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.

Materials and Methods

The protocol for this review was registered in advance with PROSPERO (International Prospective Register of Systematic Reviews, CRD42019135559). We conducted and reported this systematic review according to the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) checklist and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.

Inclusion Criteria, Exclusion Criteria and Study Outcome

Studies were included if they were a randomized controlled trial (RCT), cross-sectional study or cohort study, including both prospective or retrospective designs, which reported fatty liver events in adult patients (more than 18 years old) taking tamoxifen. The study participants were restricted to breast cancer patients without restrictions for comorbid conditions. Fatty liver was defined based on radiological imaging [ultrasound sonography (USG), computed tomography (CT)], histology or noninvasive serum markers using serum liver enzymes. Studies that met the following three inclusion criteria were selected for the analysis: (a) the study population consisted of breast cancer patients taking tamoxifen, (b) the association between tamoxifen and the development of fatty liver was assessed and (c) the outcome of interest was the prevalence or the incidence of fatty liver. The exclusion criteria were: (a) case reports, (b) case series for patients with total numbers less than five, (c) review articles, (d) cell studies or animal studies, (e) studies not showing the incidence of fatty liver and (f) studies including patients taking tamoxifen for prophylactic use without breast cancer.

The primary outcome of this study was the prevalence and incidence of fatty liver in patients taking tamoxifen. The secondary outcomes were comparisons of fatty liver incidence according to basal characteristics and the derivation of risk factors for fatty liver induced by tamoxifen.

Search Strategy

We searched synonymous terms and used these terms to develop the search strategy. The keywords used in the Patient/Problem, Intervention, Comparison and Outcome (PICO) model are shown in the Supplementary Material. We searched PubMed (Medline), EMBASE and OVID Medline, the Cochrane Library, KoreaMed, MedRIC and KSI KISS to identify studies published in English between 1 January 1987 and 31 May 2018. The search strategies and search results of each database are shown in the Supplementary Material. We excluded studies published before 1987 since the first case report of fatty liver due to tamoxifen was reported in 1987. All these search processes were conducted by a professional librarian (EAJ).

The search words were breast cancer-related index words ("breast neoplasms" OR "breast tumor" OR "breast carcinoma" OR "breast cancer" OR "mammary neoplasm" OR "mammary cancer" OR "mammary carcinoma" OR "mammary tumor" OR "breast malignant neoplasm"), tamoxifen-related index words ("tamoxifen" OR "antineoplastic agents, hormonal" OR "nolvadex" OR "tomaxithen" OR "zitazonium" OR "soltamox" OR "crisafeno") and non-alcoholic fatty liver disease-related index words ("non-alcoholic fatty liver" OR "NAFLD" OR "non-alcoholic steatohepatitis" OR "visceral steatosis" OR "liver steatosis"). Other details are shown in the Supplementary Material.

Study Selection and Data Extraction

The titles and abstracts were independently screened by two authors. Two reviewers (JJY, CBL) independently screened the relevant full-text articles. If any discrepancy between the two reviewers was found, it was resolved by SGK after discussion. In addition, two researchers independently screened all the other remnant stages, including full-text screening and the risk of bias assessment. Two reviewers (JJY, BL) extracted the study characteristics and the results and recorded these data in a standard form with any discrepancy resolved by YSK and SGK.

Methodological Quality and Risk of Bias Assessment

We used two tools to determine the risk of bias, the Cochrane risk of bias tool and the Suggested Quality Scoring System, which was proposed in 2008 by Doi^[10] to conduct quality-effects analysis. This information is provided in the Supplementary Material. If any discrepancy occurred, it was resolved by other authors (YSK and SGK) after a discussion. The overall result of the risk of bias is shown in the Supplementary Material.

Statistical Analysis

We derived the pooled prevalence using a random-effects model and a quality-effects (QE) model using the eight cross-sectional studies. We used the metaphor function from R package. The incidence, person-time and the number of fatty liver events among the patients treated with or without tamoxifen were calculated from the cohort studies or RCTs. The incidence rate ratios were polled by the DerSimonian–Laird estimator for τ ² with an inverse variance weight after log-transforming the study-specific incidence rate per 100 person-years. The risk factors were recorded as HRs with 95% CIs on a log-scale. They were weighted by the inverse of their corresponding variances to obtain pooled estimates.

We fitted the random-effects meta-analysis to account for the moderate to substantial heterogeneity in the prevalence and incidence among the studies according to the Cochrane collaboration. Additionally, a quality-effects model was applied to avoid confounding effects in the meta-analyses of the observational studies, using the quality score computed based on the criteria by Doi^[10] et al. We scored the quality of each study based on Doi's criteria and analysed the prevalence, incidence and incidence rate ratio using the metaXL program. To assess the effect of individual studies on the pooled estimates, a sensitivity analysis was conducted by re-estimation after omitting each study, one at a time. Publication bias was assessed using a funnel plot.

We used fixed-effects or random-effects meta-analysis, depending on the heterogeneity between studies. To explain the heterogeneity between the studies, subgroup analyses were conducted on the geographic region (eastern and western) and the fatty liver diagnostic method. Meta-regression was conducted to examine the influence of other factors on the clinical outcomes.

Statistical analyses were performed using RevMan 5 (Cochrane library) to assess the risk of bias and MetaXL (version 5.3; EpiGear International) for the quality-effects model. The overall meta-analyses were performed using the meta package in R (version 3.6.1; The R Foundation for Statistical Computing).

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Table 1. Demographics and characteristics of studies included in the systematic review and meta-analysis
Author (publication year)	Study design		F/U duration (y)	Ethnicity		No. of patients			Subject characteristic
Author (publication year)	Time point	Design	F/U duration (y)	Country	Continent	Total	Cases	Controls	Age	Menopause status	Type of participant	Comparator
Ogawa et al (1998)¹¹	Prospective	Cohort	8	Japan	Asia	66	66		49.6	All	Breast cancer patients
Saibara et al (1999)¹²	Retrospective	Cross-sectional	NA	Japan	Asia	51	51		NA	All	Breast cancer patients
Murata et al (2000)¹³	Retrospective	Cohort	5	Japan	Asia	136	105	31	52.51	All	Breast cancer patients	No tamoxifen use
Coskun et al (2002)¹⁴	Retrospective	Cohort	0.5	Turkey	Middle East	52	52		52	All	Breast cancer patients
Nemoto et al (2002)¹⁵	Retrospective	Cross-sectional	2.5	Japan	Asia	56	56		NA	Premenopause	Breast cancer patients who underwent breast conservation treatment
Gunel et al (2003)¹⁶	Retrospective	Cross-sectional	0.25	Turkey	Middle East	34	34		53	All	Breast cancer patients
Murata et al (2003)¹⁷	Prospective	Cross-sectional	NA	Japan	Asia	38	38		51	All	Breast cancer patients
Nishino et al (2003)¹⁸	Retrospective	Cohort	5	Japan	Asia	67	67		56.1	All	Breast cancer patients who underwent surgery
Ioannis et al (2004)¹⁹	Retrospective	Cohort	3.125	Greece	Western	60	60		60.7	All	Breast cancer patients
Nagaie et al (2005)²⁰	Retrospective	Cohort	2	Japan	Asia	156	156		55.2	All	Breast cancer patients who underwent surgery
Ohnishi et al (2005)²¹	Retrospective	Cross-sectional	5	Japan	Asia	180	180		49.6	All	Breast cancer patients
Liu et al (2006)²²	Prospective	Cohort	5.17	Taiwan	Asia	218	156	62	48.4	All	Stage 1 or 2 breast cancer who underwent surgery	No tamoxifen use
Bilici et al (2007)²³	Prospective	Cross-sectional	NA	Turkey	Middle East	30	17	13	48.5	All	Breast cancer patients treated with systemic therapy	Chemotherapy
Ashraf et al (2009)²⁴	Retrospective	Cross-sectional	0.58	India	Asia	3000	3000		NA	All	Breast cancer patients
Saphner et al (2009)⁵	Retrospective	Cohort	1.83	USA	Western	1105	806	292	58.67	All	Breast cancer patients	No tamoxifen use
Akhondi et al (2011)²⁵	Prospective	Cohort	0.5	Iran	Middle East	70	70		NA	All	Breast cancer patients who underwent chemotherapy
Lin et al (2014)²⁶	Prospective	RCT	3	China	Asia	353	175	178	59.6	Postmenopause	Breast cancer patients who underwent surgery or chemotherapy	Anastrozole 1 mg
Zheng et al (2015)²⁷	Retrospective	Cohort	6.33	China	Asia	417	417		43.5	All	Breast cancer patients who underwent surgery
Pan et al (2016)²⁸	Retrospective	Cohort	2.225	Taiwan	Asia	406	266	140	53.2	All	HER2-negative breast cancer or no tamoxifen use	Aromatase inhibitor
Yang et al (2016)²⁹	Retrospective	Cohort	4.42	Korea	Asia	185	90	95	50	All	Breast cancer patients	non-Selective estrogen receptor modulator group
Change et al (2017)³⁰	Retrospective	Cohort	2.69	Taiwan	Asia	266	266		52.9	All	Breast cancer patients
Hong et al (2017)³¹	Retrospective	Cohort	3.01	Korea	Asia	328	164	164	53.5	Postmenopause	Breast cancer patients who underwent surgery	Aromatase inhibitor
Wickramage et al (2017)³²	Retrospective	Cross-sectional	2.6	Sri Lanka	Asia	24	24		NA	All	Breast cancer patients
Yan et al (2017)³³	Retrospective	Cohort	5.58	China	Asia	646	646		NA	All	Breast cancer patients

Abbreviations: NA, not available; RCT, randomized controlled trial.

Table 2. Prevalence of tamoxifen-related fatty liver in patients with breast cancer
Author (y)	Prevalence per 100 person (95% CI)
Saibara et al (1999)	41.18 (56.85–63.61)
Nemoto et al (2002)	33.93 (55.43–61.73)
Gunel et al (2003)	44.12 (56.75–65.05)
Murata et al (2003)	34.21 (54.89–62.56)
Ohnishi et al (2005)	31.67 (56.20–59.63)
Bilici et al (2007)	70.59 (60.84–71.03)
Ashraf et al (2009)	55.00 (62.99–63.83)
Wickramage et al (2017)	16.67 (51.18–59.24)
Overall by random-effects model	40.25 (31.35–49.84)
Overall by quality-effects model	50.36 (30.04–70.55)
Heterogeneity, I ² (%), P by Q-statistic	83.78%, P < .001

Abbreviation: CI, confidence interval.

Table 3. Incidence rate and IRR of fatty liver due to tamoxifen
Author (y)	Incidence rate per 100 person-year (95% CI)		IRR (95% CI) Total
Author (y)	Tamoxifen	Control	IRR (95% CI) Total
Ogawa et al (1998)	4.55 (3.05–6.78)	—	—
Murata et al (2000)	7.62 (5.59–10.39)	0.32 (0.02–5.16)	23.91 (1.47–388.91)
Coskun et al (2002)	84.62 (55.72–128.51)	—	—
Nishino et al (2003)	8.66 (6.02–12.46)	—	—
Ioannis et al (2004)	13.87 (9.44–20.37)	—	—
Nagaie et al (2005)	89.86 (75.76–106.57)	—	—
Liu et al (2006)	10.17 (8.19–12.63)	2.5 (1.25–4.99)	4.07 (1.97–8.42)
Saphner et al (2009)	1.08 (0.66–1.77)	0.19 (0.03–1.33)	5.8 (0.77–43.71)
Akhondi et al (2011)	100 (71.8–139.28)	—	—
Lin et al (2014)	11.43 (8.87–14.72)	3.18 (1.98–5.12)	3.59 (2.1–6.15)
Zheng et al (2015)	2.88 (2.3–3.6)	—	—
Pan et al (2016)	20.03 (16.79–23.9)	5.53 (3.39–9.03)	3.62 (2.15–6.1)
Yang et al (2016)	9.33 (6.82–12.77)	3.04 (1.94–4.76)	3.07 (1.77–5.31)
Change et al (2017)	17.19 (14.41–20.51)	—	—
Hong et al (2017)	12.56 (9.79–16.11)	8.3 (6.11–11.28)	1.51 (1.02–2.24)
Yan et al (2017)	6.13 (5.37–6.99)	—	—
Overall by random-effects model	12.37 (7.22–21.20)	3.15 (1.78–5.57)	3.12 (2.05–4.75)
Overall by quality-effects model	11.71 (6.37–21.53)	3.82 (1.12–13.05)	2.87 (1.88–4.38)
Heterogeneity, I ² (%), P by Q-statistic	98.75%, P < .001	83.82%, P < .001	61.67%, P = .016

Abbreviations: CI, confidence interval; IRR, incidence rate ratio; NA, not available.

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

A Systematic Review and Meta-analysis

Materials and Methods

Inclusion Criteria, Exclusion Criteria and Study Outcome

Search Strategy

Study Selection and Data Extraction

Methodological Quality and Risk of Bias Assessment

Statistical Analysis

Tables

Tables

Tables

References

Authors and Disclosures

Authors and Disclosures

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