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Hepatocellular Carcinoma in the Absence of Cirrhosis in United States Veterans Is Associated With Nonalcoholic Fatty Liver Disease
Open accessAbstract
Background & aims Hepatocellular carcinoma (HCC) can develop in individuals without cirrhosis. We investigated risk factors for development of HCC in the absence of cirrhosis in a U.S.Methods We identified a national cohort of 1500 patients with verified HCC during 2005 to 2010 in the U.S. Veterans Administration (VA) and reviewed their full VA medical records for evidence of cirrhosis and risk factors for HCC. Patients without cirrhosis were assigned to categories of level 1 evidence for no cirrhosis (very high probability) or level 2 evidence for no cirrhosis (high probability), which were based on findings from histologic analyses, laboratory test results, markers of fibrosis from noninvasive tests, and imaging features.Results A total of 43 of the 1500 patients with HCC (2.9%) had level 1 evidence for no cirrhosis, and 151 (10.1%) had level 2 evidence for no cirrhosis; the remaining 1203 patients (80.1%) had confirmed cirrhosis. Compared with patients with HCC in presence of cirrhosis, greater proportions of patients with HCC without evidence of cirrhosis had metabolic syndrome, nonalcoholic fatty liver disease (NAFLD), or no identifiable risk factors. Patients with HCC without evidence of cirrhosis were less likely to have abused alcohol or have hepatitis C virus infection than patients with cirrhosis. Patients with HCC and NAFLD (unadjusted odds ratio, 5.4; 95% confidence interval, 3.4-8.5) or metabolic syndrome (unadjusted odds ratio, 5.0; 95% confidence interval, 3.1-7.8) had more than 5-fold risk of having HCC in the absence of cirrhosis, compared with patients with HCV-related HCC.Conclusions Approximately 13% of patients with HCC in the VA system do not appear to have cirrhosis. NAFLD and metabolic syndrome are the main risk factors for HCC in the absence of cirrhosis.
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“In the same cohort, the risk of HCC in the absence of cirrhosis was 5-fold higher in individuals with MASLD than in those with chronic hepatitis C.”
From EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). (2024) · cites this paper as [123]
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“Although HCC may develop in non-cirrhotic MASLD, cirrhosis remains the key risk factor for HCC.”
From EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). (2024) · cites this paper as [123]
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“In a US Veterans Administration cohort 123 including 1,500 individuals with HCC from 2005 to 2010, metabolic syndrome was particularly prevalent in the subgroup who had no cirrhosis.”
From EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). (2024) · cites this paper as [123]
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“[19,20,28,29] The Veterans Affairs administrative database provided that the annual HCC incidence of non-cirrhotic MASLD was only 0.008 per 100 person-years, parallel to a prospective multicenter study involving 1773 MASLD patients and found that only 0.04% person-years of patients with F0 – F2…”
InfluentialThe Impact of Metabolic Health and Obesity on Liver Transplant Candidates and Recipients
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BackgroundPersisting challenges in the early detection of hepatocellular carcinoma
Arvind, A., Redmon, K., & Singal, A. G. (2025) · Expert Review of Anticancer Therapy · doi:10.1080/14737140.2025.2467184 · Cited by 5
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“Moreover, given that HCC arises almost exclusively in patients with evidence of underlying liver disease (>95%), most often in the setting of a high-risk condition (>87% cirrhosis) [15,16], the pre-test probability of a positive diagnosis is strikingly high.”
Analysis of the therapeutic potential of miR-124 and miR-16 in non-alcoholic fatty liver disease.
Mahmoudi, A., Jalili, A., Aghaee-Bakhtiari, S. H., Oskuee, R. K., Butler, A. E., Rizzo, M., & Sahebkar, A. (2024) · Journal of diabetes and its complications · doi:10.1016/j.jdiacomp.2024.108722 · Cited by 5
Llamoza-Torres, C. J., Fuentes-Pardo, M., & Ramos‐Molina, B. (2024) · Metabolism and Target Organ Damage · doi:10.20517/mtod.2024.64 · Cited by 6
Species differences of fatty liver diseases: comparisons between human and feline
Ling, L., Li, R., Xu, M., Zhou, J., Hu, M., Zhang, X., & Zhang, X.-J. (2024) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00014.2024 · Cited by 5
Priyadharshini, A., & Emerson, I. A. (2025) · Discover Oncology · doi:10.1007/s12672-025-02638-5 · Cited by 4
“Although some studies have suggested a potential association between hepatitis C virus (HCV) and alcoholism with HCC development, the causal relationship between HCV and alcoholic HCC remains controversial [30].”
Younossi, Z. M., & Henry, L. L. (2020) · Springer eBooks · doi:10.1007/978-3-319-95828-6_2 · Cited by 4
Desjonqueres, E., & Gigante, E. (2022) · Hepatoma Research · doi:10.20517/2394-5079.2021.136 · Cited by 4
How useful is the machine perfusion in liver transplantation? An answer from a national survey
Scalera, I., Carlis, R. D., Patrono, D., Gringeri, E., Olivieri, T., Pagano, D., Lai, Q., Rossi, M., Gruttadauria, S., Benedetto, F. D., et al. (2022) · Frontiers in Surgery · doi:10.3389/fsurg.2022.975150 · Cited by 4
“Finally, steatotic livers might develop HCC, even skipping the cirrhotic stage (35, 36), and the risk of HCC recurrence on steatotic graft used in HCC candidates is unknown.”
BackgroundDirican, A., Uncu, D., Sekacheva, M. I., Artaç, M., Aladashvil, A., Erdoğan, A. P., Ma, K., Alacacıoğlu, A., Boukovinas, I., & Turhal, N. S. (2023) · Eastern Mediterranean Health Journal · doi:10.26719/emhj.23.087 · Cited by 4
“In Europe and the United States of America, HCV is the main risk factor for HCC.”
BackgroundIdentification of pyroptosis-related genes in NASH based on bioinformatic analysis.
Chen, X.-X., Wang, D., Wang, Z., & Huang, W.-X. (2023) · Biochemical and Biophysical Research Communications - BBRC · doi:10.1016/j.bbrc.2023.08.067 · Cited by 4
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The Changing Liver Transplant Recipient
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Venkatesh, S. K. (2026) · Expert Review of Gastroenterology & Hepatology · doi:10.1080/17474124.2026.2636184 · Cited by 3
“HCC can occur even in the absence of cirrhosis (Figure 5), and in about 35% of the patients with MASLD [107,108].”
Siriwong, N., Sriphoosanaphan, S., Decharatanachart, P., Yongpisarn, T., Kerr, S. J., Treeprasertsuk, S., Tiyarattanachai, T., Apiparakoon, T., Hagström, H., Akbari, C., et al. (2025) · European Journal of Gastroenterology & Hepatology · doi:10.1097/meg.0000000000002912 · Cited by 3
“NAFLD-related HCC can develop in the absence of cirrhosis [7,8].”
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“The sequential progression from chronic liver disease to fibrosis and cirrhosis leads to HCC in 80% of cases, but approximately 20% of all HCC cases occur in the context of non-alcoholic steatohepatitis (NASH) [3–5].”
Nerusch, J., Schicht, G., Herzog, N., Küpper, J.-H., Seehofer, D., & Damm, G. (2025) · Cells · doi:10.3390/cells14161254 · Cited by 3
NAFLD-Associated Hepatocellular Carcinoma: a Threat to Patients with Metabolic Disorders
Sasdelli, A., Brodosi, L., & Marchesini, G. (2016) · Current Hepatology Reports · doi:10.1007/s11901-016-0297-7 · Cited by 3
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Obesity and cancers of the liver, gallbladder, and pancreas
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Risk Stratification for Hepatocellular Carcinoma in Patients with Non-alcoholic Fatty Liver Disease
Truong, E., Han, C., Muthiah, M. D., & Noureddin, M. (2023) · Current Hepatology Reports · doi:10.1007/s11901-023-00595-7 · Cited by 3
Wang, B., Zhang, Y.-Q., Gai, L.-P., He, Y., Qiu, H., & Li, P. (2023) · Cellular and Molecular Biology · doi:10.14715/cmb/2023.69.7.28 · Cited by 2
“/ Biomarkers in NASH-induced hepatocellular carcinoma, 2023, 69(7): 174-180”
BackgroundInfluentialS3-Leitlinie „Diagnostik und Therapie biliärer Karzinome“ – Langversion 4.0
Groß, S., Bitzer, M., Albert, J., Blödt, S., Boda‐Heggemann, J., Brunner, T. B., Caspari, R., Toni, E. D., Dombrowski, F., Evert, M., et al. (2024) · Zeitschrift für Gastroenterologie · doi:10.1055/a-2189-8567 · Cited by 3
Lara, I. P., Ortiz‐López, M. G., Bonilla‐Delgado, J., Pérez-Escobar, J., Godínez-Aguilar, R., Luévano‐Contreras, C., Espinosa-García, A. M., Duran, J. P., Alonso-Themann, P. G., Nolasco‐Quiroga, M., et al. (2024) · Annals of Hepatology · doi:10.1016/j.aohep.2024.101562 · Cited by 5
Evaluation of Adjuvant Chemotherapy-Associated Steatosis (CAS) in Colorectal Cancer
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“More ominous complications of the spectrum of fatty liver diseases include cirrhosis and hepatocellular carcinoma [3,4].”
BackgroundNontumor Prognostic Factors in Hepatocellular Carcinoma
Goossens, N., Labgaa, I., & Villanueva, A. (2016) · Springer eBooks · doi:10.1007/978-3-319-34214-6_8 · Cited by 3
Epidemiology of hepatocellular carcinoma in nonalcoholic fatty liver disease
Moriguchi, M., Seko, Y., Takahashi, A., & Itoh, Y. (2019) · Hepatoma Research · doi:10.20517/2394-5079.2019.20 · Cited by 4
“There has been an increase in the number of cases of HCC that developed in NAFLD patients without cirrhosis([92,93]).”
BackgroundHepatocellular Carcinoma Screening and Nonalcoholic Fatty Liver Disease: How is it Different?
Acharya, S., & Bopanna, S. (2020) · Journal of Clinical and Experimental Hepatology · doi:10.1016/j.jceh.2020.04.004 · Cited by 3
Mitochondrial and anabolic pathways in hepatocellular carcinoma
Timchenko, N. A. (2017) · Hepatology · doi:10.1002/hep.29559 · Cited by 3
“(3) The liver is a key tissue in metabolic homeostasis regulation, and recent discoveries have shown that certain metabolic alterations are critical in the development of HCC.(2,3) However, very little is known about the specific mechanisms and key factors that drive the metabolicdependent pathways of HCC.”
BackgroundResultInfluentialLavekar, A. S., Deshpande, A., & Raje, D. (2020) · Clinical and Experimental Hepatology · doi:10.5114/ceh.2020.102152 · Cited by 2
“Despite the serious long-term effects associated with NAFLD, the awareness about NAFLD in the general population is low [20, 21].”
BackgroundTkachuk, B., Stukalin, I., Wang, Y., & Congly, S. E. (2025) · ACG Case Reports Journal · doi:10.14309/crj.0000000000001620 · Cited by 2
S3-Leitlinie Diagnostik und Therapie biliärer Karzinome – Langversion
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S3-Leitlinie Diagnostik und Therapie des Hepatozellulären Karzinoms – Langversion
Bitzer, M., Groß, S., Albert, J., Blödt, S., Boda‐Heggemann, J., Borucki, K., Brunner, T. B., Caspari, R., Dombrowski, F., Evert, M., et al. (2025) · Zeitschrift für Gastroenterologie · doi:10.1055/a-2460-6298 · Cited by 4
Ding, X., Yin, X. S., Zheng, L., Zhou, L., Hu, J., Sun, W., Sun, L., Shen, Y., Teng, Y., Xu, Y., et al. (2025) · Acta Oncologica · doi:10.2340/1651-226x.2025.42652 · Cited by 3
“Hepatocellular carcinoma (HCC) accounts for 90% of primary liver tumors and is the third leading cause of cancer-related deaths worldwide [1, 2].”
Metabolites involvement in the growth and spread of liver cancer
Gautam, A. K., Kumar, V. B., Sonkar, A. B., Singh, A., Yadav, D., Rajan, N., Kumar, P., Singh, S., Saha, S., & Rajamanickam, V. M. (2025) · Liver Research · doi:10.1016/j.livres.2025.10.005 · Cited by 2
“55”
Metadata
- Authors
- Mittal, S., El-Serag, H. B., Sada, Y. H., Kanwal, F., Duan, Z., Temple, S., May, S. B., Kramer, J. R., Richardson, P. A., & Davila, J. A.
- Affiliations
- Michael E. DeBakey VA Medical Center (US)
- Corresponding author
- Mittal, Sahil
- Venue
- Clinical Gastroenterology and Hepatology
- Publisher
- Elsevier BV
- Published
- 2016-01
- Volume
- 14
- Issue
- 1
- Pages
- 124-131.e1
- ISSN
- 1542-3565 (ISSN-L)
- PMC
- PMC4690789
- OpenAlex
- W1258381707
- Cited by
- 648
- References
- 34
- Citations by year
- 2026: 27 · 2025: 63 · 2024: 61 · 2023: 64 · 2022: 77 · 2021: 99 · 2020: 85 · 2019: 60 · 2018: 47 · 2017: 41 · 2016: 19
- FWCI
- 22.09
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Clinical Gastroenterology and Hepatology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA160738)
- Topics
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- hepatocellular carcinoma, non-alcoholic fatty liver disease, liver cirrhosis, metabolic syndrome, risk factors, veterans, hepatitis C virus, alcohol abuse, liver fibrosis markers
- MeSH terms
- Aged, Aged, 80 and over, Female, Carcinoma, Hepatocellular, Humans, Male, Middle Aged, Risk Factors, United States, Veterans, Cohort Studies, Metabolic Syndrome, Non-alcoholic Fatty Liver Disease
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