Fatty liver disease: Disparate predictive ability for cardiometabolic risk and all-cause mortality

Table 1 Baseline characteristics of the study sample, by gender and fatty liver disease categories (n = 1822)

	n	Men (n = 877)				Women (n = 945)
		No NAFLD	Probable NAFLD	NAFLD	ANOVAP value	No NAFLD	Probable NAFLD	NAFLD	ANOVA P value
		mean ± SD	mean ± SD	mean ± SD		mean ± SD	mean ± SD	mean ± SD
		n = 198	n = 263	n = 416		n = 252	n = 241	n = 452
Age, yr	1822	52.8 ± 12.7	53.4 ± 12	51.7 ± 9.3	0.16	47.5 ± 10.3	51.92± 10.5	54.8 ± 9.9	< 0.001
Waist circumference, cm	1811	83.3 ± 8.1	92.42± 7.4	100.6 ± 9	< 0.001	79 ± 9	892± 7.5	99.4 ± 9.7	< 0.001
Body mass index, kg/m2	1808	24.1 ± 3.3	27.22± 2.7	30.9 ± 4	< 0.001	26.2 ± 4.4	30.22± 3.8	34.5 ± 5.5	< 0.001
Systolic BP, mmHg	1822	120 ± 18	1262± 21	132.5 ± 23	< 0.001	121 ± 19	1322± 24	142 ± 27	< 0.001
Diastolic BP, mmHg	1822	75 ± 11	802± 11	85.6 ± 13.5	< 0.001	77 ± 12	832± 13	88 ± 14	< 0.001
Total cholesterd, mg/dL	1822	168 ± 34	1782± 34	192 ± 39	< 0.001	174 ± 34	1902± 37	201 ± 41	< 0.001
LDL cholesterd, mg/dL	1424	108 ± 32	112 ± 29	1162± 33	0.037	1052± 28	120 ± 33	126 ± 36	< 0.001
HDL cholesterd mg/dL	1820	422± 12	37 ± 11	35.3 ± 11	< 0.001	47.7 ± 13	46 ± 13	432± 12	< 0.001
Lipoprotein(a)1, mg/dL	1186	8.3 × 2.74	7.76 × 2.77	9.12 × 3.14	0.34	11.8 × 2.76	12.7 × 3.13	10.47 × 2.9	0.11
Fasted glucose, mg/dL	1822	99 ± 27	100 ± 30	104 ± 37	0.099	97 ± 19	100 ± 31	1052± 35	0.001
F. triglyceride1, mg/dL	1413	95 × 1.48	1262× 1.55	174 × 1.72	< 0.001	87 × 1.47	1102× 1.53	148 × 1.69	< 0.001
γ-glutamyl transferase1, U/L	1822	17 × 1.48	21.92× 1.59	37.2 × 1.87	< 0.001	12.9 × 1.62	15.82× 1.65	24.5 × 1.87	< 0.001
Fasted insulin, mIU/L	1636	6.94 × 2.36	8.00 × 2.00	11.02× 2.02	< 0.001	6.98 × 1.87	8.752× 1.97	11.0 × 1.87	< 0.001
Apolipoprotein A-I, g/L	1740	1.40 ± 0.24	1.35 ± 0.24	1.3462± 0.24	0.042	1.55 ± 0.30	1.51 ± 0.26	1.50 ± 0.28	0.082
Apolipoprotein B, g/L	1759	0.942± 0.26	1.05 ± 0.19	1.09 ± 0.29	< 0.001	1.03 ± 0.27	1.04 ± 0.28	1.132± 0.31	< 0.001
Creatinine, mg/dL	1504	0.937± 0.17	0.976 ± 0.26	1.01 ± 0.37	0.023	0.80 ± 0.42	0.80 ± 0.44	0.805 ± 0.20	0.98
SHBG1, nmol/L	1304	43.8 × 1.7	39 × 1.6	33.42× 1.63	< 0.001	55.4 × 1.7	46.22× 1.7	48.2 × 1.73	< 0.001
Testosterone1, nmol/L	1412	19.2 × 4.2	15.8 × 3.3	15.1 × 3.3	0.16	0.79 × 3.66	0.70 × 3.1	0.79 × 3.8	0.50
Uric acid, mg/dL	1821	5.51 ± 1.3	5.82 ± 1.3	6.362± 1.6	< 0.001	4.23 ± 1.2	4.62± 1.1	5.15 ± 1.4	< 0.001
C-reactive protein1, mg/L	1788	1.642× 3.13	1.93 × 3.0	2.39 × 2.75	< 0.001	1.41 × 3.15	2.532× 2.8	3.75 × 2.65	< 0.001
Current; past smokers, %	1817	59.42; 18.8	47.5; 23.4	46.1; 25.4	0.037	27.42 ; 3.2	14.1; 3.3	10.2; 4.4	< 0.001
CHD prevalence, n (%)	1820	5 (2.5)	11 (4.2)	31 (7.52)	0.02	6 (2.4)	11 (4.6)	29 (6.4)	0.056

¹Log-transformed values, SD range is obtained by dividing or multiplying with the given SD;

²Denote significant difference, from the remaining two groups, those in italics borderline significant difference. NAFLD: Non-alcoholic fatty liver disease; CHD: Coronary heart disease; LDL: Low density lipoprotein; BP: Blood pressure; HDL: High-density lipoprotein; SHBG: Sex hormone-binding globulin.

Table 2 Pearson correlations of fatty liver index (n = 1822) with relevant variables

	Men		Women
	n	r	n	r
Age	877	-0.04	945	0.28
Body mass index	869	0.71	939	0.68
Systolic BP	877	0.27	945	0.38
Diastolic BP	877	0.34	945	0.36
Total cholesterol	877	0.27	945	0.28
HDL cholesterol	877	-0.22	945	-0.19
C-reactive protein1	864	0.16	924	0.41
Apo A-I	841	-0.08	899	-0.07
Apo B	844	0.18	915	0.19
Lipoprotein(a)1	549	0.02	637	-0.05
Fasting glucose	877	0.09	945	0.12
Sex h-b globulin1	623	-0.23	681	-0.26
Testosterone1	642	-0.08	708	0.01
Uric acid	869	0.23	938	0.20
Creatinine	735	0.04	785	0.00
Fasting insulin	775	0.33	861	0.33
Alcohol usage	873	0.11	941	-0.06

¹Coefficients in bold denote P≤ 0.002, in italics P < 0.05. BP: Blood pressure; HDL: High-density lipoprotein.

Table 3 Adjusted Cox regression analyses of fatty liver disease for prediction of type-2 diabetes and incident coronary heart disease, by gender (and diabetic status)

	Total		Men		Women
	HR	95%CI	HR	95%CI	HR	95%CI
Diabetes n =	203/14901		110/7071		93/7831
Gender, female	0.82	0.56; 1.20
Age, 11 yr2	1.14	0.97; 1.34	1.13	0.90; 1.41	1.14	0.90; 1.46
Current smoking, n = 480	1.38	0.94; 2.00	1.35	0.84; 2.16	1.39	0.74; 2.69
Former smoking, n = 183	1.32	0.83; 2.08	1.22	0.72; 2.06	1.98	0.72; 5.48
HDL-cholesterol, 12 mg/dL	0.91	0.78; 1.06	0.96	0.77; 1.21	0.89	0.71; 1.10
Systolic BP, 25 mmHg	1.16	1.00; 1.38	1.28	1.03; 1.60	1.08	0.88; 1.35
Uric acid, 1.3 mg/dL	0.87	0.76; 0.996	0.81	0.67; 0.97	0.94	0.76; 1.15
Probable FLD, n = 423	1.44	0.80; 2.57	1.57	0.72; 3.43	1.28	0.52; 3.12
FLD, n = 673	4.93	2.98; 8.14	4.80	2.40; 9.59	5.33	2.53; 11.2
DM incid. per 1000 person-yr	16.6		18.8		14.5
CHD: Diabetic sample n =	88/4091		45/1921		43/2171
Gender, female	0.95	0.55; 1.63
Age, 11 years	1.18	0.94; 1.49	1.27	0.90; 1.80	1.10	0.79; 1.56
Current smoking	1.12	0.64; 1.95	1.46	0.68; 3.15	0.66	0.25; 1.75
Former smoking	1.13	0.56; 2.31	1.36	0.59; 3.13	1.12	0.15; 8.52
Alcohol usage, yes/no	0.50	0.12; 2.10	0.58	0.14; 2.45		No user
HDL-cholesterol, 12 mg/dL	0.78	0.61; 1.00	0.90	0.62; 1.28	0.69	0.48; 0.99
Systolic BP, 25 mmHg	0.95	0.72; 1.28	0.98	0.60; 1.60	0.93	0.65; 1.31
Uric acid, 1.3 mg/dL	0.98	0.79: 1.23	0.73	0.54: 0.999	1.35	0.99: 1.84
Probable FLD	1.45	0.66; 3.18	1.68	0.56; 5.05	1.32	0.42; 4.11
FLD	3.59	1.78; 7.23	4.61	1.72; 12.4	3.12	1.17; 8.35
CHD inciden. per 1000 person-yr	25.3		27.4		23.4
CHD: Whole sample n =	237/15051		104/716		133/7891
Gender, female	1.34	0.96; 1.86
Age, 11 yr	1.48	1.27; 1.71	1.54	1.26; 2.00	1.43	1.17; 1.73
Current smoking	1.50	1.06; 2.13	1.80	1.12; 2.90	1.13	0.64; 1.98
Former smoking	1.02	0.64; 1.63	0.92	0.51; 1.64	1.82	0.79; 4.17
Alcohol usage, yes/no	0.80	0.37; 1.74	0.79	0.36; 1.75		Too few
HDL-cholesterol, 12 mg/dL	0.90	0.78; 1.02	1.04	0.84; 1.28	0.81	0.69; 0.98
Systolic BP, 25 mmHg	1.25	1.08; 1.42	1.31	1.12; 1.27	1.25	1.05; 1.45
Presence of diabetes	1.44	0.98; 2.13	1.81	1.04; 3.17	1.13	0.65; 1.95
Probable FLD	1.26	0.83; 1.92	1.79	0.92; 3.47	0.99	0.57; 1.73
FLD	1.72	1.17; 2.53	2.35	1.25; 4.43	1.42	0.86; 2.35
CHD incid. per 1000 person-yr	18.9		17.5		19.7

¹Number of cases/number at risk;

²Referent was no FLD (n = 393 in the model for CHD). Mean age at baseline was 52.1 yr. Prevalent diabetes/coronary diseases were excluded. HDL: High-density lipoprotein; FLD: Fatty liver disease; CHD: Coronary heart disease; BP: Blood pressure.

Table 4 Adjusted Cox regression analyses of fatty liver disease for prediction of overall mortality, by gender and diabetic status

	Total		Men		Women
	HR	95%CI	HR	95%CI	HR	95%CI
Diabetic sample n =	30/1181		20/591		10/591
Gender, female	0.71	0.25; 2.00
Age, 11 yr	2.74	1.43; 5.22	2.61	1.19; 5.73	3.48	1.02; 12.0
Current vs non-smoker	0.94	0.30; 3.02	1.38	0.37; 5.18	n = 2	protecting
Former smoking, n = 170	1.17	0.40; 3.40	2.20	0.61; 7.85	n = 2	Too few
HDL-cholesterol, 12 mg/dL	0.81	0.55; 1.20	0.72	0.41; 1.24	0.77	0.43; 1.36
Systolic BP, 25 mmHg	1.16	0.74; 1.81	0.82	0.40; 1.72	1.25	0.62; 2.60
HOMA index, 2-fold	1.15	0.89; 1.49	1.03	0.75; 1.41	1.47	0.95; 2.27
Probable FLD, n = 25	0.48	0.15; 1.55	0.35	0.09; 1.34	n = 12	risk-
FLD, n = 66	0.74	0.24; 2.24	0.72	0.20; 2.57	n = 36	conferring
Death rate per 1000 person-yr	30.2		38.2		22.4
Prediabetic sample2n =	32/2681		17/1191		15/1491
HOMA index, 2-fold	1.25	0.93; 1.68	1.33	0.80; 2.23	1.32	0.87; 2.00
Probable FLD n = 57	1.05	0.25; 4.40	0.70	0.10; 4.77	1.19	0.10; 14.5
FLD n = 116	2.07	0.52; 8.19	2.69	0.42; 17.0	1.30	0.12; 14.7
Death rate per 1000 person-yr	14.0		17.2		11.8
Normoglycemic sample n =	89/12681		54/6101		35/6581
Gender, female	0.77	0.42; 1.40
Age, 11 yr	3.76	2.85; 4.97	3.91	2.69; 5.68	3.41	2.24; 5.17
Current vs never smoking	2.39	1.27; 4.51	2.99	1.36; 6.56	0.98	0.22; 4.38
Former smoking, n = 170	1.04	0.46; 2.34	1.16	0.47; 2.87	n = 15	Too few
HDL-cholesterol, 12 mg/dL	1.05	0.84; 1.31	1.07	0.78; 1.46	1.07	0.78; 1.51
Systolic BP, 25 mmHg	1.03	0.80; 1.31	1.13	0.80; 1.64	0.98	0.67; 1.38
HOMA index, 2-fold	1.02	0.88; 1.17	1.10	0.94; 1.29	0.79	0.62; 1.007
Probable FLD n = 312	0.89	0.47; 1.68	0.55	0.24; 1.31	2.02	0.75; 5.39
FLD n = 500	0.68	0.34; 1.36	0.58	0.24; 1.40	0.96	0.32; 2.88
Death rate per 1000 person-yr	8.1		10.0		6.3
Whole sample n =	151/16541		91/7881		60/8661
Gender, female	0.73	0.46; 1.17
Age, 11 yr3	3.38	2.69; 4.19	3.48	2.60; 4.65	3.34	2.36; 4.74
Current vs never smoking, n = 414	1.67	1.03; 2.70	2.01	1.13; 3.57	0.96	0.29; 3.17
Former smoking, n = 170	0.92	0.52; 1.64	0.99	0.52; 1.88	n = 22	Too few
Alcohol usage, yes/no, n = 116	0.84	0.37; 1.90	0.73	0.32; 1.67	n = 2	Too few
HDL-cholesterol, 12 mg/dL	1.02	0.87; 1.11	1.09	0.85; 1.38	0.94	0.73; 1.22
Systolic BP, 25 mmHg	1.03	0.86; 1.25	1.00	0.78; 1.31	1.08	0.84; 1.42
Prediabetes, n = 220	1.30	0.82; 2.07	1.08	0.56; 2.09	1.73	0.89; 3.35
Presence of diabetes, n = 104	2.70	1.73; 4.22	2.22	1.52; 4.86	2.76	1.32; 5.76
HOMA index, 2-fold	1.08	0.97; 1.21	1.12	0.99; 1.27	0.98	0.80; 1.20
Probable FLD, n = 394	0.79	0.48; 1.31	0.58	0.31; 1.11	1.42	0.57; 3.50
FLD n = 681	0.84	0.50; 1.39	0.83	0.44; 1.56	1.03	0.41; 2.59
Death rate per 1000 person-yr	10.8		13.3		7.9

¹Number of deaths/number at risk;

²Adjusted also for sex, age, current smoking, systolic BP, HDL-cholesterol;

³Referent was no FLD (n = 412). Mean age at baseline was 52.1 years. Missing HOMA index values limited by 15% the sample and deaths. HDL: High-density lipoprotein; FLD: Fatty liver disease; HOMA: Homeostatic assessment; BP: Blood pressure.

Table 5 Adjusted Cox regression analyses of components of fatty liver index for prediction of type-2 diabetes, incident coronary heart disease and mortality, by gender

	Total		Men		Women
	HR	95%CI	HR	95%CI	HR	95%CI
Diabetes
Waist circumference, 12 cm	1.70	1.33; 2.15	1.64	1.13; 2.38	1.78	1.27; 2.46
Body mass index, 5 kg/m2	1.10	0.91; 1.33	1.06	0.80; 1.40	1.11	0.86; 1.44
Triglycerides, 90 mg/dL	1.22	1.06; 1.40	1.09	0.91; 1.31	1.43	1.20; 1.71
γ-glutamyltransferase, 1.7-fold	2.19	1.61; 2.99	2.44	1.52; 3.92	2.22	1.44; 3.43
CHD
Waist circumference, 12 cm	1.21	0.80; 1.82	1.21	0.20; 1.82	1.02	0.78; 1.33
Body mass index, 5 kg/m2	1.01	0.84; 1.20	0.77	0.52; 1.14	0.98	0.80; 1.20
Triglycerides, 90 mg/dL	1.19	1.03; 1.35	1.20	1.01; 1.43	1.12	0.84; 1.31
γ-glutamyltransferase, 1.7-fold	1.52	0.94; 2.44	1.52	0.94; 2.44	1.64	1.16; 2.31
Mortality
Waist circumference, 12 cm	1.31	1.00; 1.74	1.21	0.81; 1.80	1.38	0.90; 2.11
Body mass index, 5 kg/m2	0.73	0.56; 0.96	0.68	0.45; 1.03	0.82	0.56; 1.20
Triglycerides, 90 mg/dL	1.12	0.96; 1.31	1.28	1.01; 1.57	0.91	0.70; 1.20
γ-glutamyltransferase, 1.7-fold	1.37	0.97; 1.93	1.28	0.79; 2.06	1.62	0.95; 2.77

Models were adjusted also to sex, age, smoking status, systolic BP, HDL-cholesterol. Further, uric acid protected men against diabetes and weakly tended to protect women against CHD.