajectories on the strength and reach of public health systems; causal inference across ecological analyses from different populations and time periods is not warranted.

Sex-stratified analysis confirmed that men bore a substantially higher LCC and HF mortality burden throughout the study period. While both sexes showed a long-term decline, the male AAMR exhibited greater temporal variation, including a mid-period plateau from 2010 to 2017 before resuming a pronounced terminal decline. In contrast, the female AAMR remained comparatively stable after 2006. These patterns are consistent with the established male predominance in liver cancer and hepatic failure risk; men disproportionately engage in hepatotoxic behaviors including tobacco use, heavy alcohol consumption, and illicit substance use, and are more frequently affected by socioeconomic stressors such as unemployment and income insecurity, all of which have been associated with elevated chronic liver disease risk [¹²]. Sex-specific differences in the molecular biology and hormonal modulation of hepatocarcinogenesis may also contribute to differential AAMR trajectories between men and women [¹⁶]. This analysis cannot determine the degree to which behavioral, biological, or healthcare-access differences drive the observed sex disparity.

In the racial/ethnic analysis (1999 – 2020), NH White individuals had the highest combined LCC and HF mortality, followed by Hispanic or Latino, NH Black, and NH Asian or Pacific Islander populations, with the latter showing the sharpest aggregate decline. These findings warrant nuanced interpretation: Perez et al. documented elevated HCC incidence in Hispanic communities along the U.S. – Mexico border in Texas, attributed to a higher background prevalence of unscreened hepatitis infection, pre-1991 blood transfusion exposure, and alcohol and illicit substance use [¹⁷]. White et al. similarly reported elevated age-adjusted HCC incidence among Hispanic Americans nationwide [¹⁸], a pattern partly explained by co-occurring hepatitis C viremia, heavy alcohol consumption, metabolic syndrome, type 2 diabetes, and nonalcoholic fatty liver disease [¹⁹,²⁰,²¹]. Race/ethnicity analyses were limited to four groups with adequate non-suppressed data, and the exclusion of other race/ethnicity categories may affect generalizability of the equity conclusions. These descriptive subgroup differences nonetheless underscore the importance of culturally tailored screening programs and targeted preventive strategies in at-risk communities.

Among urbanization strata, non-metropolitan populations experienced a continuous rise in AAMR from 1999 to 2020, while metropolitan populations saw an overall decline, most pronounced after 2018. These patterns may partly reflect the concentration of specialized hepatology and oncology services within major urban centers, which could limit timely access to guideline-concordant care for rural residents [²²]. Non-metropolitan communities may also face structural barriers such as lower educational attainment, constrained household incomes, and reduced access to transportation, all of which may delay diagnosis and restrict therapeutic options [²³]. Comprehensive rural health strategies that address tobacco cessation, alcohol reduction, obesity prevention, and equitable access to screening represent potential levers to narrow this mortality gap. However, the ecological design of the current study precludes drawing specific causal conclusions. Geographically targeted research is needed to characterize and remediate the observed urban-rural difference in liver disease outcomes.

Regional analysis revealed that the West consistently carried the highest LCC and HF mortality burden, followed by the Northeast, South, and Midwest in descending order. Substantial state- and region-level heterogeneity was evident across 1999 – 2020, with the highest rates disproportionately concentrated in western states [¹³]. These patterns call for geographically differentiated policy responses; however, because this study cannot account for between-region differences in population age structure, risk-factor prevalence, or healthcare infrastructure, the observed geographic variation should be interpreted descriptively rather than causally.

State-level AAMR varied markedly across the country. Hawaii, California, Texas, Oregon, and Rhode Island clustered in the uppermost 90th percentile, while Arkansas, Alabama, Louisiana, Mississippi, and Florida recorded the lowest rates. Prior analyses have linked elevated liver cancer mortality in states such as Texas, Louisiana, and Alabama to higher regional prevalence of hepatitis C infection, obesity, and alcohol-use disorder [²⁴]. Declining trends in northern and Midwestern states may reflect improved uptake of hepatitis C treatment, enhanced surveillance, and advances in liver disease management [¹³]. These interstate disparities reinforce the need for state-specific public health programming, though direct causal attribution is beyond the scope of this descriptive surveillance analysis.

Globally, primary liver cancer – of which hepatocellular carcinoma (HCC) constitutes the predominant subtype – ranked as the sixth most commonly diagnosed malignancy and the third leading cause of cancer-related mortality worldwide in 2020 [²⁵]. Sustained reduction of this burden requires investment across multiple domains: universal hepatitis B vaccination, scaled-up direct-acting antiviral therapy for hepatitis C, rigorous blood-product safety protocols, and expanded harm-reduction services. Equally critical are efforts to address the social determinants of liver health, poverty, hazardous substance use, and food insecurity that perpetuate the inequities identified in our analyses. Embedding these preventive and therapeutic strategies within national and regional policy frameworks holds the greatest promise for translating the observed downward trends in mortality into durable, equitable improvements in population liver health.