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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

¹ Department of Radiology, Kyoto City Hospital, 1-2 Higashi-takada-cho, Mibu, Nakagyo-ku, Kyoto 604-8845, Japan.
² Department of Surgery, Kyoto City Hospital, Kyoto 604-8845, Japan.

Received February 28, 2002; accepted after revision June 18, 2002.

 
Presented at the annual meeting of the Radiological Society of North America, Chicago, November 2001.

Address correspondence to M. Nishino.

Abstract

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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.

Introduction

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Tamoxifen is a potent antiestrogen agent that has become the most common form of adjuvant hormonal therapy for breast cancer [1, 2]. Although its overall safety record has been good, tamoxifen has been associated with some adverse effects, including endometrial cancer, deep vein thrombosis, pulmonary embolism, and retinopathy [1]. However, to our knowledge, hepatic steatosis has been relatively unrecognized as an adverse effect and remains to be studied systematically.

A number of case reports have described hepatic steatosis associated with adjuvant tamoxifen [3,4,5,6,7,8]. The hepatic steatosis was transient and occurred with or without hepatic dysfunction, histologically proven nonalcoholic steatohepatitis, or even cirrhosis of the liver. However, few systematic studies are concerned with the frequency, clinical course, and imaging appearances of this condition. Such details should be clarified for the benefit of radiologists so that they can be alerted to possible hepatic dysfunction and can differentiate hepatic steatosis from metastasis.

In this study, we examined retrospectively the follow-up unenhanced CT records of postoperative patients with breast cancer who were receiving tamoxifen to obtain their hepatic CT attenuation values and to evaluate the changes in hepatic fat content and the development of hepatic steatosis. Our aim was to determine the effects of tamoxifen on hepatic fat content, the frequency of hepatic steatosis, and its clinical course in postoperative patients with breast cancer.

Materials and Methods

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From among 201 patients who underwent surgery for breast cancer in our institution from 1990 to 1996, we selected 67 patients (age range, 34-79 years; mean, 56.1 years) who had completed one preoperative and five postoperative abdominal CT examinations to rule out metastasis. Twenty-four patients had stage I breast cancer, and 43 had stage II breast cancer. Fifty-eight patients had undergone mastectomy, and nine had breast-conserving treatment consisting of lumpectomy, local radiation therapy, and adjuvant hormonal therapy. Forty-two patients were treated with adjuvant tamoxifen (Astra Zeneca, Osaka, Japan) at 20 mg per day for 2 years, and 25 patients received the same regimen for 5 years. UFT (Taiho Pharmaceutical, Tokyo, Japan), a drug composed of uracil and tegafur at a molar ratio of 4:1, was added along with tamoxifen for all patients with stage II disease, at a dose of 600 mg/day for 1 year. Patients with excessive consumption of alcohol (weekly consumption, >150 g), severe obesity (body mass index, >30 kg/m²), diabetes mellitus, chronic hepatitis type B or type C, autoimmune hepatitis, hemochromatosis, or steroid therapy were excluded on the basis of their history and results of laboratory tests. Patients who had been found to have hepatic steatosis in the preoperative examination were also excluded.

The patients underwent preoperative examination and postoperative annual follow-up abdominal CT for 5 years to rule out metastasis. We obtained both unenhanced and contrast-enhanced CT images at a slice thickness of 10 mm with a 10-mm interval using single-detector helical CT, either a ProSeed scanner (General Electric Yokogawa Medical Systems, Tokyo, Japan) or a ProSeed SA Libra scanner (General Electric Yokogawa Medical Systems). The CT techniques, including slice thickness and intervals, were not changed from 1990 to 2000. Because the study was retrospective, informed consent was not obtained specifically, and CT was performed as part of the clinical follow-up to rule out metastasis. Two radiologists who were familiar with the patients' histories of breast cancer reviewed these CT images retrospectively and obtained the CT attenuation values in eight Couinaud segments of the liver and in one region of the spleen on unenhanced scans, using a 1.0-cm diameter region of interest and avoiding vessels. One region of interest was used in each Couinaud segment and in the spleen. The averages of the CT attenuation values obtained by two radiologists were calculated and used as representative values.

The changes in mean hepatic CT attenuation values of eight segments in individuals before, during, and after therapy were monitored to evaluate the effect of tamoxifen on hepatic fat content.

To detect the development of hepatic steatosis and to monitor the degree of steatosis, we calculated the liver—spleen ratio using the lowest CT value for the liver. Hepatic steatosis was defined as a liver—spleen CT ratio of less than 0:9, and the degree of steatosis was classified as mild (liver—spleen ratio, 0:5-0.9), moderate (0-0:5), or severe (<0). The lowest liver—spleen ratio throughout the study in each patient was used for the classification.

In patients who showed reversal of hepatic steatosis after tamoxifen therapy, the recovery time was assessed, and the correlation of the degree of steatosis with the recovery time was evaluated statistically, using the chi-square test.

In patients who developed hepatic steatosis, body mass index before, during, and after the tamoxifen therapy was calculated. To evaluate the effect of the length of tamoxifen therapy on hepatic steatosis, we correlated the number of patients who developed hepatic steatosis in the 2-year therapy group and the 5-year therapy group. We also compared the frequency of steatosis in stage I patients with that of stage II patients to evaluate whether UFT influenced the development of hepatic steatosis. To monitor hepatic function, we obtained liver aminotransferase levels annually. No patients underwent liver biopsy. The pattern of steatosis was classified as generalized, lobar, segmental, or focal, on the basis of the liver—spleen ratio and imaging findings.

A paired t test was used to assess the statistical significance of changes in hepatic CT attenuation values, liver—spleen ratios, and body mass indexes during and after tamoxifen therapy. The chi-square test was used to assess the correlation between the development of hepatic steatosis and the duration of therapy, the effect of UFT on the development of steatosis, and the correlation between the degree of steatosis and recovery time.

Results

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Effect of Tamoxifen on Hepatic Fat Content
The mean CT values for eight Couinaud segments in each patient showed a statistically significant decrease during therapy (p < 0.0001, paired t test) and an increase after therapy (p < 0.0001, paired t test) (Fig. 1). The mean hepatic CT attenuation value for the study population also decreased during therapy and increased after therapy (Table 1). The splenic CT attenuation values remained unchanged during tamoxifen therapy (p > 0.1, paired t test) (p > 0.1, Wilcoxon's signed rank test) but increased slightly after therapy (p = 0.03, paired t test; p > 0.1, Wilcoxon's signed rank test). Tamoxifen showed a statistically significant influence on hepatic fat content. However, 10 patients showed an increase in hepatic CT attenuation values during tamoxifen therapy (range of increase, 1-9 H; mean, 6.5 H). Five of these patients showed a further increase after therapy (range of increase, 5-13 H; mean, 5.6 H). Two showed no change after therapy, and three showed a decrease after therapy (range of decrease, 3-6 H; mean, 4.7 H).

View larger version (38K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 1. —Chart shows mean hepatic CT attenuation values of all patients throughout study. Among mean CT attenuation values of liver obtained each year while patients were undergoing tamoxifen therapy, lowest value was used as "During" (p < 0.0001, paired t test). Each color represents a different patient.

Frequency and Clinical Course of Hepatic Steatosis
Twenty-nine patients (43.2%) developed hepatic steatosis within the first 2 years of therapy: 17, in the first year and 12, in the second. No patient developed steatosis after the first 2 years of therapy. Among 42 and 25 patients who received tamoxifen for 2 and 5 years, 15 and 14 patients, respectively, developed hepatic steatosis. No significant correlation occurred between the duration of therapy and the development of steatosis (p > 0.1, chi-square test). The mean duration of tamoxifen therapy before the development of steatosis was 1.4 years (SD, ± 5 years). The degree of steatosis was mild in 16 patients, moderate in nine, and severe in four. After completing therapy, 23 patients (79.3%) showed an increase in the liver—spleen ratio to within the normal range. In 21 patients (degree of steatosis mild in 13, moderate in six, and severe in two), resolution of steatosis required 1 year. In six patients (degree of steatosis mild in three, moderate in two, and severe in one), resolution took 2 years, with a mean recovery time of 1.2 years (SD, ± 4 years). No significant correlation occurred between the degree of steatosis and the length of recovery time (p > 0.5, chi-square test).

During tamoxifen therapy, body mass index increased in 31 patients, showed no change in 30, and decreased in six, compared with the body mass index before therapy, but the changes were not statistically significant (p > 0.1, paired t test). After tamoxifen therapy, body mass index increased in 23 patients, showed no change in 24, and decreased in 20, but the changes were not statistically significant (p > 0.1, paired t test).

Among 24 patients with stage I disease who received tamoxifen alone, eight developed hepatic steatosis (mild in five and moderate in three). Of 43 patients with stage II disease who received UFT along with tamoxifen, 21 developed hepatic steatosis (mild in 11, moderate in six, and severe in four). No significant difference was found in either the frequency or degree of hepatic steatosis between patients with stage I disease and those with stage II disease (p > 0.2, p > 0.4, respectively; chi-square test).

Figure 2A,2B,2C,2D shows a representative case, in which the CT attenuation of the liver decreased dramatically during therapy and reversed rapidly after therapy. Figure 3 shows the liver—spleen ratio before, during, and after therapy of each patient who developed hepatic steatosis.

View larger version (95K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 2A. —55-year-old woman with representative CT findings of transient hepatic steatosis. Unenhanced abdominal CT image obtained before tamoxifen therapy shows normal homogeneous CT attenuation of liver, which is slightly higher than that of spleen. Liver—spleen ratio was 1.3.

View larger version (98K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 2B. —55-year-old woman with representative CT findings of transient hepatic steatosis. Unenhanced abdominal CT image obtained after 1 year of tamoxifen therapy shows decrease in CT attenuation of liver predominantly in right lobe, with liver—spleen ratio of 0.3. Note development of moderate hepatic steatosis.

View larger version (102K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 2C. —55-year-old woman with representative CT findings of transient hepatic steatosis. Unenhanced abdominal CT image obtained after 2 years of tamoxifen therapy shows further decrease in CT attenuation of liver in right lobe, with liver—spleen ratio of 0.1. Degree of steatosis is still moderate.

View larger version (102K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 2D. —55-year-old woman with representative CT findings of transient hepatic steatosis. Unenhanced abdominal CT image obtained 1 year after completion of tamoxifen therapy shows that CT attenuation of liver has returned to normal, with liver—spleen ratio of 1.1. Steatosis is not present.

View larger version (26K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 3. —Chart shows liver—spleen ratio in 29 patients with hepatic steatosis before, during, and after tamoxifen therapy. Liver—spleen ratio was calculated using lowest CT attenuation value of liver among values in the eight Couinaud segments. Each color represents a different patient.

Two patients showed persistent steatosis for more than 2 years after therapy. Both patients had stage II disease and received tamoxifen for 5 years along with 1 year of UFT therapy. The degree of steatosis was severe in one and moderate in the other. Four patients completed tamoxifen therapy within 1 year of the study period and required further follow-up.

Liver aminotransferase levels before tamoxifen therapy were normal in all patients included in the study. In 38 patients who did not develop hepatic steatosis, liver aminotransferase levels remained normal during and after tamoxifen therapy, except for transient elevation in two patients due to acute cholecystitis during therapy. Among 29 patients who developed hepatic steatosis, four (13.8%) showed an increase in aminotransferase levels of the liver during therapy, the highest alanine aminotransferase and aspartate aminotransferase levels reaching 140 U/L and 146 U/L, respectively. The details of these patients are summarized in Table 2. Aminotransferase levels of the liver readily returned to normal after discontinuation of tamoxifen, and steatosis was resolved. The reversal of the aminotransferase levels coincided with, or was earlier than, the reversal of steatosis and occurred within 2 years after the end of therapy (Table 2). The remaining patients with hepatic steatosis showed normal liver aminotransferase levels during and after tamoxifen therapy. No patients showed hyperbilirubinemia, hypoalbuminemia, or coagulopathy, and the development of cirrhosis was not observed. None underwent liver biopsy.

Pattern of Steatosis
Seventeen patients showed a generalized pattern of steatosis, and the other 12 showed a lobar pattern with right lobe involvement.

Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
To date, the effect of tamoxifen on hepatic fat content has not been precisely investigated. In our study, the hepatic CT attenuation value, and thus hepatic fat content, was significantly influenced by the administration and withdrawal of tamoxifen. The increase of fat content during therapy and the decrease after therapy were observed not only in patients who developed obvious hepatic steatosis but also in patients without steatosis. Although we did not perform a histologic evaluation of hepatic fat content, the correlation between hepatic CT attenuation value and hepatic fat content has been studied in detail and is well established [9]. Therefore, we concluded that tamoxifen influenced the hepatic fat content. Although, to our knowledge, the mechanism responsible for the effects of tamoxifen on hepatic fat content has not yet been elucidated, tamoxifen may block the role of estrogen in maintaining hepatic lipid homeostasis by supporting the expression of genes involved in lipid ß-oxidation [10].

Ten patients in our study showed an increase in hepatic CT attenuation during tamoxifen therapy, although these values might have been influenced by other factors, such as diet or certain systemic conditions.

The mean CT attenuation value of the spleen slightly increased after the end of tamoxifen therapy. The increase was statistically significant in the paired t test (p = 0.03) but was not statistically significant in Wilcoxon's test (p > 0.1). The increase in splenic CT attenuation values can be due to the differences in examination dates, CT scanners, and the regions in which the CT attenuation values were obtained.

Our study showed that hepatic steatosis was a frequent complication associated with tamoxifen, occurring in 43.2% of patients. This rate of involvement is much higher than that of other tamoxifen-related conditions, such as deep vein thrombosis, observed in 1-2% of patients, and endometrial hyperplasia, observed in 16% of patients [2]. For the diagnosis of hepatic steatosis, we used the liver—spleen ratio; the major diagnostic criterion for hepatic steatosis is a liver—spleen ratio of less than 0:9 or a hepatic CT attenuation value of 10 H less than that of the spleen [11].

The distribution of fatty infiltration was right-lobe dominant, compatible with other reports of hepatic steatosis due to other causes [12]. This distribution may be due in part to the higher content of medium-chain fatty acids and glucose and the absorbed content of tamoxifen in the superior mesenteric venous blood, directed predominantly to the right lobe by so-called streamline flow [13]. In this study, no patients showed a focal pattern of steatosis. However, there may be cases in which fatty infiltration of the liver is difficult to differentiate from metastatic liver tumor [14]. Thus, radiologists should be aware of the common occurrence of hepatic steatosis in patients receiving tamoxifen.

Many factors may influence hepatic fat content and the development of hepatic steatosis during tamoxifen therapy. In this study, therapy duration did not seem to influence the development of hepatic steatosis because no significant difference in frequency occurred between patients given tamoxifen for 2 years and those given the drug for 5 years.

To avoid the influence of other factors as much as possible, we excluded patients with excessive consumption of alcohol, severe obesity, diabetes mellitus, chronic hepatitis type B or type C, autoimmune hepatitis, and hemochromatosis and those having undergone steroid therapy. The body mass index of patients with steatosis did not show any significant change throughout therapy, suggesting that steatosis was not due to development of obesity during therapy.

In patients with colorectal cancer, 5-fluorouracil is known to cause reversible hepatic steatosis [14,15,16]. UFT, a chemotherapeutic agent used in patients with stage II disease, is composed of uracil and tegafur and serves as a prodrug of 5-fluorouracil. Although UFT itself has not been reported to cause steatosis, it may show such a tendency because of its uracil content. In our study, no significant difference in the frequency or degree of hepatic steatosis was seen between patients given tamoxifen alone and those given tamoxifen and UFT. This finding might be due to the steatotic influence of tamoxifen masking the effect of UFT, although further studies with appropriate control groups would be needed for confirmation.

Hepatic steatosis was readily reversed in most cases (79.3%) within 1 or 2 years after therapy. This prompt recovery can be recognized as one of the characteristics of tamoxifen-associated hepatic steatosis. No correlation was seen between recovery time and the severity of steatosis.

It is reported that nonalcoholic steatohepatitis and even liver cirrhosis can be associated with tamoxifen [6, 8]. In our study, only four patients showed a transient increase in aminotransferase levels of the liver during tamoxifen therapy. In two patients, steatosis persisted after therapy and required further follow-up. Therefore, although the likelihood of developing steatohepatitis and cirrhosis is low after tamoxifen therapy, the possibility must be borne in mind.

The limitations of the study included lack of a control group and limited follow-up after discontinuation of tamoxifen. An appropriate group of control patients was not available because of the limited number of patients with breast cancer treated without tamoxifen. Thus, we could not exclude all possible factors other than tamoxifen that might have influenced hepatic fat content and the development of hepatic steatosis.

In conclusion, we found that tamoxifen has a strong influence on hepatic fat content and is strongly associated with the frequent development and rapid reversal of hepatic steatosis in patients with breast cancer. Annual CT studies are useful for detecting and monitoring the clinical course of tamoxifen-induced hepatic steatosis. The frequent occurrence of hepatic steatosis should be recognized as an indication of possible hepatic dysfunction and highlights the need to differentiate steatosis from metastatic liver tumors.

Acknowledgments
 
We thank Yuji Itai, Kaori Togashi, and Hiroto Hatabu for their valuable comments and suggestions.

References

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