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Han X, He L, Li S, Zhu Y. Trends in liver cancer rehabilitation needs, disease burden, and attributable risk factors in China, 1990-2021. Sci Rep 2025; 15:15682. [PMID: 40325048 PMCID: PMC12053601 DOI: 10.1038/s41598-025-00317-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2025] [Accepted: 04/28/2025] [Indexed: 05/07/2025] Open
Abstract
This study investigates trends in liver cancer rehabilitation needs, disease burden, and attributable risk factors in China from 1990 to 2021 using data from the Global Burden of Disease Study 2021. Key metrics included age-standardized prevalence (ASPR), years lived with disability (YLDs), and risk factor attribution. Between 1990 and 2021, the number of liver cancer patients requiring rehabilitation surged by 100.1% (132,779 to 265,539 cases), with YLDs rising by 102.8% (22,981 to 46,602). While ASPR and age-standardized YLD rates (ASYR) showed modest declines (ASPR: - 0.1% annual change; ASYR: - 0.23%), males exhibited a disproportionately higher burden, with 2021 cases and YLDs 2.98- and 2.74-fold greater than females, respectively. Risk factor analysis revealed smoking (14.0%), drug use (11.5%), and alcohol consumption (11.4%) as primary contributors, while metabolic factors like high BMI (7.5%) and fasting plasma glucose (1.9%) demonstrated accelerating impacts (YLDs EAPC: + 4.47% and + 1.31%, respectively). Aging populations and shifting etiologies drove increased rehabilitation demands, particularly among those ≥ 80 years. These findings underscore urgent needs for gender-specific interventions targeting modifiable risks and integrated nursing rehabilitation strategies to mitigate China's growing liver cancer burden.
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Affiliation(s)
- Xiangping Han
- Department of Oncology II, Zhumadian Central Hospital, No. 747, West Section of Zhonghua Road, Yicheng District, Zhumadian City, 463000, Henan, China.
| | - Lei He
- Third Department of Psychological Medicine, Zhumadian Second People's Hospital, No. 51 Xuesong Road, Zhumadian City, 463000, Henan Province, China
- Department of Nursing, Zhumadian Second People's Hospital, No. 51 Xuesong Road, Zhumadian City, Henan Province, China
| | - Shaoying Li
- Department of Oncology II, Zhumadian Central Hospital, No. 747, West Section of Zhonghua Road, Yicheng District, Zhumadian City, 463000, Henan, China
| | - Yuxing Zhu
- Third Department of Psychological Medicine, Zhumadian Second People's Hospital, No. 51 Xuesong Road, Zhumadian City, 463000, Henan Province, China
- Department of Nursing, Zhumadian Second People's Hospital, No. 51 Xuesong Road, Zhumadian City, Henan Province, China
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Kim JH, Bae GH, Jung J, Noh TI. Secondary Cancer after Androgen Deprivation Therapy in Prostate Cancer: A Nationwide Study. World J Mens Health 2025; 43:123-133. [PMID: 38606859 PMCID: PMC11704168 DOI: 10.5534/wjmh.230237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 10/15/2023] [Accepted: 12/05/2023] [Indexed: 04/13/2024] Open
Abstract
PURPOSE Androgen signaling is associated with various secondary cancer, which could be promising for potential treatment using androgen deprivation therapy (ADT). This study investigated whether ADT use was associated with secondary cancers other than prostate cancer in a nationwide population-based cohort. MATERIALS AND METHODS A total, 278,434 men with newly diagnosed prostate cancer between January 1, 2002 and December 31, 2017 were identified. After applying the exclusion criteria, 170,416 men were enrolled. The study cohort was divided into ADT and non-ADT groups by individual matching followed by propensity score matching (PSM). Study outcomes were incidence of all male cancers. Cox proportional hazard regression models were used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of events. RESULTS During a median follow-up of 4.5 years, a total of 11,059 deaths (6,329 in the ADT group and 4,730 in the non-ADT group) after PSM were found. After PSM, the overall all-cause of secondary cancer incidence risk of the ADT group was higher than that of the non-ADT group (HR: 1.312, 95% CI: 1.23-1.36; adjusted HR: 1.344, 95% CI: 1.29-1.40). The ADT group showed higher risk of overall brain and other central nervous system (CNS) cancer-specific incidence than the non-ADT group (adjusted HR: 1.648, 95% CI: 1.21-2.24). The ADT group showed lower risks of overall cancer-specific incidence for stomach, colon/rectum, liver/inflammatory bowel disease (IBD), gall bladder/extrahepatic bile duct, lung, bladder, and kidney cancers than the non-ADT group. When the duration of ADT was more than 2 years of ADT, the ADT group showed higher risk of cancer-specific incidence for brain and other CNS cancers but lower risk of cancer-specific incidence for liver/IBD and lung cancers than the non-ADT group. CONCLUSIONS This study demonstrates that ADT could affect cancer-specific incidence for various cancers.
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Affiliation(s)
- Jae Heon Kim
- Department of Urology, Soonchunhyang University Seoul Hospital, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Gi Hwan Bae
- Artificial Intelligence and Big-Data Convergence Center, Gil Medical Center, Gachon University College of Medicine, Incheon, Korea
| | - Jaehun Jung
- Artificial Intelligence and Big-Data Convergence Center, Gil Medical Center, Gachon University College of Medicine, Incheon, Korea
- Department of Preventive Medicine, Gachon University College of Medicine, Incheon, Korea.
| | - Tae Il Noh
- Department of Urology, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Korea.
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Cao LQ, Xie Y, Fleishman JS, Liu X, Chen ZS. Hepatocellular carcinoma and lipid metabolism: Novel targets and therapeutic strategies. Cancer Lett 2024; 597:217061. [PMID: 38876384 DOI: 10.1016/j.canlet.2024.217061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 05/10/2024] [Accepted: 06/11/2024] [Indexed: 06/16/2024]
Abstract
Hepatocellular carcinoma (HCC) is an increasingly prevalent disease that is associated with high and continually rising mortality rates. Lipid metabolism holds a crucial role in the pathogenesis of HCC, in which abnormalities pertaining to the delicate balance of lipid synthesis, breakdown, and storage, predispose for the pathogenesis of the nonalcoholic fatty liver disease (NAFLD), a disease precursor to HCC. If caught early enough, HCC treatment may be curative. In later stages, treatment is only halting the inevitable outcome of death, boldly prompting for novel drug discovery to provide a fighting chance for this patient population. In this review, we begin by providing a summary of current local and systemic treatments against HCC. From such we discuss hepatic lipid metabolism and highlight novel targets that are ripe for anti-cancer drug discovery. Lastly, we provide a targeted summary of current known risk factors for HCC pathogenesis, providing key insights that will be essential for rationalizing future development of anti-HCC therapeutics.
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Affiliation(s)
- Lu-Qi Cao
- Institute for Biotechnology, St. John's University, New York, NY, 11439, USA; College of Pharmacy and Health Sciences, St. John's University, New York, NY, 11439, USA
| | - Yuhao Xie
- College of Pharmacy and Health Sciences, St. John's University, New York, NY, 11439, USA
| | - Joshua S Fleishman
- College of Pharmacy and Health Sciences, St. John's University, New York, NY, 11439, USA
| | - Xuan Liu
- Shenzhen Hospital (Futian) of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, 518034, China.
| | - Zhe-Sheng Chen
- Institute for Biotechnology, St. John's University, New York, NY, 11439, USA; College of Pharmacy and Health Sciences, St. John's University, New York, NY, 11439, USA.
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Cao M, Xia C, Cao M, Yang F, Yan X, He S, Zhang S, Teng Y, Li Q, Tan N, Wang J, Chen W. Attributable liver cancer deaths and disability-adjusted life years in China and worldwide: profiles and changing trends. Cancer Biol Med 2024; 21:j.issn.2095-3941.2024.0149. [PMID: 39015006 PMCID: PMC11359490 DOI: 10.20892/j.issn.2095-3941.2024.0149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Accepted: 06/12/2024] [Indexed: 07/18/2024] Open
Abstract
OBJECTIVE Liver cancer is a major health concern globally and in China. This analysis investigated deaths and disability-adjusted life years (DALYs) with respect to etiologies and risk factors for liver cancer in China and worldwide. METHODS Global and China-specific data were collected on liver cancer deaths, DALYs, and age-standardized rates (ASRs) from the Global Burden of Disease Study 2019 database. Liver cancer etiologies were classified into five groups and risk factors were categorized into three levels. Each proportion of liver cancer burden was calculated in different geographic regions. The joinpoint regression model were used to assess the trends from 1990-2019. RESULTS Liver cancer accounted for 484,577 deaths worldwide in 2019 with an ASR of 5.9 per 100,000 population. China had an elevated liver cancer death ASR in 2019 and males had an ASR 1.7 times the global rate. The global ASR for DALYs peaked at 75-79 years of age but peaked earlier in China. Hepatitis B virus was the prominent etiology globally (39.5%) and in China (62.5%), followed by hepatitis C virus and alcohol consumption. In high sociodemographic index countries, non-alcoholic steatohepatitis has gained an increasing contribution as an etiologic factor. The liver cancer burden due to various etiologies has decreased globally in both genders. However, metabolic risk factors, particularly obesity, have had a growing contribution to the liver cancer burden, especially among males. CONCLUSIONS Despite an overall decreasing trend in the liver cancer burden in China and worldwide, there has been a rising contribution from metabolic risk factors, highlighting the importance of implementing targeted prevention and control strategies that address regional and gender disparities.
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Affiliation(s)
- Mengdi Cao
- Office of Cancer Screening, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Changfa Xia
- Office of Cancer Screening, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Maomao Cao
- Office of Cancer Screening, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Fan Yang
- Office of Cancer Screening, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Xinxin Yan
- Office of Cancer Screening, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Siyi He
- Office of Cancer Screening, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Shaoli Zhang
- Office of Cancer Screening, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yi Teng
- Office of Cancer Screening, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Qianru Li
- Office of Cancer Screening, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Nuopei Tan
- Office of Cancer Screening, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Jiachen Wang
- Office of Cancer Screening, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Wanqing Chen
- Office of Cancer Screening, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
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Kusnik A, Najim M, Renjith KM, Vyas C, Renjithlal SLM, Alweis R. The Influence of Urbanization on the Patterns of Hepatocellular Carcinoma Mortality From 1999 to 2020. Gastroenterology Res 2024; 17:116-125. [PMID: 38993549 PMCID: PMC11236338 DOI: 10.14740/gr1743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Accepted: 06/15/2024] [Indexed: 07/13/2024] Open
Abstract
Background Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related fatalities despite early diagnosis and treatment progress, creating a significant public health issue in the United States. This investigation utilized death certificate data from the Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research (CDC WONDER) database to investigate HCC mortality patterns and death locations from 1999 to 2020. The objective was to analyze trends in HCC mortality across different population groups, considering the impact of urbanicity. Methods In this study, death certificate data obtained from the CDC WONDER database were utilized to investigate the trends in HCC mortality and location of death between 1999 and 2020. The annual percent change (APC) method was applied to estimate the average annual rate of change during the specified timeframe for the relevant health outcome. Furthermore, including data on the location of death and geographic areas allowed us to gain deeper insights into the patterns and characteristics of HCC and its impact on different regions. Results Between 1999 and 2020, there were 184,073 reported deaths attributed to HCC, and data on the location of death were available for all cases. Most deaths occurred during inpatient admissions (34.93%) or at home (41.19%). The study also found that the highest age-adjusted mortality rate (AAMR) for HCC was observed among male patients, particularly among those identified as Asian or Pacific Islander. Variations in AAMR were determined based on the level of urbanization or rurality of the area, with higher rates observed in more densely populated and urbanized regions. In contrast, less urbanized and populated areas experienced a profound increase in AAMR over the past two decades. Conclusion The HCC-related AAMRs have worsened over time for most ethnic groups, except for Asian or Pacific Islanders, which showed a reduction in APC despite having the worst AAMR. Although rural and less densely populated areas have substantially increased AAMR over the past two decades, more urbanized areas continued to have higher AAMR rates.
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Affiliation(s)
- Alexander Kusnik
- Department of Internal Medicine, Unity Hospital, Rochester, NY, USA
| | - Mostafa Najim
- Department of Internal Medicine, Unity Hospital, Rochester, NY, USA
| | | | - Charmee Vyas
- Division of Palliative Care, University of Kentucky, Lexington, KY, USA
| | | | - Richard Alweis
- Department of Internal Medicine, Unity Hospital, Rochester, NY, USA
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Dobrowolska K, Pawłowska M, Zarębska-Michaluk D, Rzymski P, Janczewska E, Tudrujek-Zdunek M, Berak H, Mazur W, Klapaczyński J, Lorenc B, Janocha-Litwin J, Parfieniuk-Kowerda A, Dybowska D, Piekarska A, Krygier R, Dobracka B, Jaroszewicz J, Flisiak R. Direct-acting antivirals in women of reproductive age infected with hepatitis C virus. J Viral Hepat 2024; 31:309-319. [PMID: 38483035 DOI: 10.1111/jvh.13936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 02/16/2024] [Accepted: 03/03/2024] [Indexed: 05/18/2024]
Abstract
Eliminating hepatitis C virus (HCV) infection in the population of women of reproductive age is important not only for the health of women themselves but also for the health of newborns. This study aimed to evaluate the implementation of this goal by analysing the effectiveness of contemporary therapy in a large cohort from everyday clinical practice along with identifying factors reducing therapeutic success. The analysed population consisted of 7861 patients, including 3388 women aged 15-49, treated in 2015-2022 in 26 hepatology centres. Data were collected retrospectively using a nationwide EpiTer-2 database. Females were significantly less often infected with HCV genotype 3 compared to males (11.2% vs. 15.7%) and less frequently showed comorbidities (40.5% vs. 44.2%) and comedications (37.2% vs. 45.2%). Hepatocellular carcinoma, liver transplantation, HIV and HBV coinfections were reported significantly less frequently in women. Regardless of the treatment type, females significantly more often reached sustained virologic response (98.8%) compared to males (96.8%). Regardless of gender, genotype 3 and cirrhosis were independent factors increasing the risk of treatment failure. Women more commonly reported adverse events, but death occurred significantly more frequently in men (0.3% vs. 0.1%), usually related to underlying advanced liver disease. We have demonstrated excellent effectiveness and safety profiles for treating HCV infection in women. This gives hope for the micro-elimination of HCV infections in women, translating into a reduced risk of severe disease in both women and their children.
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Affiliation(s)
| | - Małgorzata Pawłowska
- Department of Infectious Diseases and Hepatology, Faculty of Medicine, Collegium Medicum Bydgoszcz, Nicolaus Copernicus University, Toruń, Poland
| | | | - Piotr Rzymski
- Department of Environmental Medicine, Poznań University of Medical Sciences, Poznań, Poland
| | - Ewa Janczewska
- Department of Basic Medical Sciences, School of Public Health in Bytom, Medical University of Silesia, Katowice, Poland
| | | | - Hanna Berak
- Outpatient Clinic, Hospital for Infectious Diseases in Warsaw, Warsaw, Poland
| | - Włodzimierz Mazur
- Clinical Department of Infectious Diseases in Chorzów, Medical University of Silesia, Katowice, Poland
| | - Jakub Klapaczyński
- Department of Internal Medicine and Hepatology, The National Institute of Medicine of the Ministry of Interior and Administration, Warszawa, Poland
| | - Beata Lorenc
- Pomeranian Center of Infectious Diseases, Medical University, Gdańsk, Poland
| | - Justyna Janocha-Litwin
- Department of Infectious Diseases and Hepatology, Wrocław Medical University, Wrocław, Poland
| | - Anna Parfieniuk-Kowerda
- Department of Infectious Diseases and Hepatology, Medical University of Białystok, Białystok, Poland
| | - Dorota Dybowska
- Department of Infectious Diseases and Hepatology, Faculty of Medicine, Collegium Medicum Bydgoszcz, Nicolaus Copernicus University, Toruń, Poland
| | - Anna Piekarska
- Department of Infectious Diseases and Hepatology, Medical University of Łódź, Łódź, Poland
| | - Rafał Krygier
- Outpatients Hepatology Department, State University of Applied Sciences, Konin, Poland
| | | | - Jerzy Jaroszewicz
- Department of Infectious Diseases and Hepatology, Medical University of Silesia in Katowice, Bytom, Poland
| | - Robert Flisiak
- Department of Infectious Diseases and Hepatology, Medical University of Białystok, Białystok, Poland
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Wei J, Ouyang G, Huang G, Wang Y, Li S, Liu J, Zhang Y, Yuan G, He S. Burden of liver cancer due to hepatitis C from 1990 to 2019 at the global, regional, and national levels. Front Oncol 2023; 13:1218901. [PMID: 38170051 PMCID: PMC10760495 DOI: 10.3389/fonc.2023.1218901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 11/30/2023] [Indexed: 01/05/2024] Open
Abstract
BACKGROUND Liver cancer due to hepatitis C (LCDHC) is one of the leading causes of cancer-related deaths worldwide, and the burden of LCDHC is increasing. We aimed to report the burden of LCDHC at the global, regional, and national levels in 204 countries from 1990 to 2019, stratified by etiology, sex, age, and Sociodemographic Index. METHODS Data on LCDHC were available from the Global Burden of Disease, Injuries, and Risk Factors (GBD) study 2019. Numbers and age-standardized mortality, incidence, and disability-adjusted life year (DALY) rates per 100,000 population were estimated through a systematic analysis of modeled data from the GBD 2019 study. The trends in the LCDHC burden were assessed using the annual percentage change. RESULTS Globally, in 2019, there were 152,225 new cases, 141,810 deaths, and 2,878,024 DALYs due to LCDHC. From 1990 to 2019, the number of incidences, mortality, and DALY cases increased by 80.68%, 67.50%, and 37.20%, respectively. However, the age-standardized incidence, mortality, and DALY rate had a decreasing trend during this period. In 2019, the highest age-standardized incidence rates (ASIRs) of LCDHC were found in high-income Asia Pacific, North Africa and the Middle East, and Central Asia. At the regional level, Mongolia, Egypt, and Japan had the three highest ASIRs in 2019. The incidence rates of LCDHC were higher in men and increased with age, with a peak incidence in the 95+ age group for women and the 85-89 age group for men in 2019. A nonlinear association was found between the age-standardized rates of LCDHC and sociodemographic index values at the regional and national levels. CONCLUSIONS Although the age-standardized rates of LCDHC have decreased, the absolute numbers of incident cases, deaths, and DALYs have increased, indicating that LCDHC remains a significant global burden. In addition, the burden of LCDHC varies geographically. Male and older adult/s individuals have a higher burden of LCDHC. Our findings provide insight into the global burden trend of LCDHC. Policymakers should establish appropriate methods to achieve the HCV elimination target by 2030 and reducing the burden of LCDHC.
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Affiliation(s)
- Jie Wei
- Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi, China
- Guangxi Key Laboratory of Immunology and Metabolism for Liver Diseases, Guangxi Medical University, Nanning, Guangxi, China
| | - Guoqing Ouyang
- Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi, China
- Guangxi Key Laboratory of Immunology and Metabolism for Liver Diseases, Guangxi Medical University, Nanning, Guangxi, China
| | - Guozhen Huang
- Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi, China
- Guangxi Key Laboratory of Immunology and Metabolism for Liver Diseases, Guangxi Medical University, Nanning, Guangxi, China
| | - Yong Wang
- Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi, China
- Guangxi Key Laboratory of Immunology and Metabolism for Liver Diseases, Guangxi Medical University, Nanning, Guangxi, China
| | - Shuangjiang Li
- Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi, China
- Guangxi Key Laboratory of Immunology and Metabolism for Liver Diseases, Guangxi Medical University, Nanning, Guangxi, China
| | - Jiaping Liu
- Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi, China
- Guangxi Key Laboratory of Immunology and Metabolism for Liver Diseases, Guangxi Medical University, Nanning, Guangxi, China
| | - Yanhong Zhang
- Comparative Oncology Laboratory, Schools of Veterinary Medicine and Medicine, University of California, Davis, Davis, CA, United States
| | - Guandou Yuan
- Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi, China
- Guangxi Key Laboratory of Immunology and Metabolism for Liver Diseases, Guangxi Medical University, Nanning, Guangxi, China
| | - Songqing He
- Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi, China
- Guangxi Key Laboratory of Immunology and Metabolism for Liver Diseases, Guangxi Medical University, Nanning, Guangxi, China
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8
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Singal AG, Kanwal F, Llovet JM. Global trends in hepatocellular carcinoma epidemiology: implications for screening, prevention and therapy. Nat Rev Clin Oncol 2023; 20:864-884. [PMID: 37884736 DOI: 10.1038/s41571-023-00825-3] [Citation(s) in RCA: 287] [Impact Index Per Article: 143.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/25/2023] [Indexed: 10/28/2023]
Abstract
Hepatocellular carcinoma (HCC) mortality rates are increasing globally, and particularly in the Western world. Cirrhosis remains the predominant risk factor for HCC. However, epidemiological shifts in the incidence of HCC from patients with virus-related liver disease to those with non-viral aetiologies, including alcohol-associated and metabolic dysfunction-associated steatotic liver disease, have important implications for prevention, surveillance and treatment. Hepatitis B vaccination and antiviral therapy for hepatitis B and C are effective for primary prevention of virus-related HCCs, but chemoprevention strategies for non-viral liver disease remain an unmet need. Emerging data suggest associations between aspirin, statins, metformin and coffee and reduced HCC incidence, although none has been proved to be causally related. Secondary prevention of HCC via semi-annual surveillance is associated with improvements in early detection and thus reduced mortality; however, current tools, including abdominal ultrasonography, have suboptimal sensitivity for the detection of early stage HCC, particularly in patients with obesity and/or non-viral liver disease. Promising blood-based or imaging-based surveillance strategies are emerging, although these approaches require further validation before adoption in clinical practice. In the interim, efforts should be focused on maximizing use of the existing surveillance tools given their prevalent underuse globally. Remarkable advances have been made in the treatment of HCC, including expanded eligibility for surgical therapies, improved patient selection for locoregional treatments and increased systemic treatment options, including immune-checkpoint inhibitors. In this Review, we discuss trends in the epidemiology of HCC and their implications for screening, prevention and therapy.
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Affiliation(s)
- Amit G Singal
- Division of Digestive and Liver Diseases, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA.
| | - Fasiha Kanwal
- Section of Gastroenterology and Hepatology and Health Services Research, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
- Section of Health Services Research, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
- VA Health Services Research & Development Center for Innovations in Quality, Effectiveness, and Safety (IQuESt), Houston, TX, USA
- Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA
| | - Josep M Llovet
- Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Translational Research in Hepatic Oncology, Liver Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clinic, University of Barcelona, Barcelona, Spain
- Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
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9
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Cooper KM, Delk M, Devuni D, Sarkar M. Sex differences in chronic liver disease and benign liver lesions. JHEP Rep 2023; 5:100870. [PMID: 37791378 PMCID: PMC10542645 DOI: 10.1016/j.jhepr.2023.100870] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 06/23/2023] [Accepted: 07/01/2023] [Indexed: 10/05/2023] Open
Abstract
The epidemiology, natural history, and therapeutic responses of chronic liver diseases and liver lesions often vary by sex. In this review, we summarize available clinical and translational data on these aspects of the most common liver conditions encountered in clinical practice, including the potential contributions of sex hormones to the underlying pathophysiology of observed differences. We also highlight areas of notable knowledge gaps and discuss sex disparities in access to liver transplant and potential strategies to address these barriers. Given established sex differences in immune response, drug metabolism, and response to liver-related therapies, emerging clinical trials and epidemiological studies should prioritize dedicated analyses by sex to inform sex-specific approaches to liver-related care.
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Affiliation(s)
- Katherine M. Cooper
- UMass Chan Medical School, Department of Medicine, Division of Gastroenterology/Hepatology, Worcester, MA, United States
| | - Molly Delk
- University of California San Francisco, Department of Medicine, Division of Gastroenterology/Hepatology, San Francisco, CA, United States
| | - Deepika Devuni
- UMass Chan Medical School, Department of Medicine, Division of Gastroenterology/Hepatology, Worcester, MA, United States
| | - Monika Sarkar
- University of California San Francisco, Department of Medicine, Division of Gastroenterology/Hepatology, San Francisco, CA, United States
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10
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Bashandy SAE, Ebaid H, Al-Tamimi J, Hassan I, Omara EA, Elbaset MA, Alhazza IM, Siddique JA. Protective Effect of Daidzein against Diethylnitrosamine/Carbon Tetrachloride-Induced Hepatocellular Carcinoma in Male Rats. BIOLOGY 2023; 12:1184. [PMID: 37759583 PMCID: PMC10525464 DOI: 10.3390/biology12091184] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 08/17/2023] [Accepted: 08/21/2023] [Indexed: 09/29/2023]
Abstract
Hepatocellular carcinoma (HCC) is the second-largest cause of death among all cancer types. Many drugs have been used to treat the disease for a long time but have been mostly discontinued because of their side effects or the development of resistance in the patients with HCC. The administration of DZ orally is a great focus to address the clinical crisis. Daidzein (DZ) is a prominent isoflavone polyphenolic chemical found in soybeans and other leguminous plants. It has various pharmacological effects, including anti-inflammatory, antihemolytic, and antioxidant. This present study investigates the protective effect of DZ on chemically induced HCC in rat models. The DZ was administered orally four weeks before HCC induction and continued during treatment. Our study included four treatment groups: control (group 1, without any treatment), HCC-induced rats (group II), an HCC group treated with DZ at 20 mg/kg (group III), and an HCC group treated with DZ at 40 mg/kg (group IV). HCC rats showed elevation in all the HCC markers (AFP, GPC3, and VEGF), liver function markers (ALP, ALT, and AST), inflammatory markers (IL-6, TNF-α, and CRP), and lipid markers concomitant with a decrease in antioxidant enzymes and protein. However, groups III and IV demonstrated dose-dependent alleviation in the previous parameters resulting from HCC. In addition, the high dose of DZ reduces many hepatological changes in HCC rats. All study parameters improved with DZ administration. Due to its antioxidant and anti-inflammatory characteristics, DZ is a promising HCC treatment option for clinical use.
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Affiliation(s)
- Samir A. E. Bashandy
- Pharmacology Department, National Research Centre, 33 El-Bohouth St., Dokki, Cairo 12622, Egypt; (S.A.E.B.); (M.A.E.)
| | - Hossam Ebaid
- Zoology Department, College of Science, King Saud University, Riyadh 11451, Saudi Arabia; (H.E.); (I.M.A.)
| | - Jameel Al-Tamimi
- Zoology Department, College of Science, King Saud University, Riyadh 11451, Saudi Arabia; (H.E.); (I.M.A.)
| | - Iftekhar Hassan
- Zoology Department, College of Science, King Saud University, Riyadh 11451, Saudi Arabia; (H.E.); (I.M.A.)
| | - Enayat A. Omara
- Pathology Department, National Research Centre, 33 El-Bohouth St., Dokki, Cairo 12622, Egypt;
| | - Marawan A. Elbaset
- Pharmacology Department, National Research Centre, 33 El-Bohouth St., Dokki, Cairo 12622, Egypt; (S.A.E.B.); (M.A.E.)
| | - Ibrahim M. Alhazza
- Zoology Department, College of Science, King Saud University, Riyadh 11451, Saudi Arabia; (H.E.); (I.M.A.)
| | - Jamal A. Siddique
- Department of Materials Engineering and Chemistry, Faculty of Civil Engineering, Czech Technical University (CVUT), Praha 6, 16629 Prague, Czech Republic;
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11
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Zhang Z, Chen C, Wang Y, Wang N, Chen Y, Lu Y, Xia F. The associations of total testosterone with probable nonalcoholic steatohepatitis and nonalcoholic fatty liver disease fibrotic progression in men with type 2 diabetes: a cross-sectional study. Eur J Med Res 2022; 27:307. [PMID: 36572925 PMCID: PMC9793685 DOI: 10.1186/s40001-022-00958-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Accepted: 12/16/2022] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Testosterone has an impact on metabolic disorders and men with type 2 diabetes mellitus (T2DM) are predisposed to hypogonadism; meanwhile, patients with T2DM have higher risk of NAFLD. Therefore, we speculate that testosterone may affect the progression of NAFLD in T2DM patients and we aim to investigate whether total testosterone is associated with NAFLD progression in men with T2DM. METHODS A cross-sectional study. A total of 1782 male participants with T2DM were enrolled from seven communities in Shanghai. Probable nonalcoholic steatohepatitis (NASH) was defined by the concurrence of NAFLD and metabolic syndrome (MetS). NAFLD fibrosis score was used to identify patients with probable advanced fibrosis. Multinomial logistic regression and ordinal logistic regression was used to measure the association of total testosterone (independent variable) and the progression category of NAFLD (dependent variable). RESULTS In male, TT quartiles were negatively associated with probable NASH (Q1 vs. Q4 OR 2.07 95% CI 1.31-3.28, P for trend = 0.001) and inflammatory progression of NAFLD with OR of 1 SD increment of ln (TT) 0.81 (95% CI 0.72-0.92, P for trend < 0.001), but positively with fibrotic progression (Q1 vs. Q4 OR 0.45, 95% CI 0.29-0.72, P for trend = 0.001) with OR of 1 SD increment of ln (TT) 1.24 (95% CI 1.07-1.45). According to stratified analyses, for inflammatory progression, the interactions of age strata, duration of diabetes strata, and dyslipidemia status with 1 SD increment of ln (TT) were significant (P for interaction 0.007, 0.003, and 0.012, respectively); as for fibrotic progression, we found no interactions (all P for interaction ≥ 0.05). CONCLUSIONS Different associations between TT and inflammatory and fibrotic progression of NAFLD in male were observed, suggesting different roles of TT in inflammatory and fibrotic stages of NAFLD.
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Affiliation(s)
- Ziteng Zhang
- grid.16821.3c0000 0004 0368 8293Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine, Zhizaoju Road No. 639, Shanghai, 200011 China
| | - Chi Chen
- grid.16821.3c0000 0004 0368 8293Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine, Zhizaoju Road No. 639, Shanghai, 200011 China
| | - Yuying Wang
- grid.16821.3c0000 0004 0368 8293Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine, Zhizaoju Road No. 639, Shanghai, 200011 China
| | - Ningjian Wang
- grid.16821.3c0000 0004 0368 8293Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine, Zhizaoju Road No. 639, Shanghai, 200011 China
| | - Yi Chen
- grid.16821.3c0000 0004 0368 8293Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine, Zhizaoju Road No. 639, Shanghai, 200011 China
| | - Yingli Lu
- grid.16821.3c0000 0004 0368 8293Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine, Zhizaoju Road No. 639, Shanghai, 200011 China
| | - Fangzhen Xia
- grid.16821.3c0000 0004 0368 8293Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine, Zhizaoju Road No. 639, Shanghai, 200011 China
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12
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Estrogen as a key regulator of energy homeostasis and metabolic health. Biomed Pharmacother 2022; 156:113808. [DOI: 10.1016/j.biopha.2022.113808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 10/02/2022] [Accepted: 10/03/2022] [Indexed: 11/23/2022] Open
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13
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Xu L, Yuan Y, Che Z, Tan X, Wu B, Wang C, Xu C, Xiao J. The Hepatoprotective and Hepatotoxic Roles of Sex and Sex-Related Hormones. Front Immunol 2022; 13:939631. [PMID: 35860276 PMCID: PMC9289199 DOI: 10.3389/fimmu.2022.939631] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 06/13/2022] [Indexed: 12/18/2022] Open
Abstract
Most liver diseases, including acute liver injury, drug-induced liver injury, viral hepatitis, metabolic liver diseases, and end-stage liver diseases, are strongly linked with hormonal influences. Thus, delineating the clinical manifestation and underlying mechanisms of the "sexual dimorphism" is critical for providing hints for the prevention, management, and treatment of those diseases. Whether the sex hormones (androgen, estrogen, and progesterone) and sex-related hormones (gonadotrophin-releasing hormone, luteinizing hormone, follicle-stimulating hormone, and prolactin) play protective or toxic roles in the liver depends on the biological sex, disease stage, precipitating factor, and even the psychiatric status. Lifestyle factors, such as obesity, alcohol drinking, and smoking, also drastically affect the involving mechanisms of those hormones in liver diseases. Hormones deliver their hepatic regulatory signals primarily via classical and non-classical receptors in different liver cell types. Exogenous sex/sex-related hormone therapy may serve as a novel strategy for metabolic liver disease, cirrhosis, and liver cancer. However, the undesired hormone-induced liver injury should be carefully studied in pre-clinical models and monitored in clinical applications. This issue is particularly important for menopause females with hormone replacement therapy (HRT) and transgender populations who want to receive gender-affirming hormone therapy (GAHT). In conclusion, basic and clinical studies are warranted to depict the detailed hepatoprotective and hepatotoxic mechanisms of sex/sex-related hormones in liver disease. Prolactin holds a promising perspective in treating metabolic and advanced liver diseases.
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Affiliation(s)
- Linlin Xu
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yuan Yuan
- Clinical Medicine Research Institute, Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Zhaodi Che
- Clinical Medicine Research Institute, Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Xiaozhi Tan
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Bin Wu
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Cunchuan Wang
- Clinical Medicine Research Institute, Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Chengfang Xu
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jia Xiao
- Clinical Medicine Research Institute, Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China
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14
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Kadiri DD, Peela S, Ganguli D. Effect of cirrhosis and hepatitis on the prognosis of liver cancer. THERANOSTICS AND PRECISION MEDICINE FOR THE MANAGEMENT OF HEPATOCELLULAR CARCINOMA 2022:51-72. [DOI: 10.1016/b978-0-323-98806-3.00002-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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15
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Bashir Hamidu R, Chalikonda DM, Hann HW. Gender Disparity in Host Responses to Hepatitis B-Related Hepatocellular Carcinoma: A Case Series. Vaccines (Basel) 2021; 9:838. [PMID: 34451963 PMCID: PMC8402514 DOI: 10.3390/vaccines9080838] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 07/25/2021] [Accepted: 07/26/2021] [Indexed: 12/11/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection is one of the most common causes of hepatocellular carcinoma (HCC), a malignant tumor with high mortality worldwide. One remarkable clinical feature of HBV-related HCC is that the risk of development is higher in males and postmenopausal females compared to other females. Increasing evidence also indicates that the prognosis of HBV-associated HCC may involve gender disparity, with females having more favorable outcomes. The proposed mechanism of this gender disparity is thought to be complex and multifactorial. Attributions have been made to gender differences in behavioral risk factors, host stress, immune response, psychology, metabolic risk factors, tumor biology, and hormonal factors. Gender disparities in hormonal factors and stress with consequent incited inflammation and hepatocarcinogenesis in HBV-related HCC is a particularly burgeoning area of investigation. Clarifying these mechanisms could provide insight into HBV-related HCC pathogenesis, and potentially provide a target for prevention and treatment of this disease. Reported herein is a case series involving two families affected by vertically transmitted chronic hepatitis B, longitudinally observed over multiple decades, with family members demonstrating discordant outcomes related to HCC, with worse outcomes among affected males. As a supplement to this case, we review the currently available literature on gender differences in outcomes from HBV-related HCC. In reporting this case series, we aim to add our important observation to the current literature and highlight the need for further research in the mechanisms involved in gender disparity in the prognosis of HBV-related HCC.
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Affiliation(s)
- Rukaiya Bashir Hamidu
- Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA;
| | - Divya M. Chalikonda
- Department of Medicine, Division of Gastroenterology and Hepatology, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA;
| | - Hie-Won Hann
- Liver Disease Prevention Center, Division of Gastroenterology and Hepatology, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
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16
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Zhang H, Spencer K, Burley SK, Zheng XFS. Toward improving androgen receptor-targeted therapies in male-dominant hepatocellular carcinoma. Drug Discov Today 2021; 26:1539-1546. [PMID: 33561464 DOI: 10.1016/j.drudis.2021.02.001] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Revised: 01/16/2021] [Accepted: 02/02/2021] [Indexed: 12/24/2022]
Abstract
Hepatocellular carcinoma (HCC) is the predominant form of liver cancer and a leading cause of cancer deaths worldwide. HCC is a male-dominant cancer with a male:female ratio of up to 7:1. The androgen receptor (AR) is the male hormone receptor known as a major oncogenic driver of prostate cancer. Although AR has been linked to the sexual dimorphism of HCC, clinical trials with AR-targeted agents failed to generate survival benefits. Recent studies provide new insights into the role of AR in liver tumorigenesis and therapeutic responses. Herein, we review current understanding of AR signaling in HCC and feedback mechanisms that limit response to AR blockade. New AR-targeting strategies that might improve outcomes in HCC therapies are also discussed.
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Affiliation(s)
- Hong Zhang
- Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903, USA; Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, 675 Hoes Lane, Piscataway, NJ 08854, USA
| | - Kristen Spencer
- Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903, USA; Department of Medicine, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, 125 Paterson Street, New Brunswick, NJ 08901, USA
| | - Stephen K Burley
- Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903, USA; RCSB Protein Data Bank and Institute for Quantitative Biomedicine, Rutgers, The State University of New Jersey, 174 Frelinghuysen Road, Piscataway, NJ 08854, USA; Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, 174 Frelinghuysen Road, Piscataway, NJ 08854, USA; RCSB Protein Data Bank, School of Pharmacy and Pharmaceutical Sciences and San Diego Supercomputing Center, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
| | - X F Steven Zheng
- Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903, USA; Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, 675 Hoes Lane, Piscataway, NJ 08854, USA.
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17
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Magri MC, Alvarez MSM, Iogi AA, Alves GM, Manchiero C, Dantas BP, Prata TVG, Nunes AKDS, Tengan FM. Study of CXCL9-11 gene polymorphisms in liver fibrosis among patients with chronic hepatitis C. Pathog Dis 2021; 79:6105222. [PMID: 33476381 DOI: 10.1093/femspd/ftab007] [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: 09/15/2020] [Accepted: 01/19/2021] [Indexed: 01/10/2023] Open
Abstract
Several factors are associated with the progression of chronic hepatitis C: comorbidities, lifestyle, and pathogenic factors, including immune response, apoptosis and heredity. Single nucleotide polymorphisms (SNPs) in the PNPLA3 and TM6SF2 genes are more widely studied genetic risk factors, while CXCL9-11 chemokines produced by hepatocytes in the process of infection are less well studied. Our aim was to evaluate the influence of CXCL9 rs10336, CXCL10 rs3921 and CXCL11 rs4619915 in liver fibrosis when analysed together with PNPLA3 rs738409 and TM6SF2 rs58542926. The study included 219 patients with chronic hepatitis C. SNP genotyping was performed by real-time PCR. Univariate and multivariate analyses were used to detect the association between SNPs and advanced fibrosis in a recessive genetic model. All SNPs had a minimum allele frequency >5%, and CXCL9 rs10336, CXCL10 rs3921 and CXCL11 rs4619915 were in high linkage disequilibrium (D' ≥ 0.84). In the multivariate analysis, we observed that male gender (P = 0.000), older age (P = 0.025), moderate to intense inflammatory activity (P = 0.002), moderate to accentuated hepatic steatosis (P = 0.026) and the CT genotype of the TM6SF2 rs58542926 SNP (P = 0.014) presented significant associations with advanced fibrosis. Overall, the CXCL9 rs10336, CXCL10 rs3921, CXCL11 rs4619915 and PNPLA3 rs738409 SNPs did not influence liver fibrosis among patients with chronic hepatitis C.
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Affiliation(s)
- Mariana Cavalheiro Magri
- Laboratorio de Investigacao Medica em Hepatologia por Virus (LIM-47), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Maria Stella Montanha Alvarez
- Laboratorio de Investigacao Medica em Hepatologia por Virus (LIM-47), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Anny Ayumi Iogi
- Laboratorio de Investigacao Medica em Hepatologia por Virus (LIM-47), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Grayce Mendes Alves
- Laboratorio de Investigacao Medica em Hepatologia por Virus (LIM-47), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Caroline Manchiero
- Laboratorio de Investigacao Medica em Hepatologia por Virus (LIM-47), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Bianca Peixoto Dantas
- Laboratorio de Investigacao Medica em Hepatologia por Virus (LIM-47), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Thamiris Vaz Gago Prata
- Laboratorio de Investigacao Medica em Hepatologia por Virus (LIM-47), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Arielle Karen da Silva Nunes
- Laboratorio de Investigacao Medica em Hepatologia por Virus (LIM-47), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Fátima Mitiko Tengan
- Laboratorio de Investigacao Medica em Hepatologia por Virus (LIM-47), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil.,Departamento de Molestias Infecciosas e Parasitarias, Faculdade de Medicina, Universidade de Sao Paulo, Av. Dr. Eneas de Carvalho Aguiar, 255. Bairro Cerqueira Cesar. Sao Paulo, SP, Brazil. CEP 05403-000
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18
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Yang M, Parikh ND, Liu H, Wu E, Rao H, Feng B, Lin A, Wei L, Lok AS. Incidence and risk factors of hepatocellular carcinoma in patients with hepatitis C in China and the United States. Sci Rep 2020; 10:20922. [PMID: 33262356 PMCID: PMC7708980 DOI: 10.1038/s41598-020-77515-y] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Accepted: 11/09/2020] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infection is the main cause of hepatocellular carcinoma (HCC) in the United States (US) and an increasingly common cause of HCC in China. We aimed to evaluate the incidence and risk factors of HCC in HCV patients in the US and China. 795 HCV RNA + patients without HCC from University of Michigan Health System (UMHS) in the US and 854 from Peking University Health Sciences Center (PUHSC) in China were prospectively followed for a median of 3.2 and 4.0 years, respectively. 45.4% UMHS and 16.2% PUHSC patients had cirrhosis. 57.6% UMHS and 52.0% PUHSC patients achieved SVR. 45 UMHS and 13 PUHSC patients developed HCC. Cumulative incidence of HCC at 5 years was 7.6% in UMHS and 1.8% in PUHSC cohort (P < 0.001). Ten patients not diagnosed with cirrhosis at enrollment but median APRI ≥ 2.0 developed HCC. Multivariate analysis showed age, gender, cirrhosis and APRI were predictors of HCC while study site and SVR were not. In this study of HCV patients, HCC incidence in the PUHSC cohort was lower than in the UMHS cohort, due to lower proportion of PUHSC patients with cirrhosis. APRI can identify risk of HCC among patients not diagnosed to have cirrhosis.
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Affiliation(s)
- Ming Yang
- Peking University People's Hospital, Peking University Hepatology Institute, Peking University Health Science Center, Beijing, China
| | - Neehar D Parikh
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Huixin Liu
- Department of Clinical Epidemiology and Biostatistics, Peking University People's Hospital, Beijing, China
| | - Elizabeth Wu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Huiying Rao
- Peking University People's Hospital, Peking University Hepatology Institute, Peking University Health Science Center, Beijing, China
| | - Bo Feng
- Peking University People's Hospital, Peking University Hepatology Institute, Peking University Health Science Center, Beijing, China
| | - Andy Lin
- The Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI, USA
| | - Lai Wei
- Peking University People's Hospital, Peking University Hepatology Institute, Peking University Health Science Center, Beijing, China
| | - Anna S Lok
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
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19
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Akl EM, Salah AA. Effect of new oral direct acting antiviral therapy on sexual function in male patients with hepatitis C virus. Andrologia 2020; 52:e13835. [PMID: 33070383 DOI: 10.1111/and.13835] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Revised: 08/14/2020] [Accepted: 08/19/2020] [Indexed: 11/29/2022] Open
Abstract
Hepatitis C virus (HCV) infection is a major health problem all over the world including Egypt. Chronic HCV infection is usually accompanied by decrease of libido and erectile dysfunction. This study aimed to evaluate the efficacy of new oral direct acting antiviral (DAA) therapy on sexual function of male patients with HCV. This study was conducted on 200 male participants divided into two groups, first group included 100 male patients with HCV and the second group included 100 healthy age matched males as a control. Patients received DAA for three months and virological free status was confirmed by polymerase chain reaction. All participants were subjected to full history taking, general examination and local genital examination, assessment of sexual function by a validated Arabic version of the international index of erectile function-5. Laboratory investigations included liver functions serum testosterone, free testosterone, sex hormone-binding globulin and bioavailable testosterone. Results of this study showed that patients with HCV suffer from sexual dysfunction than controls that significantly improved after DAA therapy, and this is accompanied by increasing of bioavailable testosterone. It could be concluded that beside its effectiveness in treatment of HCV infection, DAA therapy can improve sexual function in male patients with HCV.
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Affiliation(s)
- Essam M Akl
- Department of Dermatology and Andrology, Faculty of Medicine, Benha University, Benha, Egypt
| | - Ahmed A Salah
- Department of Dermatology and Andrology, Faculty of Medicine, Benha University, Benha, Egypt
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20
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Khalid J, Umar M, Ur-Rehman T, Ali M, Khan GM. Tumor aggression among hepatitis-C related hepatocellular carcinoma patients: an observational study regarding the impact of anti-HCV therapy. Infect Agent Cancer 2020; 15:35. [PMID: 32508980 PMCID: PMC7251734 DOI: 10.1186/s13027-020-00300-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2019] [Accepted: 05/04/2020] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Hepatitis C virus (HCV) represents a major risk factor for hepatocellular carcinoma (HCC) development and anti-HCV therapy is a significant measure to reduce the incidence of HCC, however development of HCC in HCV treated patients is an emerging clinical problem which needs to be investigated. In this study we aim to analyze association between anti-HCV therapy and tumor pattern of HCV related HCC patients. METHODS Hepatocellular Carcinoma (HCC) patients with seropositivity for hepatitis C virus (HCV) antibodies, registered at three tertiary care hospitals of Rawalpindi and Islamabad, Pakistan during August 2017 to July 2018 were enrolled. Selected patients were then segregated in two groups on the basis of their HCV treatment history i.e., "TN" (HCV Treatment Naïve i.e. having no history/medical record for treatment prior to HCC diagnosis) and "TH" (Treated for HCV infection). Aggressiveness index (AgI) scoring system was applied to determine the tumor pattern. Univariate and multivariate analysis was carried out to analyze the independent effect of anti-HCV therapy on tumor pattern. RESULTS Out of 234 consecutive HCC patients, 171 HCV-related HCC patients were enrolled in final analysis and labeled as "TN" (n = 120) and "TH" (n = 51). Tumor pattern was found to be significantly aggressive (P = 0.02) in the treated cohort with an adjusted odds of 2.47 for aggressive and 6.92 for highly aggressive tumor. Neutrophil to lymphocyte ratio (NLR) was strongly associated with highly aggressive tumor pattern (P = 0.012). Patients in TN group were found to be marginally older than those in the TH group (59.5 vs. 55 years) where mean age of the patients treated with direct acting anti-viral agents was found to be visibly lower than mean age of patients who received interferon based treatment (53.5 vs. 57 years) with significant masculine predominance (62.1 vs. 37.9%, P = 0.049). CONCLUSION We observed raised neutrophil to lymphocyte ratio and prominence of younger age with aggressive tumor biology in HCV treated HCC patients. These observations highlight the need for a longitudinal prospective study on HCV positive subjects treated with antivirals, irrespective of treatment response.
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Affiliation(s)
- Javeria Khalid
- Department of Pharmacy, Quaid-i-Azam University, Islamabad, 45320 Pakistan
- Clinical Pharmacist at Shifa International Hospital Islamabad, Islamabad, Pakistan
| | - Mohammad Umar
- Center for Liver and Digestive Diseases, Holy Family Hospital, Rawalpindi Medical University, Rawalpindiand, 46300 Pakistan
| | - Tofeeq Ur-Rehman
- Department of Pharmacy, Quaid-i-Azam University, Islamabad, 45320 Pakistan
| | - Mashhood Ali
- Gasteroenterology Department, Pakistan Institute of Medical Sciences (PIMS) Hospital, Islamabad, 44000 Pakistan
| | - Gul Majid Khan
- Department of Pharmacy, Quaid-i-Azam University, Islamabad, 45320 Pakistan
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21
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Thrift AP, Liu Y, Tsavachidis S, White DL, El-Serag HB. Ancestry and Risk of Hepatic Fibrosis and Inflammation in Patients With HCV Infection. Clin Gastroenterol Hepatol 2019; 17:1912-1914. [PMID: 30342914 PMCID: PMC7050728 DOI: 10.1016/j.cgh.2018.10.024] [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: 08/22/2018] [Revised: 10/02/2018] [Accepted: 10/15/2018] [Indexed: 02/07/2023]
Abstract
Worldwide, ∼184 million people have chronic hepatitis C virus (HCV) infection.1 Persistent racial disparities in outcomes are observed among HCV-infected patients. Hispanic patients with chronic HCV are more likely than non-Hispanic white (NHW) patients to develop advanced hepatic fibrosis and inflammation.2,3 Conversely, black patients with HCV infection are at lowest risk. The factors that contribute to this racial disparity are multifactorial, including lifestyle, genetics, and medical care. Limited data in other diseases suggest that genetic ancestry determined using ancestry-informative markers (AIMs) may help explain racial and ethnic differences in disease risk or severity.4 AIMs are sets of single-nucleotide polymorphisms (SNPs) that determine a person's ancestral continent of origin and the genetic ancestry proportions assigned to each individual serves as a proxy for his or her genetic ancestral background. We examined the risk of hepatic fibrosis and inflammation in HCV-infected patients according to both genetic ancestry and self-reported race/ethnicity.
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Affiliation(s)
- Aaron P. Thrift
- Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, Texas;,Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas
| | - Yanhong Liu
- Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, Texas;,Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas
| | - Spiridon Tsavachidis
- Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, Texas;,Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas
| | - Donna L. White
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas;,Center for Innovations in Quality, Effectiveness and Safety Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas;,Center for Translational Research in Inflammatory Disease, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas
| | - Hashem B. El-Serag
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas;,Center for Innovations in Quality, Effectiveness and Safety Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas
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22
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Chaudhury CS, Mee T, Chairez C, McLaughlin M, Silk R, Gross C, Kattakuzhy S, Rosenthal E, Kottilil S, Stanley TL, Hadigan C. Testosterone in Men With Chronic Hepatitis C Infection and After Hepatitis C Viral Clearance. Clin Infect Dis 2019; 69:571-576. [PMID: 30715229 PMCID: PMC6669296 DOI: 10.1093/cid/ciy965] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Accepted: 11/08/2018] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Hepatitis C virus (HCV) and hepatic dysfunction are associated with low total and free testosterone (TT and FT) and high sex hormone-binding globulin (SHBG). However, little is known about changes in testosterone following successful HCV treatment. METHODS We evaluated testosterone levels and the prevalence of low testosterone in a cohort of 327 men with chronic HCV infection (human immunodeficiency virus [HIV] coinfection = 150) and in a subset of 85 men with testosterone levels obtained pre-HCV treatment and after sustained virologic response (SVR). Median follow-up was 36 months. RESULTS Participants with active HCV at baseline had higher TT (P < .0001) and SHBG (P < .0001) compared with participants who had achieved SVR, whereas FT did not differ. Low TT (<10.4 nmol/L) was more prevalent in participants with SVR compared with active HCV (P = .002); however, low FT (<0.1735 nmol/L) was common (50% active HCV, 43% SVR) and did not different between groups. For participants with longitudinal determinations, TT and SHBG decreased significantly (P < .0001) while FT remained unchanged post-SVR. Low FT persisted after SVR (pre-treatment 58%, post-SVR 54%, P = .72). HIV status and change in aspartate aminotrasferase-to-platelet ratio were significant independent predictors of change in FT following SVR. CONCLUSIONS During active HCV infection, testosterone deficiency may be masked due to elevated SHBG. Despite improvements in SHBG following SVR, low FT was common and persisted after HCV clearance, indicating the need for enhanced awareness and screening using estimates of FT following successful treatment of chronic HCV. CLINICAL TRIALS REGISTRATION NCT01350648.
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Affiliation(s)
- Chloe S Chaudhury
- National Institute of Allergy and Infectious Diseases, University of Maryland, Baltimore
| | - Thomas Mee
- Critical Care Medicine Department, Clinical Center, National Institutes of Health, University of Maryland, Baltimore
| | - Cheryl Chairez
- National Institute of Allergy and Infectious Diseases, University of Maryland, Baltimore
| | - Mary McLaughlin
- National Institute of Allergy and Infectious Diseases, University of Maryland, Baltimore
| | - Rachel Silk
- Institute of Human Virology, Division of Infectious Diseases, University of Maryland, Baltimore
| | - Chloe Gross
- Institute of Human Virology, Division of Infectious Diseases, University of Maryland, Baltimore
| | - Sarah Kattakuzhy
- Institute of Human Virology, Division of Infectious Diseases, University of Maryland, Baltimore
| | - Elana Rosenthal
- Institute of Human Virology, Division of Infectious Diseases, University of Maryland, Baltimore
| | - Shyam Kottilil
- Institute of Human Virology, Division of Infectious Diseases, University of Maryland, Baltimore
| | - Takara L Stanley
- Massachusetts General Hospital for Children Pediatric Endocrine Unit, Boston
| | - Colleen Hadigan
- National Institute of Allergy and Infectious Diseases, University of Maryland, Baltimore
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23
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Grossmann M, Wierman ME, Angus P, Handelsman DJ. Reproductive Endocrinology of Nonalcoholic Fatty Liver Disease. Endocr Rev 2019; 40:417-446. [PMID: 30500887 DOI: 10.1210/er.2018-00158] [Citation(s) in RCA: 77] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2018] [Accepted: 11/19/2018] [Indexed: 02/07/2023]
Abstract
The liver and the reproductive system interact in a multifaceted bidirectional fashion. Sex steroid signaling influences hepatic endobiotic and xenobiotic metabolism and contributes to the pathogenesis of functional and structural disorders of the liver. In turn, liver function affects the reproductive axis via modulating sex steroid metabolism and transport to tissues via sex hormone-binding globulin (SHBG). The liver senses the body's metabolic status and adapts its energy homeostasis in a sex-dependent fashion, a dimorphism signaled by the sex steroid milieu and possibly related to the metabolic costs of reproduction. Sex steroids impact the pathogenesis of nonalcoholic fatty liver disease, including development of hepatic steatosis, fibrosis, and carcinogenesis. Preclinical studies in male rodents demonstrate that androgens protect against hepatic steatosis and insulin resistance both via androgen receptor signaling and, following aromatization to estradiol, estrogen receptor signaling, through regulating genes involved in hepatic lipogenesis and glucose metabolism. In female rodents in contrast to males, androgens promote hepatic steatosis and dysglycemia, whereas estradiol is similarly protective against liver disease. In men, hepatic steatosis is associated with modest reductions in circulating testosterone, in part consequent to a reduction in circulating SHBG. Testosterone treatment has not been demonstrated to improve hepatic steatosis in randomized controlled clinical trials. Consistent with sex-dimorphic preclinical findings, androgens promote hepatic steatosis and dysglycemia in women, whereas endogenous estradiol appears protective in both men and women. In both sexes, androgens promote hepatic fibrosis and the development of hepatocellular carcinoma, whereas estradiol is protective.
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Affiliation(s)
- Mathis Grossmann
- Department of Medicine Austin Health, University of Melbourne, Heidelberg, Victoria, Australia.,Department of Endocrinology, Austin Health, Heidelberg, Victoria, Australia
| | - Margaret E Wierman
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.,Research Service, Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, Colorado
| | - Peter Angus
- Department of Medicine Austin Health, University of Melbourne, Heidelberg, Victoria, Australia.,Departments of Gastroenterology and Hepatology, Heidelberg, Victoria, Australia
| | - David J Handelsman
- ANZAC Research Institute, University of Sydney, Concord Hospital, Sydney, New South Wales, Australia
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24
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Colaci M, Malatino L, Antonelli A, Fallahi P, Giuggioli D, Ferri C. Endocrine disorders associated with hepatitis C virus chronic infection. Rev Endocr Metab Disord 2018; 19:397-403. [PMID: 30499080 DOI: 10.1007/s11154-018-9475-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The term "HCV syndrome" encompasses several organ- and systemic pathophysiological states, which often recognize autoimmunity or neoplastic evolution in their pathophysiology, as well as chronic HCV infection as trigger. The clinical features of HCV patients are heterogenous, and may include endocrine or metabolic disorders, namely autoimmune thyroiditis, type 2 diabetes mellitus, and erectile/sexual dysfunctions. In this review, we summarize current knowledge on the endocrine/metabolic diseases associated with chronic HCV infection, focusing on the main concepts emerged in the recent literature in this field. The application of this knowledge in everyday clinical practice may be relevant, in order to reinforce a holistic vision of the patient with chronic HCV infection, stimulating in turn a multi-disciplinary approach, thus increasing the probability of early diagnosis, more effective treatments, and a better prognostic outcome.
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Affiliation(s)
- Michele Colaci
- Internal Medicine Unit, Cannizzaro Hospital, Department of Clinical and Experimental Medicine, University of Catania, Via Messina, 829, 95100, Catania, Italy.
| | - Lorenzo Malatino
- Internal Medicine Unit, Cannizzaro Hospital, Department of Clinical and Experimental Medicine, University of Catania, Via Messina, 829, 95100, Catania, Italy
| | - Alessandro Antonelli
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Poupak Fallahi
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Dilia Giuggioli
- Rheumatology Unit, Azienda Ospedaliero-Universitaria di Modena, University of Modena and Reggio Emilia, Modena, Italy
| | - Clodoveo Ferri
- Rheumatology Unit, Azienda Ospedaliero-Universitaria di Modena, University of Modena and Reggio Emilia, Modena, Italy
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25
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Jang TY, Yeh ML, Huang CI, Lin ZY, Chen SC, Hsieh MH, Dai CY, Huang JF, Huang CF, Chuang WL, Yu ML. Association of hyperuricemia with disease severity in chronic hepatitis C patients. PLoS One 2018; 13:e0207043. [PMID: 30395654 PMCID: PMC6218088 DOI: 10.1371/journal.pone.0207043] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2018] [Accepted: 10/23/2018] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND/AIMS Hepatitis C virus (HCV) infection is associated with extrahepatic manifestations such as metabolic abnormalities. The association between chronic hepatitis C (CHC) and uric acid levels has rarely been investigated. We aimed to evaluate the levels of serum uric acid in CHC patients. METHODS Three hundred and seventy-three histologically confirmed CHC patients who were scheduled to receive antiviral therapy were consecutively enrolled, and 746 age- and sex-matched uninfected controls were included for comparison. Hyperuricemia was defined as a uric acid level > 7 mg/dL in men and > 6.0 mg/dL in women. RESULTS Hyperuricemia was identified in 15.8% of the CHC patients. The uric acid levels did not differ between the CHC patients and the controls (5.54 ± 1.20 mg/dL vs. 5.45 ± 1.45 mg/dL, P = 0.3). Among the 373 CHC patients, the factors associated with hyperuricemia included body mass index (BMI) (OR/CI: 1.13/1.04-1.21, P = 0.003) and estimated glomerular filtration rate (eGFR) (OR/CI: 0.98/0.97-1.00, P = 0.02). Logistic regression analysis revealed that the factors associated with hyperuricemia in male patients included BMI (OR/CI: 1.12/1.05-1.30, P = 0.006) and advanced fibrosis (F3-4) (OR/CI: 0.27/0.09-0.83, P = 0.02), whereas the factors associated with hyperuricemia in female patients included eGFR (OR/CI: 0.97/0.95-0.99, P = 0.02) and diabetes (OR/CI: 3.03/1.11-8.25, P = 0.03). There was a significant decreasing trend of serum uric acid levels with the progression of fibrotic stages among male patients (6.21 ± 1.03 mg/dL 5.82 ± 1.16 mg/dL and 5.44 ± 1.28 mg/dL in stages F0-2, F3, and F4, respectively, trend P = 0.01). CONCLUSIONS Hyperuricemia was inversely associated with liver disease severity in CHC male patients.
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Affiliation(s)
- Tyng-Yuan Jang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Lun Yeh
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ching-I Huang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Zu-Yau Lin
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Shinn-Cherng Chen
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Meng-Hsuan Hsieh
- Department of Occupational Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Preventive Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chia-Yen Dai
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Occupational Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Preventive Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jee-Fu Huang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chung-Feng Huang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Occupational Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Wan-Long Chuang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Lung Yu
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan
- College of Biological Science and Technology, National Chiao Tung University, Hsin-Chu, Taiwan
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26
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Himoto T, Fujita K, Sakamoto T, Nomura T, Morishita A, Yoneyama H, Haba R, Masaki T. Clinical efficacy of free androgen index, a surrogate hallmark of circulating free testosterone level, in male patients with HCV-related chronic liver disease. J Clin Biochem Nutr 2018; 63:238-245. [PMID: 30487676 PMCID: PMC6252299 DOI: 10.3164/jcbn.18-30] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Accepted: 03/28/2018] [Indexed: 12/15/2022] Open
Abstract
The role of free testosterone, that not bound to sex hormone-binding globulin, in male patients with HCV infection remains uncertain. We investigated whether free testosterone is involved in the progression to hepatic fibrosis/steatosis or insulin resistance in male patients with HCV-related chronic liver disease or not. Free androgen indices, which reflect circulating free testosterone levels, were calculated as 100 × total testosterone levels/sex hormone-binding globulin levels in 30 male patients with HCV-related chronic liver disease. Degrees of hepatic fibrosis and steatosis were evaluated by the New Inuyama Classification and the classification proposed by Brunt and colleagues, respectively. Insulin resistance was estimated by HOMA-IR values. Serum total testosterone levels were independent of hepatic fibrosis staging in the enrolled patients. However, circulating sex hormone-binding globulin levels were significantly increased in proportion to the severity of hepatic fibrosis. Therefore, free androgen indices were inversely correlated with the severity of hepatic fibrosis. Moreover, free androgen indices were inversely correlated with the grades of hepatic steatosis and HOMA-IR values in those patients. Our data suggest that lower circulating free testosterone levels may be recognized as the risk factor for more advanced hepatic fibrosis, steatosis and/or higher insulin resistance in male patients with HCV-related chronic liver disease.
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Affiliation(s)
- Takashi Himoto
- Department of Medical Technology, Kagawa Prefectural University of Health Sciences, 281-1 Hara, Mure-Cho, Takamatsu, Kagawa 761-0123, Japan
| | - Koji Fujita
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki-Cho, Kagawa 761-0793, Japan
| | - Teppei Sakamoto
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki-Cho, Kagawa 761-0793, Japan
| | - Takako Nomura
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki-Cho, Kagawa 761-0793, Japan
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki-Cho, Kagawa 761-0793, Japan
| | - Hirohito Yoneyama
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki-Cho, Kagawa 761-0793, Japan
| | - Reiji Haba
- Department of Diagnosis Pathology, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki-Cho, Kagawa 761-0793, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki-Cho, Kagawa 761-0793, Japan
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27
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Abdel-Hamid NM, Abass SA, Mohamed AA, Muneam Hamid D. Herbal management of hepatocellular carcinoma through cutting the pathways of the common risk factors. Biomed Pharmacother 2018; 107:1246-1258. [PMID: 30257339 PMCID: PMC7127621 DOI: 10.1016/j.biopha.2018.08.104] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2018] [Revised: 08/11/2018] [Accepted: 08/15/2018] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is considered the most frequent tumor that associated with high mortality rate. Several risk factors contribute to the pathogenesis of HCC, such as chronic persistent infection with hepatitis C virus or hepatitis B virus, chronic untreated inflammation of liver with different etiology, oxidative stress and fatty liver disease. Several treatment protocols are used in the treatment of HCC but they also associated with diverse side effects. Many natural products are helpful in the co-treatment and prevention of HCC. Several mechanisms are involved in the action of these herbal products and their bioactive compounds in the prevention and co-treatment of HCC. They can inhibit the liver cancer development and progression in several ways as protecting against liver carcinogens, enhancing effects of chemotherapeutic drugs, inhibiting tumor cell growth and metastasis, and suppression of oxidative stress and chronic inflammation. In this review, we will discuss the utility of diverse natural products in the prevention and co-treatment of HCC, through its capturing of the common risk factors known to lead to HCC and shed the light on their possible mechanisms of action. Our theory assumes that shutting down the risk factor to cancer development pathways is a critical strategy in cancer prevention and management. We recommend the use of these plants side by side to recent chemical medications and after stopping these chemicals, as a maintenance therapy to avoid HCC progression and decrease its global incidence.
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Affiliation(s)
- Nabil M Abdel-Hamid
- Biochemistry Department, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, 33516, Egypt.
| | - Shimaa A Abass
- Biochemistry Department, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, 33516, Egypt
| | - Ahmed A Mohamed
- Biochemistry Department, Faculty of Pharmacy, Mansura University, Mansura, Egypt
| | - Daniah Muneam Hamid
- Biotechnology Department, Technical Medical Institute Al-Mansour, Middle Technological University, Baghdad, Iraq
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28
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Wu EM, Wong LL, Hernandez BY, Ji JF, Jia W, Kwee SA, Kalathil S. Gender differences in hepatocellular cancer: disparities in nonalcoholic fatty liver disease/steatohepatitis and liver transplantation. ACTA ACUST UNITED AC 2018; 4. [PMID: 30687780 PMCID: PMC6347119 DOI: 10.20517/2394-5079.2018.87] [Citation(s) in RCA: 110] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Aim: Worldwide, hepatocellular cancer (HCC) is the fourth leading cause of cancer death and occurs 3 times more commonly in males than females. Current surveillance practices do not fully address gender differences in HCC. Methods: Clinical characteristics and survival were compared between males and females using a prospectively collected database of HCC patients. Results: In a cohort of 1206 patients, 307 (25%) were female who presented with older age, more non-alcoholic fatty liver disease/steatohepatitis (NAFLD/NASH), family history of HCC, and hypertension. Males (75%) were more likely to use alcohol and cigarettes. Females were more likely to undergo HCC surveillance, have smaller tumor size at diagnosis, and less vascular involvement. Males who met Milan criteria were more likely to undergo liver transplant than women who met the criteria. Median/mean survival was similar between the genders. Multivariate analysis showed that NAFLD/NASH was predictive of mortality for both males and females, age and smoking were predictive of mortality for males, and transplant was predictive of survival for males. Conclusion: Gender differences in HCC appear related to both behavioral risk factors and biologic factors. Older females with HCC have more NAFLD/NASH and may be overlooked by current surveillance guidelines. These gender disparities may lend support to future studies of gender-based HCC screening.
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Affiliation(s)
- Eric M Wu
- Department of Surgery, University of Hawaii, John A. Burns School of Medicine, Hawaii, 96813, USA
| | - Linda L Wong
- Department of Surgery, University of Hawaii, John A. Burns School of Medicine, Hawaii, 96813, USA
| | | | - Jun-Fang Ji
- Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Wei Jia
- Cancer Center, University of Hawaii, Hawaii, 96813, USA
| | - Sandi A Kwee
- Cancer Center, University of Hawaii, Hawaii, 96813, USA
| | - Sumodh Kalathil
- Department of Medicine, University of Hawaii, John A. Burns School of Medicine, Hawaii, 96813, USA
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29
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Exemestane Attenuates Hepatic Fibrosis in Rats by Inhibiting Activation of Hepatic Stellate Cells and Promoting the Secretion of Interleukin 10. J Immunol Res 2017; 2017:3072745. [PMID: 29464186 PMCID: PMC5804406 DOI: 10.1155/2017/3072745] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2017] [Accepted: 10/23/2017] [Indexed: 01/07/2023] Open
Abstract
Exemestane (EXE) is an irreversible steroidal aromatase inhibitor mainly used as an adjuvant endocrine therapy for postmenopausal women suffering from breast cancer. Besides inhibiting aromatase activity, EXE has multiple biological functions, such as antiproliferation, anti-inflammatory, and antioxidant activities which are all involved in hepatic fibrosis. Therefore, we investigated the role of EXE during the progress of hepatic fibrosis. The effect of EXE on liver injury and fibrosis were assessed in two hepatic fibrosis rat models, which were induced by either carbon tetrachloride (CCl4) or bile duct ligation (BDL). The influence of EXE treatment on activation and proliferation of primary rat hepatic stellate cells (HSCs) was observed in vitro. The results showed that EXE attenuated the liver fibrosis by decreasing the collagen deposition and α-SMA expression in vivo and inhibited the activation and proliferation of primary rat HSCs in vitro. Additionally, EXE promoted the secretion of antifibrotic and anti-inflammatory cytokine IL-10 in vivo and in HSC-T6 culture media. In conclusion, our findings reveal a new function of EXE on hepatic fibrosis and prompted its latent application in liver fibrotic-related disease.
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30
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Lin M, Kramer J, White D, Cao Y, Tavakoli-Tabasi S, Madu S, Smith D, Asch SM, El-Serag HB, Kanwal F. Barriers to hepatitis C treatment in the era of direct-acting anti-viral agents. Aliment Pharmacol Ther 2017; 46:992-1000. [PMID: 28949020 PMCID: PMC5800315 DOI: 10.1111/apt.14328] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2017] [Revised: 05/22/2017] [Accepted: 08/26/2017] [Indexed: 01/04/2023]
Abstract
BACKGROUND Direct-acting anti-virals (DAA) are safe, effective treatment of hepatitis C virus (HCV). Suboptimal linkage to specialists and access to DAAs are the leading barriers to treatment; however, data are limited. AIM To determine predictors of follow-up, receipt of DAAs, and reasons for the lack thereof. METHODS We used clinical data from retrospective cohort of HCV-infected patients with previously established HCV care in the US Department of Veterans Affairs to examine predictors of follow-up in HCV clinics and DAA treatment (during 12/1/2013-4/30/2015). We then conducted a structured review of medical charts of HCV patients to determine reasons for lack of follow-up and treatment. RESULTS We identified 84 221 veterans who were previously seen in HCV clinics during the pre-DAA era. Of these, 47 165 (56.0%) followed-up in HCV specialty clinics, 13 532 (28.7%) of whom received DAAs. Older age, prior treatment, presence of cirrhosis or HCC, HIV/HBV co-infection and psychiatric illness were predictors of follow-up. Alcohol/drug abuse and medical co-morbidity were predictors of lack of treatment. Of the 905 prospectively recruited patients, 56.2% patients had a specialist visit and 28% received DAAs. Common reasons for lack of follow-up were relocation (n = 148, 37.4%) and missed/cancelled appointments (n = 63, 15.9%). Reasons for lack of treatment included waiting for newer therapy (n = 99, 38.8%), co-morbidities (n = 66, 25.9%) and alcohol/drug abuse (n = 63, 24.7%). CONCLUSIONS Half of patients with established HCV care were followed-up in the DAA era and only 29% received DAAs. Targeted efforts focusing on patient and system-levels may improve the reach of treatment with the new DAAs.
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Affiliation(s)
- Michael Lin
- Department of Gastroenterology and Hepatology, Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, Houston, TX, USA
| | - Jennifer Kramer
- Center of Innovation, Effectiveness and Quality, Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA,Sections of Health Services Research, Baylor College of Medicine, Houston, TX, USA
| | - Donna White
- Center of Innovation, Effectiveness and Quality, Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA,Sections of Health Services Research, Baylor College of Medicine, Houston, TX, USA
| | - Yumei Cao
- Center of Innovation, Effectiveness and Quality, Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA,Sections of Health Services Research, Baylor College of Medicine, Houston, TX, USA
| | - Shahriar Tavakoli-Tabasi
- Department of Infectious Diseases, Michael E. DeBakey Veterans Affairs Medical Center, Baylor College of Medicine, Houston, TX, USA
| | - Stella Madu
- Department of Gastroenterology and Hepatology, Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, Houston, TX, USA
| | - Donna Smith
- Department of Gastroenterology and Hepatology, Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, Houston, TX, USA,Center of Innovation, Effectiveness and Quality, Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA
| | - Steven M. Asch
- Center for Innovation to Implementation (Ci2i), Palo Alto Veterans Affairs Medical Center, Palo Alto, California,Division of General Medical Disciplines, Stanford University, Palo Alto, California
| | - Hashem B. El-Serag
- Department of Gastroenterology and Hepatology, Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, Houston, TX, USA,Center of Innovation, Effectiveness and Quality, Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA,Sections of Health Services Research, Baylor College of Medicine, Houston, TX, USA
| | - Fasiha Kanwal
- Department of Gastroenterology and Hepatology, Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, Houston, TX, USA,Center of Innovation, Effectiveness and Quality, Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA,Sections of Health Services Research, Baylor College of Medicine, Houston, TX, USA
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Rao H, Wu E, Fu S, Yang M, Feng B, Lin A, Fei R, Fontana RJ, Lok AS, Wei L. The higher prevalence of truncal obesity and diabetes in American than Chinese patients with chronic hepatitis C might contribute to more rapid progression to advanced liver disease. Aliment Pharmacol Ther 2017; 46:731-740. [PMID: 28833342 DOI: 10.1111/apt.14273] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2017] [Revised: 05/03/2017] [Accepted: 07/27/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND Chronic hepatitis C virus (HCV) infection is the leading cause of cirrhosis and hepatocellular carcinoma (HCC) in the United States (US) and an emerging cause in China. AIM To compare the clinical characteristics of hepatitis C patients in the US and China, and factors influencing disease stage. METHODS Prospective study of 2 cohorts of HCV patients recruited at 1 site in the US and 3 sites in China. Standardised questionnaire on risk factors and medical history were used and diagnosis of cirrhosis and HCC was based on pre-defined criteria. RESULTS One thousand nine hundred and fifty seven patients (1000 US and 957 China) were enrolled. US patients were more likely to be men (61.4% vs 48.5%), older (median age 57 vs 53 years), obese (38.4% vs 16.8%) and diabetic (21.8% vs 10.8%). A significantly higher per cent of US patients had cirrhosis (38.2% vs 16.0%) and HCC (14.1% vs 2.7%). Investigator estimated time at infection in US was 10 years earlier than in Chinese patients but US patients were more likely to have advanced disease even after stratifying for duration of infection. Study site in the US, older age, truncal obesity, diabetes and prior HCV treatment were significant predictors of advanced disease on multivariate analysis. CONCLUSIONS HCV patients in the US had more advanced liver disease than those in China. We speculate that underlying fatty liver disease may be a major contributor to this difference, and management of glycometabolic abnormalities should occur in parallel with anti-viral therapy to achieve optimal outcomes.
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Affiliation(s)
- H Rao
- Peking University Hepatology Institute, Peking University People's Hospital, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing, China
| | - E Wu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, USA
| | - S Fu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, USA
| | - M Yang
- Peking University Hepatology Institute, Peking University People's Hospital, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing, China
| | - B Feng
- Peking University Hepatology Institute, Peking University People's Hospital, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing, China
| | - A Lin
- The Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI, USA
| | - R Fei
- Peking University Hepatology Institute, Peking University People's Hospital, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing, China
| | - R J Fontana
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, USA
| | - A S Lok
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, USA
| | - L Wei
- Peking University Hepatology Institute, Peking University People's Hospital, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing, China
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Wang FP, Zhang PA, Yang XY. Relationship between sex hormones and RIG-I signaling in peripheral blood mononuclear cells of patients infected with hepatitis C virus. Exp Ther Med 2017; 14:2728-2732. [PMID: 28962219 DOI: 10.3892/etm.2017.4829] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2017] [Accepted: 07/14/2017] [Indexed: 01/22/2023] Open
Abstract
It has previously been suggested that men and women demonstrate differing immune responses to hepatitis C virus (HCV) infection, resulting in the investigation of the role of sex hormones and if they influence the anti-HCV response. The present study aimed to examine if hormone levels were associated with interferon (IFN) signaling pathways in peripheral blood mononuclear cells of 131 patients infected with HCV and 113 healthy controls. HCV infection was diagnosed based on the presence of anti-HCV antibodies and HCV RNA in serum. Expression of testosterone and estrogen was measured at the protein level using a competitive chemiluminescence immunoassay, and at the mRNA level using reverse transcription-quantitative polymerase chain reaction. HCV-infected males had increased levels of estrogen and a decreased ratio of testosterone to estrogen compared with healthy male controls (all P<0.001). HCV-infected patients demonstrated a significantly decreased expression of IFN and retinoic acid-induced gene protein I (RIG-I), RIG-I mRNA compared with controls. Pearson correlation analysis revealed that among males, levels of RIG-I correlated with levels of IFN-β mRNA (r=0.460), testosterone (r=-0.500), and the ratio of testosterone to estrogen (r=-0.477; all P<0.001). However, levels of RIG-I did not correlate with levels of IFN-α mRNA (r=0.158) or estrogen (r=0.173; both P>0.05). These results suggested that testosterone or the ratio of testosterone to estrogen may inhibit RIG-I signaling and thereby influence immune responses to HCV infection.
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Affiliation(s)
- Fang Ping Wang
- Department of Clinical Laboratory, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Ping An Zhang
- Department of Clinical Laboratory, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Xiao Yan Yang
- Department of Clinical Laboratory, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
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Magri A, Barbaglia MN, Foglia CZ, Boccato E, Burlone ME, Cole S, Giarda P, Grossini E, Patel AH, Minisini R, Pirisi M. 17,β-estradiol inhibits hepatitis C virus mainly by interference with the release phase of its life cycle. Liver Int 2017; 37:669-677. [PMID: 27885811 PMCID: PMC5448036 DOI: 10.1111/liv.13303] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2016] [Accepted: 10/31/2016] [Indexed: 12/16/2022]
Abstract
BACKGROUND & AIMS Oestrogen and oestrogen-mediated signalling protect from hepatitis C virus through incompletely understood mechanisms. We aimed to ascertain which phase(s) of hepatitis C virus life cycle is/are affected by oestrogens. METHODS Huh7 cells infected with the JFH1 virus (genotype 2a) were exposed to dehydroepiandrosterone, testosterone, progesterone and 17β-estradiol (tested with/without its receptor antagonist fulvestrant). Dose-response curves were established to calculate half maximal inhibitory concentration values. To dissect how 17β-estradiol interferes with phases of hepatitis C virus life cycle, its effects were measured on the hepatitis C virus pseudo-particle system (viral entry), the subgenomic replicon N17/JFH1 and the replicon cell line Huh7-J17 (viral replication). Finally, in a dual-step infection model, infectious supernatants, collected from infected cells exposed to hormones, were used to infect naïve cells. RESULTS Progesterone and testosterone showed no inhibitory effect on hepatitis C virus; dehydroepiandrosterone was only mildly inhibitory. In contrast, 17β-estradiol inhibited infection by 64%-67% (IC50 values 140-160 nmol/L). Fulvestrant reverted the inhibition by 17β-estradiol in a dose-dependent manner. 17β-estradiol exerted only a slight inhibition (<20%) on hepatitis C virus pseudo-particles, and had no effect on cells either transiently or stably (Huh7-J17 cells) expressing the N17/JFH1 replicon. In the dual-step infection model, a significant half maximal inhibitory concentration decline occurred between primary (134 nmol/L) and secondary (100 nmol/L) infections (P=.02), with extracellular hepatitis C virus RNA and infectivity being reduced to a higher degree in comparison to its intracellular counterpart. CONCLUSIONS 17β-estradiol inhibits hepatitis C virus acting through its intracellular receptors, mainly interfering with late phases (assembly/release) of the hepatitis C virus life cycle.
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Affiliation(s)
- Andrea Magri
- Department of Translational MedicineUniversità del Piemonte OrientaleNovaraItaly,MRC‐University of Glasgow Centre for Virus ResearchGlasgowUK
| | - Matteo N. Barbaglia
- Department of Translational MedicineUniversità del Piemonte OrientaleNovaraItaly
| | - Chiara Z. Foglia
- Department of Translational MedicineUniversità del Piemonte OrientaleNovaraItaly
| | - Elisa Boccato
- Department of Translational MedicineUniversità del Piemonte OrientaleNovaraItaly
| | - Michela E. Burlone
- Department of Translational MedicineUniversità del Piemonte OrientaleNovaraItaly,CRRF Mons. Luigi NovareseMoncrivelloVercelliItaly
| | - Sarah Cole
- MRC‐University of Glasgow Centre for Virus ResearchGlasgowUK
| | - Paola Giarda
- Department of Translational MedicineUniversità del Piemonte OrientaleNovaraItaly
| | - Elena Grossini
- Department of Translational MedicineUniversità del Piemonte OrientaleNovaraItaly
| | - Arvind H. Patel
- MRC‐University of Glasgow Centre for Virus ResearchGlasgowUK
| | - Rosalba Minisini
- Department of Translational MedicineUniversità del Piemonte OrientaleNovaraItaly
| | - Mario Pirisi
- Department of Translational MedicineUniversità del Piemonte OrientaleNovaraItaly
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AR-Signaling in Human Malignancies: Prostate Cancer and Beyond. Cancers (Basel) 2017; 9:cancers9010007. [PMID: 28085048 PMCID: PMC5295778 DOI: 10.3390/cancers9010007] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Revised: 01/04/2017] [Accepted: 01/05/2017] [Indexed: 12/11/2022] Open
Abstract
In the 1940s Charles Huggins reported remarkable palliative benefits following surgical castration in men with advanced prostate cancer, and since then the androgen receptor (AR) has remained the main therapeutic target in this disease. Over the past couple of decades, our understanding of AR-signaling biology has dramatically improved, and it has become apparent that the AR can modulate a number of other well-described oncogenic signaling pathways. Not surprisingly, mounting preclinical and epidemiologic data now supports a role for AR-signaling in promoting the growth and progression of several cancers other than prostate, and early phase clinical trials have documented preliminary signs of efficacy when AR-signaling inhibitors are used in several of these malignancies. In this article, we provide an overview of the evidence supporting the use of AR-directed therapies in prostate as well as other cancers, with an emphasis on the rationale for targeting AR-signaling across tumor types.
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Natarajan Y, White DL, El-Serag HB, Ramsey D, Richardson P, Kuzniarek J, Shukla R, Tansel A, Kanwal F. Role of Non-hepatic Medical Comorbidity and Functional Limitations in Predicting Mortality in Patients with HCV. Dig Dis Sci 2017; 62:76-83. [PMID: 27655101 DOI: 10.1007/s10620-016-4303-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2016] [Accepted: 09/07/2016] [Indexed: 01/05/2023]
Abstract
BACKGROUND Medical comorbidities and functional status limitations are determinants of mortality in many chronic diseases. The extent to which survival in the rapidly aging cohort of patients with HCV is affected by these competing causes of mortality remains unclear. AIM We sought to determine the effect of medical/functional comorbidities on survival after adjusting for liver disease severity in a cohort of patients with HCV infection. METHODS We prospectively recruited consecutive patients from an HCV clinic 2009-2014. We calculated an index of survival (Schonberg Index, SI) based on age, gender, medical comorbidities, and functional status variables. We defined cirrhosis with the FibroSure test (F3/4-F4). We used multivariable Cox modeling to assess association between functional/survival measure and survival after adjustment for severity of liver disease. RESULTS The cohort consisted of 1052 HCV patients. The average age was 56.8 years; 36 % had cirrhosis. The mean SI was 8.2 (SD = 2.7). During a mean follow-up of 5610 person-years, 102 (9.7 %) patients died. In unadjusted analysis, higher baseline SI predicted mortality (HR 1.17; 95 % CI 1.09-1.25). SI similarly predicted mortality in cirrhotic patients (HR 1.23, 95 % CI 1.13-1.34) and non-cirrhotic patients (HR 1.21, 95 % CI 1.08-1.36). This did not change after adjusting for age, drug use, or coronary artery disease. DISCUSSION Comorbidities and functional limitations predict higher mortality in patients with HCV; this relationship is independent of cirrhosis. Use of general prognostic indices may help identify HCV patients at high risk for mortality, which could further guide clinical care in a manner not achievable with assessment of liver disease alone.
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Affiliation(s)
- Yamini Natarajan
- Section of Gastroenterology and Hepatology, Michael E. DeBakey VA Medical Center and Baylor College of Medicine, Houston, TX, USA.
| | - Donna L White
- Section of Gastroenterology and Hepatology, Michael E. DeBakey VA Medical Center and Baylor College of Medicine, Houston, TX, USA.,Clinical Epidemiology and Comparative Effectiveness Program, Section of Health Services Research (IQuESt), Michael E. DeBakey VA Medical Center and Baylor College of Medicine, Houston, TX, USA.,Texas Medical Center Digestive Disease Center, Houston, TX, USA.,Dan L. Duncan Cancer Center at Baylor College of Medicine, Houston, TX, USA.,Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA
| | - Hashem B El-Serag
- Section of Gastroenterology and Hepatology, Michael E. DeBakey VA Medical Center and Baylor College of Medicine, Houston, TX, USA.,Clinical Epidemiology and Comparative Effectiveness Program, Section of Health Services Research (IQuESt), Michael E. DeBakey VA Medical Center and Baylor College of Medicine, Houston, TX, USA.,Texas Medical Center Digestive Disease Center, Houston, TX, USA.,Dan L. Duncan Cancer Center at Baylor College of Medicine, Houston, TX, USA
| | - David Ramsey
- Clinical Epidemiology and Comparative Effectiveness Program, Section of Health Services Research (IQuESt), Michael E. DeBakey VA Medical Center and Baylor College of Medicine, Houston, TX, USA
| | - Peter Richardson
- Clinical Epidemiology and Comparative Effectiveness Program, Section of Health Services Research (IQuESt), Michael E. DeBakey VA Medical Center and Baylor College of Medicine, Houston, TX, USA
| | - Jill Kuzniarek
- Clinical Epidemiology and Comparative Effectiveness Program, Section of Health Services Research (IQuESt), Michael E. DeBakey VA Medical Center and Baylor College of Medicine, Houston, TX, USA
| | - Richa Shukla
- Section of Gastroenterology and Hepatology, Michael E. DeBakey VA Medical Center and Baylor College of Medicine, Houston, TX, USA
| | - Aylin Tansel
- Section of Gastroenterology and Hepatology, Michael E. DeBakey VA Medical Center and Baylor College of Medicine, Houston, TX, USA
| | - Fasiha Kanwal
- Section of Gastroenterology and Hepatology, Michael E. DeBakey VA Medical Center and Baylor College of Medicine, Houston, TX, USA.,Clinical Epidemiology and Comparative Effectiveness Program, Section of Health Services Research (IQuESt), Michael E. DeBakey VA Medical Center and Baylor College of Medicine, Houston, TX, USA.,Texas Medical Center Digestive Disease Center, Houston, TX, USA.,Dan L. Duncan Cancer Center at Baylor College of Medicine, Houston, TX, USA
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Balogh J, Victor D, Asham EH, Burroughs SG, Boktour M, Saharia A, Li X, Ghobrial RM, Monsour HP. Hepatocellular carcinoma: a review. J Hepatocell Carcinoma 2016; 3:41-53. [PMID: 27785449 PMCID: PMC5063561 DOI: 10.2147/jhc.s61146] [Citation(s) in RCA: 798] [Impact Index Per Article: 88.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and is a leading cause of cancer-related death worldwide. In the United States, HCC is the ninth leading cause of cancer deaths. Despite advances in prevention techniques, screening, and new technologies in both diagnosis and treatment, incidence and mortality continue to rise. Cirrhosis remains the most important risk factor for the development of HCC regardless of etiology. Hepatitis B and C are independent risk factors for the development of cirrhosis. Alcohol consumption remains an important additional risk factor in the United States as alcohol abuse is five times higher than hepatitis C. Diagnosis is confirmed without pathologic confirmation. Screening includes both radiologic tests, such as ultrasound, computerized tomography, and magnetic resonance imaging, and serological markers such as α-fetoprotein at 6-month intervals. Multiple treatment modalities exist; however, only orthotopic liver transplantation (OLT) or surgical resection is curative. OLT is available for patients who meet or are downstaged into the Milan or University of San Francisco criteria. Additional treatment modalities include transarterial chemoembolization, radiofrequency ablation, microwave ablation, percutaneous ethanol injection, cryoablation, radiation therapy, systemic chemotherapy, and molecularly targeted therapies. Selection of a treatment modality is based on tumor size, location, extrahepatic spread, and underlying liver function. HCC is an aggressive cancer that occurs in the setting of cirrhosis and commonly presents in advanced stages. HCC can be prevented if there are appropriate measures taken, including hepatitis B virus vaccination, universal screening of blood products, use of safe injection practices, treatment and education of alcoholics and intravenous drug users, and initiation of antiviral therapy. Continued improvement in both surgical and nonsurgical approaches has demonstrated significant benefits in overall survival. While OLT remains the only curative surgical procedure, the shortage of available organs precludes this therapy for many patients with HCC.
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Affiliation(s)
- Julius Balogh
- Sherrie and Alan Conover Center for Liver Disease and Transplantation
- Division of Transplantation, Department of Surgery
| | - David Victor
- Sherrie and Alan Conover Center for Liver Disease and Transplantation
- Department of Gastroenterology and Transplant Hepatology
- Department of Medicine, Houston Methodist Hospital, Houston, TX, USA
| | - Emad H Asham
- Sherrie and Alan Conover Center for Liver Disease and Transplantation
- Division of Transplantation, Department of Surgery
| | - Sherilyn Gordon Burroughs
- Sherrie and Alan Conover Center for Liver Disease and Transplantation
- Division of Transplantation, Department of Surgery
| | - Maha Boktour
- Sherrie and Alan Conover Center for Liver Disease and Transplantation
- Division of Transplantation, Department of Surgery
| | - Ashish Saharia
- Sherrie and Alan Conover Center for Liver Disease and Transplantation
- Division of Transplantation, Department of Surgery
| | - Xian Li
- Sherrie and Alan Conover Center for Liver Disease and Transplantation
- Division of Transplantation, Department of Surgery
| | - R Mark Ghobrial
- Sherrie and Alan Conover Center for Liver Disease and Transplantation
- Division of Transplantation, Department of Surgery
| | - Howard P Monsour
- Sherrie and Alan Conover Center for Liver Disease and Transplantation
- Department of Gastroenterology and Transplant Hepatology
- Department of Medicine, Houston Methodist Hospital, Houston, TX, USA
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Pastore F, Martocchia A, Stefanelli M, Prunas P, Giordano S, Toussan L, Devito A, Falaschi P. Hepatitis C virus infection and thyroid autoimmune disorders: A model of interactions between the host and the environment. World J Hepatol 2016; 8:83-91. [PMID: 26807204 PMCID: PMC4716530 DOI: 10.4254/wjh.v8.i2.83] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 10/28/2015] [Accepted: 12/04/2015] [Indexed: 02/06/2023] Open
Abstract
The hepatitis C virus (HCV) infection is an important public health problem and it is associated with hepatic and extrahepatic manifestations. Autoimmune thyroid diseases are common in HCV infected patients and the standard interferon-based treatment is associated with an increase of the immune-mediated thyroid damage. Recent evidence in the literature analyzed critical points of the mechanisms of thyroid damage, focusing on the balance between the two sides of the interaction: The environment (virus infection with potential cross-reaction) and the host (susceptibility genes with consistent immune response). The spectrum of antiviral treatment for chronic HCV infection is rapidly expanding for the development of dual o triple therapy. The availability of interferon-free combined treatment with direct antiviral agents for HCV is very promising, in order to ameliorate the patient compliance and to reduce the development of thyroid autoimmunity.
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Reiss CS. Innate Immunity in Viral Encephalitis. NEUROTROPIC VIRAL INFECTIONS 2016. [PMCID: PMC7153449 DOI: 10.1007/978-3-319-33189-8_8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Affiliation(s)
- Carol Shoshkes Reiss
- Departments of Biology and Neural Science, New York University, New York, New York USA
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40
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Acquired Hypogonadotropic Hypogonadism (AHH) in Thalassaemia Major Patients: An Underdiagnosed Condition? Mediterr J Hematol Infect Dis 2016; 8:e2016001. [PMID: 26740862 PMCID: PMC4696472 DOI: 10.4084/mjhid.2016.001] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2015] [Accepted: 11/18/2015] [Indexed: 11/08/2022] Open
Abstract
INTRODUCTION In males, acquired hypogonadotropic hypogonadism (AHH) includes all disorders that damage or alter the function of gonadotropin-releasing hormone (GnRH) neurons and/or pituitary gonadotroph cells. The clinical characteristics of AHH are androgen deficiency and lack, delay or halt of pubertal sexual maturation. AHH lead to decreased libido, impaired erectile function, and strength, a worsened sense of well-being and degraded quality of life (QOL). PATIENTS AND METHODS We studied 11 adult men with thalassemia major (TM) aged between 26 to 54 years (mean ± SD: 34.3 ± 8.8 years) with AHH. Twelve age- and sex-matched TM patients with normal pubertal development were used as a control group. All patients were on regular transfusions and iron chelation therapy. Fasting venous blood samples were collected two weeks after transfusion to measure serum concentrations of IGF-1, free thyroxine (FT4), thyrotropin (TSH), cortisol, luteinizing hormone (LH), follicle stimulating hormone (FSH), total testosterone (TT), prolactin and estradiol (E2), glucose, urea, creatinine and electrolytes (including calcium and phosphate). Liver functions and screening for hepatitis C virus seropositivity (HCVab and HCV-RNA) were performed. Iron status was assessed by measuring serum ferritin levels, and evaluation of iron concentrations in the liver (LIC) and heart using MRI- T2*. Bone mineral density was measured at the lumbar spine (L1-L4) for all patients with AHH by dual energy X-ray absorptiometry (DXA) using Hologic QDR 4000 machine. RESULTS The mean basal serum LH and FSH concentrations in AHH patients were 2.4 ± 2.2 IU/L and 1.2 ± 0.9 IU/L respectively; these, values were significantly lower compared to the control group. Semen analysis in 5 patients with AHH showed azoospermia in 3 and oligoasthenozoospermia in 2. The percentage of patients with serum ferritin level >2000 ng/ml (severe iron load) was significantly higher in AHH patients compared to controls, 5/11 (45.4 %) versus1/12 (8.3%), p=0.043. Heart iron concentrations (T2* values) were significantly lower in AHH patients compared to controls (p=0.004). Magnetic resonance imaging in the 3 azoospermic patients revealed volume loss and reduction of pituitary signal intensity. Heart T2* values were significantly reduced in the AHH group vs. the controls (p=0.004). On the other hand, liver iron concentration (mg/g dry weight) was not different between the two groups of TM patients. Using DXA, 63.6 % (7/11) of patients with AHH were osteoporotic, and 36.3 % (4/11) were osteopenic. CONCLUSIONS In this cohort of thalassemic patients iron overload and chronic liver disease appear to play a role in the development of AHH. Treatment of AHH in TM patients is a vital and dynamic field for improving their health and QOL. Early identification and management of AHH are very crucial to avoid long-term morbidity, including sexual dysfunction and infertility. Therapy aims to restore serum testosterone levels to the mid-normal range. Many exciting opportunities remain for further research and therapeutic development.
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Abstract
Hepatitis C infection is a common cause of cirrhosis and indication for liver transplantation in the United States. The incidence of chronic hepatitis C has been declining, but rates of cirrhosis and hepatocellular carcinoma are projected to increase. The outcome of chronic hepatitis C is variable. It is estimated that 20% to 25% will develop cirrhosis over a 25-year to 30-year period. The rate of disease progression is influenced by many host, viral, and environmental factors. Few can be modified.
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Steffens JP, Wang X, Starr JR, Spolidorio LC, Van Dyke TE, Kantarci A. Associations Between Sex Hormone Levels and Periodontitis in Men: Results From NHANES III. J Periodontol 2015; 86:1116-25. [DOI: 10.1902/jop.2015.140530] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
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Association Between Endogenous Sex Hormones and Liver Fat in a Multiethnic Study of Atherosclerosis. Clin Gastroenterol Hepatol 2015; 13:1686-93.e2. [PMID: 25592661 PMCID: PMC4500744 DOI: 10.1016/j.cgh.2014.12.033] [Citation(s) in RCA: 72] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2014] [Revised: 12/05/2014] [Accepted: 12/24/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Levels of circulating of sex hormones are associated with glucose metabolism and adiposity, but little is known about their association with ectopic fat. We aimed to characterize the association between circulating sex hormones and liver fat. METHODS We conducted a cross-sectional analysis by using data from the Multiethnic Study of Atherosclerosis to assess the association of the circulating levels of bioavailable testosterone, estradiol, dehydroepiandrosterone, and sex hormone binding globulin (SHBG) with fatty liver. Fatty liver was defined as a reduction of ≤40 Hounsfield units, measured by computed tomography, in 2835 postmenopausal women and 2899 men (45-84 years old; white, black, Hispanic, or Chinese) at 6 centers in the United States. RESULTS Women in the highest tertile of bioavailable testosterone were significantly more likely to have fatty liver than women in the lowest tertile (odds ratio, 1.77; 95% confidence interval, 1.07-2.92). We found an even greater difference for level of estradiol (odds ratio, 2.49; 95% confidence interval, 1.41-4.39) after adjusting for age, race/ethnicity, waist-to-hip ratio, hypertension, total and high-density lipoprotein cholesterol, smoking, insulin sensitivity, and hormone replacement therapy use. Men in the highest tertile of estradiol level were significantly more likely to have fatty liver than men in the lowest tertile (odds ratio, 2.10; 95% confidence level, 1.29-3.40). Men in the highest tertile of SHBG were less likely to have fatty liver than those in the lowest tertile (odds ratio, 0.46; 95% confidence interval, 0.27-0.77). Other associations between hormone levels and fatty liver were not statistically significant. CONCLUSIONS On the basis of a cross-sectional study, postmenopausal women with high levels of bioavailable testosterone are at greater risk for fatty liver. In men, higher levels of SHBG are associated with reduced risk for fatty liver. Higher levels of estradiol are associated with fatty liver in both sexes. This pattern is consistent with the sex-specific associations of sex hormones with other cardiometabolic risk factors.
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Female Sex Hormones Pattern and Its Relation to Disease Severity and Treatment in Pre- and Postmenopausal Patients with Chronic Hepatitis C Virus (Genotype 4) Infection. Int J Chronic Dis 2015; 2015:927974. [PMID: 26464874 PMCID: PMC4590939 DOI: 10.1155/2015/927974] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2015] [Revised: 08/04/2015] [Accepted: 08/05/2015] [Indexed: 01/09/2023] Open
Abstract
Chronic hepatitis C (CHC) course revealed differences between men and women. Male gender and postmenopausal women are thought to be of the critical factors affecting HCV infection progression. The study aimed to assess female sex hormones and their relation to disease severity and treatment in HCV infected females. Subjects were divided to 2 groups: 44 CHC female patients and 44 controls. Both groups were classified to premenopausal and postmenopausal females. Serum estradiol (E2), progesterone (PRG), and total testosterone (TT) were assessed using chemiluminescent immunoassay. Our results showed that menopausal patients had significantly higher levels of estradiol, total testosterone, and progesterone compared to controls (P < 0.001). Reproductive aged patients had lower level of total testosterone compared to menopausal patients (P < 0.001). HCV infected females of reproductive age had higher level of progesterone compared to menopausal HCV infected females (P = 0.0014). Indicators of disease severity and treatment response were significantly worse in menopausal women compared to reproductive aged women (fibrosis: P < 0.001, activity: P = 0.045, and treatment: P < 0.001). We observed that lower estradiol level may be related to fibrosis severity in CHC females. Higher total testosterone and progesterone levels may be related to fibrosis severity and poor response to treatment in CHC menopausal females only.
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Khalaf N, White D, Kanwal F, Ramsey D, Mittal S, Tavakoli-Tabasi S, Kuzniarek J, El-Serag HB. Coffee and Caffeine Are Associated With Decreased Risk of Advanced Hepatic Fibrosis Among Patients With Hepatitis C. Clin Gastroenterol Hepatol 2015; 13:1521-31.e3. [PMID: 25777972 DOI: 10.1016/j.cgh.2015.01.030] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2014] [Revised: 01/12/2015] [Accepted: 01/28/2015] [Indexed: 12/23/2022]
Abstract
BACKGROUND & AIMS Coffee or caffeine has been proposed to protect against hepatic fibrosis, but few data are available on their effects in patients with chronic hepatitis C virus (HCV) infection. METHODS We conducted a cross-sectional study of veterans with chronic HCV infection to evaluate the association between daily intake of caffeinated and decaffeinated coffee, tea, and soda, and level of hepatic fibrosis, based on the FibroSURE test (BioPredictive, Paris, France) (F0-F3, mild [controls] vs. F3/F4-F4, advanced). Models were adjusted for multiple potential confounders including age, alcohol abuse, and obesity. RESULTS Among 910 patients with chronic HCV infection, 98% were male and 38% had advanced hepatic fibrosis. Daily intake of caffeinated coffee was higher among controls than patients with advanced fibrosis (1.37 vs. 1.05 cups/d; P = .038). In contrast, daily intake of caffeinated tea (0.61 vs. 0.56 cups/d; P = .651) or soda (1.14 vs. 0.95 cans/d; P = .106) did not differ between the groups. A higher percentage of controls (66.0%) than patients with advanced fibrosis (57.9%) consumed 100 mg or more of caffeine daily from all sources (P = .014); controls also received a larger proportion of their caffeine from coffee (50.2% vs. 43.0%; P = .035). Hepatoprotective effects of an average daily intake of 100 mg or more of caffeine (adjusted odds ratio, 0.71; 95% confidence interval, 0.53-0.95; P = .020) and 1 cup or more of caffeinated tea by non-coffee drinkers (adjusted odds ratio, 0.56; 95% confidence interval, 0.34-0.94; P = .028) persisted after adjustment for confounders, including insulin resistance. CONCLUSIONS A modest daily caffeine intake (as little as 100 mg) may protect against advanced hepatic fibrosis in men with chronic HCV infection. Additional research is needed to confirm these findings in women and in people with other chronic liver diseases.
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Affiliation(s)
- Natalia Khalaf
- Section of Gastroenterology and Hepatology, Michael E. DeBakey VA Medical Center and Baylor College of Medicine, Houston, Texas; Section of Health Services Research, Michael E. DeBakey VA Medical Center and Baylor College of Medicine, Houston, Texas
| | - Donna White
- Section of Gastroenterology and Hepatology, Michael E. DeBakey VA Medical Center and Baylor College of Medicine, Houston, Texas; Section of Health Services Research, Michael E. DeBakey VA Medical Center and Baylor College of Medicine, Houston, Texas
| | - Fasiha Kanwal
- Section of Gastroenterology and Hepatology, Michael E. DeBakey VA Medical Center and Baylor College of Medicine, Houston, Texas; Section of Health Services Research, Michael E. DeBakey VA Medical Center and Baylor College of Medicine, Houston, Texas
| | - David Ramsey
- Section of Gastroenterology and Hepatology, Michael E. DeBakey VA Medical Center and Baylor College of Medicine, Houston, Texas; Section of Health Services Research, Michael E. DeBakey VA Medical Center and Baylor College of Medicine, Houston, Texas
| | - Sahil Mittal
- Section of Gastroenterology and Hepatology, Michael E. DeBakey VA Medical Center and Baylor College of Medicine, Houston, Texas; Section of Health Services Research, Michael E. DeBakey VA Medical Center and Baylor College of Medicine, Houston, Texas
| | - Shahriar Tavakoli-Tabasi
- Section of Infectious Diseases, Michael E. DeBakey VA Medical Center and Baylor College of Medicine, Houston, Texas
| | - Jill Kuzniarek
- Section of Health Services Research, Michael E. DeBakey VA Medical Center and Baylor College of Medicine, Houston, Texas
| | - Hashem B El-Serag
- Section of Gastroenterology and Hepatology, Michael E. DeBakey VA Medical Center and Baylor College of Medicine, Houston, Texas; Section of Health Services Research, Michael E. DeBakey VA Medical Center and Baylor College of Medicine, Houston, Texas.
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Kanwal F, White DL, Jiao L, Tavakoli-Tabasi S, Sansgiry S, Ramsey DJ, Kuzniarek J, Spiegelman A, El-Serag HB. Genetic Variants in Interleukin-28B Are Associated with Diabetes and Diabetes-Related Complications in Patients with Chronic Hepatitis C Virus Infection. Dig Dis Sci 2015; 60:2030-7. [PMID: 25663241 DOI: 10.1007/s10620-015-3545-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2014] [Accepted: 01/19/2015] [Indexed: 12/16/2022]
Abstract
BACKGROUND Few studies have shown that host interleukin-28B (IL28B) genetic polymorphisms are associated with insulin resistance in patients with chronic hepatitis C virus (HCV) infection. However, the clinical relevance of this relationship is unclear. AIMS We examined the association between IL28B genotype for rs12980275 and risk of type 2 diabetes and diabetes-related complications. METHODS We used a cross-sectional study of prospectively recruited male veterans with chronic HCV. We employed logistic regression analysis and adjusted for patients' age, race, body mass index, and hepatic fibrosis. RESULTS A total of 528 participants were recruited (mean age 59.1 years; 38.5 % African-American; 40.3 % advanced fibrosis). Of these, 36.1 % were homozygous for favorable AA allele for rs12980275, 49.0 % were heterozygous (AG), and 14.0 % were homozygous for the unfavorable allele (GG). Prevalence of diabetes was significantly lower in patients with both favorable alleles (AA) than that with at least one unfavorable IL28B G allele (21.1 vs. 30.2 %, p = 0.02). Similarly, patients who were homozygous for the favorable alleles had lower prevalence of diabetes-related complications than patients with any unfavorable IL28B allele (5.7 vs. 12.2 %, p = 0.01). This association did not change after adjusting for sociodemographic characteristics, body mass index, and stage of hepatic fibrosis (adjusted ORdiabetes 0.56, 95 % CI 0.35-0.89; ORdiabetes-related complications 0.47, 95 % CI 0.23-0.96). CONCLUSIONS Patients who have favorable AA IL28B alleles have a lower prevalence of diabetes and related complications compared with patients with unfavorable IL28B rs12980275 genotype. IL28B genotype information may be used to counsel HCV patients regarding their individualized risk of diabetes and diabetes-related complications.
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Affiliation(s)
- Fasiha Kanwal
- Clinical Epidemiology and Comparative Effectiveness Program, Section of Health Services Research (IQuESt), Michael E. DeBakey VA Medical Center, Baylor College of Medicine, Houston, TX, USA
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Popp W, Gantumur T, Ross B, Zorigt K, Davaadorj D, Rossburg M, Sowa JP, Canbay A. Aflatoxin exposure may not play a role in liver cancer development in Mongolia. Digestion 2015; 89:268-71. [PMID: 25011557 DOI: 10.1159/000362229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND/AIMS The incidence of hepatocellular carcinoma (HCC) in Mongolia is growing at an alarming rate. Traditional dried food was suggested as the major reason for high HCC numbers, due to possible aflatoxin contamination during manufacturing. We thus aimed to measure aflatoxin concentrations in Mongolian food samples. METHODS Samples of traditional Mongolian food ('aaruul', dried meat, and dried noodles; in total 11 samples) were collected and shipped to Germany. The food samples were analyzed for aflatoxins by extraction, immunoaffinity purification, and subsequent HPLC with fluorescence detection. RESULTS The traditional Mongolian food samples did not contain any detectable amounts of aflatoxin. CONCLUSION Since Mongolian food does not contain aflatoxins, the cause for the increasing HCC incidence in Mongolia is probably due to a high prevalence of viral hepatitides. Further studies to identify the reason for this development are warranted.
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Affiliation(s)
- Walter Popp
- Institute for Hygiene, University Hospital, University Duisburg-Essen, Essen, Germany
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White DL, Liu Y, Garcia J, El-Serag HB, Jiao L, Tsavachidis S, Franco LM, Lee JS, Tavakoli-Tabasi S, Moore D, Goldman R, Kuzniarek J, Ramsey DJ, Kanwal F, Marcelli M. Sex hormone pathway gene polymorphisms are associated with risk of advanced hepatitis C-related liver disease in males. INTERNATIONAL JOURNAL OF MOLECULAR EPIDEMIOLOGY AND GENETICS 2014; 5:164-76. [PMID: 25379136 PMCID: PMC4214264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Subscribe] [Scholar Register] [Received: 09/10/2014] [Accepted: 09/18/2014] [Indexed: 06/04/2023]
Abstract
BACKGROUND Males have excess advanced liver disease and cirrhosis risk including from chronic hepatitis C virus (HCV) infection though the reasons are unclear. GOAL To examine the role variants in genes involved in androgen and estrogen biosynthesis and metabolism play in HCV-related liver disease risk in males. METHODS We performed a cross-sectional study evaluating single nucleotide polymorphisms (SNPs) in 16 candidate genes involved in androgen and estrogen ligand and receptor synthesis and risk of advanced hepatic fibrosis (F3/F4-F4) and inflammation (A2/A3-A3). We calculated adjusted odds ratios (ORs) using logistic regression and used multifactor dimensionality reduction (MDR) analysis to assess for gene-environment interaction. RESULTS Among 466 chronically HCV-infected males, 59% (n = 274) had advanced fibrosis and 54% (n = 252) had advanced inflammation. Nine of 472 SNPs were significantly associated with fibrosis risk; 4 in AKR1C3 (e.g., AKR1C3 rs2186174: ORadj = 2.04, 95% CI 1.38-3.02), 1 each in AKR1C2 and ESR1, and 1 in HSD17B6. Four SNPs were associated with inflammation risk, 2 in SRD5A1 (e.g., SRD5A1 rs248800: ORadj = 1.86, 95% CI 1.20-2.88) and 1 each in AKR1C2 and AKR1C3. MDR analysis identified a single AKR1C3 locus (rs2186174) as the best model for advanced fibrosis; while a 4-locus model with diabetes, AKR1C2 rs12414884, SRD5A1 rs6555406, and SRD5A1 rs248800 was best for inflammation. CONCLUSIONS The consistency of our findings suggests AKR1C isoenzymes 2 and 3, and potentially SRD5A1, may play a role in progression of HCV-related liver disease in males. Future studies are needed to validate these findings and to assess if similar associations exist in females.
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Affiliation(s)
- Donna L White
- Clinical Epidemiology and Comparative Effectiveness Program, Section of Health Services Research (IQuESt), Michael E. DeBakey VA Medical Center and Baylor College of MedicineHouston, TX, USA
- Texas Medical Center Digestive Disease CenterHouston, TX, USA
- Dan L. Duncan Cancer Center at Baylor College of MedicineHouston, TX, USA
- Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey Veterans Affairs Medical CenterHouston, TX, USA
| | - Yanhong Liu
- Dan L. Duncan Cancer Center at Baylor College of MedicineHouston, TX, USA
- Department of Pediatrics, Baylor College of MedicineHouston, TX, USA
| | - Jose Garcia
- Dan L. Duncan Cancer Center at Baylor College of MedicineHouston, TX, USA
- Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey Veterans Affairs Medical CenterHouston, TX, USA
- Section of Endocrinology, Michael E. DeBakey VA Medical Center and Baylor College of MedicineHouston, TX, USA
| | - Hashem B El-Serag
- Section of Gastroenterology and Hepatology, Michael E. DeBakey VA Medical Center and Baylor College of MedicineHouston, TX, USA
- Clinical Epidemiology and Comparative Effectiveness Program, Section of Health Services Research (IQuESt), Michael E. DeBakey VA Medical Center and Baylor College of MedicineHouston, TX, USA
- Texas Medical Center Digestive Disease CenterHouston, TX, USA
- Dan L. Duncan Cancer Center at Baylor College of MedicineHouston, TX, USA
| | - Li Jiao
- Section of Gastroenterology and Hepatology, Michael E. DeBakey VA Medical Center and Baylor College of MedicineHouston, TX, USA
- Clinical Epidemiology and Comparative Effectiveness Program, Section of Health Services Research (IQuESt), Michael E. DeBakey VA Medical Center and Baylor College of MedicineHouston, TX, USA
- Texas Medical Center Digestive Disease CenterHouston, TX, USA
- Dan L. Duncan Cancer Center at Baylor College of MedicineHouston, TX, USA
- Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey Veterans Affairs Medical CenterHouston, TX, USA
| | - Spiridon Tsavachidis
- Dan L. Duncan Cancer Center at Baylor College of MedicineHouston, TX, USA
- Department of Pediatrics, Baylor College of MedicineHouston, TX, USA
| | - Luis M Franco
- Department of Molecular and Human Genetics, Baylor College of MedicineHouston, TX, USA
| | - Ju-Seog Lee
- Department of Systems Biology, MD Anderson Cancer CenterHouston, TX, USA
| | - Shahriar Tavakoli-Tabasi
- Section of Infectious Diseases, Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of MedicineHouston, TX, USA
| | - David Moore
- Department Molecular and Cell Biology and Department of Medicine, Baylor College of MedicineHouston, TX, USA
| | - Radoslav Goldman
- Department of Oncology, Georgetown University Medical CenterWashington, DC, USA
| | - Jill Kuzniarek
- Clinical Epidemiology and Comparative Effectiveness Program, Section of Health Services Research (IQuESt), Michael E. DeBakey VA Medical Center and Baylor College of MedicineHouston, TX, USA
| | - David J Ramsey
- Clinical Epidemiology and Comparative Effectiveness Program, Section of Health Services Research (IQuESt), Michael E. DeBakey VA Medical Center and Baylor College of MedicineHouston, TX, USA
| | - Fasiha Kanwal
- Section of Gastroenterology and Hepatology, Michael E. DeBakey VA Medical Center and Baylor College of MedicineHouston, TX, USA
- Clinical Epidemiology and Comparative Effectiveness Program, Section of Health Services Research (IQuESt), Michael E. DeBakey VA Medical Center and Baylor College of MedicineHouston, TX, USA
- Texas Medical Center Digestive Disease CenterHouston, TX, USA
- Dan L. Duncan Cancer Center at Baylor College of MedicineHouston, TX, USA
| | - Marco Marcelli
- Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey Veterans Affairs Medical CenterHouston, TX, USA
- Section of Endocrinology, Michael E. DeBakey VA Medical Center and Baylor College of MedicineHouston, TX, USA
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Kanda T, Jiang X, Yokosuka O. Androgen receptor signaling in hepatocellular carcinoma and pancreatic cancers. World J Gastroenterol 2014; 20:9229-9236. [PMID: 25071315 PMCID: PMC4110552 DOI: 10.3748/wjg.v20.i28.9229] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2014] [Revised: 03/07/2014] [Accepted: 04/30/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) and pancreatic cancer remain difficult to treat, and despite the ongoing development of new treatments, the overall survival rate has only modestly improved over the past decade. Liver and pancreatic progenitors commonly develop from endoderm cells in the embryonic foregut. A previous study showed that HCC and pancreatic cancer cell lines variably express androgen receptor (AR), and these cancers and the surrounding tissues also express AR. AR is a ligand-dependent transcription factor that belongs to the nuclear receptor superfamily. Androgen response element is present in regulatory elements on the AR-responsive target genes, such as transforming growth factor beta-1 (TGF beta-1) and vascular endothelial growth factor (VEGF). It is well known that the activation of AR is associated with human carcinogenesis in prostate cancer as well as HCC and pancreatic cancer and that GRP78, TGF beta, and VEGF all play important roles in carcinogenesis and cancer development in these cancers. HCC is a male-dominant cancer irrespective of its etiology. Previous work has reported that vertebrae forkhead box A 1/2 are involved in estrogen receptors and/or AR signaling pathways, which may contribute to the gender differences observed with HCC. Our recent work also showed that AR has a critical role in pancreatic cancer development, despite pancreatic cancer not being a male dominant cancer. Aryl hydrocarbon (or dioxin) receptor is also involved in both HCC and pancreatic cancer through the formation of complex with AR. It is possible that AR might be involved in their carcinogenesis through major histocompatibility complex class I chain-related gene A/B. This review article describes AR and its role in HCC and pancreatic cancer and suggests that more specific AR signaling-inhibitors may be useful in the treatment of these "difficult to treat" cancers.
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Ma WL, Lai HC, Yeh S, Cai X, Chang C. Androgen receptor roles in hepatocellular carcinoma, fatty liver, cirrhosis and hepatitis. Endocr Relat Cancer 2014; 21:R165-82. [PMID: 24424503 PMCID: PMC4165608 DOI: 10.1530/erc-13-0283] [Citation(s) in RCA: 125] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Androgen/androgen receptor (AR) signaling plays important roles in normal liver function and in progression of liver diseases. In studies of noncancerous liver diseases, AR knockout mouse models of liver disease have revealed that androgen/AR signaling suppresses the development of steatosis, virus-related hepatitis, and cirrhosis. In addition, studies have shown that targeting AR in bone marrow-derived mesenchymal stem cells (BM-MSCs) improves their self-renewal and migration potentials, thereby increasing the efficacy of BM-MSC transplantation as a way to control the progression of cirrhosis. Androgen/AR signaling is known to be involved in the initiation of carcinogen- or hepatitis B virus-related hepatocellular carcinoma (HCC). However, studies have demonstrated that AR, rather than androgen, plays the dominant role in cancer initiation. Therefore, targeting AR might be an appropriate therapy for patients with early-stage HCC. In contrast, androgen/AR signaling has been shown to suppress metastasis of HCC in patients with late-stage disease. In addition, there is evidence that therapy comprising Sorafenib and agents that enhance the functional expression of AR may suppress the progression of late-stage HCC.
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Affiliation(s)
- Wen-Lung Ma
- Sex Hormone Research Center, Department of
Gastroenterology, and Graduate Institute of Clinical Medical Science, China Medical
University/Hospital, Taichung 404, Taiwan
- George Whipple Lab for Cancer Research, Departments of
Pathology and Urology and The Wilmot Cancer Center, University of Rochester Medical
Center, Rochester, NY 14642, USA
| | - Hsueh-Chou Lai
- Sex Hormone Research Center, Department of
Gastroenterology, and Graduate Institute of Clinical Medical Science, China Medical
University/Hospital, Taichung 404, Taiwan
| | - Shuyuan Yeh
- George Whipple Lab for Cancer Research, Departments of
Pathology and Urology and The Wilmot Cancer Center, University of Rochester Medical
Center, Rochester, NY 14642, USA
| | - Xiujun Cai
- Department of General Surgery, Chawnshang Chang Liver
Cancer Center, Sir Run-run Shaw Hospital, Zhejiang University, Hangzhou, China
- Corresponding author: Chawnshang
Chang () and Xiujun Cai
()
| | - Chawnshang Chang
- Sex Hormone Research Center, Department of
Gastroenterology, and Graduate Institute of Clinical Medical Science, China Medical
University/Hospital, Taichung 404, Taiwan
- George Whipple Lab for Cancer Research, Departments of
Pathology and Urology and The Wilmot Cancer Center, University of Rochester Medical
Center, Rochester, NY 14642, USA
- Corresponding author: Chawnshang
Chang () and Xiujun Cai
()
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