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1
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Subhaharan D, Murphy G, Commins N, Azer M. Drug-induced liver injury secondary to tamoxifen. BMJ Case Rep 2024; 17:e260098. [PMID: 38839414 DOI: 10.1136/bcr-2024-260098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/07/2024] Open
Abstract
Tamoxifen is a non-steroidal selective oestrogen receptor modulator commonly used in the treatment of breast cancer. It is associated with the development of fatty liver and steatohepatitis however drug-induced liver injury is rare. We report a woman in her 50s who developed malaise with an acute moderate aminotransferase elevation without jaundice 6 months after starting tamoxifen. She was not commenced on any other recent drugs and extensive investigation including infective and autoimmune liver screen, cross-sectional imaging and FibroScan were unremarkable. Liver biopsy revealed moderate lobular hepatitis with hepatocyte drop-out. Tamoxifen was ceased and the liver enzymes showed resolution over the following 3 months and improvement of her symptoms.
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Affiliation(s)
- Deloshaan Subhaharan
- Department of Hepatology, Sunshine Coast University Hospital, Birtinya, Queensland, Australia
| | - Grace Murphy
- Department of Medical Oncology, Sunshine Coast University Hospital, Birtinya, Queensland, Australia
| | - Natalie Commins
- Department of Hepatology, Sunshine Coast University Hospital, Birtinya, Queensland, Australia
| | - Mary Azer
- Department of Medical Oncology, Sunshine Coast University Hospital, Birtinya, Queensland, Australia
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2
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Fang Z, Xu H, Duan J, Ruan B, Liu J, Song P, Ding J, Xu C, Li Z, Dou K, Wang L. Short-term tamoxifen administration improves hepatic steatosis and glucose intolerance through JNK/MAPK in mice. Signal Transduct Target Ther 2023; 8:94. [PMID: 36864030 PMCID: PMC9981902 DOI: 10.1038/s41392-022-01299-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 11/30/2022] [Accepted: 12/22/2022] [Indexed: 03/04/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) which is a leading cause of chronic liver diseases lacks effective treatment. Tamoxifen has been proven to be the first-line chemotherapy for several solid tumors in clinics, however, its therapeutic role in NAFLD has never been elucidated before. In vitro experiments, tamoxifen protected hepatocytes against sodium palmitate-induced lipotoxicity. In male and female mice fed with normal diets, continuous tamoxifen administration inhibited lipid accumulation in liver, and improved glucose and insulin intolerance. Short-term tamoxifen administration largely improved hepatic steatosis and insulin resistance, however, the phenotypes manifesting inflammation and fibrosis remained unchanged in abovementioned models. In addition, mRNA expressions of genes related to lipogenesis, inflammation, and fibrosis were downregulated by tamoxifen treatment. Moreover, the therapeutic effect of tamoxifen on NAFLD was not gender or ER dependent, as male and female mice with metabolic disorders shared no difference in response to tamoxifen and ER antagonist (fulvestrant) did not abolish its therapeutic effect as well. Mechanistically, RNA sequence of hepatocytes isolated from fatty liver revealed that JNK/MAPK signaling pathway was inactivated by tamoxifen. Pharmacological JNK activator (anisomycin) partially deprived the therapeutic role of tamoxifen in treating hepatic steatosis, proving tamoxifen improved NAFLD in a JNK/MAPK signaling-dependent manner.
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Affiliation(s)
- Zhiqiang Fang
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Hao Xu
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Juanli Duan
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Bai Ruan
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi'an, 710032, China.,Center of Clinical Aerospace Medicine & Department of Aviation Medicine, Fourth Military Medical University, Xi'an, 710032, China
| | - Jingjing Liu
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Ping Song
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Jian Ding
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Chen Xu
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Zhiwen Li
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Kefeng Dou
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi'an, 710032, China.
| | - Lin Wang
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi'an, 710032, China.
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Xie X, Maharjan S, Kelly C, Liu T, Lang RJ, Alperin R, Sebastian S, Bonilla D, Gandolfo S, Boukataya Y, Siadat SM, Zhang YS, Livermore C. Customizable Microfluidic Origami Liver-on-a-Chip (oLOC). ADVANCED MATERIALS TECHNOLOGIES 2022; 7:2100677. [PMID: 35754760 PMCID: PMC9231824 DOI: 10.1002/admt.202100677] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Indexed: 05/03/2023]
Abstract
The design and manufacture of an origami-based liver-on-a-chip device are presented, together with demonstrations of the chip's effectiveness at recapitulating some of the liver's key in vivo architecture, physical microenvironment, and functions. Laser-cut layers of polyimide tape are folded together with polycarbonate nanoporous membranes to create a stack of three adjacent flow chambers separated by the membranes. Endothelial cells are seeded in the upper and lower flow chambers to simulate sinusoids, and hepatocytes are seeded in the middle flow chamber. Nutrients and metabolites flow through the simulated sinusoids and diffuse between the vascular pathways and the hepatocyte layers, mimicking physiological microcirculation. Studies of cell viability, metabolic functions, and hepatotoxicity of pharmaceutical compounds show that the endothelialized liver-on-a-chip model is conducive to maintaining hepatocyte functions and evaluation of the hepatotoxicity of drugs. Our unique origami approach speeds chip development and optimization, effectively simplifying the laboratory-scale fabrication of on-chip models of human tissues without necessarily reducing their structural and functional sophistication.
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Affiliation(s)
- Xin Xie
- Department of Mechanical and Industrial Engineering, Northeastern University, Boston, MA 02115, USA
| | - Sushila Maharjan
- Division of Engineering in Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA 02139, USA
| | - Chastity Kelly
- Department of Mechanical and Industrial Engineering, Northeastern University, Boston, MA 02115, USA
| | - Tian Liu
- Department of Mechanical and Industrial Engineering, Northeastern University, Boston, MA 02115, USA
| | | | - Roger Alperin
- Department of Mathematics, San Jose State University, San Jose, CA 95192
| | - Shikha Sebastian
- Division of Engineering in Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA 02139, USA
| | - Diana Bonilla
- Division of Engineering in Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA 02139, USA
| | - Sakura Gandolfo
- Department of Mechanical and Industrial Engineering, Northeastern University, Boston, MA 02115, USA
| | - Yasmine Boukataya
- Department of Mechanical and Industrial Engineering, Northeastern University, Boston, MA 02115, USA
| | | | - Yu Shrike Zhang
- Division of Engineering in Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA 02139, USA
| | - Carol Livermore
- Department of Mechanical and Industrial Engineering, Northeastern University, Boston, MA 02115, USA
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Lee D, Trinh TA, Shin MS, Kang KS. Adipose tissue. RECENT ADVANCEMENTS IN MICROBIAL DIVERSITY 2022:209-228. [DOI: 10.1016/b978-0-12-822368-0.00009-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Tanaka N, Mukaiyama K, Morikawa A, Kawakami S, Ichise Y, Kimura T, Horiuchi A. Pemafibrate, a novel selective PPARα modulator, attenuates tamoxifen-induced fatty liver disease. Clin J Gastroenterol 2021; 14:846-851. [PMID: 33751406 DOI: 10.1007/s12328-021-01386-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 03/10/2021] [Indexed: 11/25/2022]
Abstract
Estrogen receptor (ER) antagonists, such as tamoxifen and toremifene, are widely used as adjuvant therapies for ER-positive breast cancer. These agents sometimes cause hepatosteatosis and steatohepatitis and it is problematic whether these agents should be withdrawn due to fatty liver disease and liver dysfunction. We herein describe a patient with fatty liver disease and hypertriglyceridemia during tamoxifen treatment, which significantly improved by adding pemafibrate, a novel PPARα activator designated as a selective PPARα modulator. Serial analysis during pemafibrate treatment revealed significant increases in circulating ketone bodies, which are indicators of hepatic fatty acid (FA) β-oxidation. As far as we know, this is the first report demonstrating the beneficial effect of pemafibrate on tamoxifen-induced fatty liver disease, which is likely due to enhanced hepatic FA β-oxidation by PPARα stimulation. Future large-scale studies will be needed to verify the current observation.
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Affiliation(s)
- Naoki Tanaka
- International Relations Office, Shinshu University School of Medicine, Matsumoto, Japan.
- Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto, Japan.
- Research Center for Social Systems, Shinshu University, Matsumoto, Japan.
| | | | - Akio Morikawa
- Department of Surgery, Showa Inan General Hospital, Komagane, Japan
| | - Satoshi Kawakami
- Department of Radiology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Yasuyuki Ichise
- Digestive Disease Center, Showa Inan General Hospital, Komagane, Japan
| | - Takefumi Kimura
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
- Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, USA
| | - Akira Horiuchi
- Digestive Disease Center, Showa Inan General Hospital, Komagane, Japan
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Raza S, Rajak S, Upadhyay A, Tewari A, Anthony Sinha R. Current treatment paradigms and emerging therapies for NAFLD/NASH. Front Biosci (Landmark Ed) 2021; 26:206-237. [PMID: 33049668 DOI: 10.2741/4892] [Citation(s) in RCA: 187] [Impact Index Per Article: 46.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is one the fastest emerging manifestations of the metabolic syndrome worldwide. Non-alcoholic steatohepatitis (NASH), the progressive form of NAFLD, may culminate into cirrhosis and hepatocellular cancer (HCC) and is presently a leading cause of liver transplant. Although a steady progress is seen in understanding of the disease epidemiology, pathogenesis and identifying therapeutic targets, the slowest advancement is seen in the therapeutic field. Currently, there is no FDA approved therapy for this disease and appropriate therapeutic targets are urgently warranted. In this review we discuss the role of lifestyle intervention, pharmacological agents, surgical approaches, and gut microbiome, with regard to therapy for NASH. In particular, we focus the role of insulin sensitizers, thyroid hormone mimetics, antioxidants, cholesterol lowering drugs, incretins and cytokines as therapeutic targets for NASH. We highlight these targets aiming to optimize the future for NASH therapy.
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Affiliation(s)
- Sana Raza
- Department of Endocrinology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
| | - Sangam Rajak
- Department of Endocrinology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
| | - Aditya Upadhyay
- Department of Endocrinology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
| | - Archana Tewari
- Department of Endocrinology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
| | - Rohit Anthony Sinha
- Department of Endocrinology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India,
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7
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DiStefano JK. NAFLD and NASH in Postmenopausal Women: Implications for Diagnosis and Treatment. Endocrinology 2020; 161:5890353. [PMID: 32776116 PMCID: PMC7473510 DOI: 10.1210/endocr/bqaa134] [Citation(s) in RCA: 128] [Impact Index Per Article: 25.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Accepted: 08/03/2020] [Indexed: 12/13/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) prevalence in women is increasing worldwide. Women of reproductive age have lower rates of NAFLD compared with men; however, this protection is lost following the menopausal transition when NAFLD prevalence in postmenopausal women becomes similar to or surpasses that in age-matched male counterparts. Ongoing epidemiological, clinical, and experimental studies indicate greater NAFLD risk and higher rates of severe hepatic fibrosis in postmenopausal women relative to premenopausal women, and that older women with NAFLD experience greater mortality than men. Investigations involving ovariectomized animal models demonstrate a causal relationship between estrogen deficiency and heightened susceptibility to the development of fatty liver and steatohepatitis, although dietary factors may exacerbate this complex relationship. The accumulated findings suggest that a better understanding of the interplay among menopausal status, metabolic comorbidities, and sex steroids in NAFLD pathogenesis is needed. Further, the mechanisms underlying the difference in NAFLD risk between postmenopausal and premenopausal women remain incompletely understood. The goals of this review are to summarize studies of NAFLD risk in postmenopausal women, discuss results from animal models of estrogen deficiency, and explore the development of NAFD within the context of altered sex hormone profiles resulting from the menopausal transition. Potential implications for the prevention, diagnosis, and treatment of NAFLD in this relatively understudied cohort are also addressed.
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Affiliation(s)
- Johanna K DiStefano
- Diabetes and Fibrotic Disease Research Unit, Translational Genomics Research Institute, Phoenix, Arizona
- Correspondence: Johanna K. DiStefano, Diabetes and Fibrotic Disease Research Unit, Translational Genomics Research Institute, Phoenix, AZ, USA. E-mail:
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Bessone F, Dirchwolf M, Rodil MA, Razori MV, Roma MG. Review article: drug-induced liver injury in the context of nonalcoholic fatty liver disease - a physiopathological and clinical integrated view. Aliment Pharmacol Ther 2018; 48:892-913. [PMID: 30194708 DOI: 10.1111/apt.14952] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Revised: 03/25/2018] [Accepted: 07/30/2018] [Indexed: 12/15/2022]
Abstract
BACKGROUND Nonalcoholic fatty disease (NAFLD) is the most common liver disease, since it is strongly associated with obesity and metabolic syndrome pandemics. NAFLD may affect drug disposal and has common pathophysiological mechanisms with drug-induced liver injury (DILI); this may predispose to hepatoxicity induced by certain drugs that share these pathophysiological mechanisms. In addition, drugs may trigger fatty liver and inflammation per se by mimicking NAFLD pathophysiological mechanisms. AIMS To provide a comprehensive update on (a) potential mechanisms whereby certain drugs can be more hepatotoxic in NAFLD patients, (b) the steatogenic effects of drugs, and (c) the mechanism involved in drug-induced steatohepatitis (DISH). METHODS A language- and date-unrestricted Medline literature search was conducted to identify pertinent basic and clinical studies on the topic. RESULTS Drugs can induce macrovesicular steatosis by mimicking NAFLD pathogenic factors, including insulin resistance and imbalance between fat gain and loss. Other forms of hepatic fat accumulation exist, such as microvesicular steatosis and phospholipidosis, and are mostly associated with acute mitochondrial dysfunction and defective lipophagy, respectively. Drug-induced mitochondrial dysfunction is also commonly involved in DISH. Patients with pre-existing NAFLD may be at higher risk of DILI induced by certain drugs, and polypharmacy in obese individuals to treat their comorbidities may be a contributing factor. CONCLUSIONS The relationship between DILI and NAFLD may be reciprocal: drugs can cause NAFLD by acting as steatogenic factors, and pre-existing NAFLD could be a predisposing condition for certain drugs to cause DILI. Polypharmacy associated with obesity might potentiate the association between this condition and DILI.
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Affiliation(s)
- Fernando Bessone
- Hospital Provincial del Centenario, Facultad de Ciencias Médicas, Servicio de Gastroenterología y Hepatología, Universidad Nacional de Rosario, Rosario, Argentina
| | - Melisa Dirchwolf
- Unidad de Transplante Hepático, Servicio de Hepatología, Hospital Privado de Rosario, Rosario, Argentina
| | - María Agustina Rodil
- Hospital Provincial del Centenario, Facultad de Ciencias Médicas, Servicio de Gastroenterología y Hepatología, Universidad Nacional de Rosario, Rosario, Argentina
| | - María Valeria Razori
- Instituto de Fisiología Experimental (IFISE-CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario, Argentina
| | - Marcelo G Roma
- Instituto de Fisiología Experimental (IFISE-CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario, Argentina
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Satapathy SK, Kuwajima V, Nadelson J, Atiq O, Sanyal AJ. Drug-induced fatty liver disease: An overview of pathogenesis and management. Ann Hepatol 2016; 14:789-806. [PMID: 26436351 DOI: 10.5604/16652681.1171749] [Citation(s) in RCA: 68] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Over the past decades, many drugs have been identified, that can potentially induce steatohepatitis in the predisposed individual. Classically this has been incriminated to amiodarone, perhexiline, and 4,4'-diethylaminoethoxyhexestrol (DH), all of which have been found to independently induce the histologic picture of non-alcoholic steatohepatitis (NASH). Pathogenetic mechanisms of hepatotoxicity although still evolving, demonstrate that mitochondrial dysfunction, deranged ATP production and fatty acid catabolism likely play an important role. Drugs like steroid hormones can exacerbate the pathogenetic mechanisms that lead to NASH, and other drugs like tamoxifen, cisplatin and irenotecan have been shown to precipitate latent fatty liver as well. Further research aiming to elucidate the pathogenesis of drug-induced steatosis and steatohepatitis is needed in order to better design therapeutic targets.
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Affiliation(s)
- Sanjaya K Satapathy
- Methodist University Hospital Transplant Institute, Division of Surgery, University of Tennessee Health Sciences Center, Memphis, Tennessee, USA
| | - Vanessa Kuwajima
- Division of Gastroenterology and Hepatology, University of Tennessee Health Sciences Center, Memphis, Tennessee, USA
| | - Jeffrey Nadelson
- Division of Gastroenterology and Hepatology, University of Tennessee Health Sciences Center, Memphis, Tennessee, USA
| | - Omair Atiq
- University of Texas Southwestern, Dallas, Texas, USA
| | - Arun J Sanyal
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University Health System, Richmond, Virginia, USA
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The influence of metabolic factors for nonalcoholic Fatty liver disease in women. BIOMED RESEARCH INTERNATIONAL 2015; 2015:131528. [PMID: 25973422 PMCID: PMC4417996 DOI: 10.1155/2015/131528] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/23/2015] [Revised: 03/27/2015] [Accepted: 03/29/2015] [Indexed: 12/12/2022]
Abstract
Background/Aims. Women after menopause have increased insulin resistance and visceral fat, which may increase the prevalence of nonalcoholic fatty liver disease (NAFLD). However, the pathogenesis of NAFLD in women has not been clearly defined. In this study, we aimed to determine the risk factors for NAFLD in women. Methods. A retrospective cohort study was conducted. Women who underwent abdominal ultrasonography and blood sampling for routine health check-ups were recruited. Results. Among 1,423 subjects, 695 women (48.9%) were in a menopausal state. The prevalence of NAFLD was higher in postmenopausal women than in premenopausal women (27.2% versus 14.4%, P < 0.001). In premenopausal women, low HDL-cholesterol, central obesity, and homeostasis model assessment-estimated insulin resistance showed a significant association with the increased risk of NAFLD in multivariate analysis. In postmenopausal women, the presence of diabetes, triglyceridemia, and central obesity showed a significant association with the risk of NAFLD. The presence of menopause and hormone replacement therapy in postmenopausal women were not risk factors for NAFLD. Conclusions. Our findings showed different metabolic factors for NAFLD in pre- and postmenopausal women. However, the key issues are the same: central obesity and insulin resistance. These results reemphasize the importance of metabolic factors irrespective of menopausal status in the pathogenesis of NAFLD in women.
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van Swelm RPL, Kramers C, Masereeuw R, Russel FGM. Application of urine proteomics for biomarker discovery in drug-induced liver injury. Crit Rev Toxicol 2014; 44:823-41. [PMID: 25264586 DOI: 10.3109/10408444.2014.931341] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Hamaguchi M, Kojima T, Ohbora A, Takeda N, Fukui M, Kato T. Aging is a risk factor of nonalcoholic fatty liver disease in premenopausal women. World J Gastroenterol 2012; 18:237-43. [PMID: 22294826 PMCID: PMC3261540 DOI: 10.3748/wjg.v18.i3.237] [Citation(s) in RCA: 113] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2011] [Revised: 09/08/2011] [Accepted: 10/28/2011] [Indexed: 02/06/2023] Open
Abstract
AIM: To clarify the relationship between age, menopause, and nonalcoholic fatty liver disease (NAFLD) in women.
METHODS: We conducted a follow-up study on nonalcoholic fatty liver disease by using abdominal ultrasonography, and investigated the relationship of age and menopause with the development of NAFLD in women. We followed 1829 women and 2572 men (response rate, 86%) selected in 2001 to represent the non-institutionalized adult population of Gifu, Japan. Data collected included self-reported medical history, lifestyle factors, and menopausal status. The postmenopausal state was defined as beginning 1 year after the cessation of menses. We diagnosed NAFLD with the aid of abdominal ultrasonography by using diagnostic criteria described previously.
RESULTS: The prevalence of NAFLD in women increases with age, but does not alter with age in men. Furthermore, the prevalence of NAFLD in premenopausal women (6%) was lower than that in men (24%) and in postmenopausal women (15%). The associations of the postmenopausal state and hormone replacement therapy with NAFLD were statistically significant in a univariate logistic regression model. At the follow-up examination, 67 women (5%) were newly diagnosed with NAFLD. The incidence of NAFLD was 3.5% (28/802) in premenopausal women, 7.5% (4/53) in menopausal women, 6.1% (24/392) in postmenopausal women, and 5.3% (11/206) in women receiving hormone replacement therapy. The weight gain in premenopausal women was equal to that in postmenopausal women. Metabolic syndrome and weight gain were independent risk factors for NAFLD in pre- and postmenopausal women, but age was an independent risk factor in premenopausal women only.
CONCLUSION: Aging is a risk factor for NAFLD in premenopausal women, independent of weight gain or influence of metabolic syndrome.
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Saphner T, Triest-Robertson S, Li H, Holzman P. The association of nonalcoholic steatohepatitis and tamoxifen in patients with breast cancer. Cancer 2009; 115:3189-95. [PMID: 19484789 DOI: 10.1002/cncr.24374] [Citation(s) in RCA: 66] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Nonalcoholic steatohepatitis (NASH) is a form of liver damage that can progress to cirrhosis. NASH is associated with obesity and diabetes. The condition also may be associated with some medications, including tamoxifen. Early case reports and small series have documented NASH in patients who received tamoxifen. METHODS The records of patients registered in the St. Vincent Hospital Cancer Registry of Green Bay Wisconsin from January 1, 1992 to December 31, 2000 were reviewed. RESULTS In total, 1105 patients with breast cancer were evaluated for NASH, and 24 cases of NASH were documented (2.2%). Seven patients had NASH before their diagnosis of breast cancer, and 17 patients developed NASH after their diagnosis of breast cancer. In multivariate analysis, the factors associated with NASH were tamoxifen use (odds ratio [OR], 8.2; 95% confidence interval [CI], 1.06-63.72), body mass index (BMI) (OR, 1.13; 95% CI, 1.06-1.20), and age (OR, 95% CI, 0.91-0.99). NASH improved after tamoxifen was stopped. After discontinuation of tamoxifen, transaminase levels returned to normal in 14 of 16 patients. CONCLUSIONS NASH was present in 24 of 1105 patients with breast cancer (2.2%). Seven patients had NASH before they were diagnosed with breast cancer, and 17 patients developed NASH after their diagnosis. NASH was associated with the use of tamoxifen and improved when tamoxifen was stopped.
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Affiliation(s)
- Tom Saphner
- Department of Oncology, St. Mary's Medical Center, Green Bay, Wisconsin, USA.
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14
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Yan BC, Hart JA. Recent developments in liver pathology. Arch Pathol Lab Med 2009; 133:1078-86. [PMID: 19642734 DOI: 10.5858/133.7.1078] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/05/2009] [Indexed: 11/06/2022]
Abstract
CONTEXT Hepatocellular carcinoma is the sixth most common malignancy and the third leading cause of cancer deaths worldwide, making pathologic identification of precursor lesions essential. Recent molecular genetic, pathologic, and clinical data have led to the stratification of hepatic adenomas into subgroups with unique molecular profiles and varying potential for malignant transformation, as well as to the reclassification of telangiectatic focal nodular hyperplasia as telangiectatic adenoma. Clinical, morphologic, and molecular genetic studies have also established juvenile hemochromatosis and pediatric nonalcoholic steatohepatitis as entities distinct from their adult counterparts. OBJECTIVE To review the recent molecular genetic characterization of telangiectatic hepatic adenomas and juvenile hemochromatosis, as well as the recent clinicopathologic characterization of pediatric nonalcoholic steatohepatitis. DATA SOURCES Literature review, personal experience, and material from the University of Chicago. CONCLUSIONS Basic science and translational research have led to the classification of many pathologic entities of the liver according to molecular genetic and protein expression profiles that correspond to traditional morphologic categories. Insights into signal transduction pathways that are activated in, and protein expression patterns unique to, an individual disease may lead to the development of new therapeutic agents and novel diagnostic biomarkers.
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Affiliation(s)
- Benjamin C Yan
- Department of Pathology, University of Chicago Hospitals, Chicago, Illinois 60637, USA
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Albukhari AA, Gashlan HM, El-Beshbishy HA, Nagy AA, Abdel-Naim AB. Caffeic acid phenethyl ester protects against tamoxifen-induced hepatotoxicity in rats. Food Chem Toxicol 2009; 47:1689-95. [DOI: 10.1016/j.fct.2009.04.021] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2009] [Revised: 04/04/2009] [Accepted: 04/16/2009] [Indexed: 10/20/2022]
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16
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Colmenero JDD, Castón JJ, Torre-Cisneros J. Fiebre, disnea e infiltrados pulmonares en una mujer de 50 años en tratamiento inmunodepresor. Med Clin (Barc) 2009; 132:638-44. [DOI: 10.1016/j.medcli.2008.10.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2008] [Accepted: 10/08/2008] [Indexed: 11/30/2022]
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Barshop NJ, Sirlin CB, Schwimmer JB, Lavine JE. Review article: epidemiology, pathogenesis and potential treatments of paediatric non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2008; 28:13-24. [PMID: 18397387 DOI: 10.1111/j.1365-2036.2008.03703.x] [Citation(s) in RCA: 97] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is the most common cause of paediatric liver disease. Similar to NAFLD in adults, NAFLD in children is associated with obesity and insulin resistance and requires liver histology for diagnosis and staging. However, significant histological differences exist between adult and paediatric NAFLD to warrant caution in extrapolation of adult data. AIM To review the available data on the epidemiology, pathogenesis, diagnosis and treatment of paediatric NAFLD. METHODS Relevant articles were identified by Medline searches using the keywords: nonalcoholic fatty liver disease, steatohepatitis, obesity and children. RESULTS The rise in childhood obesity has been accompanied by an increase in paediatric NAFLD. Age, gender and race/ethnicity are significant determinants of risk, and sex hormones, insulin sensitivity and adipocytokines are implicated in the pathogenesis of paediatric NAFLD. There is no consensus for treatment of NAFLD; however, data suggest that diet, exercise and some pharmacological therapies may be of benefit. CONCLUSIONS To evaluate and effectively treat paediatric NAFLD, the pathophysiology and natural history of the disease should be clarified and non-invasive methods for screening, diagnosis, and longitudinal assessment developed. Randomized, controlled, double-blind trials of pharmacological therapies in children with biopsy-proven disease are necessary.
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Affiliation(s)
- N J Barshop
- Department of Pediatrics, University of California, San Diego, CA, USA
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18
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Shimizu I, Kohno N, Tamaki K, Shono M, Huang HW, He JH, Yao DF. Female hepatology: Favorable role of estrogen in chronic liver disease with hepatitis B virus infection. World J Gastroenterol 2007; 13:4295-305. [PMID: 17708600 PMCID: PMC4250853 DOI: 10.3748/wjg.v13.i32.4295] [Citation(s) in RCA: 108] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis B virus (HBV) infection is the most common cause of hepatic fibrosis and hepatocellular carcinoma (HCC), mainly as a result of chronic necroinflammatory liver disease. A characteristic feature of chronic hepatitis B infection, alcoholic liver disease and nonalcoholic fatty liver disease (NAFLD) is hepatic steatosis. Hepatic steatosis leads to an increase in lipid peroxidation in hepatocytes, which, in turn, activates hepatic stellate cells (HSCs). HSCs are the primary target cells for inflammatory and oxidative stimuli, and these cells produce extracellular matrix components. Chronic hepatitis B appears to progress more rapidly in males than in females, and NAFLD, cirrhosis and HCC are predominately diseases that tend to occur in men and postmenopausal women. Premenopausal women have lower hepatic iron stores and a decreased production of proinflammatory cytokines. Hepatic steatosis has been observed in aromatase-deficient mice, and has been shown to decrease in animals after estradiol treatment. Estradiol is a potent endogenous antioxidant which suppresses hepatic fibrosis in animal models, and attenuates induction of redox sensitive transcription factors, hepatocyte apoptosis and HSC activation by inhibiting a generation of reactive oxygen species in primary cultures. Variant estrogen receptors are expressed to a greater extent in male patients with chronic liver disease than in females. These lines of evidence suggest that the greater progression of hepatic fibrosis and HCC in men and postmenopausal women may be due, at least in part, to lower production of estradiol and a reduced response to the action of estradiol. A better understanding of the basic mechanisms underlying the sex-associated differences in hepatic fibrogenesis and carciogenesis may open up new avenues for the prevention and treatment of chronic liver disease.
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Affiliation(s)
- Ichiro Shimizu
- Department of Digestive and Cardiovascular Medicine, Institute of Health Biosciences, University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
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19
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Abstract
Although chemotherapy generally is accompanied by regular testing for liver enzyme abnormalities, atypical reactions may occur that escape ordinary detection, because hepatocyte injury is not the primary event. The presence of fatty liver, mitochondrial changes, and even biliary abnormalities can be associated with normal or nearly normal liver enzyme levels. This article discusses unique aspects of liver damage associated with cancer chemotherapy. These unique reactions merit special attention and a special vigilance from clinicians.
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Affiliation(s)
- Edmundo A Rodriguez-Frias
- Department of Internal Medicine, The University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA
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20
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Harvey HA, Kimura M, Hajba A. Toremifene: an evaluation of its safety profile. Breast 2005; 15:142-57. [PMID: 16289904 DOI: 10.1016/j.breast.2005.09.007] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2005] [Revised: 07/06/2005] [Accepted: 09/21/2005] [Indexed: 12/14/2022] Open
Abstract
Toremifene has been in clinical use for 8 years for the treatment of advanced hormone-sensitive breast cancer and the adjuvant treatment of early breast cancer. More than 350,000 patient treatment years have accumulated, sufficient to allow evaluation of its longer-term safety profile in comparison with tamoxifen and, where possible, with raloxifene and aromatase inhibitors. We reviewed all preclinical and clinical safety data from 1978 to 2004 and comparative clinical safety data between October 1995 and the end of 2004. Secondary endometrial cancer incidence was lower with toremifene than with tamoxifen and was similar to that with raloxifene. It is speculated that toremifene may unmask existing endometrial tumors rather than induce new events. The risk of stroke, pulmonary embolism, and cataract may be lower with toremifene than with tamoxifen and the risk of pulmonary embolism and deep vein thrombosis lower than with raloxifene. Beneficial estrogen agonistic effects were equivalent to those of tamoxifen regarding bone mineral density and superior regarding lipid profiles.
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Affiliation(s)
- Harold A Harvey
- Division of Hematology/Oncology, Penn State College of Medicine, Penn State Milton S. Hershey Medical Center, 500 University Drive, Hershey, PA 17033, USA.
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21
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Bruno S, Maisonneuve P, Castellana P, Rotmensz N, Rossi S, Maggioni M, Persico M, Colombo A, Monasterolo F, Casadei-Giunchi D, Desiderio F, Stroffolini T, Sacchini V, Decensi A, Veronesi U. Incidence and risk factors for non-alcoholic steatohepatitis: prospective study of 5408 women enrolled in Italian tamoxifen chemoprevention trial. BMJ 2005; 330:932. [PMID: 15746106 PMCID: PMC556336 DOI: 10.1136/bmj.38391.663287.e0] [Citation(s) in RCA: 166] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
OBJECTIVE To assess the incidence, cofactors, and excess risk of development of non-alcoholic fatty liver disease, including non-alcoholic steatohepatitis, attributable to tamoxifen in women. DESIGN Prospective, randomised, double blind, placebo controlled trial. SETTING AND PARTICIPANTS 5408 healthy women who had had hysterectomies, recruited into the Italian tamoxifen chemoprevention trial from 58 centres in Italy. INTERVENTION Women were randomly assigned to receive tamoxifen (20 mg daily) or placebo for five years. MAIN OUTCOME MEASURE Development of non-alcoholic fatty liver disease in all women with normal baseline liver function who showed at least two elevations of alanine aminotransferase (> or = 1.5 times upper limit of normal) over a six month period. RESULTS During follow up, 64 women met the predefined criteria: 12 tested positive for hepatitis C virus, and the remaining 52 were suspected of having developed non-alcoholic fatty liver disease (34 tamoxifen, 18 placebo)--hazard ratio = 2.0 (95% confidence interval 1.1 to 3.5; P = 0.04). In all 52 women ultrasonography confirmed the presence of fatty liver. Other factors associated with the development of non-alcoholic fatty liver disease included overweight (2.4, 1.2 to 4.8), obesity (3.6, 1.7 to 7.6), hypercholesterolaemia (3.4, 1.4 to 7.8), and arterial hypertension (2.0, 1.0 to 3.8). Twenty women had liver biopsies: 15 were diagnosed as having mild to moderate steatohepatitis (12 tamoxifen, 3 placebo), and five had fatty liver alone (1 tamoxifen, 4 placebo). No clinical, biochemical, ultrasonic, or histological signs suggestive of progression to cirrhosis were observed after a median follow up of 8.7 years. CONCLUSIONS Tamoxifen was associated with higher risk of development of non-alcoholic steatohepatitis only in overweight and obese women with features of metabolic syndrome, but the disease, in both the tamoxifen and the placebo group, after 10 years of follow up seems to be indolent.
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Affiliation(s)
- Savino Bruno
- Liver Unit, Azienda Ospedaliera Fatebenefratelli e Oftalmico, Corso di Porta Nuova 23, 20121 Milan, Italy.
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22
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Abstract
Drugs rarely cause steatohepatitis, but amiodarone, perhexiline, and DH, have unequivocally been found to independently induce the histologic picture of alcoholic liver disease or NASH. All three agents have similar pathogenetic mechanisms of hepatotoxicity, targeting mitochondrial ATP production and fatty acid catabolism. Other drugs that occasionally cause steatohepatitis, most importantly steroid hormones, likely exacerbate the pathogenetic mechanisms leading to NASH. Similar to NASH, lipid peroxidation resulting from mitochondrial injury may account for all of the histologic findings in drug-induced steatohepatitis. Further research should determine the mechanisms by which drug-induced steatosis, a benign lesion, evolves to steatohepatitis and progressive fibrosis.
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Affiliation(s)
- R Todd Stravitz
- Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University, 1200 East Broad Street, Room 1496, Richmond, VA 23298, USA.
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23
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Egawa T, Toda K, Nemoto Y, Ono M, Akisaw N, Saibara T, Hayashi Y, Hiroi M, Enzan H, Onishi S. Pitavastatin ameliorates severe hepatic steatosis in aromatase-deficient (Ar-/-) mice. Lipids 2003; 38:519-23. [PMID: 12880107 DOI: 10.1007/s11745-003-1093-x] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
Tamoxifen is a potent antagonist of estrogen, and hepatic steatosis is a frequent complication in adjuvant tamoxifen for breast cancer. Impaired hepatic FA beta-oxidation in peroxisomes, microsomes, and mitochondria results in progression of massive hepatic steatosis in estrogen deficiency. This impairment, although latent, is potentially serious: About 3% of the general population in the United States is now suffering from nonalcoholic steatohepatitis associated with obesity and hyperlipidemia. Therefore, in the present study we tried to restore impaired hepatic FA beta-oxidation by administering a novel statin, pitavastatin, to aromatase-deficient (Ar-/-) mice defective in intrinsic estrogen synthesis. Northern blot analysis of Ar-/- mice liver revealed a significant restoration of mRNA expression of essential enzymes involved in FA beta-oxidation such as very long fatty acyl-CoA synthetase in peroxisome, peroxisomal fatty acyl-CoA oxidase, and medium-chain acyl-CoA dehydrogenase. Severe hepatic steatosis observed in Ar-/- mice substantially regressed. Consistent findings were obtained in the in vitro assays of FA beta-oxidation activity. These findings demonstrate that pitavastatin is capable of restoring impaired FA beta-oxidation in vivo via the peroxisome proliferator-activated receptor-alpha-mediated signaling pathway and is potent enough to ameliorate severe hepatic steatosis in mice deficient in intrinsic estrogen.
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Affiliation(s)
- Tetsu Egawa
- Department of Medicine, Kochi Medical School, Nankoku, 783-8505 Japan
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Nishino M, Hayakawa K, Nakamura Y, Morimoto T, Mukaihara S. Effects of tamoxifen on hepatic fat content and the development of hepatic steatosis in patients with breast cancer: high frequency of involvement and rapid reversal after completion of tamoxifen therapy. AJR Am J Roentgenol 2003; 180:129-34. [PMID: 12490491 DOI: 10.2214/ajr.180.1.1800129] [Citation(s) in RCA: 89] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
OBJECTIVE A study was conducted on hepatic fat content to investigate the frequency and clinical course of hepatic steatosis induced by tamoxifen. MATERIALS AND METHODS Sixty-seven patients with breast cancer treated with adjuvant tamoxifen were included. The patients underwent postoperative annual abdominal CT, both with and without contrast enhancement, for 5 years. We retrospectively reviewed unenhanced CT images and obtained hepatic and splenic CT attenuation values to calculate the liver-spleen ratio. Hepatic steatosis was defined as a liver-spleen ratio of less than 0:9, and its degree was classified as mild (liver-spleen ratio, 0:5-0:9), moderate (0-0:5), or severe (<0). The pattern of steatosis was classified as generalized, lobar, segmental, or focal. RESULTS In the study population, hepatic CT values decreased during therapy (p < 0.0001, t test) and increased after therapy (p < 0.0001, paired t test). Twenty-nine patients (43.2%) developed hepatic steatosis within the first 2 years; its degree was mild in 16, moderate in nine, and severe in four. Seventeen patients showed a generalized pattern of steatosis, and the other 12 showed a lobar pattern. Twenty-three of these patients showed an increase in the liver-spleen ratio after therapy to within the normal range, with a mean recovery time of 1.2 years after therapy ended. None progressed to steatohepatitis or cirrhosis. CONCLUSION Tamoxifen had a statistically significant influence on hepatic fat content and was associated with frequent development of hepatic steatosis. Radiologists should be aware of this phenomenon and the possible occurrence of hepatic dysfunction and should differentiate steatosis from metastasis in postoperative patients with breast cancer.
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Affiliation(s)
- Mizuki Nishino
- Department of Radiology, Kyoto City Hospital, 1-2 Higashi-takada-cho, Mibu, Nakagyo-ku, Kyoto 604-8845, Japan
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25
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Günel N, Coşkun U, Toruner FB, Sancak B, Yilmaz E, Cengiz O, Elbeg S, Uner A, Ozkan S. Serum leptin levels are associated with tamoxifen-induced hepatic steatosis. Curr Med Res Opin 2003; 19:47-50. [PMID: 12661780 DOI: 10.1185/030079902125001308] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
PURPOSE Tamoxifen, used in breast cancer treatment, may induce hepatic steatosis. It has been suggested that leptin, which has a relationship with body fat stores, may be involved in the pathogenesis of hepatic steatosis. In this study, we compared serum leptin levels in tamoxifen-treated patients with and without hepatic steatosis. METHODS Thirty-four women with breast cancer receiving tamoxifen were included in the study. Serum samples were obtained from the patients before and 3 months after tamoxifen therapy. RESULTS Increased hepatic steatosis was detected in 15 of 34 (44%) patients after 3 months of tamoxifen therapy. Serum leptin levels were found to be significantly elevated in patients with increased hepatic steatosis (37.3 +/- 17.7 to 50.5 +/- 22.4 ng/ml, p = 0.023) compared to (48.2 +/- 20.2 to 42.6 +/- 14.9 ng/ml, p > 0.05) after tamoxifen treatment. CONCLUSION Leptin may play a role in tamoxifen-induced hepatic steatosis. The exact mechanism involved should be investigated in further studies.
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Affiliation(s)
- Nazan Günel
- Department of Medical Oncology, Gazi University Medical School, Ankara, Turkey.
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26
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Lasso De La Vega MC, Zapater P, Such J, Sola-Vera J, Payá A, Horga JF, Pérez-Mateo M. [Toxic hepatitis associated with tamoxifen use. A case report and literature review]. GASTROENTEROLOGIA Y HEPATOLOGIA 2002; 25:247-50. [PMID: 11975873 DOI: 10.1016/s0210-5705(02)70254-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Tamoxifen is an antiestrogenic drug that acts by binding to the estrogen receptor. The drug is used as a co-adjuvant treatment in advanced breast cancer expressing the oestrogen-receptor protein. Clinical trials of tamoxifen have shown its efficacy in reducing mortality and recurrence rates over a five-year treatment. Cases of tamoxifen-associated hepatotoxicity have been described, including cholestasis with or without cytolysis and steatohepatitis. We report the case of a female patient who developed hepatic alterations while undergoing continuous tamoxifen treatment. We also present an overview of similar cases published to date and comment on the advisability of continuing or suppressing this treatment in patients with hepatotoxicity or after a five-year treatment period.
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Affiliation(s)
- M C Lasso De La Vega
- Unidad de Farmacología Clínica, Hospital General Universitario de Alicante, Spain.
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27
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Affiliation(s)
- G Kotiloglu
- Department of Internal Medicine, Bayindir Medical Center, Sogutozu/Ankara, Turkey
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28
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Abstract
Nonalcoholic steatohepatitis (NASH) is a condition characterized by hepatomegaly, elevated serum aminotransferase levels, and a histologic picture similar to alcoholic hepatitis in the absence of alcohol abuse. Most patients with NASH are obese women, and many have diabetes mellitus, hypercholesterolemia, or hypertriglyceridemia. NASH has also been associated with a number of metabolic conditions, surgical procedures, and drug treatments. Most patients are asymptomatic. The most common sign of NASH is hepatomegaly. Stigmata of chronic liver disease are rare. Laboratory abnormalities include a 2-4-fold elevation of serum aminotransferase levels; other liver function test results are usually normal. Histologically, there is moderate to severe macrovesicular steatosis and lobular hepatitis with necrosis or ballooning degeneration and/or fibrosis. The pathogenesis of NASH is poorly understood, but lipid peroxidation and oxidative stress are the leading culprits. The natural history of NASH is unknown, but NASH seems to be a stable disease in most patients. Treatment of NASH is unproven, but weight reduction is recommended in obese patients. Small pilot studies of several drugs have shown promise, but large randomized clinical trials are awaited. Orthotopic liver transplantation is the treatment of choice for end-stage liver disease secondary to NASH.
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Affiliation(s)
- A E Reid
- Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
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Nemoto Y, Toda K, Ono M, Fujikawa-Adachi K, Saibara T, Onishi S, Enzan H, Okada T, Shizuta Y. Altered expression of fatty acid-metabolizing enzymes in aromatase-deficient mice. J Clin Invest 2000; 105:1819-25. [PMID: 10862797 PMCID: PMC378513 DOI: 10.1172/jci9575] [Citation(s) in RCA: 162] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hepatic steatosis is a frequent complication in nonobese patients with breast cancer treated with tamoxifen, a potent antagonist of estrogen. In addition, hepatic steatosis became evident spontaneously in the aromatase-deficient (ArKO) mouse, which lacks intrinsic estrogen production. These clinical and laboratory observations suggest that estrogen helps to maintain constitutive lipid metabolism. To clarify this hypothesis, we characterized the expression and activity in ArKO mouse liver of enzymes involved in peroxisomal and mitochondrial fatty acid beta-oxidation. Northern analysis showed reduced expression of mRNAs for very long fatty acyl-CoA synthetase, peroxisomal fatty acyl-CoA oxidase, and medium-chain acyl-CoA dehydrogenase, enzymes required in fatty acid beta-oxidation. In vitro assays of fatty acid beta-oxidation activity using very long (C24:0), long (C16:0), or medium (C12:0) chain fatty acids as the substrates confirmed that the corresponding activities are also diminished. Impaired gene expression and enzyme activities of fatty acid beta-oxidation were restored to the wild-type levels, and hepatic steatosis was substantially diminished in animals treated with 17beta-estradiol. Wild-type and ArKO mice showed no difference in the binding activities of the hepatic nuclear extracts to a peroxisome proliferator response element. These findings demonstrate the pivotal role of estrogen in supporting constitutive hepatic expression of genes involved in lipid beta-oxidation and in maintaining hepatic lipid homeostasis.
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Affiliation(s)
- Y Nemoto
- Department of Medicine, Kochi Medical School, Nankoku, Japan
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30
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Abstract
Tamoxifen is one of the most commonly used anticancer medications. Hepatic damage secondary to tamoxifen treatment is rare. Tamoxifen-induced multifocal hepatic fatty infiltration has not been reported previously. This report describes one case of steatohepatitis caused by tamoxifen in an elderly woman with a history of breast cancer. The patient had multifocal hepatic fatty infiltration secondary to tamoxifen therapy. After tamoxifen was discontinued, the features of multifocal hepatic fatty infiltration on CT improved dramatically, and hepatic transaminases normalized.
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Affiliation(s)
- Q Cai
- Department of General Internal Medicine, Marshfield Clinic, Wisconsin, USA
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31
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Oien KA, Moffat D, Curry GW, Dickson J, Habeshaw T, Mills PR, MacSween RN. Cirrhosis with steatohepatitis after adjuvant tamoxifen. Lancet 1999; 353:36-7. [PMID: 10023952 DOI: 10.1016/s0140-6736(05)74872-8] [Citation(s) in RCA: 86] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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