Unrecognized hepatic steatosis and non-alcoholic steatohepatitis in adjuvant tamoxifen for breast cancer patients.

Nonalcoholic fatty liver disease (NAFLD) is strongly linked to central obesity, insulin resistance (IR), and metabolic syndrome ( 1 ), and its increasing prevalence is estimated at 20-30% among the adult population in industrialized countries ( 2 ).Although estrogen and androgen are important regulators of lipid homeostasis ( 3, 4 ), data on their possible infl uence on the prevention or treatment of NAFLD are scarce. Clinically, tamoxifen (Tam) is widely used for the treatment of estrogen-responsive breast cancer, but its frequent side effect is the development of NAFLD. Forty-three percent of patients with Tam-treated breast cancer develop steatosis Abstract It is important to clarify the distinct contributions of estrogen/estrogen receptor (ER) and androgen/androgen receptor (AR) signaling and their reciprocal effects on the regulation of hepatic lipid homeostasis. We studied the molecular mechanisms underlying the preventive effects of estradiol (E2), dihydrotestosterone (DHT), or E2+DHT on high-fat diet-induced nonalcoholic fatty liver disease (NAFLD) in an orchidectomized Sprague-Dawley (SD) rat model. E2 is shown to be associated with decreased fatty acid synthesis in hepatic zone 3-specifi c manner by increasing the phosphorylation of acetyl coenzyme-A carboxylase via an ER ␣ -mediated pathway. DHT is shown to be associated with decreased lipid accumulation and cholesterol synthesis in a hepatic zone 1-specifi c manner by increasing expression of carnitine palmitotyltransferase1 and phosphorylation of 3-hydroxy-3-methyl-glutaryl-CoA reductase via an AR-mediated pathway. E2+DHT showed an additive positive effect and normalized all three impaired zones of the liver. Gene expression changes in human severe liver steatosis were similar to those of experimental rat NAFLD. Steroids reversed the histopathological NAFLD changes, likely by decreasing fatty acid and cholesterol synthesis and increasing ␤ -oxidation. The diverse steroid effects (ER/AR) on NAFLD prevention in male rats indicate the potential applicability of ER/AR modulators for NAFLD treatment. -

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“…within the fi rst 2 years of treatment ( 5 ). Human estrogen receptor (ER) and aromatase defi ciency are very rare clinical conditions ( 6,7 ).…”

Section: Human Liver Specimensmentioning

confidence: 99%

“…6A ). In this de novo lipogenesis by [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C-labeling acetic acid procedure, we traced the total radiation that can refl ect the lipogenesis. Acetate is the precursor of lipid synthesis, and fatty acid is the substrate of sterols and lipid synthesis.…”

Section: Molecular Actions Of Estrogen and Androgen In A Rat Brl3a Hementioning

confidence: 99%

Differential effects of estrogen/androgen on the prevention of nonalcoholic fatty liver disease in the male rat

Zhang

Liu

Wang

et al. 2013

Journal of Lipid Research

123

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“…However, in clinical practice, there have been reports that patients with breast cancer developed NASH upon the administration of TAM (Murata et al, 2000). The causes were associated with obesity, but the detailed mechanism has not been elucidated.…”

mentioning

confidence: 99%

Hepatoprotective effect of tamoxifen on steatosis and non-alcoholic steatohepatitis in mouse models

et al. 2012

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-Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic lipid accumulation that starts with steatosis and progresses to non-alcoholic steatohepatitis (NASH). Recently, the number of patients with such liver diseases has increased, but the understanding of the fundamental mechanisms and appropriate therapies are lacking. Tamoxifen (TAM) is a selective estrogen receptor modulator. We previously reported that TAM plays a protective role against drug-induced and chemical-induced acute liver injuries. However, the effects of TAM on chronic liver injury, including steatosis and NASH, remain to be addressed. We first found that the administration of TAM to mouse models of steatosis and NASH significantly decreased the plasma ALT and AST levels. The administration of TAM decreased the accumulated fat and inflammation in the livers in both mouse models. In addition, we observed decreased hepatic mRNA levels of triglyceride synthesis, acyl-CoA: diacylglycerol acyltransferase 2 (DGAT2), proinflammatory cytokines, tumor necrosis factor (TNF) α, and chemokines, monocyte chemoattractant protein (MCP) -1. TAM increased the extracellular signal-regulated kinase (ERK) phosphorylation, which is related to the proliferation and regeneration of liver and to decreased DGAT2 gene expression. Furthermore, a decrease in eukaryotic translational initiation factor (eIF2α), which is involved in apoptosis, was observed in both models. These findings suggest that TAM treatment exerts a hepatoprotective effect against steatosis and NASH, presumably via up-regulation of the ERK pathways and attenuation of eIF2α activation. These pathways represent a potential therapeutic target for steatosis and NASH in drug development.

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“…Coşkun et al (8) demonstrated that hepatic steatosis may develop in relation to tamoxifen use. Hepatic steatosis may lead to severe liver dysfunction in some patients (9). Tamoxifen-induced hepatic steatosis may be followed by nonalcoholic steatohepatitis (NASH) development; and NASH may develop into cirrhosis (10).…”

Section: öZetmentioning

confidence: 99%

Tamoxifen-induced hepatic steatosis in premenopausal breast cancer patients

Parlak¹,

Süren²,

Dilli³

et al. 2011

Gaziantep Med J

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While aromatase inhibitors are replacing tamoxifen in postmenopausal breast cancer patients, tamoxifen continues to be the first-line hormonal therapy in premenopausal patients. Tamoxifen-induced hepatosteatosis may lead to nonalcoholic steatohepatitis (NASH), and NASH may develop into cirrhosis. If the development of hepatosteatosis is predicted, these patients may be treated with fibrates and statins. This study examines the development of hepatosteatosis in our premenopausal breast cancer patients that were taking tamoxifen for adjuvant therapy and were positive for the hormone receptors. Patients histopathologically diagnosed with breast cancer and with immunohistochemically demonstrated estrogen and/or progestron receptor expression were recruited for the study. All patients were assessed with ultrasonography by the same radiologist before tamoxifen therapy, at the sixth month of the follow-up and at the end of the first year. The study results were evaluated in thirty patients. Initial ultrasonography revealed grade 2 hepatosteatosis in four patients (13.3%), no change occurring at the repeat ultrasonography performed at the sixth month of the follow-up. Seven patients (23. 3%) were diagnosed as having grade 1 hepatosteatosis. A total of 12 patients (40%) were found to have hepatosteatosis at the end of the first year. Findings at the outset and those at the end of the first year were significantly different (p=0.021) as determined with the Wilcoxon test and Bonferroni correction performed to ascertain the difference in hepatosteatosis between the outset and the follow-up periods. No difference was obtained between the findings for the sixth month and those obtained at the end of the first year. In conclusion, the rate of hepatosteatosis as assessed with ultrasonography shows an increase with tamoxifen use in premenopausal patients. There was no difference between ultrasonography findings at the end of the first year and those at the sixth month of the follow-up. We think that the sitxh-month ultrasonography bears importance from the viewpoint of hepatosteatosis in these patients. Keywords: Breast cancer; hepatosteatosis; tamoxifen Özet Meme kanserli postmenopozal hastalarda aromataz inhibitörleri tamoksifenin yerini alırken premenopazal hastalarda tamoksifen ilk basamak hormonal tedavi olmaya devam etmektedir. Tamoksifen kullanımına bağlı hepatosteatoz sonrası nonalkolik steatohepatit (NASH) gelişebilmekte ve NASH siroza ilerleyebilmektedir. Hepatosteatoz gelişimi önceden tespit edilirse fibratlar veya statinler ile bu hastalar tedavi edilebilirler. Biz bu çalışmamızda adjuvan tedavisinde tamoksifen kullandığımız hormon reseptörü pozitif premenopozal meme kanseri hastalarımızda hepasteatoz gelişimini araştırdık. Histopatolojik olarak meme kanseri olduğu tespit edilmiş ve östrojen ve/veya progesteron reseptör ekspresyonu immünohistokimyasal olarak gösterilmiş premenopozal hastalar çalışmaya alındı. Bütün hastalara tamoksifen kullanmadan önce, takibinin altıncı ayında ve birinci yılı sonunda aynı ra...

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Unrecognized hepatic steatosis and non-alcoholic steatohepatitis in adjuvant tamoxifen for breast cancer patients.

Cited by 48 publications

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Differential effects of estrogen/androgen on the prevention of nonalcoholic fatty liver disease in the male rat

Differential effects of estrogen/androgen on the prevention of nonalcoholic fatty liver disease in the male rat

Hepatoprotective effect of tamoxifen on steatosis and non-alcoholic steatohepatitis in mouse models

Tamoxifen-induced hepatic steatosis in premenopausal breast cancer patients

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