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Impact of the COVID-19 pandemic on liver disease-related mortality rates in the United States

  • Author Footnotes
    † These authors contributed equally to the work.
    Xu Gao
    Footnotes
    † These authors contributed equally to the work.
    Affiliations
    Division of Gastroenterology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, PR China

    Department of Infectious Diseases, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, PR China
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  • Author Footnotes
    † These authors contributed equally to the work.
    Fan Lv
    Footnotes
    † These authors contributed equally to the work.
    Affiliations
    School of Mathematics and Statistics, Xi’an Jiaotong University, Xi’an, PR China
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  • Xinyuan He
    Affiliations
    Department of Infectious Diseases, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, PR China
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  • Yunyu Zhao
    Affiliations
    Department of Infectious Diseases, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, PR China
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  • Yi Liu
    Affiliations
    Department of Infectious Diseases, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, PR China
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  • Jian Zu
    Correspondence
    Corresponding authors. Addresses: School of Mathematics and Statistics, Xi’an Jiaotong University, Xi’an, Shaanxi, 710049, PR China.
    Affiliations
    School of Mathematics and Statistics, Xi’an Jiaotong University, Xi’an, PR China
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  • Linda Henry
    Affiliations
    Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, CA, USA
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  • Jinhai Wang
    Affiliations
    Division of Gastroenterology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, PR China
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  • Yee Hui Yeo
    Affiliations
    Division of General Internal Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
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  • Fanpu Ji
    Correspondence
    Department of Infectious Diseases, The Second Affiliated Hospital of Xian Jiaotong University, No. 157 Xi Wu Road, Xi'an 710004, Shaanxi Province, PR China
    Affiliations
    Department of Infectious Diseases, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, PR China

    National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, PR China

    Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, PR China

    Key Laboratory of Environment and Genes Related to Diseases, Xi’an Jiaotong University, Ministry of Education of China, Xi’an, PR China
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  • Mindie H. Nguyen
    Correspondence
    Division of Gastroenterology and Hepatology, Stanford University Medical Center, 750 Welch Road, Suite 210, Palo Alto, CA 94304, USA.
    Affiliations
    Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, CA, USA

    Department of Epidemiology and Population Health, Stanford University Medical Center, Palo Alto, CA, USA
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  • Author Footnotes
    † These authors contributed equally to the work.
Published:August 17, 2022DOI:https://doi.org/10.1016/j.jhep.2022.07.028

      Highlights

      • All-cause ASMR for ALD increased several fold between 2010–2019 and 2020-2021 (APC 3.5% to 17.6%, p <0.01).
      • For NAFLD, all-cause ASMRs also rose steadily across the entire study period but with a sharper rise after 2019.
      • ASMR rise for ALD and NAFLD was particularly severe for the 25–44 years age group.
      • ASMR rise for ALD was also most pronounced in non-Hispanic Alaska Indians/Native American and White people.

      Background & Aims

      The pandemic has resulted in an increase of deaths not directly related to COVID-19 infection. We aimed to use a national death dataset to determine the impact of the pandemic on people with liver disease in the USA, focusing on alcohol-associated liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD).

      Methods

      Using data from the National Vital Statistic System from the Center for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research (CDC WONDER) platform and ICD-10 codes, we identified deaths associated with liver disease. We evaluated observed vs. predicted mortality for 2020–2021 based on trends from 2010–2019 with joinpoint and prediction modelling analysis.

      Results

      Among 626,090 chronic liver disease-related deaths between 2010 and 2021, Age-standardised mortality rates (ASMRs) for ALD dramatically increased between 2010–2019 and 2020–2021 (annual percentage change [APC] 3.5% to 17.6%, p <0.01), leading to a higher observed ASMR (per 100,000 persons) than predicted for 2020 (15.67 vs. 13.04) and 2021 (17.42 vs. 13.41). ASMR for NAFLD also increased during the pandemic (APC: 14.5%), whereas the rates for hepatitis B and C decreased. Notably, the ASMR rise for ALD was most pronounced in non-Hispanic Whites, Blacks, and Alaska Indians/Native Americans (APC: 11.7%, 10.8%, 18.0%, all p <0.05), with similar but less critical findings for NAFLD, whereas rates were steady for non-Hispanic Asians throughout 2010–2021 (APC: 4.9%). The ASMR rise for ALD was particularly severe for the 25–44 age group (APC: 34.6%, vs. 13.7% and 12.6% for 45–64 and ≥65, all p <0.01), which were also all higher than pre-COVID-19 rates (all p <0.01).

      Conclusions

      ASMRs for ALD and NAFLD increased at an alarming rate during the COVID-19 pandemic with the largest disparities among the young, non-Hispanic White, and Alaska Indian/Native American populations.

      Impact and implications

      The pandemic has led to an increase of deaths directly and indirectly related to SARS-CoV-2 infection. As shown in this study, age-standardised mortality rates for alcohol-associated liver disease and non-alcoholic fatty liver disease substantially increased during the COVID-19 pandemic in the USA and far exceeded expected levels predicted from past trends, especially among the young, non-Hispanic White, and Alaska Indian/Native American populations. However, much of this increase was not directly related to COVID-19. Therefore, for the ongoing pandemic as well as its recovery phase, adherence to regular monitoring and care for people with chronic liver disease should be prioritised and awareness should be raised among patients, care providers, healthcare systems, and public health policy makers.

      Graphical abstract

      Keywords

      Linked Article

      • Comment on: Impact of the COVID-19 pandemic on liver disease-related mortality rates in the United States
        Journal of Hepatology
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          We read with great interest the article by Gao et al. 1, who used a national death dataset to determine the impact of the COVID-19 pandemic on people with liver disease in the USA. Finally, they found that age-standardised mortality rates for alcohol-associated liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) increased at an alarming rate during the COVID-19 pandemic. Hospitalization for ALD is also on the rise during the COVID-19 pandemic due to increased alcohol consumption. We conducted a relevant analysis in support of this view to confirm it (Fig.
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      Introduction

      Chronic liver disease (CLD) can lead to cirrhosis, which is the 11th most common cause of death globally according to a recent report in 2019.
      • Asrani S.K.
      • Devarbhavi H.
      • Eaton J.
      • Kamath P.S.
      Burden of liver diseases in the world.
      ,
      • Heron M.
      Deaths: leading causes for 2017.
      In the United States, the incidence of cirrhosis has been increasing steadily with rising mortality, hospitalisation, and costs over the past decades.
      • Kim D.
      • Li A.A.
      • Gadiparthi C.
      • Khan M.A.
      • Cholankeril G.
      • Glenn J.S.
      • et al.
      Changing trends in etiology-based annual mortality from chronic liver disease, from 2007 through 2016.
      • Tapper E.B.
      • Parikh N.D.
      Mortality due to cirrhosis and liver cancer in the United States, 1999–2016: observational study.
      • Zou B.
      • Yeo Y.H.
      • Jeong D.
      • Park H.
      • Sheen E.
      • Lee D.H.
      • et al.
      A nationwide study of inpatient admissions, mortality, and costs for patients with cirrhosis from 2005 to 2015 in the USA.
      Although highly effective treatment has been available for hepatitis B since 2005 and for hepatitis C virus since 2015, none are currently available for alcohol-associated liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) resulting in increasing burden and mortality for ALD and NAFLD.
      • Kim D.
      • Li A.A.
      • Gadiparthi C.
      • Khan M.A.
      • Cholankeril G.
      • Glenn J.S.
      • et al.
      Changing trends in etiology-based annual mortality from chronic liver disease, from 2007 through 2016.
      ,
      • Zou B.
      • Yeo Y.H.
      • Jeong D.
      • Park H.
      • Sheen E.
      • Lee D.H.
      • et al.
      A nationwide study of inpatient admissions, mortality, and costs for patients with cirrhosis from 2005 to 2015 in the USA.
      ,
      • Harrison S.A.
      • Gawrieh S.
      • Roberts K.
      • Lisanti C.J.
      • Schwope R.B.
      • Cebe K.M.
      • et al.
      Prospective evaluation of the prevalence of non-alcoholic fatty liver disease and steatohepatitis in a large middle-aged US cohort.
      In March of 2020, the World Health Organization declared the world was experiencing a pandemic as the result of SARS-CoV-2 infection, adeptly named, the COVID-19 pandemic. To date, this pandemic has had a dramatic and broad impact on both the physical and mental health of people. A nationwide USA survey demonstrated a 14% increase in alcohol consumption in 2020 compared with 2019.
      • Pollard M.S.
      • Tucker J.S.
      • Green Jr., H.D.
      Changes in adult alcohol use and consequences during the COVID-19 pandemic in the US.
      ,
      • Weerakoon S.M.
      • Jetelina K.K.
      • Knell G.
      Longer time spent at home during COVID-19 pandemic is associated with binge drinking among US adults.
      Recent studies also showed that ALD was an independent risk factor for death from COVID-19. In fact, individuals with ALD now constitute the majority of those listed for liver transplantation,
      • Cholankeril G.
      • Goli K.
      • Rana A.
      • Hernaez R.
      • Podboy A.
      • Jalal P.
      • et al.
      Impact of COVID-19 pandemic on liver transplantation and alcohol-associated liver disease in the USA.
      ,
      • Marjot T.
      • Moon A.M.
      • Cook J.A.
      • Abd-Elsalam S.
      • Aloman C.
      • Armstrong M.J.
      • et al.
      Outcomes following SARS-CoV-2 infection in patients with chronic liver disease: an international registry study.
      with waiting-list mortality also increasing with the current pandemic.
      • Phipps M.M.
      • Verna E.C.
      Coronavirus disease 2019 and liver transplantation: lessons from the first year of the pandemic.
      COVID-19 itself is associated with a 3.5-fold increase in mortality in individuals with known cirrhosis compared with those without cirrhosis, while cirrhosis contributes an additional 70% higher risk of death among those with COVID-19.
      • Ioannou G.N.
      • Liang P.S.
      • Locke E.
      • Green P.
      • Berry K.
      • O’Hare A.M.
      • et al.
      Cirrhosis and severe acute respiratory syndrome coronavirus 2 infection in us veterans: risk of infection, hospitalization, ventilation, and mortality.
      ,
      • Mallet V.
      • Beeker N.
      • Bouam S.
      • Sogni P.
      • Pol S.
      Demosthenes Research Group
      Prognosis of French COVID-19 patients with chronic liver disease: a national retrospective cohort study for 2020.
      The COVID-19 pandemic has also shattered the many care processes by which we deliver quality care for individuals with cirrhosis. Liver clinic visits, hepatocellular carcinoma surveillance, and diagnostic abdominal imaging have all fallen dramatically as social distancing measures were instituted in 2020.
      • Tapper E.B.
      • Asrani S.K.
      The COVID-19 pandemic will have a long-lasting impact on the quality of cirrhosis care.
      ,
      • Toyoda H.
      • Huang D.Q.
      • Le M.H.
      • Nguyen M.H.
      Liver care and surveillance: the global impact of the COVID-19 pandemic.
      Additionally, limited access to primary care provider and mental health services has exacerbated the rise in prevalence and severity of alcohol use disorders as well as other CLDs,
      • Mallet V.
      • Beeker N.
      • Bouam S.
      • Sogni P.
      • Pol S.
      Demosthenes Research Group
      Prognosis of French COVID-19 patients with chronic liver disease: a national retrospective cohort study for 2020.
      especially NAFLD as these individuals tend to have multiple comorbidities, predisposing them to higher risk of care disruption, morbidity, and mortality during the pandemic.
      Nationally representative data to guide the optimal allocation of resources and preventive efforts for the most affected populations during the COVID-19 pandemic are limited. Therefore, the aims of this population-based study were to examine the temporal trends and COVID-19 pandemic impact on mortality rates of people with CLD in the USA from January 1, 2010 to December 31, 2021, with a special focus on ALD and NAFLD, the 2 populations likely to be most affected by the pandemic. We also aimed to investigate potential age, sex, and race and ethnicity-related disparities in mortality among people with CLD.

      Patients and Methods

      Study design and study population

      Data were obtained from the National Vital Statistics System (NVSS) dataset through the Center for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research (CDC WONDER) website. This database collected annual death data of >99% of decedents in 50 USA states and the District of Columbia. The data were updated through December 31, 2021. Each record within the database represents the death data of 1 decedent. Demographic data including age, sex, race and ethnicity, and cause of death (all-cause and liver-related) were obtained.
      Institutional review board approval was not sought as all data from NVSS are publicly available and completely de-identified. The study is compliant with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines.

      Inclusion and exclusion criteria

      We included data on deaths associated with a CLD among USA adults aged ≥25 years from January 1, 2010 to December 31, 2021. However, analyses involving race/ethnicity were only up to the end of 2020 because the CDC modified the race/ethnicity categories in 2021 to include a new category of ‘multiple-race’ people, making the 2021 race/ethnicity data not compatible with data from 2020 and before. All causes of death were recorded using the 10th edition of the International Classification of Diseases (ICD-10). For the purpose of this study, CLD included HCV infection (B17.1, B18.2), HBV infection (B16, B17.0, B18.0, B18.1), ALD (K70), and NAFLD (K75.8, K76.0).

      Statistical analysis

      Demographic characteristics of decedents with CLD were presented as frequencies with percentages. The crude mortality rate (per 100,000 persons) was computed by dividing the number of deaths of each CLD by the total USA population of the corresponding year. Age-standardised mortality rates (ASMRs, per 100,000 persons) were developed using the age structure (25–85+ years) from the 2000 USA Census Standard Population and the direct standardisation method (by multiplying the age-specific mortality rates of the study population to the number of persons in each age group of the standard population).
      First, to determine the nationwide trend of mortality in people with CLD, we conducted joinpoint regression analysis (a piecewise linear regression that utilises the grid search method).
      • Kim H.J.
      • Fay M.P.
      • Feuer E.J.
      • Midthune D.N.
      Permutation tests for joinpoint regression with applications to cancer rates.
      We then used this method combined with the Monte Carlo Permutation test to determine whether the overall trend was best depicted by one or more segments to determine the annual percentage change (APC) with 95% CI of each segment and their associated p values. The positivity/negativity and magnitude of APCs denote the direction and steepness of trends. To compare APCs among the subgroups during the pandemic, we set the subgroup with the lowest APC as reference and analysed the difference between each subgroup to the referent subgroup by permutation test and pairwise comparison.
      • Kim H.J.
      • Fay M.P.
      • Feuer E.J.
      • Midthune D.N.
      Permutation tests for joinpoint regression with applications to cancer rates.
      Next, to determine the predicted mortality rates in 2020 and 2021 based on the mortality rates from 2010 to 2019 to compare with observed rates, we performed predictive analysis using constructed linear regression models between the study years and ASMR. The changing trends of ASMR during 2010–2019 were fitted to the model to predict mortality rates in 2020 and 2021 for ALD, NAFLD, and HBV. For HCV, the changing trend of ASMR was fitted with 2016–2019 data to coincide with the availability of direct antiviral agents in 2015. The predicted value was compared with the observed value and assessed whether the observed value falls within the 95% CI of the fitting model. Linear regression coefficients and 95% CI were calculated with the ordinary least squares method.
      Additionally, we performed subgroup analyses by using the following preplanned groups: age (25–44, 45–64, and ≥65 years), sex (male and female), race and ethnicity (Hispanic, non-Hispanic Whites, non-Hispanic Blacks, non-Hispanic Asians (including Pacific Islanders), and non-Hispanic American Indian/Alaska Natives). We elected to perform subgroup analysis by age, sex, and race/ethnicity, as these factors may be clinically meaningful and have been reported to associate with mortality for many conditions including liver disease.
      • Andrasfay T.
      • Goldman N.
      Reductions in 2020 US life expectancy due to COVID-19 and the disproportionate impact on the Black and Latino populations.
      • Islam N.
      • Shkolnikov V.M.
      • Acosta R.J.
      • Klimkin I.
      • Kawachi I.
      • Irizarry R.A.
      • et al.
      Excess deaths associated with covid-19 pandemic in 2020: age and sex disaggregated time series analysis in 29 high income countries.
      • Bassett M.T.
      • Chen J.T.
      • Krieger N.
      Variation in racial/ethnic disparities in COVID-19 mortality by age in the United States: a cross-sectional study.
      Subgroups with ≤20 deaths may produce unreliable estimates for mortality rates and were excluded.
      All-cause mortality is defined as mortality of any cause – liver related or non-liver related. Liver-related mortality is defined as mortality caused by liver complications as the primary underlying cause of death. We calculated the ASMR of all-cause mortality and liver-related mortality for the overall analysis. For subgroup analysis of ASMR, calculations were based on all-cause mortality as all-cause mortality can better reflect the overall health and vital status of people. This is especially relevant in this setting when many downstream effects on disease and health were expected with the COVID-19 pandemic, which has brought on much economic and social change that can lead to both liver and non-liver consequences for people with CLD. All calculations were performed using the National Cancer Institute’s joinpoint regression (Joinpoint Trend Analysis Software version 4.9.0.0; National Cancer Institute, Bethesda, MD), R 4.0.2 statistical software (R Foundation for Statistical Computing, Vienna, Austria), and PyCharm 3.9.0. A 2-sided p value with the threshold of significance at 0.05 was used.

      Results

      Decedent population and characteristics

      A total of 626,090 deaths among adults aged 25 years and older with CLD were documented from 2010 to 2021. ALD was the most common, accounting for 55% of deaths, followed by HCV (33%), NAFLD (9%), and HBV (3%) (Table S1). Although the majority of decedents with ALD were male (71%) or between 45 and 64 years of age (62%) at the time of death, the majority of those with NAFLD were females (55%) or ≥65 years old (52%). The majority of decedents with HCV or HBV were male (71–73%) and in the middle age group (53–66%). Decendents with ALD or NAFLD were overwhelmingly non-Hispanic Whites (71% and 80%) followed by Hispanics (16% and 11%), respectively. Although non-Hispanic Blacks and Asians only made up 8% and 1% of decedents with ALD, 5% and 2% for NAFLD, they made up 18% and 2% of decedents with HCV and 19% and 26% for HBV, respectively.
      There was significant heterogeneity in the distribution of mortality among the states, with also some shifting in the density of mortality before and during the pandemic (Fig. 1A and B). States including Alaska, Montana, Wyoming, Colorado, New Mexico, and South Dakota experienced the highest ALD-related deaths during the COVID-19 pandemic (Fig. 1A). Oklahoma, Indiana, Kentucky, Tennessee, and West Virginia experienced the highest NAFLD-related deaths in 2020–2021 (Fig. 1B). State-level ASMR data for ALD and NAFLD from 2019 to 2021 are provided in Fig. S1.
      Figure thumbnail gr1
      Fig. 1All-cause age-standardised mortality rate by states in United States adults with ALD and NAFLD during the pandemic.
      ALD, alcohol associated liver disease; NAFLD, non-alcoholic fatty liver disease.

      Impact of COVID-19 pandemic on ASMR for CLD

      Overall analysis for all-cause and liver-related ASMR

      All-cause ASMR (per 100,000) for ALD increased from 9.49 in 2010 to 17.42 in 2021 yielding an average APC of 5.9% for 2010–2021 (95% CI 5.1–6.7) (Table 1 upper panel and Fig. 2A). However, on trend segment analysis, we found accelerated APC from 3.5% (95% CI 3.0–3.9) for 2010–2019 to 17.6% (95% CI 12.2–23.2) for 2019–2021. As a result, the observed ASMRs of 15.67 for ALD in 2020 and 17.42 in 2021 were much higher than the predicted values of 13.04 (95% CI 12.65–13.43) for 2020 and 13.41 (95% CI 13.0–13.82) for 2021 (Fig. 2C and D).
      Table 1ASMR and APC in mortality in United States adults with liver disease, by liver disease aetiology for all-cause mortality and liver-related mortality, 2010–2021.
      Deaths (age-standardised rate per 100,000)Average APC (95% CI)Trend segmentp value
      2010 (Pre-pandemic referent epoch)2020 (Pandemic epoch 1)2021 (Pandemic epoch 2)2010–2021YearAPC (95% CI)
      All-cause mortality
      ALD20,983 (9.49)38,603 (15.67)42,666 (17.42)5.9 (5.1–6.7)2010–2019

      2019–2021
      3.5 (3.0–3.9)

      17.6 (12.2–23.2)
      <0.001

      <0.001
      NAFLD2,367 (1.1)8,145 (3.11)8,940 (3.44)10.7 (8.2–13.3)2010–2014

      2014–2019

      2019–2021
      7.6 (3.5–11.9)

      11.8 (7.5–16.2)

      14.5 (1.1–29.6)
      0.007

      0.001

      0.039
      HCV16,520 (7.14)14,733 (5.28)13,654 (4.92)-3.3 (-4.0 to -2.5)2010–2014

      2014–2019

      2019–2021
      2.5 (1.1–3.8)

      -7.8 (-9.0 to -6.6)

      -2.8 (-6.8 to 1.4)
      0.007

      <0.001

      0.138
      HBV1,777 (0.8)1,738 (0.69)1,725 (0.67)-1.9 (-2.6 to -1.2)2010–2021-1.9 (-2.6 to -1.2)<0.001
      Liver-related mortality
      ALD15,905 (7.22)29,399 (12.1)32,756 (13.53)6.1 (5.2–7.1)2010–2019

      2019–2021
      3.7 (3.2–4.2)

      17.8 (11.4–24.6)
      <0.001

      <0.001
      NAFLD987 (0.46)3,852 (1.41)4,251 (1.57)12.0 (10.4–13.7)2010–2018

      2018–2021
      12.6 (11.3–14.0)

      10.3 (4.3–16.7)
      <0.001

      0.004
      HCV6,807 (2.96)3,227 (1.19)2,838 (1.02)-9.2 (-9.9 to -8.4)2010–2014

      2014–2019

      2019–2021
      0.1 (-1.3 to 1.5)

      -15.1 (-16.3 to -13.9)

      -11.4 (-15.2 to -7.4)
      0.882

      <0.001

      0.002
      HBV585 (0.24)410 (0.17)408 (0.18)-3.8 (-4.9 to -2.7)2010–2021-3.8 (-4.9 to -2.7)<0.001
      The temporal trend analysis was performed using joinpoint analysis. APCs and p values were estimated using the Monte Carlo permutation test.
      ALD, alcohol-associated liver disease; APC, annual percentage change; ASMR, age-standardised mortality rate; NAFLD, non-alcoholic fatty liver disease.
      Figure thumbnail gr2
      Fig. 2Age-standardised mortality rates for liver disease in the United States in 2010–2021 by liver disease aetiology, with comparisons between observed (blue dot) vs. predicted (blue arrow) mortality for 2020–2021 based on 2010–2019 trends for each liver disease aetiology.
      The prediction of mortality rates in 2020 and 2021 were performed using linear regression using ordinary least squares according to the mortality rates in 2012-2019. ALD, alcohol associated liver disease; NAFLD, non-alcoholic fatty liver disease; OLS, ordinary least squares.
      For NAFLD, all-cause ASMR also rose steadily across the entire study period but with sharper rise after 2019, yielding an APC of 14.5% (95% CI 1.1–29.6) during pandemic (Table 1 upper panel and Fig. 2A). Similar to ALD, the observed ASMR of 3.11 in 2020 to 3.44 in 2021 were both higher than the predicted rates of 2.64 (95% CI 2.33–2.95) in 2020 and 2.80 (95% CI 2.48–3.13) in 2021 (Fig. 2E). As shown in Fig. 3, we also found consistent changes when we analysed the observed vs. predicted monthly mortality from January 2018 to December 2021 based on trends from 2010 to 2017 monthly with prediction modelling analysis for all-cause and liver-related mortality in both ALD and NAFLD.
      Figure thumbnail gr3
      Fig. 3Age-standardised mortality for ALD and NAFLD in the United States in 2018–2021 by month.
      (A) All-cause mortality for ALD, (B) liver-related mortality for ALD, (C) all-cause mortality for NAFLD, (D) liver-related mortality for NAFLD. The prediction of mortality rates in 2020 and 2021 were performed using linear regression using ordinary least squares according to the mortality rates in 2012–2019. Pairwise comparison between trends was performed to assess the difference between observed and predicted mortality. ALD, alcohol-associated liver disease; NAFLD, non-alcoholic fatty liver disease.
      In contrast, the all-cause ASMR trend for viral hepatitis was either stable or declining (Table 1 upper panel and Fig. 2A). For HBV, ASMR decreased from 2010 to 2021 at an average APC of -1.9% (95% CI, -2.6 to -1.2, p <0.01) and without significant segmental variation. For HCV, the ASMR increased from 2010 to 2014 then decreased from 2014 onwards, yielding APC percentages of -7.8% for 2014–2019 (95% CI -9.0 to -6.6) but this decreasing trend slowed down by almost 3-fold at -2.8% for 2019–2021 (95% CI -6.8 to 1.4). However, the observed ASMRs for 2020 and 2021 were still higher than predicted levels for HCV (5.28 vs. 4.58 for 2020, 4.92 vs. 4.02 for 2021) (Fig. 2G).
      Data for liver-related ASMRs followed similar trends for all liver aetiologies (Table 1 lower panel and Fig. 2B), with an even more dramatic decline in liver-related ASMRs for viral hepatitis in more recent years.

      Subgroup analysis for all-cause ASMR

      By race and ethnicity

      As shown in Table S2 and Fig. 4A and B, all-cause ASMR for ALD and NAFLD increased steadily across all races and ethnicities during the study period, but the most dramatic APC rise was for ALD and during 2018–2020 in non-Hispanic American Indians/Alaska Natives (18.0%, 95% CI 6.1–31.4, p <0.05) followed by non-Hispanic Whites (11.7%, 95% CI 6.9–16.6, p <0.01), and non-Hispanic Blacks (10.8%, 95% CI 1.8–20.7, p <0.05), with a much more modest rise during the same time period in non-Hispanic Asians (APC 4.9%). For NAFLD, the racial ethnic groups with the steepest all-cause ASMR rise during the pandemic with APCs of 11.9%,11.9%, 12.9%, 13.1% and 10.9% in non-Hispanic Whites, non-Hispanic Blacks, non-Hispanic Asians, Hispanics and American Indians/Alaska Natives, respectively. As a result, the observed ASMRs in 2020 were much higher than rates predicted from 2010 to 2019 trends for both ALD and NAFLD for all race and ethnicities (Fig. 4CC–L). The observed vs. predicted ASMRs for ALD in 2020 were 88.42 vs. 63.72 for non-Hispanic American Indians/Alaska Natives, 16.52 vs. 13.75 non-Hispanic Whites, and 10.30 vs. 8.62 for non-Hispanic Blacks, respectively. For NAFLD, the observed vs. predicted ASMRs in 2020 were 8.31 vs. 6.15 for non-Hispanic American Indians/Alaska Natives, 3.44 vs. 2.97 non-Hispanic Whites, and 1.34 vs. 1.03 for non-Hispanic Blacks, respectively. With the Hispanics group with the lowest APC as a reference, the APC of all-cause mortality and liver-related mortality for non-Hispanic White and Alaska Indian/Native American populations trends were higher but without statistically meaningful in ALD (Table S3). However, there was a 6.3 times increased APC in non-Hispanic White in NAFLD, compared with that in non-Hispanic Blacks (Table S4). The effect of the COVID-19 pandemic on NAFLD and mortality in Hispanic and non-Hispanic Asians were relatively small.
      Figure thumbnail gr4
      Fig. 4All-cause age-standardised mortality for ALD and NAFLD in the United States in 2010–2020 by race and ethnicity, with comparisons between observed (blue dot) vs. predicted (black arrow) mortality for 2020 based on 2010–2019 trend for each race and ethnicity.
      The prediction of mortality rates in 2020 and 2021 were performed using linear regression using OLS according to the mortality rates in 2012–2019. ALD, alcohol-associated liver disease; NAFLD, non-alcoholic fatty liver disease; non-Hispanic AI/AN, non-Hispanic American Indian/Alaska Native; OLS, ordinary least squares.
      For HCV and HBV, the effect of the COVID-19 pandemic on mortality was fairly consistent across the different racial ethnic groups (Table S2 and Fig. S2).

      By age group

      Subgroup analysis by age found significant ASMR rise throughout the entire study period 2010–2021 among the youngest group (25–44 years) for ALD and among the older groups (45–64 and ≥65 years) for NAFLD; however, significant rise was also observed for ALD for the older groups since 2019 and for the youngest group with NAFLD since 2019 (Table 2 and Fig. 5A and B). As a result, the 2019–2021 A PCs for ASMR in ALD showed a significant increase for all age groups with the highest change (34.6%) for the youngest group aged 25–44 years for ALD (vs. 13.7% and 12.6% for 45–64 and ≥65 years age groups, respectively, all p <0.01), which were also all higher than pre-COVID-19 rates (all p <0.05).
      Table 2All-cause ASMR and APC in mortality in U.S. adults with liver disease, by liver disease aetiology and by age, 2010–2021.
      AgeDeaths (age-standardised rate per 100,000)Average APC (95% CI)Trend segmentp value
      2010 (Pre-pandemic referent epoch)2020 (Pandemic epoch 1)2021 (Pandemic epoch 2)2010–2021YearAPC (95% CI)
      ALD
      25–442,656 (3.44)6,358 (7.69)7,367 (8.96)10.2 (8.2–12.2)2010–2019

      2019–2021
      5.3 (4.3–6.4)

      34.6 (20.5–50.5)
      <0.001

      <0.001
      45–6414,227 (17.23)21,945 (25.18)23,980 (27.60)4.3 (3.8–4.8)2010–2019

      2019–2021
      2.3 (1.8–2.9)

      13.7 (7.3–20.5)
      <0.001

      0.001
      ≥654,100 (10.15)10,300 (17.81)11,319 (19.48)6.5 (5.1–7.9)2010–2019

      2019–2021
      5.2 (4.5–6.0)

      12.6 (3.9–22.0)
      <0.001

      0.010
      NAFLD
      25–44453 (0.57)720 (0.83)840 (1.04)5.5 (1.8–9.3)2010–2019

      2019–2021
      1.0 (-1.0 to 3.0)

      28.1 (3.0–59.4)
      0.275

      0.032
      45–641,158 (1.36)2,622 (2.95)2,848 (3.19)7.4 (6.1–8.8)2010–20217.4 (6.1–8.8)<0.001
      ≥65756 (1.91)4,803 (8.78)5,252 (9.58)16.0 (14.2–17.9)2010–2019

      2019–2021
      16.9 (15.9–18.0)

      12.0 (1.5–23.6)
      <0.001

      0.029
      HCV
      25–44810 (1.06)753 (0.94)737 (0.95)-0.5 (-3.2 to 2.3)2010–2019

      2019–2021
      -2.9 (-4.3 to -1.3)

      11.0 (-6.3 to 31.5)
      0.003

      0.188
      45–6412,532 (14.86)7,556 (7.89)6,675 (7.00)-6.7 (-7.5 to -5.8)2010–2014

      2014–2019

      2019–2021
      1.6 (-0.1 to 3.3)

      -11.8 (-13.3 to -10.4)

      -9.1 (-13.7 to -4.3)
      0.053

      <0.001

      0.007
      ≥653,178 (7.91)6,424 (10.93)6,242 (10.63)3.0 (1.7–4.3)2010–2015

      2015–2019

      2019–2021
      6.6 (5.0–8.2)

      -1.9 (-5.1 to 1.4)

      4.1 (-2.6 to 11.2)
      <0.001

      0.182

      0.167
      HBV
      25–44184 (0.21)138 (0.21)150 (0.21)-0.4 (-1.5 to 0.8)2010–2021-0.4 (-1.5 to 0.8)0.495
      45–641,050 (1.28)749 (0.86)741 (0.80)-4.2 (-5.6 to -2.8)2010–2013

      2013–2021
      -0.4 (-5.9 to 5.3)

      -5.5 (-6.7 to -4.4)
      0.855

      <0.001
      ≥65543 (1.36)851 (1.54)834 (1.52)1.0 (-0.0 to 2.0)2010–20211.0 (-0.0 to 2.0)0.056
      The temporal trend analysis was performed using joinpoint analysis. APCs and p values were estimated using the Monte Carlo permutation test.
      ALD, alcohol-associated liver disease; APC, annual percentage change; ASMR, age-standardised mortality rate; NAFLD, non-alcoholic fatty liver disease.
      Figure thumbnail gr5
      Fig. 5All-cause age-standardised mortality for ALD and NAFLD in the United States in 2010–2021 by age group, with comparisons between observed (blue dot) vs. predicted (black arrow) mortality for 2020–2021 based on 2010–2019 trends for each age group.
      The prediction of mortality rates in 2020 and 2021 were performed using linear regression using OLS according to the mortality rates in 2012–2019. ALD, alcohol-associated liver disease; NAFLD, non-alcoholic fatty liver disease; non-Hispanic AI/AN, non-Hispanic American Indian/Alaska Native; OLS, ordinary least squares.
      For NAFLD, although a significant change in trend was observed mainly for the youngest group (2019–2021 APC 28.1%), the older groups have had steady rise since 2010 with the ≥65 years age group having the highest ASMR change (2010–2021 average APC 16.0, 95% CI 14.2–17.9, p <0.05) (Table 2). There were also differences by age for HCV and HBV, with significant decline observed mainly for the 45–64 years age group since 2013 for HBV and since 2014 for HCV (Table 2).
      When used the older group (aged ≥65 years) as a reference, the APC of all-cause mortality and liver-related mortality in the young group (aged 25–44 years) saw a 17.1 and 16.9 times difference in ALD (Table S5); and 12.1 times increased APC of all-cause mortality in NAFLD (Table S6 upper panel).
      In addition, we found the observed all-cause ASMRs to be significantly higher than predicted levels for all age groups for both ALD and NAFLD (Fig. 5C–H). For ALD, the observed vs. predicted all-cause ASMRs were 7.69 vs. 5.26, 25.18 vs. 21.86, and 17.81. vs. 15.91 for age groups 25–44, 45–64, and ≥65 years for 2020, and 8.96 vs. 5.47, 27.60 vs. 22.29, and 19.48 vs. 16.54 for 2021. Meanwhile, although the overall impact of COVID-19 pandemic on the ASMR for viral hepatitis was relatively mild, the observed ASMRs were still higher than predicted for the 45–64 years age group for HCV (7.89 vs. 6.76 in 2020, 7.00 vs. 5.26 in 2021) and the ≥65 years age group for HBV (1.54 vs. 1.33 in 2020, 1.52 vs. 1.33 in 2021) (Table 2 and Fig. S3A–H).

      By sex

      The sharp rise during the 2019–2021 period was observed for both males and females for ALD (2019–2021 APC 16.7% for males, 19.1% for females, both p <0.01), whereas the ASMR increase was steady throughout the whole study period 2010–2021 for both sexes for NAFLD, and there was no significant increase for HCV and HBV (Table S7). As a result, for ALD, the observed ASMRs were significantly higher than expected for both males (22.30 vs. 18.85 in 2020, 24.92 vs. 19.31 in 2021) and females (9.58 vs. 7.74 in 2020, 10.52 vs. 8.01 in 2021) (Fig. S4). Similarly, for NAFLD, the observed ASMR was higher than predicted for males (3.02 vs. 2.52 in 2020, 3.29 vs. 2.67 in 2021) and females (3.16 vs. 2.71 in 2020, 3.56 vs. 2.88 in 2021). Furthermore, we found consistent sharp rise with the highest APC in 2019–2021 compared with earlier time periods in all age groups in both males and females for ALD (Table 3).
      Table 3All-cause age- and sex-standardised mortality rate and APC in mortality in United States adults with ALD, by age, 2010–2021.
      ALDDeaths (age-standardised rate per 100,000)Average APC (95% CI)Trend segmentp value
      2010 (Pre-pandemic referent epoch)2020 (Pandemic epoch 1)2021 (Pandemic epoch 2)2010–2021YearAPC (95% CI)
      Female
      25–44884 (2.26)2,305 (5.60)2,630 (6.43)10.9 (8.1–13.7)2010–2019

      2019–2021
      6.7 (5.2–8.3)

      31.5 (12.5–53.8)
      <0.001

      0.004
      45–643,802 (9.12)6,853 (15.63)7,416 (16.80)5.7 (4.2–7.2)2010–2019

      2019–2021
      3.9 (3.0–4.7)

      14.2 (4.6–24.7)
      <0.001

      0.009
      ≥65981 (4.40)2,632 (8.34)2,899 (9.16)7.7 (5.6–9.8)2010–2019

      2019–2021
      5.5 (4.3–6.6)

      18.3 (4.9–33.4)
      <0.001

      0.013
      Male
      25–441,772 (4.61)4,053 (9.84)4,737 (11.55)9.3 (8.1–10.6)2010–2014

      2014–2019

      2019–2021
      2.3 (0.4–4.3)

      6.2 (4.2–8.2)

      34.4 (26.4–42.8)
      0.030

      0.001

      <0.001
      45–6410,425 (25.81)15,092 (35.14)16,564 (38.85)3.7 (2.8–4.6)2010–2019

      2019–2021
      1.7 (1.2–2.2)

      13.3 (7.4–19.5)
      <0.001

      0.001
      ≥653,119 (17.32)7,668 (29.14)8,420 (31.98)5.8 (4.3–7.2)2010–2012

      2012–2019

      2019–2021
      2.4 (-4.5 to 9.9)

      5.5 (4.2–6.7)

      10.2 (2.7–18.2)
      0.395

      <0.001

      0.018
      The temporal trend analysis was performed using joinpoint analysis. APCs and p values were estimated using the Monte Carlo permutation test.
      ALD, alcohol-associated liver disease; APC, annual percentage change.

      Discussion

      In this study, we assessed the temporal trends of mortality for 4 major CLDs (namely ALD, NAFLD, HCV, and HBV) from 2010 to 2021 to determine the effect of the COVID-19 pandemic on mortality of people with these CLDs. We found alarming rise in both all-cause and liver-related mortality among people with ALD and NAFLD during the 2019–2021 time period that were significantly higher than levels predicted from pre-pandemic trend, whereas the impact on HCV and HBV was fortunately none to mild. Importantly, we also found that the pandemic effect on ALD and NAFLD mortality spans across the sex, age, and racial and ethnic spectrum. However, there were marked disparities.
      For ALD, the most affected groups were the young population (aged 25–44 years), with a 17.1 and 16.9 times increase in APC of all-cause and liver-related mortality compared with older group aged ≥65 years (Table S5), non-Hispanic American Indian/Alaska Natives, and non-Hispanic Whites. In fact, the APC during 2019–2021 was 34.6% for the young population, about 3 times the rate for those ≥45 years of age. The racial disparity was also stark, with the APC during pandemic for non-Hispanic American Indian/Alaska Natives topped at 18.0% (compared with the next group, non-Hispanic Whites at 11.7%), despite lack of statistical significance (Table S3). In 2020, the observed ASMR in American Indian/Alaska Natives with ALD was 40% higher than the pre-pandemic predicted level (89 vs. 64 per 100,000 persons). The disparity was smaller between females (19.1%) and males (16.7%) but notable because ALD historically has affected males more than females. The disparities in ASMRs for NAFLD were less pronounced and affected more of the middle-aged and elderly populations, as well as females and non-Hispanic American Indian/Alaska Natives and Whites more than the other groups. Noteworthy, there was 12.1 times increased APC of all-cause mortality in NAFLD compared with the older group aged ≥65 years (Table S6).
      In addition, for liver-related mortality associated with NAFLD, the time segments were unchanged with a slightly smaller upward trend for the period involving the pandemic. This observation suggested that liver-related mortality contributed a relatively lower proportion of death burden to the overall death burden during the pandemic as compared with non-liver causes. Indeed, cardiovascular deaths are well known to be the most common cause of mortality, and diabetes and cardiovascular deaths have also been reported to increase disproportionately during the pandemic,
      • Liu J.
      • Zhang L.
      • Yan Y.
      • Zhou Y.
      • Yin P.
      • Qi J.
      • et al.
      Excess mortality in Wuhan city and other parts of China during the three months of the covid-19 outbreak: findings from nationwide mortality registries.
      • Magliano D.J.
      • Chen L.
      • Carstensen B.
      • Gregg E.W.
      • Pavkov M.E.
      • Salim A.
      • et al.
      Trends in all-cause mortality among people with diagnosed diabetes in high-income settings: a multicountry analysis of aggregate data.
      • Wadhera R.K.
      • Shen C.
      • Gondi S.
      • Chen S.
      • Kazi D.S.
      • Yeh R.W.
      Cardiovascular deaths during the COVID-19 pandemic in the United States.
      likely attributable to disruption of routine care for related illnesses that normally require intensive monitoring such as diabetes, hypertension, hyperlipidaemia, chronic kidney disease, angina, and congestive heart disease.
      • Islam N.
      • Shkolnikov V.M.
      • Acosta R.J.
      • Klimkin I.
      • Kawachi I.
      • Irizarry R.A.
      • et al.
      Excess deaths associated with covid-19 pandemic in 2020: age and sex disaggregated time series analysis in 29 high income countries.
      ,
      • Bassett M.T.
      • Chen J.T.
      • Krieger N.
      Variation in racial/ethnic disparities in COVID-19 mortality by age in the United States: a cross-sectional study.
      ,
      • Bhaskaran K.
      • Bacon S.
      • Evans S.J.
      • Bates C.J.
      • Rentsch C.T.
      • MacKenna B.
      • et al.
      Factors associated with deaths due to COVID-19 versus other causes: population-based cohort analysis of UK primary care data and linked national death registrations within the OpenSAFELY platform.
      In addition, individuals with NAFLD are frequently obese, and obese individuals are known to have higher risk of cancer in general. Thus, delay in cancer diagnosis and treatment during the pandemic may also increase the death burden by cancer causes in this population.
      • Bhaskaran K.
      • Bacon S.
      • Evans S.J.
      • Bates C.J.
      • Rentsch C.T.
      • MacKenna B.
      • et al.
      Factors associated with deaths due to COVID-19 versus other causes: population-based cohort analysis of UK primary care data and linked national death registrations within the OpenSAFELY platform.
      • Kim N.J.
      • Rozenberg-Ben-Dror K.
      • Jacob D.A.
      • Berry K.
      • Ioannou G.N.
      The COVID-19 pandemic highlights opportunities to improve hepatocellular carcinoma screening and diagnosis in a national health system.
      • Yabroff K.R.
      • Wu X.C.
      • Negoita S.
      • Stevens J.
      • Coyle L.
      • Zhao J.
      • et al.
      Association of the COVID-19 pandemic with patterns of statewide cancer services.
      Factors that could potentially help to explain the increases in ASMRs in general include access to medical care, vulnerability to COVID-19 infection, rate of liver transplant referral, loss of insurance coverage, and severity of the pandemic in local areas. A multinational, multicentre study showed that during the pandemic there was significantly less follow-up care for those with CLD to include less laboratory testing to detect the presence of liver disease, fewer endoscopies for oesophageal varices as well as less hepatocellular carcinoma surveillance for liver cancer.
      • Toyoda H.
      • Huang D.Q.
      • Le M.H.
      • Nguyen M.H.
      Liver care and surveillance: the global impact of the COVID-19 pandemic.
      Another study highlighted the decrease in liver transplantation and the increased waiting-list deaths that have occurred during the pandemic.
      • Phipps M.M.
      • Verna E.C.
      Coronavirus disease 2019 and liver transplantation: lessons from the first year of the pandemic.
      We showed that, although ALD mortality has been increasing in a linear fashion during the past decade, ALD has had a higher mortality increase during the pandemic. This is a distressing finding but not surprising given a recent report on the escalation in alcoholic beverage sales and alcohol use during the COVID-19 pandemic which may be outcomes related to increased depression, mounting stress from economic uncertainty, social isolation, disturbance of inpatient medical resources, deferral of outpatient visit, as well as the closure of resources for alcohol treatment that have occurred during the pandemic.
      • Da B.L.
      • Im G.Y.
      • Schiano T.D.
      Coronavirus disease 2019 hangover: a rising tide of alcohol use disorder and alcohol-associated liver disease.
      Adding to this confluence of factors is a prior study reporting that patients with ALD constituted the majority of the population listed for transplantation during the pandemic, adding to the burden of those already waiting for a transplant given that some transplant centres continue to maintain a mandatory 6-month sobriety for individuals with ALD before liver transplantation.
      • Cholankeril G.
      • Goli K.
      • Rana A.
      • Hernaez R.
      • Podboy A.
      • Jalal P.
      • et al.
      Impact of COVID-19 pandemic on liver transplantation and alcohol-associated liver disease in the USA.
      Meanwhile, the mortality of individuals with viral hepatitis appears to be less affected by the pandemic when compared with ALD because their mortality has been decreasing for the past decades with the advent of effective antiviral therapy. The increased HCV-related mortality could be attributed to the decrease in HCV surveillance and treatment in the United States during the first few months of the pandemic, as well as the ongoing opioid crisis occurring in the United States at this same time.
      • Alexander G.C.
      • Stoller K.B.
      • Haffajee R.L.
      • Saloner B.
      An epidemic in the midst of a pandemic: opioid use disorder and COVID-19.
      However, with the increased use of telemedicine during the pandemic, challenges in delayed appointments and access to chronic use of antiviral medications is now being addressed.
      NAFLD has been associated with higher mortality in those with COVID-19 which could also have contributed to an increase in their mortality rate.
      • Younossi Z.M.
      • Stepanova M.
      • Lam B.
      • Cable R.
      • Felix S.
      • Jeffers T.
      • et al.
      Independent predictors of mortality among patients with NAFLD hospitalized with COVID-19 infection.
      Among decedents with NAFLD, the major causes of death included cardiovascular disease, metabolic disease, and end-stage liver disease.
      • Kim D.
      • Li A.A.
      • Gadiparthi C.
      • Khan M.A.
      • Cholankeril G.
      • Glenn J.S.
      • et al.
      Changing trends in etiology-based annual mortality from chronic liver disease, from 2007 through 2016.
      These conditions were reported to be disproportionally vulnerable to COVID-19 infection and with distorted cascade of care during the pandemic.
      • Wadhera R.K.
      • Shen C.
      • Gondi S.
      • Chen S.
      • Kazi D.S.
      • Yeh R.W.
      Cardiovascular deaths during the COVID-19 pandemic in the United States.
      ,
      • Iavarone M.
      • D’Ambrosio R.
      • Soria A.
      • Triolo M.
      • Pugliese N.
      • Del Poggio P.
      • et al.
      High rates of 30-day mortality in patients with cirrhosis and COVID-19.
      Regarding our findings suggesting that the young and middle-aged populations had steeper upward mortality trends when compared with those above the age of 65 years old especially for those with ALD and NAFLD, the cause can be multifactorial with multiple potential reasons already discussed above. However, understanding the increase in mortality related to NAFLD may require more research but, as noted in a recent study,
      • Younossi Z.M.
      • Stepanova M.
      • Lam B.
      • Cable R.
      • Felix S.
      • Jeffers T.
      • et al.
      Independent predictors of mortality among patients with NAFLD hospitalized with COVID-19 infection.
      those with NAFLD were at an increased risk for mortality if they contracted COVID-19. In addition, because morbid obesity has also been found to be an independent risk factor for COVID-19 mortality, this risk factor also places persons with NAFLD and obesity at high risk for mortality. Together, these risk factors may also help to explain the increase in NAFLD related mortality at least at the beginning of the pandemic.
      We showed that females had a steeper increasing trend of mortality for all 4 CLDs than males during the pandemic. A recent meta-analysis showed that females are at higher risk for developing cirrhosis than males with the same amount of alcohol consumption,
      • Rehm J.
      • Taylor B.
      • Mohapatra S.
      • Irving H.
      • Baliunas D.
      • Patra J.
      • et al.
      Alcohol as a risk factor for liver cirrhosis: a systematic review and meta-analysis.
      which may explain the higher APC between 2019 and 2021 in females. In addition, the COVID-19 pandemic has posed a greater socioeconomic impact on females than males, which includes disruption of access to medical resources and loss of employment opportunities along with increased childcare burden with closure of schools and childcare facilities.
      • Nordhues H.C.
      • Bhagra A.
      • Stroud N.N.
      • Vencill J.A.
      • Kuhle C.L.
      COVID-19 gender disparities and mitigation recommendations: a narrative review.
      Less access to life-saving interventions such as liver transplantation most likely also played an important role in the increased deaths among females with CLD. It has long been known that females have a lower likelihood of receiving liver transplantation owing to differences in MELD exception points, anthropometric, and liver measurements (body surface area, liver volume, and liver weight).
      • Locke J.E.
      • Shelton B.A.
      • Olthoff K.M.
      • Pomfret E.A.
      • Forde K.A.
      • Sawinski D.
      • et al.
      Quantifying sex-based disparities in liver allocation.
      A nationwide study showed that during the first period of the COVID-19 pandemic, March to November 2020, female candidates on the liver transplant waiting-list had a significantly reduced liver transplant rate when compared with pre-pandemic era.
      • MacConmara M.
      • Wang B.
      • Patel M.S.
      • Hwang C.S.
      • DeGregorio L.
      • Shah J.
      • et al.
      Liver transplantation in the time of a pandemic: a widening of the racial and socioeconomic health care gap during COVID-19.
      Our findings also indicated a disparate impact of the pandemic across different racial/ethnic groups. During the COVID-19 pandemic, non-Hispanic Blacks sustained the highest percentage of excess deaths when compared with other races and ethnicities in general.
      • Woolf S.H.
      • Chapman D.A.
      • Sabo R.T.
      • Zimmerman E.B.
      Excess deaths from COVID-19 and other causes in the US, March 1, 2020, to January 2, 2021.
      Non-Hispanic American Indian/Alaska Natives and non-Hispanic Whites suggested the highest ALD-related mortality rates and the steepest upward trend during pandemic. Despite these findings, a recent study noted that ethnic and racial minorities experienced a disproportionally lower chance of undergoing liver transplantation.
      • Kim N.J.
      • Rozenberg-Ben-Dror K.
      • Jacob D.A.
      • Berry K.
      • Ioannou G.N.
      The COVID-19 pandemic highlights opportunities to improve hepatocellular carcinoma screening and diagnosis in a national health system.
      We showed that American Indian/Alaska Natives had the mildest downward trend for HCV-related deaths and the highest NAFLD-related mortality rate. The social determinants, access to care, and the quality of care should be targeted to improve the health of these populations.
      • Sequist T.D.
      Improving the health of the American Indian and Alaska Native population.
      The surging HCV-related deaths in 2020 was more dramatic in non-Hispanic Whites. Given the widespread use of curative therapy, decedents from HCV-related deaths were likely those with recent infection through intravenous drug use or high-risk sexual behaviour or those who did not have access to curative antiviral therapy. Either population subgroup was highly vulnerable to the pandemic. Non-Hispanic Asians and Pacific Islanders was the only racial group which saw significant increase in HBV-related deaths in 2020. This is likely a result of the high disease prevalence among Asians and Pacific Islanders.
      • Le M.H.
      • Yeo Y.H.
      • Cheung R.
      • Henry L.
      • Lok A.S.
      • Nguyen M.H.
      • et al.
      Chronic hepatitis B prevalence among foreign-born and U.S.-born adults in the United States, 1999–2016.
      The death rate fell back to the predicted range in 2021, which was consistent with a recent finding that Asians had fewer excess deaths among all racial and ethnic groups.
      • Shiels M.S.
      • Haque A.T.
      • Haozous E.A.
      • Albert P.S.
      • Almeida J.S.
      • García-Closas M.
      • et al.
      Racial and ethnic disparities in excess deaths during the COVID-19 pandemic, March to December 2020.
      The strength of our study was that we used a dataset that captures >99% of deaths in the USA which allowed us to provide trends in mortality both yearly and monthly with minimal selection bias. Leveraging the trend from 2010 to 2019, we were able to estimate the predicted mortality rates of CLD with high accuracy which provided the latest information on the impact of the COVID-19 pandemic on CLD-related mortality. However, we also acknowledge several limitations with this study. Firstly, the CDC assume that the numbers of the total United States population in 2021 and 2020 were same, so further analyses when the total population in 2021 is available from the CDC will be needed. Secondly, socioeconomic status and health coverage which, to some extent, could explain the observed disparities was not available and thus not assessed. Thirdly, our study provided mortality data for people with CLD and not the overall health status of the population with CLD who were still living. Fourthly, our study is an observational study and we reported all-cause and liver-related mortality in people with CLD, and the data do not infer a causal relationship between specific CLD and mortality. Lastly, there can be miscoding in the cause of death with large administrative databases such as the WONDER database. During the pandemic, especially early on, there could also be underreporting of COVID-19 related deaths owing to lack of testing and other logistic problems with early public health response.

      Conclusions

      The current study provided updated and comprehensive data to include both liver-related and all-cause mortality rates for people with liver disease. The study found a decreasing trend in mortality for viral hepatitis but rising mortality for NAFLD and ALD in the United States. However, with the COVID-19 pandemic, the progress for viral hepatitis has slowed down, while the increasing mortality trend for ALD and NAFLD became accelerated. The study also found widened gaps in the disparities among the different racial and ethnic groups. Our findings can inform medical practice and public health intervention to address the observed mortality trends and associated inequities for the USA. We also encourage future studies to examine these trends for other geographic regions to inform local practice and policy makers for the ongoing pandemic and during its recovery phase.

      Abbreviations

      ALD, alcohol-associated liver disease; APC, annual percentage change; ASMR, age-standardized mortality rates; CDC WONDER, Center for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research; CLD, chronic liver disease; ICD-10, International Classification of Diseases – 10th edition; NAFLD, non-alcoholic fatty liver disease; NVSS, National Vital Statistics System.

      Financial support

      The study was supported by National Natural Science Foundation of China (11971375). The funding body did not play any role in the design, conduction, or reporting of the study.

      Conflicts of interest

      FJ: Speaker: Gilead Sciences, MSD, and Ascletis. Consulting/advisory board: Gilead, MSD. MHN: Grants: Gilead , Pfizer , Enanta, Vir, Glycotest, National Cancer Institute , B.K. Kee Foundation, Exact Sciences; Helio Health; Consulting or advisory board: Intercept, Gilead, Exact Sciences, Laboratory of Advanced Medicine, Bayer, Eisai, GSK, Novartis. All other authors do not have any conflicts of interest.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Authors’ contributions

      Study design and data analysis: XG, FL, XH, JZ, YHY, FJ, MHN. Drafting of the manuscript: XG, FL, YHY, FJ. Critical review of the manuscript: JZ, YHY, FJ, MHN. Critical revision of the manuscript: MHN. Study conception and study supervision: JZ, FJ, MHN. Data interpretation and approval of the manuscript: all authors.

      Data availability statement

      The NVSS can be accessed through this website: https://wonder.cdc.gov/mcd-icd10-provisional.html.

      Supplementary data

      The following are the supplementary data to this article:

      References

        • Asrani S.K.
        • Devarbhavi H.
        • Eaton J.
        • Kamath P.S.
        Burden of liver diseases in the world.
        J Hepatol. 2019; 70: 151-171
        • Heron M.
        Deaths: leading causes for 2017.
        Natl Vital Stat Rep. 2019; 68: 1-77
        • Kim D.
        • Li A.A.
        • Gadiparthi C.
        • Khan M.A.
        • Cholankeril G.
        • Glenn J.S.
        • et al.
        Changing trends in etiology-based annual mortality from chronic liver disease, from 2007 through 2016.
        Gastroenterology. 2018; 155: 1154-1163.e3
        • Tapper E.B.
        • Parikh N.D.
        Mortality due to cirrhosis and liver cancer in the United States, 1999–2016: observational study.
        BMJ. 2018; 362k2817
        • Zou B.
        • Yeo Y.H.
        • Jeong D.
        • Park H.
        • Sheen E.
        • Lee D.H.
        • et al.
        A nationwide study of inpatient admissions, mortality, and costs for patients with cirrhosis from 2005 to 2015 in the USA.
        Dig Dis Sci. 2020; 65: 1520-1528
        • Harrison S.A.
        • Gawrieh S.
        • Roberts K.
        • Lisanti C.J.
        • Schwope R.B.
        • Cebe K.M.
        • et al.
        Prospective evaluation of the prevalence of non-alcoholic fatty liver disease and steatohepatitis in a large middle-aged US cohort.
        J Hepatol. 2021; 75: 284-291
        • Pollard M.S.
        • Tucker J.S.
        • Green Jr., H.D.
        Changes in adult alcohol use and consequences during the COVID-19 pandemic in the US.
        JAMA Netw Open. 2020; 3e2022942
        • Weerakoon S.M.
        • Jetelina K.K.
        • Knell G.
        Longer time spent at home during COVID-19 pandemic is associated with binge drinking among US adults.
        Am J Drug Alcohol Abuse. 2021; 47: 98-106
        • Cholankeril G.
        • Goli K.
        • Rana A.
        • Hernaez R.
        • Podboy A.
        • Jalal P.
        • et al.
        Impact of COVID-19 pandemic on liver transplantation and alcohol-associated liver disease in the USA.
        Hepatology. 2021; 74: 3316-3329
        • Marjot T.
        • Moon A.M.
        • Cook J.A.
        • Abd-Elsalam S.
        • Aloman C.
        • Armstrong M.J.
        • et al.
        Outcomes following SARS-CoV-2 infection in patients with chronic liver disease: an international registry study.
        J Hepatol. 2021; 74: 567-577
        • Phipps M.M.
        • Verna E.C.
        Coronavirus disease 2019 and liver transplantation: lessons from the first year of the pandemic.
        Liver Transpl. 2021; 27: 1312-1325
        • Ioannou G.N.
        • Liang P.S.
        • Locke E.
        • Green P.
        • Berry K.
        • O’Hare A.M.
        • et al.
        Cirrhosis and severe acute respiratory syndrome coronavirus 2 infection in us veterans: risk of infection, hospitalization, ventilation, and mortality.
        Hepatology. 2021; 74: 322-335
        • Mallet V.
        • Beeker N.
        • Bouam S.
        • Sogni P.
        • Pol S.
        • Demosthenes Research Group
        Prognosis of French COVID-19 patients with chronic liver disease: a national retrospective cohort study for 2020.
        J Hepatol. 2021; 75: 848-855
        • Tapper E.B.
        • Asrani S.K.
        The COVID-19 pandemic will have a long-lasting impact on the quality of cirrhosis care.
        J Hepatol. 2020; 73: 441-445
        • Toyoda H.
        • Huang D.Q.
        • Le M.H.
        • Nguyen M.H.
        Liver care and surveillance: the global impact of the COVID-19 pandemic.
        Hepatol Commun. 2020; 4: 1751-1757
        • Kim H.J.
        • Fay M.P.
        • Feuer E.J.
        • Midthune D.N.
        Permutation tests for joinpoint regression with applications to cancer rates.
        Stat Med. 2000; 19: 335-351
        • Andrasfay T.
        • Goldman N.
        Reductions in 2020 US life expectancy due to COVID-19 and the disproportionate impact on the Black and Latino populations.
        Proc Natl Acad Sci U S A. 2021; 118e2014746118
        • Islam N.
        • Shkolnikov V.M.
        • Acosta R.J.
        • Klimkin I.
        • Kawachi I.
        • Irizarry R.A.
        • et al.
        Excess deaths associated with covid-19 pandemic in 2020: age and sex disaggregated time series analysis in 29 high income countries.
        BMJ. 2021; 373: n1137
        • Bassett M.T.
        • Chen J.T.
        • Krieger N.
        Variation in racial/ethnic disparities in COVID-19 mortality by age in the United States: a cross-sectional study.
        PLoS Med. 2020; 17e1003402
        • Liu J.
        • Zhang L.
        • Yan Y.
        • Zhou Y.
        • Yin P.
        • Qi J.
        • et al.
        Excess mortality in Wuhan city and other parts of China during the three months of the covid-19 outbreak: findings from nationwide mortality registries.
        BMJ. 2021; 372: n415
        • Magliano D.J.
        • Chen L.
        • Carstensen B.
        • Gregg E.W.
        • Pavkov M.E.
        • Salim A.
        • et al.
        Trends in all-cause mortality among people with diagnosed diabetes in high-income settings: a multicountry analysis of aggregate data.
        Lancet Diabetes Endocrinol. 2022; 10: 112-119
        • Wadhera R.K.
        • Shen C.
        • Gondi S.
        • Chen S.
        • Kazi D.S.
        • Yeh R.W.
        Cardiovascular deaths during the COVID-19 pandemic in the United States.
        J Am Coll Cardiol. 2021; 77: 159-169
        • Bhaskaran K.
        • Bacon S.
        • Evans S.J.
        • Bates C.J.
        • Rentsch C.T.
        • MacKenna B.
        • et al.
        Factors associated with deaths due to COVID-19 versus other causes: population-based cohort analysis of UK primary care data and linked national death registrations within the OpenSAFELY platform.
        Lancet Reg Health Eur. 2021; 6100109
        • Kim N.J.
        • Rozenberg-Ben-Dror K.
        • Jacob D.A.
        • Berry K.
        • Ioannou G.N.
        The COVID-19 pandemic highlights opportunities to improve hepatocellular carcinoma screening and diagnosis in a national health system.
        Am J Gastroenterol. 2022; 117: 678-684
        • Yabroff K.R.
        • Wu X.C.
        • Negoita S.
        • Stevens J.
        • Coyle L.
        • Zhao J.
        • et al.
        Association of the COVID-19 pandemic with patterns of statewide cancer services.
        J Natl Cancer Inst. 2022; 114: 907-909
        • Da B.L.
        • Im G.Y.
        • Schiano T.D.
        Coronavirus disease 2019 hangover: a rising tide of alcohol use disorder and alcohol-associated liver disease.
        Hepatology. 2020; 72: 1102-1108
        • Alexander G.C.
        • Stoller K.B.
        • Haffajee R.L.
        • Saloner B.
        An epidemic in the midst of a pandemic: opioid use disorder and COVID-19.
        Ann Intern Med. 2020; 173: 57-58
        • Younossi Z.M.
        • Stepanova M.
        • Lam B.
        • Cable R.
        • Felix S.
        • Jeffers T.
        • et al.
        Independent predictors of mortality among patients with NAFLD hospitalized with COVID-19 infection.
        Hepatol Commun. 2021; https://doi.org/10.1002/hep4.1802
        • Iavarone M.
        • D’Ambrosio R.
        • Soria A.
        • Triolo M.
        • Pugliese N.
        • Del Poggio P.
        • et al.
        High rates of 30-day mortality in patients with cirrhosis and COVID-19.
        J Hepatol. 2020; 73: 1063-1071
        • Rehm J.
        • Taylor B.
        • Mohapatra S.
        • Irving H.
        • Baliunas D.
        • Patra J.
        • et al.
        Alcohol as a risk factor for liver cirrhosis: a systematic review and meta-analysis.
        Drug Alcohol Rev. 2010; 29: 437-445
        • Nordhues H.C.
        • Bhagra A.
        • Stroud N.N.
        • Vencill J.A.
        • Kuhle C.L.
        COVID-19 gender disparities and mitigation recommendations: a narrative review.
        Mayo Clin Proc. 2021; 96: 1907-1920
        • Locke J.E.
        • Shelton B.A.
        • Olthoff K.M.
        • Pomfret E.A.
        • Forde K.A.
        • Sawinski D.
        • et al.
        Quantifying sex-based disparities in liver allocation.
        JAMA Surg. 2020; 155e201129
        • MacConmara M.
        • Wang B.
        • Patel M.S.
        • Hwang C.S.
        • DeGregorio L.
        • Shah J.
        • et al.
        Liver transplantation in the time of a pandemic: a widening of the racial and socioeconomic health care gap during COVID-19.
        Ann Surg. 2021; 274: 427-433
        • Woolf S.H.
        • Chapman D.A.
        • Sabo R.T.
        • Zimmerman E.B.
        Excess deaths from COVID-19 and other causes in the US, March 1, 2020, to January 2, 2021.
        JAMA. 2021; 325: 1786-1789
        • Sequist T.D.
        Improving the health of the American Indian and Alaska Native population.
        JAMA. 2021; 325: 1035-1036
        • Le M.H.
        • Yeo Y.H.
        • Cheung R.
        • Henry L.
        • Lok A.S.
        • Nguyen M.H.
        • et al.
        Chronic hepatitis B prevalence among foreign-born and U.S.-born adults in the United States, 1999–2016.
        Hepatology. 2020; 71: 431-443
        • Shiels M.S.
        • Haque A.T.
        • Haozous E.A.
        • Albert P.S.
        • Almeida J.S.
        • García-Closas M.
        • et al.
        Racial and ethnic disparities in excess deaths during the COVID-19 pandemic, March to December 2020.
        Ann Intern Med. 2021; 174: 1693-1699