The introduction of direct-acting antiviral (DAA) agents has led to high rates of sustained virological response (SVR), contributing to a notable decrease in hepatitis C virus (HCV)-related mortality in the US [
1,
2]. The clinical burden of chronic HCV includes liver-related and extrahepatic complications [
3]. HCV-infected individuals face a higher risk of metabolic dysfunction than those without HCV [
4]. Additionally, there are emerging data connecting chronic HCV to various extrahepatic cancers, although the mechanistic pathway remains unclear [
5,
6]. Achieving SVR in individuals with HCV and optimal suppression of viral replication in chronic hepatitis B virus (HBV) have improved outcomes for end-stage liver disease. Therefore, understanding trends in extrahepatic mortality is essential during the post-DAA era, especially as mortality from viral hepatitis has declined. In the US, age-standardized alcohol-related liver disease (ALD)-related mortality increased before the pandemic and surged during the early COVID-19 period [
1]. Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease (CLD) in the US and worldwide [
7], with cardiovascular disease (CVD) being the leading cause of death, followed by extrahepatic cancer and liver-related mortality [
8]. However, recent trends in ALD and MASLD-related extrahepatic complications compared to viral hepatitis remain underreported. This study analyzed the up-to-date mortality data from the US National Vital Statistics System (NVSS) to assess trends and burdens in extrahepatic mortality of CLD during the post-DAA era (2014–2023) in the US.
We analyzed de-identified death records from NVSS among US adults aged 25 years and older with CLD. We selected the year 2014 as the starting point for our investigation into extrahepatic mortality following the FDA’s approval of sofosbuvir in late 2013, marking the introduction of DAAs. Since this NVSS dataset is de-identified and publicly accessible, the study did not require an institutional review board. We employed ICD-10 codes to define etiology of CLD [
3]. We investigated the proportion of extrahepatic mortality to assess trends using the age-standardized mortality or crude mortality rate. Cause-specific mortality for individuals with CLD as an underlying or contributing cause of death was defined by deaths attributed to liver disease, CVD, extrahepatic cancer, diabetes, or drug overdose. The detailed methodologies are shown in the
Supplementary Materials.
We examined 29,236,380 deaths among US adults from 2014 to 2023.
Table 1 and Figure 1 provide liver-related and extrahepatic mortality among individuals with CLD using age-standardized mortality. While there was a significant decline in liver-related deaths due to HCV, the annual proportion of extrahepatic deaths among individuals with HCV showed a statistically significant increase, with annual percentage change (APCs) of 4.8% (95% confidence interval [CI]: 4.0–5.6%) for CVD, 3.2% (1.1– 5.1%) for extrahepatic cancer, and 1.9% (0.8–3.0%) for diabetes. Among individuals with HBV, the yearly trends in the proportions of CVD (APC: 3.0%, 95% CI 1.3–4.8%) and extrahepatic cancer (APC: 2.2%, 95% CI 0.3–4.2%)-related mortality increased steadily. For those with MASLD, extrahepatic cancer- related mortality increased significantly (APC: 8.1%, 95% CI 6.8–9.4%), particularly during the period from 2019 to 2023. CVD was the most common extrahepatic cause of death in MASLD, accounting for approximately 15%, although its proportion showed a declining trend (APC: –2.2%, 95% CI –4.0% to –0.4%). In contrast, the annual trends in the proportion of CVD and extrahepatic cancer-related mortality among individuals with ALD remained unchanged. Regarding drug overdose-related deaths, the trends in proportions rose sharply, with an APC of 12.2% (95% CI 10.6–13.8%) for HCV, 8.4% (2.0–15.1%) for HBV, and 3.9% (2.9–5.5% [2018–2023]) for ALD. In contrast, the proportion of drug overdose deaths significantly decreased in individuals with MASLD.
Since age-standardized mortality rates naturally account for shifts in the US population structure over time, we have also presented crude mortality rates as an additional measure to better assess the societal burden of mortality (
Supplementary Table 1). When comparing aging cohorts in more recent years than the early period of the post-DAA era using the crude mortality rate, we noted slightly greater effects on extrahepatic mortality, such as CVD and extrahepatic cancer-related mortality in viral hepatitis, compared to findings based on age-standardized mortality rates. As expected, the rise in drug overdose-related mortality rates was less pronounced because these deaths predominantly occurred among younger individuals. Conversely, for patients with ALD or MASLD, extrahepatic mortality outcomes remained comparable between the two analytical approaches.
Following the introduction of DAA agents and potent antiviral treatments, there has been a notable decline in the proportion of liver-related mortality. However, the proportion of extrahepatic mortality related to viral hepatitis has risen, in particular, from CVD, extrahepatic cancer, and drug overdose-related mortality. In contrast, the proportion of extrahepatic mortality from ALD has remained relatively stable. The divergent trends in liver-related and extrahepatic mortality among individuals with viral hepatitis and ALD highlight the temporal relationship between the advent of highly effective therapies and the ‘orphan status’ of ALD due to the lack of therapeutic interventions.
A study reported that individuals with viral hepatitis have a 30% higher risk of developing extrahepatic cancer compared to the general population [
9]. Although liver-related deaths are expected to decrease due to potent antiviral agents, the increased life expectancy of these individuals may expose them to a higher risk of extrahepatic cancers [
9]. A study showed that individuals who achieved SVR with interferon-based therapy had higher rates of incident extrahepatic cancer [
10]. Our study found a significant increase in the proportion of extrahepatic cancer among individuals with viral hepatitis during the DAA and potent antiviral era. It is still uncertain whether effective antiviral treatment affects the risk of extrahepatic cancer. In terms of CVD, individuals with HCV infection face higher risks of CVD-related mortality, cardiovascular events, and cerebrovascular events compared to uninfected individuals [
11]. The mechanisms linking HCV infection to CVD and diabetes are likely to be multifactorial, involving viral replication in extrahepatic cells, the release of pro-inflammatory cytokines and chemokines, insulin resistance, endothelial damage, and oxidative stress, all contributing to a pro-fibrogenic and inflammatory environment with systemic effects [
12,
13]. We noted that the aging cohort with a more recent period in the analyses using the crude mortality rate may partly explain this issue, as it is associated with a rise in extrahepatic comorbidities. As the use of potent antiviral agents expands and the population ages, individuals with viral hepatitis should be closely monitored and screened for potential extrahepatic complications, extending beyond traditional management of portal hypertension and monitoring for hepatocellular carcinoma.
One of the key strengths of this study is its ability to capture longitudinal trends and the ability to analyze individuallevel data on a national scale over ten years after the introduction of DAA agents. Our study has several limitations. First, the underlying cause of death recorded on death certificates may be prone to misclassification and underestimation. However, since the methodology has remained consistent over time, this is unlikely to account for the observed temporal trends in CLD. Second, we were unable to assess the impact of antiviral therapy at the individual level due to limitations within the database. It remains unclear whether effective antiviral therapy directly affects the risk of extrahepatic mortality. Therefore, cautions are needed to interpret our findings.
In conclusion, following effective antiviral agents for viral hepatitis, there has been a notable increase in extrahepatic mortality. Our findings at the national level provide valuable insights into the burden of hepatic and extrahepatic mortality associated with CLD, which can inform and influence health policy decisions.
FOOTNOTES
-
Data Transparency Statement
The National Vital Statistics System’s Mortality Data are publicly available at the National Center for Health Statistics of the Centers for Disease Control and Prevention (https://www.cdc.gov/nchs/nvss/deaths.htm).
-
Authors’ contribution
Donghee Kim and Aijaz Ahmed were responsible for the study concept and design, acquisition of data, statistical analysis, interpretation of data, drafting of the manuscript, critical revision of the manuscript for important intellectual content, and approval of the final draft manuscript.
Pojsakorn Danpanichkul and Karn Wijarnpreecha were responsible for the interpretation and presentation of data, critical revision of the manuscript for important intellectual content, and approval of the final manuscript.
-
Conflicts of Interest
The authors have no conflicts to disclose.
SUPPLEMENTARY MATERIAL
Supplementary material is available at Clinical and Molecular Hepatology website (
http://www.e-cmh.org).
Supplementary Table 1.
Proportion of cause-specific mortality among individuals with chronic liver disease and annual percentage change (APC) using crude mortality rates among US adults ≥25 years, 2014–2023
Table 1.Proportion of cause-specific mortality among individuals with chronic liver disease and annual percentage change (APC) using age-standardized mortality rates among US adults ≥25 years, 2014–2023
Table 1.
|
Cause-specific mortality |
Proportion
|
Average APC (95% CI)
|
Trend segment 1
|
Trend segment 2
|
|
2014 |
2023 |
2014–2023 |
Year |
APC (95% CI) |
Year |
APC (95% CI) |
|
Cause-Specific Death among Individuals with HCV |
|
Liver disease |
61.4% |
47.5% |
–3.3 (–4.0, –2.5)*
|
|
|
|
|
|
Cardiovascular disease |
8.2% |
12.8% |
4.8 (4.0, 5.6)*
|
|
|
|
|
|
Extrahepatic cancer |
7.7% |
10.6% |
3.2 (1.1, 5.1)*
|
2014–2018 |
6.0 (1.6, 17.3)*
|
2018–2023 |
0.9 (–8.9, 4.9) |
|
Diabetes |
1.8% |
2.1% |
1.9 (0.8, 3.0)*
|
2014–2017 |
7.9 (4.0, 15.1)*
|
2017–2023 |
–1.0 (–3.2, 0.4) |
|
Drug overdose |
1.8% |
5.1% |
12.2 (10.6, 13.8)*
|
2014–2017 |
6.5 (–0.9, 11.3) |
2017–2023 |
15.1 (13.2, 21.1)*
|
|
Cause-Specific Death among Individuals with HBV |
|
Liver disease |
58.6% |
48.5% |
–2.3 (–3.4, –1.4)*
|
2014–2016 |
0.9 (–3.3, 5.6) |
2016–2023 |
–3.1 (–7.6, –1.4)*
|
|
Cardiovascular disease |
7.7% |
9.7% |
3.0 (1.3, 4.8)*
|
2014–2018 |
–2.6 (–10.5, 1.3) |
2018–2023 |
7.8 (4.7, 16.4)*
|
|
Extrahepatic cancer |
11.6% |
14.2% |
2.2 (0.3, 4.2)*
|
|
|
|
|
|
Diabetes |
1.4% |
2.1% |
3.4 (–2.7, 9.3) |
2014–2018 |
13.3 (3.2, 51.9)*
|
2018–2023 |
–4.0 (–29.1, 3.4) |
|
Drug overdose |
0.6% |
1.1% |
8.4 (2.0, 15.1)*
|
|
|
|
|
|
Cause-specific Death in MASLD |
|
Liver disease |
53.1% |
57.5% |
0.5 (–0.8, 1.5) |
2014–2016 |
5.2 (0.0, 10.7)*
|
2016–2023 |
–0.8 (–5.8, 0.7) |
|
Cardiovascular disease |
17.2% |
14.4% |
–2.2 (–4.0, –0.4)*
|
|
|
|
|
|
Extrahepatic cancer |
2.3% |
4.7% |
8.1 (6.8, 9.4)*
|
2014–2019 |
6.1 (–0.1, 11.3) |
2019–2023 |
10.7 (5.7, 18.1)*
|
|
Diabetes |
3.7% |
3.7% |
–0.0 (–2.5, 2.5) |
2014–2019 |
2.5 (–2.5, 16.2) |
2019–2023 |
–3.1 (–15.5, 2.4) |
|
Drug overdose |
6.3% |
3.4% |
–5.2 (–9.2, –1.3)*
|
2014–2019 |
–9.3 (–24.6, 11.2) |
2019–2023 |
0.2 (–18.5, 22.0) |
|
Cause-Specific Death among Individuals with ALD |
|
Liver disease |
82.3% |
80.2% |
–0.3 (–0.4, –0.3)*
|
2014–2016 |
0.0 (–0.4, 0.4) |
2016–2023 |
–0.4 (–0.8, –0.3)*
|
|
Cardiovascular disease |
4.7% |
5.4% |
0.7 (–0.3, 1.6) |
|
|
|
|
|
Extrahepatic cancer |
1.8% |
2.1% |
0.8 (–1.1, 2.7) |
|
|
|
|
|
Diabetes |
0.4% |
0.7% |
3.9 (1.0, 6.8)*
|
|
|
|
|
|
Drug overdose |
1.5% |
1.5% |
0.0 (–0.5, 0.5) |
2014–2018 |
–4.7 (–6.8, –3.4)*
|
2018–2023 |
3.9 (2.9, 5.5)*
|
Abbreviations
alcohol-related liver disease
metabolic dysfunction-associated steatotic liver disease
National Vital Statistics System
sustained virological response
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