Drug and herbal/dietary supplements-induced liver injury: A tertiary care center experience

Table 1 Clinical features of patients with DILI/HDS according to the histopathological pattern of injury

	Hepatocellular	Cholestatic	Mixed
n (%)	18 (49)	5 (14)	15 (39)
Age (mean ± SD)	50 ± 8	65 ± 5	49 ± 18
Gender (M:F)	5:13	3:2	7:8
Initial ALT (mean ± SD)	870 ± 280	37 ± 32	470 ± 190
Initial AST (mean ± SD)	780 ± 110	44 ± 54	360 ± 600
Initial ALP (mean ± SD)	190 ± 93	300 ± 25	220 ± 91
R ratio (mean ± SD)	12 ± 0.4	0.5 ± 0.1	6.4 ± 0.9
Total bilirubin (mean ± SD)	5.5 ± 0.4	4.3 ± 4.5	3.7 ± 1.5
Platelet count/µL (mean ± SD)	230000 ± 92000	230000 ± 130000	220000 ± 31000

ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; ALP: Alkaline phosphatase.

Table 2 Causative agents summarized according to the histopathological pattern of injury

Drugs	Hepatocellular (n = 18)	Cholestatic (n = 5)	Mixed (n = 14)
Anti-infective agents	3	1	4
Analgesics	7	0	0
Psychotropic agents	2	0	0
Antineoplastic agents	1	0	1
Antilipedemic agents	0	1	1
Immunomodulatory agents	2	0	0
Others	0	Antithyroid: 1; Thrombolytic: 1; Total parenteral nutrition: 1	Triptan: 1; Antiemetic: 1; Methyldrostanolone: 1; Anti-inflammatory: 1; Antiarrythmic: 2
Herbal/Dietary supplements	3	0	3

Table 3 Histopathological patterns, R ratios and Drugs/HDS in our study

Histopathological pattern	R ratio	Total, n = 38 (%)	Drugs/HDS (n)
Hepatitis	12 ± 0.4	18 (47.4)
Acute	16 ± 0.1	5 (13.2)	Nitrofurantoin (1)
			Black cohosh1 (1)
			Sertraline (1)
			Lamotrigine (1)
			Green tea extract (1)
Acute with extensive necrosis	11 ± 3.3	8 (21.1)	Diclofenac (1)
			Acetaminophen (6)
			Black cohosh1 (1)
Autoimmune-like	6.2 ± 0.1	3 (7.9)	Infliximab (2)
			Isoniazid (1)
Chronic	8.8	1 (2.6)	Nitrofurantoin (1)
Non-necrotizing granulomatous hepatitis	14	1 (2.6)	BCG (1)
Cholestasis	0.5 ± 0.1	5 (13.2)
Acute	0.4 ± 0.5	4 (10.5)	Ceftriaxone (1)
			Methimazole (1)
			Total parenteral nutrition (1)
			Rivaroxaban (1)
Chronic	0.8	1 (2.6)	Triazolam and statin (1)
Cholestatic hepatitis	9.0 ± 5.6	8 (21.1)	Ezetimibe (1)
			Cefazolin (1)
			Hydroxycut2 (1)
			Rizatriptan5 (1)
			Methyldrostanolone (1)
			Trimethobenzamide Hydrochloride5 (1)
			Mesalamine (1)
			C4 extreme3 (1)
Macrovesicular steatohepatitis	1.4 ± 1.2	5 (13.2)	Trimethoprim-sulfamethoxazole6 (1)
			L-asparaginase (1)
			Valproic acid (1)
			Haart4 (1)
			Amiodarone (1)
Mixed cholestatic hepatitis with steatosis and bile duct injury	1.1 ± 0.8	2 (5.3)	Dronedarone6 (1)
			Hydroxycut26 (1)

¹Actaea racemosa or cimicifuga racemose.

²Contains caffeine, lady's mantle extract (Alchemilla vulgaris), wild olive extract (Olea europaea), cumin extract (Cuminum cyminum), wild mint extract (Mentha longifolia), and, in some products, green coffee bean extract (Coffea canephora).

³CarnoSyn Beta Alanine to support muscular endurance, TeaCrine to prolong tolerance buildup, Rauwolfia, and Toothed Clubmoss.

⁴Highly active antiretroviral therapy.

⁵Not previously reported.

⁶Unusual patterns for this drug/HDS. HDS: Herbal/Dietary supplements; BCG: Bacillus Calmette Guerin.

Table 4 Clinical features, histopathological patterns and outcomes of patients presenting with previously unreported drugs/HDS or with unusual pattern of injury

Cases	ALT (U/L)	ALP (U/L)	R ratio	Total Bilirubin (mg/dL)	Platelet count (/µL)	Histopathologi-cal pattern	Outcome
Rivaroxaban	76	214	0.9	6.8	123000	Acute hepatocellular and canalicular cholestasis associated with bile duct damage, mild steatohepatitis with portal, periportal and pericentral fibrosis (stage 2 of 4), and nodular regenerative hyperplasia	LFTs downtrended after 15 d of drug removal
Rizatriptan	147	135	2.7	1.2	132000	Moderate to severe acute hepatitis with associated cholestasis and bile duct damage	LFTs downtrended after 45 d of drug removal
Trimethobenz-amide hydrochloride	630	135	11.4	1.5	350000	Cholestatic hepatitis with portal and lobular mononuclear inflammatory infiltrate, bile duct damage and bile ductular proliferation	LFTs downtrended after 60 d of drug removal
Trimethoprim-sulfamethoxazo-le	152	198	1.9	10.9	116000	Panacinar macrovesicular steatosis/mild steatohepatitis, cholestasis and mild portal tract fibrous expansion. (steatohepatitis necroinflammatory grade I; fibrosis stage 0-1)	LFTs downtrended after 90 d of drug removal
Dronedarone	93	477	0.5	3.3	114000	Pericentral hepatocyte and canalicular cholestasis, bile duct injury with bile ductular proliferation, mixed portal inflammatory infiltrates, mild interface hepatitis, lobular necroinflammatory activity with ballooning degeneration; mild macro and microvesicular steatosis	LFTs downtrended after 85 d of drug removal
C4 Extreme	3384	175	49.5	22.5	144000	Severe cholestatic hepatitis with sub massive hepatic necrosis involving approximately 70% of the liver parenchyma accompanied by severe centrilobular congestion, necrosis and extravasation of red blood cells	Underwent transplant; Alive and doing well
Hydroxycut	344	500	1.7	0.7	350000	Cholestatic hepatitis with bile duct injury and steatosis	LFTs downtrended after 45 d of drug removal

LFTs: Liver function tests; HDS: Herbal dietary supplements; ALT: Alanine aminotransferase; ALP: Alkaline phosphatase.