Noriyuki Takeda

The Metabolic Syndrome as a Predictor of Nonalcoholic Fatty Liver Disease

Context The metabolic syndrome is often present in patients with nonalcoholic fatty liver disease (NAFLD), but no one knows whether it precedes NAFLD. Content At baseline, 812 members of a cohort of 4401 apparently healthy Japanese adults had NAFLD on abdominal ultrasonography. In 1 year, the authors identified 308 new cases, and NAFLD had resolved in 113 participants. Participants with the metabolic syndrome were much more likely to develop NAFLD and were less likely to experience disease resolution. Limitations Abdominal ultrasonography is not a perfect gold standard test for NAFLD. Implication The metabolic syndrome appears to predispose people to develop NAFLD. The Editors Nonalcoholic fatty liver disease is increasingly recognized as a major cause of liver-related morbidity and mortality (1-3). Because of its potential to progress to cirrhosis and liver failure (4), interest in this disease is increasing among researchers and clinicians in the relevant basic and clinical science fields. The pathologic picture of nonalcoholic fatty liver disease, ranging from simple steatosis to steatohepatitis, advanced fibrosis, and cirrhosis, resembles that of alcohol-induced liver disease, but it occurs in patients who do not abuse alcohol (3). Nonalcoholic steatohepatitis that is characterized by hepatic steatosis and liver cell injury, hepatic inflammation, and fibrosis and necrosis is believed to be an intermediate stage of nonalcoholic fatty liver disease. (1) This disease is often associated with obesity (5), type 2 diabetes mellitus (6, 7), dyslipidemia (8), and hypertension (9). Each of these abnormalities carries a cardiovascular disease risk, and together they are often categorized as the insulin resistance syndrome or the metabolic syndrome (10). The third report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III [ATP III]) (11) recommended the use of 5 variables for diagnosing the metabolic syndrome, namely waist circumference, serum triglyceride level, serum high-density lipoprotein (HDL) cholesterol level, blood pressure, and fasting plasma glucose level. As stated above, the frequent association of nonalcoholic fatty liver disease with individual components of the metabolic syndrome is now well known. However, it is unknown whether the risk for this disease is increased in patients with the metabolic syndrome. This is important because the metabolic syndrome is an emerging problem worldwide and its prevalence is likely increasing (12). The current study was designed first to evaluate the cross-sectional relationship between the metabolic syndrome, defined by the modified ATP III criteria, and the prevalence of nonalcoholic fatty liver disease in Japanese persons. Second, and more important, we addressed longitudinal aspects of the disease and its development and regression and tried to clarify the role of the metabolic syndrome in its pathogenesis. Despite serious concern about a possible future epidemic of this disease in the Asia-Pacific region (13), information regarding a possible association with the metabolic syndrome in Asia is very limited; our study may have special clinical relevance for people who live in this part of the world. Methods Study Participants We designed a prospective cohort study to investigate the role of the metabolic syndrome in the pathogenesis of nonalcoholic fatty liver disease in participants in a medical health checkup program at Murakami Memorial Hospital, Gifu, Japan. Each participant had abdominal ultrasonography. The purpose of the medical health checkup program is to promote public health through early detection of chronic diseases and their risk factors. Medical service of this kind, known as a human dock, is very popular in Japan. The center at which the checkups were performed was founded in 1994 and currently evaluates more than 8000 examinees annually. Of these examinees, 60% repeatedly have annual or biannual examinations and 40% are newly registered examinees. Most of the participants were employees of various companies and local governmental organizations in Gifu, Japan, and their spouses. These companies and organizations recruit employees each year according to a contract with our center. The cost of the medical examination was largely paid for by the employers. Fewer than 10% of the participants individually registered for the program and paid for it themselves, and they are citizens of local communities. Because many participants were expected to have repeated examinations, we took advantage of this opportunity to conduct a follow-up study on nonalcoholic fatty liver disease by using abdominal ultrasonography. The ethics committee of Murakami Memorial Hospital approved the study. All participants who were examined in the health checkup programs between January and December 2001 were invited to enroll in the study. Data Collection and Measurements The health checkup programs included the following: urinalysis, blood cell counts, blood chemistry, measurements of hepatitis B antigen and hepatitis C antibody, electrocardiography, chest radiography, barium examination of the upper gastrointestinal tract, and abdominal ultrasonography. Medical history and lifestyle factors, including physical activity, habits regarding smoking, and habits regarding alcohol consumption, were surveyed by using a self-administered questionnaire. When the participants had difficulty completing the questionnaire, trained nurses provided assistance. Smoking status was expressed by using the Brinkman index, which is calculated as the number of cigarettes smoked per day multiplied by the number of years that the participant smoked. Habits regarding alcohol consumption were evaluated by asking the participants about the amount and type of alcoholic beverages consumed per week, then estimating the mean ethanol intake per day. The diagnosis of fatty liver was based on the results of abdominal ultrasonography, which was done by trained technicians. All ultrasonographic images were stored in the image server. One gastroenterologist reviewed the images and made the diagnosis of fatty liver without reference to any of the participants other individual data. Of 4 known criteria (hepatorenal echo contrast, liver brightness, deep attenuation, and vascular blurring) (14), the participants were required to have hepatorenal contrast and liver brightness to be given a diagnosis of nonalcoholic fatty liver disease. Body mass index (BMI) was calculated as body weight in kilograms divided by the square of the participants height in meters. The ATP III proposed the following 5 abnormalities to define the metabolic syndrome: 1) abdominal obesity (abdominal circumference> 102 cm for men and> 88 cm for women); 2) elevated serum triglyceride level (1.70 mmol/L [150 mg/dL]); 3) decreased HDL cholesterol level (<1.04 mmol/L [<40 mg/dL] for men and <1.30 mmol/L [<50 mg/dL] for women); 4) elevated blood pressure (systolic and diastolic blood pressure 130/85 mm Hg); and 5) an elevated fasting glucose level (6.11 mmol/L (110 mg/dL]). Because waist measurements were not available for the entire study sample, we substituted a BMI of 25 kg/m2 or greater for all participants as an index of obesity. A BMI of 25 kg/m2 or greater has been proposed as a cutoff for the diagnosis of obesity in Asian people (15). Individuals with 3 or more of the 5 abnormalities were considered to have the metabolic syndrome. Exclusion criteria were an alcohol intake of more than 20 g/d, known liver disease, or current use of medication. Regarding liver disease, participants who tested positive for hepatitis B antigen or hepatitis C antibody and those who reported a history of known liver disease, including viral, genetic, autoimmune, and drug-induced liver disease, were also excluded (16). Statistical Analysis The SPSS statistical package, version 11.0.1 J (SPSS, Inc., Chicago, Illinois) was used for all statistical analyses, and a P value less than 0.05 was considered statistically significant. Because the incidence rate of nonalcoholic fatty liver disease was unknown, a formal sample size estimate was not made a priori. Participants with and without follow-up visits were compared to determine the appropriateness of an analysis based on participants with complete data only. Two groups of participants were compared by using the unpaired t-test and the chi-square test. Logistic regression was used to analyze associations between the development and regression of nonalcoholic fatty liver disease and the metabolic syndrome while controlling for potential confounders. The potential confounders were selected from clinical variables, which were different between participants with and without the disease at baseline. As will be described later, weight change was also selected as a confounder because the development and regression of nonalcoholic fatty liver disease generally occurred with weight changes. Unadjusted and adjusted odds ratios and 95% CIs were calculated. Data are expressed as means and SDs for continuous variables. Role of the Funding Source No funding was received for this study. Results Between January and December 2001, we invited 8056 participants in the health checkup program to enroll in the study. A total of 6654 Japanese participants (4601 men and 2053 women) gave informed consent to be included in the study. We excluded 290 participants (216 men and 74 women) who had known liver disease. In addition, 1657 participants (1577 men and 80 women) who consumed more than 20 g of ethanol per day and 306 participants (236 men and 70 women) who were currently receiving medication were excluded. As a result, there were 4401 participants (2572 men and 1829 women). Mean age and BMI were 47.6 years (SD, 8.8) (range, 21 to 80 years) and 22.6 kg/m2 (SD, 3.0) (range, 14.2 to 38.1 kg/m2), respectively. By the end of June 2003, 387

The Severity of Ultrasonographic Findings in Nonalcoholic Fatty Liver Disease Reflects the Metabolic Syndrome and Visceral Fat Accumulation

BACKGROUND:Nonalcoholic fatty liver disease (NAFLD) is closely associated with the metabolic syndrome.AIM:We evaluated the association among the metabolic syndrome, visceral fat accumulation, and the severity of fatty liver with a new scoring system of ultrasonographic findings in apparently healthy Japanese adults.METHODS:Subjects consisted of 94 patients who received liver biopsy and 4,826 participants who were selected from the general population. Two hepatologists scored the ultrasonographic findings from 0 to 6 points. We calculated Cohens kappa of within-observer reliability and between-observer reliability. We evaluated the predictive value of the score by the area under a conventional receiver operating characteristic curve (AUC).RESULTS:Within-observer reliability was 0.95 (95% CI 0.93–0.97, P < 0.001) and between-observer reliability was 0.95 (95% CI 0.93–0.97, P < 0.001). The AUC to diagnose NAFLD was 0.980. The sensitivity was 91.7% (95% CI 87.0–95.1, P < 0.001) and the specificity was 100% (95% CI 95.4–100.0, P < 0.001). The AUC to diagnose visceral obesity was 0.821. The sensitivity was 68.3% (95% CI 51.9–81.9, P = 0.028) and the specificity was 95.1% (95% CI 86.3–99.0, P < 0.001). Adjusted odds ratio of the score for the metabolic syndrome was 1.37 (95% CI 1.26–1.49, P < 0.001).CONCLUSIONS:The scoring system with abdominal ultrasonography could provide accurate information about hepatic steatosis, visceral obesity, and the metabolic syndrome in apparently healthy people who do not consume alcohol.

Association of intakes of fat, dietary fibre, soya isoflavones and alcohol with uterine fibroids in Japanese women.

Certain dietary components which could affect oestrogen may have implications in the aetiology of uterine fibroids. We previously found that soya intake was inversely associated with a subsequent risk of hysterectomy, suggesting a potentially protective effect of soya against uterine fibroids, the major clinical indication for hysterectomy. We cross-sectionally assessed the associations of intakes of fat, soya foods, dietary fibre and alcohol with uterine fibroids. Study subjects were 285 premenopausal Japanese women participating in a health-check up programme, including gynaecological examinations, provided by a general hospital between October 2003 and March 2006. The presence of fibroids was confirmed by transvaginal sonogram. If women had undergone hysterectomy, self-report of fibroids was accepted. Each subjects usual diet, including alcohol, was determined with the use of a validated FFQ. Fifty-four women were identified as prevalent cases of fibroids or having had hysterectomy due to fibroids. The mean alcohol intake was statistically significantly higher among women with fibroids than among those without fibroids after controlling for known or suspected risk factors. For the highest compared with the lowest tertile of alcohol intake, the OR of uterine fibroids was 2.78 (95% CI 1.25, 6.20). There was no significant association of intake of fats, soya isoflavones or dietary fibre with uterine fibroids. The data suggest that higher alcohol intake is associated with a higher prevalence of uterine fibroids. Further studies on diet, especially phyto-oestrogens, and uterine fibroids are needed given the limited data currently available.

Association of dietary fat, vegetables and antioxidant micronutrients with skin ageing in Japanese women.

Daily diet may have implications for skin ageing. However, data on the relationship between diet and the parameters of skin conditions are scarce. The present study aimed to examine the associations of biophysical properties of the skin of women with intakes of fats and antioxidant micronutrients as well as food groups as sources of these nutrients. In a cross-sectional study, we measured the hydration, surface lipids and elasticity of the skin of 716 Japanese women using non-invasive techniques. The extent of facial wrinkles in the crows-foot area was determined by observation using the Daniell scale. Each subjects usual diet was determined with the use of a validated FFQ. After controlling for covariates including age, smoking status, BMI and lifetime sun exposure, the results showed that higher intakes of total fat, saturated fat and monounsaturated fat were significantly associated with increased skin elasticity. A higher intake of green and yellow vegetables was significantly associated with a decreased Daniell wrinkling score. Intake of saturated fat was significantly inversely associated with the Daniell wrinkling score after additional adjustment for green and yellow vegetable intake. Further studies with more accurate measurement methods are needed to investigate the role of daily diet in skin ageing.

Metabolic syndrome as a risk factor for high-ocular tension

Objective:To investigate the relationship between the metabolic syndrome and intraocular pressure (IOP).Methods:An observational study was conducted in a medical health checkup program at a general hospital. This study involved 14 003 apparently healthy Japanese men and women, 18–83 years of age, with a mean IOP of 14.8 (3.0) mm Hg. IOP was examined by noncontact tonometer. High-ocular tension was defined as IOP >21 mm Hg without optic-disc abnormalities or history of receiving any anti-glaucoma therapy. Modified criteria of the revised National Cholesterol Education Program Adult Treatment Panel III (rATPIII), the new International Diabetes Federation definition, and the Japan Society for The Study of Obesity definition were used to characterize the metabolic syndrome. Air temperature was assessed from the Gifu Meteorological Observatory, Gifu, Japan.Results:In the male and female subjects, mean IOP and the prevalence of high-ocular tension became high in direct correlation with the increased number of metabolic syndrome components. To analyze by logistic regression, the metabolic syndrome defined by rATPIII was positively and maximum temperature was negatively correlated with high-ocular tension in males (adjusted odds ratio: 2.0 [95% confidence interval, CI, 1.43–2.78] and 0.63 [95% CI, 0.54–0.73], respectively) and in females (adjusted odds ratio: 7.09 [95% CI, 3.74–13.43] and 0.67 [95% CI, 0.53–0.87], respectively). Three of five metabolic syndrome components (fasting plasma glucose, blood pressure, and triglycerides) were related to high-ocular tension.Conclusion:The metabolic syndrome is a risk factor for high-ocular tension.

Associations of acrylamide intake with circulating levels of sex hormones and prolactin in premenopausal Japanese women

Background: It has been hypothesized that alteration of hormone systems is involved in the carcinogenesis of acrylamide. The aim of the present study was to examine the cross-sectional associations between dietary acrylamide intake and sex hormone levels in premenopausal Japanese women. Methods: Study subjects were 393 women who had regular menstrual cycles less than 40 days long. Acrylamide intake was assessed with a food-frequency questionnaire and was based on acrylamide concentration reported from analyses of Japanese foods. We measured the plasma concentrations of estradiol, testosterone, dehydroepiandrosterone sulfate, sex hormone–binding globulin, follicle-stimulating hormone, luteinizing hormone, and prolactin. Results: After controlling for age, the phase of the menstrual cycle, and other covariates, acrylamide intake was statistically significantly inversely associated with total and free estradiol levels and statistically significantly positively associated with follicle-stimulating hormone level. Total and free estradiol levels were 18.2% and 19.3% lower, respectively, in women in the highest quartile of acrylamide intake than in those in the lowest quartile of intake. Follicle-stimulating hormone levels were 23.5% higher in women in the highest quartile of acrylamide intake than in those in the lowest quartile of intake. Conclusion: The data suggest that acrylamide intake may alter estradiol and follicle-stimulating hormone levels. Impact: High estradiol levels have been associated with an increased risk of breast cancer. Although the results need confirmation, they highlight the need to investigate the relationships among dietary acrylamide, sex hormones, and breast cancer risk. Cancer Epidemiol Biomarkers Prev; 24(1); 249–54. ©2014 AACR.

Plasma amino acid profiles are associated with biomarkers of breast cancer risk in premenopausal Japanese women

ObjectiveRecently, profiles of plasma amino acids have been utilized to detect diseases including breast cancer. However, there is a possibility that the amino acid status may be associated with the risk of breast cancer. We investigated the relationship of plasma levels of amino acids with levels of sex hormones and insulin-like growth factor (IGF)-1, which are relevant to the etiology of premenopausal breast cancer, in normal premenopausal women.MethodsParticipants were 350 Japanese women who had regular menstrual cycles less than 40-day long. Fasting plasma samples were assayed for estradiol, testosterone, dehydroepiandrosterone sulfate, sex-hormone-binding globulin (SHBG), and IGF-1. A total of 20 amino acids in plasma were quantified by liquid chromatography–mass spectrometry. Information on lifestyle and reproductive factors was obtained using a self-administered questionnaire.ResultsThe plasma arginine level was significantly inversely correlated with plasma levels of total and free estradiol and IGF-1 after adjusting for age, body mass index, and phase of the menstrual cycle. Plasma leucine and tyrosine levels were significantly positively correlated with the free testosterone level. The ratio of plasma asparagine to the total amino acids was significantly positively correlated with SHBG level.ConclusionsPlasma levels of some specific amino acids, such as arginine, leucine, tyrosine, and asparagine, were associated with the levels of sex hormones, SHBG, or IGF-1 in premenopausal women. However, the present cross-sectional study cannot provide a cause–effect relation. The implication of amino acids in the etiology of breast cancer needs to be addressed in future studies.

Associations of urinary 6-sulfatoxymelatonin with biomarkers related to cardiovascular disease in Japanese women

Melatonins potential preventive effect against cardiovascular disease (CVD) remains hypothetical. No study has evaluated the relationships between endogenous melatonin and the established blood biomarkers related to CVD. The objective of the present study is to examine the association between the endogenous melatonin level and various established blood biomarkers of risk of CVD, including white blood cell (WBC) count and plasma concentrations of lipids, homocysteine, uric acid (UA), and high-sensitivity C-reactive protein (hs-CRP). This cross-sectional study included 181 Japanese women who attended a health checkup program provided by a general hospital between March 2005 and March 2006. All study subjects responded to a self-administered questionnaire and were measured for weight, height, and blood pressure. Venous fasting blood and first-void morning urine were obtained from all subjects. Statistically significant inverse correlations were observed between urinary 6-sulfatoxymelatonin (aMT6s), the major metabolite of melatonin in urine, and WBC count, UA, and hs-CRP after controlling for age, body mass index, menopausal status, smoking status, diet, sleeping habits, and exercise (r = -0.19, -0.21, and -0.24, respectively). There were no significant correlations between urinary aMT6s and plasma lipids and homocysteine. These data suggested that the urinary aMT6s level was inversely associated with established independent risk factors for CVD, such as WBC, UA, and hs-CRP. Endogenous melatonin may have implications for the risk of CVD.

Lifestyle and health factors associated with stress urinary incontinence in Japanese women

OBJECTIVES Studies focusing on lifestyle and health factors and stress urinary incontinence (SUI) are scarce in Japan. The aim of this study is to examine the association of lifestyle and health factors in SUI. METHODS Study subjects were retrieved from Japanese women participating in a health checkup program provided by a general hospital between October 2003 and March 2006. The presence of SUI was confirmed by responses to a self-administered questionnaire assessing lower urinary tract symptoms. The questionnaire included other questions on lifestyle and health factors. Each subject underwent weight and height measurements. RESULTS A total of 823 women completed the questionnaire and were included in the analyses (the response rate was 62.6%). Of them, 70 (8.5%) women had SUI. BMI and parity were significantly positively associated with SUI (OR=3.47 and 7.17, 95% CI 1.65-7.33 and 1.71-30.04, respectively). Multiple logistic regression analysis controlling for age, parity, and BMI showed that first delivery at age >27 (OR=1.82, 95% CI 0.97-3.41), past estrogen use (OR=2.50, 95% CI 1.14-5.47), and unilateral ovariectomy (OR=3.07, 95% CI 1.16-8.13) were also significantly associated with SUI. CONCLUSIONS The data suggested that lifestyle and health factors such as parity, BMI, age at first delivery, past estrogen use, and unilateral ovariectomy were associated with SUI in Japanese women.

Association of cigarette smoking with skin colour in Japanese women

Objectives Having a lighter skin tone is highly valued among many Asian women. If skin colour is affected by smoking, women may be motivated to avoid tobacco or quit smoking. The present study examined the association of tobacco smoking with skin colour in Japanese women. Method Information on smoking habits was obtained through a self-administered questionnaire completed by 939 Japanese women aged 20–74 in Gifu, Japan, during 2003–2006. Skin colour was examined on the inner side of the upper and lower arm and on the forehead using a Mexameter device (a narrow-band reflective spectrophotometer), which expressed results as a melanin index and erythema index. Results Current smokers had higher melanin indices than never-smokers and former smokers for all measured sites. The number of cigarettes smoked per day, the years of smoking and pack-years were significantly positively associated with melanin indices for all measured sites after adjustments for age, body mass index, lifetime sun exposure, and room temperature and humidity. Smoking was also significantly associated with erythema indices on the inner upper and lower arms. Conclusions These data suggest that smoking is associated with a darker skin colour. If our findings are confirmed by further studies, they could be used in antismoking campaigns or by smoking cessation services.