Gut barrier failure biomarkers are associated with poor disease outcome in patients with primary sclerosing cholangitis

Table 1 Clinical and laboratory characteristics of primary sclerosing cholangitis patients

	Patients with PSC (n = 67)
Age at diagnosis (yr)	25 (17-36)
Disease duration (yr)	6 (3-10)
Children	10 (14.5)
Male	49 (71.0)
Cirrhosis	14 (20.3)
Prior OLTx	4 (5.8)
IBD	52 (75.4)
Crohn's Disease	17 (32.7)
Ulcerative Colitis	35 (67.3)
Overlap syndrome	9 (13.0)
Small duct PSC	5 (7.2)
Celiac disease	1 (1.5)
Albumin (g/L)	44 (40-47)
Bilirubin (μmol/L)	15 (11-22)
ALT (U/L)	52 (26-99)
AST (U/L)	41 (28–66)
GGT (U/L)	152 (60-310)
ALP (U/L)	524 (307-822)
INR	1 (1.0-1.2)
Platelet (109/L)	252 (173-319)
Mayo risk score	-0.595 (-1.194-0.102)
Atypical P-ANCA IgG	57 (85.1)
EMA IgA	1 (1.5)
EMA IgG	1 (1.5)

Data are summarized as median, (interquartile range: 25^th-75^th percentile) or as n (%). ALP: Alkaline phosphatase; ALT: Alanine transaminase; AST: Aspartate transaminase; GGT: Gamma glutamyl transferase; INR: International normalized ratio; P-ANCA: Perinuclear anti-neutrophil cytoplasmic antibodies; EMA: Anti-endomysial antibodies; OLTx: Orthotopic liver transplantation; IBD: Inflammatory bowel disease; IQR: inter-quartile range.

Table 2 Gut failure markers in patients with primary sclerosing cholangitis and various healthy and diseases control groups n (%)

	PSC (n = 67)	UC (n = 172)	P value1	HC (n = 153)	P value1
AAA
IgA	19 (28.4)	19 (11.2)	0.003	5 (4.4)	< 0.001
IgG	17 (25.4)	7 (4.1)	< 0.001	3 (2.7)	< 0.001
IgA or IgG	27 (40.3)	25 (14.7)	< 0.001	7 (6.2)	< 0.001
IgA and IgG	9 (13.4)	1 (0.6)	< 0.001	1 (0.9)	0.001
AGA
IgA	6 (9.0)	6 (3.5)	0.101	4 (2.6)	0.071
IgG	14 (20.9)	15 (8.7)	0.014	9 (5.9)	0.002
IgA or IgG	15 (22.4)	20 (11.6)	0.042	11 (7.2)	0.003
IgA and IgG	5 (7.5)	1 (0.6)	0.007	2 (1.3)	0.029

¹P-values pertain to comparisons between PSC and the given control group. AAA IgA/G was measured in 170 patients with UC and 113 healthy controls. PSC: Primary sclerosing cholangitis; UC: Ulcerative colitis; HC: Healthy controls; AAA: Anti-F-actin antibody; AGA: Anti-gliadin antibody.

Table 3 Associations between gut failure markers and disease or laboratory characteristics in patients with primary sclerosing cholangitis at enrolment

	Anti-F-actin IgA			Anti-F-actin IgG			Anti-gliadin IgA			Anti-gliadin IgG
	Negative (n = 48)	Positive (n = 19)	P value	Negative (n = 50)	Positive (n = 17)	P value	Negative (n = 61)	Positive (n = 6)	P value	Negative (n = 53)	Positive (n = 14)	P value
Male gender, n (%)	35 (72.9)	13 (68.4)	0.713	38 (76.0)	10 (58.8)	0.175	44 (72.1)	4 (66.7)	0.777	37 (69.8)	11 (78.6)	0.518
Presence of cirrhosis, n (%)	8 (16.7)	5 (26.3)	0.368	9 (18.0)	4 (23.5)	0.618	11 (18)	2 (33.3)	0.366	10 (18.9)	3 (21.4)	0.829
Presence of IBD, n (%)	36 (75)	15 (78.9)	0.733	40 (80.0)	11 (64.7)	0.201	47 (77)	4 (66.7)	0.569	40 (75.5)	11 (78.6)	0.809
Median, IQR
Age at diagnosis (yr)	23 (17-33)	26 (18-37)	0.713	25 (17-37)	20 (11-31)	0.220	23 (17-35)	23 (18-29)	0.925	23 (17-37)	22 (17-29)	0.502
Disease duration (yr)	6 (3-8)	7 (2-12)	0.240	6 (4-10)	6 (1-9)	0.219	6 (3-9)	9 (1-12)	0.760	6 (3-8)	6 (2-17)	0.506
Albumin (g/L)	44 (42-46)	39 (38-47)	0.020	44 (40-46)	43 (39-47)	0.442	44 (40-47)	39 (39-42)	0.210	44 (40-46)	43 (39-47)	0.726
Bilirubin (μmol/L)	15 (11-20)	14 (11-37)	0.704	15 (11-20)	13 (10-22)	0.705	14 (10-22)	17 (16-21)	0.216	15 (11-23)	17 (12-20)	0.813
AST (U/L)	35 (25-56)	55 (37-94)	0.006	36 (27-56)	44 (34-85)	0.182	39 (28-61)	41 (34-48)	0.861	42 (28-61)	35 (25-55)	0.524
ALT (U/L)	46 (21-92)	65 (45-165)	0.030	50 (25-97)	55 (32-165)	0.532	52 (25-100)	44 (37-52)	0.294	54 (32-111)	42 (24-65)	0.188
GGT (U/L)	142 (45-269)	193 (112-478)	0.041	153 (63-305)	153 (60-420)	0.748	154 (60-310)	140 (93-305)	0.943	160 (54-310)	126 (88-305)	0.895
ALP (U/L)	406 (253-643)	1198 (595-1766)	< 0.001	469 (268-734)	715 (507-1496)	0.040	524 (312-784)	1204 (307-1299)	0.336	507 (326-746)	652 (268-1204)	0.394
PLT (G/L)	238 (181-292)	315 (162-494)	0.212	235 (175-274)	320 (162-466)	0.066	248 (165-316)	274 (232-494)	0.292	253 (165-316)	241 (187-356)	0.751
Mayo risk score	-0.834 (-1.378 to -0.131)	0.021 (-0.554-1.248)	0.016	-0.62 (-1.142-0.102)	-0.226 (-1.578-0.292)	0.623	-0.595 (-1.194-0.102)	0.021 (-0.843-1.327)	0.429	-0.579 (-1.102-0.174)	-0.651 (-1.194-0.021)	0.762

AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; GGT: γ-glutamyl-transferase; ALP: Alkaline phosphatase.

Table 4 Serum level of bacterial translocation and enterocyte damage markers according to the different serologic antibody statuses

	Anti-F-actin IgA			Anti-F-actin IgG			Anti-gliadin IgA			Anti-gliadin IgG
	Negative (n = 48)	Positive (n = 19)	P value	Negative (n = 50)	Positive (n = 17)	P value	Negative (n = 61)	Positive (n = 6)	P value	Negative (n = 53)	Positive (n = 14)	P value
Median, IQR
LBP (μg/L)	7132 (5150-9806)	7374 (4348-12100)	0.931	7377 (5795-9880)	6847 (3828-13300)	0.852	6959 (5044-9806)	11450 (5836-15200)	0.239	6959 (4951-9806)	8090 (6077-12700)	0.274
EndoCab IgA (U)	58 (40-92)	123 (93-215)	< 0.001	68 (49-97)	113 (52-150)	0.195	70 (43-106)	134 (66-241)	0.079	70 (43-112)	94 (52-150)	0.301
OMP Plus IgA, n (%)	5 (10.60)	7 (36.80)	0.012	11 (22)	1 (6.30)	0.155	12 (20)	0 (0)	0.226	11 (21.20)	1 (7.10)	0.228
I-FABP (pg/mL)	166 (90-365)	365 (203-1079)	0.011	199 (143-513)	300 (90-365)	0.794	216 (99-443)	342 (143-942)	0.642	195 (99-379)	342 (179-1020)	0.092

LBP: Lipopolysaccharide [LPS]-binding protein; EndoCab: Endotoxin core antibody; I-FABP: Intestinal fatty acid-binding protein; sIgA: Secretory IgA; IQR: Inter-quartile range.