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Hosseinkhan N, Najafi L, Jahangiri S, Emami Z, Khamseh ME. Statin use and risk of HCC in patients with MASLD and T2DM: an umbrella review and meta-analysis. BMC Cancer 2025; 25:875. [PMID: 40369443 PMCID: PMC12080120 DOI: 10.1186/s12885-025-14299-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Accepted: 05/08/2025] [Indexed: 05/16/2025] Open
Abstract
BACKGROUND The effect of statin use on hepatocellular carcinoma (HCC) in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) or type two diabetes mellitus (T2DM) is still unclear. In this umbrella review, we aimed to assess the available evidence for the association of statin use and HCC risk in the target population. METHODS We carried out an umbrella review of previous systematic reviews/meta-analyses indexed in Cochrane, Embase, Scopus, and PubMed databases and published between Jan 1st, 2013, and Oct 22, 2024. We used random effects models to recalculate summary risk estimates for HCC incidence. Using A Measurement Tool to Assess methodological quality of systematic Review (AMSTAR2) tool, two independent reviewers evaluated each article for eligibility and methodologic quality and gathered data from the included studies. RESULTS Of the initially identified 1,038 systematic reviews/meta-analyses, three non-overlapping studies with medium/high quality were included for qualitative synthesis. Statin use in people with T2DM was reported in six studies belonging to two meta-analyses. The results showed that statins were associated with a decreased risk of HCC (RR: 0.16, 95% CI: [0.03, 0.98]). However, the association was nonsignificant in patients with MASLD comprising five studies from one meta-analysis (RR: 0.89, 95% CI: [0.56, 1.40]). CONCLUSION Statin use is associated with a decreased incidence of HCC in people with T2DM. In patients with MASLD, the association is not significant. However, the effects of other variables including the stage of inflammation and/or liver fibrosis on the outcome need to be explored in future studies.
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Affiliation(s)
- Nazanin Hosseinkhan
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences, Tehran, Iran, No 10, Firoozeh St, Vali Asr Sq
| | - Laily Najafi
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences, Tehran, Iran, No 10, Firoozeh St, Vali Asr Sq
| | - Soodeh Jahangiri
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences, Tehran, Iran, No 10, Firoozeh St, Vali Asr Sq
| | - Zahra Emami
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences, Tehran, Iran, No 10, Firoozeh St, Vali Asr Sq
| | - Mohammad E Khamseh
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences, Tehran, Iran, No 10, Firoozeh St, Vali Asr Sq.
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Cornberg M, Sandmann L, Jaroszewicz J, Kennedy P, Lampertico P, Lemoine M, Lens S, Testoni B, Lai-Hung Wong G, Russo FP. EASL Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol 2025:S0168-8278(25)00174-6. [PMID: 40348683 DOI: 10.1016/j.jhep.2025.03.018] [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] [Received: 03/20/2025] [Accepted: 03/20/2025] [Indexed: 05/14/2025]
Abstract
The updated EASL Clinical Practice Guidelines on the management of hepatitis B virus (HBV) infection provide comprehensive, evidence-based recommendations for its management. Spanning ten thematic sections, the guidelines address diagnostics, treatment goals, treatment indications, therapeutic options, hepatocellular carcinoma surveillance, management of special populations, HBV reactivation prophylaxis, post-transplant care, HBV prevention strategies, and finally address open questions and future research directions. Chronic HBV remains a global health challenge, with over 250 million individuals affected and significant mortality due to cirrhosis and hepatocellular carcinoma. These guidelines emphasise the importance of early diagnosis, risk stratification based on viral and host factors, and tailored antiviral therapy. Attention is given to simplified algorithms, vaccination, and screening to support global HBV elimination targets. The guidelines also discuss emerging biomarkers and evolving definitions of functional and partial cure. Developed through literature review, expert consensus, and a Delphi process, the guidelines aim to equip healthcare providers across disciplines with practical tools to optimise HBV care and outcomes worldwide.
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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; 185:522-530. [PMID: 40094696 PMCID: PMC11915111 DOI: 10.1001/jamainternmed.2025.0115] [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: 11/25/2024] [Accepted: 01/16/2025] [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
| | | | - 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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Liu Y, Yang J, Yu F, Li L, Zhao N, Lu C, Lu A, He X. Research advances in traditional Chinese medicine formulae and active components targeting lipid metabolism for hepatocellular carcinoma therapy. Front Pharmacol 2025; 16:1528671. [PMID: 40351413 PMCID: PMC12062747 DOI: 10.3389/fphar.2025.1528671] [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: 11/15/2024] [Accepted: 04/11/2025] [Indexed: 05/14/2025] Open
Abstract
Hepatocellular carcinoma (HCC) has a relatively poor prognosis and a high degree of malignancy. However, the therapeutic drugs are limited. In recent years, abnormal lipid metabolism and its important role in HCC has been reported, and emerging studies found that some formulae and active components of traditional Chinese medicine (TCM) can regulate abnormal lipid metabolism in HCC, showing their good application prospects. Therefore, this article summarizes the changes and the roles of lipid metabolites in HCC progression, and discusses the role of formulae and active components of TCM for the treatment of HCC based on their regulation on abnormal lipid metabolism. A deeper understanding of their relationship may help the precise use of these formulae and active components in HCC.
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Affiliation(s)
- Yang Liu
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Jie Yang
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Fenghua Yu
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Li Li
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Ning Zhao
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Cheng Lu
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Aiping Lu
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China
- Institute of Systems Medicine and Health Sciences, School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China
- Shanghai GuangHua Hospital of Integrated Traditional Chinese and Western Medicine, Institute of Arthritis Research, Shanghai Academy of Chinese Medical Sciences, Shanghai, China
| | - Xiaojuan He
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
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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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6
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Lee TC, Ho PS. Response to Letter to the Editor. Diabetes Metab Res Rev 2024; 40:e3742. [PMID: 37862071 DOI: 10.1002/dmrr.3742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/21/2023]
Affiliation(s)
- Tien-Ching Lee
- Orthopaedic Research Center, College of Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Orthopedics, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Orthopedics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Pei-Shan Ho
- Faculty of Dental Hygiene, College of Dental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
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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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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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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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Zhang X, Wong GLH, Wong VWS, Yip TCF. Editorial: improvement of cardiovascular risk factor control in patients with type 2 diabetes and nonalcoholic fatty liver disease-time for action! Authors' reply. Aliment Pharmacol Ther 2023; 57:1172-1173. [PMID: 37094323 DOI: 10.1111/apt.17474] [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: 04/26/2023]
Abstract
LINKED CONTENTThis article is linked to Zhang et al papers. To view these articles, visit https://doi.org/10.1111/apt.17428 and https://doi.org/10.1111/apt.17467
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Affiliation(s)
- Xinrong Zhang
- Medical Data Analytics Centre, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
- State Key Laboratory of Digestive Disease, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China
| | - Grace Lai-Hung Wong
- Medical Data Analytics Centre, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
- State Key Laboratory of Digestive Disease, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China
| | - Vincent Wai-Sun Wong
- Medical Data Analytics Centre, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
- State Key Laboratory of Digestive Disease, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China
| | - Terry Cheuk-Fung Yip
- Medical Data Analytics Centre, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
- State Key Laboratory of Digestive Disease, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China
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Zhang X, Yip TCF, Tse YK, Hui VWK, Li G, Lin H, Liang LY, Lai JCT, Lai MSM, Cheung JTK, Chan HLY, Chan SL, Kong APS, Wong GLH, Wong VWS. Trends in risk factor control and treatment among patients with non-alcoholic fatty liver disease and type 2 diabetes between 2000 and 2020: A territory-wide study. Aliment Pharmacol Ther 2023; 57:1103-1116. [PMID: 36815548 DOI: 10.1111/apt.17428] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 10/03/2022] [Accepted: 02/10/2023] [Indexed: 02/24/2023]
Abstract
BACKGROUND & AIMS We aimed to determine the trends in risk factor control and treatment among patients with non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D) in 2000-2020. METHODS We conducted a territory-wide cohort study of adult patients with NAFLD and T2D diagnosed between 1 January 2000 and 31 July 2021 in Hong Kong. T2D was defined by use of any anti-diabetic agents, laboratory tests and/or diagnosis codes. RESULTS This study included 16,084 patients with NAFLD and T2D (mean age, 54.8 ± 12.0 years; 7124 male [44.3%]). The percentage of patients achieving individualised haemoglobin A1c (HbA1c ) targets increased from 44.5% (95% confidence interval [CI], 42.9-46.1) to 64.8% (95% CI, 64.1-65.5), and percentage of patients achieving individualised low-density lipoprotein-cholesterol (LDL-C) targets increased from 23.3% (95% CI, 21.9-24.7) to 54.3% (95% CI, 53.5-55.1) from 2000-2005 to 2016-2020, whereas percentage of patients achieving blood pressure control (<140/90 mm Hg) remained static at 53.1-57.2%. Combination therapy for diabetes increased, especially among those with poor glycaemic control, but there was no increase in combination therapy for hypertension. Fewer cirrhotic patients achieved blood pressure control and individualised LDL-C targets, but they were more likely to achieve individualised HbA1c targets than non-cirrhotics. Metformin and statins were underused in cirrhotic patients. Younger patients (18-44 years) were less likely to achieve individualised HbA1c targets than middle-aged (45-64 years) and older ones (≥65 years). CONCLUSIONS From 2000 to 2020, glycaemic and lipid control improved significantly, whereas blood pressure control remained static among patients with NAFLD and T2D.
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Affiliation(s)
- Xinrong Zhang
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
- Medical Data Analytics Centre, The Chinese University of Hong Kong, Hong Kong, China
- State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China
| | - Terry Cheuk-Fung Yip
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
- Medical Data Analytics Centre, The Chinese University of Hong Kong, Hong Kong, China
- State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China
| | - Yee-Kit Tse
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
- Medical Data Analytics Centre, The Chinese University of Hong Kong, Hong Kong, China
- State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China
| | - Vicki Wing-Ki Hui
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
- Medical Data Analytics Centre, The Chinese University of Hong Kong, Hong Kong, China
- State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China
| | - Guanlin Li
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
- Medical Data Analytics Centre, The Chinese University of Hong Kong, Hong Kong, China
- State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China
| | - Huapeng Lin
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
- Medical Data Analytics Centre, The Chinese University of Hong Kong, Hong Kong, China
- State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China
| | - Lilian Yan Liang
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
- Medical Data Analytics Centre, The Chinese University of Hong Kong, Hong Kong, China
- State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China
| | - Jimmy Che-To Lai
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
- Medical Data Analytics Centre, The Chinese University of Hong Kong, Hong Kong, China
- State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China
| | - Mandy Sze-Man Lai
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
- Medical Data Analytics Centre, The Chinese University of Hong Kong, Hong Kong, China
- State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China
| | - Johnny T K Cheung
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
| | - Henry Lik-Yuen Chan
- Medical Data Analytics Centre, The Chinese University of Hong Kong, Hong Kong, China
- Department of Internal Medicine, Union Hospital, Hong Kong, China
| | - Stephen Lam Chan
- Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong, China
- State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Hong Kong, China
| | - Alice Pik-Shan Kong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
| | - Grace Lai-Hung Wong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
- Medical Data Analytics Centre, The Chinese University of Hong Kong, Hong Kong, China
- State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China
| | - Vincent Wai-Sun Wong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
- Medical Data Analytics Centre, The Chinese University of Hong Kong, Hong Kong, China
- State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China
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12
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Zeng RW, Yong JN, Tan DJH, Fu CE, Lim WH, Xiao J, Chan KE, Tan C, Goh XL, Chee D, Syn N, Tan EX, Muthiah MD, Ng CH, Tamaki N, Lee SW, Kim BK, Nguyen MH, Loomba R, Huang DQ. Meta-analysis: Chemoprevention of hepatocellular carcinoma with statins, aspirin and metformin. Aliment Pharmacol Ther 2023; 57:600-609. [PMID: 36625733 PMCID: PMC10792521 DOI: 10.1111/apt.17371] [Citation(s) in RCA: 50] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 11/12/2022] [Accepted: 12/11/2022] [Indexed: 01/11/2023]
Abstract
BACKGROUND Emerging data suggest that statins, aspirin and metformin may protect against hepatocellular carcinoma (HCC) development. However, prior meta-analyses were limited by heterogeneity and inclusion of studies without adequate adjustment for baseline risks. AIM To examine by an updated meta-analysis the association between these medications and HCC risk. METHODS Medline and Embase databases were searched from inception to March 2022 for studies that balanced baseline risks between study groups via propensity score matching or inverse probability of treatment weighting, that reported the impact of statins, aspirin or metformin on HCC risk. Multivariable-adjusted hazard ratios (HRs) for HCC were pooled using a random effects model. RESULTS Statin use was associated with reduced HCC risk overall (HR: 0.52; 95% CI: 0.37-0.72) (10 studies, 1,774,476), and in subgroup analyses for cirrhosis, hepatitis B/C, non-alcoholic fatty liver disease, studies accounting for concurrent aspirin and metformin consumption and lipophilic statins. Aspirin use was associated with reduced HCC risk overall (HR: 0.48; 95% CI: 0.27-0.87) (11 studies, 2,190,285 patients) but not in studies accounting for concurrent statin and metformin use. Metformin use was not associated with reduced HCC risk overall (HR: 0.57; 95% CI: 0.31-1.06) (3 studies, 125,458 patients). Most analyses had moderate/substantial heterogeneity, except in follow-up <60 months for aspirin (I2 = 0%). CONCLUSION Although statin and aspirin use were associated with reduced HCC risk, only statin use was significant in subgroup analyses accounting for concurrent medications. Metformin use was not associated with reduced HCC risk. These data have implications for future clinical trial design.
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Affiliation(s)
- Rebecca W. Zeng
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Jie Ning Yong
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Darren J. H. Tan
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Clarissa E. Fu
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Wen Hui Lim
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Jieling Xiao
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Kai En Chan
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Caitlyn Tan
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Xin Lei Goh
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Douglas Chee
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore
| | - Nicholas Syn
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Eunice X. Tan
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore
- National University Centre for Organ Transplantation, National University Health System, Singapore, Singapore
| | - Mark D. Muthiah
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore
- National University Centre for Organ Transplantation, National University Health System, Singapore, Singapore
| | - Cheng Han Ng
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Nobuharu Tamaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Sung Won Lee
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
- The Catholic University Liver Research Centre, Seoul, Korea
| | - Beom Kyung Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Yonsei University Health System, Seoul, Republic of Korea
| | - Mindie H. Nguyen
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California, USA
| | - Rohit Loomba
- NAFLD Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, University of California at San Diego, San Diego, California, USA
| | - Daniel Q. Huang
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore
- National University Centre for Organ Transplantation, National University Health System, Singapore, Singapore
- NAFLD Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, University of California at San Diego, San Diego, California, USA
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13
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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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14
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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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15
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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] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Accepted: 12/06/2022] [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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16
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Vogel A, Meyer T, Sapisochin G, Salem R, Saborowski A. Hepatocellular carcinoma. Lancet 2022; 400:1345-1362. [PMID: 36084663 DOI: 10.1016/s0140-6736(22)01200-4] [Citation(s) in RCA: 1100] [Impact Index Per Article: 366.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Revised: 05/31/2022] [Accepted: 06/15/2022] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma is one of the most common cancers worldwide and represents a major global health-care challenge. Although viral hepatitis and alcohol remain important risk factors, non-alcoholic fatty liver disease is rapidly becoming a dominant cause of hepatocellular carcinoma. A broad range of treatment options are available for patients with hepatocellular carcinoma, including liver transplantation, surgical resection, percutaneous ablation, and radiation, as well as transarterial and systemic therapies. As such, clinical decision making requires a multidisciplinary team that longitudinally adapts the individual treatment strategy according to the patient's tumour stage, liver function, and performance status. With the approval of new first-line agents and second-line agents, as well as the establishment of immune checkpoint inhibitor-based therapies as standard of care, the treatment landscape of advanced hepatocellular carcinoma is more diversified than ever. Consequently, the outlook for patients with hepatocellular carcinoma has improved. However, the optimal sequencing of drugs remains to be defined, and predictive biomarkers are urgently needed to inform treatment selection. In this Seminar, we present an update on the causes, diagnosis, molecular classification, and treatment of hepatocellular carcinoma.
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Affiliation(s)
- Arndt Vogel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
| | - Tim Meyer
- Research Department of Oncology, UCL Cancer Institute, University College London, Royal Free Hospital, London, UK
| | - Gonzalo Sapisochin
- Abdominal Transplant & HPB Surgical Oncology, University Health Network, University of Toronto, ON, Canada
| | - Riad Salem
- Department of Radiology, Northwestern University, Chicago, IL, USA
| | - Anna Saborowski
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
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17
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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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18
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Yip TCF, Lai JCT, Liang LY, Hui VWK, Wong VWS, Wong GLH. Risk of HCC in Patients with HBV, Role of Antiviral Treatment. CURRENT HEPATOLOGY REPORTS 2022; 21:76-86. [DOI: 10.1007/s11901-022-00588-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 08/19/2022] [Indexed: 08/08/2023]
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19
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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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20
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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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21
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Aberrant cholesterol metabolic signaling impairs antitumor immunosurveillance through natural killer T cell dysfunction in obese liver. Cell Mol Immunol 2022; 19:834-847. [DOI: 10.1038/s41423-022-00872-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Accepted: 04/14/2022] [Indexed: 12/24/2022] Open
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22
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Lee HA, Chang Y, Sung PS, Yoon EL, Lee HW, Yoo JJ, Lee YS, An J, Song DS, Cho YY, Kim SU, Kim YJ. Therapeutic mechanisms and beneficial effects of non-antidiabetic drugs in chronic liver diseases. Clin Mol Hepatol 2022; 28:425-472. [PMID: 35850495 PMCID: PMC9293616 DOI: 10.3350/cmh.2022.0186] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Accepted: 06/29/2022] [Indexed: 11/05/2022] Open
Abstract
The global burden of chronic liver disease (CLD) is substantial. Due to the limited indication of and accessibility to antiviral therapy in viral hepatitis and lack of effective pharmacological treatment in nonalcoholic fatty liver disease, the beneficial effects of antidiabetics and non-antidiabetics in clinical practice have been continuously investigated in patients with CLD. In this narrative review, we focused on non-antidiabetic drugs, including ursodeoxycholic acid, silymarin, dimethyl4,4'-dimethoxy-5,6,5',6'-dimethylenedixoybiphenyl-2,2'-dicarboxylate, L-ornithine L-aspartate, branched chain amino acids, statin, probiotics, vitamin E, and aspirin, and summarized their beneficial effects in CLD. Based on the antioxidant, anti-inflammatory properties, and regulatory functions in glucose or lipid metabolism, several non-antidiabetic drugs have shown beneficial effects in improving liver histology, aminotransferase level, and metabolic parameters and reducing risks of hepatocellular carcinoma and mortality, without significant safety concerns, in patients with CLD. Although the effect as the centerpiece management in patients with CLD is not robust, the use of these non-antidiabetic drugs might be potentially beneficial as an adjuvant or combined treatment strategy.
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Affiliation(s)
- Han Ah Lee
- Departments of Internal Medicine, Ewha Womans University College of Medicine, Seoul, Korea
| | - Young Chang
- Department of Internal Medicine, Institute for Digestive Research, Digestive Disease Center, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Pil Soo Sung
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
- The Catholic University Liver Research Center, Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Eileen L. Yoon
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea
| | - Hye Won Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Jeong-Ju Yoo
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Korea
| | - Young-Sun Lee
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Jihyun An
- Department of Gastroenterology and Hepatology, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, Korea
| | - Do Seon Song
- Department of Internal Medicine, St. Vincent’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Young Youn Cho
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Yoon Jun Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
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Yeh YC, Chen YY, Chen PC. Statins was not associated with hepatocellular carcinoma after controlling for time-varying confounders in patients with diabetes. J Clin Epidemiol 2022; 150:98-105. [PMID: 35779823 DOI: 10.1016/j.jclinepi.2022.06.014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 06/05/2022] [Accepted: 06/24/2022] [Indexed: 12/24/2022]
Abstract
OBJECTIVE We examined the association between statin use and hepatocellular carcinoma (HCC) incidence in patients with diabetes using marginal structural models (MSMs) estimated by inverse probability weight (IPW), which adjusts for time-varying confounders that are also mediators, and we compared the results with conventional regression methods. STUDY DESIGN AND SETTING This retrospective cohort study included 245,122 patients with type 2 diabetes who were new users of lipid-lowering drugs identified using the claims data of a universal health insurance program. Statin exposure was time-updated every 3 months during the follow-up period. Stabilized IPW was calculated and accounted for chronic liver diseases considering as time-dependent confounders affected by past statin exposure. RESULTS Over a median follow-up of 5.2 years, 1,694 patients developed HCC. In the conventional regression analysis, the hazard ratio of HCC associated with statin use was 0.88 (95% CI: 0.79-0.97) after adjusting for baseline covariates and 0.97 (95% CI: 0.87-1.08) after additionally adjusting for time-varying covariates. The hazard ratio increased to 1.11 (95% CI: 0.94-1.31) using the MSM approach. CONCLUSION Statins use was not associated with the risk of developing HCC in patients with diabetes. Our findings highlight the importance of controlling time-varying confounders in observational studies.
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Affiliation(s)
- Yi-Chun Yeh
- Department of Public Health, China Medical University, Taichung, Taiwan; Research Education and Epidemiology Center, Changhua Christian Hospital, Changhua, Taiwan
| | - Yen-Yu Chen
- Research Education and Epidemiology Center, Changhua Christian Hospital, Changhua, Taiwan; Department of Neurology, Changhua Christian Hospital, Changhua, Taiwan
| | - Pei-Chun Chen
- Department of Public Health, China Medical University, Taichung, Taiwan.
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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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25
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KASL clinical practice guidelines for management of chronic hepatitis B. Clin Mol Hepatol 2022; 28:276-331. [PMID: 35430783 PMCID: PMC9013624 DOI: 10.3350/cmh.2022.0084] [Citation(s) in RCA: 69] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 04/01/2022] [Indexed: 01/10/2023] Open
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26
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Wang Y, Wang W, Wang M, Shi J, Jia X, Dang S. 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] [MESH Headings] [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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Affiliation(s)
- Yikai Wang
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, China
| | - Wenjun Wang
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, China
| | - Muqi Wang
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, China
| | - Juanjuan Shi
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, China
| | - Xiaoli Jia
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, China
| | - Shuangsuo Dang
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, China
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27
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Jo AJ, Choi WM, Kim HJ, Choi SH, Han S, Ko MJ, Lim YS. A risk scoring system to predict clinical events in chronic hepatitis B virus infection: A nationwide cohort study. J Viral Hepat 2022; 29:115-123. [PMID: 34762757 DOI: 10.1111/jvh.13631] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 10/19/2021] [Accepted: 11/02/2021] [Indexed: 02/06/2023]
Abstract
Many patients with chronic hepatitis B do not receive adequate follow-up. This study aimed to develop a risk score to predict clinical events in patients with chronic hepatitis B virus (HBV) infection at the population level for identifying patients at high risk to warrant regular follow-up. This study analysed population-based data from the nationwide claims database of South Korea obtained between 2005 and 2015. We identified 507,239 non-cirrhotic patients with chronic HBV infection who are not under antiviral treatment. A risk score for predicting clinical events (hepatocellular carcinoma, death or liver transplantation) was developed based on multivariable Cox proportional hazard model in a development cohort (n = 401,745) and validated in a validation cohort (n = 105,494). The cumulative incidence rates of clinical events at 5 years were 2.56% and 2.44% in the development and validation cohorts, respectively. Clinical events in asymptomatic patients with chronic HBV infection (CAP-B) score ranging from 0 to 7.5 points based on age, sex, socioeconomic status, chronic hepatitis C co-infection, diabetes mellitus, statin or antiplatelet exposure, smoking, alcohol consumption, alanine aminotransferase and gamma-glutamyltransferase had good discriminatory accuracy in both the development and validation cohorts (c-indices for 3-, 5- and 10-year risk prediction: all 0.786). The predicted and observed probabilities of clinical events were calibrated in both cohorts. A score of >3.5 points identified subjects at distinctly high risk. The CAP-B score using easily accessible variables can predict clinical events and may allow selection of patients with chronic HBV infection for priority of regular follow-up.
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Affiliation(s)
- Ae Jeong Jo
- Division for Healthcare Technology Assessment Research, National Evidence-Based Healthcare Collaborating Agency, Seoul, Republic of Korea
| | - Won-Mook Choi
- Department of Gastroenterology, Liver Center, 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
| | - 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
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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28
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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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29
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Bakrania A, Zheng G, Bhat M. Nanomedicine in Hepatocellular Carcinoma: A New Frontier in Targeted Cancer Treatment. Pharmaceutics 2021; 14:41. [PMID: 35056937 PMCID: PMC8779722 DOI: 10.3390/pharmaceutics14010041] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 12/17/2021] [Accepted: 12/22/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death and is associated with a dismal median survival of 2-9 months. The fundamental limitations and ineffectiveness of current HCC treatments have led to the development of a vast range of nanotechnologies with the goal of improving the safety and efficacy of treatment for HCC. Although remarkable success has been achieved in nanomedicine research, there are unique considerations such as molecular heterogeneity and concomitant liver dysfunction that complicate the translation of nanotheranostics in HCC. This review highlights the progress, challenges, and targeting opportunities in HCC nanomedicine based on the growing literature in recent years.
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Affiliation(s)
- Anita Bakrania
- Toronto General Hospital Research Institute, Toronto, ON M5G 2C4, Canada;
- Ajmera Transplant Program, University Health Network, Toronto, ON M5G 2N2, Canada
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada;
| | - Gang Zheng
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada;
- Institute of Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada
| | - Mamatha Bhat
- Toronto General Hospital Research Institute, Toronto, ON M5G 2C4, Canada;
- Ajmera Transplant Program, University Health Network, Toronto, ON M5G 2N2, Canada
- Division of Gastroenterology, Department of Medicine, University Health Network, Toronto, ON M5G 2C4, Canada
- Department of Medical Sciences, University of Toronto, Toronto, ON M5S 1A1, Canada
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30
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Zhou F, Sun X. Cholesterol Metabolism: A Double-Edged Sword in Hepatocellular Carcinoma. Front Cell Dev Biol 2021; 9:762828. [PMID: 34869352 PMCID: PMC8635701 DOI: 10.3389/fcell.2021.762828] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Accepted: 10/27/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) represents a leading cause of cancer-related deaths globally. The rising incidence of metabolic syndrome and its hepatic manifestation, nonalcoholic fatty liver disease (NAFLD), have emerged as the fastest-growing cause of HCC in recent years. Cholesterol, a major lipid component of the cell membrane and lipoprotein particles, is primarily produced and metabolized by the liver. Numerous studies have revealed an increased cholesterol biosynthesis and uptake, reduced cholesterol exportation and excretion in HCC, which all contribute to lipotoxicity, inflammation, and fibrosis, known HCC risk factors. In contrast, some clinical studies have shown that higher cholesterol is associated with a reduced risk of HCC. These contradictory observations imply that the relationship between cholesterol and HCC is far more complex than initially anticipated. Understanding the role of cholesterol and deciphering the underlying molecular events in HCC development is highly relevant to developing new therapies. Here, we discuss the current understanding of cholesterol metabolism in the pathogenesis of NAFLD-associated HCC, and the underlying mechanisms, including the roles of cholesterol in the disruption of normal function of specific cell types and signaling transduction. We also review the clinical progression in evaluating the association of cholesterol with HCC. The therapeutic effects of lowering cholesterol will also be summarized. We also interpret reasons for the contradictory observations from different preclinical and human studies of the roles of cholesterol in HCC, aiming to provide a critical assessment of the potential of cholesterol as a therapeutic target.
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Affiliation(s)
- Fangli Zhou
- Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaoli Sun
- Department of Pharmacology, Mays Cancer Center, Transplant Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States
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31
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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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32
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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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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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Lee HW, Cho YY, Lee H, Lee JS, Kim SU, Park JY, Kim DY, Ahn SH, Kim BK, Park SY. Effect of tenofovir alafenamide vs. tenofovir disoproxil fumarate on hepatocellular carcinoma risk in chronic hepatitis B. J Viral Hepat 2021; 28:1570-1578. [PMID: 34435412 DOI: 10.1111/jvh.13601] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 07/27/2021] [Accepted: 08/17/2021] [Indexed: 12/15/2022]
Abstract
It is unclear whether tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF) is more effective for preventing hepatocellular carcinoma (HCC) development in patients with chronic hepatitis B (CHB). In this study, we compared the effectiveness of these two antiviral agents for preventing HCC. We included treatment-naïve CHB patients undergoing antiviral therapy with TDF only (TDF group) or a TAF-based regimen (TAF group) at three academic teaching hospitals from 2012 to 2019. The TAF group included patients receiving TAF as first-line treatment and patients switching from TDF to TAF. Patients with decompensated cirrhosis or HCC at enrollment were excluded. Cumulative probabilities of HCC were assessed using Kaplan-Meier methodology. In total, 2,117 patients were included: 1,832 in the TDF group and 285 in the TAF group. The annual HCC incidence was not significantly different between TDF and TAF groups: 1.66 vs. 1.19 per 100 person-years [PY], respectively (multivariate analysis: adjusted hazard ratio [HR] 0.774 [reference: TDF group]; p = .438). Male, liver cirrhosis, hepatitis B e antigen negativity, Fibrosis-4 index>3.25 and low albumin were independently associated with a higher risk of HCC. Propensity score-matched and inverse probability of treatment weighting analyses yielded similar results: 1.56 vs. 1.19 per 100 PY, respectively (HR 1.175; p = .708) and 1.66 vs. 1.29 per 100 PY, respectively (HR 0.888; p = .446). The risk of HCC development was not significantly different between TDF and TAF groups of CHB patients. Further studies with a larger sample size and longer follow-up are required to validate our results.
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Affiliation(s)
- Hye Won Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Yonsei University Health System, Seoul, Republic of Korea
| | - Young Youn Cho
- Department of Internal Medicine, Chung Ang University College of Medicine, Seoul, Republic of Korea
| | - Hyein Lee
- Yonsei Liver Center, Severance Hospital, Yonsei University Health System, Seoul, Republic of Korea
| | - Jae Seung Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Yonsei University Health System, Seoul, Republic of Korea
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Yonsei University Health System, Seoul, Republic of Korea
| | - Jun Yong Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Yonsei University Health System, Seoul, Republic of Korea
| | - Do Young Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Yonsei University Health System, Seoul, Republic of Korea
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Yonsei University Health System, Seoul, Republic of Korea
| | - Beom Kyung Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Yonsei University Health System, Seoul, Republic of Korea
| | - Soo Young Park
- Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Republic of Korea
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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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Muñoz AE, Pollarsky FD, Marino M, Cartier M, Vázquez H, Salgado P, Romero G. Addition of statins to the standard treatment in patients with cirrhosis: Safety and efficacy. World J Gastroenterol 2021; 27:4639-4652. [PMID: 34366626 PMCID: PMC8326251 DOI: 10.3748/wjg.v27.i28.4639] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 02/26/2021] [Accepted: 07/05/2021] [Indexed: 02/06/2023] Open
Abstract
This review summarizes the safety and efficacy of statins in patients with cirrhosis. Due to concerns about the safety of statins in patients with impaired liver function, they have recently been investigated as a potential treatment option in cirrhosis. The most clinically significant adverse event is statin-related myopathy, and this may be related to the high serum statin concentrations in the setting of severely impaired liver function. Rhabdomyolysis is the most serious and potentially life-threatening manifestation. It has recently been demonstrated that the recommended dose of simvastatin in patients with decompensated cirrhosis would be 20 mg/d because higher values, such as 40 mg/d, are associated with many adverse events, especially muscle injury. Likewise, simvastatin should not be administered to patients with Model for End-stage Liver Disease score > 12 and/or Child-Pugh class C because of the high risk of severe muscle injury. Due to the pleiotropic effects, the focus on statins has shifted from being considered harmful to something useful. Through these effects, statins could prevent liver-related morbidity and mortality in cirrhotic patients. Observational studies in large populations of patients with cirrhosis have shown that treatment with statins to decrease high cholesterol levels was associated with a reduced risk of hepatic decompensation, hepatocellular carcinoma development and death. The few randomized controlled trials in patients with cirrhosis and portal hypertension showed that statins lower portal pressure, quite likely through a reduction in hepatic resistance. Another large randomized controlled trial in patients with variceal bleeding showed that simvastatin in addition to standard of care did not prevent rebleeding but improved survival rate. Despite these encouraging outcomes, the quality of the evidence regarding the use of statins is low or very low due to the observational characteristics of most of the studies involved. Therefore, it is advisable to perform further randomized controlled trials on a large series of patients with hard clinical endpoints, using different statin types and varying doses. The objectives would be to prevent liver-related morbidity and mortality rather than treating cirrhosis complications to take additional information that makes it possible to add statins to the standard of care of these patients.
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Affiliation(s)
- Alberto E Muñoz
- Sección Hepatología, Hospital de Gastroenterología Dr. Carlos Bonorino Udaondo, Facultad de Medicina, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires 1264, Argentina
- Instituto de Investigaciones en Salud Pública, Facultad de Odontología, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires 1122, Argentina
| | - Florencia D Pollarsky
- Sección Hepatología, Hospital de Gastroenterología Dr. Carlos Bonorino Udaondo, Facultad de Medicina, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires 1264, Argentina
| | - Mónica Marino
- Sección Hepatología, Hospital de Gastroenterología Dr. Carlos Bonorino Udaondo, Facultad de Medicina, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires 1264, Argentina
| | - Mariano Cartier
- Sección Hepatología, Hospital de Gastroenterología Dr. Carlos Bonorino Udaondo, Facultad de Medicina, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires 1264, Argentina
| | - Horacio Vázquez
- Unidad Clínica, Hospital de Gastroenterología Dr. Carlos Bonorino Udaondo, Investigador Asociado del Gobierno de la Ciudad Autónoma de Buenos Aires, Ciudad Autónoma de Buenos Aires 1264, Argentina
| | - Pablo Salgado
- Instituto de Investigaciones en Salud Pública, Facultad de Odontología, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires 1122, Argentina
| | - Gustavo Romero
- Sección Hepatología, Hospital de Gastroenterología Dr. Carlos Bonorino Udaondo, Facultad de Medicina, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires 1264, Argentina
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Liver stiffness across different chronic liver disease under therapy with statin in a real life cohort. Eur J Gastroenterol Hepatol 2021; 32:223-229. [PMID: 32282399 DOI: 10.1097/meg.0000000000001719] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
INTRODUCTION Statins have been associated with improved clinical outcomes in patients with viral hepatitis and after variceal bleeding. Still, the clinical benefit of statins is not well defined for different liver diseases. Moreover, associations between statin use and liver stiffness as well as event free survival have not been established. METHODS Liver stiffness was evaluated in 6490 patients with liver disease (January 2012 till December 2016). Two hundred thirty-four of those received statin therapy, 468 controls without statins were selected by a 1:2 case by case matching using age, sex, underlying liver disease and BMI. RESULTS Statins were given to 234 patients with chronic virus hepatitis (n = 104), nonalcoholic fatty liver disease (n = 52), autoimmune liver disease including autoimmune hepatitis, primary biliary cholangitis and primary sclerosing cholangitis (n = 31) and hepatitis of unknown origin (n = 47). Follow-up data were available for 96 and 119 pairs (mean follow-up 2 years). Statin users showed reduced inflammatory activity. Elevated liver enzymes were reported in 57% of statin-treated compared with 70% of controls (mean alanine aminotransferase level 53 vs. 74 U/l; P < 0.001). Statin use was well tolerated in this cohort. Mean liver stiffness values were 10.7 kPa (SEM 0.7) and 15.5 kPa (SEM 0.7) accordingly (P < 0.0001). Decompensation was less likely to occur in the statin group, both groups do not defer in the incidence of liver tumor occurrence, transplantation or death (odds ratio = 1, P = nonsignificant). CONCLUSIONS Use of statins was well tolerated irrespective of liver disease. Statin users showed reduced hepatic inflammatory activity, less severe markers of liver stiffness and portal hypertension. There might be a beneficial effect of statin on the risk to experience hepatic decompensation.
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Statin use is associated with a lower risk of recurrence after curative resection in BCLC stage 0-A hepatocellular carcinoma. BMC Cancer 2021; 21:70. [PMID: 33446127 PMCID: PMC7808883 DOI: 10.1186/s12885-021-07796-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Accepted: 01/06/2021] [Indexed: 01/06/2023] Open
Abstract
Background Use of statins is associated with a reduced risk of hepatocellular carcinoma (HCC). However, the effect of statin use on HCC recurrence is unclear. This study aimed to evaluate the effect of statin use on recurrence after curative resection among patients with HCC. Methods We retrospectively assessed 820 patients with Barcelona Clinic Liver Cancer (BCLC) stage 0 or A HCC who underwent primary resection between January 2001 and June 2016 at Kaohsiung Chang Gung Memorial Hospital. Exposure to statins was defined as use of a statin for at least 3 months before HCC recurrence. Factors that influenced overall survival (OS) and recurrence-free survival (RFS) were analyzed using Cox proportional hazards models. Results Of the 820 patients, 46 (5.6%) used statins (statin group) and 774 (94.4%) did not (non-statin group). During the mean follow-up of 76.5 months, 440 (53.7%) patients experienced recurrence and 146 (17.8%) patients died. The cumulative incidence of HCC recurrence was significantly lower in the statin group than the non-statin group (p = 0.001); OS was not significantly different between groups. In multivariate analysis, age (hazard ratio [HR]: 1.291; p = 0.010), liver cirrhosis (HR: 1.743; p < 0.001), diabetes (HR:1.418; p = 0.001), number of tumors (HR: 1.750; p < 0.001), tumor size (HR: 1.406; p = 0.004) and vascular invasion (HR: 1.659; p < 0.001) were independent risk factors for HCC recurrence, whereas statin use (HR: 0.354; p < 0.001) and antiviral therapy (HR: 0.613; p < 0.001) significantly reduced the risk of HCC recurrence. The statin group still had lower RFS than the non-statin group after one-to-four propensity score matching. Conclusion Statins may exert a chemo-preventive effect on HCC recurrence after curative resection. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-021-07796-7.
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Kusnik A, Hunter N, Rasbach E, Miethke T, Reissfelder C, Ebert MP, Teufel A. Co-Medication and Nutrition in Hepatocellular Carcinoma: Potentially Preventative Strategies in Hepatocellular Carcinoma. Dig Dis 2021; 39:526-533. [PMID: 33429390 DOI: 10.1159/000514277] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Accepted: 01/11/2021] [Indexed: 02/02/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide, with about 841,000 new cases and 782,000 deaths annually. Given the clearly defined population at risk, mostly patients with liver cirrhosis, prevention of HCC could be highly effective. SUMMARY Besides regular ultrasound surveillance, numerous publications have suggested protective effects of diverse drugs and nutrients. However, none of those preventive options has made it into clinical routine or practice guidelines. We therefore summarize the current status of preventive effects of drugs such as statins, acetylsalicylic acid (ASA), and metformin, but also dietary aspects and nutrients such as coffee, tea, and vitamin D supplementation. A successful implementation of some of these strategies may potentially lead to improved prevention of HCC development in patients with liver cirrhosis. Key Messages: Accumulating data suggest that particularly ASA, antidiabetic therapies, and statins may substantially decrease HCC incidence in patients at risk.
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Affiliation(s)
- Alexander Kusnik
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.,Center for Preventive Medicine and Digital Health Baden-Württemberg (CPDBW), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Nicole Hunter
- Institute of Medical Microbiology and Hygiene, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Erik Rasbach
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Thomas Miethke
- Institute of Medical Microbiology and Hygiene, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Christoph Reissfelder
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Matthias Philip Ebert
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.,Center for Preventive Medicine and Digital Health Baden-Württemberg (CPDBW), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Andreas Teufel
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.,Center for Preventive Medicine and Digital Health Baden-Württemberg (CPDBW), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
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Li W, Deng R, Liu S, Wang K, Sun J. Hepatitis B virus-related hepatocellular carcinoma in the era of antiviral therapy: The emerging role of non-viral risk factors. Liver Int 2020; 40:2316-2325. [PMID: 32666675 DOI: 10.1111/liv.14607] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Revised: 06/17/2020] [Accepted: 07/09/2020] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC), one of the major malignant lethal tumours, is most prevalent in Asian patients with chronic hepatitis B virus (HBV) infection. Both viral and non-viral factors contribute to the development of HCC. It is established that viral factors associated with HBV DNA level, HBV genotype, designated gene mutation, HBV DNA integration, HBx protein, hepatitis B surface antigen (HBsAg), hepatitis B core-related antigen (HBcrAg) and HBV RNA are correlated with hepatocarcinogenesis. Before the introduction of antiviral therapy, viral factors once attracted more attention during the development of HCC. With the widespread use of antiviral therapy, predominantly nucleos(t)ide analogues (NAs), most patients with chronic hepatitis B (CHB) have achieved sustained viral control. The role of non-viral factors, especially modifiable factors, is anticipated to be reinforced in the future. Herein, we reviewed the modifiable non-viral risk factors of HBV-related HCC, in the hope of providing substantial evidence for further development of novel precautionary measures for HCC. In addition, the therapeutic interventions for reducing the risk of HCC, like potential conventional pharmaceutical interventions and lifestyle modification are also discussed in this review. Future studies that would explore the specific mechanism of HBV-related HCC development in patients with satisfactory viral control and related precision treatment are warranted.
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Affiliation(s)
- Wanying Li
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Rui Deng
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Shi Liu
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Kaifeng Wang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jian Sun
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Yip TCF, Wong VWS, Chan HLY, Tse YK, Hui VWK, Liang LY, Lee HW, Lui GCY, Kong APS, Wong GLH. Thiazolidinediones reduce the risk of hepatocellular carcinoma and hepatic events in diabetic patients with chronic hepatitis B. J Viral Hepat 2020; 27:904-914. [PMID: 32340077 DOI: 10.1111/jvh.13307] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Revised: 03/27/2020] [Accepted: 04/05/2020] [Indexed: 12/22/2022]
Abstract
Thiazolidinediones (TZDs) improve glycaemic control and ameliorate liver steatosis, inflammation and fibrosis in patients with fatty liver disease. We aimed to study the impact of TZD and glycaemic control on the risk of hepatocellular carcinoma (HCC) and hepatic events in diabetic patients with chronic hepatitis B (CHB). We performed a retrospective cohort study on diabetic patients with CHB in 2000-2017 using a territory-wide electronic healthcare database in Hong Kong. Diabetes mellitus was identified by use of any antidiabetic medication, haemoglobin A1c (HbA1c ) ≥6.5%, fasting glucose ≥7 mmol/L in two measurements or ≥11.1 mmol/L in one measurement and/or diagnosis codes. Use of antidiabetic medications was modelled as time-dependent covariates. Of 28 999 diabetic patients with CHB, 3963 (13.7%) developed liver-related events (a composite endpoint of HCC and hepatic events) at a median (interquartile range) follow-up of 7.1 (3.7-11.8) years; 1153 patients received TZD during follow-up. After adjusted for important confounders, TZD use was associated with a reduced risk of liver-related events (adjusted hazard ratio [aHR] 0.46, 95% confidence interval [CI] 0.24-0.88; P = .019). Similar trends were observed in HCC (aHR 0.57) and hepatic events (aHR 0.35) separately. Compared to HbA1c of 6.5% at baseline, patients with HbA1c ≥7% had an increased risk of liver-related events; the risk further increased in 5795 (20.0%) patients with HbA1c ≥9% at baseline (aHR 1.14, 95% CI 1.04-1.26; P = .006). TZD use is associated with a lower risk of liver-related events in diabetic patients with CHB. Liver-related events are more common in patients with high HbA1c levels.
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Affiliation(s)
- Terry Cheuk-Fung Yip
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Vincent Wai-Sun Wong
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Henry Lik-Yuen Chan
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Yee-Kit Tse
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Vicki Wing-Ki Hui
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Lilian Yan Liang
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Hye Won Lee
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Grace Chung-Yan Lui
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Alice Pik-Shan Kong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Grace Lai-Hung Wong
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
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Goh MJ, Sinn DH, Kim S, Woo SY, Cho H, Kang W, Gwak GY, Paik YH, Choi MS, Lee JH, Koh KC, Paik SW. Statin Use and the Risk of Hepatocellular Carcinoma in Patients With Chronic Hepatitis B. Hepatology 2020; 71:2023-2032. [PMID: 31556128 DOI: 10.1002/hep.30973] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Accepted: 09/22/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS Statins have pleiotropic effects that may include chemoprevention. Several observational studies have suggested that statins may prevent hepatocellular carcinoma (HCC), but they have not yet been fully studied in patients with chronic hepatitis B virus (HBV) infections. APPROACH AND RESULTS A hospital-based retrospective cohort of 7,713 chronic HBV-infected individuals between January 2008 and December 2012 were analyzed. The primary outcome was the development of HCC. Patients who used statins for at least 28 cumulative defined daily doses during the follow-up period were defined as statin users (n = 713). The association between the use of statin and the incidence of HCC was analyzed using the multivariable Cox regression model with time-dependent covariates. During a median follow-up of 7.2 years (min-max: 0.5-9.9), HCC newly developed in 702 patients (9.1%). Statin use was associated with a lower risk of HCC (adjusted hazard ratio = 0.36, 95% confidence interval: 0.19-0.68, adjusted for age, sex, cirrhosis, diabetes, hypertension, serum alanine aminotransferase, cholesterol, HBV DNA level, antiviral treatment, and antiplatelet therapy). The observed benefit of the statin use was dose-dependent (adjusted hazard ratio [95% confidence interval], 0.63 [0.31-1.29]; 0.51 [0.21-1.25]; 0.32 [0.07,1.36]; and 0.17 [0.06, 0.48] for patients with statin use of 28-365, 366-730, 731-1095, and more than 1,095 cumulative defined daily doses, respectively). In subgroup analysis, the association between statin use and reduced risk of HCC was observed in all prespecified subgroups analyzed. CONCLUSION Statin use was associated with a reduced risk of HCC development in chronic HBV-infected patients, suggesting that statins may have a chemopreventive role in this population. These findings warrant a prospective evaluation.
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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
| | - Seonwoo Kim
- Statistics and Data Center, Samsung Medical Center, Seoul, Korea
| | - Sook Young Woo
- Statistics and Data Center, Samsung Medical Center, Seoul, Korea
| | - Hyun Cho
- Statistics and Data Center, Samsung Medical Center, Seoul, Korea
| | - Wonseok Kang
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Geum-Youn Gwak
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Yong-Han Paik
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Moon Seok Choi
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Joon Hyeok Lee
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Kwang Cheol Koh
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Seung Woon Paik
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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Statin inhibits large hepatitis delta antigen-Smad3 -twist-mediated epithelial-to-mesenchymal transition and hepatitis D virus secretion. J Biomed Sci 2020; 27:65. [PMID: 32434501 PMCID: PMC7240974 DOI: 10.1186/s12929-020-00659-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2020] [Accepted: 05/14/2020] [Indexed: 01/01/2023] Open
Abstract
Background Hepatitis D virus (HDV) infection may induce fulminant hepatitis in chronic hepatitis B patients (CHB) or rapid progression of CHB to cirrhosis or hepatocellular carcinoma. There is no effective treatment for HDV infection. HDV encodes small delta antigens (S-HDAg) and large delta antigens (L-HDAg). S-HDAg is essential for HDV replication. Prenylated L-HDAg plays a key role in HDV assembly. Previous studies indicate that L-HDAg transactivates transforming growth factor beta (TGF-β) and induces epithelial-mesenchymal transition (EMT), possibly leading to liver fibrosis. However, the mechanism is unclear. Methods The mechanisms of the activation of Twist promoter by L-HDAg were investigated by luciferase reporter assay, chromatin immunoprecipitation, and co-immunoprecipitation analysis. ELISA and Western blotting were used to analyze L-HDAg prenylation, TGF-β secretion, expression of EMT markers, and to evaluate efficacy of statins for HDV treatment. Results We found that L-HDAg activated Twist expression, TGF-β expression and consequently induced EMT, based on its interaction with Smad3 on Twist promoter. The treatment of statin, a prenylation inhibitor, resulted in reduction of Twist promoter activity, TGF-β expression, and EMT, and reduces the release of HDV virions into the culture medium. Conclusions We demonstrate that L-HDAg activates EMT via Twist and TGF-β activation. Treatment with statins suppressed Twist expression, and TGF-β secretion, leading to downregulation of EMT. Our findings clarify the mechanism of HDV-induced EMT, and provide a basis for possible novel therapeutic strategies against HDV infection.
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Li X, Sheng L, Liu L, Hu Y, Chen Y, Lou L. Statin and the risk of hepatocellular carcinoma in patients with hepatitis B virus or hepatitis C virus infection: a meta-analysis. BMC Gastroenterol 2020; 20:98. [PMID: 32272891 PMCID: PMC7147033 DOI: 10.1186/s12876-020-01222-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Accepted: 03/13/2020] [Indexed: 12/13/2022] Open
Abstract
Background Statin may confer anticancer effect. However, the association between statin and risk of hepatocellular carcinoma (HCC) in patients with hepatitis B virus (HBV) or hepatitis C (HCV) virus infection remains inconsistent according to results of previous studies. A meta-analysis was performed to summarize current evidence. Methods Related follow-up studies were obtained by systematic search of PubMed, Cochrane’s Library, and Embase databases. A random-effect model was used to for the meta-analysis. Stratified analyses were performed to evaluate the influences of study characteristics on the outcome. Results Thirteen studies with 519,707 patients were included. Statin use was associated with reduced risk of HCC in these patients (risk ratio [RR]: 0.54, 95% CI: 0.44 to 0.66, p < 0.001; I2 = 86%). Stratified analyses showed that the association between statin use and reduced HCC risk was consistent in patients with HBV or HCV infection, in elder (≥ 50 years) or younger (< 50 years) patients, in males or females, in diabetic or non-diabetic, and in those with or without cirrhosis (all p < 0.05). Moreover, lipophilic statins was associated with a reduced HCC risk (RR: 0.52, p < 0.001), but not for hydrophilic statins (RR: 0.89, p = 0.21). The association was more remarkable in patients with highest statin accumulative dose compared to those with lowest accumulative dose (p = 0.002). Conclusions Satin use was independently associated with a reduced risk of HCC in patients with HBV or HCV infection.
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Affiliation(s)
- Xiaofei Li
- Department of infectious diseases, Yiwu Central Hospital, No. 519 Nanmen Street, Yiwu, 322000, China.
| | - Lina Sheng
- Department of infectious diseases, Yiwu Central Hospital, No. 519 Nanmen Street, Yiwu, 322000, China
| | - Liwen Liu
- Department of infectious diseases, Yiwu Central Hospital, No. 519 Nanmen Street, Yiwu, 322000, China
| | - Yongtao Hu
- Department of infectious diseases, Yiwu Central Hospital, No. 519 Nanmen Street, Yiwu, 322000, China
| | - Yongxin Chen
- Department of infectious diseases, Yiwu Central Hospital, No. 519 Nanmen Street, Yiwu, 322000, China
| | - Lianqing Lou
- Department of infectious diseases, Yiwu Central Hospital, No. 519 Nanmen Street, Yiwu, 322000, China
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Facciorusso A, Abd El Aziz MA, Singh S, Pusceddu S, Milione M, Giacomelli L, Sacco R. Statin Use Decreases the Incidence of Hepatocellular Carcinoma: An Updated Meta-Analysis. Cancers (Basel) 2020; 12:874. [PMID: 32260179 PMCID: PMC7225931 DOI: 10.3390/cancers12040874] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 03/26/2020] [Accepted: 04/01/2020] [Indexed: 02/07/2023] Open
Abstract
Statins can decrease hepatocellular carcinoma (HCC) occurrence, but the magnitude and the predictors of these effects remain unclear. This meta-analysis provides a pooled estimate of the impact of statin use on HCC occurrence. Pooled effects were calculated using a random-effects model by means of the DerSimonian and Laird test. Primary endpoint was the time-dependent correlation between statin use and HCC incidence expressed as hazard ratio (HR), both crude and adjusted. The crude and adjusted odds ratios (OR) for HCC occurrence between statin users and non-users were analyzed. Twenty-five studies with 1,925,964 patients were included. Crude OR for HCC incidence was 0.59 (95% CI: 0.47-0.74), confirmed in adjusted analysis (OR: 0.74, 95% CI: 0.70-0.78). Adjusted HR was 0.73 (95% CI: 0.69-0.76). This effect was more pronounced in HBV patients (HR: 0.46, 95% CI: 0.36-0.60) and with a cumulative daily dose beyond 365 (HR: 0.27, 95% CI: 0.11-0.67). Lipophilic statins were associated with reduced HCC incidence (HR: 0.49, 95% CI: 0.39-0.62). Atorvastatin determined the greater magnitude of effect (HR: 0.43, 95% CI: 0.28-0.65). This meta-analysis demonstrates the beneficial chemopreventive effect of statins against HCC occurrence. This effect is dose-dependent and more pronounced with lipophilic statins.
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Affiliation(s)
- Antonio Facciorusso
- Section of Gastroenterology, Department of Medical Sciences, University of Foggia, 71122 Foggia, Italy;
| | | | - Siddharth Singh
- Division of Gastroenterology, University of California, San Diego, CA 92093, USA;
| | - Sara Pusceddu
- Fondazione IRCCS—Istituto Nazionale dei Tumori Via G. Venezian 1 IT, 20133 Milan, Italy; (S.P.); (M.M.)
| | - Massimo Milione
- Fondazione IRCCS—Istituto Nazionale dei Tumori Via G. Venezian 1 IT, 20133 Milan, Italy; (S.P.); (M.M.)
| | - Luca Giacomelli
- Department of Surgical Sciences and Integrated Diagnostics, University of Genoa, 16126 Genoa, Italy;
- Polistudium SRL, 20124 Milan, Italy
| | - Rodolfo Sacco
- Section of Gastroenterology, Department of Medical Sciences, University of Foggia, 71122 Foggia, Italy;
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Statin Use and the Risk of Hepatocellular Carcinoma: A Meta-Analysis of Observational Studies. Cancers (Basel) 2020; 12:cancers12030671. [PMID: 32183029 PMCID: PMC7139959 DOI: 10.3390/cancers12030671] [Citation(s) in RCA: 68] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Revised: 02/24/2020] [Accepted: 03/11/2020] [Indexed: 01/27/2023] Open
Abstract
Background and Aims: Statins are the first-line medication to treating hypercholesterolemia. Several studies have investigated the impact of statins on the risk of hepatocellular carcinoma (HCC). However, the extent to which statins may prevent HCC remains uncertain. Therefore, we performed a meta-analysis of relevant studies to quantify the magnitude of the association between statins use and the risk of HCC. Methods: A systematic literature search of PubMed, EMBASE, Google Scholar, Web of Science, and Scopus was performed for studies published between January 1, 1990, and September 1, 2019, with no restriction of language. Two reviewers independently evaluated the literature and included observational and experimental studies that reported the association between statin use and HCC risk. The random-effect model was used to calculate the overall risk ratio (RR) with a 95% confidence interval (CI), and the heterogeneity among the studies was assessed using the Q statistic and I2 statistic. The Newcastle Ottawa Scale (NOS) was also used to evaluate the quality of the included studies. Results: A total of 24 studies with 59,073 HCC patients was identified. Statin use was associated with a reduced risk of HCC development (RR: 0.54, 95% CI: 0.47–0.61, I2 = 84.39%) compared with nonusers. Moreover, the rate of HCC reduction was also significant among patients with diabetes (RR: 0.44, 95% CI: 0.28–0.70), liver cirrhosis (RR: 0.36, 95% CI: 0.30–0.42), and antiviral therapy (RR: 0.21, 95% CI: 0.08–0.59) compared with nonusers. Conclusion: This study serves as additional evidence supporting the beneficial inhibitory effect of statins on HCC incidence. The subgroup analyses of this study also highlight that statins are significantly associated with a reduced risk of HCC and may help to direct future prevention efforts. Additional large clinical studies are needed to determine whether statins are associated with a lower risk of HCC.
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Francis P, Forman L. Use of Statins in Patients With and Without Liver Disease. Clin Liver Dis (Hoboken) 2020; 15:40-45. [PMID: 32104577 PMCID: PMC7041958 DOI: 10.1002/cld.866] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2019] [Accepted: 06/27/2019] [Indexed: 02/04/2023] Open
Affiliation(s)
- Prashanth Francis
- Division of Gastroenterology and HepatologyUniversity of Colorado Anschutz Medical CampusAuroraCO
| | - Lisa Forman
- Division of Gastroenterology and HepatologyUniversity of Colorado Anschutz Medical CampusAuroraCO
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Chang Y, Liu Q, Zhou Z, Ding Y, Yang M, Xu W, Chen K, Zhang Q, Wang Z, Li H. Can Statin Treatment Reduce the Risk of Hepatocellular Carcinoma? A Systematic Review and Meta-Analysis. Technol Cancer Res Treat 2020; 19:1533033820934881. [PMID: 32552476 PMCID: PMC7307281 DOI: 10.1177/1533033820934881] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 02/24/2020] [Accepted: 03/30/2020] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Whether statins can reduce the incidence of cancers has been an interesting topic in recent years. This meta-analysis aimed to determine the relationship between statin treatment with the risk of hepatocellular carcinoma. METHODS Studies published up to July 2019 were screened from databases. The data from approved studies were pooled. Random-effects or fixed-effects model was used to calculate the relative risk with 95% CIs in the overall group and subgroups. Sensitivity and meta-regression analyses were performed, and publication bias was evaluated. RESULTS A total of 18 studies involving 1 611 596 patients were included in this meta-analysis. The overall result showed a significantly reduced risk of hepatocellular carcinoma (relative risk = 0.54, 95% CI: 0.42-0.66) in statin users. In comparison to the risk in nonstatin users, the risk of hepatocellular carcinoma was reduced in all subgroups. The dose of statins and their pharmacokinetics can partly explain the heterogeneity in the overall meta-analysis (I2 = 94.6%, P = .000). A dose-dependent effect of statin use for the reduced risk of hepatocellular carcinoma was found. CONCLUSIONS Findings from this meta-analysis support that statin use can significantly reduce the incidence of hepatocellular carcinoma.
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Affiliation(s)
- Yue Chang
- Department of Hepatopancreatobiliary and Splenic Medicine,
Characteristic Medical Center of People’s Armed Police Force, Tianjin, China
- Tianjin Key Laboratory of Hepatopancreatic Fibrosis and Molecular
Diagnosis and Treatment, Tianjin, China
| | - Qinyu Liu
- Department of Hepatopancreatobiliary and Splenic Medicine,
Characteristic Medical Center of People’s Armed Police Force, Tianjin, China
- Tianjin Key Laboratory of Hepatopancreatic Fibrosis and Molecular
Diagnosis and Treatment, Tianjin, China
| | - Zidong Zhou
- Department of Hepatopancreatobiliary and Splenic Medicine,
Characteristic Medical Center of People’s Armed Police Force, Tianjin, China
- Tianjin Key Laboratory of Hepatopancreatic Fibrosis and Molecular
Diagnosis and Treatment, Tianjin, China
| | - Yuping Ding
- Department of Hepatopancreatobiliary and Splenic Medicine,
Characteristic Medical Center of People’s Armed Police Force, Tianjin, China
- Tianjin Key Laboratory of Hepatopancreatic Fibrosis and Molecular
Diagnosis and Treatment, Tianjin, China
| | - Mei Yang
- Department of Hepatopancreatobiliary and Splenic Medicine,
Characteristic Medical Center of People’s Armed Police Force, Tianjin, China
- Tianjin Key Laboratory of Hepatopancreatic Fibrosis and Molecular
Diagnosis and Treatment, Tianjin, China
| | - Wei Xu
- Department of Hepatopancreatobiliary and Splenic Medicine,
Characteristic Medical Center of People’s Armed Police Force, Tianjin, China
- Tianjin Key Laboratory of Hepatopancreatic Fibrosis and Molecular
Diagnosis and Treatment, Tianjin, China
| | - Kai Chen
- Department of Hepatopancreatobiliary and Splenic Medicine,
Characteristic Medical Center of People’s Armed Police Force, Tianjin, China
- Tianjin Key Laboratory of Hepatopancreatic Fibrosis and Molecular
Diagnosis and Treatment, Tianjin, China
| | - Qing Zhang
- Tianjin Key Laboratory of Hepatopancreatic Fibrosis and Molecular
Diagnosis and Treatment, Tianjin, China
- Division of Gastroenterology and Hepatology, Tianjin Xiqing
Hospital, Tianjin, China
| | - Zhenguo Wang
- Department of Hepatopancreatobiliary and Splenic Medicine,
Characteristic Medical Center of People’s Armed Police Force, Tianjin, China
| | - Hai Li
- Tianjin Key Laboratory of Hepatopancreatic Fibrosis and Molecular
Diagnosis and Treatment, Tianjin, China
- Division of Gastroenterology and Hepatology, Tianjin Xiqing
Hospital, Tianjin, China
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Young SH, Chau GY, Lee IC, Yeh YC, Chao Y, Huo TI, Su CW, Lin HC, Hou MC, Lee MH, Huang YH. Aspirin is associated with low recurrent risk in hepatitis B virus-related hepatocellular carcinoma patients after curative resection. J Formos Med Assoc 2020; 119:218-229. [DOI: 10.1016/j.jfma.2019.04.018] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Revised: 04/08/2019] [Accepted: 04/25/2019] [Indexed: 02/07/2023] Open
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Kim GA, Shim JJ, Lee JS, Kim BH, Kim JW, Oh CH, Oh CM, Oh IH, Park SY. Effect of Statin Use on Liver Cancer Mortality Considering Hypercholesterolemia and Obesity in Patients with Non-Cirrhotic Chronic Hepatitis B. Yonsei Med J 2019; 60:1203-1208. [PMID: 31769252 PMCID: PMC6881704 DOI: 10.3349/ymj.2019.60.12.1203] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Revised: 09/17/2019] [Accepted: 10/16/2019] [Indexed: 01/01/2023] Open
Abstract
Little is known about the benefits of statin use on liver cancer mortality among patients with chronic hepatitis B (CHB) considering hypercholesterolemia and obesity. A nationwide retrospective cohort study was conducted using data from a Health Examination Cohort of the National Health Insurance Service of Korea. Data on CHB patients with no other concurrent liver disease were acquired, and statin use was defined as a cumulative daily dose ≥28. A 3-year landmark analysis was performed to avoid immortal time bias. Patients who started statin therapy within the landmark date were considered statin users. A Cox regression analysis was applied to assess associations between statin use and liver cancer mortality considering hypercholesterolemia and obesity. Among 13063 patients, 193 (1.5%) died of liver cancer during the mean follow-up period of 10.6 years. After adjusting for demographic and metabolic factors, statin use [hazard ratio (HR), 0.17; 95% confidence interval (CI), 0.04-0.70] and hypercholesterolemia (HR, 0.46; 95% CI, 0.24-0.88 for total cholesterol ≥240 mg/dL) were associated with a decreased risk of liver cancer mortality, whereas body mass index (BMI) ≥30 kg/m² was associated with an increased risk of liver cancer mortality (HR, 2.46; 95% CI, 1.20-5.06). This study showed that statin use was associated with decreased liver cancer mortality when adjusting for cholesterol levels and BMI. This study found that hypercholesterolemia was independently associated with decreased liver cancer mortality regardless of statin use.
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Affiliation(s)
- Gi Ae Kim
- Department of Internal Medicine, School of Medicine, Kyung Hee University, Seoul, Korea
| | - Jae Jun Shim
- Department of Internal Medicine, School of Medicine, Kyung Hee University, Seoul, Korea.
| | - Ji Sung Lee
- Department of Clinical Epidemiology and Biostatistics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
- Clinical Research Center, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Byung Ho Kim
- Department of Internal Medicine, School of Medicine, Kyung Hee University, Seoul, Korea
| | - Jung Wook Kim
- Department of Internal Medicine, School of Medicine, Kyung Hee University, Seoul, Korea
| | - Chi Hyuk Oh
- Department of Internal Medicine, School of Medicine, Kyung Hee University, Seoul, Korea
| | - Chang Mo Oh
- Department of Preventive Medicine, School of Medicine, Kyung Hee University, Seoul, Korea
| | - In Hwan Oh
- Department of Preventive Medicine, School of Medicine, Kyung Hee University, Seoul, Korea
| | - So Youn Park
- Department of Medical Education and Humanities, School of Medicine, Kyung Hee University, Seoul, Korea
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