Baseline characteristics
A total of 1048 patients with NAFLD were included in this study and were divided into 4 groups based on the normalization of baseline ALT and/or GGT levels after follow-up: both ALT and GGT abnormal group (n = 415), ALT-only abnormal group (n = 52), GGT-only abnormal group (n = 222), and both ALT and GGT normalization group (n = 359) (Fig. 1). Significant differences in gender, age, fasting glucose level, prevalence of type 2 diabetes, hypertension, partial lipid metabolism and medications were not observed between groups (Table 1). The group with both abnormal ALT and GGT levels had a higher BMI (kg/m2) (median 26.2 vs. 26.0 vs. 25.9 vs. 25.6, P < 0.001, Table 1), but the waist-hip ratio of this group was not increased. Among the 1048 patients with NAFLD, 637 patients presented with abnormal GGT levels, and the percentage of patients with abnormal GGT levels was 60.7%. Meanwhile, 467 patients presented with abnormal ALT, and the percentage of patients with abnormal ALT levels was 44.6%. Compared with the other three groups (ALT-only abnormal group, GGT-only abnormal group, and both ALT and GGT normalization group), the both ALT and GGT abnormal group had higher liver function indices, such as GGT, ALT, AST, alkaline phosphatase, total bilirubin, direct bilirubin, total bile acid, lactate dehydrogenase, leucine arylamidase and glutamate dehydrogenase levels (all, P < 0.05, Table 1). However, compared with the other three groups, a significant increase in blood lipid metabolism was not observed in the both ALT and GGT abnormal group (Table 1). Furthermore, compared with the other three groups, the group with both abnormal ALT and GGT levels had higher uric acid levels, fasting insulin levels, and HOMA-IR levels (all, P < 0.001, Table 1). Of the 630 patients with NAFLD who underwent MRI-PDFF, the group with abnormal levels of both ALT and GGT presented a significantly higher liver fat content (%) measured using MRI-PDFF than the other three groups (median 15.4 vs. 14.9 vs. 12.5 vs. 10.8, P < 0.001, Table 1), but no difference was identified in the pancreas fat content and abdominal subcutaneous fat thickness (all, P > 0.05, Table 1).
Table 1
Baseline characteristics of patients with NAFLD presenting different ALT and GGT statuses.
Variables
|
Both GGT and ALT abnormal
(N = 415)
|
ALT Abnormal only
(N = 52)
|
GGT Abnormal only
(N = 222)
|
GGT and ALT normalization
(N = 359)
|
P
|
Post-hoc
|
1# vs. 2#
|
1# vs. 3#
|
1# vs. 4#
|
2# vs. 3#
|
2# vs. 4#
|
3# vs. 4#
|
Age, years
|
39.6 ± 12.4
|
40.9 ± 11.2
|
42.9 ± 11.5
|
44.8 ± 12.5
|
0.21
|
|
|
|
|
|
|
Male, n (%)
|
322 (77.6)
|
38 (73.1)
|
167 (75.2)
|
252 (70.2)
|
0.13
|
|
|
|
|
|
|
BMI, kg/m2
|
26.2 (24.9,28.5)
|
26.0 (23.2,27.8)
|
25.9 (23.5,27.4)
|
25.6 (23.5,27.3)
|
< 0.001
|
0.19
|
< 0.001
|
< 0.001
|
0.22
|
0.13
|
0.70
|
Waist-hip ratio
|
0.89 (0.86,0.94)
|
0.89 (0.85,0.92)
|
0.90 (0.87,0.94)
|
0.89 (0.84,0.97)
|
< 0.001
|
0.97
|
0.80
|
0.004
|
0.59
|
0.72
|
< 0.001
|
Smoke, n (%)
|
87 (21.0)
|
8 (15.4)
|
44 (19.8)
|
45 (12.5)
|
0.01
|
0.35
|
0.73
|
0.002
|
0.46
|
0.57
|
0.02
|
Complication, n (%)
|
|
|
|
Type 2 diabetes
|
30 (7.2)
|
4 (7.6)
|
15 (6.7)
|
31 (8.6)
|
0.84
|
|
|
|
|
|
|
Hypertension
|
135 (32.5)
|
16 (30.8)
|
65 (29.3)
|
103 (28.7)
|
0.68
|
|
|
|
|
|
|
Liver biochemistry
|
|
|
|
GGT, U/L
|
84 (61,140)
|
32 (27,37)
|
64 (50,103)
|
25 (19,30)
|
< 0.001
|
< 0.001
|
< 0.001
|
< 0.001
|
0.002
|
0.74
|
< 0.001
|
ALT, U/L
|
96 (69,140)
|
69 (57,94)
|
34 (26,41)
|
24 (18,32)
|
< 0.001
|
< 0.001
|
< 0.001
|
< 0.001
|
< 0.001
|
< 0.001
|
0.29
|
AST, U/L
|
51 (38,76)
|
40 (36,51)
|
27 (22,33)
|
22 (19,26)
|
< 0.001
|
0.001
|
< 0.001
|
< 0.001
|
0.16
|
0.03
|
0.21
|
Alkaline phosphatase, U/L
|
84 (70,98)
|
76 (61,85)
|
78 (64,93)
|
70 (58,84)
|
< 0.001
|
0.02
|
0.01
|
< 0.001
|
0.43
|
0.47
|
0.01
|
Total bilirubin, umol/L
|
15.2 (11.2,15.7)
|
15.2 (12.2,15.8)
|
15.2 (10.6,15.5)
|
15.2 (11.5,15.3)
|
0.04
|
0.73
|
0.06
|
0.01
|
0.18
|
0.12
|
0.76
|
Direct bilirubin, umol/L
|
3.6 (2.6,3.8)
|
3.6 (2.6,4.3)
|
3.4 (2.1,3.6)
|
3.6 (2.4,3.7)
|
0.02
|
0.43
|
0.002
|
0.001
|
0.36
|
0.38
|
0.91
|
Total bile acid, umol/L
|
3.1 (2.2,5.6)
|
1.6 (1.2,3.4)
|
2.6 (1.7,4.2)
|
2.3 (1.6,4.2)
|
0.03
|
0.08
|
0.06
|
0.01
|
0.46
|
0.59
|
0.69
|
Lactate dehydrogenase, U/L
|
201 (176,230)
|
183 (164,199)
|
184 (168,205)
|
187 (171,210)
|
< 0.001
|
0.002
|
< 0.001
|
< 0.001
|
0.33
|
0.16
|
0.44
|
Choline esterase, U/L
|
9064 (7921,10411)
|
8647 (7687,9092)
|
8963 (8035,9800)
|
8997 (8074,10084)
|
0.10
|
0.03
|
0.15
|
0.64
|
0.15
|
0.04
|
0.33
|
Leucine arylamidase, U/L
|
73 (64,90)
|
58 (52,65)
|
66 (59,78)
|
55 (50,62)
|
< 0.001
|
0.001
|
0.02
|
< 0.001
|
0.05
|
0.72
|
< 0.001
|
Glutamate dehydrogenase, U/L
|
9.6 (5.5,14.0)
|
5.3 (3.6,7.8)
|
5.2 (3.6,8.6)
|
3.3 (2.4,5.3)
|
< 0.001
|
0.002
|
0.001
|
< 0.001
|
0.19
|
0.27
|
< 0.001
|
Metabolism
|
|
|
|
|
Uric acid, umol/L
|
424 (363,493)
|
412 (355,506)
|
413 (353,484)
|
392 (331,447)
|
< 0.001
|
0.10
|
0.89
|
< 0.001
|
0.13
|
0.12
|
< 0.001
|
Hyperuricemia, n%
|
170 (40.9)
|
19 (36.5)
|
104 (46.8)
|
97 (27.0)
|
< 0.001
|
0.54
|
0.15
|
< 0.001
|
0.18
|
0.15
|
< 0.001
|
Cholesterol, mmol/L
|
5.5 (4.9,6.1)
|
5.1 (4.6,5.5)
|
5.5 (4.9,6.3)
|
5.1 (4.5,6.2)
|
0.11
|
0.08
|
0.19
|
0.95
|
0.02
|
0.09
|
0.18
|
Hyper-cholesterol, n%
|
162 (39.0)
|
16 (30.8)
|
93 (41.9)
|
132 (36.7)
|
0.41
|
|
|
|
|
|
|
Triglyceride, mmol/L
|
1.8 (1.3,2.4)
|
1.7 (1.6,2.1)
|
1.9 (1.5,2.8)
|
1.6 (1.1,2.1)
|
< 0.001
|
0.32
|
0.09
|
0.004
|
0.06
|
0.67
|
< 0.001
|
Hyper-triglyceride,
n%
|
246 (59.3)
|
30 (57.7)
|
136 (61.3)
|
166 (46.2)
|
< 0.001
|
0.83
|
0.63
|
< 0.001
|
0.64
|
0.12
|
< 0.001
|
HDL-cholesterol, mmol/L
|
1.1 (1.0,1.3)
|
1.1 (1.0,1.2)
|
1.2 (1.0,1.4)
|
1.2 (1.0,1.4)
|
0.74
|
|
|
|
|
|
|
LDL-cholesterol, mmol/L
|
3.5 (3.0,4.0)
|
3.4 (3.0,3.7)
|
3.5 (3.0,4.0)
|
3.4 (2.8,4.1)
|
0.55
|
|
|
|
|
|
|
Free fatty acid, mmol/L
|
537 (436,710)
|
472 (380,542)
|
548 (393,646)
|
525 (426,693)
|
0.47
|
|
|
|
|
|
|
Apolipoprotein-A, mmol/L
|
1.3 (1.1,1.4)
|
1.2 (1.2,1.3)
|
1.3 (1.2,1.5)
|
1.3 (1.1,1.4)
|
0.37
|
|
|
|
|
|
|
Apolipoprotein-B, mmol/L
|
1.0 (0.9,1.2)
|
0.9 (0.8,1.2)
|
1.0 (0.9,1.2)
|
1.0 (0.8,1.2)
|
0.15
|
|
|
|
|
|
|
Apolipoprotein-E, mmol/L
|
49 (40,56)
|
39 (33,43)
|
47 (42,55)
|
42 (34,49)
|
0.13
|
|
|
|
|
|
|
Lipoprotein-a, mmol/L
|
139 (52,203)
|
142 (70,314)
|
132 (56,239)
|
137 (60,276)
|
0.03
|
0.63
|
0.03
|
0.01
|
0.49
|
0.37
|
0.74
|
Fasting glucose, mmol/L
|
5.1 (4.6,5.6)
|
5.0 (4.5,5.4)
|
5.0 (4.6,5.7)
|
5.0 (4.6,5.4)
|
0.47
|
|
|
|
|
|
|
Fasting insulin, uU/mL
|
10.9 (7.7,15.0)
|
9.5 (7.2,22.0)
|
8.4 (6.5,10.7)
|
8.2 (5.9,11.3)
|
< 0.001
|
0.81
|
< 0.001
|
< 0.001
|
0.01
|
< 0.001
|
0.09
|
HOMA-IR
|
2.5 (1.5,3.4)
|
2.4 (1.5,5.6)
|
2.0 (1.4,2.4)
|
1.8 (1.3,2.5)
|
< 0.001
|
0.92
|
0.002
|
< 0.001
|
0.06
|
0.01
|
0.21
|
LFC †, %
|
15.4 (10.0,21.9)
|
14.9 (9.3,20.8)
|
12.5 (7.6,19.1)
|
10.8 (7.1,14.8)
|
< 0.001
|
0.61
|
0.01
|
< 0.001
|
0.15
|
0.01
|
0.16
|
PFC ‡, %
|
2.1 (1.6,2.6)
|
2.1 (1.4,2.7)
|
2.1 (1.5,2.9)
|
1.9 (1.4,2.7)
|
0.68
|
|
|
|
|
|
|
ASFT ‖, mm
|
23 (18,30)
|
23 (19,25)
|
23 (17,28)
|
23 (18,27)
|
0.62
|
|
|
|
|
|
|
Medication
|
|
|
|
|
|
|
|
|
|
|
|
Anti-hyperlipidemic drug, n(%)
|
129 (31.1)
|
16 (30.8)
|
66 (29.7)
|
105 (29.2)
|
0.95
|
|
|
|
|
|
|
Anti-Diabetes drug, n(%)
|
29 (7.0)
|
4 (7.7)
|
8 (3.6)
|
21 (5.8)
|
0.35
|
|
|
|
|
|
|
Uric acid lowering drug, n(%)
|
33 (8.0)
|
7 (13.5)
|
18 (8.1)
|
25 (7.0)
|
0.45
|
|
|
|
|
|
|
Data are median (first quartile, third quartile), n (%), or mean ± SD (standard deviation). |
† mean N = 630; ‡ mean N = 628; ‖ mean N = 630. |
# 1- both GGT and ALT abnormal group; 2- ALT abnormal only group; 3- GGT abnormal only group; 4- GGT and ALT normalization group. |
Comparison of metabolic control among the four groups stratified according to ALT and GGT levels
In the baseline group with abnormal levels of both ALT and GGT, 74 patients were excluded after a median follow-up of 10.6 months because they attended less than 2 follow-up visits within 12 months, and the remaining 341 patients were further analyzed. Both ALT and GGT normalization were observed in 74 (21.7%) patients, including 105 (30.8%) patients with ALT normalization alone, 39 (11.4%) patients with GGT normalization alone, and 123 (36.1%) patients with persistent abnormal levels of both enzymes (Fig. 1). Compared with the other three groups, the weight and BMI of both the ALT and GGT normalization groups exhibited the greatest decrease (weight %: 5.6 vs. 1.3 vs. 1.4 vs. 0.5, P < 0.001; BMI (kg/m2): 1.6 vs. 0.4 vs. 0.4 vs. 0.1, P < 0.001, Table 2). A similar trend was also observed in lipid metabolism-related parameters in the group with both ALT and GGT normalization, including CHOL, TG, LDL-C and APOB (all, P < 0.05, Table 2). Significant differences in fasting blood glucose levels, fasting insulin levels and HOMA-IR levels were observed among the four groups (all, P < 0.05, Table 2).
Table 2
Biochemical and metabolic changes from baseline to month 12 in 341 patients with NAFLD presenting abnormal levels of both GGT and ALT at baseline.
Variables
|
Both GGT and ALT normalization
(N = 74)
|
ALT normalization Only (N = 105)
|
GGT normalization Only (N = 39)
|
Both GGT and ALT abnormal
(N = 123)
|
P
|
Post-hoc
|
1# vs. 2#
|
1# vs. 3#
|
1# vs. 4#
|
2# vs. 3#
|
2# vs. 4#
|
3# vs. 4#
|
Weight change, kg
|
-4.7 ± 6.1
|
-1.1 ± 4.1
|
-1.1 ± 2.4
|
-0.4 ± 3.0
|
< 0.001
|
< 0.001
|
< 0.001
|
< 0.001
|
0.94
|
0.18
|
0.40
|
Weight change, %
|
-5.6 ± 6.9
|
-1.3 ± 5.5
|
-1.4 ± 3.0
|
-0.5 ± 3.9
|
< 0.001
|
< 0.001
|
< 0.001
|
< 0.001
|
0.93
|
0.26
|
0.39
|
BMI, kg/m2
|
-1.6 ± 2.0
|
-0.4 ± 1.2
|
-0.4 ± 0.8
|
-0.1 ± 1.1
|
< 0.001
|
< 0.001
|
< 0.001
|
< 0.001
|
0.94
|
0.13
|
0.33
|
Waist-hip ratio
|
-0.05 ± 0.2
|
-0.02 ± 0.1
|
0.01 ± 0.1
|
-0.03 ± 0.2
|
0.51
|
|
|
|
|
|
|
ALT, U/L
|
-70 (-88,-55)
|
-43 (-73,-29)
|
-27 (-37,-26)
|
-20 (-33,0)
|
0.05
|
|
|
|
|
|
|
AST, U/L
|
-23 (-44,-17)
|
-14 (429,-7)
|
-5 (-13,-2)
|
0 (-16,-2)
|
0.03
|
0.79
|
0.12
|
0.02
|
0.15
|
0.01
|
0.87
|
GGT, U/L
|
-46 (-57,-28)
|
-26 (-82,-3)
|
-12 (-21,0)
|
0 (-25,6)
|
< 0.001
|
0.48
|
0.01
|
0.18
|
0.01
|
0.01
|
0.97
|
ALP, U/L
|
-1 (-5,2)
|
-4 (-22,1)
|
0 (-1,7)
|
-2 (-36,-0)
|
0.16
|
|
|
|
|
|
|
TBil, umol/L
|
-0.4 ± 6.5
|
-1.9 ± 9.5
|
-0.7 ± 5.0
|
-1.2 ± 8.2
|
0.76
|
|
|
|
|
|
|
DBil, umol/L
|
-0.3 ± 2.1
|
-0.8 ± 4.2
|
-0.1 ± 1.5
|
-0.9 ± 4.7
|
0.63
|
|
|
|
|
|
|
TBA, umol/L
|
0.3 ± 3.4
|
0.2 ± 4.2
|
-1.3 ± 3.4
|
1.6 ± 8.1
|
0.60
|
|
|
|
|
|
|
LDH, U/L
|
-9.6 ± 46.9
|
-4.9 ± 36.7
|
-6.6 ± 29.7
|
-9.3 ± 36.9
|
0.96
|
|
|
|
|
|
|
CHE, U/L
|
-913 (-1668,-539)
|
-1009 (-1339,-576)
|
-1046 (-1227,-363)
|
-338 (-511,-137)
|
0.20
|
|
|
|
|
|
|
LAP, U/L
|
-4.6 ± 21.3
|
-9.4 ± 22.2
|
-1.6 ± 8.8
|
-6.6 ± 19.1
|
0.77
|
|
|
|
|
|
|
GLDH, U/L
|
-3.4 ± 8.6
|
-1.3 ± 7.6
|
-2.7 ± 5.9
|
-2.1 ± 9.8
|
0.86
|
|
|
|
|
|
|
UA, umol/L
|
-34 (-86,-4)
|
-25 (-154,49)
|
-26 (-58,2)
|
-19 (-55,16)
|
0.28
|
|
|
|
|
|
|
CHOL, mmol/L
|
-1.2 ± 1.9
|
-0.3 ± 1.3
|
-0.2 ± 1.1
|
-0.6 ± 1.6
|
0.01
|
0.01
|
0.01
|
0.02
|
0.79
|
0.25
|
0.29
|
TG, mmol/L
|
-0.7 ± 1.1
|
-0.2 ± 0.8
|
-0.1 ± 0.8
|
-0.3 ± 1.1
|
0.01
|
0.02
|
0.01
|
0.01
|
0.73
|
0.38
|
0.34
|
HDL-C, mmol/L
|
-0.2 ± 0.5
|
-0.1 ± 0.3
|
0.1 ± 0.2
|
-0.1 ± 0.6
|
0.54
|
|
|
|
|
|
|
LDL-C, mmol/L
|
-0.8 ± 1.4
|
-0.3 ± 1.1
|
-0.2 ± 0.9
|
-0.3 ± 1.1
|
0.02
|
0.01
|
0.02
|
0.01
|
0.72
|
0.84
|
0.81
|
FFA, mmol/L
|
-20 (-93,25)
|
-44 (-133,-6)
|
-95 (-150,55)
|
-17 (-159,20)
|
0.37
|
|
|
|
|
|
|
APOA, mmol/L
|
-0.1 ± 0.4
|
0.1 ± 0.4
|
0.1 ± 0.3
|
-0.1 ± 0.5
|
0.06
|
|
|
|
|
|
|
APOB, mmol/L
|
-0.1 ± 0.3
|
-0.1 ± 0.3
|
-0.1 ± 0.2
|
-0.2 ± 0.4
|
0.03
|
0.82
|
0.79
|
0.02
|
0.93
|
0.02
|
0.12
|
APOE, mmol/L
|
-4.0 (-11.5,15.5)
|
1.0 (-13.9,8.5)
|
4.0 (-12.0,5.0)
|
-6.5 (-16.0,3.0)
|
0.39
|
|
|
|
|
|
|
LPA, mmol/L
|
-70 (-140,40)
|
-7 (-71,74)
|
-34 (-116,19)
|
-30 (-102,63)
|
0.61
|
|
|
|
|
|
|
FBG, mmol/L
|
-0.7 ± 1.6
|
-0.2 ± 1.3
|
-0.2 ± 1.2
|
-0.1 ± 1.4
|
0.04
|
0.06
|
0.04
|
0.02
|
0.96
|
0.18
|
0.14
|
FINS, uU/mL
|
-2.9 ± 5.7
|
-1.2 ± 8.7
|
-1.1 ± 6.3
|
-0.7 ± 4.9
|
0.02
|
0.04
|
0.03
|
0.01
|
0.81
|
0.07
|
0.26
|
HOMA-IR
|
-0.9 ± 1.3
|
-0.2 ± 2.1
|
-0.3 ± 1.2
|
-0.1 ± 1.4
|
0.02
|
0.04
|
0.02
|
0.01
|
0.93
|
0.59
|
0.65
|
Data are median (first quartile, third quartile) or mean ± SD (standard deviation). |
# 1- both GGT and ALT normalization group; 2- ALT normalization only group; 3- GGT normalization only group; 4- both GGT and ALT abnormal group. |
Patients in the baseline group with abnormal levels of both ALT and GGT were monitored for 12 months to detect the normalization rate of GGT and ALT levels during treatment. After 6, 9, and 12 months of follow-up, the cumulative normalization rates of GGT levels were 17%, 25% and 33%, and the cumulative normalization rates of ALT levels were 27%, 41%, and 52% (all, P < 0.01, Fig. 2A), respectively. These patients were further divided into 5 groups according to the weight change after 12 months of treatment as follows: ≤ 3% (n = 232), 3–5% (n = 43), 5–7% (n = 30), 7–10% (n = 21) and > 10% (n = 15). In patients with a weight change ratio ≤ 3%, the cumulative normalization rates of GGT levels were significantly lower than in the other four groups (15% vs. 20%, P < 0.05, Fig. 2B).
We also described the changes in normalization rates in the ALT-only abnormal group and GGT-only abnormal group after 12 months of treatment. For the patients in the ALT-only abnormal group, the cumulative normalization rate of ALT levels was 62% after 12 months of follow-up (Fig. 2C), with the lowest cumulative normalization rates observed in patients with weight change ratios ≤ 3% (Fig. 2D). In the GGT-only abnormal group, the cumulative normalization rate of GGT levels after 12 months of follow-up was 37% (Fig. 2E), and a similar association with weight change was found (Fig. 2F).
Predictors of GGT remission in patients with NAFLD after 12 months of treatment
A univariate logistic regression analysis showed that weight loss, baseline levels of GGT, CHOL, TG and FINS and the normalization of ALT, UA, TG, FBG and HOMA-IR after treatment were independent factors influencing the recovery of GGT levels in 341 patients with both baseline ALT and GGT abnormalities (Table 3). After multivariate adjustment, weight loss (OR = 1.27, 95%CI:1.15–1.41, P < 0.001), normalization of ALT level (OR = 4.32, 95%CI:1.87–9.96, P = 0.01) and HOMA-IR level after treatment (OR = 3.48, 95%CI:1.60–7.57, P = 0.01) were independent protective factors for GGT normalization (Table 3). Baseline GGT level (OR = 0.99, 95%CI:0.98–0.99, P = 0.01), CHOL level (OR = 0.47, 95%CI:0.23–0.96, P = 0.04) and FINS level (OR = 0.91, 95%CI:0.86–0.96, P = 0.01) were independent risk factors related to GGT normalization (Table 3). In the subgroup of 179 patients with NAFLD whose ALT levels returned to normal after 12 months of treatment, the multivariate regression analysis showed that weight loss (OR = 1.56, 95%CI:1.27–1.92, P < 0.001) and decrease in HOMA-IR to normal levels after treatment (OR = 3.55, 95%CI:1.11–11.34, P = 0.03) remained independent factors related to GGT normalization (Table 3).
Table 3
Factors associated with GGT normalization in patients with NAFLD after 12 months of treatment predicted by the logistic regression model.
Factors
|
Overall cohort (N = 341)
|
Achieve ALT normalization subgroup (N = 179)
|
Univariate analysis
|
Multivariable analysis
|
Univariate analysis
|
Multivariable analysis
|
OR (95%CI)
|
p
|
OR (95%CI)
|
p
|
OR (95%CI)
|
p
|
OR (95%CI)
|
p
|
Baseline body weight, kg
|
1.01 (0.99–1.03)
|
0.15
|
|
|
1.01 (0.99–1.04)
|
0.29
|
|
|
Weight loss, %
|
1.23 (1.14–1.33)
|
< 0.001
|
1.27 (1.15–1.41)
|
< 0.001
|
1.53 (1.26–1.84)
|
< 0.001
|
1.56 (1.27–1.92)
|
< 0.001
|
Hypertension a
|
0.86 (0.54–1.38)
|
0.54
|
|
|
0.83 (0.35–1.95)
|
0.67
|
|
|
Smoke a
|
0.16 (0.02–1.72)
|
0.13
|
|
|
0.17 (0.02–1.78)
|
0.21
|
|
|
Baseline ALT, U/L
|
0.99 (0.99–1.01)
|
0.36
|
|
|
1.00 (0.99–1.01)
|
0.57
|
|
|
ALT decreased to normal a
|
17.91 (9.80-32.74)
|
< 0.001
|
4.32 (1.87–9.96)
|
0.01
|
|
|
|
|
Baseline GGT, U/L
|
0.67 (0.54–0.83)
|
< 0.001
|
0.99 (0.98–0.99)
|
0.01
|
0.86 (0.75–0.99)
|
0.04
|
1.00 (0.99–1.01)
|
0.74
|
Change of TBil, umol/L
|
0.99 (0.97–1.02)
|
0.66
|
|
|
0.97 (0.93–1.02)
|
0.24
|
|
|
Change of DBil, umol/L
|
0.98 (0.92–1.05)
|
0.54
|
|
|
0.93 (0.81–1.06)
|
0.27
|
|
|
UA decreased to normal a
|
1.78 (1.10–2.89)
|
0.02
|
1.30 (0.66–2.57)
|
0.45
|
1.07 (0.49–2.33)
|
0.87
|
|
|
Baseline CHOL, mmol/L
|
0.60 (0.37–0.96)
|
0.03
|
0.47 (0.23–0.96)
|
0.04
|
0.73 (0.33–1.61)
|
0.43
|
|
|
CHOL decreased to normal a
|
0.58 (0.30–1.10)
|
0.09
|
|
|
4.58 (1.37–15.32)
|
0.01
|
2.73 (0.84–8.79)
|
0.09
|
Baseline TG, mmol/L
|
0.79 (0.64–0.98)
|
0.03
|
0.82 (0.58–1.15)
|
0.26
|
0.87 (0.41–1.88)
|
0.73
|
|
|
TG decreased to normal a
|
2.37 (1.21–4.63)
|
0.01
|
1.84 (0.86–3.96)
|
0.12
|
2.29 (1.00-5.27)
|
0.05
|
|
|
Baseline LDL-C, mmol/L
|
0.98 (0.79–1.22)
|
0.91
|
|
|
0.63 (0.38–1.04)
|
0.07
|
|
|
LDL-C decreased to normal a
|
1.53 (0.96–2.44)
|
0.07
|
|
|
1.93 (0.87–4.26)
|
0.11
|
|
|
FBG decreased to normal a
|
2.37 (1.21–4.63)
|
0.01
|
2.22 (0.79–6.23)
|
0.13
|
1.04 (0.64–1.71)
|
0.86
|
|
|
Baseline FINS, uU/mL
|
0.93 (0.89–0.97)
|
< 0.001
|
0.91 (0.86–0.96)
|
0.01
|
0.92 (0.85–0.99)
|
0.03
|
1.04 (0.94–1.14)
|
0.46
|
FINS decreased to normal a
|
2.26 (0.79–6.44)
|
0.13
|
|
|
3.33 (0.36–31.03)
|
0.29
|
|
|
HOMA-IR decreased to normal a
|
4.35 (2.36–8.01)
|
< 0.001
|
3.48 (1.60–7.57)
|
0.01
|
3.85 (1.62–9.18)
|
0.01
|
3.55 (1.11–11.34)
|
0.03
|
a Hypertension was defined as systolic blood pressure (SBP) ≥ 140 mmHg or diastolic blood pressure (DBP) ≥ 90 mmHg; Smoke was defined as smoking at least one cigarette in the last 1 month; ALT decreased to normal was defined as ALT level ≤ 40 U/L; UA decreased to normal was defined as uric acid level ≤ 420 umol/L for male and ≤ 360 umol/L for female; CHOL decreased to normal was defined as CHOL level ≤ 5.7 mmol/L; TG decreased to normal was defined as TG level ≤ 1.7 mmol/L; LDL-C decreased to normal was defined as LDL-C level ≤ 3.4 mmol/L; FBG decreased to normal was defined as FBG level ≤ 6 mmol/L; FINS decreased to normal was defined as FINS level ≤ 23 uU/mL; HOMA-IR decreased to normal was defined as HOMA-IR level ≤ 2.69.
|
We further explored the application of the factors identified by the logistic model as predictors of GGT normalization and found that the weight change, baseline GGT level, ALT normalization, baseline FINS level and normalization of HOMA-IR, but not CHOL level at baseline, exhibited significant values for areas under the ROC curves (P < 0.05, Fig. 3A). The combination of these factors obtained an area under curve (AUC) of 0.905 (P < 0.001, Fig. 3A). For patients with ALT remission, we identified that a weight change, normalization of HOMA-IR, and their combination were able to predict GGT remission with AUCs of 0.814, 0.729 and 0.905, respectively (all, P < 0.001, Fig. 3B).
Predictors of ALT remission in patients with NAFLD after 12 months of treatment
The univariate logistic regression analysis showed that changes in weight loss, baseline levels of ALT, TG and FINS and the normalization of GGT, UA, TG and LDL-C after treatment were independent factors influencing the recovery of ALT levels in subjects with both abnormal ALT and GGT levels at baseline (Table 4). After the multivariate analysis, weight loss (OR = 1.15, 95%CI:1.07–1.25, P = 0.01) and GGT level that decreased to normal (OR = 3.05, 95%CI:1.57–5.94, P < 0.001) remained independent protective factors for ALT normalization (Table 4). In 113 patients with NAFLD whose GGT levels returned to normal after 12 months of treatment, only weight loss was an independent protective factor influencing the recovery of ALT levels (OR = 1.14, 95%CI:1.01–1.29,P = 0.04, Table 4).
Table 4
Factors associated with ALT normalization in patients with NAFLD after 12 months of treatment predicted by the logistic regression model.
Factors
|
Overall cohort (N = 341)
|
Achieve GGT normalization subgroup (N = 113)
|
Univariate analysis
|
Multivariable analysis
|
Univariate analysis
|
Multivariable analysis
|
OR (95%CI)
|
p
|
Odds ratio
|
p
|
OR (95%CI)
|
p
|
OR (95%CI)
|
p
|
Baseline body
weight, kg
|
0.99 (0.97–1.01)
|
0.47
|
|
|
0.99 (0.96–1.01)
|
0.28
|
|
|
Weight loss, %
|
1.14 (1.06–1.22)
|
< 0.001
|
1.15 (1.07–1.25)
|
0.01
|
1.15 (1.03–1.28)
|
0.01
|
1.14 (1.01–1.29)
|
0.04
|
Hypertension b
|
0.85 (0.55–1.32)
|
0.47
|
|
|
0.58 (0.25–1.34)
|
0.21
|
|
|
Smoke b
|
0.87 (0.08–9.79)
|
0.91
|
|
|
0.86 (0.05–8.51)
|
0.54
|
|
|
Baseline ALT, U/L
|
0.90 (0.81–0.99)
|
0.04
|
0.99 (0.99–1.01)
|
0.06
|
0.99 (0.99–1.01)
|
0.47
|
0.99 (0.98–1.01)
|
0.26
|
Baseline GGT, U/L
|
1.00 (0.99-1.00)
|
0.56
|
|
|
1.02 (0.99–1.03)
|
0.62
|
|
|
GGT decreased to normal b
|
15.03 (7.52–26.01)
|
< 0.001
|
3.05 (1.57–5.94)
|
< 0.001
|
|
|
|
|
Change of TBil, umol/L
|
1.01 (0.98–1.03)
|
0.56
|
|
|
1.02 (0.95–1.09)
|
0.54
|
|
|
Change of DBil, umol/L
|
1.01 (0.96–1.06)
|
0.85
|
|
|
1.01 (0.82–1.25)
|
0.92
|
|
|
Change of CHE, U/L
|
1.00 (1.00–1.00)
|
0.47
|
|
|
1.00 (1.00–1.00)
|
0.71
|
|
|
Change of LAP, U/L
|
0.99 (0.98–1.02)
|
0.87
|
|
|
0.99 (0.92–1.06)
|
0.76
|
|
|
UA decreased to normal b
|
2.46 (1.53–3.95)
|
< 0.001
|
1.99 (0.92–4.35)
|
0.08
|
1.62 (0.71–3.71)
|
0.25
|
|
|
Baseline CHOL, mmol/L
|
0.77 (0.50–1.18)
|
0.22
|
|
|
1.09 (0.47–2.49)
|
0.85
|
|
|
CHOL decreased to normal b
|
0.78 (0.44–1.37)
|
0.38
|
|
|
3.35 (0.96–11.67)
|
0.06
|
2.13 (0.34–13.14)
|
0.42
|
Baseline TG, mmol/L
|
0.78 (0.64–0.95)
|
0.01
|
0.81 (0.61–1.06)
|
0.13
|
0.73 (0.33–1.59)
|
0.42
|
|
|
TG decreased to normal b
|
5.59 (3.47–9.03)
|
< 0.001
|
1.53 (0.76–3.07)
|
0.23
|
2.26 (0.98–5.24)
|
0.06
|
1.76 (0.54–5.81)
|
0.35
|
Baseline LDL-C, mmol/L
|
0.93 (0.76–1.14)
|
0.52
|
|
|
0.64 (0.38–1.09)
|
0.09
|
|
|
LDL-C decreased to normal b
|
1.89 (1.21–2.98)
|
0.01
|
1.78(0.84–3.76)
|
0.13
|
1.91 (0.86–4.27)
|
0.11
|
|
|
FBG decreased to normal b
|
1.53 (0.76–3.08)
|
0.24
|
|
|
1.14 (0.40–3.26)
|
0.81
|
|
|
Baseline FINS, uU/mL
|
0.96 (0.93–0.99)
|
0.04
|
0.95 (0.91–1.01)
|
0.06
|
0.99 (0.92–1.06)
|
0.73
|
0.91 (0.82–1.01)
|
0.06
|
FINS decreased to normal b
|
2.21 (0.78–6.32)
|
0.14
|
|
|
3.25 (0.35–30.28)
|
0.30
|
|
|
HOMA-IR decreased to normal b
|
1.51 (0.87–2.62)
|
0.14
|
|
|
1.18 (0.46–2.99)
|
0.73
|
|
|
b Hypertension was defined as systolic blood pressure (SBP) ≥ 140 mmHg or diastolic blood pressure (DBP) ≥ 90 mmHg; Smoke was defined as smoking at least one cigarette in the last 1 month; GGT decreased to normal was defined as GGT level ≤ 50 U/L; UA decreased to normal was defined as uric acid level ≤ 420 umol/L for male and ≤ 360 umol/L for female; CHOL decreased to normal was defined as CHOL level ≤ 5.7 mmol/L; TG decreased to normal was defined as TG level ≤ 1.7 mmol/L; LDL-C decreased to normal was defined as LDL-C level ≤ 3.4 mmol/L; FBG decreased to normal was defined as FBG level ≤ 6 mmol/L; FINS decreased to normal was defined as FINS level ≤ 23 uU/mL; HOMA-IR decreased to normal was defined as HOMA-IR level ≤ 2.69. |
We also compared the accuracy of these factors derived from the logistic model when predicting ALT normalization. Weight loss and GGT normalization presented significant AUCs (AUC = 0.592, P = 0.008 and AUC = 0.768, P < 0.001, Fig. 3C). The combination of these two factors achieved a higher AUC of 0.808 (P < 0.001, Fig. 3C). However, only normal weight loss had a significant AUC of 0.703 in the subgroup of patients who achieved GGT normalization (P < 0.001, Fig. 3D).
In addition, 630 patients with NAFLD underwent MRI-PDFF to quantify liver fat. We identified a weak correlation between baseline GGT levels and the LFC (R = 0.08, P = 0.04, Fig. 4A). After 12 months of treatment, the correlation between GGT levels and LFC increased (R = 0.26, P = 0.01, Fig. 4B), as well as the changes in GGT levels and the changes in the LFC(R = 0.22, P = 0.02, Fig. 4C).