Chronic liver disease (CLD) affects more than just the liver, frequently leading to extrahepatic complications through complex underlying mechanisms [
1-
3]. Viral hepatitis is a systemic disease with both hepatic and extrahepatic manifestations [
2,
4]. However, the risk of mortality may have been underestimated due to the exclusion of extrahepatic complications related to chronic hepatitis C virus (HCV) infection [
5]. Achieving sustained virological response in chronic HCV infection and effectively suppressing the viral replication in chronic hepatitis B virus (HBV) infection have led to better outcomes for end-stage liver disease. With improved survival due to effective antiviral therapy, there may be an increase in the risk of extrahepatic complications like extrahepatic cancer, diabetes, and cardiovascular disease (CVD), which can offset the benefit of a reduction in liverrelated mortality [
1]. Furthermore, the extrahepatic mortality from alcohol-related liver disease (ALD) and metabolic dysfunction-associated steatotic liver disease (MASLD) are poorly captured and less frequently reported during the recent decade [
1,
2]. Cirrhosis, the end-stage liver disease, significantly affects the pattern and impact of extrahepatic complications and related mortality [
1]. In the absence of cirrhosis, extrahepatic complications are more often linked to metabolic diseases or extrahepatic cancers [
1]. Once cirrhosis develops, the risk of liver-related and extrahepatic mortality may interchange [
1]. Therefore, we assessed the burden of extrahepatic mortality in CLD, stratified by cirrhosis status, using mortality data from the US National Vital Statistics System for 2014 to 2024.
To examine trends in extrahepatic mortality from CLD based on the presence or absence of cirrhosis among US adults aged 25 years and older, we analyzed de-identified death records from the National Vital Statistics System. Because the National Vital Statistics System’s Mortality Data, based on the death certificate, are publicly available and de-identified, this study received an exemption from the institutional review board. We chose 2014 as the starting point because it marks the beginning of the all-oral, interferon-free direct-acting antivirals (DAA) era following the FDA approval of sofosbuvir in December 2013 and additional approvals of other DAA agents in 2014. This period represents a paradigm shift in HCV management. Anchor-ing the study to this year allows us to capture the changing trends in the improved cure rates of HCV infection—by reducing liver-related deaths—may have unmasked or accelerated trends in extrahepatic mortality. As liver-related mortality from viral hepatitis decreased due to new treatments, observing ALD and MASLD over this identical timeline highlights how metabolic and alcohol-related etiologies of liver disease have grown to dominate the clinical landscape. CLD etiologies were classified using ICD-10 codes: HCV (B17.1, B18.2, B19.2), HBV (B16, B17.0, B18.0, B18.1, B19.1), ALD (K70), and MASLD (K76.0, K75.81), excluding co-infections. Cirrhosis was determined using codes for cirrhosis (K70.3, K74.0-K74.4, K74.6), portal hypertension (K76.6), or related complications: hepatic encephalopathy (K72.11, K72.91), spontaneous bacterial peritonitis (K65.2), variceal bleeding (I85.0, I85.1), or hepatorenal syndrome (K76.7).1 Liver-related deaths were defined using ICD-10 codes for viral hepatitis, liver cancer, cirrhosis, and complications. Extrahepatic causes of death, such as CVD, extrahepatic cancer, diabetes, and drug overdose, were defined with corresponding ICD-10 codes, based on already established methodologies [
1,
6].
Age-standardized mortality for hepatic and extrahepatic deaths was calculated per 100,000 individuals using US Census data, and adjusted to the 2010 US population across age groups (25–34 up to 85+) [
7,
8]. We included liver disease, CVD, extrahepatic cancer, diabetes, or drug overdose-related death as an extrahepatic cause. The Joinpoint Regression Program (National Cancer Institute, version 5.4.0.0) was utilized to analyze trends and identify significant changes, with trends summarized as annual percentage change (APC) and corresponding 95% confidence interval (CI) [
9].
This study analyzed 32,249,203 deaths (≥age 25) from 2014 to 2024. Most CLD-related deaths occurred in males, except MASLD. The proportion of liver-related mortality was higher among individuals with cirrhosis compared to those without, regardless of the underlying etiology of CLD (
Fig. 1 and
Supplementary Tables 1,
2). Conversely, the proportions of extrahepatic mortality were more pronounced in individuals without cirrhosis than in those with cirrhosis. For viral hepatitis, liver-related mortality decreased more steeply in the absence of cirrhosis than in the presence of cirrhosis. Extrahepatic cancer-related, diabetes-related, and CVD-related mortality increased more steeply in HCV-related cirrhosis than in the absence of cirrhosis. In terms of HBV, CVD-related and extrahepatic cancer-related mortality increased only in HBV without cirrhosis. Notably, the proportion of mortality due to CVD and diabetes among individuals with ALD, irrespective of cirrhosis, showed a steady increase, especially a sharp increase after the pandemic (2022–2024), while there was an increase in extrahepatic cancer-related mortality for individuals with ALD without cirrhosis (
Fig. 1 and
Supplementary Table 2). Among individuals with MASLD, the proportions of extrahepatic cancer-related mortality increased more steeply in those without cirrhosis. In terms of diabetes-related mortality, divergent mortality in the presence and absence of cirrhosis was noted (APC 3.6%, 95% CI 0.1% to 7.2% for those without cirrhosis; APC -2.5%, 95% CI -4.7% to -0.3%). Drug overdose-related mortality increased more steeply among individuals with HCV, followed by those with ALD, irrespective of cirrhosis status. In contrast, mortality among individuals with MASLD without cirrhosis was initially high but has since declined during the study period.
In this national study, we observed important distinctions in mortality trends among individuals with CLD, particularly by etiology of CLD and cirrhosis status. For viral hepatitis, findings were generally consistent across cirrhosis status, although some differences were noted. Liver-related mortality decreased more sharply among those without cirrhosis, highlighting the impact of recent advances in antiviral therapies, especially for earlier-stage disease. However, more intriguing is the rising trend in the rates of extrahepatic mortality in the setting of cirrhosis. The proportion of mortality due to extrahepatic cancer, diabetes, and CVD increased more steeply in individuals with HCV-related cirrhosis than in those with HCV without cirrhosis, although proportions of extrahepatic mortality were more pronounced in individuals without cirrhosis. However, CVD and extrahepatic cancer-related mortality increased signifi-cantly only in HBV without cirrhosis.
In contrast to a previous study [
1,
2], CVD-related mortality increased steadily among ALD showed a steady increase, especially a sharp increase after the pandemic, irrespective of cirrhosis. Likewise, we noted a surge of extrahepatic cancer-related mortality after the pandemic among ALD without cirrhosis. For MASLD, the proportion of mortality from diabetes increased significantly in non-cirrhotic patients. In contrast, mortality due to diabetes declined among those with cirrhosis, suggesting possible differences in risk profiles, pathologic mechanisms, and competing mortality among individuals with an advanced stage of liver disease. CVD-related mortality in MASLD further exemplified these divergent patterns. While CVD-related mortality decreased before and during the pandemic among individuals without cirrhosis, it increased in those with cirrhosis, suggesting the complex interaction of cirrhosis and underlying metabolic risk factors. These findings emphasize the importance of individualized risk assessment and targeted therapeutic approach to manage both hepatic and extrahepatic CLD-related mortality.
The increase in all-cause mortality [
6] and extrahepatic cancer-related mortality among individuals with MASLD may indicate insufficient utilization of approved pharmacologic therapy for metabolic dysfunction-associated steatohepatitis (MASH), coinciding with the growing prevalence of MASLD. Notably, extrahepatic cancer and diabetes-related mortality among MASLD without cirrhosis were higher with a steeper trajectory, which may partially be explained by MASH.
Drug overdose-related mortality in individuals with MASLD without cirrhosis was notably high in 2014 but has exhibited a decrease during the study period. From 2014 to 2024, extrahepatic cancer and diabetes-related deaths among non-cirrhotic MASLD patients surged, mathematically crowding out drug overdose as a proportional cause of death. Additionally, early-decade opioid overdoses disproportionately affected younger demographics (25–54 years). As awareness of MASLD has grown, MASLD has been diagnosed by primary care providers in older patients with obesity, type 2 diabetes, and cardiovascular disease, diluting the younger demographic most vulnerable to overdose. Finally, recent widespread use of GLP-1 receptor agonists, which have been shown to reduce opioid overdoses by 40% [
10] in this specific population for weight-loss and diabetes medications, may actively reduce substance use risks and fatal drug overdoses. Future studies are needed to confirm these hypotheses.
A major strength of this study is the availability of national, individual-level data collected for more than a decade after the introduction of DAA therapy, which enables sufficient comparisons of hepatic and extrahepatic mortality by CLD etiology, with and without cirrhosis. There are also several limitations. First, the cause of death recorded on certificates may be misclassified or underestimated, though consistent methodology over time makes this unlikely to bias temporal trends. Second, the database did not permit assessment of the effects of antiviral therapy and pharmacotherapy for MASH at the individual level. It remains unclear whether effective antiviral therapy or pharmacotherapy for MASH directly affects the risk of extrahepatic mortality. Therefore, our findings should be interpreted with caution. Finally, higher rates of smoking and alcohol use among individuals with HCV or ALD may further increase their risk of extrahepatic complications, independent of the underlying etiology [
11].
The increasing burden of extrahepatic complications, notably as liver-related mortality decline, emphasizes that healthcare approaches encompass cancer surveillance, cardiovascular risk management, and metabolic disease prevention to improve outcomes in CLD. Future research should further explore the mechanisms underlying these trends to help develop management strategies. Based on these limited observations, individualized risk assessment is recommended until further prospective data are generated.
FOOTNOTES
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Authors’ contributions
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.
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Data availability 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).
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 viral hepatitis and annual percentage change (APC) according to the presence or absence of cirrhosis among US adults ≥25 years, 2014–2024
Supplementary Table 2.
Proportion of cause-specific mortality among individuals with ALD and MASLD and annual percentage change (APC) according to the presence or absence of cirrhosis among US adults ≥25 years, 2014–2024
Figure 1.Annual trends in the proportion of extrahepatic mortality among individuals with chronic liver disease according to the presence or absence of cirrhosis in the United States between 2014 and 2024. (A) HCV without cirrhosis, (B) HCV-related cirrhosis, (C) HBV without cirrhosis, (D) HBV-related cirrhosis, (E) ALD without cirrhosis, (F) ALD-related cirrhosis, (G) MASLD without cirrhosis, and (H) MASLD-related cirrhosis. CVD, cardiovascular disease; DM, diabetes; COVID-19, coronavirus disease 2019; HCV, hepatitis C virus; HBV, hepatitis B virus; ALD, alcohol-related liver disease; MASLD, metabolic dysfunction-associated steatotic liver disease.
Abbreviations
alcohol-related liver disease
metabolic dysfunction-associated steatotic liver disease
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