Causes of mortality among patients with early-stage hepatocellular carcinoma.
| Title: | Causes of mortality among patients with early-stage hepatocellular carcinoma. |
|---|---|
| Authors: | Seif El Dahan K; Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA.; Daher D; Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA.; Rich NE; Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA.; Nayak AJ; Department of Internal Medicine, Baylor College of Medicine, Houston, Texas, USA.; Ankoma-Sey C; Department of Internal Medicine, Baylor College of Medicine, Houston, Texas, USA.; Govalan R; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.; Bhongade MB; Department of Internal Medicine, Baylor College of Medicine, Houston, Texas, USA.; Molina E; Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA.; Amador E; Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA.; Pitts H; Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA.; Jalal PK; Department of Internal Medicine, Baylor College of Medicine, Houston, Texas, USA.; Kanwal F; Department of Internal Medicine, Baylor College of Medicine, Houston, Texas, USA.; Parikh ND; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.; Singal AG; Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA. |
| Source: | Hepatology (Baltimore, Md.) [Hepatology] 2025 Jul 22. Date of Electronic Publication: 2025 Jul 22. |
| Publication Model: | Ahead of Print |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Wolters Kluwer Health, Inc Country of Publication: United States NLM ID: 8302946 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1527-3350 (Electronic) Linking ISSN: 02709139 NLM ISO Abbreviation: Hepatology Subsets: MEDLINE |
| Imprint Name(s): | Publication: 2023- : [Philadelphia] : Wolters Kluwer Health, Inc.; Original Publication: Baltimore, MD : Williams & Wilkins, [c1981]- |
| Abstract: | Background and Aims: Early detection of hepatocellular carcinoma (HCC) can reduce cancer-related mortality; however, there are often competing risks from comorbid conditions, including cirrhosis. Understanding causes of death among patients with early-stage HCC can inform strategies to improve surveillance effectiveness.; Approach and Results: We conducted a retrospective cohort study of patients with early-stage HCC [Barcelona Clinic Liver Cancer (BCLC) stages 0/A] at 4 U.S. health systems between 2008 and 2022. We defined the primary cause of death as HCC-related, liver-related (non-HCC), and death from other causes. We used multivariable and Fine-Gray analysis, with liver transplant as a competing outcome, to identify factors associated with mortality. Among 1336 patients with early-stage HCC, 598 (44.8%) died during a median follow-up of 32.4 months-220 (37%) HCC-related, 114 (19%) liver-related, and 179 (30%) from other causes. Median time to death was similar between the groups: 24 (95% CI 22-31), 19 (95% CI 15-23), and 23 (95% CI 19-27) months for HCC-related, liver-related, and other causes of mortality, respectively. Curative treatment was associated with reduced HCC-related (HR 0.34; 95% CI 0.23-0.48) and liver-related mortality (HR 0.23; 95% CI 0.14-0.38). Predictors of HCC-related mortality included alpha-fetoprotein (AFP) >20 ng/mL (HR 2.19; 95% CI 1.59-3.03) and tumor diameter >3 cm (HR 1.69; 95% CI 1.20-2.37). Liver-related mortality was associated with MASLD (metabolic dysfunction-associated steatotic liver disease) etiology (HR 1.99; 95% CI 1.09-3.65), Child-Pugh B cirrhosis (HR 2.64; 95% CI 1.58-4.42), and Albumin-Bilirubin (ALBI) grade 2 (vs. grade 1: HR 2.47; 95% CI 1.21-5.06).; Conclusions: Cause of death varies among patients with early-stage HCC, although HCC-related death remains the most common cause. Efforts are needed to optimize curative treatment effectiveness among patients with early-stage HCC to reduce cancer-related mortality.; (Copyright © 2025 American Association for the Study of Liver Diseases.) |
| References: | Llovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, et al. Hepatocellular carcinoma. Nat Rev Dis Primers. 2021;7:6.; Huang DQ, Singal AG, Kono Y, Tan DJH, El-Serag HB, Loomba R, et al. Changing global epidemiology of liver cancer from 2010 to 2019: NASH is the fastest growing cause of liver cancer. Cell Metab. 2022;34:969–977.e2.; Rich NE, Yopp AC, Singal AG, Murphy CC. Hepatocellular carcinoma incidence is decreasing among younger adults in the United States. Clin Gastroenterol Hepatol. 2020;18:242–248.e5.; Wolf E, Rich NE, Marrero JA, Parikh N, Singal AG. Utilization of hepatocellular carcinoma surveillance in patients with cirrhosis: A systematic review and meta-analysis. Hepatology. 2021;73:713–725.; Singal AG, Kudo M, Bruix J. Breakthroughs in hepatocellular carcinoma therapies. Clin Gastroenterol Hepatol. 2023;21:2135–2149.; Singal AG, Kanwal F, Llovet JM. Global trends in hepatocellular carcinoma epidemiology: Implications for screening, prevention and therapy. Nat Rev Clin Oncol. 2023;20:864–884.; Singal AG, Zhang E, Narasimman M, Rich NE, Waljee AK, Hoshida Y, et al. HCC surveillance improves early detection, curative treatment receipt, and survival in patients with cirrhosis: A meta-analysis. J Hepatol. 2022;77:128–139.; Yang JD, Kim WR, Coelho R, Mettler TA, Benson JT, Sanderson SO, et al. Cirrhosis is present in most patients with hepatitis B and hepatocellular carcinoma. Clin Gastroenterol Hepatol. 2011;9:64–70.; Celsa C, Cabibbo G, Fulgenzi CAM, Battaglia S, Enea M, Scheiner B, et al. Hepatic decompensation is the major driver of mortality in patients with HCC treated with atezolizumab plus bevacizumab: The impact of successful antiviral treatment. Hepatology. 2025;81:837–852.; Kondo T, Koroki K, Kanzaki H, Kobayashi K, Kiyono S, Nakamura M, et al. Impact of acute decompensation on the prognosis of patients with hepatocellular carcinoma. PLoS One. 2022;17:e0261619.; Parikh ND, Mehta N, Hoteit MA, Yang JD, John BV, Moon AM, et al. Association between sustained virological response and clinical outcomes in patients with hepatitis C infection and hepatocellular carcinoma. Cancer. 2022;128:3470–3478.; Cao L, Wang X, Yan Y, Ning Z, Ma L, Li Y, et al. Analysis of competing risks of cardiovascular death in patients with hepatocellular carcinoma: A population-based study. Medicine (Baltimore). 2023;102:e36705.; Yang Z, Leng K, Shi G. Causes of death among patients with hepatocellular carcinoma in United States from 2000 to 2018. Cancer Med. 2023;12:13076–13085.; Yen YH, Kee KM, Li WF, Liu YW, Wang CC, Hu TH, et al. Causes of death among patients with hepatocellular carcinoma according to chronic liver disease etiology. Cancers (Basel). 2023;15:1687.; Chu J, Cholankeril G, Yu X, Rana A, Natarajan Y, El-Serag HB, et al. Clinical course and outcomes of patients with nonalcoholic fatty liver disease-related hepatocellular cancer (NAFLD-HCC). Dig Dis Sci. 2023;68:1060–1070.; Singal AG, Lok AS, Feng Z, Kanwal F, Parikh ND. Conceptual model for the hepatocellular carcinoma screening continuum: Current status and research agenda. Clin Gastroenterol Hepatol. 2022;20:9–18.; Tan D, Yopp A, Beg MS, Gopal P, Singal AG. Meta-analysis: Underutilisation and disparities of treatment among patients with hepatocellular carcinoma in the United States. Aliment Pharmacol Ther. 2013;38:703–712.; Tabrizian P, Jibara G, Shrager B, Schwartz M, Roayaie S. Recurrence of hepatocellular cancer after resection: Patterns, treatments, and prognosis. Ann Surg. 2015;261:947–955.; Singal AG, Rich NE, Mehta N, Branch AD, Pillai A, Hoteit M, et al. Direct-acting antiviral therapy for hepatitis C virus infection is associated with increased survival in patients with a history of hepatocellular carcinoma. Gastroenterology. 2019;157:1253–1263.e2.; Singal AG, Ghaziani TT, Mehta N, Zhou K, Grinspan LT, Benhammou JN, et al. Recall patterns and risk of primary liver cancer for subcentimeter ultrasound liver observations: A multicenter study. Hepatol Commun. 2023;7:e0073.; Rich NE, John BV, Parikh ND, Rowe I, Mehta N, Khatri G, et al. Hepatocellular carcinoma demonstrates heterogeneous growth patterns in a multicenter cohort of patients with cirrhosis. Hepatology. 2020;72:1654–1665.; Singal AG, Llovet JM, Yarchoan M, Mehta N, Heimbach JK, Dawson LA, et al. AASLD practice guidance on prevention, diagnosis, and treatment of hepatocellular carcinoma. Hepatology. 2023;78:1922–1965.; CT/MRI LI-RADS v2018. https://www.acr.org/Clinical-Resources/Reporting-and-Data-Systems/LI-RADS/LI-RADS-CT-MRI-v2018 . American College of Radiology, 2018.; European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol. 2018;69:182–236.; Moon AM, Weiss NS, Beste LA, Su F, Ho SB, Jin GY, et al. No association between screening for hepatocellular carcinoma and reduced cancer-related mortality in patients with cirrhosis. Gastroenterology. 2018;155:1128–1139.e6.; Singal AK, Kamath PS. Model for End-stage Liver Disease. J Clin Exp Hepatol. 2013;3:50–60.; Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996;334:693–699.; Govalan R, Luu M, Lauzon M, Kosari K, Ahn JC, Rich NE, et al. Therapeutic underuse and delay in hepatocellular carcinoma: Prevalence, associated factors, and clinical impact. Hepatol Commun. 2022;6:223–236.; Wagle NS, Park S, Washburn D, Ohsfeldt RL, Rich NE, Kum HC. Racial, ethnic, and socioeconomic disparities in curative treatment receipt and survival in hepatocellular carcinoma. Hepatol Commun. 2022;6:1186–1197.; Rich NE, Hester C, Odewole M, Murphy CC, Parikh ND, Marrero JA, et al. Racial and ethnic differences in presentation and outcomes of hepatocellular carcinoma. Clin Gastroenterol Hepatol. 2019;17:551–559.e1.; Mokdad AA, Murphy CC, Pruitt SL, Mansour JC, Marrero JA, Singal AG, et al. Effect of hospital safety net designation on treatment use and survival in hepatocellular carcinoma. Cancer. 2018;124:743–751.; Seif El Dahan K, Reczek A, Daher D, Rich NE, Yang JD, Hsiehchen D, et al. Multidisciplinary care for patients with HCC: A systematic review and meta-analysis. Hepatol Commun. 2023;7:e0143.; Singal AG, Tiro JA, Murphy CC, Blackwell JM, Kramer JR, Khan A, et al. Patient-reported barriers are associated with receipt of hepatocellular carcinoma surveillance in a multicenter cohort of patients with cirrhosis. Clin Gastroenterol Hepatol. 2021;19:987–995.e1.; Yang WJ, Kang D, Song MG, Seo TS, Kim JH. The impact of socioeconomic status on mortality in patients with hepatocellular carcinoma: A Korean National Cohort Study. Gut Liver. 2022;16:976–984.; Nephew LD, Gupta D, Carter A, Desai AP, Ghabril M, Patidar KR, et al. Social determinants of health impact mortality from HCC and cholangiocarcinoma: A population-based cohort study. Hepatol Commun. 2023;7:e0058.; Rich NE, Carr C, Yopp AC, Marrero JA, Singal AG. Racial and ethnic disparities in survival among patients with hepatocellular carcinoma in the United States: A systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2022;20:e267–e288.; Garwood ER, Fidelman N, Hoch SE, Kerlan RK Jr, Yao FY. Morbidity and mortality following transarterial liver chemoembolization in patients with hepatocellular carcinoma and synthetic hepatic dysfunction. Liver Transpl. 2013;19:164–173.; Reincke M, Schultheiss M, Doppler M, Verloh N, Uller W, Sturm L, et al. Hepatic decompensation after transarterial radioembolization: A retrospective analysis of risk factors and outcome in patients with hepatocellular carcinoma. Hepatol Commun. 2022;6:3223–3233.; De La Pinta Alonso C. Radiation-induced liver disease in the era of SBRT: A review. Expert Rev Gastroenterol Hepatol. 2020;14:1195–1201.; Nathani P, Gopal P, Rich N, Yopp A, Yokoo T, John B, et al. Hepatocellular carcinoma tumour volume doubling time: A systematic review and meta-analysis. Gut. 2021;70:401–407.; Miksad RA, Ogasawara S, Xia F, Fellous M, Piscaglia F. Liver function changes after transarterial chemoembolization in US hepatocellular carcinoma patients: The LiverT study. BMC Cancer. 2019;19:795.; Salem R, Johnson GE, Kim E, Riaz A, Bishay V, Boucher E, et al. Yttrium-90 radioembolization for the treatment of solitary, unresectable HCC: The LEGACY study. Hepatology. 2021;74:2342–2352.; Kudo M, Ueshima K, Chan S, Minami T, Chishina H, Aoki T, et al. Lenvatinib as an initial treatment in patients with intermediate-stage hepatocellular carcinoma beyond up-to-seven criteria and Child–Pugh A liver function: A proof-of-concept study. Cancers (Basel). 2019;11:1084.; Tyson GL, Duan Z, Kramer JR, Davila JA, Richardson PA, El-Serag HB, et al. Level of α-fetoprotein predicts mortality among patients with hepatitis C-related hepatocellular carcinoma. Clin Gastroenterol Hepatol. 2011;9:989–994.; Huang S, Zhu Z, Ruan Y, Zhang F, Xu Y, Jin L, et al. Prognostic factors and survival prediction in hepatocellular carcinoma: Development and validation of a novel nomogram based on the SEER database. J Gastrointest Oncol. 2023;14:1817–1829.; Kanneganti M, Al-Hasan M, Bourque S, Deodhar S, Yang JD, Huang DQ, et al. Older age but not comorbidity is associated with worse survival in patients with hepatocellular carcinoma. Clin Gastroenterol Hepatol. 2025;23:1377–1386.e2.; Tandon P, Garcia-Tsao G. Prognostic indicators in hepatocellular carcinoma: A systematic review of 72 studies. Liver Int. 2009;29:502–510.; Toyoda H, Johnson PJ. The ALBI score: From liver function in patients with HCC to a general measure of liver function. JHEP Rep. 2022;4:100557.; Issa G, Shang Y, Strandberg R, Hagström H, Wester A. Cause-specific mortality in 13,099 patients with metabolic dysfunction-associated steatotic liver disease in Sweden. J Hepatol. 2025. doi:10.1016/j.jhep.2025.03.001. (PMID: 10.1016/j.jhep.2025.03.001) |
| Contributed Indexing: | Keywords: hepatocellular carcinoma; liver dysfunction; mortality; prognosis |
| Entry Date(s): | Date Created: 20250722 Latest Revision: 20250820 |
| Update Code: | 20260130 |
| DOI: | 10.1097/HEP.0000000000001471 |
| PMID: | 40694813 |
| Database: | MEDLINE |
Journal Article