Clinical and Molecular Hepatology

"Death"

Research Letter

Contemporary burden of mortality from chronic liver disease by sex and race/ethnicity in the United States: Donghee Kim, Pojsakorn Danpanichkul, Karn Wijarnpreecha, George Cholankeril, Aijaz Ahmed; Clin Mol Hepatol 2025;31(3):e268-e272.
Published online May 8, 2025; DOI: https://doi.org/10.3350/cmh.2025.0384

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Advancing policy and practice in alcohol-associated liver disease and alcohol-attributable cancer: Correspondence to the editorial on “Sex disparities in alcohol-associated liver disease and subtype differences in alcohol-attributable cancers in the Unite
Pojsakorn Danpanichkul, Donghee Kim, Karn Wijarnpreecha, Amit G. Singal, Ju Dong Yang
Clinical and Molecular Hepatology.2026; 32(1): e96. CrossRef
Rising drug overdose deaths in chronic liver disease in the United States, 2015–2023
Donghee Kim, Brittany B Dennis, Pojsakorn Danpanichkul, Karn Wijarnpreecha, George Cholankeril, Aijaz Ahmed
Clinical and Molecular Hepatology.2025; 31(3): e277. CrossRef
Extrahepatic manifestation of metabolic dysfunction-associated steatotic liver disease
Anoushka Shenoy, Aijaz Ahmed, Donghee Kim
Metabolism and Target Organ Damage.2025;[Epub] CrossRef

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Original Article

Impacts of metabolic syndrome diseases on long-term outcomes of chronic hepatitis B patients treated with nucleos(t)ide analogues: Rui Huang, Dae Won Jun, Hidenori Toyoda, Yao-Chun Hsu, Huy Trinh, Akito Nozaki, Toru Ishikawa, Tsunamasa Watanabe, Haruki Uojima, Daniel Q. Huang, Takashi Honda, Yasuhito Tanaka, Philip Vutien, Sebastián Marciano, Hiroshi Abe, Masaru Enomoto, Masanori Atsukawa, Hirokazu Takahashi, Kunihiko Tsuji, Koichi Takaguchi, Pei-Chien Tsai, Chia-Yen Dai, Jee-Fu Huang, Chung-Feng Huang, Ming-Lun Yeh, Eileen Yoon, Sung Eun Kim, Sang Bong Ahn, Gi-Ae Kim, Jang Han Jung, Soung Won Jeong, Hyunwoo Oh, Cheng-Hao Tseng, Masatoshi Ishigami, Angela Chau, Mayumi Maeda, Satoshi Yasuda, Makoto Chuma, Takanori Ito, Keigo Kawashima, Joanne Kimiko Liu, Adrian Gadano, Ritsuzo Kozuka, Norio Itokawa, Kaori Inoue, Tomonori Senoh, Jie Li, Wan-Long Chuang, Ramsey Cheung, Chao Wu, Ming-Lung Yu, Mindie H. Nguyen; Clin Mol Hepatol 2025;31(3):1003-1017.
Published online March 17, 2025; DOI: https://doi.org/10.3350/cmh.2024.1070

Background/Aims
Given the increase in prevalence of metabolic diseases, we investigated their long-term impacts on the outcomes of chronic hepatitis B (CHB) patients receiving nucleos(t)ide analogue (NA) treatment.
Methods
We analyzed data from CHB patients for whom initiated NA treatment from 30 centers. We balanced patient characteristics with and without metabolic disease (diabetes, obesity, dyslipidemia, and hypertension) via propensity-score matching (PSM) to evaluate adverse outcomes.
Results
The study included 4,500 patients. PSM yielded 909 pairs of patients with balanced characteristics. When stratified by the number of metabolic diseases, only patients with ≥2 metabolic diseases had an increased cumulative incidence of cirrhosis and overall death. However, when stratified by the presence of diabetes (regardless of the presence or number of other metabolic diseases), patients with diabetes (versus those without) had a significantly higher cumulative incidence of all outcomes: cirrhosis (P=0.009), hepatocellular carcinoma (HCC, P=0.023), and overall, liver-related, and non-liver-related death (P<0.001, P=0.026 and P<0.001, respectively). Having ≥2 metabolic diseases was associated with cirrhosis, overall death, and non-liver-related death but not HCC or liver-related death, while diabetes was significantly associated with a higher risk of all outcomes: cirrhosis (hazard ratio [HR]=3.75, P=0.004), HCC (HR=2.02, P=0.020), and overall, liver-related, and non-liver-related death (HR=2.53, P<0.001; HR=2.65, P=0.016; HR=2.38, P<0.001).
Conclusions
Having two or more metabolic diseases was associated with a higher risk of cirrhosis, overall death, and non-liver-related death, but having diabetes as a single metabolic disease was significantly associated with all adverse outcomes including cirrhosis, HCC, and overall, liver-related, and non-liver-related death.

Citations

Citations to this article as recorded by

Advancing metabolic risk profiling in chronic hepatitis B: Reply to correspondence on “Metabolic health in antiviral era of chronic hepatitis B”
Shang-Chin Huang, Jia-Horng Kao
Clinical and Molecular Hepatology.2026; 32(1): e117. CrossRef
Metabolic health in antiviral era of chronic hepatitis B: Editorial on “Impacts of metabolic syndrome diseases on long-term outcomes of chronic hepatitis B patients treated with nucleos(t)ide analogues”
Shang-Chin Huang, Jia-Horng Kao
Clinical and Molecular Hepatology.2026; 32(1): 423. CrossRef
Differential HCC risk among HBV indeterminate types at baseline and by phase transition
Rui Huang, Huy N Trinh, Satoshi Yasuda, Angela Chau, Mayumi Maeda, Ai-Thien Do, Daniel Q Huang, Takanori Ito, Takashi Honda, Masatoshi Ishigami, Ritsuzo Kozuka, Carmen Monica Preda, Cheng-Hao Tseng, Sebastián Marciano, Pei-Chien Tsai, Dong Hyun Lee, Chris
Gut.2025; 74(11): 1873. CrossRef
Type 2 diabetes mellitus as an independent predictor of significant fibrosis in treatment-naïve chronic hepatitis B patients with concurrent hepatic steatosis
Jie Li, Liang Xu, Fajuan Rui, Sally Tran, Pei-Chien Tsai, Youwen Tan, Hidenori Toyoda, Qing-Lei Zeng, Huy Trinh, Yao-Chun Hsu, Tsunamasa Watanabe, Hiroshi Abe, Hiroyuki Motoyama, Yoko Yoshimaru, Takanori Suzuki, Taeang Arai, Masanori Atsukawa, Phillip Vut
Hepatology.2025;[Epub] CrossRef
Incidence and determinants of achieving HBsAg <100 IU/mL in HBeAg-negative CHB patients with nucleos(t)ide analogue treatment
Jian Wang, Tao Fan, Zhiyi Zhang, Li Zhu, Shaoqiu Zhang, Ye Xiong, Chun Shan, Chao Jiang, Shengxia Yin, Xin Tong, Renling Yao, Juan Xia, Xiaomin Yan, Yu Shi, Yuxin Chen, Xingxiang Liu, Huali Wang, Haixia Zhang, Chuanwu Zhu, Qun Zhang, Chao Wu, Rui Huang
Emerging Microbes & Infections.2025;[Epub] CrossRef
Impact of metabolic dysfunction on treatment responses to nucleos(t)ide analogues in chronic hepatitis B: a retrospective multi-center REAL-B cohort study
Rui Huang, Dae Won Jun, Hidenori Toyoda, Yao-Chun Hsu, Huy Trinh, Akito Nozaki, Toru Ishikawa, Tsunamasa Watanabe, Haruki Uojima, Daniel Q. Huang, Takashi Honda, Yasuhito Tanaka, Philip Vutien, Sebastián Marciano, Hiroshi Abe, Masaru Enomoto, Masanori Ats
eClinicalMedicine.2025; 87: 103407. CrossRef
Aspirin Use and Risk of HCC and Gastrointestinal Bleeding in Patients With HBV‐Related Cirrhosis: A Landmark Analysis
Mi Na Kim, Geun U. Park, Seng Chan You, Jae Seung Lee, Hye Won Lee, Beom Kyung Kim, Seung Up Kim, Jun Yong Park, Do Young Kim, Sang Hoon Ahn
Journal of Gastroenterology and Hepatology.2025; 40(11): 2750. CrossRef
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Shengnan Zhang, Hui Gao, Kevin H. Mayo, Jingang Mo, Le Deng
Gels.2025; 11(12): 960. CrossRef

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Letter to the Editor

Steatotic liver disease

Leukocyte telomere shortening in metabolic dysfunction-associated steatotic liver disease and all-cause/cause-specific mortality: Donghee Kim, Pojsakorn Danpanichkul, Karn Wijarnpreecha, George Cholankeril, Aijaz Ahmed; Clin Mol Hepatol 2024;30(4):982-986.
Published online August 27, 2024; DOI: https://doi.org/10.3350/cmh.2024.0691

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Increased MASH-associated liver cancer in younger demographics
Pojsakorn Danpanichkul, Yanfang Pang, Kanokphong Suparan, Thanida Auttapracha, Supapitch Sirimangklanurak, Abdelrahman M. Attia, Chanattha Thimphitthaya, Michelle Shi Ni Law, Zhenning Yu, Mostafa A. Soliman, Natchaya Polpichai, Chanakarn Kanitthamniyom, D
Hepatology Communications.2025;[Epub] CrossRef

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72 Download
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Original Article

Hepatic neoplasm

Burden of mortality from hepatocellular carcinoma and biliary tract cancers by race and ethnicity and sex in US, 2018–2023: Donghee Kim, Richie Manikat, Karn Wijarnpreecha, George Cholankeril, Aijaz Ahmed; Clin Mol Hepatol 2024;30(4):756-770.
Published online June 24, 2024; DOI: https://doi.org/10.3350/cmh.2024.0318

Backgrounds/Aims
The trends in mortality of hepatocellular carcinoma (HCC) and biliary tract cancers stratified by sex and race/ethnicity in the US continue to evolve. We estimated the sex- and race/ethnicity-based trends in HCC and biliary tract cancers-related mortality in US adults with a focus on disease burden.
Methods
We performed a population-based analysis using the US national mortality records from 2018 to 2023. We identified HCC and biliary tract cancer using appropriate ICD-10 codes. Temporal trends in mortality were calculated by joinpoint analysis with annual percentage change (APC).
Results
Annual age-standardized mortality from HCC decreased steadily with an APC of –1.4% (95% confidence interval [CI]: –2.0% to –0.7%). While there was a linear increase in intrahepatic cholangiocarcinoma-related mortality (APC: 3.1%, 95% CI: 1.2–4.9%) and ampulla of Vater cancer-related mortality (APC: 4.1%, 95% CI: 0.5–7.9%), gallbladder cancer-related mortality decreased (APC: –1.9%, 95% CI: –3.8% to –0.0%). Decreasing trends in mortality from HCC were noted in males, not females. HCC-related mortality decreased more steeply in racial and ethnic minority individuals compared with non-Hispanic White individuals. Racial and ethnic differences in trends in mortality for biliary tract cancers depended on the malignancy’s anatomical site.
Conclusions
While the annual mortality for HCC and gallbladder cancer demonstrated declining trends, ICC- and AVC-related mortality continued to increase from 2018 to 2023. Although racial and ethnic minority individuals in the US experienced disproportionately higher HCC and biliary tract cancer, recent declines in HCC may be primarily due to declines among racial and ethnic minority individuals and males.

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Global Burden, Trends, and Inequalities of Gallbladder and Biliary Tract Cancer, 1990–2021: A Decomposition and Age–Period–Cohort Analysis
Sen Lei, Guizhong Huang, Xiaohui Li, Pu Xi, Zehui Yao, Xiaojun Lin
Liver International.2025;[Epub] CrossRef
Alcohol–Related Liver Disease, Followed by Metabolic Dysfunction–Associated Steatotic Liver Disease, Emerges as the Fastest‐Growing Aetiologies for Primary Liver Cancer in the United States
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Alimentary Pharmacology & Therapeutics.2025; 61(6): 959. CrossRef
Increased MASH-associated liver cancer in younger demographics
Pojsakorn Danpanichkul, Yanfang Pang, Kanokphong Suparan, Thanida Auttapracha, Supapitch Sirimangklanurak, Abdelrahman M. Attia, Chanattha Thimphitthaya, Michelle Shi Ni Law, Zhenning Yu, Mostafa A. Soliman, Natchaya Polpichai, Chanakarn Kanitthamniyom, D
Hepatology Communications.2025;[Epub] CrossRef
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Donghee Kim, Won Kim, Aijaz Ahmed
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Long-term outcomes and risk modifiers of metabolic dysfunction-associated steatotic liver disease between lean and non-lean populations
Pojsakorn Danpanichkul, Kanokphong Suparan, Vitchapong Prasitsumrit, Aijaz Ahmed, Karn Wijarnpreecha, Donghee Kim
Clinical and Molecular Hepatology.2025; 31(1): 74. CrossRef
From past to pandemic: Health disparities in US hepatobiliary cancer mortality before and during COVID-19: Editorial on “Burden of mortality from hepatocellular carcinoma and biliary tract cancers by race and ethnicity and sex in US, 2018–2023”
Ilona Argirion
Clinical and Molecular Hepatology.2025; 31(1): 286. CrossRef
The burden of steatotic liver disease before and during the COVID-19 pandemic: Correspondence to editorial on “Current burden of steatotic liver disease and fibrosis among adults in the United States, 2017-2023”
Donghee Kim, Pojsakorn Danpanichkul, Karn Wijarnpreecha, George Cholankeril, Rohit Loomba, Aijaz Ahmed
Clinical and Molecular Hepatology.2025; 31(2): e183. CrossRef
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Contemporary burden of mortality from chronic liver disease by sex and race/ethnicity in the United States
Donghee Kim, Pojsakorn Danpanichkul, Karn Wijarnpreecha, George Cholankeril, Aijaz Ahmed
Clinical and Molecular Hepatology.2025; 31(3): e268. CrossRef
Rising drug overdose deaths in chronic liver disease in the United States, 2015–2023
Donghee Kim, Brittany B Dennis, Pojsakorn Danpanichkul, Karn Wijarnpreecha, George Cholankeril, Aijaz Ahmed
Clinical and Molecular Hepatology.2025; 31(3): e277. CrossRef
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Hepatobiliary & Pancreatic Diseases International.2025; 24(6): 666. CrossRef
Extrahepatic manifestation of metabolic dysfunction-associated steatotic liver disease
Anoushka Shenoy, Aijaz Ahmed, Donghee Kim
Metabolism and Target Organ Damage.2025;[Epub] CrossRef
Paired snRNA-seq and scRNA-seq analysis of MASLD patients to identify early-stage markers for disease progression
Suebin Park, Su-Hyeon Lee, Se-eun Han, Beom Kyung Kim, Byungjin Hwang
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Editorial: Understanding How Social Determinants of Health Impact Mortality in MASLD—Insights From a National Analysis. Authors' Reply
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Alimentary Pharmacology & Therapeutics.2025;[Epub] CrossRef

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17 Web of Science
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Review

Steatotic liver disease

Causes and risk profiles of mortality among individuals with nonalcoholic fatty liver disease: Peter Konyn, Aijaz Ahmed, Donghee Kim; Clin Mol Hepatol 2023;29(Suppl):S43-S57.
Published online November 22, 2022; DOI: https://doi.org/10.3350/cmh.2022.0351

Abstract
PDF

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the United States and worldwide. Though nonalcoholic fatty liver per se may not be independently associated with an increased risk for all-cause mortality, it is associated with a number of harmful metabolic risk factors, such as type 2 diabetes mellitus, hyperlipidemia, obesity, a sedentary lifestyle, and an unhealthy diet. The fibrosis stage is a predictor of all-cause mortality in NAFLD. Mortality in individuals with NAFLD has been steadily increasing, and the most common cause-specific mortality for NAFLD is cardiovascular disease, followed by extra-hepatic cancer, liver-related mortality, and diabetes. High-risk profiles for mortality in NAFLD include PNPLA3 I148M polymorphism, low thyroid function and hypothyroidism, and sarcopenia. Achieving weight loss through adherence to a high-quality diet and sufficient physical activity is the most important predictor of improvement in NAFLD severity and the benefit of survival. Given the increasing health burden of NAFLD, future studies with more long-term mortality data may demonstrate an independent association between NAFLD and mortality.

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Original Article

Hepatic neoplasm

Cause of death and cause-specific mortality for primary liver cancer in South Korea: A nationwide population-based study in hepatitis B virus-endemic area: Bo Hyun Kim, Dahhay Lee, Kyu-Won Jung, Young-Joo Won, Hyunsoon Cho; Clin Mol Hepatol 2022;28(2):242-253.
Published online February 7, 2022; DOI: https://doi.org/10.3350/cmh.2021.0355

Background/Aims
Primary liver cancer is one of the leading causes of cancer mortality worldwide. However, the causes of death have not been studied in detail in patients with liver cancer.
Methods
The causes of death and cause-specific mortality risks in patients with primary liver cancer, diagnosed during 2000–2016, were investigated using the nationwide population-based cancer registry data in South Korea (n=231,388). The cumulative incidence function and Fine-Gray models were used to estimate the cause-specific mortality under the competing risks. Risks of non-cancer deaths relative to the general population were compared by standardized mortality ratios (SMRs).
Results
Among 179,921 total deaths, 92.4%, 1.7%, and 6.0% of patients died of primary liver cancer, cancer from other sites, and non-cancer illnesses, respectively. Proportionate mortality from liver cancer remained high. The 5-year competing risks probability of death from liver cancer varied by tumor stage, from 42% to 94%, and it remained high 10 years after the diagnosis (61–95%). Competing mortality from other causes has continuously increased. The most common non-cancer causes of death were underlying liver diseases (SMR, 15.6; 95% confidence interval [CI], 15.1–16.1) and viral hepatitis (SMR, 46.5; 95% CI, 43.9–49.2), which demonstrated higher mortality risks compared to the Korean general population. Higher mortality risks of suicide (SMR, 2.6; 95% CI, 2.4–2.8) was also noted.
Conclusions
Patients with liver cancer are most likely to die from liver cancer and related liver disease, even 10 years after the diagnosis, highlighting a need for specialized long-term follow-up care.

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Editorial

Hepatic neoplasm

Exploring the mythical abscopal effect: Radiation and programmed cell death protein 1 (PD-1) blockade for hepatocellular carcinoma: Jun Won Kim, Ik Jae Lee; Clin Mol Hepatol 2021;27(1):103-106.
Published online December 14, 2020; DOI: https://doi.org/10.3350/cmh.2020.0297

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Pathology - Research and Practice.2024; 256: 155266. CrossRef

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Special topic: Alcoholic liver diseases
The 14th International Symposium on Alcoholic Liver and Pancreatic Diseases and Cirrhosis (ISALPDC)

Alcohol-related liver disease

Programmed cell death in alcohol-associated liver disease: Tatsunori Miyata, Laura E. Nagy; Clin Mol Hepatol 2020;26(4):618-625.
Published online September 21, 2020; DOI: https://doi.org/10.3350/cmh.2020.0142

Abstract
PDF

Alcohol-associated liver disease (ALD), which ranges from mild disease to alcohol-associated hepatitis and cirrhosis, is the most prevalent type of chronic liver disease and a leading cause of morbidity and mortality worldwide. Accumulating evidence reveals that programmed cell death (PCD) plays a crucial role in progression of ALD involving crosstalk between hepatocytes and immune cells. Multiple pathways of PCD, including apoptosis, necroptosis, autophagy, pyroptosis and ferroptosis, are reported in ALD. Interestingly, PCD pathways are intimately linked and interdependent, making it difficult to therapeutically target a single pathway. This review clarifies the multiple types of PCD occurring in liver and focuses on crosstalk between hepatocytes and innate immune cells in ALD.

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Review

Viral hepatitis

Prediction of fibrosis progression in chronic viral hepatitis: Grace Lai-Hung Wong; Clin Mol Hepatol 2014;20(3):228-236.
Published online September 25, 2014; DOI: https://doi.org/10.3350/cmh.2014.20.3.228

Abstract
PDF

Prediction of liver fibrosis progression has a key role in the management of chronic viral hepatitis, as it will be translated into the future risk of cirrhosis and its various complications including hepatocellular carcinoma. Both hepatitis B and C viruses mainly lead to fibrogenesis induced by chronic inflammation and a continuous wound healing response. At the same time direct and indirect profibrogenic responses are also elicited by the viral infection. There are a handful of well-established risk factors for fibrosis progression including older age, male gender, alcohol use, high viral load and co-infection with other viruses. Metabolic syndrome is an evolving risk factor of fibrosis progression. The new notion of regression of advanced fibrosis or even cirrhosis is now strongly supported various clinical studies. Even liver biopsy retains its important role in the assessment of fibrosis progression, various non-invasive assessments have been adopted widely because of their non-invasiveness, which facilitates serial applications in large cohorts of subjects. Transient elastography is one of the most validated tools which has both diagnostic and prognostic role. As there is no single perfect test for liver fibrosis assessment, algorithms combining the most validated noninvasive methods should be considered as initial screening tools.

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Original Article

The Change of the Etiology , Complications and Cause of Death of the Liver Cirrhosis in 1990 s: Yo Seb Han,Byung Ho Kim,Il Yyun Baek,Dong Kuen Lee,Kyung Jin Kim,Seok Ho Dong,Hyo Jong Kim,Yung Woon Chang,Joung Il Lee,Rin Chang; Korean J Hepatol 2000;6(3):328-339.

Abstract
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Background
Alcoholic liver disease has increased. The causes of death in liver cirrhosis have changed. The author tried to categorize the etiology and complications of liver cirrhosis and analyze the causes of death in the 1990s. Method: The author retrospectively reviewed medical records of 1,175 patients diagnosed as having liver cirrhosis at Kyung Hee University Hospital from January 1991 through December 1998. The etiology, complications and the cause of death were compared between the early (1991-1994) and the late (1995-1998) periods. Results: The proportion of male patients (73.3%) was still about 3 times that of female patients. There was no difference in age at the time of diagnosis between early and late periods (51.4 11.1 and 51.2 11.2 years respectively). Hepatitis B virus (HBV) infection was still the most common cause of liver cirrhosis (57.0%) and alcohol was the next (31.1%). The complications of liver cirrhosis at the time of diagnosis were, in order: esophageal varices, ascites, and variceal bleeding. But there was no significant difference between the periods. The proportion of Child grade B was the most common at the time of diagnosis in both periods, but Child grade A increased in the late period. The most common cause of death was liver failure and the next cause was variceal bleeding in the early period. Hepatorenal syndrome was the second most common cause in the late period. Conclusion: There was no change in the etiology between early and late periods. HBV infection was still the most common etiology but the incidence of alcoholic liver cirrhosis might have increased in the 1990s. The proportion of the Child B at initial diagnosis was the highest (around 50%) but that of Child A increased in the late period. Among the causes of death, liver failure and hepatorenal syndrome had a tendency to increase in the late period.

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Special topic: Alcoholic liver diseases
The 14th International Symposium on Alcoholic Liver and Pancreatic Diseases and Cirrhosis (ISALPDC)