Serum metabolic profiling of targeted bile acids reveals potentially novel biomarkers for primary biliary cholangitis and autoimmune hepatitis

doi:10.3748/wjg.v28.i39.5764

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World J Gastroenterol. Oct 21, 2022; 28(39): 5764-5783
Published online Oct 21, 2022. doi: 10.3748/wjg.v28.i39.5764

Table 1 Characteristics of enrolled population in the metabolic profiling study

Clinical parameters	PBC (n = 54)	AIH (n = 26)	Control (n = 30)	P value (PBC vs control)	P value (AIH vs control)	P value (PBC vs AIH)
Age (mean, range) (yr), n	56 (38-73)	54.6 (17-75)	54.9(34-70)	0.922	0.805	0.890
Sex (Male/Female), n	7/47	3/23	4/26	-	-	-
AST (U/L) median, range	113.3 (14-1300)	168.8 (23-961)	23.3 (7-38)	< 0.001	< 0.001	0.423
ALT (U/L) median, range	95.9 (12-734)	153.3 (10-780)	19.0 (7-39)	< 0.001	< 0.001	0.125
ALP (U/L) median, range	292.4 (55-953)	240.1 (46-795)	73.6 (32-116)	< 0.001	< 0.001	0.123
γ-GT (U/L) median, range	299.4 (32-1631)	245.2 (26-957)	21.1 (9-77)	< 0.001	< 0.001	0.377
TBA (μmol/L) median, range	60.0 (2.7-295.7)	126.0 (1.1-1335)	-	-	-	0.696
TBiL (μmol/L) median, range	65.5 (5.6-825.8)	89.1 (6.5-543.9)	10.9 (6.3-19.5)	< 0.001	< 0.001	0.481
DBIL (μmol/L) median range	35.9 (2.4-407.4)	52.9 (2.1-300.8)	3.3 (0.4-6)	< 0.001	< 0.001	0.648
Liver cirrhosis (%)	65 (35/54)	62 (16/26)	-	-	-	-
Liver biopsy (%)	18 (10/54)	53 (14/26)	-	-	-	-
Positive of AMA (%)	81 (44/54)	0 (0/26)	-	-	-	-
Positive of ANA (%)	61 (33/54)	100 (26/26)	-	-	-	-

PBC: Primary biliary cirrhosis; AIH: Autoimmune hepatitis; AST: Aspartatetransaminase; ALT: Alanine aminotransferase; ALP: Alkaline phosphatase; γ-GT: γ-glutamyl transpeptidase; TBiL: Totalbilirubin; DBiL: Direct bilirubin; TBA: Total bile acid; AMA: Anti-mitochondrial antibody; ANA: Anti-nuclear antibody. All data are presented as median and range. Statistically significant differences between controls and patients were determined by the rank sums Mann-Whitney.

Table 2 Characteristics of classified enrolled population according to Child-Pugh in the metabolic profiling study

Clinical parameters	PBC-A (n = 26)	PBC-B (n = 19)	PBC-C (n = 9)	AIH-A (n = 17)	AIH-B (n = 9)
Age (mean, range) (yr), n	54 (38, 68)	57.11 (40, 73)	59.33 (51, 67)	52.35 (17, 75)	59.11 (36, 73)
Sex (Male/Female), n	6/20	3/16	0/9	2/15	1/8
AST (U/L) median, range	62.77 (20, 210)	182.62 (14, 1300)	113.27 (35, 235)	122.28 (23, 961)	256.78 (64, 472)
ALT (U/L) median, range	74.18 (15, 293)	130.32 (12, 734)	84.51 (17, 236)	100.54 (10, 780)	253.11 (103, 598)
ALP (U/L) median, range	276.41 (75, 53)	352.73 (79, 913)	211.43 (55, 483)	230.33 (57, 795)	258.78 (46, 738)
γ-GT (U/L) median, range	380.18 (40, 631)	281.77 (40, 744)	103.49 (32, 235)	166.46 (26, 654)	393.89 (73, 957)
TBA (μmol/L) median, range	31.04 (2.9, 09.3)	75.16 (2.7, 295.7)	127.37 (23.4, 267.5)	116.46 (1, 1335)	144.29 (15, 379)
TBiL (μmol/L) median, range	19.7 (5.6, 48.8)	81.0 (11.3, 306.5)	181.62 (17.7, 825.8)	48.33 (6.5, 229.5)	166.23 (50.0, 543.9)
DBIL (μmol/L) median, range	9.18 (2.4, 32.0)	48.3 (4.1, 207.9)	99.71 (6.6, 407.4)	27.40 (2.1, 139.3)	101.24 (30.6, 300.8)
Liver cirrhosis (%)	0.38 (10/26)	0.84 (16/19)	1 (9/9)	0.47 (8/17)	0.33 (3/9)
Liver biopsy (%)	0.35 (9/26)	0.05 (1/19)	0 (0/9)	0.64 (11/17)	0.33 (3/9)
Positive of AMA (%)	80 (21/26)	80 (15/19)	89 (8/9)	0 (0/17)	0 (0/9)
Positive of ANA (%)	73 (19/26)	52 (10/19)	44 (4/9)	100 (17/17)	100 (9/9)

Table 3 Potential serum biomarkers for primary biliary cirrhosis compared to healthy control in positive and negative ions model

Name	VIP	MZ	Time	PBC/control
Name	VIP	MZ	Time	t-test	Fold change (P/C)
ESI+
Taurodeoxycholic acid	1.747	500.3033	10.598	0.001	8.146
Glycodeoxycholate	2.175	450.3207	12.146	0.000	4.558
Tetracosahexaenoic acid	1.100	357.2786	9.333	0.045	3.490
Bilirubin	1.511	585.2701	10.218	0.006	3.334
Sphinganine	1.953	302.3052	12.792	0.000	3.285
Phytosphingosine	2.482	318.2999	10.734	0.000	3.039
L-Phenylalanine	1.690	166.0860	2.037	0.002	0.372
L-Proline	1.194	116.0706	0.725	0.030	0.180
12-Ketodeoxycholic acid	1.573	391.2842	15.210	0.004	-0.324
ESI-
Taurocholic acid	1.493	514.2805	9.146	0.000	6.634
LysoPC [18:3(6Z, 9Z, 12Z)]	1.184	516.3064	13.057	0.001	5.263
Tauroursodeoxycholic acid	1.843	498.2861	10.456	0.000	4.627
Glycocholic Acid	1.866	464.2988	9.957	0.000	3.644
LysoPE [0:0/18:4 (6Z, 9Z, 12Z, 15Z)]	1.316	472.2430	9.798	0.000	3.274
LysoPE [20:3 (11Z, 14Z, 17Z)/0:0]	1.882	500.2947	10.456	0.000	3.225
L-Urobilinogen	1.027	595.3478	11.784	0.003	3.202
L-Urobilin	1.032	593.3315	11.665	0.003	2.411
Deoxycholic acid	1.032	391.2833	11.641	0.003	2.121
α-ketoisovaleric acid	1.040	115.0399	1.831	0.003	-0.348
Pyroglutamic acid	1.252	128.0350	0.931	0.000	-0.392
Lactic acid	1.548	89.0242	0.938	0.000	-0.402
Hypoxanthine	1.384	135.0308	0.886	0.000	-0.431
LysoPE [0:0/20:2 (11Z, 14Z)]	1.335	504.3072	14.333	0.000	-0.453
Ketoleucine	1.392	129.0555	4.110	0.000	-0.486
LysoPE [0:0/22:4 (7Z, 10Z, 13Z, 16Z)]	1.333	528.2850	13.617	0.000	-0.544
MG [0:0/18:4 (6Z, 9Z, 12Z, 15Z)/0:0]	2.060	349.2373	8.969	0.000	-2.181

PBC: Primary biliary cirrhosis; VIP: Variable importance in the projection.

Table 4 Potential serum biomarkers for autoimmune hepatitis compared to healthy control

Name	VIP	MZ	Time	AIH/control
Name	VIP	MZ	Time	t-test	Fold change (A/C)
ESI+
Taurodeoxycholic acid	1.900	500.3033	10.598	0.000	8.791
Glycodeoxycholate	1.912	450.3207	12.146	0.000	5.217
L-Urobilin	1.442	595.3484	7.835	0.007	5.164
Sphinganine	2.308	302.3052	12.792	0.000	4.509
Phytosphingosine	2.344	318.2999	10.734	0.000	4.118
I-Urobilin	1.454	591.3169	7.628	0.006	3.661
Bilirubin	1.876	585.2701	10.218	0.000	3.578
Kynurenine	2.279	209.0919	1.944	0.000	0.592
L-Threonine	1.446	120.0655	0.708	0.007	0.386
L-Phenylalanine	1.551	166.0860	2.037	0.004	0.262
Urea	1.160	61.0395	0.730	0.032	0.113
12-Ketodeoxycholic acid	1.125	391.2842	15.210	0.037	-0.270
Uric acid	1.208	169.0354	1.035	0.025	-0.265
Pyroglutamic acid	2.489	130.0499	1.029	0.000	-0.517
ESI-
Taurocholic acid	1.605	514.281	9.146	0.000	7.368
LysoPC [18:3 (6Z, 9Z, 12Z)]	1.454	516.306	13.057	0.000	6.614
Tauroursodeoxycholic acid	1.807	498.286	10.456	0.000	5.151
Glycocholic Acid	1.961	464.299	9.957	0.000	3.946
LysoPE [20:3 (11Z, 14Z, 17Z)/0:0]	1.807	500.295	10.456	0.000	3.670
LysoPE [0:0/20:2 (11Z, 14Z)]	1.234	504.307	14.333	0.001	-0.471
Lactic acid	1.489	89.024	0.938	0.000	-0.489
Hypoxanthine	1.380	135.031	0.886	0.000	-0.562
CPA (16:0/0:0)	1.629	391.224	26.118	0.000	-2.159
MG [0:0/18:4 (6Z, 9Z, 12Z, 15Z)/0:0]	1.771	349.237	8.969	0.000	-2.464

AIH: Autoimmune hepatitis; VIP: Variable importance in the projection.

Table 5 Changes of the serum bile acid profile between primary biliary cirrhosis, autoimmune hepatitis and controls

	AIH (mean ± SD)	PBC (mean ± SD)	Control (mean ± SD)	PBC/AIH	AIH/control	PBC/control
	AIH (mean ± SD)	PBC (mean ± SD)	Control (mean ± SD)	P value	P value	P value
CA	2.38 ± 0.69	2.26 ± 0.85	1.60 ± 0.51	0.53	< 0.001^b	< 0.001^a
GCA	3.00 ± 1.02	2.91 ± 0.91	1.33 ± 0.50	0.69	< 0.001^b	< 0.001^a
TCA	2.12 ± 1.23	2.12 ± 0.93	0.03 ± 0.46	0.99	< 0.001^b	< 0.001^a
UDCA	2.41 ± 1.03	2.60 ± 1.05	2.05 ± 0.36	0.62	0.2	0.01^a
GUDCA	2.59 ± 1.17	3.04 ± 1.14	1.64 ± 0.50	0.09	< 0.001^b	< 0.001^a
TUDCA	1.48 ± 1.07	1.84 ± 1.09	0.13 ± 0.25	0.15	< 0.001^b	< 0.001^a
CDCA	2.88 ± 0.39	3.07 ± 0.48	2.63 ± 0.38	0.046^c	0.01^b	< 0.001^a
GCDCA	3.78 ± 0.80	3.79 ± 0.67	2.93 ± 0.33	0.96	< 0.001^b	< 0.001^a
TCDCA	2.73 ± 0.40	2.84 ± 0.44	2.49 ± 0.57	0.27	0.09	0.004^a
GCDCS	2.39 ± 0.82	2.42 ± 0.70	1.08 ± 0.39	0.95	< 0.001^b	< 0.001^a
DCA	2.76 ± 0.35	2.75 ± 0.40	2.76 ± 0.18	0.87	0.7	0.59
GDCA	3.18 ± 0.58	3.14 ± 0.53	2.64 ± 0.32	0.8	< 0.001^b	< 0.001^a
TDCA	3.32 ± 0.64	3.16 ± 0.50	2.57 ± 0.19	0.33	< 0.001^b	< 0.001^a
LCA	0.94 ± 0.68	1.28 ± 0.66	0.72 ± 0.43	0.04^c	0.14	< 0.001^a
TLCA	0.30 ± 0.41	0.48 ± 0.47	0.02 ± 0.06	0.07	< 0.001^b	< 0.001^a
LCA + TLCA	1.25 ± 0.18	1.75 ± 0.14	0.74 ± 0.07	0.034^c	0.031^b	< 0.001^a
CDCA/CA	1.30 ± 0.35	1.56 ± 0.65	1.74 ± 0.42	0.26	< 0.001^b	< 0.001^a
pBA	3.11 ± 0.45	3.17 ± 0.51	2.67 ± 0.38	0.98	< 0.001^b	< 0.001^a
sBA	3.14 ± 0.52	3.19 ± 0.61	2.87 ± 0.17	0.75	0.003^b	0.002^a
pBA/sBA	1.02 ± 0.18	1.01 ± 0.17	1.08 ± 0.13	0.85	0.087	< 0.001
sBA	2.77 ± 0.35	2.79 ± 0.40	2.77 ± 0.18	0.81	0.02^b	0.003^a
G-BA	4.14 ± 0.70	4.12 ± 0.64	3.16 ± 0.31	0.97	< 0.001^b	< 0.001^a
T-BA	3.58 ± 0.54	3.47 ± 0.46	2.89 ± 0.27	0.34	< 0.001^b	< 0.001^a
G-BA/T-BA	0.55 ± 0.34	0.65 ± 0.34	0.27 ± 0.30	0.25	< 0.001^b	< 0.001^a
total BA	36.31 ± 6.00	37.69 ± 7.40	24.80 ± 3.12	0.41	< 0.001^b	0.026^a

^aP < 0.05 Primary biliary cirrhosis (PBC) vs control.

^bP < 0.05 Autoimmune hepatitis (AIH) vs control.

^cP < 0.05 PBC vs AIH

Bile acid (BA) levels are expressed in log10 concentrations. Statistically significant differences in BA concentrations between controls and patients were determined by the rank sums Mann-Whitney test. CA: Cholic acid; CDCA: Chenodeoxycholic acid; DCA: Deoxycholic acid; GCA: Glycocholic acid; GCDCA: Glycochenodeoxycholic acid; GCDCS: Glycochenodeoxycholic sulfate; GDCA: Glycodeoxycholic acid; GUDCA: Glycoursodeoxycholic acid; LCA: Lithocholic acid; TCA: Taurocholic acid; TCDCA: Taurochenodeoxycholic acid; TDCA: Taurodeoxycholic acid; TLCA: Taurolithocholic acid; TUDCA: Tauroursodeoxycholic acid; UDCA: Ursodeoxycholic acid; PBA: Primary bile acid; PBC: Primary biliary cirrhosis; AIH: Autoimmune hepatitis.

Table 6 Area under the curve, sensitivity and specificity of difference bile acids, conventional biochemical indicators in primary biliary cirrhosis, autoimmune hepatitis and control group

	AUC	Sensitivity	Specificity
LCA	0.68	0.82	0.50
LCA + TLCA	0.73	0.74	0.46
CDCA	0.74	0.74	0.54
AST	0.54	0.67	0.58
ALT	0.61	0.64	0.61
ALP	0.41	0.56	0.35
GGT	0.43	0.50	0.46
TBiL	0.53	0.59	0.42
DBiL	0.47	0.44	0.62
TBA	0.52	0.52	0.42

CDCA: Chenodeoxycholic acid; LCA: Lithocholic acid; TLCA: Taurolithocholic acid; ALT: Alanine transaminase; AST: Aspartate transaminase; GGT: Gamma glutamyl transpeptidase; ALP: Alkaline phosphatase; TBiL: Total bilirubin; DBiL: Direct bilirubin; TBA: Total bile acid; AUC: Area under the curve.

Table 7 Changes of the serum bile acid profile between primary biliary cirrhosis and autoimmune hepatitis in different grade of Child-Pugh

	AIH-A/PBC/A	AIH-B/PBC-B	AIH-A/AIH-B	PBC-A/PBC-B	PBC-B/PBC-C	PBC-A/PBC-C	AIH-A/control	AIH-B/control	PBC-A/control	PBC-B/control	PBC-C/control
	P value	P value	P value	P value	P value	P value	P value	P value	P value	P value	P value
CA	0.75	0.34	0.24	0.67	0.82	0.50	< 0.001	< 0.001	< 0.001	< 0.001	0.03
GCA	0.79	0.03	< 0.001	0.07	0.43	0.02	< 0.001	< 0.001	< 0.001	< 0.001	< 0.001
TCA	0.79	0.03	< 0.001	0.0522	0.71	0.0567	< 0.001	< 0.001	< 0.001	< 0.001	< 0.001
UDCA	0.77	0.26	0.07	0.70	0.30	0.38	< 0.001	0.52	<0.001	0.05	< 0.001
GUDCA	0.60	0.33	0.40	0.58	0.21	0.06	< 0.001	0.13	< 0.001	< 0.001	< 0.001
TUDCA	0.97	0.22	1.00	0.10	0.29	0.02	< 0.001	< 0.001	< 0.001	< 0.001	< 0.001
CDCA	0.26	0.09	0.07	0.30	0.44	0.78	< 0.001	0.47	< 0.001	< 0.001	< 0.001
GCDCA	0.89	0.19	0.01	0.06	0.17	< 0.001	< 0.001	< 0.001	< 0.001	< 0.001	< 0.001
TCDCA	0.82	0.20	0.31	0.34	0.92	0.26	0.05	0.48	0.02	0.01	0.04
GCDCS	0.33	0.04	< 0.001	0.15	0.24	0.01	< 0.001	< 0.001	< 0.001	< 0.001	< 0.001
DCA	0.71	0.26	0.02	0.13	0.66	0.38	0.24	0.01	0.64	0.21	0.45
GDCA	0.50	0.08	0.09	0.37	0.09	0.11	< 0.001	< 0.001	< 0.001	0.01	< 0.001
TDCA	0.69	0.03	< 0.001	0.01	0.33	< 0.001	< 0.001	< 0.001	< 0.001	< 0.001	< 0.001
LCA	0.29	0.13	0.57	0.82	0.24	0.33	0.08	0.51	< 0.001	< 0.001	< 0.001
TLCA	0.07	0.88	0.05	0.13	0.74	0.29	0.01	< 0.001	< 0.001	< 0.001	< 0.001
CDCA/CA	0.46	0.04	0.04	0.66	0.50	0.27	< 0.001	< 0.001	< 0.001	0.06	0.26
Primary bile acid	0.75	0.81	0.96	0.42	0.70	0.96	< 0.001	0.02	< 0.001	< 0.001	< 0.001
Secondary bile acid	0.92	0.80	0.20	0.33	0.20	0.45	< 0.001	0.45	< 0.001	0.15	< 0.001
Secondary/primary	0.61	0.99	0.32	0.27	0.23	0.44	0.30	0.05	0.06	0.01	0.78
Secondary bile acid	0.89	0.91	0.08	0.05	0.24	0.79	0.13	0.08	0.09	0.12	0.35
Glycoconjugates	0.53	0.16	< 0.001	0.21	0.16	< 0.001	< 0.001	< 0.001	< 0.001	< 0.001	< 0.001
Tauroconjugted	0.48	0.08	< 0.001	0.02	0.42	< 0.001	< 0.001	< 0.001	< 0.001	< 0.001	< 0.001
Glyco/tauro	0.21	0.56	0.23	0.63	0.07	0.18	0.01	< 0.001	< 0.001	< 0.001	< 0.001
Total BA	0.62	0.72	0.05	0.26	0.19	0.01	< 0.001	< 0.001	< 0.001	< 0.001	< 0.001

Citation: Ma ZH, Wang XM, Wu RH, Hao DL, Sun LC, Li P, Niu JQ. Serum metabolic profiling of targeted bile acids reveals potentially novel biomarkers for primary biliary cholangitis and autoimmune hepatitis. World J Gastroenterol 2022; 28(39): 5764-5783
URL: https://www.wjgnet.com/1007-9327/full/v28/i39/5764.htm
DOI: https://dx.doi.org/10.3748/wjg.v28.i39.5764