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.
“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]
The Results section reports an unadjusted odds ratio of 5.4 for HCC without cirrhosis in patients with NAFLD-related HCC versus patients with HCV-related HCC. But the cohort comprised patients who already had HCC; the analysis does not establish a fivefold higher risk of developing HCC among all individuals with MASLD than among those with chronic hepatitis C. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAlthough HCC may develop in non-cirrhotic MASLD, cirrhosis remains the key risk factor for HCC.
“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]
In a US Veterans Administration cohort including 1,500 individuals with HCC from 2005 to 2010, metabolic syndrome was particularly prevalent in the subgroup who had no cirrhosis.
“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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“Unlike other chronic liver diseases, such as viral or alcoholic hepatitis, this may happen even in the absence of cirrhosis.(65,66) Indeed, Ertle et al.”
BackgroundNonalcoholic Fatty Liver Disease
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Non-alcoholic fatty liver disease: A patient guideline
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“Importantly, HCC has also been reported in patients with NASH who do not have cirrhosis, and even in patients with NAFL.(41,42) It is not clear how big this risk is exactly, but in general, the more severe the disease is, the higher the risk is.”
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“In Western societies, infl mmation with non-alcoholic fatty liver disease leads to the development of HCC, along with obesity nd type 2 diabetes mellitus [14,15].”
BackgroundMahmud, N., Kaplan, D. E., Taddei, T. H., & Goldberg, D. S. (2019) · Hepatology · doi:10.1002/hep.30494 · Cited by 190 · see citing works
“The VOCAL cohort has also been used for numerous prior studies focused on patients with chronic liver disease(13-16) and is very representative of the United Network for Organ Sharing (UNOS) liver transplant distribution from an etiology standpoint (Supporting Fig.”
MethodZheng, Y., Wang, S., Wu, J., & Wang, Y. (2023) · Journal of Translational Medicine · doi:10.1186/s12967-023-04367-1 · Cited by 192 · see citing works
Global Epidemiology of Nonalcoholic Fatty Liver Disease and Perspectives on US Minority Populations
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“USA 27–34 % [13, 41, 47, 114] 3–5 % [13] 10–20 % [48]”
Pathogenesis and Current Treatment Strategies of Hepatocellular Carcinoma
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“Especially in industrialized nations, the proportion of patients with an HCC based on the presence of NAFLD without cirrhosis is increasing [30].”
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Should we undertake surveillance for HCC in patients with NAFLD?
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Ciaula, A. D., Baj, J., Garruti, G., Celano, G., Angelis, M. D., Wang, H. H., Palo, D. M. D., Bonfrate, L., Wang, D. Q. ‐., & Portincasa, P. (2020) · Journal of Clinical Medicine · doi:10.3390/jcm9082648 · Cited by 164 · see citing works
“Furthermore, hepatocellular carcinoma (HCC) can originate from cirrhosis [6,16–18] but also from NASH [19].”
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Kaplan, D. E., Serper, M., Mehta, R. L., Fox, R. K., John, B. V., Aytaman, A., Baytarian, M. L., Hunt, K. K., Albrecht, J. H., Njei, B. M., et al. (2019) · Gastroenterology · doi:10.1053/j.gastro.2019.01.026 · Cited by 158 · see citing works
Nonalcoholic Fatty Liver Disease
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Nonalcoholic Fatty Liver Disease and Recent Guideline Updates
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Mittal, S., Kanwal, F., Ying, J., Chung, R., Sada, Y. H., Temple, S., Davila, J. A., & El‐Serag, H. B. (2016) · Journal of Hepatology · doi:10.1016/j.jhep.2016.07.025 · Cited by 145 · see citing works
“HCC Surveillance Two hepatologists (HES, SM) manually reviewed the EMR including imaging reports, laboratory tests, and physician notes within the 2 years prior to the HCC diagnosis date to determine receipt of HCC surveillance, presence or absence of cirrhosis, and recognition of cirrhosis status by providers [20,21].”
MethodKhalaf, N. I., Ying, J., Mittal, S., Temple, S., Kanwal, F., Davila, J. A., & El‐Serag, H. B. (2016) · Clinical Gastroenterology and Hepatology · doi:10.1016/j.cgh.2016.07.033 · Cited by 138 · see citing works
“0.(16) Model for End-Stage Liver Disease (MELD) and ChildPugh scores were calculated from laboratory tests and clinical features obtained from progress notes.”
MethodThe microbiome and hepatobiliary-pancreatic cancers
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“Experimental studies using a mouse model of diethylnitrosamine-induced HCC suggest that lipopolysaccharide from intestinal Gram-negative microbes can potentiate tumor progression through the activation of TLR4 expressed on hepatocytes and hepatic stellate cells [33,34].”
BackgroundInfluentialNonalcoholic Fatty Liver Disease (NAFLD). Mitochondria as Players and Targets of Therapies?
Ciaula, A. D., Passarella, S., Shanmugam, H., Noviello, M., Bonfrate, L., Wang, D. Q. ‐., & Portincasa, P. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22105375 · Cited by 133 · see citing works
“Carriers of the variant p.I148M have an increased risk of developing NAFLD [7], liver fibrosis and cirrhosis [8], and hepatocellular carcinoma (HCC) [9–11]; - Membrane-bound O-acyltransferase domain-containing 7 gene (MBOAT7) has lysophosphatidylinositol acyltransferase activity with the regulation of arachidonic acid…”
BackgroundInfluentialNonalcoholic fatty liver disease and liver transplantation - Where do we stand?
Mikolašević, I., Filipec-Kanižaj, T., Mijić, M., Jakopčić, I., Milić, S., Hrstić, I., Sobočan, N., Štimac, D., & Burra, P. (2018) · World Journal of Gastroenterology · doi:10.3748/wjg.v24.i14.1491 · Cited by 131 · see citing works
Gawrieh, S., Dakhoul, L., Miller, E., Scanga, A. E., deLemos, A. S., Kettler, C. D., Burney, H. N., Liu, H., Abu‐Sbeih, H., Chalasani, N., et al. (2019) · Alimentary Pharmacology & Therapeutics · doi:10.1111/apt.15464 · Cited by 130 · see citing works
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MASLD and the Development of HCC: Pathogenesis and Therapeutic Challenges
Phoolchund, A. G. S., & Khakoo, S. (2024) · Cancers · doi:10.3390/cancers16020259 · Cited by 127 · see citing works
“As a result of this, they are less likely to be o ff ered curative surgical therapies, such as orthotopic liver transplantation (OLT) or resection [81], with fewer options for HCC-speci fi c treatment [55], and, hence, they have worse outcomes.”
BackgroundThe Race to Bash NASH: Emerging Targets and Drug Development in a Complex Liver Disease
Romero, F. A., Jones, C. T., Xu, Y., Fenaux, M., & Halcomb, R. L. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b01701 · Cited by 126 · see citing works
Risk stratification and early detection biomarkers for precision HCC screening
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“NASH represents a particular high-risk situation for HCC, and HCC can even arise in non-cirrhotic livers [68, 69].”
BackgroundHuman biomimetic liver microphysiology systems in drug development and precision medicine
Gough, A., Soto-Gutierrez, A., Vernetti, L., Ebrahimkhani, M. R., Stern, A. M., & Taylor, D. L. (2021) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-020-00386-1 · Cited by 117 · see citing works
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Hepatocellular Carcinoma: An Overview of the Changing Landscape of Treatment Options
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“patients not only lacking signs of cirrhosis but also without histological evidence of hepatitis.(5,6) However, cirrhosis is still present at the time of diagnosis in the majority of cases.”
BackgroundA Practical Guideline for Hepatocellular Carcinoma Screening in Patients at Risk
Frenette, C. T., Isaacson, A., Bargellini, I., Saab, S., & Singal, A. G. (2019) · Mayo Clinic Proceedings Innovations Quality & Outcomes · doi:10.1016/j.mayocpiqo.2019.04.005 · Cited by 108 · see citing works
“In a retrospective cohort study among 1500 US veterans, 13% of HCC cases developed in the absence of cirrhosis, with NAFLD being the main risk factor.(36) Furthermore, it has been suggested that patients with noncirrhotic NAFLD have a higher mortality rate than patients with HCC at the background of cirrhotic NAFLD.”
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Progress in Nonalcoholic Fatty Liver Disease: SIRT Family Regulates Mitochondrial Biogenesis
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Natural history of NASH and HCC
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“In this context, understanding the global burden of complications of CLD (cirrhosis and LC) according to etiology of CLD, geographic location, and trends over time will be important.(8) Although there are adequate data on the prevalence and mortality associated with CLD, data on morbidity and DALYs related to CLD are…”
BackgroundNASH and Hepatocellular Carcinoma: Immunology and Immunotherapy
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“In addition, NAFLD is one of the fastest growing causes for liver cancer in the USA (63).”
BackgroundInflammatory and fibrotic mechanisms in NAFLD—Implications for new treatment strategies
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Characteristics and outcome of hepatocellular carcinoma in patients with NAFLD without cirrhosis
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“Having NAFLD or metabolic syndrome was independently associated with HCC in the absence of cirrhosis [73].”
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“Liver-targeted uncoupling also leads to reduced hepatic VLDL production [4], reducing intramyocellular plasma membrane sn-1,2-DAG content and PKCq/PKCε activity and reversing muscle insulin resistance [5].”
BackgroundMAFLD enhances clinical practice for liver disease in the Asia-Pacific region
Kawaguchi, T., Tsutsumi, T., Nakano, D., Eslam, M., George, J., & Torimura, T. (2021) · Clinical and Molecular Hepatology · doi:10.3350/cmh.2021.0310 · Cited by 92 · see citing works
Statins Are Underutilized in Patients with Nonalcoholic Fatty Liver Disease and Dyslipidemia
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“However, several studies have employed this approach to account for limitations of preexisting clinical data [13, 20].”
BackgroundEpigenetic remodelling in human hepatocellular carcinoma
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The metabolic basis of nonalcoholic steatohepatitis
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- 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 · 2015: 5
- 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 › Epidemiology › 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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