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Choi J, Nguyen VH, Przybyszewski E, Song J, Carroll A, Michta M, Almazan E, Simon TG, Chung RT. Statin Use and Risk of Hepatocellular Carcinoma and Liver Fibrosis in Chronic Liver Disease. JAMA Intern Med 2025:2831392. [PMID: 40094696 PMCID: PMC11915111 DOI: 10.1001/jamainternmed.2025.0115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/19/2025]
Abstract
Importance Statins may lower the risk of hepatocellular carcinoma (HCC) by mitigating liver fibrosis progression. Objective To evaluate the association between statin use and the risk of HCC and hepatic decompensation, with an emphasis on liver fibrosis progression, among adult patients with chronic liver disease (CLD). Design, Setting, and Participants This cohort study used data from the Research Patient Data Registry from 2000 to 2023 on patients 40 years or older with CLD and a baseline Fibrosis-4 (FIB-4) score of 1.3 or higher. Participants were grouped into statin users and nonusers. Data analysis was conducted from August 5, 2024, to January 3, 2025. Exposures Statin use. Main Outcomes and Measures Outcomes included 10-year cumulative incidence of HCC and hepatic decompensation as well as transitions in liver fibrosis risk categories based on FIB-4 scores. Statin use was defined as exposure to a cumulative defined daily dose (cDDD) of 30 or more. Fibrosis progression was assessed through FIB-4 group transitions (low, intermediate, and high) over time. Outcomes were analyzed using adjusted subhazard ratio (aSHR) and trends in serial FIB-4 scores. Results The analysis included 16 501 participants (mean [SD] age, 59.7 [11.0] years; 6750 females [40.9%] and 9751 males [59.1%]) with CLD, including 3610 statin users and 12 891 nonusers. Statin users exhibited a significantly lower 10-year cumulative incidence of HCC (3.8% vs 8.0.%; risk difference, -4.2%; 95% CI, -5.3 to -3.1%) and hepatic decompensation (10.6% vs 19.5%; risk difference, -9.0%; 95% CI, -10.6 to -7.3) compared with nonusers. The aSHR was 0.67 (95% CI, 0.59 to 0.76) for HCC and 0.78 (95% CI, 0.67 to 0.91) for hepatic decompensation. Exposure to lipophilic statins and duration of statin use (≥600 cDDDs) were associated with further reductions in HCC and hepatic decompensation risks. Among 7038 patients with serial FIB-4 data, patients with intermediate baseline FIB-4 scores, 14.7% (95% CI, 13.0% to 16.6%) of statin users transitioned to the high group compared with 20.0% (95% CI, 18.6% to 21.5%) of nonusers. For patients with high baseline FIB-4 scores, 31.8% (95% CI, 28.0% to 35.9%) of statin users transitioned to the intermediate group and 7.0% (95% CI, 5.2% to 9.6%) transitioned to the low-risk group, compared to 18.8% (95% CI, 17.2% to 20.6%) and 4.3% (95% CI, 3.5% to 5.2%) of nonusers, respectively (P < .001). Conclusions and Relevance This cohort study found that statin use was associated with a reduced risk of HCC and hepatic decompensation in patients with CLD, as well as improved FIB-4 group transitions over time. These findings provide support for the potential role of statins in prevention of HCC and liver disease progression.
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Affiliation(s)
- Jonggi Choi
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
- Liver Center, Gastroenterology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
- Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Vy H Nguyen
- Harvard Medical School, Boston, Massachusetts
| | - Eric Przybyszewski
- Liver Center, Gastroenterology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
- Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Jiunn Song
- Liver Center, Gastroenterology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
- Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Allison Carroll
- Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Megan Michta
- Liver Center, Gastroenterology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Erik Almazan
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Tracey G Simon
- Liver Center, Gastroenterology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
- Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Raymond T Chung
- Liver Center, Gastroenterology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
- Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
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Suzuki H, Fujiwara N, Singal AG, Baumert TF, Chung RT, Kawaguchi T, Hoshida Y. Prevention of liver cancer in the era of next-generation antivirals and obesity epidemic. Hepatology 2025:01515467-990000000-01139. [PMID: 39808821 DOI: 10.1097/hep.0000000000001227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2024] [Accepted: 10/07/2024] [Indexed: 01/16/2025]
Abstract
Preventive interventions are expected to substantially improve the prognosis of patients with primary liver cancer, predominantly HCC and cholangiocarcinoma. HCC prevention is challenging in the face of the evolving etiological landscape, particularly the sharp increase in obesity-associated metabolic disorders, including metabolic dysfunction-associated steatotic liver disease. Next-generation anti-HCV and HBV drugs have substantially reduced, but not eliminated, the risk of HCC and have given way to new challenges in identifying at-risk patients. The recent development of new therapeutic agents and modalities has opened unprecedented opportunities to refine primary, secondary, and tertiary HCC prevention strategies. For primary prevention (before exposure to risk factors), public health policies, such as universal HBV vaccination, have had a substantial prognostic impact. Secondary prevention (after or during active exposure to risk factors) includes regular HCC screening and chemoprevention. Emerging biomarkers and imaging modalities for HCC risk stratification and detection may enable individual risk-based personalized and cost-effective HCC screening. Clinical studies have suggested the potential utility of lipid-lowering, antidiabetic/obesity, and anti-inflammatory agents for secondary prevention, and some of them are being evaluated in prospective clinical trials. Computational and experimental studies have identified potential chemopreventive strategies directed at diverse molecular, cellular, and systemic targets for etiology-specific and/or agnostic interventions. Tertiary prevention (in conjunction with curative-intent therapies for HCC) is an area of active research with the development of new immune-based neoadjuvant/adjuvant therapies. Cholangiocarcinoma prevention may advance with recent efforts to elucidate risk factors. These advances will collectively lead to substantial improvements in liver cancer mortality rates.
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Affiliation(s)
- Hiroyuki Suzuki
- Department of Internal Medicine, Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, Texas, USA
- Department of Medicine, Division of Gastroenterology, Kurume University School of Medicine, Kurume, Japan
| | - Naoto Fujiwara
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Mie University, Tsu, Japan
| | - Amit G Singal
- Department of Internal Medicine, Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Thomas F Baumert
- Inserm, Institute for Translational Medicine and Liver Diseases, University of Strasbourg, France
- IHU Strasbourg, Strasbourg, France
- Gastroenterology and Hepatology Service, Strasbourg University Hospitals, Strasbourg, France
| | - Raymond T Chung
- Department of Medicine, GI Division, Liver Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Takumi Kawaguchi
- Department of Medicine, Division of Gastroenterology, Kurume University School of Medicine, Kurume, Japan
| | - Yujin Hoshida
- Department of Internal Medicine, Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, Texas, USA
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Tarar ZI, Farooq U, Inayat F, Basida SD, Ibrahim F, Gandhi M, Nawaz G, Afzal A, Chaudhary AJ, Kamal F, Ali AH, Ghouri YA. Statins decrease the risk of hepatocellular carcinoma in metabolic dysfunction-associated steatotic liver disease: A systematic review and meta-analysis. World J Exp Med 2024; 14:98543. [PMID: 39713070 PMCID: PMC11551700 DOI: 10.5493/wjem.v14.i4.98543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2024] [Revised: 10/02/2024] [Accepted: 10/24/2024] [Indexed: 10/31/2024] Open
Abstract
BACKGROUND Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of chronic liver disease with a significant risk of developing hepatocellular carcinoma (HCC). Recent clinical evidence indicates the potential benefits of statins in cancer chemoprevention and therapeutics. However, it is still unclear if these drugs can lower the specific risk of HCC among patients with MASLD. AIM To investigate the impact of statin use on the risk of HCC development in patients with MASLD. METHODS A systematic review and meta-analysis of all the studies was performed that measured the effect of statin use on HCC occurrence in patients with MASLD. The difference in HCC risk between statin users and non-users was calculated among MASLD patients. We also evaluated the risk difference between lipophilic versus hydrophilic statins and the effect of cumulative dose on HCC risk reduction. RESULTS A total of four studies consisting of 291684 patients were included. MASLD patients on statin therapy had a 60% lower pooled risk of developing HCC compared to the non-statin group [relative risk (RR) = 0.40, 95%CI: 0.31-0.53, I 2 = 16.5%]. Patients taking lipophilic statins had a reduced risk of HCC (RR = 0.42, 95%CI: 0.28-0.64), whereas those on hydrophilic statins had not shown the risk reduction (RR = 0.57, 95%CI: 0.27-1.20). The higher (> 600) cumulative defined daily doses (cDDD) had a 70% reduced risk of HCC (RR = 0.30, 95%CI: 0.21-0.43). There was a 29% (RR = 0.71, 95%CI: 0.55-0.91) and 43% (RR = 0.57, 95%CI: 0.40-0.82) decreased risk in patients receiving 300-599 cDDD and 30-299 cDDD, respectively. CONCLUSION Statin use lowers the risk of HCC in patients with MASLD. The higher cDDD and lipophilicity of statins correlate with the HCC risk reduction.
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Affiliation(s)
- Zahid Ijaz Tarar
- Department of Gastroenterology and Hepatology, University of Missouri, Columbia, MO 65212, United States
| | - Umer Farooq
- Department of Gastroenterology and Hepatology, St. Louis University, St. Louis, MO 63104, United States
| | - Faisal Inayat
- Department of Internal Medicine, Allama Iqbal Medical College, Lahore, Punjab 54550, Pakistan
| | - Sanket D Basida
- Department of Internal Medicine, University of Missouri, Columbia, MO 65212, United States
| | - Faisal Ibrahim
- Department of Internal Medicine, Wexham Park Hospital, Wexham SL24HL, Slough, United Kingdom
| | - Mustafa Gandhi
- Department of Gastroenterology and Hepatology, University of Missouri, Columbia, MO 65212, United States
| | - Gul Nawaz
- Department of Internal Medicine, Allama Iqbal Medical College, Lahore, Punjab 54550, Pakistan
| | - Arslan Afzal
- Department of Hospital Medicine, ECU Health Medical Center, Greenville, NC 27834, United States
| | - Ammad J Chaudhary
- Department of Internal Medicine, Henry Ford Hospital, Detroit, MI 48202, United States
| | - Faisal Kamal
- Department of Gastroenterology and Hepatology, Thomas Jefferson University, Philadelphia, PA 19107, United States
| | - Ahmad H Ali
- Department of Gastroenterology and Hepatology, University of Missouri, Columbia, MO 65212, United States
| | - Yezaz A Ghouri
- Department of Gastroenterology and Hepatology, University of Missouri, Columbia, MO 65212, United States
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Yang F, Li O, Gao B, Chen Z, Li B, He J, Yang X. Association between antithrombotic agents use and hepatocellular carcinoma risk: a two-sample mendelian randomization analysis. J Cancer Res Clin Oncol 2024; 150:470. [PMID: 39436427 PMCID: PMC11496351 DOI: 10.1007/s00432-024-05960-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Accepted: 09/18/2024] [Indexed: 10/23/2024]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the most common primary liver cancer worldwide. Multiple observational studies demonstrated a negative association between the use of antithrombotic agents and the risk of HCC. However, the precise causal relationship between these factors remains uncertain. Therefore, our study used a two-sample Mendelian randomization (MR) analysis to assess the causal link between these two factors. METHOD The summary statistics of single nucleotide polymorphisms (SNPs) associated with the use of antithrombotic agents were acquired from a genome-wide association study (GWAS) performed on individuals of European descent. A two-sample MR analysis was performed using the inverse variance weighting (IVW), the weighted median estimate, the MR-Egger regression, and the weighted-mode estimate. Sensitivity analysis of the primary findings was performed using MR-PRESSO, MR-Egger regression, Cochran's Q test, and Leave-one-out analysis. RESULTS Ten SNPs associated with the use of antithrombotic agents were selected as instrumental variables. The MR analysis performed using the four methods mentioned above revealed a negative causal association between the use of antithrombotic agents and HCC. Univariate MR estimates based on the inverse variance weighting (IVW) method suggested a negative causal association between the use of antithrombotic agents and HCC [odds ratio (OR) 0.444, 95% confidence interval (CI) 0.279 to 0.707, P = 0.001]. The other methods also produced similar results. No heterogeneity and horizontal pleiotropy were found. CONCLUSION Our findings suggested an inverse causal association of antithrombotic agents with the risk of HCC.
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Affiliation(s)
- Fengyi Yang
- Department of General Surgery (Hepatopancreatobiliary Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Academician (Expert) Workstation of Sichuan Province, Metabolic Hepatobiliary and Pancreatic Diseases Key Laboratory of Luzhou City, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Ouyang Li
- Department of Gastroenterology, Huadong Hospital Affiliated to Fudan University, Shanghai, China
- Department of General Surgery, Huadong Hospital Affiliated to Fudan University, Shanghai, China
| | - Benjian Gao
- Department of General Surgery (Hepatopancreatobiliary Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Academician (Expert) Workstation of Sichuan Province, Metabolic Hepatobiliary and Pancreatic Diseases Key Laboratory of Luzhou City, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Zhuo Chen
- Department of General Surgery (Hepatopancreatobiliary Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Academician (Expert) Workstation of Sichuan Province, Metabolic Hepatobiliary and Pancreatic Diseases Key Laboratory of Luzhou City, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Bo Li
- Department of General Surgery (Hepatopancreatobiliary Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Academician (Expert) Workstation of Sichuan Province, Metabolic Hepatobiliary and Pancreatic Diseases Key Laboratory of Luzhou City, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Jiaqi He
- Department of General Surgery, Huadong Hospital Affiliated to Fudan University, Shanghai, China.
| | - Xiaoli Yang
- Department of General Surgery (Hepatopancreatobiliary Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, China.
- Academician (Expert) Workstation of Sichuan Province, Metabolic Hepatobiliary and Pancreatic Diseases Key Laboratory of Luzhou City, The Affiliated Hospital of Southwest Medical University, Luzhou, China.
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Zamani SA, Graubard BI, Hyer M, Carver E, Petrick JL, McGlynn KA. Use of cholesterol-lowering medications in relation to risk of primary liver cancer in the Clinical Practice Research Datalink. Cancer 2024; 130:3506-3518. [PMID: 39072717 DOI: 10.1002/cncr.35436] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 04/30/2024] [Accepted: 05/29/2024] [Indexed: 07/30/2024]
Abstract
BACKGROUND Although the relation between statin use and liver cancer risk has been extensively examined, few studies have examined other cholesterol-lowering medications in relation to liver cancer risk. The authors examined five classes of nonstatin medications and liver cancer risk. METHODS A nested case-control including 3719 cases and 14,876 matched controls was conducted within the Clinical Practice Research Datalink. Additional matches on type 2 diabetes and chronic liver disease were also implemented. The medications examined included cholesterol absorption inhibitors, bile acid sequestrants, fibrates, niacin, and omega-3 fatty acids. Conditional logistic regression estimated odds ratios and 95% confidence intervals. RESULTS Cholesterol absorption inhibitor use was associated with reduced liver cancer risk in the overall analysis (odds ratio, 0.69; 95% confidence interval, 0.50-0.96) and in analyses based on type 2 diabetes and chronic liver disease status. Although bile acid sequestrant use was associated with increased liver cancer risk in the overall analysis (odds ratio, 5.31; 95% confidence interval, 3.53-7.97), the results of the analyses based on type 2 diabetes and chronic liver disease status were inconsistent. [Correction added on 19 August 2024, after first online publication: In the preceding sentence, the value '3.534' has been changed to '3.54'.]. No associations were observed for the other medications. CONCLUSIONS Cholesterol absorption inhibitors may be associated with reduced liver cancer risk. Whether bile acid sequestrant use was associated with increased risk was only partially supported in the current study.
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Affiliation(s)
- Shahriar A Zamani
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland, USA
- Cancer Prevention Fellowship Program, Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Rockville, Maryland, USA
| | - Barry I Graubard
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland, USA
| | - Marianne Hyer
- Information Management Services, Rockville, Maryland, USA
| | - Emily Carver
- Information Management Services, Rockville, Maryland, USA
| | - Jessica L Petrick
- Slone Epidemiology Center, Boston University, Boston, Massachusetts, USA
| | - Katherine A McGlynn
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland, USA
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Mak LY. Disease modifiers and novel markers in hepatitis B virus-related hepatocellular carcinoma. JOURNAL OF LIVER CANCER 2024; 24:145-154. [PMID: 39099070 PMCID: PMC11449577 DOI: 10.17998/jlc.2024.08.03] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/23/2024] [Revised: 07/25/2024] [Accepted: 08/03/2024] [Indexed: 08/06/2024]
Abstract
Chronic hepatitis B (CHB) infection is responsible for 40% of the global burden of hepatocellular carcinoma (HCC) with a high case fatality rate. The risk of HCC differs among CHB subjects owing to differences in host and viral factors. Modifiable risk factors include viral load, use of antiviral therapy, co-infection with other hepatotropic viruses, concomitant metabolic dysfunctionassociated steatotic liver disease or diabetes mellitus, environmental exposure, and medication use. Detecting HCC at early stage improves survival, and current practice recommends HCC surveillance among individuals with cirrhosis, family history of HCC, or above an age cut-off. Ultrasonography with or without serum alpha feto-protein (AFP) every 6 months is widely accepted strategy for HCC surveillance. Novel tumor-specific markers, when combined with AFP, improve diagnostic accuracy than AFP alone to detect HCC at an early stage. To predict the risk of HCC, a number of clinical risk scores have been developed but none of them are clinically implemented nor endorsed by clinical practice guidelines. Biomarkers that reflect viral transcriptional activity and degree of liver fibrosis can potentially stratify the risk of HCC, especially among subjects who are already on antiviral therapy. Ongoing exploration of these novel biomarkers is required to confirm their performance characteristics, replicability and practicability.
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Affiliation(s)
- Lung-Yi Mak
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong SAR, China
- State Key Laboratory of Liver Research, The Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
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Takamoto T, Nara S, Ban D, Mizui T, Mukai M, Minoru E, Shimada K. Comparative analysis of liver resection in Non-B Non-C and hepatitis virus-associated hepatocellular carcinoma. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2024; 50:108381. [PMID: 38728963 DOI: 10.1016/j.ejso.2024.108381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Revised: 04/23/2024] [Accepted: 04/30/2024] [Indexed: 05/12/2024]
Abstract
BACKGROUND The incidence of non-hepatitis B and non-hepatitis C hepatocellular carcinoma (NBNC-HCC) is increasing in our country. This study assesses the feasibility of employing an identical surgical treatment strategy for resectable NBNC-HCC as that for hepatitis virus-associated HCC (HV-HCC). METHODS A retrospective analysis (1993-2023) of 1321 curative liver resections for HCC at a single institution was performed. Propensity score matching ensured a balanced comparison of preoperative clinical factors, including tumor status and background liver condition. RESULTS The proportion of NBNC-HCC cases has gradually increased, reaching up to 70 %. After matching, 294 of 473 NBNC-HCC patients and 294 of 848 HV-HCC patients were compared. Operative outcomes, including operation time, blood loss, type of surgical procedure, and morbidity, were comparable. Long-term outcome analysis showed similar recurrence-free survival (HR: 0.86, 95 % CI: 0.70-1.06, P = 0.167) and overall survival (HR: 0.98, 95 % CI: 0.79-1.23, P = 0.865) for NBNC-HCC. Multivariable analysis identified ICGR15 ≥ 15 %, ALBI grade 2 or 3, aspartate aminotransferase ≥40, tumor size > 5 cm, multiple tumors, macrovascular invasion, and microvascular invasion as independent prognostic factors for overall survival, while hepatitis B or C virus status lost significance. CONCLUSIONS Despite the increasing incidence of NBNC-HCC, comparable outcomes were achieved between the two groups of matched cohort.
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Affiliation(s)
- Takeshi Takamoto
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital, Tokyo, Japan.
| | - Satoshi Nara
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital, Tokyo, Japan
| | - Daisuke Ban
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital, Tokyo, Japan
| | - Takahiro Mizui
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital, Tokyo, Japan
| | - Masami Mukai
- Department of Medical Informatics, National Cancer Center Hospital, Japan
| | - Esaki Minoru
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital, Tokyo, Japan
| | - Kazuaki Shimada
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital, Tokyo, Japan
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Pham N, Benhammou JN. Statins in Chronic Liver Disease: Review of the Literature and Future Role. Semin Liver Dis 2024; 44:191-208. [PMID: 38701856 DOI: 10.1055/a-2319-0694] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/05/2024]
Abstract
Chronic liver disease (CLD) is a major contributor to global mortality, morbidity, and healthcare burden. Progress in pharmacotherapeutic for CLD management is lagging given its impact on the global population. While statins are indicated for the management of dyslipidemia and cardiovascular disease, their role in CLD prevention and treatment is emerging. Beyond their lipid-lowering effects, their liver-related mechanisms of action are multifactorial and include anti-inflammatory, antiproliferative, and immune-protective effects. In this review, we highlight what is known about the clinical benefits of statins in viral and nonviral etiologies of CLD and hepatocellular carcinoma (HCC), and explore key mechanisms and pathways targeted by statins. While their benefits may span the spectrum of CLD and potentially HCC treatment, their role in CLD chemoprevention is likely to have the largest impact. As emerging data suggest that genetic variants may impact their benefits, the role of statins in precision hepatology will need to be further explored.
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Affiliation(s)
- Nguyen Pham
- Department of Medicine, University of California, Los Angeles, Los Angeles, California
| | - Jihane N Benhammou
- Department of Medicine, University of California, Los Angeles, Los Angeles, California
- Veterans Affairs Greater Los Angeles, Los Angeles, California
- Comprehensive Liver Research Center at University of California, Los Angeles, Los Angeles, California
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Piscaglia F, Ikeda K, Cheng AL, Kudo M, Ikeda M, Breder V, Ryoo BY, Mody K, Ren M, Ramji Z, Sung MW. Association between treatment-emergent hypertension and survival with lenvatinib treatment for patients with hepatocellular carcinoma in the REFLECT study. Cancer 2024; 130:1281-1291. [PMID: 38261521 DOI: 10.1002/cncr.35185] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 11/13/2023] [Accepted: 11/17/2023] [Indexed: 01/25/2024]
Abstract
BACKGROUND Lenvatinib is approved as a first-line treatment for patients with unresectable and/or recurrent hepatocellular carcinoma (HCC). Lenvatinib achieved promising clinical benefits in REFLECT but was associated with clinically significant treatment-emergent hypertension (CSTE-HTN, a grouped term), a common class effect of tyrosine kinase inhibitors. This post hoc analysis assessed the impact of CSTE-HTN on the efficacy and safety of lenvatinib in HCC. METHODS Patients from REFLECT who received lenvatinib (n = 476) were stratified according to CSTE-HTN. Tumors were assessed by mRECIST. Overall survival (OS) and progression-free survival (PFS) were evaluated using landmark analyses at 4 and 8 weeks. RESULTS A total of 212 patients in the lenvatinib arm developed CSTE-HTN, and 264 did not. CSTE-HTN first occurred at 3.7 weeks (median); the worst grade CSTE-HTN occurred at 4.1 weeks (median). No patients had life-threatening CSTE-HTN and/or died due to CSTE-HTN. Median OS was numerically longer in patients with versus without CSTE-HTN (at 4 weeks: 16.3 vs. 11.6 months; hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.621-1.004; at 8 weeks: 13.5 vs. 11.6 months; HR, 0.87; 95% CI, 0.696-1.089). Median PFS was similar between patients with and without CSTE-HTN (at 4 weeks: 6.6 vs. 6.4 months; HR, 0.887; 95% CI, 0.680-1.157; at 8 weeks: 5.7 vs. 6.4 months; HR, 1.09; 95% CI, 0.84-1.41). Objective response rate was numerically higher in patients with (48.6%) versus without CSTE-HTN (34.5%). CONCLUSIONS In this retrospective analysis, CSTE-HTN was associated with improved OS but not PFS. CSTE-HTN did not impair the outcomes of patients with HCC treated with lenvatinib when detected early and managed appropriately.
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Affiliation(s)
- Fabio Piscaglia
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | | | - Ann-Lii Cheng
- National Taiwan University Hospital and National Taiwan University Cancer Center, Taipei, Taiwan
| | | | | | - Valery Breder
- N.N. Blokhin Russian Cancer Research Center, Moscow, Russia
| | - Baek-Yeol Ryoo
- Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | | | - Min Ren
- Eisai Inc, Nutley, New Jersey, USA
| | | | - Max W Sung
- Tisch Cancer Institute at Mount Sinai, New York, New York, USA
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Nguyen P, Singh V, Thakur V, Dwivedi AK, Chattopadhyay M. Effectiveness of HMG-CoA reductase inhibitors on inflammation and metabolic markers in the US-Mexico border Hispanic population. J Investig Med 2024; 72:359-369. [PMID: 38369491 DOI: 10.1177/10815589241234962] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/20/2024]
Abstract
HMG-CoA reductase inhibitors (statins) are commonly used to manage dyslipidemia to reduce cardiovascular disease (CVD) risk. High-sensitivity C-reactive protein (hs-CRP) is an emerging systematic low-grade inflammatory marker associated with atherosclerotic CVD development. Despite racial/ethnic disparities in the use and response of statins and the anti-inflammatory effects of statins, the effectiveness of statins on inflammation and metabolic markers is unknown among Hispanics. We performed a retrospective cohort study using 150 adult patients scheduled for an annual physical examination at a family medicine clinic between January 1, 2021 and December 31, 2021. Effect size with a 95% confidence interval (CI) was estimated using adjusted regression analyses. Among 150 patients, 52 (34.7%) patients received statins. Patients who received statins had significantly reduced median hs-CRP (1.9 vs 3.2, p = 0.007), mean low-density lipoprotein (LDL-C; 101.2 vs 124.6, p < 0.001), and total cholesterol (172.6 vs 194.5, p < 0.001) concentrations compared to those who did not receive statins. In the propensity-scores matched analysis, lower concentrations of log-transformed hs-CRP (regression coefficient (RC), -0.48; 95% CI: -0.89, -0.07), LDL-C (RC, -19.57; 95% CI: -33.04, -6.10), and total cholesterol (RC, -23.47; 95% CI: -38.96, -7.98) were associated with statin use. In addition, hepatic steatosis (adjusted relative risk (aRR) = 0.25; 95% CI: 0.08, 0.78, p = 0.017) was significantly lower among patients with the use of statins. Our study suggests that HMG-CoA reductase inhibitors may help reduce inflammation among Hispanic patients with dyslipidemia and hypertension. These findings have useful implications for preventing risk and disparities associated with cardiovascular and other inflammatory-induced diseases among the fastest-growing US Hispanic minorities.
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Affiliation(s)
- Phong Nguyen
- Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX, USA
| | - Vishwajeet Singh
- Biostatistics and Epidemiology Consulting Lab, Texas Tech University Health Sciences Center El Paso, El Paso, TX, USA
| | - Vikram Thakur
- Department of Molecular and Translational Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX, USA
| | - Alok Kumar Dwivedi
- Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX, USA
- Biostatistics and Epidemiology Consulting Lab, Texas Tech University Health Sciences Center El Paso, El Paso, TX, USA
- Department of Molecular and Translational Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX, USA
| | - Munmun Chattopadhyay
- Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX, USA
- Department of Molecular and Translational Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX, USA
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11
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Alizadehasl A, Alavi MS, Boudagh S, Alavi MS, Mohebi S, Aliabadi L, Akbarian M, Ahmadi P, Mannarino MR, Sahebkar A. Lipid-lowering drugs and cancer: an updated perspective. Pharmacol Rep 2024; 76:1-24. [PMID: 38015371 DOI: 10.1007/s43440-023-00553-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 10/27/2023] [Accepted: 10/27/2023] [Indexed: 11/29/2023]
Abstract
Statins and non-statin medications used for the management of dyslipidemia have been shown to possess antitumor properties. Since the use of these drugs has steadily increased over the past decades, more knowledge is required about their relationship with cancer. Lipid-lowering agents are heterogeneous compounds; therefore, it remains to be revealed whether anticancer potential is a class effect or related to them all. Here, we reviewed the literature on the influence of lipid-lowering medications on various types of cancer during development or metastasis. We also elaborated on the underlying mechanisms associated with the anticancer effects of antihyperlipidemic agents by linking the reported in vivo and in vitro studies.
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Affiliation(s)
- Azin Alizadehasl
- Cardio-Oncology Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
- Echocardiography Research CenterRajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Maryam Sadat Alavi
- Echocardiography Research CenterRajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Shabnam Boudagh
- Echocardiography Research CenterRajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Mohaddeseh Sadat Alavi
- Pharmacological Research Center of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Somaye Mohebi
- Echocardiography Research CenterRajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Leila Aliabadi
- Echocardiography Research CenterRajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Mahsa Akbarian
- Echocardiography Research CenterRajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Parisa Ahmadi
- Echocardiography Research CenterRajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | | | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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12
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Wang J, Liu C, Hu R, Wu L, Li C. Statin therapy: a potential adjuvant to immunotherapies in hepatocellular carcinoma. Front Pharmacol 2024; 15:1324140. [PMID: 38362156 PMCID: PMC10867224 DOI: 10.3389/fphar.2024.1324140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Accepted: 01/23/2024] [Indexed: 02/17/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most prevalent cancers worldwide and accounts for more than 90% of primary liver cancer. The advent of immune checkpoint inhibitor (ICI)-related therapies combined with angiogenesis inhibition has revolutionized the treatment of HCC in late-stage and unresectable HCC, as ICIs alone were disappointing in treating HCC. In addition to the altered immune microenvironment, abnormal lipid metabolism in the liver has been extensively characterized in various types of HCC. Stains are known for their cholesterol-lowering properties and their long history of treating hypercholesterolemia and reducing cardiovascular disease risk. Apart from ICI and other conventional therapies, statins are frequently used by advanced HCC patients with dyslipidemia, which is often marked by the abnormal accumulation of cholesterol and fatty acids in the liver. Supported by a body of preclinical and clinical studies, statins may unexpectedly enhance the efficacy of ICI therapy in HCC patients through the regulation of inflammatory responses and the immune microenvironment. This review discusses the abnormal changes in lipid metabolism in HCC, summarizes the clinical evidence and benefits of stain use in HCC, and prospects the possible mechanistic actions of statins in transforming the immune microenvironment in HCC when combined with immunotherapies. Consequently, the use of statin therapy may emerge as a novel and valuable adjuvant for immunotherapies in HCC.
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Affiliation(s)
- Jiao Wang
- Department of Laboratory Medicine, Wuhan Hospital of Traditional Chinese and Western Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chengyu Liu
- Department of Transfusion Medicine, Wuhan Hospital of Traditional Chinese and Western Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ronghua Hu
- Department of Transfusion Medicine, Wuhan Hospital of Traditional Chinese and Western Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Licheng Wu
- School of Clinical Medicine, Nanchang Medical College, Nanchang, China
| | - Chuanzhou Li
- Department of Medical Genetics, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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13
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Zhang X, Lou D, Fu R, Wu F, Zheng D, Ma X. Association between Statins Types with Incidence of Liver Cancer: An Updated Meta-analysis. Curr Med Chem 2024; 31:762-775. [PMID: 37393552 PMCID: PMC10661961 DOI: 10.2174/0929867330666230701000400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 03/21/2023] [Accepted: 04/23/2023] [Indexed: 07/04/2023]
Abstract
BACKGROUND Previous studies have found a potential role for statins in liver cancer prevention. OBJECTIVE This study aimed to explore the effect of different types of statins on the incidence of liver cancer. METHODS Relevant articles were systematically retrieved from PubMed, EBSCO, Web of Science, and Cochrane Library databases from inception until July 2022 to explore the relationship between lipophilic statins or hydrophilic statins exposure and the incidence of liver cancer. The main outcome was the incidence of liver cancer. RESULTS Eleven articles were included in this meta-analysis. The pooled results showed a reduced incidence of liver cancer in patients exposed to lipophilic statins (OR=0.54, p < 0.001) and hydrophilic statins (OR=0.56, p < 0.001) compared with the non-exposed cohort. Subgroup analysis showed that both exposures to lipophilic (Eastern countries: OR=0.51, p < 0.001; Western countries: OR=0.59, p < 0.001) and hydrophilic (Eastern countries: OR=0.51, p < 0.001; Western countries: OR=0.66, p=0.019) statins reduced the incidence of liver cancer in Eastern and Western countries, and the reduction was most significant in Eastern countries. Moreover, atorvastatin (OR=0.55, p < 0.001), simvastatin (OR=0.59, p < 0.001), lovastatin (OR=0.51, p < 0.001), pitavastatin (OR=0.36, p=0.008) and rosuvastatin (OR=0.60, p=0.027) could effectively reduce the incidence of liver cancer, unlike fluvastatin, cerivastatin and pravastatin. CONCLUSION Both lipophilic and hydrophilic statins contribute to the prevention of liver cancer. Moreover, the efficacy was influenced by the region and the specific type of statins used.
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Affiliation(s)
- Xingfen Zhang
- Department of Liver Disease, Ningbo No. 2 Hospital, Ningbo, Zhejiang, China
- Key Laboratory of Diagnosis and Treatment of Digestive System Tumors of Zhejiang Province, Ningbo No. 2 Hospital, Ningbo, Zhejiang, China
| | - Dandi Lou
- The First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Rongrong Fu
- The First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Feng Wu
- Department of General Surgery, Ningbo No. 2 Hospital, Ningbo, Zhejiang, China
| | - Dingcheng Zheng
- Department of General Surgery, Ningbo No. 2 Hospital, Ningbo, Zhejiang, China
| | - Xueqiang Ma
- Department of Hepatobiliary Surgery, Zhuji People's Hospital, Shaoxing, Zhejiang, China
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14
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Fung SK, Pan CQ, Wong GLH, Seto WK, Ahn SH, Chen CY, Hann HWL, Jablkowski MS, Kim YJ, Yurdaydin C, Peng CY, Nguyen T, Yatsuhashi H, Flaherty JF, Yee LJ, Abramov F, Wang H, Abdurakhmanov D, Lim YS, Buti M. Atherosclerotic cardiovascular disease risk profile of patients with chronic hepatitis B treated with tenofovir alafenamide or tenofovir disoproxil fumarate for 96 weeks. Aliment Pharmacol Ther 2024; 59:217-229. [PMID: 37905449 DOI: 10.1111/apt.17764] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Revised: 07/04/2023] [Accepted: 10/04/2023] [Indexed: 11/02/2023]
Abstract
BACKGROUND Patients with chronic hepatitis B (CHB) who switch from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF) show changes in lipid profiles. AIM To evaluate how these changes affect cardiovascular risk. METHODS This pooled analysis, based on two large prospective studies, evaluated fasting lipid profiles of patients with CHB who were treated with TAF 25 mg/day or TDF 300 mg/day for 96 weeks. Patients who fulfilled the American College of Cardiology criteria (age 40-79 years, high-density lipoprotein [HDL] 20-100 mg/dL, total cholesterol [TC] 130-320 mg/dL and systolic blood pressure 90-200 mmHg) required to assess 10-year atherosclerotic cardiovascular disease (ASCVD) risk with baseline lipid data and at least one post-baseline measurement were included in the ASCVD-risk population. The 10-year ASCVD risk was calculated for patients in this population, and changes from baseline to Week 96 were assessed using intermediate- (≥7.5%) and high-risk (≥20%) cut-offs. RESULTS Among 1632 patients, 620 (38%) met the criteria for the ASCVD-risk population. At Week 96, fasting levels of all lipids, except TC:HDL ratio, were lower with TDF than TAF. No significant increase was observed in overall ASCVD risk or in any ASCVD-risk categories during the 96-week treatment period compared with baseline. A similar proportion of patients in the TAF and TDF treatment groups (1.3% and 2.3%, respectively; p = 0.34) reported cardiovascular events. CONCLUSION Despite on-treatment differences in lipid profiles with TAF and TDF, predicted cardiovascular risk and clinical events were similar for both groups after 96 weeks.
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Affiliation(s)
- Scott K Fung
- Department of Medicine, University of Toronto, Ontario, Toronto, Canada
| | - Calvin Q Pan
- Division of Gastroenterology and Hepatology, NYU Langone Health, New York University Grossman School of Medicine, New York, New York, USA
| | - Grace Lai-Hung Wong
- Medical Data Analytics Centre (MDAC), Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Wai-Kay Seto
- Department of Medicine and State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Chi-Yi Chen
- Ditmanson Medical Foundation, Chia-Yi Christian Hospital, Chiayi City, Taiwan
| | - Hie-Won L Hann
- Division of Gastroenterology and Hepatology, Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Pennsylvania, Philadelphia, USA
| | - Maciej S Jablkowski
- Department of Infectious and Liver Diseases, Medical University of Lodz, Lodz, Poland
| | - Yoon Jun Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Cihan Yurdaydin
- Department of Gastroenterology, University of Ankara, Ankara, Turkey
- Department of Gastroenterology and Hepatology, Koç University Medical School, Istanbul, Turkey
| | - Cheng-Yuan Peng
- Center for Digestive Medicine, China Medical University Hospital, China Medical University, Taichung, Taiwan
| | - Tuan Nguyen
- T Nguyen Research and Education, Inc., California, San Diego, USA
| | - Hiroshi Yatsuhashi
- Clinical Research Center, National Hospital Organization Nagasaki Medical Center, Nagasaki, Japan
| | | | | | | | | | | | - Young-Suk Lim
- Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Maria Buti
- Liver Unit Hospital Universitari Valle Hebron, Liver Unit Hospital Universitari Valle Hebron, Barcelona, Spain
- IBER-EHD del Institute Carlos III, Barcelona, Spain
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15
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Hur MH, Park MK, Yip TCF, Chen CH, Lee HC, Choi WM, Kim SU, Lim YS, Park SY, Wong GLH, Sinn DH, Jin YJ, Kim SE, Peng CY, Shin HP, Chen CY, Kim HY, Lee HA, Seo YS, Jun DW, Yoon EL, Sohn JH, Ahn SB, Shim JJ, Jeong SW, Cho YK, Kim HS, Jang MJ, Kim YJ, Yoon JH, Lee JH. Personalized Antiviral Drug Selection in Patients With Chronic Hepatitis B Using a Machine Learning Model: A Multinational Study. Am J Gastroenterol 2023; 118:1963-1972. [PMID: 36881437 DOI: 10.14309/ajg.0000000000002234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 03/01/2023] [Indexed: 03/08/2023]
Abstract
INTRODUCTION Tenofovir disoproxil fumarate (TDF) is reportedly superior or at least comparable to entecavir (ETV) for the prevention of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B; however, it has distinct long-term renal and bone toxicities. This study aimed to develop and validate a machine learning model (designated as Prediction of Liver cancer using Artificial intelligence-driven model for Network-antiviral Selection for hepatitis B [PLAN-S]) to predict an individualized risk of HCC during ETV or TDF therapy. METHODS This multinational study included 13,970 patients with chronic hepatitis B. The derivation (n = 6,790), Korean validation (n = 4,543), and Hong Kong-Taiwan validation cohorts (n = 2,637) were established. Patients were classified as the TDF-superior group when a PLAN-S-predicted HCC risk under ETV treatment is greater than under TDF treatment, and the others were defined as the TDF-nonsuperior group. RESULTS The PLAN-S model was derived using 8 variables and generated a c-index between 0.67 and 0.78 for each cohort. The TDF-superior group included a higher proportion of male patients and patients with cirrhosis than the TDF-nonsuperior group. In the derivation, Korean validation, and Hong Kong-Taiwan validation cohorts, 65.3%, 63.5%, and 76.4% of patients were classified as the TDF-superior group, respectively. In the TDF-superior group of each cohort, TDF was associated with a significantly lower risk of HCC than ETV (hazard ratio = 0.60-0.73, all P < 0.05). In the TDF-nonsuperior group, however, there was no significant difference between the 2 drugs (hazard ratio = 1.16-1.29, all P > 0.1). DISCUSSION Considering the individual HCC risk predicted by PLAN-S and the potential TDF-related toxicities, TDF and ETV treatment may be recommended for the TDF-superior and TDF-nonsuperior groups, respectively.
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Affiliation(s)
- Moon Haeng Hur
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Min Kyung Park
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Terry Cheuk-Fung Yip
- Medical Data Analytics Centre (MDAC), Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Chien-Hung Chen
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Hyung-Chul Lee
- Department of Anesthesiology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Won-Mook Choi
- Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Seung Up Kim
- Department of Internal Medicine and Yonsei Liver Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Young-Suk Lim
- Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Soo Young Park
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea
| | - Grace Lai-Hung Wong
- Medical Data Analytics Centre (MDAC), Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Dong Hyun Sinn
- Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Young-Joo Jin
- Department of Internal Medicine, Inha University Hospital, Inha University School of Medicine, Incheon, Republic of Korea
| | - Sung Eun Kim
- Department of Internal Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Republic of Korea
| | - Cheng-Yuan Peng
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, China Medical University, Taichung, Taiwan
| | - Hyun Phil Shin
- Department of Gastroenterology and Hepatology, Kyung Hee University Hospital at Gangdong, Kyung Hee University School of Medicine, Seoul, Republic of Korea
| | - Chi-Yi Chen
- Division of Hepatogastroenterology, Department of Internal Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi, Taiwan
| | - Hwi Young Kim
- Department of Internal Medicine, College of Medicine, Ewha Womans University, Seoul, Republic of Korea
| | - Han Ah Lee
- Department of Internal Medicine, College of Medicine, Ewha Womans University, Seoul, Republic of Korea
| | - Yeon Seok Seo
- Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Republic of Korea
| | - Dae Won Jun
- Department of Internal Medicine, Hanyang University Hospital, Hanyang University College of Medicine, Seoul, Republic of Korea
| | - Eileen L Yoon
- Department of Internal Medicine, Hanyang University Hospital, Hanyang University College of Medicine, Seoul, Republic of Korea
- Department of Internal Medicine, Sanggye Paik Hospital, Inje University College of Medicine, Seoul, Republic of Korea
| | - Joo Hyun Sohn
- Department of Internal Medicine, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, Republic of Korea
| | - Sang Bong Ahn
- Department of Internal Medicine, Nowon Eulji Medical Center, Eulji University College of Medicine, Seoul, Republic of Korea
| | - Jae-Jun Shim
- Department of Internal Medicine, Kyung Hee University School of Medicine, Seoul, Republic of Korea
| | - Soung Won Jeong
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Soonchunhyang University Seoul Hospital, Seoul, Republic of Korea
| | - Yong Kyun Cho
- Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Hyoung Su Kim
- Department of Internal Medicine, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Republic of Korea
| | - Myoung-Jin Jang
- Medical Research Collaboration Center, Seoul National University Hospital, Seoul, Republic of Korea
| | - Yoon Jun Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jung-Hwan Yoon
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jeong-Hoon Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
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Piekuś-Słomka N, Mocan LP, Shkreli R, Grapă C, Denkiewicz K, Wesolowska O, Kornek M, Spârchez Z, Słomka A, Crăciun R, Mocan T. Don't Judge a Book by Its Cover: The Role of Statins in Liver Cancer. Cancers (Basel) 2023; 15:5100. [PMID: 37894467 PMCID: PMC10605163 DOI: 10.3390/cancers15205100] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 10/16/2023] [Accepted: 10/20/2023] [Indexed: 10/29/2023] Open
Abstract
Statins, which are inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, are an effective pharmacological tool for lowering blood cholesterol levels. This property makes statins one of the most popular drugs used primarily to prevent cardiovascular diseases, where hyperlipidemia is a significant risk factor that increases mortality. Nevertheless, studies conducted mainly in the last decade have shown that statins might prevent and treat liver cancer, one of the leading causes of cancer-related mortality worldwide. This narrative review summarizes the scientific achievements to date regarding the role of statins in liver tumors. Molecular biology tools have revealed that cell growth and proliferation can be inhibited by statins, which further inhibit angiogenesis. Clinical studies, supported by meta-analysis, confirm that statins are highly effective in preventing and treating hepatocellular carcinoma and cholangiocarcinoma. However, this effect may depend on the statin's type and dose, and more clinical trials are required to evaluate clinical effects. Moreover, their potential hepatotoxicity is a significant caveat for using statins in clinical practice. Nevertheless, this group of drugs, initially developed to prevent cardiovascular diseases, is now a key candidate in hepato-oncology patient management. The description of new drug-statin-like structures, e.g., with low toxicity to liver cells, may bring another clinically significant improvement to current cancer therapies.
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Affiliation(s)
- Natalia Piekuś-Słomka
- Department of Inorganic and Analytical Chemistry, Nicolaus Copernicus University in Toruń, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Jurasza 2, 85-089 Bydgoszcz, Poland;
| | - Lavinia Patricia Mocan
- Department of Histology, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania;
| | - Rezarta Shkreli
- Department of Pharmacy, Faculty of Medical Sciences, Aldent University, 1001-1028 Tirana, Albania;
| | - Cristiana Grapă
- Department of Physiology, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400006 Cluj-Napoca, Romania;
| | - Kinga Denkiewicz
- Department of Pathophysiology, Nicolaus Copernicus University in Toruń, Ludwik Rydygier Collegium Medicum in Bydgoszcz, 85-094 Bydgoszcz, Poland; (K.D.); (O.W.); (A.S.)
| | - Oliwia Wesolowska
- Department of Pathophysiology, Nicolaus Copernicus University in Toruń, Ludwik Rydygier Collegium Medicum in Bydgoszcz, 85-094 Bydgoszcz, Poland; (K.D.); (O.W.); (A.S.)
| | - Miroslaw Kornek
- Department of Internal Medicine I, University Hospital Bonn of the Rheinische Friedrich-Wilhelms-University, 53127 Bonn, Germany;
| | - Zeno Spârchez
- 3rd Medical Department, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400162 Cluj-Napoca, Romania;
| | - Artur Słomka
- Department of Pathophysiology, Nicolaus Copernicus University in Toruń, Ludwik Rydygier Collegium Medicum in Bydgoszcz, 85-094 Bydgoszcz, Poland; (K.D.); (O.W.); (A.S.)
| | - Rareș Crăciun
- 3rd Medical Department, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400162 Cluj-Napoca, Romania;
- Department of Gastroenterology, “Octavian Fodor” Institute for Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania
| | - Tudor Mocan
- Department of Gastroenterology, “Octavian Fodor” Institute for Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania
- UBBMed Department, Babeș-Bolyai University, 400349 Cluj-Napoca, Romania
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17
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Ogawa E. Letter: Entecavir versus tenofovir on serum lipoprotein levels of hepatitis B virus-related hepatocellular carcinoma after curative hepatectomy-Author's reply. Aliment Pharmacol Ther 2023; 58:845-846. [PMID: 37768288 DOI: 10.1111/apt.17693] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/29/2023]
Abstract
LINKED CONTENTThis article is linked to Ogawa et al papers. To view these articles, visit https://doi.org/10.1111/apt.17107 and https://doi.org/10.1111/apt.17668
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Affiliation(s)
- Eiichi Ogawa
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
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18
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Wu SY, Chen WM, Chiang MF, Lo HC, Wu MS, Lee MC, Soong RS. Protective effects of statins on the incidence of NAFLD-related decompensated cirrhosis in T2DM. Liver Int 2023; 43:2232-2244. [PMID: 37381761 DOI: 10.1111/liv.15656] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 06/02/2023] [Accepted: 06/12/2023] [Indexed: 06/30/2023]
Abstract
BACKGROUND AND AIMS Non-alcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome and poses a significant threat to patients with type 2 diabetes mellitus (T2DM) and metabolic dysregulation. Statins exert anti-inflammatory, antioxidative and antithrombotic effects that target mechanisms underlying NAFLD. However, the protective effects of the different doses, intensities and types of statins on the incidence of NAFLD-related decompensated liver cirrhosis (DLC) in patients with T2DM remain unclear. METHODS This study used the data of patients with T2DM who were non-HBV and non-HCV carriers from a national population database to examine the protective effects of statin use on DLC incidence through propensity score matching. The incidence rate (IR) and incidence rate ratios (IRRs) of DLC in patients with T2DM with or without statin use were calculated. RESULTS A higher cumulative dose and specific types of statins, namely rosuvastatin, pravastatin, atorvastatin, simvastatin and fluvastatin, reduced the risk of DLC in patients with T2DM. Statin use was associated with a significant reduction in the risk of DLC (HR: .65, 95% CI: .61-.70). The optimal daily intensity of statin use with the lowest risk of DLC was .88 defined daily dose (DDD). CONCLUSIONS The results revealed the protective effects of specific types of statins on DLC risk in patients with T2DM and indicated a dose-response relationship. Additional studies are warranted to understand the specific mechanisms of action of different types of statins and their effect on DLC risk in patients with T2DM.
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Affiliation(s)
- Szu-Yuan Wu
- Graduate Institute of Business Administration, College of Management, Fu Jen Catholic University, New Taipei City, Taiwan
- Artificial Intelligence Development Center, Fu Jen Catholic University, New Taipei City, Taiwan
- Department of Food Nutrition and Health Biotechnology, College of Medical and Health Science, Asia University, Taichung City, Taiwan
- Big Data Center, Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital, Taiwan
- Division of Radiation Oncology, Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital, Yilan, Taiwan
- Department of Healthcare Administration, College of Medical and Health Science, Asia University, Taichung City, Taiwan
- Centers for Regional Anesthesia and Pain Medicine, Taipei Municipal Wan Fang Hospital, Taipei Medical University, Taipei City, Taiwan
| | - Wan-Ming Chen
- Graduate Institute of Business Administration, College of Management, Fu Jen Catholic University, New Taipei City, Taiwan
- Artificial Intelligence Development Center, Fu Jen Catholic University, New Taipei City, Taiwan
| | - Ming-Feng Chiang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital, Yilan, Taiwan
| | - Hung-Chieh Lo
- Department of Traumatology, Wan Fang Hospital, Taipei Medical University, Taipei City, Taiwan
| | - Ming-Shun Wu
- Division of Gastroenterology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei City, Taiwan
| | - Ming-Che Lee
- Division of General Surgery, Department of Surgery, Wan Fang Hospital, Taipei Medical University, Taipei City, Taiwan
- College of Medicine, Taipei Medical University, Taipei City, Taiwan
- Division of Transplantation Surgery, Department of Surgery, Wan Fang Hospital, Taipei Medical University, Taipei City, Taiwan
- TMU Research Center for Organ Transplantation, College of Medicine, Taipei Medical University, Taipei City, Taiwan
- Taipei Cancer Center, Taipei Medical University, Taipei City, Taiwan
| | - Ruey-Shyang Soong
- Division of General Surgery, Department of Surgery, Wan Fang Hospital, Taipei Medical University, Taipei City, Taiwan
- College of Medicine, Taipei Medical University, Taipei City, Taiwan
- Division of Transplantation Surgery, Department of Surgery, Wan Fang Hospital, Taipei Medical University, Taipei City, Taiwan
- TMU Research Center for Organ Transplantation, College of Medicine, Taipei Medical University, Taipei City, Taiwan
- Taipei Cancer Center, Taipei Medical University, Taipei City, Taiwan
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19
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Kim DG, Yim SH, Min EK, Choi MC, Kim MS, Joo DJ, Lee JG. Effect of statins on the recurrence of hepatocellular carcinoma after liver transplantation: An illusion revealed by exposure density sampling. Liver Int 2023; 43:2017-2025. [PMID: 37365992 DOI: 10.1111/liv.15653] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 05/09/2023] [Accepted: 06/11/2023] [Indexed: 06/28/2023]
Abstract
BACKGROUND Statins have been reported to reduce overall death and hepatocellular carcinoma (HCC) recurrence in liver transplantation (LT) recipients. However, previous retrospective studies have significant flaws in immortal time bias. METHODS Using data from 658 patients who received LT for HCC, we matched 140 statin users with statin nonusers in a 1:2 ratio at the time of the first statin administration after LT using the exposure density sampling (EDS). The propensity score, calculated using baseline variables (including explant pathology), was used for EDS to equilibrate both groups. HCC recurrence and overall death were compared after adjusting for information at the time of sampling. RESULTS Among statin users, the median time to statin start was 219 (IQR 98-570) days, and intensity of statins was mainly moderate (87.1%). Statin users and nonusers sampled using EDS showed well-balanced baseline characteristics, including detailed tumour pathology, and similar HCC recurrence with cumulative incidences of 11.3% and 11.8% at 5 years, respectively (p = .861). In multivariate Cox models (HR 1.04, p = .918) and subgroup analyses, statins did not affect HCC recurrence. Conversely, statin users showed a significantly lower risk of overall death than nonusers (HR 0.28, p < .001). There was no difference in the type and intensity of statin usage between statin users who experienced HCC recurrence and those who did not. CONCLUSION Upon controlling immortal time bias by EDS, statins did not affect HCC recurrence but reduced mortality after LT. Statin usage is encouraged for survival benefits but not for preventing HCC recurrence in LT recipients.
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Affiliation(s)
- Deok-Gie Kim
- Department of Surgery, The Research Institute for Transplantation, Yonsei University College of Medicine, Seoul, South Korea
| | - Seung Hyuk Yim
- Department of Surgery, The Research Institute for Transplantation, Yonsei University College of Medicine, Seoul, South Korea
| | - Eun-Ki Min
- Department of Surgery, The Research Institute for Transplantation, Yonsei University College of Medicine, Seoul, South Korea
| | - Mun Chae Choi
- Department of Surgery, The Research Institute for Transplantation, Yonsei University College of Medicine, Seoul, South Korea
| | - Myoung Soo Kim
- Department of Surgery, The Research Institute for Transplantation, Yonsei University College of Medicine, Seoul, South Korea
| | - Dong Jin Joo
- Department of Surgery, The Research Institute for Transplantation, Yonsei University College of Medicine, Seoul, South Korea
| | - Jae Geun Lee
- Department of Surgery, The Research Institute for Transplantation, Yonsei University College of Medicine, Seoul, South Korea
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20
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Zou B, Odden MC, Nguyen MH. Statin Use and Reduced Hepatocellular Carcinoma Risk in Patients With Nonalcoholic Fatty Liver Disease. Clin Gastroenterol Hepatol 2023; 21:435-444.e6. [PMID: 35158055 DOI: 10.1016/j.cgh.2022.01.057] [Citation(s) in RCA: 39] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Accepted: 01/28/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Recent evidence suggests potential clinical benefits of statin in cancer chemoprevention and treatment. Nonalcoholic fatty liver disease (NAFLD) is expected to become the leading cause of hepatocellular carcinoma (HCC). We aimed to investigate the association between statin initiation and the risk of HCC among patients with NAFLD. METHODS In this study using the Optum de-identified Clinformatics database, Cox proportional hazards regression model was performed to determine the risk of HCC in statin initiators versus nonusers. We incorporated inverse probability of treatment weighting (IPTW) to minimize potential confounding. RESULTS Among 272,431 adults with NAFLD diagnosis, IPTW model shows that statin initiators had 53% less risk of developing HCC compared with nonusers (hazard ratio [HR], 0.47; 95% confidence interval, 0.36-0.60). In the subcohort with fibrosis-4 index data available, statin initiation was associated with 56% hazard reduction of developing HCC in NAFLD after adjusting for fibrosis-4 index score (HR, 0.44; 0.30-0.65). The association between statin initiation and lower risk of HCC development was observed for both lipophilic statin (HR, 0.49; 0.37-0.65) and hydrophilic statin (HR, 0.40; 0.21-0.76). Moreover, we observed greater hazards reduction as the dose and duration of statin use increased. NAFLD patients with more than 600 cumulative defined daily doses of statin had 70% reduction in hazards of developing HCC (HR, 0.30; 0.20-0.43). CONCLUSIONS Our study provides strong evidence for the association between statin initiation and reduced risk of HCC development in NAFLD patients. These findings imply that statin can be used as a protective medication for NAFLD patients to reduce the risk of HCC.
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Affiliation(s)
- Biyao Zou
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, Palo Alto, California; Department of Epidemiology and Population Health, Stanford University Medical Center, Palo Alto, California
| | - Michelle C Odden
- Department of Epidemiology and Population Health, Stanford University Medical Center, Palo Alto, California
| | - Mindie H Nguyen
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, Palo Alto, California; Department of Epidemiology and Population Health, Stanford University Medical Center, Palo Alto, California.
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21
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Oura K, Morishita A, Tani J, Masaki T. Antitumor Effects and Mechanisms of Metabolic Syndrome Medications on Hepatocellular Carcinoma. J Hepatocell Carcinoma 2022; 9:1279-1298. [PMID: 36545268 PMCID: PMC9760577 DOI: 10.2147/jhc.s392051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Accepted: 12/04/2022] [Indexed: 12/15/2022] Open
Abstract
Liver cancer has a high incidence and mortality rate worldwide, with hepatocellular carcinoma (HCC) being the most common histological type. With the decrease in the number of newly infected patients and the spread of antiviral therapy, hepatitis virus-negative chronic liver diseases including steatohepatitis are increasingly accounting for a large proportion of HCC, and an important clinical characteristic is the high prevalence of metabolic syndrome including hypertension, type 2 diabetes (T2D), dyslipidemia, and obesity. Since patients with steatohepatitis are less likely to undergo surveillance for early detection of HCC, they may be diagnosed at an advanced stage and have worse prognosis. Therefore, treatment strategies for patients with HCC caused by steatohepatitis, especially in advanced stages, become increasingly important. Further, hypertension, T2D, and dyslipidemia may occur as side effects during systemic treatment, and there will be increasing opportunities to prescribe metabolic syndrome medications, not only for originally comorbid diseases, but also for adverse events during HCC treatment. Interestingly, epidemiological studies have shown that patients taking some metabolic syndrome medications are less likely to develop various types of cancers, including HCC. Basic studies have also shown that these drugs have direct antitumor effects on HCC. In particular, angiotensin II receptor blockers (a drug group for treating hypertension), biguanides (a drug group for treating T2D), and statins (a drug group for treating dyslipidemia) have shown to elucidate antitumor effects against HCC. In this review, we focus on the antitumor effects of metabolic syndrome medications on HCC and their mechanisms based on recent literature. New therapeutic agents are also increasingly being reported. Analysis of the antitumor effects of metabolic syndrome medications on HCC and their mechanisms will be doubly beneficial for HCC patients with metabolic syndrome, and the use of these medications may be a potential strategy against HCC.
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Affiliation(s)
- Kyoko Oura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan,Correspondence: Kyoko Oura, Department of Gastroenterology and Neurology, Kagawa University, 1750-1 Ikenobe, Miki, Kida, Kagawa, Japan, Tel +81-87-891-2156, Fax +81-87-891-2158, Email
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Joji Tani
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan
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22
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Jaffe A, Taddei TH, Giannini EG, Ilagan-Ying YC, Colombo M, Strazzabosco M. Holistic management of hepatocellular carcinoma: The hepatologist's comprehensive playbook. Liver Int 2022; 42:2607-2619. [PMID: 36161463 PMCID: PMC10878125 DOI: 10.1111/liv.15432] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 08/26/2022] [Accepted: 09/21/2022] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) is a common complication in patients with chronic liver disease and leads to significant morbidity and mortality. Liver disease and liver cancer are preventable by mitigating and managing common risk factors, including chronic hepatitis B and C infection, alcohol use, diabetes, obesity and other components of the metabolic syndrome. The management of patients with HCC requires treatment of the malignancy and adequate control of the underlying liver disease, as preserving liver function is critical for successful cancer treatment and may have a relevant prognostic role independent of HCC management. Hepatologists are the ideal providers to guide the care of patients with HCC as they are trained to identify patients at risk, apply appropriate surveillance strategies, assess and improve residual liver function, evaluate candidacy for transplant, provide longitudinal care to optimize and preserve liver function during and after HCC treatment, survey for cancer recurrence and manage its risk factors, and prevent and treat decompensating events. We highlight the need for a team-based holistic approach to the patient with liver disease and HCC and identify necessary gaps in current care and knowledge.
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Affiliation(s)
- Ariel Jaffe
- Liver Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
- Smilow Cancer Hospital and Liver Cancer Program, New Haven, CT, USA
| | - Tamar H. Taddei
- Liver Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Edoardo G. Giannini
- Gastroenterology Unit, Department of Internal Medicine, University of Genoa, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Ysabel C. Ilagan-Ying
- Liver Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
| | | | - Mario Strazzabosco
- Liver Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
- Smilow Cancer Hospital and Liver Cancer Program, New Haven, CT, USA
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23
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Ejam SS, Saleh RO, Catalan Opulencia MJ, Najm MA, Makhmudova A, Jalil AT, Abdelbasset WK, Al-Gazally ME, Hammid AT, Mustafa YF, Sergeevna SE, Karampoor S, Mirzaei R. Pathogenic role of 25-hydroxycholesterol in cancer development and progression. Future Oncol 2022; 18:4415-4442. [PMID: 36651359 DOI: 10.2217/fon-2022-0819] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Cholesterol is an essential lipid that serves several important functions, including maintaining the homeostasis of cells, acting as a precursor to bile acid and steroid hormones and preserving the stability of membrane lipid rafts. 25-hydroxycholesterol (25-HC) is a cholesterol derivative that may be formed from cholesterol. 25-HC is a crucial component in various biological activities, including cholesterol metabolism. In recent years, growing evidence has shown that 25-HC performs a critical function in the etiology of cancer, infectious diseases and autoimmune disorders. This review will summarize the latest findings regarding 25-HC, including its biogenesis, immunomodulatory properties and role in innate/adaptive immunity, inflammation and the development of various types of cancer.
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Affiliation(s)
| | - Raed Obaid Saleh
- Department of Pharmacy, Al-Maarif University College, Al-Anbar, Iraq
| | | | - Mazin Aa Najm
- Pharmaceutical Chemistry Department, College of Pharmacy, Al-Ayen University, Thi-Qar, Iraq
| | - Aziza Makhmudova
- Department of Social Sciences & Humanities, Samarkand State Medical Institute, Samarkand, Uzbekistan
- Department of Scientific Affairs, Tashkent State Dental Institute, Makhtumkuli Street 103, Tashkent, 100047, Uzbekistan
| | - Abduladheem Turki Jalil
- Medical Laboratories Techniques Department, Al-Mustaqbal University College, Babylon, Hilla, 51001, Iraq
| | - Walid Kamal Abdelbasset
- Department of Health & Rehabilitation Sciences, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al Kharj, Saudi Arabia
- Department of Physical Therapy, Kasr Al-Aini Hospital, Cairo University, Giza, Egypt
| | | | - Ali Thaeer Hammid
- Computer Engineering Techniques Department, Faculty of Information Technology, Imam Ja'afar Al-Sadiq University, Baghdad, Iraq
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, 41001, Iraq
| | - Sergushina Elena Sergeevna
- National Research Ogarev Mordovia State University, 68 Bolshevitskaya Street, Republic of Mordovia, Saransk, 430005, Russia
| | - Sajad Karampoor
- Gastrointestinal & Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Rasoul Mirzaei
- Venom & Biotherapeutics Molecules Lab, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
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24
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Shin HS, Jun BG, Yi SW. Impact of diabetes, obesity, and dyslipidemia on the risk of hepatocellular carcinoma in patients with chronic liver diseases. Clin Mol Hepatol 2022; 28:773-789. [PMID: 35934813 PMCID: PMC9597232 DOI: 10.3350/cmh.2021.0383] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 04/20/2022] [Indexed: 01/05/2023] Open
Abstract
Despite the increasing prevalence of metabolic disorders, the potential effects of metabolic factors on hepatocellular carcinoma (HCC) development in individuals with chronic liver diseases (CLDs) are not well understood. For a metabolic factor to be identified as a risk factor for HCC in patients with CLDs, such as hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, there should be a strong synergistic interaction between the carcinogenic mechanisms of the metabolic factor and the CLD itself. This review aims to comprehensively summarize the published data on the relationship between metabolic factors such as diabetes mellitus (DM), obesity, and blood lipids and the risk of HCC in patients with CLDs. DM consistently increases the risk of HCC in patients with CLD. When associated with DM, the risk of HCC seems to be highest in HCV and non-alcoholic fatty liver disease (NAFLD), followed by alcoholic liver disease (ALD) and HBV. Obesity may increase the risk of HCC. Among CLDs, the evidence is relatively consistent and clear for ALD, while clear evidence is limited in other CLDs including HBV, HCV, and NAFLD. Total cholesterol, potentially low-density lipoprotein cholesterol and triglyceride, seems to have strong inverse associations with HCC in individuals with CLDs. Despite evidence from observational studies, statins had no effect in preventing HCC in randomized controlled trials. Whether statins have a preventive effect against HCC is unclear. A better understanding and management of metabolic factors may be beneficial to reduce the risk of HCC in patients with CLDs.
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Affiliation(s)
- Hwang Sik Shin
- Department of Family Medicine, Soonchunhyang University Hospital Cheonan, Soonchunhyang University College of Medicine, Cheonan, Korea
| | - Baek Gyu Jun
- Department of Internal Medicine, Sanggye Paik Hospital, Inje University College of Medicine, Seoul, Korea,Corresponding author : Baek Gyu Jun Department of Internal Medicine, Sanggye Paik Hospital, Inje University College of Medicine, 1342 Dongil-ro, Nowon-gu, Seoul 01757, Korea Tel: +82-2-950-8889, Fax: +82-2-950-1955, E-mail:
| | - Sang-Wook Yi
- Department of Preventive Medicine and Public Health, College of Medicine, Catholic Kwandong University, Gangneung, Korea,Sang-Wook Yi Department of Preventive Medicine and Public Health, College of Medicine, Catholic Kwandong University, 24 Beomil-ro 579beon-gil, Gangneung 25601, Korea Tel: +82-33-649-7468, Fax: +82-33-641-1074, E-mail:
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25
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Li YJ, Chen CY, Yang JH, Chiu YF. Modulating cholesterol-rich lipid rafts to disrupt influenza A virus infection. Front Immunol 2022; 13:982264. [PMID: 36177026 PMCID: PMC9513517 DOI: 10.3389/fimmu.2022.982264] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 08/15/2022] [Indexed: 11/13/2022] Open
Abstract
Influenza A virus (IAV) is widely disseminated across different species and can cause recurrent epidemics and severe pandemics in humans. During infection, IAV attaches to receptors that are predominantly located in cell membrane regions known as lipid rafts, which are highly enriched in cholesterol and sphingolipids. Following IAV entry into the host cell, uncoating, transcription, and replication of the viral genome occur, after which newly synthesized viral proteins and genomes are delivered to lipid rafts for assembly prior to viral budding from the cell. Moreover, during budding, IAV acquires an envelope with embedded cholesterol from the host cell membrane, and it is known that decreased cholesterol levels on IAV virions reduce infectivity. Statins are commonly used to inhibit cholesterol synthesis for preventing cardiovascular diseases, and several studies have investigated whether such inhibition can block IAV infection and propagation, as well as modulate the host immune response to IAV. Taken together, current research suggests that there may be a role for statins in countering IAV infections and modulating the host immune response to prevent or mitigate cytokine storms, and further investigation into this is warranted.
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Affiliation(s)
- Yu-Jyun Li
- Department of Microbiology and Immunology, Chang Gung University, Taoyuan, Taiwan
- Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan
| | - Chi-Yuan Chen
- Department of Microbiology and Immunology, Chang Gung University, Taoyuan, Taiwan
| | - Jeng-How Yang
- Division of Infectious Diseases, Department of Medicine, Chang Gung Memorial Hospital, New Taipei, Taiwan
| | - Ya-Fang Chiu
- Department of Microbiology and Immunology, Chang Gung University, Taoyuan, Taiwan
- Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan
- Research Center for Emerging Viral Infections, Chang Gung University, Taoyuan, Taiwan
- Department of Laboratory Medicine, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
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26
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Clark EH, Ahmed ST, Chang E, Chiao EY, White DL. Can statins lessen the burden of virus mediated cancers? Infect Agent Cancer 2022; 17:47. [PMID: 36058947 PMCID: PMC9441070 DOI: 10.1186/s13027-022-00460-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2022] [Accepted: 08/22/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Oncogenic viruses, including hepatitis B virus (HBV), hepatitis C virus (HCV), human papillomavirus (HPV), Epstein Barr virus (EBV), and Kaposi Sarcoma Herpes virus (KSHV) contribute to a significant proportion of the world's cancers. Given the sizeable burden of virus mediated cancers, development of strategies to prevent and/or treat these cancers is critical. While large population studies suggest that treatment with hydroxymethylglutaryl-CoA reductase inhibitors, commonly known as statins, may reduce the risk of many cancer types including HBV/HCV related hepatocellular carcinoma, few studies have specifically evaluated the impact of statin use in populations at risk for other types of virus mediated cancers. MAIN BODY Studies of populations with HBV and HCV suggest a protective, dose-dependent effect of statins on hepatocellular carcinoma risk and support the theory that statins may offer clinical benefit if used as chemoprophylactic agents to reduce liver cancer incidence. However, no population level data exists describing the impact of statins on populations with other oncogenic viral infections, such as HPV, EBV, and KSHV. CONCLUSION Further study of statin use in diverse, global populations with or at high risk for oncogenic viral infections is essential to determine the impact of statin therapy on virus mediated cancer risk.
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Affiliation(s)
- Eva H Clark
- Section of Infectious Diseases, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
- Center for Innovation, Quality, Effectiveness and Safety (IQuESt), Michael E. DeBakey VA Medical Center, Houston, TX, USA.
- Section of Pediatric Tropical Medicine, Baylor College of Medicin, Feigin Building Suite 550, Houston, TX, 77030, USA.
| | - Sarah T Ahmed
- Center for Innovation, Quality, Effectiveness and Safety (IQuESt), Michael E. DeBakey VA Medical Center, Houston, TX, USA
- Section of Health Services Research, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Elaine Chang
- Center for Innovation, Quality, Effectiveness and Safety (IQuESt), Michael E. DeBakey VA Medical Center, Houston, TX, USA
- Section of Health Services Research, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Elizabeth Y Chiao
- Departments of Epidemiology and General Oncology, MD Anderson Cancer Center, Houston, TX, USA
| | - Donna L White
- Center for Innovation, Quality, Effectiveness and Safety (IQuESt), Michael E. DeBakey VA Medical Center, Houston, TX, USA
- Section of Health Services Research, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
- Section of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, TX, USA
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27
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Khazaaleh S, Sarmini MT, Alomari M, Al Momani L, El Kurdi B, Asfari M, Almomani Z, Romero-Marrero C. Statin Use Reduces the Risk of Hepatocellular Carcinoma: An Updated Meta-Analysis and Systematic Review. Cureus 2022; 14:e27032. [PMID: 35989795 PMCID: PMC9388192 DOI: 10.7759/cureus.27032] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/21/2022] [Indexed: 11/05/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary tumor of the liver resulting in approximately 800,000 deaths annually. A growing body of research investigating statin use and HCC risk has shown conflicting results. We aim to evaluate the current evidence of statin impact on HCC risk. We performed a comprehensive literature search in PubMed, PubMed Central, Embase, and ScienceDirect databases from inception through May 2019 to identify all studies that evaluated the association between statin use and HCC. We included studies that presented an odds ratio (OR) with a 95% confidence interval (CI) or presented data sufficient to calculate the OR with a 95% CI. Statistical analysis was performed using the Comprehensive Meta-Analysis (CMA), Version 3 software, and a Forrest plot was generated. We assessed for publication bias using conventional techniques. Twenty studies (three randomized controlled trials, six cohorts, and 11 case-controls) with 2,668,497 patients including 24,341 cases of HCC were included in the meta-analysis. Our findings indicate a significant risk reduction of HCC among all statin users with a pooled odds ratio of 0.573 (95% CI: 0.491-0.668, I2= 86.57%) compared to non-users. No publication bias was found using Egger’s regression test or on visual inspection of the generated Funnel plot. The results indicate that statin use was associated with a 43% lower risk of HCC compared to statin non-users. Further prospective randomized research is needed to confirm the association.
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28
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Association of statin treatment with hepatocellular carcinoma risk in end-stage kidney disease patients with chronic viral hepatitis. Sci Rep 2022; 12:10807. [PMID: 35752695 PMCID: PMC9233705 DOI: 10.1038/s41598-022-14713-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Accepted: 06/10/2022] [Indexed: 11/12/2022] Open
Abstract
Statin use in end-stage kidney disease (ESKD) patients are not encouraged due to low cardioprotective effects. Although the risk of hepatocellular carcinoma (HCC), a frequently occurring cancer in East Asia, is elevated in ESKD patients, the relationship between statins and HCC is not known despite its possible chemopreventive effect. The relationship between statin use and HCC development in ESKD patients with chronic hepatitis was evaluated. In total, 6165 dialysis patients with chronic hepatitis B or C were selected from a national health insurance database. Patients prescribed with ≥ 28 cumulative defined daily doses of statins during the first 3 months after dialysis commencement were defined as statin users, while those not prescribed with statins were considered as non-users. Primary outcome was the first diagnosis of HCC. Sub-distribution hazard model with inverse probability of treatment weighting was used to estimate HCC risk considering death as competing risk. During a median follow-up of 2.8 years, HCC occurred in 114 (3.2%) statin non-users and 33 (1.2%) statin users. The HCC risk was 41% lower in statin users than in non-users (sub-distribution hazard ratio, 0.59; 95% confidence interval [CI], 0.42-0.81). The weighted incidence rate of HCC was lower in statin users than in statin non-users (incidence rate difference, - 3.7; 95% CI - 5.7 to - 1.7; P < 0.001). Incidence rate ratio (IRR) was also consistent with other analyses (IRR, 0.56; 95% CI, 0.41 to 0.78; P < 0.001). Statin use was associated with a lower risk of incident HCC in dialysis patients with chronic hepatitis B or C infection.
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Thiruvengadam NR, Schaubel DE, Forde K, Lee P, Saumoy M, Kochman ML. Association of Statin Usage and the Development of Diabetes Mellitus after Acute Pancreatitis. Clin Gastroenterol Hepatol 2022; 21:1214-1222.e14. [PMID: 35750248 DOI: 10.1016/j.cgh.2022.05.017] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Revised: 04/21/2022] [Accepted: 05/09/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND Patients with acute pancreatitis (AP) have at least a 2-fold higher risk for developing postpancreatitis diabetes mellitus (PPDM). No therapies have prevented PPDM. Statins were demonstrated to possibly lower the incidence and severity of AP but have not been studied to prevent PPDM. METHODS Data from a commercial insurance claim database (Optum Clinformatics) were used to assess the impact of statins on patients without pre-existing DM admitted for a first episode of AP in 118,479 patients. Regular statin usage was defined as filled statin prescriptions for at least 80% of the year prior to AP. The primary outcome was defined as PPDM. We constructed a propensity score and applied inverse probability of treatment weighting to balance baseline characteristics between groups. Using Cox proportional hazards regression modeling, we estimated the risk of PPDM, accounting for competing events. RESULTS With a median of 3.5 years of follow-up, the 5-year cumulative incidence of PPDM was 7.5% (95% confidence interval [CI], 6.9% to 8.0%) among regular statin users and 12.7% (95% CI, 12.4% to 12.9%) among nonusers. Regular statin users had a 42% lower risk of developing PPDM compared with nonusers (hazard ratio, 0.58; 95% CI, 0.52 to 0.65; P < .001). Irregular statin users had a 15% lower risk of PPDM (hazard ratio, 0.85; 95% CI, 0.81 to 0.89; P < .001). Similar benefits were seen with low, moderate, and high statin doses. CONCLUSIONS In a large database-based study, statin usage reduced the risk of developing DM after acute pancreatitis. Further prospective studies with long-term follow-up are needed to study the impact of statins on acute pancreatitis and prevention of PPDM.
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Affiliation(s)
- Nikhil R Thiruvengadam
- Division of Gastroenterology and Hepatology, Loma Linda University School of Medicine, Loma Linda, California; Gastroenterology Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Center for Endoscopic Innovation, Research and Training, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.
| | - Douglas E Schaubel
- Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Kimberly Forde
- Department of Gastroenterology and Hepatology, Temple University, Philadelphia, Pennsylvania
| | - Peter Lee
- Department of Gastroenterology, Hepatology, and Nutrition, Ohio State University Wexner Medical Center, Columbus, Ohio
| | - Monica Saumoy
- Center for Digestive Health, Penn Medicine Princeton Medical Center, Plainsboro, New Jersey
| | - Michael L Kochman
- Gastroenterology Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Center for Endoscopic Innovation, Research and Training, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
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Kim DS, Kim HJ, Ahn HS. Statins and the risk of gastric, colorectal, and esophageal cancer incidence and mortality: a cohort study based on data from the Korean national health insurance claims database. J Cancer Res Clin Oncol 2022; 148:2855-2865. [PMID: 35660949 DOI: 10.1007/s00432-022-04075-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Accepted: 05/16/2022] [Indexed: 12/24/2022]
Abstract
BACKGROUND This study investigated the association between the use of statins, the incidence of gastric, colorectal, and esophageal cancers, and mortality between January 2005 and June 2013 in South Korea. METHODS We compared patients aged 45-70 years statin users for at least 6 months to non-statin users matched by age and sex, from 2004 to June 2013 using the National Health Insurance database. Main outcomes were gastric, colorectal, and esophageal cancer incidence and mortality. Cox proportional hazard regression was used to calculate the adjusted hazard ratios (aHRs) and 95% confidence intervals (95% CIs) among overall cohort and matched cohort after propensity score matching with a 1:1 ratio. RESULTS Out of 1,008,101 people, 20,473 incident cancers, 3938 cancer deaths occurred and 7669 incident cancer, 1438 cancer death in matched cohort. The aHRs for the association between the risk of cancers and statin use were 0.7 (95% CI 0.65-0.74) for gastric cancer, 0.73 (95% CI 0.69-0.78) for colorectal cancer, and 0.55 (95% CI 0.43-0.71) for esophageal cancer. There were associations between statin use and decreased gastric cancer mortality (HR 0.46, 95% CI 0.52-0.57), colorectal cancer mortality (HR 0.43, 95% CI 0.36-0.51), and esophageal cancer mortality (HR 0.41, 95% CI 0.27-0.50) in the overall cohort and this pattern was similar in the matched cohort. DISCUSSION Statin use for at least 6 months was significantly associated with a lower risk of stomach, colorectal, and esophageal cancer incidence as well as cancer mortality after a diagnosis.
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Affiliation(s)
- Dong-Sook Kim
- Department of Research, Health Insurance Review and Assessment Service, Wonju, Republic of Korea
| | - Hyun Jung Kim
- Department of Preventive Medicine, College of Medicine, Korea University, 126-1, 5-ga, Anam-dong, Sungbuk-gu, Seoul, 136-705, Republic of Korea
| | - Hyeong Sik Ahn
- Department of Preventive Medicine, College of Medicine, Korea University, 126-1, 5-ga, Anam-dong, Sungbuk-gu, Seoul, 136-705, Republic of Korea.
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31
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Ahmad MI, Khan MU, Kodali S, Shetty A, Bell SM, Victor D. Hepatocellular Carcinoma Due to Nonalcoholic Fatty Liver Disease: Current Concepts and Future Challenges. J Hepatocell Carcinoma 2022; 9:477-496. [PMID: 35673598 PMCID: PMC9167599 DOI: 10.2147/jhc.s344559] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 05/14/2022] [Indexed: 12/24/2022] Open
Abstract
Obesity has been labeled as the global pandemic of the 21st century, resulting from a sedentary lifestyle and caloric excess. Nonalcoholic fatty liver disease (NAFLD), characterized by excessive hepatic steatosis, is strongly associated with obesity and metabolic syndrome and is estimated to be present in one-quarter of the world population, making it the most common cause of the chronic liver disease (CLD). NAFLD spectrum varies from simple steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis. The burden of NAFLD has been predicted to increase in the coming decades resulting in increased rates of decompensated cirrhosis, hepatocellular carcinoma (HCC), and liver-related deaths. In the current review, we describe the pathophysiology of NAFLD and NASH, risk factors associated with disease progression, related complications, and mortality. Later, we have discussed the changing epidemiology of HCC, with NAFLD emerging as the most common cause of CLD and HCC. We have also addressed the risk factors of HCC development in the NAFLD population (including demographic, metabolic, genetic, dietary, and lifestyle factors), presentation of NAFLD-associated HCC, its prognosis, and the issue of HCC development in non-cirrhotic NAFLD. Lastly, the problems related to HCC screening in the NAFLD population, the remaining challenges, and future directions, especially the need to identify the high-risk individuals, will be discussed. We will conclude the review by summarizing the clinical evidence for treating fibrosis and preventing HCC in those at risk with NAFLD-associated HCC.
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Affiliation(s)
- Muhammad Imran Ahmad
- Lynda K and David M Underwood Center for Digestive Disorders, Division of Gastroenterology and Hepatology, Houston Methodist Hospital Houston, Houston, TX, USA
| | - Muhammad Umair Khan
- Department of Gastroenterology and Hepatology, Hamad Medical Corporation, Doha, Qatar
- ECPE- Executive and Continuing Professional Education, Harvard T.H Chan School of Public Health, Boston, MA, 02115-5810, USA
| | - Sudha Kodali
- Lynda K and David M Underwood Center for Digestive Disorders, Division of Gastroenterology and Hepatology, Houston Methodist Hospital Houston, Houston, TX, USA
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston Methodist Hospital, Houston, TX, USA
| | - Akshay Shetty
- Lynda K and David M Underwood Center for Digestive Disorders, Division of Gastroenterology and Hepatology, Houston Methodist Hospital Houston, Houston, TX, USA
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston Methodist Hospital, Houston, TX, USA
| | - S Michelle Bell
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston Methodist Hospital, Houston, TX, USA
| | - David Victor
- Lynda K and David M Underwood Center for Digestive Disorders, Division of Gastroenterology and Hepatology, Houston Methodist Hospital Houston, Houston, TX, USA
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston Methodist Hospital, Houston, TX, USA
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32
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The anti-angiogenic effect of atorvastatin loaded exosomes on glioblastoma tumor cells: An in vitro 3D culture model. Microvasc Res 2022; 143:104385. [DOI: 10.1016/j.mvr.2022.104385] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 05/03/2022] [Accepted: 05/18/2022] [Indexed: 01/10/2023]
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Liou JW, Mani H, Yen JH. Viral Hepatitis, Cholesterol Metabolism, and Cholesterol-Lowering Natural Compounds. Int J Mol Sci 2022; 23:ijms23073897. [PMID: 35409259 PMCID: PMC8999150 DOI: 10.3390/ijms23073897] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Revised: 03/27/2022] [Accepted: 03/30/2022] [Indexed: 11/24/2022] Open
Abstract
Hepatitis is defined as inflammation of the liver; it can be acute or chronic. In chronic cases, the prolonged inflammation gradually damages the liver, resulting in liver fibrosis, cirrhosis, and sometimes liver failure or cancer. Hepatitis is often caused by viral infections. The most common causes of viral hepatitis are the five hepatitis viruses—hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis D virus (HDV), and hepatitis E virus (HEV). While HAV and HEV rarely (or do not) cause chronic hepatitis, a considerable proportion of acute hepatitis cases caused by HBV (sometimes co-infected with HDV) and HCV infections become chronic. Thus, many medical researchers have focused on the treatment of HBV and HCV. It has been documented that host lipid metabolism, particularly cholesterol metabolism, is required for the hepatitis viral infection and life cycle. Thus, manipulating host cholesterol metabolism-related genes and proteins is a strategy used in fighting the viral infections. Efforts have been made to evaluate the efficacy of cholesterol-lowering drugs, particularly 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, in the treatment of hepatitis viral infections; promising results have been obtained. This review provides information on the relationships between hepatitis viruses and host cholesterol metabolism/homeostasis, as well as the discovery/development of cholesterol-lowering natural phytochemicals that could potentially be applied in the treatment of viral hepatitis.
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Affiliation(s)
- Je-Wen Liou
- Department of Biochemistry, School of Medicine, Tzu Chi University, Hualien 97004, Taiwan;
- Institute of Medical Sciences, Tzu Chi University, Hualien 97004, Taiwan;
| | - Hemalatha Mani
- Institute of Medical Sciences, Tzu Chi University, Hualien 97004, Taiwan;
| | - Jui-Hung Yen
- Institute of Medical Sciences, Tzu Chi University, Hualien 97004, Taiwan;
- Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien 97004, Taiwan
- Correspondence: or ; Tel.: +886-3-856-5301 (ext. 2683)
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A Meta-Analysis of Statin Use and Risk of Hepatocellular Carcinoma. Can J Gastroenterol Hepatol 2022; 2022:5389044. [PMID: 35356132 PMCID: PMC8958112 DOI: 10.1155/2022/5389044] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 02/25/2022] [Accepted: 02/26/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND The use of statins is a potential protective factor against the development of hepatocellular carcinoma. Therefore, we conducted a meta-analysis to evaluate the contribution of statins to the risk of hepatocellular carcinoma. METHODS We searched for PubMed and EMBASE through January 2021. RESULTS Thirty-two studies (eighteen cohort, eleven case-control, and three randomized controlled trials) reporting 56,838 cases of hepatocellular carcinoma in 4,963,518 persons were included. Statin users were less likely to develop hepatocellular carcinoma than nonusers (adjusted odds ratio, 0.58; 95% CI: 0.51-0.67). Stratified analysis showed that statins reduced the risk of hepatocellular carcinoma in Asian and Western populations (odds ratio, 0.54 vs. 0.60). Besides, statins have protective effects against hepatocellular carcinoma after hepatitis B virus (odds ratio, 0.44; 95% CI: 0.22-0.85) and hepatitis C virus infections (odds ratio, 0.53; 95% CI: 0.49-0.57). Statins have protective effects on people with chronic liver disease (odds ratio, 0.52; 95% CI: 0.40-0.68) and on the general population (odds ratio, 0.60; 95% CI: 0.50-0.72). Lipophilic statins can prevent hepatocellular carcinoma (odds ratio, 0.51, 95% CI: 0.46-0.57), while hydrophilic statins cannot (odds ratio, 0.77, 95% CI: 0.58-1.02). The single-drug analyses showed that simvastatin (odds ratio, 0.53, 95% CI: 0.48-0.59), atorvastatin (odds ratio, 0.54, 95% CI: 0.45-0.64), rosuvastatin (odds ratio, 0.55, 95% CI: 0.37-0.83), lovastatin (odds ratio, 0.30, 95% CI: 0.15-0.62), and pitavastatin (odds ratio, 0.36, 95% CI: 0.17-0.75) had significant benefits. Further studies have shown that those in the high-dose group experienced better effects in preventing hepatocellular carcinoma (adjusted hazard ratio, 0.38 vs. 0.55). Further research found that the combined use of aspirin did not increase the chemoprevention effect of liver cancer (odds ratio, 0.57; 95% CI: 0.40-0.81). In addition, the preventive effect of statins improved with the extension of follow-up time (odds ratio, 0.54 vs. 0.65). CONCLUSION Our meta-analysis shows that the use of statins is associated with a lower risk of liver cancer.
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Chrysavgis L, Giannakodimos I, Diamantopoulou P, Cholongitas E. Non-alcoholic fatty liver disease and hepatocellular carcinoma: Clinical challenges of an intriguing link. World J Gastroenterol 2022; 28:310-331. [PMID: 35110952 PMCID: PMC8771615 DOI: 10.3748/wjg.v28.i3.310] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 10/19/2021] [Accepted: 01/06/2022] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) has emerged as the most common liver disorder worldwide mainly attributed to the epidemic spread of obesity and type 2 diabetes mellitus. Although it is considered a benign disease, NAFLD can progress to non-alcoholic steatohepatitis, liver cirrhosis and hepatocellular carcinoma (HCC). Most data regarding the epidemiology of NAFLD-related HCC are derived from cohort and population studies and show that its incidence is increasing as well as it is likely to emerge as the leading indication for liver transplantation, especially in the Western World. Although cirrhosis constitutes the main risk factor for HCC development, in patients with NAFLD, HCC can arise in the absence of cirrhosis, indicating specific carcinogenic molecular pathways. Since NAFLD as an underlying liver disease for HCC is often underdiagnosed due to lack of sufficient surveillance in this population, NAFLD-HCC patients are at advanced HCC stage at the time of diagnosis making the management of those patients clinically challenging and affecting their prognostic outcomes. In this current review, we summarize the latest literature on the epidemiology, other than liver cirrhosis-pathogenesis, risk factors and prognosis of NAFLD-HCC patients. Finally, we emphasize the prevention of the development of NAFLD-associated HCC and we provide some insight into the open questions and issues regarding the appropriate surveillance policies for those patients.
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Affiliation(s)
- Lampros Chrysavgis
- Department of Experimental Physiology, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Ilias Giannakodimos
- First Department of Internal Medicine, "Laiko" General Hospital of Athens, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Panagiota Diamantopoulou
- First Department of Internal Medicine, "Laiko" General Hospital of Athens, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Evangelos Cholongitas
- First Department of Internal Medicine, "Laiko" General Hospital of Athens, National and Kapodistrian University of Athens, Athens 11527, Greece
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Shen YC, Hsu HC, Lin TM, Chang YS, Hu LF, Chen LF, Lin SH, Kuo PI, Chen WS, Lin YC, Chen JH, Liang YC, Chang CC. H1-Antihistamines Reduce the Risk of Hepatocellular Carcinoma in Patients With Hepatitis B Virus, Hepatitis C Virus, or Dual Hepatitis B Virus-Hepatitis C Virus Infection. J Clin Oncol 2022; 40:1206-1219. [PMID: 35044851 PMCID: PMC8987217 DOI: 10.1200/jco.21.01802] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
H1-antihistamines (AHs) may exert protective effects against cancer. This study investigated the association of AH use with the risk of hepatocellular carcinoma (HCC) in patients with hepatitis B virus (HBV), hepatitis C virus (HCV), or dual HBV-HCV virus infection.
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Affiliation(s)
- Yu-Chuan Shen
- Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
| | - Hui-Ching Hsu
- Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.,Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Tzu-Min Lin
- Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Division of Rheumatology, Immunology, and Allergy, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan
| | - Yu-Sheng Chang
- Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan
| | - Li-Fang Hu
- Division of Rheumatology, Immunology, and Allergy, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan
| | - Lung-Fang Chen
- Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.,Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Sheng-Hong Lin
- Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan
| | - Pei-I Kuo
- Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine, Cardinal Tien Hospital, Yonghe Branch, Taipei, Taiwan
| | - Wei-Sheng Chen
- Division of Allergy, Immunology, and Rheumatology, Department of Internal Medicine, Taipei Veterans General Hospital, National Yang-Ming University, Taipei, Taiwan
| | - Yi-Chun Lin
- Biostatistics Center, College of Management, Taipei Medical University, Taipei, Taiwan
| | - Jin-Hua Chen
- Biostatistics Center, College of Management, Taipei Medical University, Taipei, Taiwan.,Graduate Institute of Data Science, College of Management, Taipei Medical University, Taipei, Taiwan
| | - Yu-Chih Liang
- School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.,Ph.D. Program in Medical Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.,Traditional Herbal Medicine Research Center, Taipei Medical University Hospital, Taipei, Taiwan
| | - Chi-Ching Chang
- Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Division of Rheumatology, Immunology, and Allergy, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan
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Uemura N, Hayashi H, Baba H. Statin as a therapeutic agent in gastroenterological cancer. World J Gastrointest Oncol 2022; 14:110-123. [PMID: 35116106 PMCID: PMC8790423 DOI: 10.4251/wjgo.v14.i1.110] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 06/19/2021] [Accepted: 11/25/2021] [Indexed: 02/06/2023] Open
Abstract
Statins inhibit 3-hydroxy-3-methylglutaryl-CoA reductase, the rate-limiting enzyme of the mevalonate pathway, and are widely used as an effective and safe approach handle hypercholesterolemia. The mevalonate pathway is a vital metabolic pathway that uses acetyl-CoA to generate isoprenoids and sterols that are crucial to tumor growth and progression. Multiple studies have indicated that statins improve patient prognosis in various carcinomas. Basic research on the mechanisms underlying the antitumor effects of statins is underway. The development of new anti-cancer drugs is progressing, but increasing medical costs from drug development have become a major obstacle. Readily available, inexpensive and well-tolerated drugs like statins have not yet been successfully repurposed for cancer treatment. Identifying the cancer patients that may benefit from statins is key to improved patient treatment. This review summarizes recent advances in statin research in cancer and suggests important considerations for the clinical use of statins to improve outcomes for cancer patients.
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Affiliation(s)
- Norio Uemura
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | - Hiromitsu Hayashi
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | - Hideo Baba
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
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Goh MJ, Sinn DH. Statin and aspirin for chemoprevention of hepatocellular carcinoma: Time to use or wait further? Clin Mol Hepatol 2022; 28:380-395. [PMID: 35021597 PMCID: PMC9293618 DOI: 10.3350/cmh.2021.0366] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2021] [Accepted: 01/08/2022] [Indexed: 11/20/2022] Open
Abstract
Preclinical studies highlighted potential therapeutic applications of aspirin and statins as anticancer agents based on their pleiotropic effects. Epidemiologic studies suggested the role of aspirin and statins in the chemoprevention of hepatocellular carcinoma (HCC). However, observational data is prone to bias, and no prospective randomized trials are currently available to assess the risks and benefits of statin or aspirin therapy for chemoprevention of HCC. It is therefore important for clinicians and researchers to be aware of the quality of current evidence regarding this issue. In this review, we summarize currently available evidence to assist clinicians with their decision to use statin or aspirin and provide information for further clinical investigations.
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Affiliation(s)
- Myung Ji Goh
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Dong Hyun Sinn
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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Wang J, Li X. Impact of statin use on the risk and prognosis of hepatocellular carcinoma: a meta-analysis. Eur J Gastroenterol Hepatol 2021; 33:1603-1609. [PMID: 33405428 DOI: 10.1097/meg.0000000000002040] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
BACKGROUND Previous studies have demonstrated that statin use might be associated with a reduced risk of hepatocellular carcinoma (HCC). However, the value of statin on the prognosis still needs to be evaluated. Based on the above considerations, we conducted a meta-analysis regarding the value of statin on the prevention and prognosis of HCC. METHODS Articles regarding the impact of statin use on the risk, prognosis of HCC and published before October 2020 were searched in the five databases. We computed odds ratio (OR)/relative risk (RR) or hazard ratio (HR) and 95% confidence intervals (CIs) regarding the association between statin use and the risk or prognosis of HCC by using STATA 12.0 software. RESULTS Twenty-six studies (including 1772 463 participants) detected the association between statin use and risk of HCC. Additionally, seven studies (including 8925 statin users and 76 487 no-statin users) explored the association between statin use and mortality of HCC. The meta-analysis showed that statin use was associated with lower risk and all-cause mortality of HCC with random effects models (risk: OR/RR = 0.57, 95% CI 0.49-0.65, I2 = 86.0%, P < 0.0001; all-cause mortality: HR = 0.80, 95% CI 0.68-0.94, I2 = 77.6%, P < 0.0001). However, statin use was not associated with cancer-specific mortality of HCC with a random effects model (HR = 0.80, 95% CI 0.62-1.03, I2 = 73.9%, P = 0.002). CONCLUSION In conclusion, our results have demonstrated the salutary effect of statin on the prevention and prognosis of HCC.
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Affiliation(s)
- Jianfeng Wang
- Department of Gastroenterology, Baoshan Branch of Shanghai Renji Hospital, Shanghai, China
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Francis P, Forman LM. Statins Show Promise Against Progression of Liver Disease. Clin Liver Dis (Hoboken) 2021; 18:280-287. [PMID: 34976372 PMCID: PMC8688902 DOI: 10.1002/cld.1143] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Revised: 04/28/2021] [Accepted: 05/05/2021] [Indexed: 02/04/2023] Open
Abstract
Content available: Audio Recording.
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Affiliation(s)
- Prashanth Francis
- Division of Gastroenterology and HepatologyUniversity of ColoradoAuroraCO
| | - Lisa M. Forman
- Division of Gastroenterology and HepatologyUniversity of ColoradoAuroraCO
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Vahedian-Azimi A, Shojaie S, Banach M, Heidari F, Cicero AFG, Khoshfetrat M, Jamialahmadi T, Sahebkar A. Statin therapy in chronic viral hepatitis: a systematic review and meta-analysis of nine studies with 195,602 participants. Ann Med 2021; 53:1227-1242. [PMID: 34296976 PMCID: PMC8317925 DOI: 10.1080/07853890.2021.1956686] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 07/13/2021] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Conflicting data suggest that statins could cause chronic liver disease in certain group of patients, while improving prognosis in those with chronic viral hepatitis (CVH). PURPOSE To quantify the potential protective role of statins on some main liver-related health outcomes in clinical studies on CVH patients.Data Sources: The search strategy was explored by a medical librarian using bibliographic databases, from January 2015 to April 2020.Data synthesis: The results showed no significant difference in the risk of mortality between statin users and non-users in the overall analysis. However, the risk of mortality significantly reduced by 39% in statin users who were followed for more than three years. Moreover, the risk of HCC, fibrosis, and cirrhosis in those on statins decreased by 53%, 45% and 41%, respectively. Although ALT and AST reduced slightly following statin therapy, this reduction was not statistically significant. LIMITATIONS A significant heterogeneity among studies was observed, resulting from differences in clinical characteristics between statin users and non-users, study designs, population samples, diseases stage, comorbidities, and confounding covariates. CONCLUSION Not only long-term treatment with statins seems to be safe in patients affected by hepatitis, but also it significantly improves their prognosis.
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Affiliation(s)
- Amir Vahedian-Azimi
- Trauma Research Center, Nursing Faculty, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Sajad Shojaie
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maciej Banach
- Department of Hypertension, Chair of Nephrology and Hypertension, Medical University of Lodz, Lodz, Poland
- Cardiovascular Research Centre, University of Zielona Gora, Zielona Gora, Poland
| | - Farshad Heidari
- Nursing Care Research Center (NCRC), School of Nursing and Midwifery, Iran University of Medical Sciences, Tehran, Iran
| | - Arrigo F. G. Cicero
- Atherosclerosis Research Unit, Medical and Surgical Sciences Department, Sant’Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Masoum Khoshfetrat
- Department of Anesthesiology and Critical Care, Khatamolanbia Hospital, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Tannaz Jamialahmadi
- Department of Food Science and Technology, Quchan Branch, Islamic Azad University, Quchan, Iran
- Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- School of Medicine, The University of Western Australia, Perth, Australia
- School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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Alqahtani SA, Colombo M. Treatment for Viral Hepatitis as Secondary Prevention for Hepatocellular Carcinoma. Cells 2021; 10:3091. [PMID: 34831314 PMCID: PMC8619578 DOI: 10.3390/cells10113091] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 11/05/2021] [Accepted: 11/07/2021] [Indexed: 02/06/2023] Open
Abstract
Chronic infections with either hepatitis B or C virus (HBV or HCV) are among the most common risk factors for developing hepatocellular carcinoma (HCC). The hepatocarcinogenic potential of these viruses is mediated through a wide range of mechanisms, including the induction of chronic inflammation and oxidative stress and the deregulation of cellular pathways by viral proteins. Over the last decade, effective anti-viral agents have made sustained viral suppression or cure a feasible treatment objective for most chronic HBV/HCV patients. Given the tumorigenic potential of HBV/HCV, it is no surprise that obtaining sustained viral suppression or eradication proves to be effective in preventing HCC. This review summarizes the mechanisms by which HCV and HBV exert their hepatocarcinogenic activity and describes in detail the efficacy of anti-HBV and anti-HCV therapies in terms of HCC prevention. Although these treatments significantly reduce the risk for HCC in patients with chronic viral hepatitis, this risk is not eliminated. Therefore, we evaluate potential strategies to improve these outcomes further and address some of the remaining controversies.
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Affiliation(s)
- Saleh A. Alqahtani
- Division of Gastroenterology and Hepatology, Johns Hopkins University, Baltimore, MD 21287, USA
- Liver Transplant Center, and Biostatistics, Epidemiology, and Scientific Computing Department, King Faisal Specialist Hospital & Research Center, Riyadh 11564, Saudi Arabia
| | - Massimo Colombo
- Liver Center, IRCCS San Raffaele Hospital, 20132 Milan, Italy;
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Prevention of NAFLD-associated HCC: Role of lifestyle and chemoprevention. J Hepatol 2021; 75:1217-1227. [PMID: 34339764 DOI: 10.1016/j.jhep.2021.07.025] [Citation(s) in RCA: 82] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 07/13/2021] [Accepted: 07/15/2021] [Indexed: 02/07/2023]
Abstract
In many countries worldwide, the burden of hepatocellular carcinoma (HCC) associated with non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) is increasing. Preventive strategies are needed to counteract this trend. In this review, we provide an overview of the evidence on preventive strategies in NAFLD-associated HCC. We consider the impact of lifestyle factors such as weight loss, physical activity, smoking, dietary patterns and food items, including coffee and alcohol, on both HCC and NAFLD/NASH. Furthermore, evidence on chemopreventive treatments, including aspirin, antidiabetic treatments and statins is summarised. The role of adjuvant therapies for tertiary prevention of HCC is briefly reviewed.
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Choi WM, Kim HJ, Jo AJ, Choi SH, Han S, Ko MJ, Lim YS. Association of aspirin and statin use with the risk of liver cancer in chronic hepatitis B: A nationwide population-based study. Liver Int 2021; 41:2777-2785. [PMID: 34242482 DOI: 10.1111/liv.15011] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Revised: 06/08/2021] [Accepted: 07/05/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Aspirin and statins have been suggested to prevent hepatocellular carcinoma (HCC). However, the combined effects of aspirin and statins on HCC risk in patients with chronic hepatitis B (CHB) are not clear. METHODS A nationwide nested case-control study was performed with data from the National Health Insurance Service gathered between 2005 and 2015 in Korea. In a cohort of 538,135 treatment-naïve, non-cirrhotic patients with CHB, 6,539 HCC cases were matched to 26,156 controls and were analysed by conditional logistic regression. Separate historical cohort studies for each drug were analysed by time-dependent Cox regression as a sensitivity analysis. RESULTS In the nested case-control study, statins (OR 0.34; 95% CI 0.32-0.37) and aspirin (OR 0.92; 95% CI 0.85-0.99) were significantly associated with a HCC risk reduction. However, dose-dependent risk reduction was observed only with statins. By sensitivity analysis in the historical cohorts, statin users (n = 244,455; HR 0.67; 95% CI 0.66-0.68) and aspirin users (n = 288,777; HR 0.81; 95% CI 0.80-0.82) had significantly lower HCC risk. In the drug-stratified analyses, statins were associated with significantly reduced risk of HCC regardless of aspirin, whereas aspirin did not show such associations. CONCLUSIONS In this nationwide population-based study of patients with CHB, statin use was consistently associated with a significant and dose-dependent reduction in HCC risk. In contrast, the association between aspirin use and HCC risk reduction was not dose-dependent and was suggested to be confounded by statins.
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Affiliation(s)
- Won-Mook Choi
- Liver Center, Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Hyo Jeong Kim
- Division for Healthcare Technology Assessment Research, National Evidence-Based Healthcare Collaborating Agency, Seoul, Republic of Korea
| | - Ae Jeong Jo
- Division for Healthcare Technology Assessment Research, National Evidence-Based Healthcare Collaborating Agency, Seoul, Republic of Korea
| | - So Hyun Choi
- Division for Healthcare Technology Assessment Research, National Evidence-Based Healthcare Collaborating Agency, Seoul, Republic of Korea.,Department of Statistics, Kyungpook National University, Daegu, Republic of Korea
| | - Seungbong Han
- Department of Biostatistics, Korea University College of Medicine, Seoul, Republic of Korea
| | - Min Jung Ko
- Division for Healthcare Technology Assessment Research, National Evidence-Based Healthcare Collaborating Agency, Seoul, Republic of Korea
| | - Young-Suk Lim
- Liver Center, Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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Chemopreventive Effect of Statin on Hepatocellular Carcinoma in Patients With Nonalcoholic Steatohepatitis Cirrhosis. Am J Gastroenterol 2021; 116:2258-2269. [PMID: 34212895 DOI: 10.14309/ajg.0000000000001347] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Accepted: 05/14/2021] [Indexed: 02/08/2023]
Abstract
INTRODUCTION To estimate the annual incidence of hepatocellular carcinoma (HCC) in patients with nonalcoholic steatohepatitis (NASH) with advanced liver fibrosis, to determine the risk factors for the development of HCC, and to evaluate the chemoprotective effect of statin use stratified by fibrosis stage. METHODS We conducted a retrospective study at 2 US tertiary academic centers, including patients with NASH-related advanced liver fibrosis (bridging fibrosis [F3] and cirrhosis [F4]) followed between July 2002 and June 2016. Patients were followed from the date of diagnosis to the time of last abdominal imaging, liver transplantation, or HCC diagnosis. Multivariable Cox regression analysis was performed to evaluate the risk factors associated with HCC development, stratified by fibrosis stage. RESULTS A total of 1,072 patients were included: 122 patients with F3 fibrosis and 950 patients with cirrhosis. No HCC was observed during 602 person-year follow-up among F3 patients. Among patients with cirrhosis, HCC developed in 82 patients with the annual incidence rate of 1.90 per 100 person-years (95% confidence interval [CI], 1.53-2.35). Multivariable analysis in patients with cirrhosis demonstrated that HCC development was associated with male sex (hazard ratio [HR] 4.06, 95% CI, 2.54-6.51, P < 0.001), older age (HR, 1.05, 95% CI, 1.03-1.08, P < 0.001), and CTP score (HR, 1.38, 95% CI, 1.18-1.60, P < 0.001). Statin use was associated with a lower risk of developing HCC (HR, 0.40, 95% CI, 0.24-0.67, P = 0.001). Each 365 increment in cumulative defined daily dose of statin use reduced HCC risk by 23.6%. DISCUSSION Our findings suggest that patients with NASH and bridging fibrosis have a low risk of HCC. Dose-dependent statin use reduced HCC risk significantly in patients with NASH cirrhosis.
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Roberts SK, Majeed A, Kemp W. Controversies in the Management of Hepatitis B: Hepatocellular Carcinoma. Clin Liver Dis 2021; 25:785-803. [PMID: 34593153 DOI: 10.1016/j.cld.2021.06.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Hepatitis B is the leading cause of hepatocellular cancer (HCC) worldwide. Untreated, annual HCC incidence rates in chronic hepatitis B subjects are 0.4% in noncirrhotics and 2% to 3% in cirrhotics. Surveillance with ultrasound with/without α-fetoprotein at 6-month intervals is recommended in at-risk persons including children. Antiviral therapy in chronic hepatitis B with entecavir or tenofovir significantly lowers the risk of HCC across all stages of liver disease, and lowers the risk of HCC recurrence following curative therapy. There are insufficient data to recommend use of tenofovir over entecavir in the prevention of de novo or recurrent HCC postcurative therapy.
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Affiliation(s)
- Stuart K Roberts
- The Alfred, 55 Commercial Road, Melbourne 3004, Australia; Monash University, Melbourne, Australia.
| | - Ammar Majeed
- The Alfred, 55 Commercial Road, Melbourne 3004, Australia; Monash University, Melbourne, Australia
| | - William Kemp
- The Alfred, 55 Commercial Road, Melbourne 3004, Australia; Monash University, Melbourne, Australia
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Effects of Metformin Exposure on Survival in a Large National Cohort of Patients With Diabetes and Cirrhosis. Clin Gastroenterol Hepatol 2021; 19:2148-2160.e14. [PMID: 32798709 DOI: 10.1016/j.cgh.2020.08.026] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 08/04/2020] [Accepted: 08/11/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Type II diabetes mellitus worsens the prognosis of cirrhosis. Multiple medications including metformin and statins often are co-administered to manage patients with diabetes. The aim of this study was to assess the impact of metformin exposure on mortality, hepatic decompensation, and hepatocellular carcinoma in individuals with diabetes and cirrhosis, controlling for multiple concomitant exposures. METHODS We performed a retrospective cohort study of patients with cirrhosis diagnosed between January 1, 2008, through June 30, 2016, in the Veterans Health administration. Marginal structural models and propensity-matching approaches were implemented to quantify the treatment effect of metformin in patients with pre-existing diabetes with or without prior metformin exposure. RESULTS Among 74,984 patients with cirrhosis, diabetes mellitus was present before the diagnosis of cirrhosis in 53.8%, and was diagnosed during follow-up evaluation in 4.8%. Before the diagnosis of cirrhosis, 11,114 patients had active utilization of metformin. In these patients, metformin, statin, and angiotensinogen-converting enzyme inhibitor/angiotensin-2-receptor blocker exposure were associated independently with reduced mortality (metformin hazard ratio, 0.68; 95% CI, 0.61-0.75); metformin was not associated with reduced hepatocellular carcinoma or hepatic decompensation after adjustment for concomitant statin exposure. For patients with diabetes before a diagnosis of cirrhosis but no prior metformin exposure, metformin similarly was associated with reduced mortality (hazard ratio, 0.72; 95% CI, 0.35-0.97), but not with reduced hepatocellular carcinoma or hepatic decompensation. CONCLUSIONS Metformin use in patients with cirrhosis and diabetes appears safe and is associated independently with reduced overall, but not liver-related, mortality, hepatocellular carcinoma, or decompensation after adjusting for concomitant statin and angiotensinogen-converting enzyme inhibitor/angiotensin-2-receptor blocker exposure.
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Tsai MC, Wang CC, Lee WC, Lin CC, Chang KC, Chen CH, Hung CH, Lin MT, Hsiao CC, Chen CL, Chien RN, Hu TH. Tenofovir Is Superior to Entecavir on Tertiary Prevention for BCLC Stage 0/A Hepatocellular Carcinoma after Curative Resection. Liver Cancer 2021; 11:22-37. [PMID: 35222505 PMCID: PMC8820175 DOI: 10.1159/000518940] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 08/09/2021] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND It is unclear whether entecavir (ETV) and tenofovir disoproxil fumarate (TDF) have different effects on hepatocellular carcinoma (HCC) recurrence and death in patients receiving curative hepatectomy for hepatitis B virus (HBV)-related HCC. AIMS The aim of this study was to compare the long-term efficacy of ETV and TDF in HCC recurrence and overall survival (OS) of patients after curative hepatectomy. METHODS From January 2010 to December 2019, 20,572 patients with HCC who received hepatectomy were screened for study eligibility. Finally, a total of 219 consecutive patients treated with ETV (n = 146) or TDF (n = 73) after curative hepatectomy for HBV-related HCC of Barcelona Clinic Liver Cancer stage 0 or A were analyzed by propensity score matching (PSM) (2:1) analysis and competing risk analysis. HCC recurrence and OS of patients were compared between ETV and TDF groups. RESULT After a median follow-up of 52.2 months, 81 patients (37.0%) had HCC recurrence, 33 (15.1%) died, and 5 (2.3%) received liver transplantation. TDF therapy was an independent protective factor for HCC recurrence compared with ETV therapy (HR, 1.687; 95% CI, 1.027-2.770, p = 0.039); however, no difference in the risk of death or liver transplantation. Results were similar in competing risk analysis. We further found that TDF therapy was significantly associated with a lower risk of late recurrence (HR, 4.705; 95% CI, 1.763-12.558, p = 0.002), but not in early recurrence. CONCLUSIONS TDF therapy is associated with a significantly lower risk of HCC recurrence, especially of late recurrence, than ETV therapy among patients who undergo curative hepatectomy for HBV-related early-stage HCC.
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Affiliation(s)
- Ming-Chao Tsai
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan,Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chih-Chi Wang
- Liver Transplantation Center and Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Wei-Chen Lee
- Division of Liver and Transplantation Surgery, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Chih-Che Lin
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Kuo-Chin Chang
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chien-Hung Chen
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chao-Hung Hung
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Ming-Tsung Lin
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chang-Chun Hsiao
- Division of Pulmonary and Critical Care Medicine, Graduate Institute of Clinical Medical Sciences, College of Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University, Kaohsiung, Taiwan
| | - Chao-Long Chen
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Rong-Nan Chien
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Linko Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Tsung-Hui Hu
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan,*Tsung-Hui Hu,
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Clinical Presentation of Hepatocellular Carcinoma in African Americans vs. Caucasians: A Retrospective Analysis. PATHOPHYSIOLOGY 2021; 28:387-399. [PMID: 35366282 PMCID: PMC8830457 DOI: 10.3390/pathophysiology28030026] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 08/10/2021] [Accepted: 08/19/2021] [Indexed: 12/27/2022] Open
Abstract
Hepatocellular carcinoma (HCC) remains an important form of cancer-related morbidity and mortality in the U.S. and worldwide. Previous U.S.-based studies on survival suggest ethnic disparities in HCC patients, but the complex interplay of multiple factors that contribute are still incompletely understood. Here we considered the influences of risk factors contributing towards HCC survival, including ethnic background, over ten years at a premier academic medical center with a majority (57.20%) African American (AA) population. Retrospective HCC data were collected from 2008–2018 at LSUHSC-Shreveport, an urban tertiary medical center. Data included demographics, comorbidities, liver disease characteristics, and tumor parameters. Statistical analysis was performed using Chi Square and one-way ANOVA. Results: 229 HCC patients were identified (male 78.6%). The mean HCC age at diagnosis was 61 years (SD = 7.3). Compared to non-Hispanic Caucasians (42.7%), AA patients (57.2% of total) were older at presentation, had more frequent diabetes/dyslipidemia/NAFLD (45 (34.3%) compared with 19 (19.3%) in non-Hispanic Caucasians, p = 0.02), and had a larger HCC burden at diagnosis. We conclude that compared to white patients, despite having similar BMI and MELD scores and rates of portal vein thrombosis, AA patients with HCC in our cohort were older at presentation, had a significantly increased incidence of modifiable metabolic risk factors including diabetes, higher AFP values, increased incidence of gallstones, and larger sized HCCs, and were more likely to be outside Milan criteria. These findings have important prognostic and diagnostic implications for developing a more targeted HCC surveillance program.
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Wong YJ, Qiu TY, Ng GK, Zheng Q, Teo EK. Efficacy and Safety of Statin for Hepatocellular Carcinoma Prevention Among Chronic Liver Disease Patients: A Systematic Review and Meta-analysis. J Clin Gastroenterol 2021; 55:615-623. [PMID: 33606427 DOI: 10.1097/mcg.0000000000001478] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Accepted: 10/29/2020] [Indexed: 02/05/2023]
Abstract
INTRODUCTION AND AIM Hepatocellular carcinoma (HCC) is a deadly complication among patients with chronic liver disease (CLD). Controversies on the efficacy and safety of statin to prevent HCC among patients with CLD remain despite the growing evidences. We aim to investigate the efficacy and safety of using statin for HCC prevention among adult with CLD. METHODS We performed a systematic search of 4 electronic databases (PubMed/MEDLINE, EMBASE, Cochrane library, and ClinicalTrial.gov) up to April 15, 2020. We selected all types of studies evaluating the statin use and the risk of HCC among CLD patients, regardless of language, region, publication date, or status. The primary endpoint was the pooled risk of HCC. The secondary endpoint was the risk of statin-associated myopathy. RESULT From 583 citations, we included a total of 13 studies (1,742,260 subjects, 7 types of statins), fulfilling the inclusion criteria, evaluating efficacy and safety of statin in CLD patients for HCC prevention. All studies were observational (2 nested case-control studies, 11 cohort studies), and no randomised trial was identified. We found that statin user has a lower pooled risk of HCC development (hazard ratio=0.57, 95% confidence interval: 0.52-0.62, I2=42%). HCC reduction was consistent among statin users in cirrhosis, hepatitis B virus, and hepatitis C virus infections. The risk of statin-associated myopathy was similar between statin user and nonuser (hazard ratio=1.07, 95% confidence interval=0.91-1.27). CONCLUSION Statin use was safe and associated with a lower pooled risk of HCC development among adults with CLD. Given the bias with observation studies, prospective randomised trial is needed to confirm this finding.
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Affiliation(s)
- Yu-Jun Wong
- Department of Gastroenterology and Hepatology, Changi General Hospital
- Yong Loo Lin School of Medicine, National University of Singapore
| | - Tian-Yu Qiu
- Department of Gastroenterology and Hepatology, Changi General Hospital
| | | | | | - Eng Kiong Teo
- Department of Gastroenterology and Hepatology, Changi General Hospital
- Yong Loo Lin School of Medicine, National University of Singapore
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