Aging is a risk factor of nonalcoholic fatty liver disease in premenopausal women

Table 1 Baseline characteristics of study participants and unadjusted associations with nonalcoholic fatty liver disease

	Women w/o NAFLD	Women with NAFLD	P value	Men w/o NAFLD	Men with NAFLD	P value
Number of subjects	1651	178		1938	634
Age, yr (SD)	46.6 (8.8)	51.0 (7.7)	< 0.001	48.1 (9)	47.9 (8.4)	0.66
Body mass index, kg/m2 (SD)	21.3 (2.5)	25.7 (3.7)	< 0.001	22.5 (2.5)	25.6 (2.8)	< 0.001
Fasting plasma glucose, mg/mL (SD)	92.7 (8.4)	100.7 (10.7)	< 0.001	99.6 (13.3)	106.8 (18.8)	< 0.001
Systolic blood pressure, mmHg (SD)	111.8 (15.9)	127.8 (18.2)	< 0.001	118.8 (15.8)	126.4 (15.5)	< 0.001
Diastolic blood pressure, mmHg (SD)	69.8 (10.1)	79.1 (10.1)	< 0.001	75.3 (10.1)	80.4 (9.9)	< 0.001
HDL-cholesterol, mg/dL (SD)	59.4 (13.9)	49.5 (11.8)	< 0.001	47.5 (12.2)	40.6 (9.7)	< 0.001
Triglycerides, mg/dL (SD)	73.8 (36.1)	119.6 (61.4)	< 0.001	105.5 (59.9)	156.7 (89.2)	< 0.001
LDL-cholesterol, mg/dL (SD)	131.8 (32.2)	151.1 (33.4)	< 0.001	137.2 (30.7)	145.8 (31.7)	< 0.001
AST, IU/mL (SD)	15.1 (5.2)	19.5 (7.9)	< 0.001	16.4 (7.7)	22.8 (10.9)	< 0.001
ALT, IU/mL (SD)	16.8 (6.5)	27.9 (15.7)	< 0.001	23.1 (15)	39.6 (21.4)	< 0.001
γGTP, IU/mL (SD)	11.7 (9.6)	18.9 (15.4)	< 0.001	22.8 (22.8)	31.4 (22.5)	< 0.001
Hemoglobin, g/dL (SD)	12.8 (1.2)	13.3 (1.2)	< 0.001	15 (1)	15.6 (0.9)	< 0.001
C reactive protein, mg/mL (SD)	0.1 (0.2)	0.2 (0.4)	0.113	0.1 (0.2)	0.1 (0.1)	0.242
Number (%) of light-drinkers	775 (46.9)	73 (41.0)	0.13	1513 (78)	464 (73)	0.013
Number (%) of current smokers	102 (6.2)	10 (5.6)	0.87	795 (41.0)	234 (36.9)	0.074
Number (%) of ex-smokers	184 (11.1)	12 (6.7)	0.074	555 (28.6)	213 (33.6)	0.02
Number (%) of regular exercisers	340 (20.6)	27 (15.2)	0.09	393 (20.3)	78 (12.3)	< 0.001
Number (%) of postmenopausal women	487 (29.5)	82 (46.1)	< 0.001
Number (%) receiving hormone replacement therapy	221 (13.4)	36 (20.2)	0.017

This table summarizes the baseline data of 1829 women and 2572 men. w/o: Without; NAFLD: Nonalcoholic fatty liver disease; HDL: High-density lipoprotein; LDL: Low-density lipoprotein; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; γGTP: γ-glutamyl transferase. Continuous variables were compared using the unpaired t test, and groups were compared with the χ² test.

Table 2 Unadjusted and adjusted associations between nonalcoholic fatty liver disease and age, menopause status, hormone replacement therapy, and metabolic syndrome in 1829 women

	Unadjusted odds ratio (95% CI)	P values	Adjusted odds ratio (95% CI)	P values
Age	1.06 (1.04-1.08)	< 0.001	1.03 (1-1.06)	0.027
Postmenopausal state	2.73 (1.92-3.87)	< 0.001	1.55 (0.92-2.61)	0.096
Active hormone replacement therapy	2.57 (1.66-3.97)	< 0.001	1.54 (0.93-2.54)	0.092
Presence of metabolic syndrome at baseline	12.52 (8.03-19.51)	< 0.001	11.28 (7.04-18.06)	< 0.001

We calculated the odds ratio of each factor for nonalcoholic fatty liver disease in a univariate logistic regression model. The columns to the left indicate unadjusted odds ratio [95% confidence interval (CI)]. We selected all parameters as cofactors in a multivariate logistic regression model. The columns to the right indicate adjusted odds ratio (95% CI).

Table 3 The association of baseline characteristics with nonalcoholic fatty liver disease in pre- or postmenopausal women

	Premenopausal women (n = 1023)			Postmenopausal women (n = 549)
	Normal US	NAFLD	P Value	Normal US	NAFLD	P Value
Number of subjects (%)	962	61 (6)		468	81 (15)
Mean age ± SD, yr	42.2 (6.4)	44.7 (6.1)	0.003	56 (5.5)	55.9 (5.4)	0.874
Number (%) who met a criterion of metabolic syndrome
Body mass index	75 (8)	32 (52)	< 0.001	37 (8)	43 (53)	< 0.001
Glucose	24 (2)	15 (25)	< 0.001	25 (5)	8 (10)	< 0.001
Blood pressure	94 (10)	21 (34)	< 0.001	104 (22)	35 (43)	< 0.001
HDL-cholesterol	221 (23)	31 (51)	< 0.001	128 (27)	48 (59)	< 0.001
Triglycerides	29 (3)	13 (21)	< 0.001	36 (8)	21 (26)	< 0.001
Number (%) who met ≥3 criteria of metabolic syndrome	18 (2)	17 (28)	< 0.001	26 (6)	23 (28)	< 0.001
Number (%) light-drinkers	472 (49.1)	24 (3.9)	0.15	190 (40.6)	34 (42.0)	0.81
Number (%) current smokers	48 (5.0)	4 (6.6)	0.54	34 (7.3)	5 (6.2)	0.64
Number (%) ex-smokers	103 (1.1)	5 (8.2)	0.67	50 (10.7)	5 (6.2)	0.31
Number (%) regular exercisers	181 (18.8)	8 (13.1)	0.31	105 (22.4)	15 (18.5)	0.47

This table summarizes the baseline data of 1572 women, excluding 257 subjects with hormone replacement therapy. We separated the subjects into pre- or postmenopausal groups. US: Abdominal ultrasonography; NAFLD: Nonalcoholic fatty liver disease; HDL: High-density lipoprotein.

Table 4 Unadjusted and adjusted associations between nonalcoholic fatty liver disease and age, menopause status, hormone replacement therapy, metabolic syndrome and weight gain in 1247 women

	Unadjusted odds ratio (95% CI)	P values	Adjusted odds ratio (95% CI)	P values
Age	1.05 (1.02-1.08)	0.001	1.06 (1.02-1.1)	0.004
Menopause	2.26 (0.76-6.69)	0.14	1.22 (0.38-3.99)	0.74
Postmenopausal state	1.8 (1.03-3.15)	0.039	0.72 (0.31-1.66)	0.44
Active hormone replacement therapy	1.56 (0.76-3.19)	0.22	1.32 (0.6-2.88)	0.49
Presence of metabolic syndrome at baseline	9.89 (4.67-20.94)	< 0.001	11.7 (5.02-27.25)	< 0.001
Weight gain	1.50 (1.30-1.74)	< 0.001	1.63 (1.39-1.9)	< 0.001

We calculated the odds ratio of each factor for nonalcoholic fatty liver disease in a univariate logistic regression model. The columns to the left indicate unadjusted odds ratio [95% confidence interval (CI)]. We selected all parameters as cofactors in a multivariate logistic regression model. The columns to the right indicate adjusted odds ratio (95% CI).

Table 5 The relationship between menopausal status and nonalcoholic fatty liver disease in 1247 women who completed follow-up examinations and received no hormone replacement therapy

	Premenopausal women (n = 855)			Postmenopausal women (n = 392)
	Normal US at both baseline and follow-up	Normal US at baseline and NAFLD at follow-up	P value	Normal US at both baseline and follow-up	Normal US at baseline and NAFLD at follow-up	P value
Number (% incidence of NAFLD)	823	32 (4)		368	24 (6)
Mean age ± SD, yr (% incidence of NAFLD)	42.2 (6.3)	45.5 (6)	0.004	55.7 (5.6)	55.7 (4.7)	0.951
Number (%) who met a criterion of metabolic syndrome
Body mass index	53 (6)	13 (41)	< 0.001	28 (8)	4 (17)	0.12
Glucose	18 (2)	5 (16)	0.001	19 (5)	3 (13)	0.14
Blood pressure	79 (10)	9 (28)	0.003	79 (21)	8 (33)	0.2
HDL-cholesterol	178 (22)	19 (59)	< 0.001	98 (27)	10 (42)	0.15
Triglycerides	18 (2)	7 (22)	< 0.001	25 (7)	4 (17)	0.091
Number (%) who met ≥ 3 criteria of metabolic syndrome	9 (1)	7 (22)	< 0.001	17 (5)	4 (17)	0.032
Weight gain, kg (SD)	0.2 (1.7)	1.4 (1.6)	< 0.001	0 (1.6)	1.3 (1.3)	< 0.001
Number (%) light-drinkers	406 (49.3)	14 (43.8)	0.59	214 (26.0)	10 (31.3)	1
Number (%) current smokers	42 (5.1)	3 (9.4)	0.23	38 (4.6)	0 (0.0)	0.4
Number (%) ex-smokers	88 (10.7)	6 (18.8)	0.15	54 (6.6)	1 (3.1)	0.5
Number (%) regular exercisers	151 (18.3)	6 (18.8)	1	81 (22.0)	4 (16.7)	0.78

US: Abdominal ultrasonography; NAFLD: Nonalcoholic fatty liver disease; HDL: High-density lipoprotein.

Table 6 Adjusted associations between nonalcoholic fatty liver disease and age in 855 premenopausal women and 392 postmenopausal women

	Premenopausal subjects (n = 855)		Postmenopausal subjects (n = 392)
	Adjusted odds ratio (95% CI)	P Value	Adjusted odds ratio (95% CI)	P Value
Age	1.12 (1.05–1.2)	0.001	1 (0.93–1.07)	0.91
Presence of metabolic syndrome at baseline	43.06 (12.66–146.51)	< 0.001	4.87 (1.29–18.34)	0.019
Weight gain	1.76 (1.4–2.21)	< 0.001	1.67 (1.27–2.21)	< 0.001

We applied a multivariate logistic regression model to calculate the odds ratio for age for development of nonalcoholic fatty liver disease after adjusting for weight gain and metabolic syndrome. After completing follow-up examinations, 1247 women who received no hormone replacement therapy were divided into pre- or postmenopausal groups. CI: Confidence interval.