Drug-induced liver injury in inflammatory bowel disease: 1-year prospective observational study

Table 1 Summary statistics table of the study group of 251 inflammatory bowel disease patients

n = 251	Median; IQR, n (%)
Age	39; 30.0-52.75
Female gender	129 (51.4)
Body mass index	24.298; 21.19-27.34
Crohn's disease	154 (61.4)
Ulcerative colitis	97 (38.6)
Inflammatory bowel disease duration (yr)	8 (5-13
Primary sclerosign cholangitis	2 (0.8)
Prior intestinal resection	73 (29.4)
Short IBDQ questionaire score	58 (50-64)
Fecal calprotectin on study entry (mg/g)	83.195 (23.45-331.8)
C-reactive protein on study entry (mg/L)	5 (2.4-8.2)
Inflammatory bowel disease therapy on entry
Mesalamine	173 (69.5)
Antibiotics	17 (6.9)
No immunosupression	66 (26.3)
Steroids	42 (16.9)
Azathioprine solo	47 (18.7)
anti TNF therapy (all)	138 (55)
anti TNF therapy solo	74 (29.5)
Infliximab solo	41 (16.3)
Adalimumab solo	33 (13.1)
Combination therapy (anti-TNF and azathioprine)	64 (25.5)
Days between 1st and 5th AT sampling	382 (353-439.8)
Liver steatosis on ultrasound (n = 155)	34 (21.9)

Table 2 Prevalence of liver injury events among all aminotransferase measurements in 251 inflammatory bowel disease patients over 1 year n (%)

Liver injury event	All measurements	Abnormal
	n	Number of events
ALT increase Grade 1 (0-3 × ULN)	917	112 (12.21)
ALT increase > 2 × ULN (hepatocellular injury)	917	26 (2.84)
ALT increase Grade 2 (> 3 × ULN)	917	6 (0.65)
AST increase Grade 1 (0-3 × ULN)	917	55 (6.0)
AST increase Grade 2 (> 3 × ULN)	917	8 (0.87)
GGT increase Grade 1 (0-2.5 × ULN)	895	80 (8.94)
GGT increase Grade 2 (> 2.5 × ULN)	895	24 (2.68)
ALP increase Grade 1 (0-2.5 × ULN)	897	34 (3.79)
ALP increase Grade 2 (> 2.5 × ULN)	897	0 (0)
Cholestasis (parallel ALP and GGT elevation)	895	11 (1.23)
Total bilirubin > 2 × ULN	370	1 (0.27)

ULN: Upper limit of normal; ALT: Alanine aminotransferase; AST: Aspratate aminotransferase; GGT: Gamma-glutamyl transpeptidase; ALP: Alkaline phosphatase.

Table 3 Prevalence of liver injury events according to the inflammatory bowel disease treatment groups

Liver injury event	IBD treatment
	Solo azathioprine		Solo adalimumab		Solo infliximab
	All measurements	Abnormal	All measurements	Abnormal	All measurements	Abnormal
	n	n (%)	n	n (%)	n	n (%)
ALT increase Grade 1 (0-3 × ULN)	154	16 (10.4)	135	25 (18.5)a	163	26 (16)
ALT > 2 × ULN (hepatocellular injury)		3 (1.9)		2 (1.5)		15 (9.2)a
ALT increase Grade 2 (> 3 × ULN)		2 (1.3)		0 (0)		4 (2.5)a
AST increase Grade 1 (0-3 × ULN)	154	6 (3.9)	135	7 (5.2)	162	20 (12.3)a
AST increase Grade 2 (> 3 × ULN)		0 (0)		1 (0.1)		2 (1.2)
ALP increase Grade 1 (0-2.5 × ULN)	148	6 (4.1)	132	2 (1.5)	163	11 (6.7)
ALP increase Grade 2 (> 2.5 × ULN)		0 (0)		0 (0)		0 (0)
Cholestasis (parallel ALP and GGT > ULN)	146	5 (3.4)a	132	1 (0.1)	162	2 (1.2)
	Azathioprine + infliximab		Azathioprine + adalimumab		No immunosupression
	All measurements	Abnormal	All measurements	Abnormal	All measurements	Abnormal
ALT increase Grade 1 (0-3 × ULN)	199	15 (7.5)	59	8 (13.6)	207	22 (10.6)
ALT > 2 × ULN (hepatocellular injury)		2 (1)		1 (1.7)		3 (1.4)
ALT increase Grade 2 (> 3 × ULN)		0 (0)		0 (0)		0 (0)
AST increase Grade 1 (0-3 × ULN)	200	11 (5.5)	59	2 (3.4)	207	9 (4.3)
AST increase Grade 2 (> 3 × ULN)		1 (0.5)		2 (3.4)		2 (0.1)
ALP increase Grade 1 (0-2.5 × ULN)	195	0 (0)	58	3 (5.2)	201	12 (6)
ALP increase Grade 2 (> 2.5 × ULN)		0 (0)		0 (0)		0 (0)
Cholestasis (parallel ALP and GGT > ULN)	195	0 (0)	58	1 (1.7)	201	2 (1)

^aP < 0.05 for comparison with the prevalence of the liver injury event among all measurements (Table 2).

Table 4 Numbers of cases with liver injury events and patterns among 251 inflammatory bowel disease patients over 1 year n (%)

Liver injury event	Numbers of cases with liver injury events
			Transient	Persisting injury
	No event	Any event	1 event	2 events	3 events	4 events	5 events
ALT increase Grade 1 (0-3 × ULN)	185 (73.7)	66 (26.3)	38 (15.1)	16 (6.4)	6 (2.4)	6 (2.4)	0 (0)
ALT increase > 2 × ULN (hepatocellular injury)	235 (93.63)	16 (6.4)	12 (4.8)	1 (0.4)	1 (0.4)	1 (0.4)	1 (0.4)
ALT increase Grade 2 (> 3 × ULN)	246 (98.0)	5 (2)	4 (1.6)	1 (0.4)	0 (0)	0 (0)	0 (0)
AST increase Grade 1 (0-3 × ULN)	217 (86.45)	34 (13.5)	25 (10)	4 (1.6)	1 (0.4)	1 (0.4)	3 (1.2)
AST increase Grade 2 (> 3 × ULN)	245 (97.6)	6 (2.3)	4 (1.6)	2 (0.8)	0 (0)	0 (0)	0 (0)
ALP increase Grade 1 (0-2.5 × ULN)	232 (92.43)	19 (7.5)	11 (4.4)	3 (1.2)	4 (1.6)	0 (0)	1 (0.4)
ALP increase Grade 2 (> 2.5 × ULN)	251 (100)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)
Cholestasis (parallel ALP and GGT elevation)	240 (95.61)	11 (4.4)	7 (2.8)	2 (0.8)	1 (0.4)	0 (0)	1 (0.4)
Total bilirubin > 2 × ULN	250 (99.6)	1 (0.4)	1 (0.4)	0 (0)	0 (0)	0 (0)	0 (0)

ULN: Upper limit of normal; ALT: Alanine aminotransferase; AST: Aspratate aminotransferase; GGT: Gamma-glutamyl transpeptidase; ALP: Alkaline phosphatase.

Table 5 Univariate analysis of risk factors for liver injury events and patterns among 251 inflammatory bowel disease patients

	Risk factors for selected liver injury events and patterns
	Persisting ALT increase		ALT > 2 × ULN		Persisting AST increase		Cholestasis
	OR; 95%CI	P value	OR; 95%CI	P value	OR; 95%CI	P value	OR; 95%CI	P value
Age1	1.01; 0.98-1.04	0.628	1.02; 0.98-1.05	0.317	1.03; 0.99-1.08	0.185	1.02; 0.98-1.06	0.300
Female gender	0.22; 0.87-0.57	0.002	0.55; 0.19-1.55	0.260	0.75; 0.20-2.86	0.672	2.62; 0.68-10.13	0.160
Body mass index1	1.13; 1.04-1.23	0.004	1.13; 1.03-1.23	0.011	1.18; 1.06-1.32	0.003	0.95; 0.82-1.08	0.413
Crohn's disease	2.03; 0.83-4.97	0.122	2.89; 0.80-10.41	0.105	1.27; 0.31-5.20	0.739	2.95; 0.62-13.94	0.173
Ulcerative colitis	0.49; 0.20-1.21	0.122	0.35; 0.10-1.25	0.105	0.79; 0.19-3.22	0.739	0.34; 0.07-1.60	0.173
Inflammatory bowel disease duration (yr)1	1.04; 0.98-1.09	0.180	1.08; 1.02-1.15	0.007	1.10; 1.03-1.18	0.006	1.04; 0.97-1.11	0.295
Prior intestinal resection	0.95; 0.40-2.28	0.915	1.10; 0.37-3.27	0.869	0.68; 0.14-3.33	0.631	7.06; 1.81-27.41	0.005
Short IBDQ questionaire score1	1.00; 0.97-1.04	0.935	0.99; 0.95-1.04	0.703	0.99; 0.94-1.06	0.925	0.98; 0.93-1.04	0.545
Fecal calprotectin on study entry (mg/g)1	0.999; 0.99-1.00	0.909	1.00; 0.99-1.00	0.895	0.99; 0.99-1.00	0.424	1.00; 0.99-1.00	0.346
C-reactive protein on study entry (mg/L)1	0.98; 0.94-1.03	0.520	0.98; 0.93-1.04	0.590	1.00; 0.95-1.06	0.907	1.04; 1.01-1.07	0.024
Inflammatory bowel disease therapy on entry
Mesalamine	0.64; 0.29-1.45	0.288	0.54; 0.19-1.51	0.241	0.34; 0.09-1.29	0.112	0.76; 0.22-2.67	0.667
No immunosupression	0.58; 0.21-1.59	0.287	0.38; 0.08-1.73	0.211	0.34; 0.41-2.77	0.314	0.61; 0.13-2.9	0.535
Steroids	0.16; 0.02-1.22	0.078	0.69; 0.15-3.13	0.627	0.60; 0.07-4.96	0.640	1.90; 0.48-7.50	0.357
Azathioprine solo	0.49; 0.14-1.69	0.258	1.00; 0.27-3.67	0.998	0.53; 0.07-4.36	0.557	3.93; 1.15-13.47	0.030
Anti-TNF therapy solo	2.72; 1.22-6.03	0.014	2.56; 0.923-7.10	0.071	5.11; 1.24-21.05	0.024	0.89; 0.23-3.46	0.870
Infliximab solo	2.80; 1.18-6.80	0.020	3.43; 1.17-10.03	0.030	4.43; 1.14-17.28	0.032	1.15; 0.24-5.50	0.866
Adalimumab solo	1.51; 0.53-4.31	0.437	0.94; 0.20-4.33	0.937	1.94; 0.39-9.79	0.420	0.65; 0.08-5.25	0.686
Combination therapy (anti-TNF and azathioprine)	0.776; 0.3-2.01	0.601	0.66; 0.18-2.39	0.525	0.36; 0.04-2.90	0.330	0.28; 0.04-2.24	0.231
Liver steatosis on ultrasound (n = 155)	7.77; 3.03-19.9	< 0.0001	7.14; 2.15-23.59	0.001	6.78; 1.53-30.03	0.012	1.45; 0.27-7.83	0.666

¹Modeled as continuous variables. ULN: Upper limit of normal; ALT: Alanine aminotransferase; AST: Aspratate aminotransferase.