Cited by 648Hepatocellular Carcinoma Treatment and PrognosisLiver Disease Diagnosis and TreatmentLiver physiology and pathology

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Hepatocellular Carcinoma in the Absence of Cirrhosis in United States Veterans Is Associated With Nonalcoholic Fatty Liver Disease

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Mittal, Sahil, El-Serag, Hashem B., Sada, Yvonne H., Kanwal, Fasiha, Duan, Zhigang, Temple, Sarah, May, Sarah B., Kramer, Jennifer R., Richardson, Peter A., Davila, Jessica A.·2016·Clinical Gastroenterology and Hepatology

DOI 10.1016/j.cgh.2015.07.019PMC PMC4690789

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Abstract

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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Method
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ResultInfluential
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Background
The interrelation of cardiometabolic risk factors and metabolic dysfunction-associated steatotic liver disease subtypes
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Background
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Mazzolini, G. D., Kaya, E., & Canbay, A. E. (2021) · HepatoBiliary Surgery and Nutrition · doi:10.21037/hbsn-21-406 · Cited by 2
“In comparison with HCV, the risk of developing HCC is increased 5-fold in NAFLD and metabolic syndrome in non-cirrhotic patients (5).”
Background
Brief Report: Accuracy of FIB-4 for Cirrhosis in People Living With HIV and Hepatocellular Carcinoma
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Background
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Romeo, M., Basile, C., Martinelli, G., Nardo, F. D., Napolitano, C., Gregorio, A. D., Vaia, P., Puorto, L. D., Indipendente, M., Federico, A., et al. (2026) · Cancers · doi:10.3390/cancers18081316 · Cited by 1
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Azzam, S. M., Straus, A. J., Senkal, C. E., & Sarkar, D. (2026) · Cancers · doi:10.3390/cancers18142335 · Cited by 1
Evaluation of Serum Level of Thioredoxin and its Gene Polymorphism in Diagnosis of Hepatocellular Carcinoma of HCV-Infected Patients
Nassar, A., El-Rauf, H. A., Mohammed, S. A., & Mostafa, A. (2020) · Benha Medical Journal · doi:10.21608/bmfj.2020.119555 · Cited by 1
“Table (3): Comparison between the studied groups regarding Serum level of thioredoxin”
Background
Response of Human Liver Tissue to Innate Immune Stimuli
Wu, X., Roberto, J. B., Knupp, A., Greninger, A. L., Truong, C. D., Hollingshead, N., Kenerson, H. L., Tuefferd, M., Chen, A., Koelle, D. M., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.811551 · Cited by 1
“Likewise, the untreated chronic HCV livers were fibrotic as expected (40).”
Background
Occurrence of Liver Cancer in People without Traditional Risk Factors
Choi, J., Park, J., Lee, J. K., & Cho, K. (2023) · Korean Journal of Clinical Geriatrics · doi:10.15656/kjcg.2023.24.1.41
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Romero-Gutiérrez, M., Pascual, S., Márquez, L., Rubio, M. G., Miquel, M., Alarcón, C., Ferrer, T., Aracil, C., Horta, D., Latorre, R., et al. (2023) · Gastroenterología y Hepatología · doi:10.1016/j.gastrohep.2023.08.008 · Cited by 1
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Niriella, M. A., Dassanayake, U. B., & de Silva, H. J. (2023) · Expert Review of Gastroenterology & Hepatology · doi:10.1080/17474124.2023.2255515 · Cited by 1
“cirrhotic NASH for HCC may not be cost-effective or widely recommended [6,8].”
Background
Natural history of nonalcoholic fatty liver disease
Crocombe, D., & Tsochatzis, E. A. (2024) · Elsevier eBooks · doi:10.1016/b978-0-323-99649-5.00014-5 · Cited by 1
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“This injury, though infrequent, is of significant concern as it can herald the progression of the disease towards more severe manifestations [3].”
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“11 Patients without cirrhosis who underwent palliative therapy with TACE had significantly improved survival compared with patients with cirrhosis.”
Prediction model of hepatocellular carcinoma development in chronic hepatitis B virus infection in a Spanish cohort
Gavilán, P., Gavilán, J.-C., Arnedo, R., Clavijo, E., Viciana, I., & Correa, J. A. G. (2024) · Medicina Clínica · doi:10.1016/j.medcli.2024.07.022 · Cited by 1
Research Progress on Multidisciplinary Intervention for Metabolic Dysfunction-Associated Steatotic Liver Disease and Related Liver Cancer
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Moolla, Y., & Ramsuran, V. (2024) · Liver international communications. · doi:10.1002/lci2.70006 · Cited by 1
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“Nevertheless, MAFLD-HCC is frequently diagnosed at an advanced stage and is associated with a higher incidence of complications, which results in fewer than 20% of patients being eligible for hepatectomy [35].”
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Kawai‐Kitahata, F., Asahina, Y., Kakinuma, S., Inada, K., Mochida, T., Watakabe, K., Nobusawa, T., Shimizu, T., Tsuchiya, J., Miyoshi, M., et al. (2025) · Hepatology Research · doi:10.1111/hepr.14214 · Cited by 1
“11,12 Genomic analyses of HCC have revealed that key pathways, frequently mutated driver genes, and mutational signatures are associated with risk factors.”
Mechanistic Insights into Proglumide’s Role in Immune Cell Efficacy and Response to Immune Checkpoint Inhibitor Therapy in Hepatocellular Carcinoma
Doneparthi, P. S., Cao, H., Chen, W., Dou, W., Fang, H., & Smith, J. P. (2025) · Cancers · doi:10.3390/cancers17182998 · Cited by 1
“Currently, hepatocellular carcinoma (HCC) is the fastest growing cause of cancer-related deaths [1].”
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“Ainsi, jusqu’à 50 % des CHC sur stéatopathie pourraient survenir en l’absence de cirrhose [20], et dans une étude récente, 34,6 % des patients avec CHC sur stéatopathie n’avaient pas de cirrhose [21].”
Background
Magnetic Resonance Elastography of the Liver
Asrani, S. K., & Talwalkar, J. A. (2018) · Springer eBooks · doi:10.1007/978-3-319-72628-1_15 · Cited by 1
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Intrahepatic crystals from elevated dietary cholesterol are sufficient to stiffen the liverPreprint
Li, D., Loneker, A. E., Safraou, Y., Ford, J., Mihelc, E. M., Levental, K. R., Levental, I., Sack, I., Janmey, P. A., & Wells, R. G. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.12.29.630682 · Cited by 1
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Virović-Jukić, L., Forgač, J., Ogresta, D., Filipec-Kanižaj, T., & Mrzljak, A. (2018) · Clinical gastroenterology · doi:10.1007/978-3-319-75856-5_21
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Mass in a fatty liver
van der Windt, D. J., Wilson, G. C., Ziogas, I. A., Tohme, S. T., Furlan, A., Nalesnik, M. A., & Geller, D. A. (2019) · Frontline Gastroenterology · doi:10.1136/flgastro-2019-101284
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Baldwin, X. L., Desai, C. S., & Gerber, D. A. (2020) · Journal of Gastrointestinal Surgery · doi:10.1007/s11605-020-04526-5
“A total of 1203 patients had confirmed cirrhosis leaving 13% of patients with HCC in the absence of cirrhosis.(1) Our patient had no findings during preoperative workup suggestive of cirrhosis or prior history of the above risk factors, creating a unique situation for the development of a large HCC tumor burden.”
Background
The Spectrum of NAFLD: From the Organ to the System
Sanchez-Torrijos, Y., & Ampuero, J. (2020) · Springer eBooks · doi:10.1007/978-3-030-37173-9_1
HCC in Patients with NAFLD/NASH
Stefano, J., Malta, F. D. M., de Campos, P. B., Andrade, P., Paranaguá-Vezzozo, D. C., Carrilho, F., & Oliveira, C. (2020) · Springer eBooks · doi:10.1007/978-3-030-37173-9_11 · Cited by 1
Hepatocellular Carcinoma in a Patient With Hepatic Steatosis
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“8) with patients with both HCC and NAFLD without cirrhosis when compared with patients with hepatitis C virus-related HCC without cirrhosis.(4) Another recent study of patients with NAFLD found approximately 20% had HCC in the absence of cirrhosis.”
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Liver Transplantation and NAFLD/NASH
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NAFLD, Hepatocellular Carcinoma, and Extrahepatic Cancers
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Editorial comment on hepatocellular carcinoma in the noncirrhotic liver: Clinical characteristics and results in Veracruz, Mexico
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Gut-Hepatic Relationship: From Disorders of the Gut Microbiota to Hepatocellular Carcinoma
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“The progression of HCC in NASH occurs in the absence of LC [6] in more than 25%, which is significantly higher than the frequency observed in other liver diseases [7].”
Comentario editorial sobre carcinoma hepatocelular en hígado no cirrótico: características clínicas y resultados en Veracruz, México
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NASH Diagnosis Made Better but Maybe Not Yet Easier
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The EMRG Consortium: a gate to identify the burden of metabolic (dysfunction)-associated fatty liver disease in Egypt
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The Correlation of Glycemic Index, Glycemic Load, and Carbohydrates with the Risk of Hepatocellular Carcinoma: A Systematic Review and Meta-AnalysisPreprint
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Viral alcoholic and fatty liver diseases
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Metabolic Syndrome and Liver Cancer
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An algorithm for the management of non-alcoholic fatty liver disease in primary care
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Abstracts
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Publisher's Note
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Background
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Gastrointestinal Sistem Tümörleri-1
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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
ORCID: Sada, Yvonne H.
Kanwal, Fasiha
May, Sarah B.
Kramer, Jennifer R.
Venue: Clinical Gastroenterology and Hepatology
Publisher: Elsevier BV
Published: 2016-01
Volume: 14
Issue: 1
Pages: 124-131.e1
ISSN: 1542-3565 (ISSN-L)
DOI: 10.1016/j.cgh.2015.07.019
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
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
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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Hepatocellular Carcinoma in the Absence of Cirrhosis in United States Veterans Is Associated With Nonalcoholic Fatty Liver Disease

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