Fatigue and circadian rhythm in non-cirrhotic primary biliary cholangitis: An exploratory comparison with primary sclerosing cholangitis and healthy controls

Table 1 Patients characteristics, median (interquartile range)/n (%)

	Overall (n = 152)	PBC (n = 61)	PSC (n = 30)	HC (n = 61)	P value
Age, years	61.50 (54.00-68.00)	63.00 (57.00-73.00)	50.50 (30.00-57.75)	62.00 (57.00-71.00)	< 0.001
BMI, kg/m2	23.67 (20.88-26.31)	24.58 (22.39-27.34)	22.56 (20.45-24.87)	23.18 (20.48-25.30)	0.012
Sleep duration hours	7.00 (6.00-7.12)	6.50 (5.50-7.00)	7.00 (6.50-7.50)	6.50 (6.00-7.00)	0.130
Number of awakenings	1.50 (1.50-1.50)	1.50 (1.50-1.50)	1.50 (0.00-2.25)	1.50 (1.50-1.50)	0.564
Working days/week	5.00 (0.00-5.00)	5.00 (0.00-5.00)	5.00 (5.00-6.00)	5.00 (0.00-5.00)	0.030
Working hours/day	5.50 (0.00-8.00)	5.00 (0.00-8.00)	7.00 (4.00-8.00)	4.00 (0.00-8.00)	0.040
Disease duration, years	10.00 (4.00-16.00)	10.50 (4.00-16.00)	10.00 (4.00-16.00)	N/A	0.914
Sex					< 0.001
Female	121 (79.6)	54 (88.5)	13 (43.3)	54 (88.5)
Male	31 (20.4)	7 (11.5)	17 (56.7)	7 (11.5)
Nocturnal light exposure					0.676
No	140 (92.1)	55 (90.2)	29 (96.7)	56 (91.8)
Yes	12 (7.9)	6 (9.8)	1 (3.3)	5 (8.2)
Employment					0.011
Employed	85 (55.9)	29 (47.5)	19 (63.3)	37 (60.7)
Retired	55 (36.2)	28 (45.9)	5 (16.7)	22 (36.1)
Unemployed	12 (7.9)	4 (6.6)	6 (20.0)	2 (3.3)
Anti-mitochondrial antibodies					1.000
Negative	11 (18.0)	11 (18.0)	N/A	N/A
Positive	50 (82.0)	50 (82.0)	N/A	N/A
Anti-Sp100					1.000
Negative	48 (78.7)	48 (78.7)	N/A	N/A
Positive	13 (21.3)	13 (21.3)	N/A	N/A
Fibroscan					0.362
F1	68 (75.6)	45 (73.8)	23 (79.3)	N/A
F2	16 (17.8)	13 (21.3)	3 (10.3)	N/A
F3	6 (6.7)	3 (4.9)	3 (10.3)	N/A
Drug					1.000
Fibrates	15 (24.6)	15 (24.6)	N/A	N/A
Obeticholic acid	8 (13.1)	8 (13.1)	N/A	N/A
Ursodeoxycholic acid	38 (62.3)	38 (62.3)	N/A	N/A

BMI: Body mass index; PBC: Primary biliary cholangitis; PSC: Primary sclerosing cholangitis; HC: Healthy controls; N/A: Not applicable.

Table 2 Biochemistry, median (interquartile range)

	Overall (n = 152)	PBC (n = 61)	PSC (n = 30)	HC (n = 61)	P value
eGFR, mL/minU/1.73 m2	90.00 (78.35-90.00)	82.00 (70.00-90.00)	90.00 (90.00-90.00)	N/A	< 0.001
Thyroid stimulating hormone, mIU/L	2.01 (1.13-2.74)	1.23 (1.11-2.04)	2.85 (2.50-3.00)	N/A	< 0.001
Haemoglobin, g/dL	13.30 (12.50-14.10)	13.10 (12.30-13.80)	13.80 (13.00-15.20)	N/A	0.007
Hematocrit, %	41.10 (38.92-42.98)	41.10 (39.10-42.50)	41.50 (38.10-45.00)	N/A	0.360
Platelets, 109/L	258.00 (212.25-300.75)	256.00 (222.00-290.00)	267.00 (202.00-312.00)	N/A	0.772
Ig(immunoglobulin), mg/dL	189.00 (148.00-303.50)	206.00 (155.50-304.25)	156.00 (105.50-269.50)	N/A	0.083
Albumin, g/dL	4.08 (3.90-4.31)	4.00 (3.80-4.30)	4.10 (4.00-4.50)	N/A	0.110
INR	1.00 (1.00-1.00)	1.00 (1.00-1.00)	1.00 (1.00-1.00)	N/A	0.277
Total bilirubin, mg/dL	0.63 (0.50-0.80)	0.60 (0.50-0.71)	0.85 (0.52-1.22)	N/A	0.008
ALT, U/L	23.00 (17.00-39.00)	22.00 (17.00-36.00)	27.50 (19.00-48.75)	N/A	0.157
AST, U/L	27.00 (21.00-33.00)	25.00 (21.00-33.00)	29.00 (22.25-41.75)	N/A	0.179
ALP, U/L	105.00 (79.00-138.00)	105.00 (77.00-138.00)	104.50 (84.75-140.50)	N/A	0.482
GGT, U/L	65.00 (32.00-118.00)	54.00 (33.00-86.00)	75.50 (30.50-154.25)	N/A	0.167

eGFR: Estimated glomerular filtrate rate; INR: International normalized ratio; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; ALP: Alkaline phosphatase; GGT: Gamma- glutamyl transferase; PBC: Primary biliary cholangitis; PSC: Primary sclerosing cholangitis; HC: Healthy controls; N/A: Not applicable.

Table 3 Core outcomes, median (interquartile range)

	Overall (n = 152)	PBC (n = 61)	PSC (n = 30)	HC (n = 61)	P value
Daytime sleepiness (ESS)	5.50 (3.75-8.00)	6.00 (3.00-9.00)	6.00 (4.00-9.00)	5.00 (3.00-8.00)	0.376
Global fatigue (FIS)	34.00 (16.00-65.50)	32.00 (16.00-100.00)	24.00 (6.50-61.25)	37.00 (21.00-56.00)	0.308
PBC-40 fatigue domain1	22.00 (14.00-30.50)	18.00 (13.00-30.00)	25.00 (15.25-30.75)	N/A	0.1312
Chronotype (MEQ-SA)	58.00 (53.00-64.00)	60.00 (55.00-63.00)	54.50 (46.75-59.00)	58.00 (53.00-65.00)	0.018

¹Primary biliary cholangitis-40 applies only to cholestatic cohorts.

²Mann-Whitney test (primary biliary cholangitis vs primary sclerosing cholangitis).

ESS: Epworth Sleepiness Scale; FIS: Fatigue Impact Scale; PBC: Primary biliary cholangitis; MEQ-SA: Morningness-Eveningness Questionnaire Self-Assessment; PSC: Primary sclerosing cholangitis; HC: Healthy controls; N/A: Not applicable.

Table 4 Multivariable analysis of fatigue phenotype, n (%)/mean ± SD

Dependent: Type of fatigue	Mental	Muscular	OR, 95%CI (univariable)	OR, 95%CI (multivariable full)	OR, 95%CI (multivariable)
Group
PBC	19 (27.9)	42 (50.0)
PSC	12 (17.6)	18 (21.4)	0.68 (0.27-1.70), P = 0.403	1.19 (0.39-3.81), P = 0.769	1.25 (0.44-3.71), P = 0.681
HC	37 (54.4)	24 (28.6)	0.29 (0.14-0.61), P = 0.001	0.29 (0.13-0.63), P = 0.002	0.30 (0.14-0.63), P = 0.002
Sex
Female	55 (80.9)	66 (78.6)
Male	13 (19.1)	18 (21.4)	1.15 (0.52-2.61), P = 0.725	1.17 (0.45-3.13), P = 0.753
Age	57.1 ± 15.2	61.7 ± 12.8	1.02 (1.00-1.05), P = 0.047	1.04 (1.00-1.08), P = 0.054	1.04 (1.01-1.07), P = 0.016
Working hours	4.8 ± 3.5	4.3 ± 3.7	0.96 (0.88-1.05), P = 0.425	0.98 (0.84-1.16), P = 0.812
Employment
Employed	42 (61.8)	43 (51.2)
Retired	20 (29.4)	35 (41.7)	1.71 (0.86-3.46), P = 0.130	0.86 (0.22-3.39), P = 0.821
Unemployed	6 (8.8)	6 (7.1)	0.98 (0.28-3.36), P = 0.970	0.84 (0.20-3.65), P = 0.808

PBC: Primary biliary cholangitis; PSC: Primary sclerosing cholangitis; HC: Healthy controls; OR: Odds ratio; CI: Confidence interval.

Table 5 Multivariable analysis of Morningness-Eveningness Questionnaire Self-Assessment score, mean ± SD

Chronotype (MEQ-SA)		Value	Coefficient (univariable)	Coefficient (multivariable full)	Coefficient (multivariable)
Group	PBC	59.3 ± 6.7
	PSC	53.8 ± 8.7	-5.46 (-8.90 to -2.02), P = 0.002	-2.29 (-6.25 to 1.66), P = 0.253	-2.38 (-6.07 to 1.30), P = 0.203
	HC	58.2 ± 8.4	-1.05 (-3.84 to 1.74), P = 0.459	-0.76 (-3.51 to 1.99), P = 0.586	-0.52 (-3.20 to 2.16), P = 0.703
Sex	Female	58.3 ± 7.7
	Male	55.7 ± 9.1	-2.58 (-5.75 to 0.59), P = 0.110	0.21 (-3.19 to 3.61), P = 0.903
Age	20.0-85.0	57.8 ± 8.0	0.20 (0.11-0.28), P < 0.001	0.20 (0.07-0.32), P = 0.002	0.22 (0.11-0.33), P < 0.001
Working hours	0.0-12.0	57.8 ± 8.0	-0.00 (-0.36 to 0.36), P = 0.997	0.33 (-0.22 to 0.89), P = 0.238	0.43 (0.06-0.80), P = 0.024
Employment	Employed	57.9 ± 7.3
	Retired	59.1 ± 7.5	1.20 (-1.46 to 3.86), P = 0.375	-0.36 (-5.07 to 4.34), P = 0.879
	Unemployed	50.8 ± 11.4	-7.14 (-11.88 to -2.41), P = 0.003	-4.03 (-9.11 to 1.06), P = 0.120

MEQ-SA: Morningness-Eveningness Questionnaire Self-Assessment; PBC: Primary biliary cholangitis; PSC: Primary sclerosing cholangitis; HC: Healthy controls.