We accessed a database from a previously reported study[8] to evaluate the possibility that aging and menopause in women could be risk factors for NAFLD. We conducted a follow-up study on nonalcoholic fatty liver disease by using abdominal ultrasonography. All participants who were examined in health checkup programs between January and December 2001 were invited to enroll in the study and 1829 women and 2572 men that satisfied the inclusion criteria in 2001 were selected to represent the non-institutionalized adult population of Gifu, Japan. By the end of June 2003, 3876 of the 4401 participants (2271 men and 1605 women) had completed the second examination (response rate, 86%). The interval between the baseline and follow-up examinations was 414 d (SD = 128). Among the 1605 women, 1603 were available for longitudinal examinations.

We collected data from self-reported medical histories, assessments of lifestyle factors [e.g., age, sex, height, weight, smoking habits, alcohol consumption, menopause status, active or previous hormone replacement therapy (HRT)], and the results of health checkup programs (e.g., urinalysis, blood cell counts, blood chemistry, electrocardiography, chest radiography, barium examination of the upper gastrointestinal tract, and abdominal ultrasonography). The postmenopausal state was defined as beginning 1 year after the cessation of menses. Reports of smoking status included active and past smoking. Habits regarding alcohol consumption were evaluated by asking the participants about the amount and type of alcoholic beverages consumed per week and then estimating the mean ethanol intake per day. We defined an alcohol consumer as someone with a mean ethanol intake of more than 20 g/d. A light drinker was defined as someone with a mean ethanol intake of 0-20 g/d. On the questionnaire, participants reported the type, duration, and frequency of their participation in sports or recreational activities[15]. When participants performed any kind of sport regularly at least once a week, we categorized them as regular exercisers[16].

The ATP III proposed the following 5 abnormalities to define 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 systolic and diastolic blood pressure, ≥ 130/85 mmHg; and (5) elevated fasting glucose level ≥ 6.11 mmol/L (≥ 110 mg/dL)[7]. Because waist measurements were not available for the entire study sample, we substituted a BMI of ≥ 25 kg/m² for all participants as an index of obesity. A BMI of ≥ 25 kg/m² has been proposed as a cutoff for the diagnosis of obesity in Asian people[17]. Individuals with ≥ 3 of the 5 abnormalities were considered to have metabolic syndrome.

We diagnosed NAFLD with the aid of abdominal ultrasonography by using diagnostic criteria described previously[18].

The SPSS statistical package, version 11.0.1 J (SPSS, Inc., Chicago, IL) was used for all statistical analyses, and a P value less than 0.05 was considered statistically significant. Because the incidence rate of NAFLD was unknown, a formal sample size estimate was not made a priori. Cases with and without follow-up visits were compared to determine the appropriateness of an analysis exclusively based on participants with complete data. Two groups of participants were compared using the unpaired t-test and the χ² test. Logistic regression was used to analyze associations between the development of NAFLD and metabolic syndrome, age, and weight gain. Adjusted odds ratios and 95% CIs were calculated. Data were expressed as means and SDs for continuous variables.

We calculated the age-specific prevalence of NAFLD among 1829 women and 2572 men (Figure 1). The prevalence of NAFLD in women increased with age, but no significant trend for age was identified in men.

Open in New Tab   Full Size Figure   Download Figure

Figure 1 Age-specific prevalence of nonalcoholic fatty liver disease among 1829 women and 2572 men. US: Abdominal ultrasonography; NAFLD: Nonalcoholic fatty liver disease.

We grouped women according to whether they had NAFLD at baseline, and investigated differences in age, weight, components of metabolic syndrome, serum enzymes, menopausal state, alcohol consumption, and smoking history (Table 1). More subjects with NAFLD were postmenopausal, received HRT, and met more criteria of metabolic syndrome than those without NAFLD (Table 1). The prevalence of NAFLD in premenopausal women (6%) was lower than that in men (24%), postmenopausal women (15%), and women receiving HRT (14.0 %, 36/221). In the cross-sectional study, we applied a logistic model to investigate the association of the menopausal state or HRT with NAFLD (Table 2). Univariate analysis showed that the odds ratios of the postmenopausal state and HRT were 2.73 (1.92-3.87), and 2.57 (1.66-3.97), respectively. However, they were not statistically significant after adjusting for age and metabolic syndrome.

Next, we excluded 257 subjects with a history of hysterectomy or HRT. We separated the subjects into pre- or postmenopausal groups and investigated the difference in age, components of metabolic syndrome, alcohol consumption, and smoking history (Table 3). An association of age with NAFLD was identified in premenopausal women, but not in postmenopausal women. On the other hand, an association of the components of metabolic syndrome with NAFLD was identified in both groups.

Of the 1603 women who completed follow up, 1453 women did not have NAFLD at baseline. Of the 1453 women who were disease-free at the baseline examination and who had the follow-up examination, 67 women (5%) received new diagnoses of NAFLD at follow-up examination. Subjects with NAFLD were older, showed more weight gain, and met more criteria for metabolic syndrome than those without NAFLD, but the 2 groups showed no differences in menopausal state, HRT, alcohol consumption, and smoking history.

Among the 1453 disease-free women at baseline, there were 855 premenopausal women and 392 postmenopausal women. Of the 855 premenopausal women, 53 women were menopausal. During the study period, 206 women received HRT. The incidence of NAFLD was 3.5% (28/802) in premenopausal women, 7.5% (4/53) in menopausal women, 6.1% (24/392) in postmenopausal women, and 5.3% (11/206) in women receiving HRT.

We applied a logistic regression model to determine the risk factors for the development of NAFLD (Table 4). Univariate analysis indicated that the postmenopausal state was a risk factor for NAFLD [odds ratio 1.8 (1.03-3.15), P = 0.039], but it was not statistically significant after adjusting for age, metabolic syndrome, and weight gain. The cross-sectional study at baseline revealed that the prevalence of NAFLD was higher in women receiving HRT than in those in the premenopausal state, but the logistic model did not indicate that HRT was a risk factor for the development of NAFLD.

Next, we excluded 206 women with HRT at the baseline and/or follow up. We separated the subjects into pre- or postmenopausal groups and compared parameters in subjects with NAFLD to those without (Table 5). Weight gain was equal in pre- and postmenopausal women. There was an association of the number of women who met ≥3 criteria of metabolic syndrome and weight gain with the development of NAFLD in pre- and postmenopausal women, but an association of age with development of NAFLD was identified in premenopausal subjects only.

Finally, we applied a multivariate logistic model to investigate the risk of NAFLD after separating women into pre- or postmenopausal groups (Table 6). Metabolic syndrome and weight gain were dependent risk factors for NAFLD in pre- and postmenopausal women, but age was a risk factor only in premenopausal women.

Nonalcoholic fatty liver disease (NAFLD) is emerging as the most common chronic liver disease. NAFLD is more common in men than women, particularly in Asians.

The prevalence of NAFLD in women increases with age, but not in men. Age and menopause may be risk factors for the incidence of NAFLD. But, this has not been clarified yet.

The prevalence of NAFLD was lower in premenopausal women than in men, but in postmenopausal women, the prevalence of NAFLD was similar to that in men. The prospective study indicated that aging is a risk factor for the development of NAFLD in premenopausal women independent of weight gain or metabolic syndrome.

The study suggests the possibility that premenopausal women have a protective factor against NAFLD, which is weakened by aging.

NAFLD was less prevalent in females than in males, but only before menopause. The prevalence of NAFLD was lower in women than in men, and increased with age in women, but a significant trend for age was not identified in men. NAFLD was independently associated with BMI and metabolic syndrome in both pre- and postmenopausal women, but with age only in premenopausal women. The results are interesting and suggest that the premenopausal state may be associated with a protective factor against NAFLD, which weakens with age.