Prevalence, Incidence and Risk Factors of Tamoxifen-related Non-alcoholic Fatty Liver Disease

A Systematic Review and Meta-analysis

Bora Lee; Eun-Ae Jung; Jeong-Ju Yoo; Sang Gyune Kim; Cheon-Beom Lee; Young Seok Kim; Soung Won Jeong; Jae Young Jang; Sae Hwan Lee; Hong Soo Kim; Baek Gyu Jun; Young Don Kim; Gab Jin Cheon

Disclosures

Liver International. 2020;40(6):1344-1355. 

In This Article

Abstract and Introduction

Abstract

Background & Aims: Tamoxifen is associated with an increased risk of developing fatty liver. The aim of this systematic review and meta-analysis was to evaluate the prevalence and incidence of fatty liver developed after tamoxifen treatment in breast cancer patients.

Methods: A systematic search of PubMed (Medline), EMBASE, OVID Medline, the Cochrane Library and other databases was performed for this review. The abstracts obtained from the search were reviewed by two investigators who chose manuscripts for full-text review. The event rates were calculated with a random-effects model and quality-effects model.

Results: The search yielded 165 references. Of these, 24 were included in the quantitative summary. We analysed the data of a total of 6,962 patients treated with tamoxifen and 975 patients not treated with tamoxifen. The prevalence of fatty liver among patients with breast cancer taking tamoxifen was 40.25 per 100 patients and the incidence rate was 12.37 per 100 person-years. The incidence of fatty liver was much higher in the tamoxifen group than in the control group [incidence rate ratio: 3.12, 95% CI (confidence interval): 2.05–4.75, I 2 = 61%], regardless of region. The main risk factors were body mass index (BMI) [hazard ratio (HR): 1.15, 95% CI: 1.09–1.22] and hypercholesterolaemia (HR: 1.01, 95% CI: 1.00–1.02).

Conclusion: The use of tamoxifen was associated with increased risks in the incidence and prevalence of fatty liver, especially in patients with high BMI and hypercholesterolaemia.

Introduction

Tamoxifen is an anti-oestrogen drug widely used in the treatment of oestrogen receptor (ER)-positive breast cancer patients.[1] Tamoxifen therapy has been shown to reduce the recurrence of breast cancer and increase the survival of breast cancer patients.[2] Recently, 10 years of tamoxifen use was shown to be more effective than 5 years of tamoxifen use in terms of mortality and recurrence.[3] Considering that the incidence of breast cancer is increasing globally, the number of patients taking tamoxifen is expected to increase.

Tamoxifen has been associated with various hepatotoxicities, including fatty liver, steatohepatitis and cirrhosis.[4–6] Specifically, tamoxifen is a well-known drug that causes drug-induced fatty liver. Several prospective studies have reported that fatty liver develops in about one-third of patients exposed to tamoxifen.[7] Since tamoxifen-induced fatty liver is insidious and physicians' attention to the disorder is relatively low, the recognition that fatty liver has occurred is often delayed. Fatty liver development can increase the incidence of other metabolic diseases, including cardiovascular disease and diabetes.[8] Furthermore, tamoxifen-associated severe fatty liver can cause cirrhosis and portal hypertension.[9]

Given the common occurrence of this side effect, there are relatively few studies on the association between tamoxifen use and fatty liver. Although the causal relationship between fatty liver and tamoxifen is strong and consistent, it is still uncertain whether there are regional differences in the incidence or risk factors of fatty liver in patients with breast cancer taking tamoxifen. To date, a meta-analysis analysing the association between tamoxifen use and fatty liver development has not been published. Since the duration of tamoxifen use is likely to be extended, it becomes more important to understand the characteristics of fatty liver caused by tamoxifen. In this context, we carried out a comprehensive systematic review and meta-analysis of published studies to determine the prevalence and incidence of fatty liver due to tamoxifen use. We also investigated the risk factors for the development of fatty liver in breast cancer patients taking tamoxifen.

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