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Prevalence and risk factors of nonalcoholic fatty liver disease in breast cancer patients

Prevalence and risk factors of nonalcoholic fatty liver disease in breast cancer patients

Tumori 2017; 103(2): 187 - 192

Article Type: ORIGINAL RESEARCH ARTICLE

DOI:10.5301/tj.5000536

Authors

Seokwon Lee, Younglae Jung, Youngtae Bae, Sung Pil Yun, Suk Kim, Hongjae Jo, Hyung-Il Seo

Abstract

Aims and background

We aimed to evaluate the prevalence of nonalcoholic fatty liver disease (NAFLD) in breast cancer patients using liver magnetic resonance imaging (MRI), and to investigate factors associated with NAFLD.

Methods

We evaluated 104 patients surgically treated for breast cancer at our hospital between September and November 2013. None of the patients had any other causes of secondary hepatic fat accumulation (such as significant alcohol consumption, use of steatogenic medication or inborn disorders). Hepatic fat accumulation was measured using liver MRI perfomed in all patients before surgical treatment.

Results

Based on the fat signal percentage from liver MRIs, 19 of 104 breast cancer patients were diagnosed with NAFLD, so the prevalence of NAFLD was 18.3%. In univariate analysis, factors associated with NAFLD were older age, high body mass index, type 2 diabetes mellitus (DM), hypertension, elevated aspartate aminotransferase, elevated alanine aminotransferase and elevated triglycerides (TG). In multivariate analysis, factors associated with NAFLD were high body mass index (BMI) (odds ratio [OR] 1.403; 95% confidence interval [CI] 1.111-1.771; p = 0.005), type 2 DM (OR 11.872; 95% CI 1.065-132.373; p = 0.044), and an elevated TG level (OR 50.267; 95% CI 4.409-573.030; p = 0.002).

Conclusions

The prevalence of NAFLD in breast cancer patients was not different from that of the general population. High BMI, type 2 DM and an elevated serum TG level were factors associated with NAFLD.

Article History

Disclosures

Financial support: This work was supported by the year 2015 clinical research grant from Pusan National University Hospital.
Conflict of interest: The authors declare that they have no conflict of interest.

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Introduction

Nonalcoholic fatty liver disease (NAFLD) refers to the presence of hepatic steatosis (HS) when no other causes for secondary hepatic fat accumulation (such as significant alcohol consumption, use of steatogenic medication or inborn disorders) are present (1). NAFLD is the most common liver disorder in Western industrialized nations, and its prevalence is increasing (2). Approximately 20%-30% of the general population suffer from NAFLD. There are various methods to detect and monitor NAFLD, including liver biopsy, ultrasonography (US), computed tomography (CT), and magnetic resonance imaging (MRI). The standard method for diagnosing NAFLD is liver biopsy, which offers histopathological confirmation. However, the recommended diagnostic method for identifying NAFLD is MRI, as it is more sensitive and specific for NAFLD than other modalities. In addition, it is less invasive than a liver biopsy and can quantify the degree of NAFLD (3). Therefore, we evaluated the presence of NAFLD using MRI as a noninvasive diagnostic modality.

Breast cancer is the most common cancer in women worldwide. Nearly 1.7 million patients are newly diagnosed with breast cancer each year, and this number is on the rise. A westernized diet and lifestyle are thought to increase the incidence of breast cancer in developing countries and they also may increase the prevalence of NAFLD. In addition, obesity and hyperlipidemia, 2 risk factors for breast cancer, are also associated with the development of NAFLD (4, 5). Although NAFLD is considered a form of metabolic syndrome, it is often overlooked in patients with breast cancer, and research into NAFLD has not been conducted in this particular population.

In this study, we evaluated the prevalence of NAFLD in breast cancer patients using liver MRI, and compared it with the reported prevalence of NAFLD in the general population. Furthermore, we investigated factors associated with NAFLD.

Materials and methods

The institutional review board of Pusan National University Hospitals approved this study (IRB approval no. E-2015026).

Study population

We evaluated 104 patients who were surgically treated for breast cancer at our hospital between September and November 2013. None of these patients had undergone prior neoadjuvant treatment (i.e., chemotherapy, endocrine therapy or targeted therapy), and none had any of the following conditions: clinical symptoms and signs of inborn metabolic disorders, elevated liver enzyme levels (aspartate aminotransferase [AST], alanine aminotransferase [ALT], and gamma glutamyl transferase [GGT]), a history of drug use associated with liver steatosis, or consumption of >20 g of alcohol per day.

Clinical data and demographic information

We also ascertained patients’ demographic characteristics and preoperative laboratory test results, including age, a history of type 2 diabetes mellitus (DM) and hypertension, body mass index (BMI, kg/m2), lipid profile (total cholesterol, low-density lipoprotein [LDL] cholesterol, high-density lipoprotein [HDL] cholesterol, and triglycerides [TG]), and liver enzymes. Abnormal values of liver enzymes and lipid profiles were defined as being over the upper limit of the normal range. We defined abnormal BMI as BMI ≥25 kg/m2, because several studies have shown that BMI ≥25 kg/m2 is the appropriate cutoff for obesity in Asian populations including the Korean population (6).

Liver MRI and interpretation

Hepatic fat accumulation was measured using MRI in all patients before surgical treatment. Liver MRI was performed using an Achieva 3.0T TX MRI scanner (Philips Medical Systems) with a multichannel phased-array surface coil. A T1-weighted double echo was taken using turbo-field echo sequencing with a respiratory trigger technique. Imaging parameters were as follows: repetition time, 10 ms; echo time, 2.3 ms (in-phase, IP) or 1.15 ms (out-of-phase, OP); flip angle, 15°; number of signal average, 1; field of view, 375 mm; matrix, 256 × 256; number of slices, 24; slice thickness, 6 mm; and slice interval, 0 mm. On a picture archiving and communication system workstation (Maroview; Maro Tech Inc.), an experienced radiologist measured the signal intensities (SI).

At the liver hilar level, 4 circular 20-mm regions of interest were outlined on the right anterior and left interior lobes of the liver and the anterior and posterior parts of the spleen, taking care to avoid large vascular structures (Fig. 1).

Measurement of signal intensities on liver magnetic resonance imaging on in-phase T1-weighted (left) and out-of-phase T1-weighted images (right). The in-phase MR image shows a hepatic-to-splenic signal intensity ratio of (894 + 1108)/(733 + 617) = 1.48. The out-of-phase MR image shows a hepatic-to-splenic signal intensity ratio of 969.5/661.5 = 1.47. The calculated fat signal percentage (FSP) is [(1.48-1.47)/(2 × 1.48)] × 100 = 0.3%, a finding indicative of no steatosis.

Liver SI was used as the mean value of the left and right lobes of the liver, whereas spleen SI was used as the mean value of the anterior and posterior parts of the spleen. A common formula for calculating the fat signal percentage (FSP) in the liver is as follows: FSP = [(SI of T1 IP − SI of T1 OP) ÷ 2(SI of T1 IP)] × 100. SI of T1 IP is the ratio of the hepatic signal intensity to the splenic signal intensity on IP T1-weighted images (Fig. 1). SI of T1 OP is the ratio of the hepatic signal intensity to the splenic signal intensity on OP T1-weighted images (Fig. 1) (7). We chose an FSP cutoff of 5% to denote steatosis, as determined by MRI, which is a value commonly attributed to the likelihood of NAFLD (1, 8). Therefore, the cohort was divided into 2 groups: a control group (FSP ≤5%) and an NAFLD group (FSP >5%).

Statistical analysis

Continuous and categorical variables are presented as mean ± standard deviation (SD) or frequency (%). Continuous variables were compared using the independent sample t-test or Mann-Whitney U-test, as appropriate. The chi-square test or Fisher’s exact test was used to determine the significance of differences in categorical variables. Binary logistic regression was used to detect major risk factors for NAFLD. Statistical analyses were performed using SPSS, version 20.0 (IBM Corp.). In all analyses, the significance level was set at 0.05.

Results

Table I shows the baseline characteristics of the 104 breast cancer patients grouped according to the presence or absence of NAFLD. Using FSPs from liver MRIs, 19 of 104 patients were diagnosed with NAFLD. As a result, the prevalence of NAFLD in breast cancer patients was 18.3%. The NAFLD group differed significantly from the control group in terms of age, prevalence of type 2 DM or hypertension, BMI, and levels of AST, ALT, TG and HDL cholesterol.

Baseline characteristics and preoperative laboratory test results of study patients according to the incidence of nonalcoholic fatty liver disease (n = 104)

Characteristic Control (n = 85) No. (%) or mean ± SD NAFLD (n = 19) No. (%) or mean ± SD P value
A p value <0.05 indicates statistical significance.
NAFLD = nonalcoholic fatty liver disease; SD = standard deviation; BMI = body mass index; DM = diabetes mellitus; HT = hypertension; AST = aspartate aminotransferase; ALT = alanine aminotransferase; GGT = gamma glutamyl transferase; LDL = low-density lipoprotein; TG = triglycerides; HDL = high-density lipoprotein; NA = not applicable.
Age (years) 49.29 ± 9.11 57.16 ± 11.51 0.002
BMI (kg/m2) 22.83 ± 2.92 26.72 ± 5.17 0.002
Comorbidities
 Type 2 DM 6 (7.1) 5 (26.3) 0.027
 HT 13 (15.3) 13 (68.4) <0.001
 Hepatitis B 4 (4.7) 0 (0.0) 1.000
 Hepatitis C 0 0 NA
Liver enzymes (IU/L)
 AST 21.24 ± 11.64 34.58 ± 29.34 <0.001
 ALT 17.31 ± 12.55 36.16 ± 21.22 <0.001
 GGT 22.18 ± 27.94 35.94 ± 24.30 <0.001
Lipid profiles (mg/dL)
 Total cholesterol 189.006 ± 34.87 200.26 ± 33.90 0.226
 LDL cholesterol 118.15 ± 32.17 125.53 ± 35.05 0.265
 TG 99.31 ± 50.06 215.37 ± 112.47 <0.001
 HDL cholesterol 60.51 ± 14.41 49.47 ± 9.45 <0.001

The proportion of abnormal values of preoperative AST, ALT, TG, and HDL cholesterol showed statistically significant differences between groups. The percentage of AST, ALT, and TG values exceeding the normal range was high in the NAFLD group (p<0.05). By contrast, high HLD cholesterol (>72 mg/dL), which is beneficial to health, was observed only in the control group (p = 0.006). The groups did not differ significantly in GGT, total cholesterol, and LDL cholesterol values (Fig. 2).

Normal values of the laboratory parameters are as follows: AST = ≤40 IU/L; ALT = ≤40 IU/L; GGT = ≤73 IU/L; total cholesterol = ≤210 mg/dL; LDL cholesterol = ≤160 mg/dL; TG = ≤262 mg/dL; HDL cholesterol = ≤72 mg/dL. Abnormal values are defined as out of the normal range. AST = aspartate aminotransferase; ALT = alanine aminotransferase; GGT = gamma glutamyl transferase; TC = total cholesterol; LDL = low-density lipoprotein cholesterol; TG = triglycerides; HDL = high-density lipoprotein cholesterol.

To identify risk factors associated with NAFLD, we performed univariate and multivariate analyses (Tab. II). In univariate analysis, factors associated with NAFLD were older age (odds ratio [OR] 1.087; 95% confidence interval [CI] 1.028-1.149), high BMI (OR 1.295; 95% CI 1.126-1.490), DM (OR 4.702; 95% CI 1.261-17.531), hypertension (OR 12.000; 95% CI 3.863-37.274), and abnormal levels of AST (OR 5.400; 95% CI 1.215-23.994), ALT (OR 9.333; 95% CI 2.548-34.184), and TG (OR 4.028; 95% CI 1.360-11.926). In multivariate analysis, factors associated with NAFLD were high BMI (OR 1.403; 95% CI 1.111-1.771), type 2 DM (OR 11.872; 95% CI 1.065-132.373), and an abnormal TG level (OR 50.267; 95% CI 4.409-573.030).

Univariate and multivariate analyses of factors associated with nonalcoholic fatty liver disease (n = 104, control vs. NAFLD)

Characteristic Unadjusted OR (95% CI) P value Adjusted OR (95% CI) P value
A p value <0.05 indicates statistical significance.
NAFLD = nonalcoholic fatty liver disease; OR = odds ratio; CI = confidence interval; DM = diabetes mellitus; HT = hypertension; BMI = body mass index; AST = aspartate aminotransferase; ALT = alanine aminotransferase; GGT = gamma glutamyl transferase; TG = triglycerides; LDL = low-density lipoprotein; HDL = high-density lipoprotein; NA = not applicable.
Age (years) 1.087 (1.028-1.149) 0.003 1.043 (0.966-1.127) 0.281
BMI (kg/m2) 1.295 (1.126-1.490) <0.001 1.403 (1.111-1.771) 0.005
Comorbidities
 Type 2 DM 4.702 (1.261-17.531) 0.021 11.872 (1.065-132.373) 0.044
 HT 12.000 (3.863-37.274) <0.001 2.958 (0.478-18.313) 0.244
Abnormal preoperative laboratory test
 AST 5.400 (1.215-23.994) 0.027 3.335 (0.126-88.424) 0.471
 ALT 9.333 (2.548-34.184) 0.001 4.505 (0.389-52.104) 0.228
 GGT 0.597 (0.124-2.877) 0.520
 Total cholesterol 0.935 (0.333-2.627) 0.899
 LDL cholesterol 2.089 (0.487-8.956) 0.321
 TG 4.028 (1.360-11.926) 0.012 50.267 (4.409-573.030) 0.002
 HDL cholesterol 0.000 (0.000-NA) 0.998

Discussion

NAFLD has become the most common liver disease worldwide (9). The estimated prevalence of NAFLD in the general population of the United States is in the range of 20% (10). It is associated with an increased incidence of obesity, combined hyperlipidemia, type 2 DM, and high blood pressure in developed countries, and it is regarded as a systemic metabolic malady (9, 11). NAFLD is also an emerging problem in the Asia-Pacific region, where it is likely to increase in the future (12). A Korean study of 2,307 people reported an NAFLD prevalence of 22.4% and 60.9% in the non-obese and obese groups, respectively (13).

The prevalence of NAFLD is rising rapidly due to the ongoing epidemics of obesity and type 2 DM. In our study, 18.3% of patients had NAFLD, which is similar to the prevalence in the general population and the non-obese group in the aforementioned Korean study.

NAFLD occurs in various forms, from simple HS to nonalcoholic steatohepatitis (NASH). HS, fat accumulation in the liver, generally follows a benign, nonprogressive clinical course without disturbing liver function. However, up to 20% of patients with HS progress to NASH, the most advanced form of NAFLD that eventually causes hepatocellular damage through fibrosis due to inflammation. NASH is regarded as a major cause of cirrhosis of the liver of unknown cause (11). Over a 10-year period, up to 20% of patients with NASH will develop cirrhosis of the liver, and 10% will die of liver disease (14). A meta-analysis that included 11 studies looked at fibrosis progression in 366 patients with NAFLD (15). Overall, fibrosis progressed in 132 (36%), remained stable in 158 (46%), and improved in 76 (21%) patients. It appears that patients with simple steatosis are at low risk of developing significant fibrosis, whereas those with NASH are at higher risk (16).

NAFLD remains a diagnosis of excluding other liver diseases (17). Most patients with NAFLD have few or no symptoms so early diagnosis and appropriate treatment tend to be delayed. Early diagnosis and treatment of NASH can prevent the development of cirrhosis and hepatocellular carcinoma (HCC) in NAFLD patients (17-18-19). Therefore, the identification and quantification of liver steatosis may be clinically important.

Although the reference method for diagnosing NAFLD is liver biopsy, it is invasive and associated with possible complications, and as it assesses only a small part of the liver, it may not reflect steatosis of the liver as a whole, particularly if the fat distribution is not homogeneous.

Noninvasive methods for diagnosing HS include US, CT, and MRI. Although US is safe and readily available, it has a reported false-negative rate of 20% for HS (20), and is dependent on visual assessment of the intensity of echogenicity (21) and operator skill (22). Moreover, it cannot detect subtle changes or small steatotic areas. A CT scan can evaluate steatosis of the entire liver quickly and accurately, but is associated with significant radiation exposure, which usually limits its widespread use for repeated measurements in longitudinal studies (23).

Reportedly, MRI would be the most reliable technique and would be preferable to other techniques if it were not for the expense and relative unavailability of this procedure to diagnose and quantify HS (24). MRI can detect a small fat fraction in the liver (21), assess HS in the entire liver, and is less subject to inter- and intraobserver variation (25). Therefore, it can offer both qualitative and quantitative advantages in evaluating liver steatosis. Furthermore, MRI does not expose patients to significant radiation compared with CT scan. Hepatic FSP >5% is consistent with a diagnosis of HS (8, 26).

Well-known risk factors for NAFLD are obesity, type 2 DM, hypertension, and a high TG level (27). Obesity – defined as BMI ≥25 kg/m2 – is a risk factor for NAFLD, and the prevalence of NAFLD has been reported to reach 90% in the obese population (28). In our study, high BMI was associated with NAFLD (p = 0.05). In 30 obese patients with BMI >25 kg/m2, 10 (33.3%) had NAFLD, whereas of 74 patients with BMI <25 kg/m2, only 9 (12.2%) had NAFLD. Dyslipidemia is characterized by high TG and LDL cholesterol levels, and a low HDL cholesterol level (29). In our study, only high TG level was associated with NAFLD. These 2 factors are also related to the incidence of breast cancer.

Thus, breast cancer patients with type 2 DM, high BMI, or abnormal TG levels have an increased risk for NAFLD. These patients may therefore require monitoring for the development of NAFLD, which can advance to NASH, cirrhosis, or HCC. In particular, if they undergo neoadjuvant or adjuvant systemic treatment, there is a need for more attention to NAFLD, because some medications including cytotoxic chemotherapeutic and endocrine therapy and targeted therapy agents are widely used for breast cancer patients and these are associated with development of NAFLD (30).

This study has several limitations. First, it was conducted at a single institution to obtain more reliable and reproducible results; in order to corroborate the results a multicenter study will be necessary. Second, we used MRI as a diagnostic modality for NAFLD in this study, but we think that initial and follow-up examinations with MRI for NAFLD will be difficult in clinical practice because of the cost of the procedure. However, MRI is a noninvasive method to accurately determine the quantitative and qualitative fat accumulation in the liver. Third, this study was performed in patients prior to receiving medical and surgical treatment for breast cancer. In the future, it is necessary to observe changes in the incidence of NAFLD and hepatic fat accumulation over time in breast cancer patients who undergo adjuvant medical treatment. Further long-term studies should be carried out in this field. Additionally, physicians should be expected to obtain more information to select patients for the diagnosis and treatment of NAFLD.

Conclusions

The prevalence of NAFLD in breast cancer patients was 18.3%, which was not different from that of the general population. High BMI, type 2 DM and an elevated serum TG level were factors associated with NAFLD.

Acknowledgment

We acknowledge the Pusan National University Hospital Clinical Trial Center Biostatistics Office for assistance with the statistical analysis.

Disclosures

Financial support: This work was supported by the year 2015 clinical research grant from Pusan National University Hospital.
Conflict of interest: The authors declare that they have no conflict of interest.
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Authors

Affiliations

  • Department of Surgery, Biomedical Research Institute, Pusan National University Hospital, Busan - Republic of Korea
  • Department of Radiology, Biomedical Research Institute, Pusan National University Hospital, Busan - Republic of Korea

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