Shifting Trends and Persistent Disparities in Mortality Related to Liver Cirrhosis and Respiratory Disease: A Population-Based Study in the United States, 1999-2023

Shifting Trends and Persistent Disparities in Mortality Related to Liver Cirrhosis and Respiratory Disease: A Population-Based Study in the United States, 1999-2023 | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Shifting Trends and Persistent Disparities in Mortality Related to Liver Cirrhosis and Respiratory Disease: A Population-Based Study in the United States, 1999-2023 Yu Zhou, Peng Ma, Lei Zhu, Bingang Xu, Hongmiao Xia, Youmin Ding This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7647383/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 8 You are reading this latest preprint version Abstract Background Liver cirrhosis and respiratory diseases represent major global health burdens, and their coexistence significantly contributes to patient morbidity and mortality. While the epidemiology of each disease has been examined individually, a critical gap persists in our understanding of the long-term mortality trends and disparities associated with their combined impact. Methods We conducted a retrospective, population-based study using the CDC WONDER Multiple Cause of Death database to analyze mortality involving both conditions in the United States from 1999 to 2023. We calculated age-adjusted mortality rates (AAMR) and employed Joinpoint regression to identify annual percentage changes (APC) and average annual percentage changes (AAPC) across diverse demographic and geographic subgroups. Results From 1999 to 2023, a total of 6,957,062 deaths were identified related to liver cirrhosis and respiratory diseases. The overall AAMR was 141.31 in 1999 and 111.04 in 2023, with a significant overall declining trend observed over the study period. Males consistently exhibited higher AAMRs than females (Males: 128.31 vs. Females: 97.26 in 2023). When stratified by race, the highest AAMR was observed in Non-Hispanic White populations, followed by Non-Hispanic Black, Hispanic, and Non-Hispanic Other populations (AAMR of 121.91, 99.07, 93.18, and 56.72, respectively, in 2023). Regionally, the highest mortality was observed in the South, followed by the Midwest, the West, and lastly, the Northeast (with values of 125.75, 120.91, 86.19, and 96.48, respectively, in 2023). Nonmetropolitan areas (150.97) exhibited consistently higher AAMRs than metropolitan areas (110.73) in 2023. Conclusion Liver cirrhosis and respiratory disease-related mortality declined in the United States from 1999 to 2023, with males, Non-Hispanic White populations, and the South exhibiting the highest AAMRs. These findings highlight the importance of improving management and addressing mortality disparities. Mortality Trends Health Disparities Liver Cirrhosis Respiratory Diseases CDC WONDER Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Liver cirrhosis is a progressive and significant public health challenge, contributing substantially to global morbidity and mortality [ 1 – 3 ]. In 2021 alone, there were an estimated 58.4 million incident cases globally, and liver disease is responsible for approximately two million deaths annually [ 4 ]. Within the United States, chronic liver disease and cirrhosis will likely be the 9th leading cause in 2023, and the death rate increased 15.3% from 2019 through 2023 [ 5 ]. Cirrhosis is also an expensive disease. In the US in 2016, liver-related expenditure was $ 32.5 billion (95% CI $ 27.0- $ 40.4 billion) with two-thirds of these costs attributable to inpatient or emergency department care. Over 20 years, healthcare spending has increased by 4% per year primarily driven by hospital-based services [ 6 , 7 ]. Concurrently, respiratory diseases impose a massive burden [ 8 , 9 ]; they were the third-leading cause of death worldwide in 2019, accounting for 4.0 million deaths [ 10 ]. By 2023, chronic lower respiratory diseases were the fifth leading cause of death in the United States, with 145,357 reported fatalities [ 11 ]. The coexistence of these two conditions presents a particularly complex and challenging clinical scenario, as one disease process can exacerbate the other [ 12 , 13 ]. The link between chronic liver disease and respiratory complications is well-documented. For instance, liver dysfunction can lead to systemic immune impairment, heightening susceptibility to respiratory infections like pneumonia. Furthermore, portal hypertension may give rise to unique pulmonary-vascular pathologies, such as hepatopulmonary syndrome, which severely compromise respiratory function and are associated with poor patient outcomes [ 14 , 15 ]. The combined effects of these disease processes place a considerable strain on patient management and prognosis. While the epidemiology of liver cirrhosis and respiratory diseases has been studied extensively in isolation, a critical gap remains in our understanding of their combined mortality burden from a long-term, population-based perspective. To address this gap, our study provides a retrospective epidemiological analysis of deaths involving both conditions in the United States from 1999 to 2023. By leveraging the comprehensive the Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiology Research (CDC WONDER) database, we aim to offer a granular overview of mortality trends and disparities that is not feasible with smaller, institutional datasets. The primary objective is to characterize temporal mortality trends and investigate variations across key demographic and geographic subgroups, including sex, age, race, census region, and urban-rural classification. The insights generated will be crucial for informing targeted public health and clinical strategies to reduce the preventable mortality associated with this critical comorbidity. Materials and Methods Study Design and Cohort This retrospective, population-based study utilized data from CDC WONDER database [ 16 ]. We analyzed liver cirrhosis and respiratory disease-related mortality among individuals aged 25 years and older in the United States between 1999 and 2023. This approach enabled a comprehensive, long-term analysis of mortality trends that would be infeasible using institutional or clinical registry data. This dataset comprises cause-of-death data from death certificates from all 50 states and the District of Columbia. This study was exempt from institutional review board approval due to the deidentified nature of the database and adhered to the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines for reporting. Data Extraction We queried the CDC WONDER Multiple Cause of Death database to identify decedents with both liver cirrhosis and respiratory disease listed on their death certificate. Liver cirrhosis was identified using the International Classification of Diseases, 10th Revision (ICD-10) codes K70.2, K70.3, K71.7, and K74, while respiratory diseases were identified by codes J00-J98. Records were included if either condition was listed as an underlying or contributing cause of death. We extracted data on sex, age (in 10-year increments: 25–34, 35–44, etc.), race/ethnicity, and geographic location, including state, census region, and urban-rural classification. Statistical Analysis Crude and age-adjusted mortality rates (AAMR) per 100,000 people were calculated for the study period, with AAMRs standardized to the 2013 United States standard population. To analyze temporal trends, we used the Joinpoint Regression Program (version 5.3.0, National Cancer Institute) to determine statistically significant changes in mortality over time [ 17 ]. The number of joinpoints was determined using the Monte Carlo permutation method. We calculated the annual percentage change (APC) for each segment and the average annual percentage change (AAPC) for the entire period. A trend was considered statistically significant if its slope differed significantly from zero (P ≤ 0.05) based on a 2-tailed t-test. In addition to trend analysis, an Autoregressive Integrated Moving Average (ARIMA) model was developed to forecast future mortality dynamics [ 18 , 19 ]. This model was built using the time series of the overall age-adjusted mortality rate from 1999 to 2023. Optimal model parameters were selected based on standard model selection criteria, such as the Akaike Information Criterion (AIC), to ensure the best fit to the historical data. The model was then used to forecast the AAMR for subsequent years. Due to the aggregated nature of the CDC WONDER database, individual-level adjustment for confounding variables was not possible; however, we conducted subgroup analyses to explore demographic and geographic variations within the national population. Results Overall Findings Between 1999 and 2023, a total of 6,957,062 deaths associated with liver cirrhosis and respiratory diseases were reported in the CDC WONDER database. The AAMR for liver cirrhosis and respiratory diseases showed a significant decline, falling from 141.31 per 100,000 population in 1999 (95% CI: 140.75-141.86) to 111.04 in 2023 (95% CI: 110.64-111.44), representing an overall decrease of 22.70% during the study period. Temporal trend analysis confirmed a statistically significant AAPC of -1.06% (95% CI: -1.40% to -0.72%, P < 0.001) for the entire period. This decline was not uniform; a steep decrease occurred from 1999 to 2007 (APC: -1.55%, 95% CI: -2.17% to -0.93%), followed by a period of stabilization from 2007 to 2017 (APC: -0.27%, 95% CI: -0.77% to 0.24%). The mortality rate then experienced an accelerated decline from 2017 to 2023 (APC: -1.72%, 95% CI: -2.59% to -0.84%). (Fig. 1 ; Table S1 ) Stratification by Sex Mortality demonstrated significant disparities between sexes. From 1999 to 2023, the number of male deaths (3,479,270) was slightly higher than female deaths (3,477,792). The male AAMR was consistently and substantially higher than that of females, with a rate of 182.18 per 100,000 in 1999 (95% CI: 181.14–183.21) compared to 115.89 for females (95% CI: 115.24–116.53). By 2023, these rates had fallen to 128.31 (95% CI: 127.66–128.96) and 97.26 (95% CI: 96.76–97.76), respectively. Trend analysis revealed a faster rate of decline for males (AAPC: -1.43%) than for females (AAPC: -0.66%, P < 0.001). The male trend was non-linear, with a rapid decline from 1999 to 2007 (APC: -2.14%, P < 0.001), a slower decline from 2007 to 2018 (APC: -0.69%), and an accelerated decline from 2018 to 2023 (APC: -1.94%). In contrast, the female AAMR experienced a more consistent and statistically significant decline throughout the entire period. (Fig. 1 ; Table S1 ) Stratification by Age Group The distribution of deaths varied significantly by age, with a clear trend of increasing death counts in older age groups. The majority of deaths were concentrated in individuals aged 65 and above, with the highest numbers in the 75–84 years group (2,132,363) and the 85 + years group (2,027,472) for the study period. While mortality rates for older age groups demonstrated a significant decline, a concerning increase was observed in younger populations. The crude death rate in the 25–34 years group increased from 3.11 per 100,000 in 1999 to 5.04 in 2023. Temporal trend analysis confirmed a statistically significant increase for this age group from 2005 to 2023 with an APC of 3.84% (95% CI: 2.79% to 4.90%, P < 0.05). Similarly, the 35–44 years group experienced a significant increase in crude death rate from 2018 to 2021 (APC: 13.60%, 95% CI: 1.39% to 27.28%, P < 0.05). (Fig. 2 ; Table S1 ) Ethnoracial Stratification Significant variations in mortality were observed across different ethnoracial groups. Non-Hispanic White individuals had the highest total number of deaths (5,839,769). The AAMR for this group was highest in 1999 at 145.28 per 100,000, and while it declined by 2023 to 121.91, it remained the highest among all groups. While all ethnoracial groups experienced a significant overall decline in mortality, the rate of decline varied. The Non-Hispanic Other group had the fastest decline with an AAPC of -1.81% (95% CI: -2.09% to -1.53%, P < 0.001). The Hispanic group’s AAMR experienced a more rapid decline from 1999 to 2012 (APC: -1.67%, 95% CI: -2.09% to -1.26%) before slowing down from 2012 to 2023 (APC: -0.55%, 95% CI: -0.96% to -0.15%). (Fig. 3 ) Geographic Variations The geographic distribution of mortality demonstrated significant variations across states. The highest AAMRs in 2023 were found in states like West Virginia (133.53 per 100,000, 95% CI: 128.53–138.53) and Oklahoma (128.96, 95% CI: 124.35–133.57). Conversely, states like the District of Columbia (68.25, 95% CI: 60.51–75.99) and Hawaii (75.02, 95% CI: 70.46–79.58) had the lowest AAMRs. The temporal trend analysis also revealed varied patterns by state, with some states in the Midwest and South, such as Arkansas (AAPC: 0.43%, 95% CI: 0.24–0.63, P < 0.05), showing a statistically significant increasing trend in AAMR. (Fig. 4 ) In terms of census regions, all regions showed a statistically significant overall decline in AAMR. The West region experienced the fastest decline with an AAPC of -1.44% (95% CI: -1.72% to -1.15%, P < 0.001), while the Midwest showed the slowest decline (AAPC: -0.62%, 95% CI: -1.01% to -0.23%, P < 0.001). (Fig. S1 ) The AAMR for metropolitan areas showed a statistically significant decline (AAPC: -1.04%, 95% CI: -1.34% to -0.74%, P 0.05). (Fig. S2) ARIMA Model Predictions Based on the ARIMA forecasting model, the age-adjusted mortality rate for liver cirrhosis and respiratory diseases is predicted to continue its significant downward trend from 2024 to 2046. The model forecasts the overall AAMR will decrease from 111.04 per 100,000 in 2023 to 82.62 in 2046 (95% CI: 62.86–102.37). This declining trend is also projected for both males (from 128.31 to 77.09) and females (from 97.26 to 79.02) during this period. However, while the AAMR is predicted to decrease, the total number of deaths is forecasted to increase from 305,629 in 2023 to 364,156 in 2046, likely due to an aging and growing population. (Fig. 5 ) Discussion This retrospective, population-based study provides a comprehensive analysis of mortality trends and disparities related to coexisting liver cirrhosis and respiratory diseases in the United States from 1999 to 2023. Our findings reveal a significant overall decline in age-adjusted mortality rates. However, this national trend masks substantial and persistent disparities across demographic and geographic subgroups. While mortality rates generally decreased in older populations, we observed a concerning increase among younger adults. Furthermore, significant variations in AAMR were noted by sex, race/ethnicity, and geography, with male, Non-Hispanic White, and nonmetropolitan populations bearing a disproportionately high mortality burden. The observed overall decline in mortality related to coexisting liver cirrhosis and respiratory diseases is consistent with broader epidemiological trends for chronic diseases over the past two decades [ 20 – 22 ]. This positive development may be attributable to advances in medical care, including improved management of chronic liver disease, like vaccinations, screenings, and antiviral treatments, which have significantly reduced the burden of chronic liver disease caused by viral hepatitis B and C [ 23 ], and effective vaccination programs for respiratory infections like influenza and pneumonia, and public health campaigns targeting key risk factors [ 7 , 10 , 24 ]. However, our finding of a paradoxical increase in mortality among younger adults represents a critical divergence from this overall trend. This alarming pattern may reflect the rising incidence of metabolic dysfunction–associated steatotic liver disease (MASLD) and alcohol-related liver disease in younger demographics, a growing public health concern [ 3 ]. Obesity is on the rise globally among adolescents and young adults, leading to an increased prevalence of MASLD in these populations [ 25 , 26 ]. In the United States, MASLD has become the most common cause of chronic liver disease in both children and young adults and it is also the second most frequent cause for liver transplantation [ 26 , 27 ]. This contributes to higher mortality rates and a greater number of disability-adjusted life years. The metabolic risks observed in adolescents and young adults are now recognized as a significant global health threat [ 28 ]. Therefore, it is critical to determine the impact of MASLD on mortality risk in young adults and to analyze the associated risk factors. Increasing awareness of MASLD and encouraging young adults to mitigate these risk factors are vital steps in developing strategies to reduce the global disease burden. The disparities observed across subgroups highlight a complex interplay of biological, behavioral, and socioeconomic factors. The consistently higher mortality rates in males may be linked to a higher prevalence of behavioral risk factors like higher rates of alcohol consumption and smoking, along with a tendency to engage in risk-taking behaviors and a lower likelihood of healthcare-seeking behaviors [ 29 , 30 ]. Biological factors, such as hormones, and societal influences, like perceived masculine norms for health behaviors, also contribute to these differences in health outcomes and mortality between sexes [ 30 , 31 ]. The sustained high mortality burden in Non-Hispanic White individuals, despite a decline, underscores the need for continued and targeted interventions for this large population group. Conversely, the faster decline in mortality among the Non-Hispanic Other group suggests that specific public health initiatives or lifestyle changes within these communities may be yielding positive results. Geographically, the stagnant, non-significant trend in nonmetropolitan areas likely reflects a critical disparity in healthcare access and resources compared to metropolitan regions. Our findings carry important implications for public health and clinical practice. The sustained mortality burden in high-risk groups, particularly males, certain racial groups, and nonmetropolitan residents, underscores the need for targeted and culturally competent public health strategies. Clinically, our results reinforce the importance of routine screening for respiratory complications in patients with cirrhosis, especially within these vulnerable populations. Furthermore, our ARIMA forecast projects a continued decline in the overall age-adjusted mortality rate in the coming years. This projection aligns with the long-term trend observed in our historical analysis, suggesting that the public health measures and clinical advancements of the past may sustain their impact in the near future. However, this forecast must be interpreted with caution. Such models assume the continuation of past trends and cannot account for unforeseen events that could alter this trajectory, such as new public health crises, major shifts in healthcare policy, or changes in the prevalence of risk factors like alcohol use and metabolic syndrome [ 32 , 33 ]. Critically, this overall optimistic projection does not negate the urgent need to address the disparities identified in our subgroup analyses, as a declining national average can conceal worsening outcomes for vulnerable populations. However, this study is not without limitations. As a retrospective database analysis, we could not adjust for individual-level confounding variables such as smoking status, alcohol use, specific comorbidities, or treatment modalities. The reliance on death certificate data also introduces the potential for misclassification or incomplete reporting of causes of death. Finally, while our analysis identifies population-level trends and disparities, it cannot elucidate the specific mechanisms driving these patterns. Future research should investigate the underlying causes of these disparities and evaluate the effectiveness of targeted, community-based interventions aimed at reducing this preventable mortality. Conclusion This study provides a comprehensive epidemiological analysis of mortality trends associated with coexisting liver cirrhosis and respiratory diseases, drawing on two decades of national data. Our findings reveal a dual narrative: one of significant overall progress in reducing mortality, overshadowed by another of persistent and, in some cases, worsening disparities across key demographic and geographic subgroups. The value of this study lies in its large-scale, population-based approach, which offers crucial insights for shaping targeted public health strategies. Acknowledging its limitations, which are inherent to retrospective database analysis, future research should focus on investigating the root causes of these disparities to inform more equitable and effective interventions. Abbreviations AAMR Age-adjusted mortality rate AAPC Average annual percent change APC Annual percent change CDC WONDER Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research CI Confidence Interval Declarations Author’s contributions HX and YD designed and supervised the study. YZ, PM, LZ and BX collected data and developed the database. YZ and PM conducted the analysis. YZ, PM and LZ were involved in manuscript writing. All authors reviewed and approved the manuscript. Funding This project was supported by grant from the Health Commission of Hubei Province research program (WJ2023F023). Data availability The datasets generated and analyzed during the current study are publicly accessible from the website for the Centers for Disease Control and Prevention, National Center for Health Statistics – https://wonder.cdc.gov/. Ethics approval and consent to participate Approval from an institutional review board was not required as the data analyzed was deidentified in a publicly available database. Consent for publication This study utilized data from publicly available databases, which do not contain identifiable personal information. Therefore, consent for publication is not applicable. Competing interests The authors declare no competing interests. References Ginès P, Krag A, Abraldes JG, Solà E, Fabrellas N, Kamath PS. 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Mahalik JR, Burns SM, Syzdek M. Masculinity and perceived normative health behaviors as predictors of men’s health behaviors. Soc Sci Med. 2007;64:2201–9. https://doi.org/10.1016/j.socscimed.2007.02.035 . Teja MD, Rayalu GM. Hybrid time series and machine learning models for forecasting cardiovascular mortality in India: An age specific analysis. BMC Public Health. 2025;25:2150. https://doi.org/10.1186/s12889-025-23318-7 . Lei Z. A comprehensive statistical analysis of COVID-19 trends: Global and U.S. insights through ARIMA, regression, and spatial models. 2024;:2024.10.22.24315932. https://doi.org/10.1101/2024.10.22.24315932 Additional Declarations No competing interests reported. Supplementary Files Supplementarymaterials.docx Table S1: Age-adjusted mortality rates (AAMR) and annual average percent changes (AAPC) of liver cirrhosis and respiratory diseases-related mortalitystratified by sex, age, ethnocracies, and geographic in the United States in 1999 and 2023. Fig S1. Census region stratified liver cirrhosis and respiratory diseases-related AAMR per 100,000 in the United States from 1999 to 2023. Fig S2. Urbanization stratified liver cirrhosis and respiratory diseases-related AAMR per 100,000 in the United States from 1999 to 2023. Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 09 Oct, 2025 Reviewers agreed at journal 01 Oct, 2025 Reviewers agreed at journal 27 Sep, 2025 Reviewers invited by journal 25 Sep, 2025 Editor invited by journal 25 Sep, 2025 Editor assigned by journal 23 Sep, 2025 Submission checks completed at journal 23 Sep, 2025 First submitted to journal 18 Sep, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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University","correspondingAuthor":false,"prefix":"","firstName":"Peng","middleName":"","lastName":"Ma","suffix":""},{"id":525077258,"identity":"919263a1-2f93-4e70-8189-d6fcfd55c5bd","order_by":2,"name":"Lei Zhu","email":"","orcid":"","institution":"Wuhan Puren Hospital","correspondingAuthor":false,"prefix":"","firstName":"Lei","middleName":"","lastName":"Zhu","suffix":""},{"id":525077259,"identity":"b721b811-097a-48d3-8ff1-a8e79836a1d6","order_by":3,"name":"Bingang Xu","email":"","orcid":"","institution":"Renmin Hospital of Wuhan University","correspondingAuthor":false,"prefix":"","firstName":"Bingang","middleName":"","lastName":"Xu","suffix":""},{"id":525077261,"identity":"ad776816-e327-43e7-92a0-a9f37521c2af","order_by":4,"name":"Hongmiao Xia","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA6UlEQVRIie3PMWsCMRTA8WcjmUJvfQdyfoUUITgI/SoXDpyu0KlkEEw5iYOIX8WpOBqFuKT7DR0sB93dHDq0u8WcW4f8pjfkz3sBiKJ/iCaVbb75KHs8VPaYq0k4uUdXcKbGA/C/w9G7cJJBKZD5ndR1KdLPGWlxGGwFpmbbedWlUFJTSOaL/HpCdDF8MB+EgHup5aYH6N/XoS22luaL0k71VktPgeNTKJEardkzRkA8S0PaJMVdqv0ekXYFtEvQkQGoMeeMFph7x4J/6a9Wpwb4aLruN/Z0VpMsmS+vJxfYbc+jKIqiP/0ANFtL+tvslJ0AAAAASUVORK5CYII=","orcid":"","institution":"Renmin Hospital of Wuhan University","correspondingAuthor":true,"prefix":"","firstName":"Hongmiao","middleName":"","lastName":"Xia","suffix":""},{"id":525077263,"identity":"963f5892-94eb-48a7-9029-0b605c93a665","order_by":5,"name":"Youmin Ding","email":"","orcid":"","institution":"Renmin Hospital of Wuhan University","correspondingAuthor":false,"prefix":"","firstName":"Youmin","middleName":"","lastName":"Ding","suffix":""}],"badges":[],"createdAt":"2025-09-18 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14:36:57","extension":"html","order_by":15,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":98286,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7647383/v1/be24921090d10a7e8eb5341d.html"},{"id":93238996,"identity":"10259612-fea5-41c2-a03b-cfc7a58ac1f6","added_by":"auto","created_at":"2025-10-10 14:36:57","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":99989,"visible":true,"origin":"","legend":"\u003cp\u003eOverall and sex-stratified liver cirrhosis and respiratory diseases-related AAMR per 100,000 in the United States from 1999 to 2023. *Indicates that the annual APC is significantly different from zero at α = 0.05. AAMR, age-adjusted mortality rate; APC, annual percent change; CI, confidence interval.\u003c/p\u003e","description":"","filename":"image1.png","url":"https://assets-eu.researchsquare.com/files/rs-7647383/v1/bbd612d80b2cd900f1894972.png"},{"id":93238998,"identity":"ac25cf8b-5c8f-454d-80ff-8b3bff16a6af","added_by":"auto","created_at":"2025-10-10 14:36:57","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":107817,"visible":true,"origin":"","legend":"\u003cp\u003eAge-stratified liver cirrhosis and respiratory diseases-related AAMR per 100,000 in the United States from 1999 to 2023. *Indicates that the APC is significantly different from zero at α = 0.05. AAMR, age-adjusted mortality rate; APC, annual percent change; CI, confidence interval.\u003c/p\u003e","description":"","filename":"image2.png","url":"https://assets-eu.researchsquare.com/files/rs-7647383/v1/3bb071cf982295b7768babe8.png"},{"id":93238995,"identity":"40cfcd53-ceff-46f4-90a4-d5cae6b8765e","added_by":"auto","created_at":"2025-10-10 14:36:57","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":116521,"visible":true,"origin":"","legend":"\u003cp\u003eEthnoracial stratified liver cirrhosis and respiratory diseases-related AAMR per 100,000 in the United States from 1999 to 2023. *Indicates that the APC is significantly different from zero at α = 0.05. AAMR, age-adjusted mortality rate; APC, annual percent change; CI, confidence interval.\u003c/p\u003e","description":"","filename":"image3.png","url":"https://assets-eu.researchsquare.com/files/rs-7647383/v1/4f8996df9f63934a094f8879.png"},{"id":93238997,"identity":"1fd84db6-e0ee-42b6-933d-6783fef6dfb1","added_by":"auto","created_at":"2025-10-10 14:36:57","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":120931,"visible":true,"origin":"","legend":"\u003cp\u003eGeographic distribution of mortality metrics for liver cirrhosis and respiratory diseases by state, United States, 1999-2023. Panel (A) displays the total number of deaths in 2023. Panel (B) shows the AAMR per 100,000 population in 2023, with higher values represented by darker shading. Panel (C) presents the APC of mortality rates, while Panel (D) illustrates the AAPC from 1999 to 2023. AAMR, age-adjusted mortality rate; APC, annual percent change; AAPC, average annual percent change.\u003c/p\u003e","description":"","filename":"image4.png","url":"https://assets-eu.researchsquare.com/files/rs-7647383/v1/f4a844f19be42a00681aa3ab.png"},{"id":93240323,"identity":"83b74abe-2591-47e6-b673-3ae1429c969f","added_by":"auto","created_at":"2025-10-10 14:44:57","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":84874,"visible":true,"origin":"","legend":"\u003cp\u003eARIMA model forecast for mortality trends related to liver cirrhosis and respiratory diseases, 1999–2046. The figure presents historical (1999–2023) and forecasted (2024–2046) trends in AAMR and total deaths. The blue lines represent the actual values and the red lines for forecasted values, while the shaded areas indicate the 95% confidence intervals for the forecasted AAMR and total death counts. Trends are stratified by sex (male, female) and for the overall population (\"Both\").\u003c/p\u003e","description":"","filename":"image5.png","url":"https://assets-eu.researchsquare.com/files/rs-7647383/v1/1ae6c7d8bb81df1d0191815f.png"},{"id":93241689,"identity":"d3cf8008-5be0-4fdc-ad4d-68a3e3f61124","added_by":"auto","created_at":"2025-10-10 14:53:02","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1022588,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7647383/v1/b16856e0-5839-42f6-868f-f56e472d60d8.pdf"},{"id":93241685,"identity":"96b7d092-2aec-4692-b06b-277091ffda83","added_by":"auto","created_at":"2025-10-10 14:52:57","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":459509,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTable S1:\u003c/strong\u003e Age-adjusted mortality rates (AAMR) and annual average percent changes (AAPC) of liver cirrhosis and respiratory diseases-related mortalitystratified by sex, age, ethnocracies, and geographic in the United States in 1999 and 2023.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFig S1. \u003c/strong\u003eCensus region stratified liver cirrhosis and respiratory diseases-related AAMR per 100,000 in the United States from 1999 to 2023.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFig S2. \u003c/strong\u003eUrbanization stratified liver cirrhosis and respiratory diseases-related AAMR per 100,000 in the United States from 1999 to 2023.\u003c/p\u003e","description":"","filename":"Supplementarymaterials.docx","url":"https://assets-eu.researchsquare.com/files/rs-7647383/v1/a8eacddf8d42aad02b8b5dcb.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Shifting Trends and Persistent Disparities in Mortality Related to Liver Cirrhosis and Respiratory Disease: A Population-Based Study in the United States, 1999-2023","fulltext":[{"header":"Introduction","content":"\u003cp\u003eLiver cirrhosis is a progressive and significant public health challenge, contributing substantially to global morbidity and mortality [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. In 2021 alone, there were an estimated 58.4\u0026nbsp;million incident cases globally, and liver disease is responsible for approximately two million deaths annually [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Within the United States, chronic liver disease and cirrhosis will likely be the 9th leading cause in 2023, and the death rate increased 15.3% from 2019 through 2023 [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Cirrhosis is also an expensive disease. In the US in 2016, liver-related expenditure was \u003cspan\u003e$\u003c/span\u003e32.5\u0026nbsp;billion (95% CI \u003cspan\u003e$\u003c/span\u003e27.0-\u003cspan\u003e$\u003c/span\u003e40.4\u0026nbsp;billion) with two-thirds of these costs attributable to inpatient or emergency department care. Over 20 years, healthcare spending has increased by 4% per year primarily driven by hospital-based services [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Concurrently, respiratory diseases impose a massive burden [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]; they were the third-leading cause of death worldwide in 2019, accounting for 4.0\u0026nbsp;million deaths [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. By 2023, chronic lower respiratory diseases were the fifth leading cause of death in the United States, with 145,357 reported fatalities [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe coexistence of these two conditions presents a particularly complex and challenging clinical scenario, as one disease process can exacerbate the other [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. The link between chronic liver disease and respiratory complications is well-documented. For instance, liver dysfunction can lead to systemic immune impairment, heightening susceptibility to respiratory infections like pneumonia. Furthermore, portal hypertension may give rise to unique pulmonary-vascular pathologies, such as hepatopulmonary syndrome, which severely compromise respiratory function and are associated with poor patient outcomes [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. The combined effects of these disease processes place a considerable strain on patient management and prognosis.\u003c/p\u003e\u003cp\u003eWhile the epidemiology of liver cirrhosis and respiratory diseases has been studied extensively in isolation, a critical gap remains in our understanding of their combined mortality burden from a long-term, population-based perspective. To address this gap, our study provides a retrospective epidemiological analysis of deaths involving both conditions in the United States from 1999 to 2023. By leveraging the comprehensive the Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiology Research (CDC WONDER) database, we aim to offer a granular overview of mortality trends and disparities that is not feasible with smaller, institutional datasets. The primary objective is to characterize temporal mortality trends and investigate variations across key demographic and geographic subgroups, including sex, age, race, census region, and urban-rural classification. The insights generated will be crucial for informing targeted public health and clinical strategies to reduce the preventable mortality associated with this critical comorbidity.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStudy Design and Cohort\u003c/h2\u003e\u003cp\u003eThis retrospective, population-based study utilized data from CDC WONDER database [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. We analyzed liver cirrhosis and respiratory disease-related mortality among individuals aged 25 years and older in the United States between 1999 and 2023. This approach enabled a comprehensive, long-term analysis of mortality trends that would be infeasible using institutional or clinical registry data. This dataset comprises cause-of-death data from death certificates from all 50 states and the District of Columbia. This study was exempt from institutional review board approval due to the deidentified nature of the database and adhered to the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines for reporting.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eData Extraction\u003c/h3\u003e\n\u003cp\u003eWe queried the CDC WONDER Multiple Cause of Death database to identify decedents with both liver cirrhosis and respiratory disease listed on their death certificate. Liver cirrhosis was identified using the International Classification of Diseases, 10th Revision (ICD-10) codes K70.2, K70.3, K71.7, and K74, while respiratory diseases were identified by codes J00-J98. Records were included if either condition was listed as an underlying or contributing cause of death. We extracted data on sex, age (in 10-year increments: 25\u0026ndash;34, 35\u0026ndash;44, etc.), race/ethnicity, and geographic location, including state, census region, and urban-rural classification.\u003c/p\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\u003cp\u003eCrude and age-adjusted mortality rates (AAMR) per 100,000 people were calculated for the study period, with AAMRs standardized to the 2013 United States standard population. To analyze temporal trends, we used the Joinpoint Regression Program (version 5.3.0, National Cancer Institute) to determine statistically significant changes in mortality over time [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. The number of joinpoints was determined using the Monte Carlo permutation method. We calculated the annual percentage change (APC) for each segment and the average annual percentage change (AAPC) for the entire period. A trend was considered statistically significant if its slope differed significantly from zero (P\u0026thinsp;\u0026le;\u0026thinsp;0.05) based on a 2-tailed t-test.\u003c/p\u003e\u003cp\u003eIn addition to trend analysis, an Autoregressive Integrated Moving Average (ARIMA) model was developed to forecast future mortality dynamics [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. This model was built using the time series of the overall age-adjusted mortality rate from 1999 to 2023. Optimal model parameters were selected based on standard model selection criteria, such as the Akaike Information Criterion (AIC), to ensure the best fit to the historical data. The model was then used to forecast the AAMR for subsequent years.\u003c/p\u003e\u003cp\u003eDue to the aggregated nature of the CDC WONDER database, individual-level adjustment for confounding variables was not possible; however, we conducted subgroup analyses to explore demographic and geographic variations within the national population.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003eOverall Findings\u003c/h2\u003e\u003cp\u003eBetween 1999 and 2023, a total of 6,957,062 deaths associated with liver cirrhosis and respiratory diseases were reported in the CDC WONDER database. The AAMR for liver cirrhosis and respiratory diseases showed a significant decline, falling from 141.31 per 100,000 population in 1999 (95% CI: 140.75-141.86) to 111.04 in 2023 (95% CI: 110.64-111.44), representing an overall decrease of 22.70% during the study period. Temporal trend analysis confirmed a statistically significant AAPC of -1.06% (95% CI: -1.40% to -0.72%, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) for the entire period. This decline was not uniform; a steep decrease occurred from 1999 to 2007 (APC: -1.55%, 95% CI: -2.17% to -0.93%), followed by a period of stabilization from 2007 to 2017 (APC: -0.27%, 95% CI: -0.77% to 0.24%). The mortality rate then experienced an accelerated decline from 2017 to 2023 (APC: -1.72%, 95% CI: -2.59% to -0.84%). (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e1\u003c/span\u003e; Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e)\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eStratification by Sex\u003c/h2\u003e\u003cp\u003eMortality demonstrated significant disparities between sexes. From 1999 to 2023, the number of male deaths (3,479,270) was slightly higher than female deaths (3,477,792). The male AAMR was consistently and substantially higher than that of females, with a rate of 182.18 per 100,000 in 1999 (95% CI: 181.14\u0026ndash;183.21) compared to 115.89 for females (95% CI: 115.24\u0026ndash;116.53). By 2023, these rates had fallen to 128.31 (95% CI: 127.66\u0026ndash;128.96) and 97.26 (95% CI: 96.76\u0026ndash;97.76), respectively. Trend analysis revealed a faster rate of decline for males (AAPC: -1.43%) than for females (AAPC: -0.66%, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The male trend was non-linear, with a rapid decline from 1999 to 2007 (APC: -2.14%, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001), a slower decline from 2007 to 2018 (APC: -0.69%), and an accelerated decline from 2018 to 2023 (APC: -1.94%). In contrast, the female AAMR experienced a more consistent and statistically significant decline throughout the entire period. (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e1\u003c/span\u003e; Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e)\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eStratification by Age Group\u003c/h3\u003e\n\u003cp\u003eThe distribution of deaths varied significantly by age, with a clear trend of increasing death counts in older age groups. The majority of deaths were concentrated in individuals aged 65 and above, with the highest numbers in the 75\u0026ndash;84 years group (2,132,363) and the 85\u0026thinsp;+\u0026thinsp;years group (2,027,472) for the study period. While mortality rates for older age groups demonstrated a significant decline, a concerning increase was observed in younger populations. The crude death rate in the 25\u0026ndash;34 years group increased from 3.11 per 100,000 in 1999 to 5.04 in 2023. Temporal trend analysis confirmed a statistically significant increase for this age group from 2005 to 2023 with an APC of 3.84% (95% CI: 2.79% to 4.90%, P\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Similarly, the 35\u0026ndash;44 years group experienced a significant increase in crude death rate from 2018 to 2021 (APC: 13.60%, 95% CI: 1.39% to 27.28%, P\u0026thinsp;\u0026lt;\u0026thinsp;0.05). (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e2\u003c/span\u003e; Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e)\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\n\u003ch3\u003eEthnoracial Stratification\u003c/h3\u003e\n\u003cp\u003eSignificant variations in mortality were observed across different ethnoracial groups. Non-Hispanic White individuals had the highest total number of deaths (5,839,769). The AAMR for this group was highest in 1999 at 145.28 per 100,000, and while it declined by 2023 to 121.91, it remained the highest among all groups. While all ethnoracial groups experienced a significant overall decline in mortality, the rate of decline varied. The Non-Hispanic Other group had the fastest decline with an AAPC of -1.81% (95% CI: -2.09% to -1.53%, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The Hispanic group\u0026rsquo;s AAMR experienced a more rapid decline from 1999 to 2012 (APC: -1.67%, 95% CI: -2.09% to -1.26%) before slowing down from 2012 to 2023 (APC: -0.55%, 95% CI: -0.96% to -0.15%). (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eGeographic Variations\u003c/h2\u003e\u003cp\u003eThe geographic distribution of mortality demonstrated significant variations across states. The highest AAMRs in 2023 were found in states like West Virginia (133.53 per 100,000, 95% CI: 128.53\u0026ndash;138.53) and Oklahoma (128.96, 95% CI: 124.35\u0026ndash;133.57). Conversely, states like the District of Columbia (68.25, 95% CI: 60.51\u0026ndash;75.99) and Hawaii (75.02, 95% CI: 70.46\u0026ndash;79.58) had the lowest AAMRs. The temporal trend analysis also revealed varied patterns by state, with some states in the Midwest and South, such as Arkansas (AAPC: 0.43%, 95% CI: 0.24\u0026ndash;0.63, P\u0026thinsp;\u0026lt;\u0026thinsp;0.05), showing a statistically significant increasing trend in AAMR. (Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e4\u003c/span\u003e)\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eIn terms of census regions, all regions showed a statistically significant overall decline in AAMR. The West region experienced the fastest decline with an AAPC of -1.44% (95% CI: -1.72% to -1.15%, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001), while the Midwest showed the slowest decline (AAPC: -0.62%, 95% CI: -1.01% to -0.23%, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). (Fig. \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e) The AAMR for metropolitan areas showed a statistically significant decline (AAPC: -1.04%, 95% CI: -1.34% to -0.74%, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) throughout the study period. In contrast, the trend for nonmetropolitan areas was not statistically significant (AAPC: 0.12%, 95% CI: -0.06% to 0.30%, P\u0026thinsp;\u0026gt;\u0026thinsp;0.05). (Fig. S2)\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eARIMA Model Predictions\u003c/h2\u003e\u003cp\u003eBased on the ARIMA forecasting model, the age-adjusted mortality rate for liver cirrhosis and respiratory diseases is predicted to continue its significant downward trend from 2024 to 2046. The model forecasts the overall AAMR will decrease from 111.04 per 100,000 in 2023 to 82.62 in 2046 (95% CI: 62.86\u0026ndash;102.37). This declining trend is also projected for both males (from 128.31 to 77.09) and females (from 97.26 to 79.02) during this period. However, while the AAMR is predicted to decrease, the total number of deaths is forecasted to increase from 305,629 in 2023 to 364,156 in 2046, likely due to an aging and growing population. (Fig.\u0026nbsp;\u003cspan refid=\"Fig10\" class=\"InternalRef\"\u003e5\u003c/span\u003e)\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis retrospective, population-based study provides a comprehensive analysis of mortality trends and disparities related to coexisting liver cirrhosis and respiratory diseases in the United States from 1999 to 2023. Our findings reveal a significant overall decline in age-adjusted mortality rates. However, this national trend masks substantial and persistent disparities across demographic and geographic subgroups. While mortality rates generally decreased in older populations, we observed a concerning increase among younger adults. Furthermore, significant variations in AAMR were noted by sex, race/ethnicity, and geography, with male, Non-Hispanic White, and nonmetropolitan populations bearing a disproportionately high mortality burden.\u003c/p\u003e\u003cp\u003eThe observed overall decline in mortality related to coexisting liver cirrhosis and respiratory diseases is consistent with broader epidemiological trends for chronic diseases over the past two decades [\u003cspan additionalcitationids=\"CR21\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. This positive development may be attributable to advances in medical care, including improved management of chronic liver disease, like vaccinations, screenings, and antiviral treatments, which have significantly reduced the burden of chronic liver disease caused by viral hepatitis B and C [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], and effective vaccination programs for respiratory infections like influenza and pneumonia, and public health campaigns targeting key risk factors [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eHowever, our finding of a paradoxical increase in mortality among younger adults represents a critical divergence from this overall trend. This alarming pattern may reflect the rising incidence of metabolic dysfunction\u0026ndash;associated steatotic liver disease (MASLD) and alcohol-related liver disease in younger demographics, a growing public health concern [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Obesity is on the rise globally among adolescents and young adults, leading to an increased prevalence of MASLD in these populations [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. In the United States, MASLD has become the most common cause of chronic liver disease in both children and young adults and it is also the second most frequent cause for liver transplantation [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. This contributes to higher mortality rates and a greater number of disability-adjusted life years. The metabolic risks observed in adolescents and young adults are now recognized as a significant global health threat [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Therefore, it is critical to determine the impact of MASLD on mortality risk in young adults and to analyze the associated risk factors. Increasing awareness of MASLD and encouraging young adults to mitigate these risk factors are vital steps in developing strategies to reduce the global disease burden.\u003c/p\u003e\u003cp\u003eThe disparities observed across subgroups highlight a complex interplay of biological, behavioral, and socioeconomic factors. The consistently higher mortality rates in males may be linked to a higher prevalence of behavioral risk factors like higher rates of alcohol consumption and smoking, along with a tendency to engage in risk-taking behaviors and a lower likelihood of healthcare-seeking behaviors [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Biological factors, such as hormones, and societal influences, like perceived masculine norms for health behaviors, also contribute to these differences in health outcomes and mortality between sexes [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. The sustained high mortality burden in Non-Hispanic White individuals, despite a decline, underscores the need for continued and targeted interventions for this large population group. Conversely, the faster decline in mortality among the Non-Hispanic Other group suggests that specific public health initiatives or lifestyle changes within these communities may be yielding positive results. Geographically, the stagnant, non-significant trend in nonmetropolitan areas likely reflects a critical disparity in healthcare access and resources compared to metropolitan regions.\u003c/p\u003e\u003cp\u003eOur findings carry important implications for public health and clinical practice. The sustained mortality burden in high-risk groups, particularly males, certain racial groups, and nonmetropolitan residents, underscores the need for targeted and culturally competent public health strategies. Clinically, our results reinforce the importance of routine screening for respiratory complications in patients with cirrhosis, especially within these vulnerable populations.\u003c/p\u003e\u003cp\u003eFurthermore, our ARIMA forecast projects a continued decline in the overall age-adjusted mortality rate in the coming years. This projection aligns with the long-term trend observed in our historical analysis, suggesting that the public health measures and clinical advancements of the past may sustain their impact in the near future. However, this forecast must be interpreted with caution. Such models assume the continuation of past trends and cannot account for unforeseen events that could alter this trajectory, such as new public health crises, major shifts in healthcare policy, or changes in the prevalence of risk factors like alcohol use and metabolic syndrome [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Critically, this overall optimistic projection does not negate the urgent need to address the disparities identified in our subgroup analyses, as a declining national average can conceal worsening outcomes for vulnerable populations.\u003c/p\u003e\u003cp\u003eHowever, this study is not without limitations. As a retrospective database analysis, we could not adjust for individual-level confounding variables such as smoking status, alcohol use, specific comorbidities, or treatment modalities. The reliance on death certificate data also introduces the potential for misclassification or incomplete reporting of causes of death. Finally, while our analysis identifies population-level trends and disparities, it cannot elucidate the specific mechanisms driving these patterns. Future research should investigate the underlying causes of these disparities and evaluate the effectiveness of targeted, community-based interventions aimed at reducing this preventable mortality.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study provides a comprehensive epidemiological analysis of mortality trends associated with coexisting liver cirrhosis and respiratory diseases, drawing on two decades of national data. Our findings reveal a dual narrative: one of significant overall progress in reducing mortality, overshadowed by another of persistent and, in some cases, worsening disparities across key demographic and geographic subgroups. The value of this study lies in its large-scale, population-based approach, which offers crucial insights for shaping targeted public health strategies. Acknowledging its limitations, which are inherent to retrospective database analysis, future research should focus on investigating the root causes of these disparities to inform more equitable and effective interventions.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eAAMR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAge-adjusted mortality rate\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eAAPC\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAverage annual percent change\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eAPC\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAnnual percent change\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCDC WONDER\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eCenters for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCI\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eConfidence Interval\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor\u0026rsquo;s contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHX and YD designed and supervised the study. YZ, PM, LZ and BX collected data and developed the database. YZ and PM conducted the analysis. YZ, PM and LZ were involved in manuscript writing. All authors reviewed and approved the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis project was supported by grant from the Health Commission of Hubei Province research program (WJ2023F023). \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and analyzed during the current study are publicly accessible from the website for the Centers for Disease Control and Prevention, National Center for Health Statistics \u0026ndash; https://wonder.cdc.gov/.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eApproval from an institutional review board was not required as the data analyzed was deidentified in a publicly available database.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study utilized data from publicly available databases, which do not contain identifiable personal information. Therefore, consent for publication is not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests \u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eGin\u0026egrave;s P, Krag A, Abraldes JG, Sol\u0026agrave; E, Fabrellas N, Kamath PS. Liver cirrhosis. Lancet. 2021;398:1359\u0026ndash;76. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/S0140-6736(21)01374-X\u003c/span\u003e\u003cspan address=\"10.1016/S0140-6736(21)01374-X\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAsrani SK, Devarbhavi H, Eaton J, Kamath PS. Burden of liver diseases in the world. 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A comprehensive statistical analysis of COVID-19 trends: Global and U.S. insights through ARIMA, regression, and spatial models. 2024;:2024.10.22.24315932. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1101/2024.10.22.24315932\u003c/span\u003e\u003cspan address=\"10.1101/2024.10.22.24315932\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-public-health","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pubh","sideBox":"Learn more about [BMC Public Health](http://bmcpublichealth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/pubh/default.aspx","title":"BMC Public Health","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Mortality Trends, Health Disparities, Liver Cirrhosis, Respiratory Diseases, CDC WONDER","lastPublishedDoi":"10.21203/rs.3.rs-7647383/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7647383/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eLiver cirrhosis and respiratory diseases represent major global health burdens, and their coexistence significantly contributes to patient morbidity and mortality. While the epidemiology of each disease has been examined individually, a critical gap persists in our understanding of the long-term mortality trends and disparities associated with their combined impact.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eWe conducted a retrospective, population-based study using the CDC WONDER Multiple Cause of Death database to analyze mortality involving both conditions in the United States from 1999 to 2023. We calculated age-adjusted mortality rates (AAMR) and employed Joinpoint regression to identify annual percentage changes (APC) and average annual percentage changes (AAPC) across diverse demographic and geographic subgroups.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eFrom 1999 to 2023, a total of 6,957,062 deaths were identified related to liver cirrhosis and respiratory diseases. The overall AAMR was 141.31 in 1999 and 111.04 in 2023, with a significant overall declining trend observed over the study period. Males consistently exhibited higher AAMRs than females (Males: 128.31 vs. Females: 97.26 in 2023). When stratified by race, the highest AAMR was observed in Non-Hispanic White populations, followed by Non-Hispanic Black, Hispanic, and Non-Hispanic Other populations (AAMR of 121.91, 99.07, 93.18, and 56.72, respectively, in 2023). Regionally, the highest mortality was observed in the South, followed by the Midwest, the West, and lastly, the Northeast (with values of 125.75, 120.91, 86.19, and 96.48, respectively, in 2023). Nonmetropolitan areas (150.97) exhibited consistently higher AAMRs than metropolitan areas (110.73) in 2023.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eLiver cirrhosis and respiratory disease-related mortality declined in the United States from 1999 to 2023, with males, Non-Hispanic White populations, and the South exhibiting the highest AAMRs. These findings highlight the importance of improving management and addressing mortality disparities.\u003c/p\u003e","manuscriptTitle":"Shifting Trends and Persistent Disparities in Mortality Related to Liver Cirrhosis and Respiratory Disease: A Population-Based Study in the United States, 1999-2023","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-10 14:36:52","doi":"10.21203/rs.3.rs-7647383/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2025-10-09T15:31:44+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"58149275820633025598251331581744583030","date":"2025-10-01T13:32:51+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"116826804474388835581944617854306395788","date":"2025-09-28T03:18:22+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-09-26T02:56:26+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-09-25T07:27:50+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-23T08:15:08+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-09-23T08:14:07+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Public Health","date":"2025-09-18T08:41:13+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-public-health","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pubh","sideBox":"Learn more about [BMC Public Health](http://bmcpublichealth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/pubh/default.aspx","title":"BMC Public Health","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"90921373-8cea-4c77-9e08-ac929eb40411","owner":[],"postedDate":"October 10th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-10-10T14:36:52+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-10 14:36:52","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7647383","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7647383","identity":"rs-7647383","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}