IMPORTANCE OF P450 POLYMORPHISM IN THE DEVELOPMENT OF DILI/HILI: HISTOLOGICAL AND BIOCHEMICAL FINDINGS

Introduction and Objectives

Drug-induced liver injury (DILI) and herb-induced liver injury (HILI) represent diagnostic and prognostic challenges in hepatology. Objective: To evaluate histological, epidemiological, biochemical variables and the prevalence of cytochrome P450 (CYP450) genotypes in individuals with DILI/HILI at a hepatotoxicity clinic.

Materials and Methods

Cross-sectional study with individuals who developed DILI/HILI and underwent liver biopsy.

Results

Sample comprised 58 individuals, divided into 2 groups: those who developed ALF (34) and those who did not (24). Mean age 38.71 (SD 14.58), 79.3% female. Hepatocellular biochemical pattern: 70.7%, mixed 12.1%, cholestatic 17.2%. The ALF group did not present a cholestatic pattern. Most frequent drugs: antituberculosis (8), nimesulide (5), diclofenac (4). Regarding biochemistry, in the group without ALF, comparing presence of the main drug with or without CYP450 metabolism: BT 5.32 mg/dL vs 4.01; ALT 289.5 U/L vs 274; AST 316 U/L vs 272.5; INR 1 vs 1; AST/ALT 1.07 vs 0.91. In the ALF group: BT 18.75 vs 29.94 mg/dL; ALT 885 vs 474.5 U/L; AST 1350 vs 498.5 U/L; AST/ALT 1.37 vs 0.79. Hy's law applied to 100% of ALF cases. Patients using two or more concomitant drugs showed worse biochemical and histological findings. Most frequent CYPs among non-ALF: CYP3A4 20.68%, CYP2C9 8.62%, CYP2D6 6.89%; among ALF: CYP3A4 31.03%, CYP2C9 15.51%, CYP2A2 8.62%. Histological findings: massive/submassive necrosis was present in 85.29% of ALF patients, mainly in those with CYP metabolism. Fibrosis was more frequent in the group without progression to ALF (9 vs 3).

Conclusions

Hepatic metabolism by CYP450 is associated with more severe DILI/HILI, including higher frequency of hepatic necrosis and elevated biochemical values. Recognizing the metabolic profile of implicated drugs may help predict injury severity and guide earlier, individualized treatment strategies.

Conflict of interest: None

Variable	DILI without ALF (n = 24)		DILI with ALF (n = 34)		p
	CYP450 (n=16)	Non-CYP (n=8)	CYP450 (n=28)	Non-CYP (n=6)
Age (years), mean (SD)	39.56 (14.23)	48.75 (13)	32.29 (12.5)	40.5 (22.28)	>0,05
Female sex, n (%)	13 (22.41)	6 (10.34)	22 (37.93)	6 (10.34)	>0,05
INR, median (IQR)	1 (0.99–1.06)	1 (0.97–1.3)	3.74 (2.2–5.25)	3.48 (2.2–9.08)	<0,05
BT (mg/dL), median (IQR)	5.32 (0.99–11.59)	4.01 (0.6–15.97)	18.75 (10.67–26.49)	26.94 (21.71–28.73)	>0,05
ALT (U/L), median (IQR)	289.5 (160.75–608.5)	274 (219–635)	885 (593–1563)	474.5 (455.75–2138)	<0,05
AST (U/L), median (IQR)	316 (110–873)	272.5 (152.7–556.5)	1350 (552–3450)	498.5 (350.5–2892.75)	<0,05
Liver injury pattern, n (%):
Hepatocellular	8 (13.7)	3 (5.17)	24 (41.37)	6 (10.34)	<0,05
Cholestatic	7 (12)	0 (0)	0 (0)	0 (0)	<0,05
Mixed	2 (3.44)	4 (6.89)	4 (6.89)	0 (0)	<0,05
AST/ALT ratio, median (IQR)	1.07 (0.51–1.52)	0.91 (0.57–1.16)	1.37 (0.75–2.38)	0.79 (0.54–2.2)	<0,5
Hy’s Law criteria met, n (%):	11 (18.9)	4 (6.89)	28 (48.27)	6 (10.34)	<0,05
Concomitant medications ≥2, n (%)	9 (15.51)	6 (10.34)	20 (34.48)	3 (5.17)	>0,05
Concomitant CYP450-metabolized drugs, n (%)	10 (17.24)	3 (5.17)	10 (17.24)	2 (3.44)	>0,05
Most frequent CYP450 isoenzymes, n (%):
CYP3A4	12 (20.68)	—	18 (31.03)	—	>0,05
CYP2C9	5 (8.62)	—	9 (15.51)	—	>0,05
CYP2D6	4 (6.89)	—	2 (3.44)	—	>0,05
CYP3A5	1 (1.72)	—	2 (3.44)	—	>0,05
CYP2C19	3 (5.17)	—	4 (6.89)	—	>0,05
CYP2E1	2 (3.44)	—	3 (5.17)	—	>0,05
CYP1A2	1 (1.72)	—	5 (8.62)	—	>0,05
Most frequent causative drugs:	Chlorpromazine (2), nimesulide (2)	Amoxicillin–clavulanate (2)	Diclofenac (4), nimesulide (3), antituberculosis drugs (8),	methyldopa (3)
Histological findings, n (%):
Chronic hepatitis	3 (5.17)	1 (1.71)	1 (1.71)	1 (1.71)	>0,05
Active chronic hepatitis	3 (5.17)	1 (1.71)	2 (3.44)	1 (1.71)	>0,05
Acute cholestasis	5 (8.62)	1 (1.71)	6 (10.34)	1 (1.71)	>0,05
Chronic cholestasis	1 (1.71)	0 (0)	0 (0)	0 (0)	>0,05
Cholestatic hepatitis	4 (6.89)	0 (0)	2 (3.44)	1 (1.71)	>0,05
Type of necrosis, n (%):
Massive/submassive necrosis	0 (0)	0 (0)	24 (41.37)	5 (8.62)	>0,05
Zonal/focal necrosis	5 (8.62)	4 (6.89)	4 (6.89)	1 (1.71)	<0,05
Other histological findings, n (%):
Steatosis	1 (1.71)	0 (0)	3 (5.17)	0 (0)	>0,05
Fibrosis	9 (15.51)	1 (1.71)	3 (5.17)	0 (0)	<0,05
Siderosis	2 (3.44)	1 (1.71)	4 (6.89)	3 (5.17)	>0,05
Mononuclear infiltrate	14 (24.13)	4 (6.89)	18 (31.03)	5 (8.62)	>0,05
Interface activity	4 (6.89)	1 (1.71)	0 (0)	0 (0)	<0,05
Hepatocyte ballooning	7 (12)	2 (3.44)	2 (3.44)	0 (0)	<0,05
Ductular reaction/proliferation	10 (17.24)	3 (5.17)	7 (12)	1 (1.71)	>0,05