Lower alanine aminotransferase levels are associated with increased all-cause and cardiovascular mortality in nonalcoholic fatty liver patients

Table 1 Baseline characteristics of the overall population and nonalcoholic fatty liver disease patients with normal or elevated alanine aminotransferase level

	Overall population (n = 11441)			NAFLD population (n = 4159)
	Normal ALT level (n = 9698)	Elevated ALT level (n = 1743)	P value	Normal ALT level (n = 3131)	Elevated ALT level (n = 1028)	P value
Age (yr)	44.4 ± 0.17	41.5 ± 0.35	< 0.001	48.0 ± 0.29	43.2 ± 0.45	< 0.001
Sex, male (%)	4397 (45.3)	710 (40.7)	< 0.001	1496 (47.8)	436 (42.4)	0.003
Race/ethnicity, n (%)			< 0.001			< 0.001
Non-Hispanic White	3725 (38.4)	527 (30.2)		1186 (37.9)	300 (29.2)
Non-Hispanic Black	2950 (30.4)	325 (18.6)		861 (27.5)	143 (13.9)
Mexican American	2620 (27.0)	815 (46.8)		967 (30.9)	540 (52.5)
Others	403 (4.2)	76 (4.4)		117 (3.7)	45 (4.4)
Waist circumference (cm)	92.3 ± 0.15	98.3 ± 0.35	< 0.001	97.9 ± 0.30	102.6 ± 0.45	< 0.001
BMI (kg/m2)	27.0 ± 0.06	29.7 ± 0.15	< 0.001	28.9 ± 0.12	31.4 ± 0.20	< 0.001
Hypertension, n (%)	3892 (40.1)	698 (40.0)	0.946	1434 (45.8)	458 (44.6)	0.486
Diabetes, n (%)	836 (8.6)	253 (14.5)	< 0.001	476 (15.2)	214 (20.8)	< 0.001
HOMA-IR, n (%)	3652 (37.7)	1117 (64.1)	< 0.001	1712 (54.7)	785 (76.4)	< 0.001
Fasting plasma glucose (mmol/L)	5.6 ± 0.02	5.9 ± 0.06	< 0.001	6.0 ± 0.05	6.3 ± 0.09	0.002
HbA1c (%)	5.5 ± 0.01	5.7 ± 0.03	< 0.001	5.8 ± 0.02	5.9 ± 0.05	0.027
TG (mg/dL)	135.2 ± 1.0	182.4 ± 3.2	< 0.001	165.9 ± 2.09	207.0 ± 4.49	< 0.001
Total cholesterol (mg/dL)	204.2 ± 0.44	209.7 ± 1.07	< 0.001	208.6 ± 0.80	212.6 ± 1.37	< 0.001
HDL (mg/dL)	51.3 ± 0.15	47.0 ± 0.36	< 0.001	48.3 ± 0.27	45.0 ± 0.47	< 0.001
ALT (IU/L)	13.7 ± 0.06	39.5 ± 0.63	< 0.001	14.9 ± 0.10	41.7 ± 0.90	< 0.001
AST (IU/L)	19.0 ± 0.06	34.2 ± 0.64	< 0.001	19.5 ± 0.11	35.6 ± 0.92	< 0.001
Albumin (g/L)	41.4 ± 0.04	41.7 ± 0.09	0.007	41.1 ± 0.07	41.8 ± 0.11	< 0.001
Smoked at least 100 cigarettes, n (%)	4872 (50.2)	752 (43.3)	< 0.001	1637 (52.3)	448 (43.6)	< 0.001
Sedentary lifestyle, n (%)	2811 (29.0)	583 (33.4)	< 0.001	1048 (33.5)	373 (36.3)	0.099
NAFLD, n (%)	3131 (32.3)	1028 (59.0)	< 0.001
Mild	1326 (13.7)	229 (13.1)		1326 (42.4)	229 (22.3)
Moderate	1268 (13.1)	490 (28.1)		1268 (40.5)	490 (47.7)
Severe	537 (5.5)	309 (1.7)	< 0.001	537 (17.2)	309 (30.1)	< 0.001

Categorical values are shown as n (%). Continuous variables are shown as mean ± SEs. Elevated alanine aminotransferase (ALT) level was defined as ALT > 30 U/L in men or > 19 U/L in women. BMI: Body mass index; HOMA-IR: Homeostasis model assessment of insulin resistance; HbA1c: Glycosylated hemoglobin; TG: Triglyceride; HDL: High-density lipoprotein cholesterol; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; NAFLD: Nonalcoholic fatty liver disease.

Table 2 Association between alanine aminotransferase level or nonalcoholic fatty liver disease status and all-cause mortality in overall population

ALT level	Unadjusted		Age-adjusted		Multivariate-adjusted
	HR (95%CI)	P value	HR (95%CI)	P value	HR (95%CI)	P value
< 0.5 ULN	1		1		1
0.5-1 ULN	0.76 (0.71-0.81)	< 0.001	0.74 (0.70-0.80)	< 0.001	0.76 (0.71-0.81)	< 0.001
1-2 ULN	0.66 (0.60-0.74)	< 0.001	0.73 (0.66-0.81)	< 0.001	0.70 (0.63-0.79)	< 0.001
≥ 2 ULN	0.60 (0.49-0.74)	< 0.001	0.92 (0.75-1.14)	0.442	0.74 (0.57-0.97)	0.017
NAFLD
No NAFLD	1		1		1
NAFLD	1.41 (1.33-1.50)	< 0.001	1.13 (1.06-1.20)	< 0.001	0.99 (0.92-1.06)	0.758

The multivariate model was adjusted for age, sex, race/ethnicity, body mass index, waist circumference, aspartate aminotransferase, albumin, triglyceride, total cholesterol, high-density lipoprotein cholesterol, smoking status, diabetes, hypertension, and sedentary lifestyle. CI: Confidence interval; HR: Hazard ratio; ULN: Upper limits of normal; ALT: Alanine aminotransferase; NAFLD: Nonalcoholic fatty liver disease.

Table 3 Association of alanine aminotransferase level, cardiovascular disease, cancer-related and others-related mortality stratified by the presence/absence of nonalcoholic fatty liver disease

	Total population		No NAFLD		NAFLD
	HR (95%CI)	P value	HR (95%CI)	P value	HR (95%CI)	P value
ALT level
Cardiovascular
< 0.5 ULN	1		1		1
0.5-1 ULN	0.74 (0.65-0.85)	< 0.001	0.82 (0.68-0.97)	0.022	0.66 (0.52-0.82)	< 0.001
1-2 ULN	0.63 (0.50-0.79)	< 0.001	0.78 (0.56-1.09)	0.149	0.55 (0.39-0.78)	< 0.001
≥ 2 ULN	0.63 (0.35-1.12)	0.113	0.70 (0.26-1.86)	0.469	0.68 (0.31-1.50)	0.342
Cancer
< 0.5 ULN	1		1		1
0.5-1 ULN	0.74 (0.64-0.86)	< 0.001	0.70 (0.58-0.84)	< 0.001	0.85 (0.66-1.11)	0.230
1-2 ULN	0.67 (0.52-0.86)	0.002	0.61 (0.42-0.88)	0.009	0.77 (0.54-1.12)	0.171
≥ 2 ULN	1.11 (0.67-1.86)	0.682	0.86 (0.35-2.11)	0.738	1.39 (0.70-2.75)	0.346
Others
< 0.5 ULN	1		1		1
0.5-1 ULN	0.89 (0.80-0.99)	0.029	0.92 (0.81-1.05)	0.227	0.80 (0.67-0.95)	0.011
1-2 ULN	0.98 (0.83-1.16)	0.809	1.25 (0.98-1.60)	0.074	0.73 (0.57-0.93)	0.012
≥ 2 ULN	0.75 (0.51-1.09)	0.131	0.69 (0.33-1.45)	0.331	0.53 (0.32-0.89)	0.015

The multivariate model was adjusted for age, sex, race/ethnicity, body mass index, waist circumference, aspartate aminotransferase, albumin, triglyceride, total cholesterol, high-density lipoprotein cholesterol, smoking status, diabetes, hypertension, and sedentary lifestyle. Others: Chronic lower respiratory diseases, accidents (unintentional injuries), cerebrovascular diseases, Alzheimer’s diseases, diabetes mellitus, influenza and pneumonia, nephritis, nephrotic syndrome and nephrosis and all other causes (residual). CI: Confidence interval; HR: Hazard ratio; ULN: Upper limits of normal; ALT: Alanine aminotransferase; NAFLD: Nonalcoholic fatty liver disease.

Table 4 Association of alanine aminotransferase level, all-cause, cardiovascular disease, cancer-related and others-related mortality among nonalcoholic fatty liver disease patients in men

Mortality outcome, ALT level	No. of death, n (%)	Unadjusted		Age-adjusted		Multivariate-adjusted
		HR (95%CI)	P value	HR (95%CI)	P value	HR (95%CI)	P value
All-cause
< 0.5 ULN	306 (61.1)	1		1		1
0.5-1 ULN	436 (45.2)	0.60 (0.52-0.70)	< 0.001	0.69 (0.59-0.80)	< 0.001	0.68 (0.58-0.80)	< 0001
1-2 ULN	115 (30.8))	0.37 (0.30-0.46)	< 0.001	0.62 (0.50-0.77)	< 0.001	0.60 (0.47-0.76)	< 0001
≥ 2 ULN	21 (22.6)	0.26 (0.16-0.40)	< 0.001	0.69 (0.44-1.09)	0.11	0.72 (0.42-1.21)	0.214
Cardiovascular disease
< 0.5 ULN	102 (20.4)	1		1		1
0.5-1 ULN	119 (22.3)	0.50 (0.39-0.65)	< 0.001	0.58 (0.44-0.76)	< 0.001	0.57 (0.43-0.77)	< 0.001
1-2 ULN	34 (9.1)	0.34 (0.23-0.50)	< 0.001	0.58 (0.39-0.87)	0.007	0.55 (0.33-0.92)	0.022
≥ 2 ULN	3 (3.2)	0.11 (0.04-0.36)	< 0.001	0.33 (0.10-1.05)	0.06	0.51 (0.13-1.97)	0.331
Cancer
< 0.5 ULN	67 (13.4)	1		1		1
0.5-1 ULN	103 (10.7)	0.65 (0.48-0.89)	0.006	0.73 (0.54-1.00)	0.051	0.79 (0.57-1.10)	0.169
1-2 ULN	25 (6.7)	0.37 (0.23-0.58)	< 0.001	0.62 (0.39-0.99)	0.047	0.76 (0.45-1.29)	0.308
≥ 2 ULN	5 (5.4)	0.28 (0.11-0.69)	0.006	0.81 (0.32-2.05)	0.654	1.05 (0.35-3.12)	0.935
Others
< 0.5 ULN	137 (44.8)	1		1		1
0.5-1 ULN	214 (49.1)	0.81 (0.65-1.00)	0.048	0.81 (0.66-1.01)	0.058	0.73 (0.57-0.92)	0.921
1-2 ULN	56 (48.7)	0.68 (0.50-0.92)	0.014	0.75 (0.55-1.03)	0.073	0.57 (0.38-0.85)	0.851
≥ 2 ULN	13 (61.9)	0.70 (0.39-1.23)	0.212	0.76 (0.42-1.37)	0.361	0.40 (0.19-0.84)	0.844

The multivariate model was adjusted for age, sex, race/ethnicity, body mass index, waist circumference, aspartate aminotransferase, albumin, triglyceride, total cholesterol, high-density lipoprotein cholesterol, smoking status, diabetes, hypertension, and sedentary lifestyle. Others: Chronic lower respiratory diseases, accidents (unintentional injuries), cerebrovascular diseases, Alzheimer’s diseases, diabetes mellitus, influenza and pneumonia, nephritis, nephrotic syndrome and nephrosis and all other causes (residual). CI: Confidence interval; HR: Hazard ratio; ULN: Upper limits of normal; ALT: Alanine aminotransferase.

Table 5 Association of alanine aminotransferase level, all-cause, cardiovascular disease, cancer-related and others-related mortality among nonalcoholic fatty liver disease patients in women

Mortality outcome, ALT level	No. of death, n (%)	Unadjusted		Age-adjusted		Multivariate-adjusted
		HR (95%CI)	P value	HR (95%CI)	P value	HR (95%CI)	P value
All-cause
< 0.5 ULN	144 (34.0)	1		1		1
0.5-1 ULN	440 (38.8)	1.16 (0.96-1.40)	0.127	0.88 (0.73-1.06)	0.176	0.91 (0.74-1.10)	0.348
1-2 ULN	187 (36.0)	1.05 (0.85-1.31)	0.632	0.83 (0.67-1.03)	0.095	0.76 (0.60-0.97)	0.027
≥ 2 ULN	46 (30.7)	0.89 (0.64-1.24)	0.484	1.10 (0.79-1.53)	0.585	0.82 (0.52-1.31)	0.416
Cardiovascular disease
< 0.5 ULN	41 (9.7)	1		1		1
0.5-1 ULN	119 (10.5)	1.10 (0.77-1.58)	0.594	0.82 (0.58-1.17)	0.282	0.86 (0.59-1.26)	0.44
1-2 ULN	442 (8.1)	0.83 (0.54-1.28)	0.41	0.65 (0.42-1.00)	0.051	0.62 (0.38-1.02)	0.061
≥ 2 ULN	99 (6.0)	0.61 (0.30-1.26)	0.182	0.78 (0.38-1.61)	0.504	0.85 (0.29-2.43)	0.756
Cancer
< 0.5 ULN	31 (7.3)	1		1		1
0.5-1 ULN	97 (8.6)	1.18 (0.79-1.77)	0.425	0.93 (0.62-1.40)	0.728	1.02 (0.66-1.57)	934
1-2 ULN	37 (7.1)	0.96 (0.60-1.55)	0.877	0.76 (0.47-1.23)	0.261	0.83 (0.49-1.44)	0.482
≥ 2 ULN	15 (10.0)	1.34 (0.72-2.48)	0.352	1.38 (0.74-2.57)	0.309	1.49 (0.61-3.68)	0.395
Others
< 0.5 ULN	71 (49.7)	1		1		1
0.5-1 ULN	224 (50.9)	0.91 (0.70-1.20)	0.526	0.92 (0.71-1.20)	0.549	0.89 (0.67-1.18)	0.411
1-2 ULN	108 (57.8)	1.01 (0.75-1.37)	0.935	1.08 (0.80-1.46)	0.627	0.85 (0.61-1.20)	0.366
≥ 2 ULN	22 (47.8)	0.99 (0.62-1.61)	0.978	1.16 (0.72-1.88)	0.548	0.62 (0.30-1.29)	0.199

The multivariate model was adjusted for age, sex, race/ethnicity, body mass index, waist circumference, aspartate aminotransferase, albumin, triglyceride, total cholesterol, high-density lipoprotein cholesterol, smoking status, diabetes, hypertension, and sedentary lifestyle. Others: Chronic lower respiratory diseases, accidents (unintentional injuries), cerebrovascular diseases, Alzheimer’s diseases, diabetes mellitus, influenza and pneumonia, nephritis, nephrotic syndrome and nephrosis and all other causes (residual). CI: Confidence interval; HR: Hazard ratio; ULN: Upper limits of normal; ALT: Alanine aminotransferase.

Table 6 Association of different models, all-cause, cardiovascular disease, cancer-related and others-related mortality among nonalcoholic fatty liver disease patients

Mortality outcome	No. of death, n (%)	Unadjusted		Age-adjusted		Multivariate-adjusted
		HR (95%CI)	P value	HR (95%CI)	P value	HR (95%CI)	P value
All-cause
Model 1	1055 (41.9)	1		1		1
Model 2	248 (31.2)	0.68 (0.59-0.78)	< 0.001	0.89 (0.77-1.02)	0.1	0.87 (0.74-1.01)	0.067
Model 3	271 (53.7)	1.45 (1.26-1.65)	< 0.001	1.11 (0.97-1.27)	0.139	0.98 (0.85-1.12)	0.727
Model 4	121 (35.5)	0.82 (0.68-0.99)	0.037	0.91 (0.75-1.10)	0.312	0.81 (0.66-0.99)	0.042
Cardiovascular disease
Model 1	309 (12.3)	1		1		1
Model 2	68 (8.6)	0.64 (0.49-0.83)	< 0.001	0.86 (0.66-1.12)	0.254	0.89 (0.65-1.20)	0.437
Model 3	72 (14.3)	1.30 (1.01-1.68)	0.045	0.99 (0.76-1.27)	0.907	0.82 (0.63-1.07)	0.146
Model 4	20 (5.9)	0.46 (0.30-0.73)	< 0.001	0.52 (0.33-0.82)	0.005	0.53 (0.33-0.87)	0.011
Cancer
Model 1	241 (9.6)	1		1		1
Model 2	50 (6.3)	0.60 (0.44-0.81)	0.001	0.74 (0.55-1.01)	0.055	0.86 (0.62-1.21)	0.387
Model 3	57 (11.3)	1.31 (0.98-1.75)	0.067	1.02 (0.76-1.36)	0.904	1.01 (0.75-1.37)	0.928
Model 4	32 (9.4)	0.94 (0.65-1.36)	0.743	1.02 (0.70-1.47)	0.938	1.07 (0.71-1.61)	0.755
Others
Model 1	504 (47.8)	1		1		1
Model 2	130 (53.4)	0.94 (0.77-1.13)	0.492	1.03 (0.84-1.25)	0.799	0.93 (0.74-1.16)	0.506
Model 3	142 (53.4)	1.28 (1.06-1.55)	0.009	1.25 (1.04-1.51)	0.019	1.15 (0.95-1.40)	0.159
Model 4	69 (57.0)	1.09 (0.85-1.41)	0.483	1.14 (0.89-1.47)	0.312	0.89 (0.67-1.20)	0.453

Model 1: Mild to moderate nonalcoholic fatty liver disease (NAFLD) with normal alanine aminotransferase (ALT) level; Model 2: Mild to moderate NAFLD with elevated ALT Level; Model 3: Severe NAFLD with normal ALT level; Model 4: Severe NAFLD with elevated ALT Level. The multivariate model was adjusted for age, sex, race/ethnicity, body mass index, waist circumference, aspartate aminotransferase, albumin, triglyceride, total cholesterol, high-density lipoprotein cholesterol, smoking status, diabetes, hypertension, and sedentary lifestyle. Others: Chronic lower respiratory diseases, accidents (unintentional injuries), cerebrovascular diseases, Alzheimer’s diseases, diabetes mellitus, influenza and pneumonia, nephritis, nephrotic syndrome and nephrosis and all other causes (residual). CI: Confidence interval; HR: Hazard ratio.