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Romeo M, Dallio M, Napolitano C, Basile C, Di Nardo F, Vaia P, Iodice P, Federico A. Clinical Applications of Artificial Intelligence (AI) in Human Cancer: Is It Time to Update the Diagnostic and Predictive Models in Managing Hepatocellular Carcinoma (HCC)? Diagnostics (Basel) 2025; 15:252. [PMID: 39941182 PMCID: PMC11817573 DOI: 10.3390/diagnostics15030252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Revised: 01/20/2025] [Accepted: 01/21/2025] [Indexed: 02/16/2025] Open
Abstract
In recent years, novel findings have progressively and promisingly supported the potential role of Artificial intelligence (AI) in transforming the management of various neoplasms, including hepatocellular carcinoma (HCC). HCC represents the most common primary liver cancer. Alarmingly, the HCC incidence is dramatically increasing worldwide due to the simultaneous "pandemic" spreading of metabolic dysfunction-associated steatotic liver disease (MASLD). MASLD currently constitutes the leading cause of chronic hepatic damage (steatosis and steatohepatitis), fibrosis, and liver cirrhosis, configuring a scenario where an HCC onset has been reported even in the early disease stage. On the other hand, HCC represents a serious plague, significantly burdening the outcomes of chronic hepatitis B (HBV) and hepatitis C (HCV) virus-infected patients. Despite the recent progress in the management of this cancer, the overall prognosis for advanced-stage HCC patients continues to be poor, suggesting the absolute need to develop personalized healthcare strategies further. In this "cold war", machine learning techniques and neural networks are emerging as weapons, able to identify the patterns and biomarkers that would have normally escaped human observation. Using advanced algorithms, AI can analyze large volumes of clinical data and medical images (including routinely obtained ultrasound data) with an elevated accuracy, facilitating early diagnosis, improving the performance of predictive models, and supporting the multidisciplinary (oncologist, gastroenterologist, surgeon, radiologist) team in opting for the best "tailored" individual treatment. Additionally, AI can significantly contribute to enhancing the effectiveness of metabolomics-radiomics-based models, promoting the identification of specific HCC-pathogenetic molecules as new targets for realizing novel therapeutic regimens. In the era of precision medicine, integrating AI into routine clinical practice appears as a promising frontier, opening new avenues for liver cancer research and treatment.
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Affiliation(s)
- Mario Romeo
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80138 Naples, Italy; (M.R.); (C.N.); (C.B.); (F.D.N.); (P.V.); (A.F.)
| | - Marcello Dallio
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80138 Naples, Italy; (M.R.); (C.N.); (C.B.); (F.D.N.); (P.V.); (A.F.)
| | - Carmine Napolitano
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80138 Naples, Italy; (M.R.); (C.N.); (C.B.); (F.D.N.); (P.V.); (A.F.)
| | - Claudio Basile
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80138 Naples, Italy; (M.R.); (C.N.); (C.B.); (F.D.N.); (P.V.); (A.F.)
| | - Fiammetta Di Nardo
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80138 Naples, Italy; (M.R.); (C.N.); (C.B.); (F.D.N.); (P.V.); (A.F.)
| | - Paolo Vaia
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80138 Naples, Italy; (M.R.); (C.N.); (C.B.); (F.D.N.); (P.V.); (A.F.)
| | | | - Alessandro Federico
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80138 Naples, Italy; (M.R.); (C.N.); (C.B.); (F.D.N.); (P.V.); (A.F.)
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Nahon P, Bamba-Funck J, Layese R, Trépo E, Zucman-Rossi J, Cagnot C, Ganne-Carrié N, Chaffaut C, Guyot E, Ziol M, Sutton A, Audureau E. Integrating genetic variants into clinical models for hepatocellular carcinoma risk stratification in cirrhosis. J Hepatol 2023; 78:584-595. [PMID: 36427656 DOI: 10.1016/j.jhep.2022.11.003] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 10/06/2022] [Accepted: 11/01/2022] [Indexed: 11/23/2022]
Abstract
BACKGROUND & AIMS Identifying individuals at higher risk of developing hepatocellular carcinoma (HCC) is pivotal to improve the performance of surveillance strategies. Herein, we aimed to evaluate the ability of single nucleotide polymorphisms (SNPs) to refine HCC risk stratification. METHODS Six SNPs in PNPLA3, TM6SF2, HSD17B13, APOE, and MBOAT7 affecting lipid turnover and one variant involved in the Wnt-β-catenin pathway (WNT3A-WNT9A rs708113) were assessed in patients with alcohol-related and/or HCV-cured cirrhosis included in HCC surveillance programmes (prospective CirVir and CIRRAL cohorts). Their prognostic value for HCC occurrence was assessed using Fine-Gray models combined into a 7-SNP genetic risk score (GRS). The predictive ability of two clinical scores (a routine non-genetic model determined by multivariate analysis and the external aMAP score) with/without the GRS was evaluated by C-indices. The standardised net benefit was derived from decision curves. RESULTS Among 1,145 patients, 86 (7.5%) developed HCC after 43.7 months. PNPLA3 and WNT3A-WNT9A variants were independently associated with HCC occurrence. The GRS stratified the population into three groups with progressively increased 5-year HCC incidence (Group 1 [n = 627, 5.4%], Group 2 [n = 276, 10.7%], and Group 3 [n = 242, 15.3%]; p <0.001). The multivariate model identified age, male sex, diabetes, platelet count, gamma-glutamyltransferase levels, albuminemia and the GRS as independent risk factors. The clinical model performance for 5-year HCC prediction was similar to that of the aMAP score (C-Index 0.769). The addition of the GRS to both scores modestly improved their performance (C-Indices of 0.786 and 0.783, respectively). This finding was confirmed by decision curve analyses showing only fair clinical net benefit. CONCLUSIONS Patients with cirrhosis can be stratified into HCC risk classes by variants affecting lipid turnover and the Wnt-β-catenin pathway. The incorporation of this genetic information modestly improves the performance of clinical scores. IMPACT AND IMPLICATIONS The identification of patients at higher risk of developing liver cancer is pivotal to improve the performance of surveillance. Risk assessment can be achieved by combining several clinical and biological parameters used in routine practice. The addition of patients' genetic characteristics can modestly improve this prediction and will ultimately pave the way for precision medicine in patients eligible for HCC surveillance, allowing physicians to trigger personalised screening strategies.
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Affiliation(s)
- Pierre Nahon
- APHP, Liver Unit, Bobigny, Université Sorbonne Paris Nord, F-93000 Bobigny, France; Inserm, UMR-1138 "Functional Genomics of Solid Tumors", Centre de Recherche des Cordeliers, Université de Paris, Paris, France.
| | - Jessica Bamba-Funck
- APHP, Biochemistry Unit, Bobigny, Université Sorbonne Paris Nord, and Inserm, UMR-1148 "Laboratory for Vascular Translational Science" Université Sorbonne Paris Nord, F-93000 Bobigny, France
| | - Richard Layese
- Univ Paris Est Créteil, INSERM, IMRB, Equipe CEpiA (Clinical Epidemiology and Ageing), Unité de Recherche Clinique (URC Mondor), Service de Santé Publique, Assistance Publique Hôpitaux de Paris (AP-HP), Hôpitaux Universitaires Henri Mondor, F-94000, Créteil, France
| | - Eric Trépo
- Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, CUB Hopital Erasme, and Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium
| | - Jessica Zucman-Rossi
- Inserm, UMR-1138 "Functional Genomics of Solid Tumors", Centre de Recherche des Cordeliers, Université de Paris, Paris, France
| | - Carole Cagnot
- Clinical Research Department, ANRS|Emerging Infectious Diseases, Paris, France
| | | | - Cendrine Chaffaut
- SBIM, APHP, Hôpital Saint-Louis, Paris, Inserm, UMR-1153, ECSTRA Team, Paris, France
| | - Erwan Guyot
- APHP, Biochemistry Unit, Bobigny, Université Sorbonne Paris Nord, and Inserm, UMR-1148 "Laboratory for Vascular Translational Science" Université Sorbonne Paris Nord, F-93000 Bobigny, France
| | - Marianne Ziol
- APHP, Pathology Unit, Bobigny, Université Sorbonne Paris Nord, F-93000 Bobigny, France; Inserm, UMR-1138 "Functional Genomics of Solid Tumors", Centre de Recherche des Cordeliers, Université de Paris, Paris, France
| | - Angela Sutton
- APHP, Biochemistry Unit, Bobigny, Université Sorbonne Paris Nord, and Inserm, UMR-1148 "Laboratory for Vascular Translational Science" Université Sorbonne Paris Nord, F-93000 Bobigny, France
| | - Etienne Audureau
- Univ Paris Est Créteil, INSERM, IMRB, Equipe CEpiA (Clinical Epidemiology and Ageing), Unité de Recherche Clinique (URC Mondor), Service de Santé Publique, Assistance Publique Hôpitaux de Paris (AP-HP), Hôpitaux Universitaires Henri Mondor, F-94000, Créteil, France
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Nahon P, Najean M, Layese R, Zarca K, Segar LB, Cagnot C, Ganne-Carrié N, N’Kontchou G, Pol S, Chaffaut C, Carrat F, Ronot M, Audureau E, Durand-Zaleski I. Early hepatocellular carcinoma detection using magnetic resonance imaging is cost-effective in high-risk patients with cirrhosis. JHEP Rep 2022; 4:100390. [PMID: 34977518 PMCID: PMC8683591 DOI: 10.1016/j.jhepr.2021.100390] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 10/02/2021] [Accepted: 10/20/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND & AIMS Reinforced hepatocellular carcinoma (HCC) surveillance using magnetic resonance imaging (MRI) could increase early tumour detection but faces cost-effectiveness issues. In this study, we aimed to evaluate the cost-effectiveness of MRI for the detection of very early HCC (Barcelona Clinic Liver Cancer [BCLC] 0) in patients with an annual HCC risk >3%. METHODS French patients with compensated cirrhosis included in 4 multicentre prospective cohorts were considered. A scoring system was constructed to identify patients with an annual risk >3%. Using a Markov model, the economic evaluation estimated the costs and life years (LYs) gained with MRI vs. ultrasound (US) monitoring over a 20-year period. The incremental cost-effectiveness ratio (ICER) was calculated by dividing the incremental costs by the incremental LYs. RESULTS Among 2,513 patients with non-viral causes of cirrhosis (n = 840) and/or cured HCV (n = 1,489)/controlled HBV infection (n = 184), 206 cases of HCC were detected after a 37-month follow-up. When applied to training (n = 1,658) and validation (n = 855) sets, the construction of a scoring system identified 33.4% and 37.5% of patients with an annual HCC risk >3% (3-year C-Indexes 75 and 76, respectively). In patients with a 3% annual risk, the incremental LY gained with MRI was 0.4 for an additional cost of €6,134, resulting in an ICER of €15,447 per LY. Compared to US monitoring, MRI detected 5x more BCLC 0 HCC. The deterministic sensitivity analysis confirmed the impact of HCC incidence. At a willingness to pay of €50,000/LY, MRI screening had a 100% probability of being cost-effective. CONCLUSIONS In the era of HCV eradication/HBV control, patients with annual HCC risk >3% represent one-third of French patients with cirrhosis. MRI is cost-effective in this population and could favour early HCC detection. LAY SUMMARY The early identification of hepatocellular carcinoma in patients with cirrhosis is important to improve patient outcomes. Magnetic resonance imaging could increase early tumour detection but is more expensive and less accessible than ultrasound (the standard modality for surveillance). Herein, using a simple score, we identified a subgroup of patients with cirrhosis (accounting for >one-third), who were at increased risk of hepatocellular carcinoma and for whom the increased expense of magnetic resonance imaging would be justified by the potential improvement in outcomes.
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Key Words
- AFP, alpha-fetoprotein
- AMRI, abbreviated magnetic resonance imaging
- BCLC, Barcelona Clinic Liver Cancer
- HCC, hepatocellular carcinoma
- HR, hazard ratio
- ICER, incremental cost-effectiveness ratio
- LY, life years
- LYG, life years gained
- MRI
- MRI, magnetic resonance imaging
- NAFLD, non-alcoholic fatty liver disease
- QALY, quality-adjusted life year
- RFA, radiofrequency ablation
- SHR, subdistribution hazard ratio
- TACE, transarterial chemoembolization
- US, ultrasound
- cirrhosis
- cost-effectiveness
- liver cancer risk
- surveillance
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Affiliation(s)
- Pierre Nahon
- AP-HP, Hôpitaux Universitaires Paris Seine Saint-Denis, Liver Unit, Bobigny, France
- Université Sorbonne Paris Nord, F-93000 Bobigny, France
- Inserm, UMR-1138 “Functional Genomics of Solid Tumors”, Centre de recherche des Cordeliers, Université de Paris, Paris, France
| | - Marie Najean
- Université de Paris, CRESS, INSERM, INRA, URCEco, AP-HP, Hôpital de l’Hôtel Dieu, F-75004, Paris, France
| | - Richard Layese
- Univ Paris Est Créteil, INSERM, IMRB, Equipe CEpiA (Clinical Epidemiology and Ageing), Unité de Recherche Clinique (URC Mondor), Service de Santé Publique, Assistance Publique Hôpitaux de Paris (AP-HP), Hôpitaux Universitaires Henri Mondor, F-94000, Créteil, France
| | - Kevin Zarca
- Université de Paris, CRESS, INSERM, INRA, URCEco, AP-HP, Hôpital de l’Hôtel Dieu, F-75004, Paris, France
| | - Laeticia Blampain Segar
- Université de Paris, CRESS, INSERM, INRA, URCEco, AP-HP, Hôpital de l’Hôtel Dieu, F-75004, Paris, France
| | - Carole Cagnot
- Clinical Research Department, ANRS | Emerging Infectious Diseases, Paris, France
| | - Nathalie Ganne-Carrié
- AP-HP, Hôpitaux Universitaires Paris Seine Saint-Denis, Liver Unit, Bobigny, France
- Université Sorbonne Paris Nord, F-93000 Bobigny, France
- Inserm, UMR-1138 “Functional Genomics of Solid Tumors”, Centre de recherche des Cordeliers, Université de Paris, Paris, France
| | - Gisèle N’Kontchou
- AP-HP, Hôpitaux Universitaires Paris Seine Saint-Denis, Liver Unit, Bobigny, France
- Université Sorbonne Paris Nord, F-93000 Bobigny, France
- Inserm, UMR-1138 “Functional Genomics of Solid Tumors”, Centre de recherche des Cordeliers, Université de Paris, Paris, France
| | - Stanislas Pol
- Université de Paris, département d’hépatologie/Addictologie, Hôpital Cochin, APHP, Paris, France
| | - Cendrine Chaffaut
- SBIM, APHP, Hôpital Saint-Louis, Paris, France
- Inserm, UMR-1153, ECSTRA Team, Paris, France
| | - Fabrice Carrat
- Sorbonne Université, Inserm, Institut Pierre Louis d'Epidémiologie et de Santé Publique, AP-HP, Hôpital Saint-Antoine, Unité de Santé Publique, Paris, France
| | - Maxime Ronot
- AP-HP, Hôpital Beaujon, Service de Radiologie, Clichy, France
| | - Etienne Audureau
- Univ Paris Est Créteil, INSERM, IMRB, Equipe CEpiA (Clinical Epidemiology and Ageing), Unité de Recherche Clinique (URC Mondor), Service de Santé Publique, Assistance Publique Hôpitaux de Paris (AP-HP), Hôpitaux Universitaires Henri Mondor, F-94000, Créteil, France
| | - Isabelle Durand-Zaleski
- Université de Paris, CRESS, INSERM, INRA, URCEco, AP-HP, Hôpital de l’Hôtel Dieu, F-75004, Paris, France
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Demirtas CO, Brunetto MR. Surveillance for hepatocellular carcinoma in chronic viral hepatitis: Is it time to personalize it? World J Gastroenterol 2021; 27:5536-5554. [PMID: 34588750 PMCID: PMC8433616 DOI: 10.3748/wjg.v27.i33.5536] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Revised: 04/28/2021] [Accepted: 08/02/2021] [Indexed: 02/06/2023] Open
Abstract
Surveillance with abdominal ultrasound with or without alpha-fetoprotein is recommended by clinical practice guidelines for patients who are considered to be at risk of developing hepatocellular carcinoma (HCC), including those with cirrhosis, advanced fibrosis and special subgroups of chronic hepatitis B (CHB). Application of the standard surveillance strategy to all patients with chronic liver disease (CLD) with or without cirrhosis imposes major sustainability and economic burdens on healthcare systems. Thus, a number of HCC risk scores were constructed, mainly from Asian cohorts, to stratify the HCC prediction in patients with CHB. Similarly, even if less than for CHB, a few scoring systems were developed for chronic hepatitis C patients or cirrhotic patients with CLD of different etiologies. Recently, a few newsworthy HCC-risk algorithms were developed for patients with cirrhosis using the combination of serologic HCC markers and clinical parameters. Overall, the HCC risk stratification appears at hand by several validated multiple score systems, but their optimal performance is obtained only in populations who show highly homogenous clinic-pathologic, epidemiologic, etiologic and therapeutic characteristics and this limitation poses a major drawback to their sustainable use in clinical practice. A better understanding of the dynamic process driving the progression from CLD to HCC derived from studies based on molecular approaches and genetics, epigenetics and liquid biopsy will enable the identification of new biomarkers to define the individual risk of HCC in the near future, with the possibility to achieve a real and cost/effective personalization of surveillance.
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Affiliation(s)
- Coskun Ozer Demirtas
- Department of Gastroenterology and Hepatology, Marmara University, School of Medicine, Istanbul 34854, Turkey
| | - Maurizia Rossana Brunetto
- Department of Clinical and Experimental Medicine, University Hospital of Pisa, Pisa 56125, Italy
- Hepatology Unit, University Hospital of Pisa, Pisa 56125, Italy
- Biostructure and Bio-imaging Institute, National Research Council of Italy, Naples 56125, Italy
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Guo J, Gao XS. Prediction models for development of hepatocellular carcinoma in chronic hepatitis B patients. World J Clin Cases 2021; 9:3238-3251. [PMID: 34002133 PMCID: PMC8107908 DOI: 10.12998/wjcc.v9.i14.3238] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 02/11/2021] [Accepted: 03/17/2021] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis B (CHB)-related hepatocellular carcinoma (HCC) is a major health problem in Asian-Pacific regions. Antiviral therapy reduces, but does not completely prevent, HCC development. Thus, there is a need for accurate risk prediction to assist prognostication and decisions on the need for antiviral therapy and HCC surveillance. A few risk scores have been developed to predict the occurrence of HCC in CHB patients. Initially, the scores were derived from untreated CHB patients. With the development and extensive clinical application of nucleos(t)ide analog(s) (NA), the number of risk scores based on treated CHB patients has increased gradually. The components included in risk scores may be categorized into host factors and hepatitis B virus factors. Hepatitis activities, hepatitis B virus factors, and even liver fibrosis or cirrhosis are relatively controlled by antiviral therapy. Therefore, variables that are more dynamic during antiviral therapy have since been included in risk scores. However, host factors are more difficult to modify. Most existing scores derived from Asian populations have been confirmed to be accurate in predicting HCC development in CHB patients from Asia, while these scores have not offered excellent predictability in Caucasian patients. These findings support that more relevant variables should be considered to provide individualized predictions that are easily applied to CHB patients of different ethnicities. CHB patients should receive different intensities of HCC surveillance according to their risk category.
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Affiliation(s)
- Jiang Guo
- Department of Interventional Oncology, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Xue-Song Gao
- Department of General Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
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Stratification of Hepatocellular Carcinoma Risk Following HCV Eradication or HBV Control. J Clin Med 2021; 10:jcm10020353. [PMID: 33477752 PMCID: PMC7832303 DOI: 10.3390/jcm10020353] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 01/07/2021] [Accepted: 01/13/2021] [Indexed: 12/18/2022] Open
Abstract
Hepatocellular carcinoma (HCC) incidence has dramatically decreased in patients infected with HCV and HBV due to the widespread use of highly effective antiviral agents. Nevertheless, a substantial proportion of patients with advanced fibrosis or cirrhosis following HCV clearance of in case of HBV control whatever the stage of fibrosis remains at risk of liver cancer development. Cancer predictors in these virus-free patients include routine parameters estimating coexisting comorbidities, persisting liver inflammation or function impairment, and results of non-invasive tests which can be easily combined into HCC risk scoring systems. The latter enables stratification according to various liver cancer incidences and allocation of patients into low, intermediate or high HCC risk probability groups. All international guidelines endorse lifelong surveillance of these patients using semi-annual ultrasound, with known sensibility issues. Refining HCC prediction in this growing population ultimately will trigger personalized management using more effective surveillance tools such as contrast-enhanced imaging techniques or circulating biomarkers while taking into account cost-effectiveness parameters.
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Audureau E, Carrat F, Layese R, Cagnot C, Asselah T, Guyader D, Larrey D, De Lédinghen V, Ouzan D, Zoulim F, Roulot D, Tran A, Bronowicki JP, Zarski JP, Riachi G, Calès P, Péron JM, Alric L, Bourlière M, Mathurin P, Blanc JF, Abergel A, Chazouillères O, Mallat A, Grangé JD, Attali P, d'Alteroche L, Wartelle C, Dao T, Thabut D, Pilette C, Silvain C, Christidis C, Nguyen-Khac E, Bernard-Chabert B, Zucman D, Di Martino V, Sutton A, Pol S, Nahon P. Personalized surveillance for hepatocellular carcinoma in cirrhosis - using machine learning adapted to HCV status. J Hepatol 2020; 73:1434-1445. [PMID: 32615276 DOI: 10.1016/j.jhep.2020.05.052] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2019] [Revised: 04/21/2020] [Accepted: 05/14/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Refining hepatocellular carcinoma (HCC) surveillance programs requires improved individual risk prediction. Thus, we aimed to develop algorithms based on machine learning approaches to predict the risk of HCC more accurately in patients with HCV-related cirrhosis, according to their virological status. METHODS Patients with compensated biopsy-proven HCV-related cirrhosis from the French ANRS CO12 CirVir cohort were included in a semi-annual HCC surveillance program. Three prognostic models for HCC occurrence were built, using (i) Fine-Gray regression as a benchmark, (ii) single decision tree (DT), and (iii) random survival forest for competing risks survival (RSF). Model performance was evaluated from C-indexes validated externally in the ANRS CO22 Hepather cohort (n = 668 enrolled between 08/2012-01/2014). RESULTS Out of 836 patients analyzed, 156 (19%) developed HCC and 434 (52%) achieved sustained virological response (SVR) (median follow-up 63 months). Fine-Gray regression models identified 6 independent predictors of HCC occurrence in patients before SVR (past excessive alcohol intake, genotype 1, elevated AFP and GGT, low platelet count and albuminemia) and 3 in patients after SVR (elevated AST, low platelet count and shorter prothrombin time). DT analysis confirmed these associations but revealed more complex interactions, yielding 8 patient groups with varying cancer risks and predictors depending on SVR achievement. On RSF analysis, the most important predictors of HCC varied by SVR status (non-SVR: platelet count, GGT, AFP and albuminemia; SVR: prothrombin time, ALT, age and platelet count). Externally validated C-indexes before/after SVR were 0.64/0.64 [Fine-Gray], 0.60/62 [DT] and 0.71/0.70 [RSF]. CONCLUSIONS Risk factors for hepatocarcinogenesis differ according to SVR status. Machine learning algorithms can refine HCC risk assessment by revealing complex interactions between cancer predictors. Such approaches could be used to develop more cost-effective tailored surveillance programs. LAY SUMMARY Patients with HCV-related cirrhosis must be included in liver cancer surveillance programs, which rely on ultrasound examination every 6 months. Hepatocellular carcinoma (HCC) screening is hampered by sensitivity issues, leading to late cancer diagnoses in a substantial number of patients. Refining surveillance periodicity and modality using more sophisticated imaging techniques such as MRI may only be cost-effective in patients with the highest HCC incidence. Herein, we demonstrate how machine learning algorithms (i.e. data-driven mathematical models to make predictions or decisions), can refine individualized risk prediction.
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Affiliation(s)
- Etienne Audureau
- AP-HP, Hôpital Henri Mondor, Département de Santé Publique, and Université Paris-Est, A-TVB DHU, CEpiA (Clinical Epidemiology and Ageing) Unit EA7376, UPEC, F-94000, Créteil, France
| | - Fabrice Carrat
- Sorbonne Université, Inserm, Institut Pierre Louis d'Epidémiologie et de Santé Publique, Paris, France; AP-HP, Hôpital Saint-Antoine, Unité de Santé Publique, Paris, France
| | - Richard Layese
- AP-HP, Hôpital Henri Mondor, Département de Santé Publique, and Université Paris-Est, A-TVB DHU, CEpiA (Clinical Epidemiology and Ageing) Unit EA7376, UPEC, F-94000, Créteil, France
| | - Carole Cagnot
- Unit for Basic and Clinical research on Viral Hepatitis, ANRS (France REcherche Nord & sud Sida-HIV Hépatites-FRENSH)
| | - Tarik Asselah
- AP-HP, Hôpital Beaujon, Service d'Hépatologie, Clichy
| | | | | | | | - Denis Ouzan
- Institut Arnaud Tzanck, Service d'Hépatologie, St Laurent du Var
| | - Fabien Zoulim
- Hospices Civils de Lyon, Service d'Hépatologie; INSERM U1052 - CRCL; Université de Lyon, Lyon
| | | | - Albert Tran
- CHU de Nice, Service d'Hépatologie, F-06202, Cedex 3, Nice; Inserm U1065, C3M, Team 8, "Hepatic Complications in Obesity", F-06204, Cedex 3, Nice
| | | | | | | | - Paul Calès
- CHU d'Angers, Service d'Hépato-Gastroentérologie, Angers
| | | | - Laurent Alric
- CHU Toulouse, Service de Médecine Interne-Pôle Digestif UMR 152, Toulouse
| | | | | | - Jean-Frédéric Blanc
- Hôpital St André, Service d'Hépatologie, Bordeaux et Hôpital Haut-Lévêque, CHU Bordeaux, 33604 Pessac
| | - Armand Abergel
- Hôpital Hôtel Dieu, Service d'Hépatologie, Clermont-Ferrand
| | - Olivier Chazouillères
- AP-HP, Hôpital Saint-Antoine, Service d'Hépatologie, and Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, Paris
| | - Ariane Mallat
- AP-HP, Hôpital Henri Mondor, Service d'Hépatologie, Créteil
| | | | - Pierre Attali
- AP-HP, Hôpital Paul Brousse, Service d'Hépatologie, Villejuif
| | | | - Claire Wartelle
- Hôpital d'Aix-En-Provence, Service d'Hépatologie, Aix-En-Provence
| | - Thông Dao
- Hôpital de la Côte de Nacre, Service d'Hépatologie, Caen
| | - Dominique Thabut
- AP-HP, Groupe Hospitalier de La Pitié-Salpêtrière, Service d'Hépatologie, Paris
| | | | | | | | | | | | - David Zucman
- Hôpital Foch, Service de Médecine Interne, Suresnes
| | | | - Angela Sutton
- CRB (liver disease biobank) Groupe Hospitalier Paris Seine-Saint-Denis BB-0033-00027; AP-HP, Hôpital Jean Verdier, Service de Biochimie, Bondy; Inserm U1148, Université Paris 13, Bobigny
| | - Stanislas Pol
- AP-HP, Hôpital Cochin, Département d'Hépatologie; Inserm UMS20 et U1223, Institut Pasteur, Université Paris Descartes, Paris
| | - Pierre Nahon
- AP-HP, Hôpital Jean Verdier, Service d'Hépatologie, Bondy; Université Paris 13, Sorbonne Paris Cité, "Equipe labellisée Ligue Contre le Cancer", F-93206 Saint-Denis; Inserm, UMR-1162, "Génomique fonctionnelle des tumeur solides", F-75000, Paris, France.
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8
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Abstract
Among clinicians, the users of medical calculators have expanded in recent years to an unprecedented number. The usefulness of some of these calculators is sometimes debatable, and experienced professionals may at times be right in avoiding their use; however, many may simply be unaware of the very existence of medical calculators applicable to their field of interest. The authors felt that this latter scenario might possibly apply to hepatocellular carcinoma (HCC). Hence, the authors concisely reviewed 10 free online medical calculators proposed in the last 8 years, categorizing them on the basis of the purpose for which they were developed (risk of harboring or developing HCC, N=4; prognostication in established HCC, N=6). In addition, the authors tried to establish the success each calculator has had so far in the medical community, by 2 criteria: having been included in the more popular app of medical calculators and being highly cited in the scientific literature.
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9
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Hepatocellular carcinoma prediction beyond year 5 of oral therapy in a large cohort of Caucasian patients with chronic hepatitis B. J Hepatol 2020; 72:1088-1096. [PMID: 31981727 DOI: 10.1016/j.jhep.2020.01.007] [Citation(s) in RCA: 77] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Revised: 11/27/2019] [Accepted: 01/04/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Hepatocellular carcinoma (HCC) may develop in patients with chronic hepatitis (CHB) even after 5 years of oral therapy and cannot be easily predicted. We assessed predictors of HCC development and the need for HCC surveillance in this setting. METHODS Of 1,951 adult Caucasians with CHB included in the PAGE-B cohort, 1,427 (73%) had completed >5 years of follow-up under therapy without developing HCC by year 5. Median follow-up was 8.4 years from treatment onset. Points-based risk scores were developed to predict HCC risk after year 5. RESULTS In years 5-12, HCC was diagnosed in 33/1,427 (2.3%) patients with cumulative incidences of 2.4%, 3.2% and 3.8% at 8, 10 and 12 years, respectively. Older age or age >50 years, baseline cirrhosis and liver stiffness (LSM) ≥12 kPa at year 5 were independently associated with increased HCC risk. The HCC incidence was lower in non-cirrhotics than cirrhotics at baseline with year-5 LSM <12; among cirrhotics at baseline, it was lower in those with year-5 LSM <12 than ≥12 kPa. CAGE-B score was based on age at year 5 and baseline cirrhosis in relation to LSM at year 5 and SAGE-B score was based only on age and LSM at year 5 (c-index = 0.809-0.814, 0.805-0.806 after bootstrap validation). Both scores offered 100% negative predictive values for HCC development in their low risk groups. CONCLUSIONS In Caucasians with CHB, the HCC risk after the first 5 years of antiviral therapy depends on age, baseline cirrhosis status and LSM at year 5. CAGE-B and particularly SAGE-B represent simple and reliable risk scores for HCC prediction and surveillance beyond year 5 of therapy. LAY SUMMARY In Caucasians with chronic hepatitis B, the risk of hepatocellular carcinoma after the first 5 years of entecavir or tenofovir therapy depends on age, baseline cirrhosis status and liver stiffness at year 5, which can provide simple and reliable risk scores for hepatocellular carcinoma prediction and surveillance beyond year 5. In patients with cirrhosis at baseline, liver stiffness <12 kPa at year 5 is associated with lower HCC risk, but surveillance may be still required.
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10
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Voulgaris T, Papatheodoridi M, Lampertico P, Papatheodoridis GV. Clinical utility of hepatocellular carcinoma risk scores in chronic hepatitis B. Liver Int 2020; 40:484-495. [PMID: 31884726 DOI: 10.1111/liv.14334] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 11/28/2019] [Accepted: 12/15/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND Several risk scores have been recently developed to predict hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients. We systematically assessed the performance of the available HCC risk scores. METHODS Literature search was performed to identify all published studies reporting development or external validation of HCC risk scores in CHB patients. RESULTS Until March 2019, 12 scores were developed in untreated Asian and 7 scores in treated Asian (n = 6) or Caucasian (n = 1) patients. All scores provided significant predictions for HCC development in the derivation and validation cohorts of their original studies (c-statistic: 0.76-0.95) and usually classified patients into low, medium and high HCC risk groups. Eleven independent studies and three studies developing their own scores have validated externally some scores in Asian (GAG-HCC:5, CU-HCC:6, REACH-B:6, REACH-Bm:4, LSM-HCC:3, PAGE-B:5) or Caucasian/mixed origin patients (GAG-HCC:4, CU-HCC:4, REACH-B:4, PAGE-B:2). All scores offered acceptable predictability in almost all independent Asian cohorts (c-statistic: 0.70-0.86), but only PAGE-B and recently modified PAGE-B (mPAGE-B) offered good predictability in all independent Caucasian and/or Asian cohorts. Negative predictive values for 5-year HCC prediction were ≤99% (95%-99%) in most independent cohorts assessing Asian risk scores and 99%-100% in all independent cohorts (Caucasian/mixed origin:2; Asian:3) assessing PAGE-B and/or recently mPAGE-B. CONCLUSIONS Direct comparison of the newest HCC risk scores in independent patient cohorts of different origin remains intriguing, although statistical associations may not be directly transferable to clinical practice. PAGE-B and recently mPAGE-B score seem to offer persistently high predictability for Caucasian and/or Asian treated patients with low HCC risk who require no surveillance.
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Affiliation(s)
- Thodoris Voulgaris
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, General Hospital of Athens "Laiko", Athens, Greece
| | - Margarita Papatheodoridi
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, General Hospital of Athens "Laiko", Athens, Greece
| | - Pietro Lampertico
- Division of Gastroenterology and Hepatology, CRC "A. M. and A. Migliavacca" Center for the Study of Liver Disease, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| | - George V Papatheodoridis
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, General Hospital of Athens "Laiko", Athens, Greece
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11
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Human genetics of HCV infection phenotypes in the era of direct-acting antivirals. Hum Genet 2020; 139:855-863. [PMID: 32100095 DOI: 10.1007/s00439-020-02136-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Accepted: 02/10/2020] [Indexed: 12/14/2022]
Abstract
The recent introduction of direct-acting antivirals (DAAs) has revolutionized hepatitis C virus (HCV) therapy by improving virus eradication rates to over 90% in most patient groups. However, the impact of DAAs on global disease burden is currently limited, and a large number of chronically infected individuals remain at risk of developing liver complications, such as liver cirrhosis and hepatocellular carcinoma (HCC). The identification of patients at risk of liver complications and a greater understanding of the biological mechanisms involved in HCV disease progression might improve disease control. Recent genome-wide association and exome sequencing studies have identified several host genetic variants influencing the progression of liver fibrosis and the development of HCC associated with HCV infection and are reviewed here. Interestingly, some of the genetic variants associated with those HCV-associated liver complications were also associated with the clinical course of non-viral chronic hepatitis. Future challenges include the incorporation of this genetic information into clinical risk models for personalized disease management and the study of emerging phenotypes such as liver fibrosis regression and HCC development after HCV eradication.
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12
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Yang HI, Yeh ML, Wong GL, Peng CY, Chen CH, Trinh HN, Cheung KS, Xie Q, Su TH, Kozuka R, Lee DH, Ogawa E, Zhao C, Ning HB, Huang R, Li J, Zhang JQ, Ide T, Xing H, Iwane S, Takahashi H, Wong C, Wong C, Lin CH, Hoang J, Le A, Henry L, Toyoda H, Ueno Y, Gane EJ, Eguchi Y, Kurosaki M, Wu C, Liu C, Shang J, Furusyo N, Enomoto M, Kao JH, Yuen MF, Yu ML, Nguyen MH. Real-World Effectiveness From the Asia Pacific Rim Liver Consortium for HBV Risk Score for the Prediction of Hepatocellular Carcinoma in Chronic Hepatitis B Patients Treated With Oral Antiviral Therapy. J Infect Dis 2020; 221:389-399. [PMID: 31550363 DOI: 10.1093/infdis/jiz477] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Accepted: 09/13/2019] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Patients on oral antiviral (OAV) therapy remain at hepatocellular carcinoma (HCC) risk. Risk prediction tools distinguishing treated patients with residual HCC risk are limited. The aim of this study was to develop an accurate, precise, simple-to-use HCC risk score using routine clinical variables among a treated Asian cohort. METHODS Adult Asian chronic hepatitis B (CHB) patients on OAV were recruited from 25 centers in the United States and the Asia-Pacific region. Excluded persons were coinfected with hepatitis C, D, or human immunodeficiency virus, had HCC before or within 1 year of study entry, or their follow-up was <1 year. Patients were randomized to derivation and validation cohorts on a 2:1 ratio. Statistically significant predictors from multivariate modeling formed the Real-world Effectiveness from the Asia Pacific Rim Liver Consortium for HBV (REAL-B) score. RESULTS A total of 8048 patients were randomized to the derivation (n = 5365) or validation group (n = 2683). The REAL-B model included 7 variables (male gender, age, alcohol use, diabetes, baseline cirrhosis, platelet count, and alpha fetoprotein), and scores were categorized as follows: 0-3 low risk, 4-7 moderate risk, and 8-13 high risk. Area under receiver operating characteristics were >0.80 for HCC risk at 3, 5, and 10 years, and these were significantly higher than other risk models (p < .001). CONCLUSIONS The REAL-B score provides 3 distinct risk categories for HCC development in Asian CHB patients on OAV guiding HCC surveillance strategy.
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Affiliation(s)
- Hwai-I Yang
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Ming-Lun Yeh
- Department of Internal Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Grace L Wong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong
| | - Cheng-Yuan Peng
- Department of Gastroenterology, China Medical University Hospital, Taichung, Taiwan
| | - Chien-Hung Chen
- Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Huy N Trinh
- San Jose Gastroenterology, San Jose, California, USA
| | - Ka-Shing Cheung
- Department of Medicine, The University of Hong Kong, Hong Kong
| | - Qing Xie
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, Peopole's Republic of China
| | - Tung-Hung Su
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Ritsuzo Kozuka
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Dong-Hyun Lee
- Department of Gastroenterology, Good Gang-An Hospital, Busan, South Korea
| | - Eiichi Ogawa
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Changqing Zhao
- Department of Cirrhosis, Institute of Liver Disease, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, Peopole's Republic of China
| | - Hui-Bin Ning
- Department of Infectious Diseases, Henan Provincial People's Hospital, Zhengzhou, Peopole's Republic of China
| | - Rui Huang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu, Peopole's Republic of China
| | - Jiayi Li
- Palo Alto Medical Foundation, Mountain View Division, Mountain View, California, USA
| | - Jian Q Zhang
- Chinese Hospital, San Francisco, California, USA
| | - Tatsuya Ide
- Department of Internal Medicine, Kurume University School of Medicine, Fukuoka, Japan
| | - Huichun Xing
- Beijing Ditan Hospital, Capital Medical University, Beijing, Peopole's Republic of China
| | - Shinji Iwane
- Department of Internal Medicine, Saga University Hospital, Saga, Japan
| | | | | | | | - Chia-Hsin Lin
- Department of Gastroenterology, China Medical University Hospital, Taichung, Taiwan
| | - Joseph Hoang
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Palo Alto, California, USA
| | - An Le
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Palo Alto, California, USA
| | - Linda Henry
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Palo Alto, California, USA
| | - Hidenori Toyoda
- Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Yoshiyuki Ueno
- Department of Gastroenterology, Yamagata University, Yamagata, Japan
| | - Edward J Gane
- Liver Transplant Unit, University of Auckland, Auckland, New Zealand
| | - Yuichiro Eguchi
- Department of Internal Medicine, Saga University Hospital, Saga, Japan
| | - Masayuki Kurosaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Chao Wu
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu, Peopole's Republic of China
| | - Chenghai Liu
- Department of Cirrhosis, Institute of Liver Disease, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, Peopole's Republic of China
| | - Jia Shang
- Department of Infectious Diseases, Henan Provincial People's Hospital, Zhengzhou, Peopole's Republic of China
| | - Norihiro Furusyo
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Masaru Enomoto
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Jia-Horng Kao
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Man-Fung Yuen
- Department of Medicine, The University of Hong Kong, Hong Kong
| | - Ming-Lung Yu
- Department of Internal Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Mindie H Nguyen
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Palo Alto, California, USA
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13
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Nahon P, Ganne-Carrié N. Management of patients with pre-therapeutic advanced liver fibrosis following HCV eradication. JHEP Rep 2019; 1:480-489. [PMID: 32039400 PMCID: PMC7005771 DOI: 10.1016/j.jhepr.2019.11.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Revised: 10/30/2019] [Accepted: 11/06/2019] [Indexed: 12/19/2022] Open
Abstract
Patients with HCV-related bridging fibrosis or cirrhosis remain at risk of developing life-threatening complications even after achieving a sustained virological response. Although it is reduced, the risk of liver-related events in these patients justifies their inclusion in surveillance programmes dedicated to the early detection of hepatocellular carcinoma and the screening for portal hypertension. Biochemical parameters or non-invasive tests might indicate the potential progression of liver injury despite viral clearance. Specific attention must be focused on the management of comorbidities, while dedicated educational programmes must be encouraged to increase compliance and commitment to surveillance. Better knowledge of the long-term evolution of these patients, who now live longer, is essential to improve risk stratification and refine screening strategies in this growing population.
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Key Words
- AFP, alpha-fetoprotein
- ALT, alanine aminotransferase
- APRI, AST-to-platelet ratio index
- AST, aspartate aminotransferase
- DAAs, direct-acting antivirals
- EHC, extrahepatic cancer
- FIB-4, fibrosis-4
- HCC, hepatocellular carcinoma
- HCV
- HR, hazard ratio
- Hepatocellular carcinoma
- LSM, liver stiffness measurement
- Liver failure
- MACEs, major adverse cardiovascular events
- PHT, portal hypertension
- Portal hypertension
- SMR, standardised mortality ratio
- SVR
- SVR, sustained virological response
- surveillance
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Affiliation(s)
- Pierre Nahon
- AP-HP, Hôpital Jean Verdier, Liver Unit, Bondy, France
- University Paris 13, Sorbonne Paris Cité, “équipe labellisée Ligue Contre le Cancer”, F-93000 Bobigny, France
- INSERM UMR-1162: Functional Genomics of Solid Tumours, F-75010, Paris, France
| | - Nathalie Ganne-Carrié
- AP-HP, Hôpital Jean Verdier, Liver Unit, Bondy, France
- University Paris 13, Sorbonne Paris Cité, “équipe labellisée Ligue Contre le Cancer”, F-93000 Bobigny, France
- INSERM UMR-1162: Functional Genomics of Solid Tumours, F-75010, Paris, France
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