Clinical features and prognosis of drug-induced liver injury in patients with non-alcoholic fatty liver

Table 1 Clinical baseline characteristics of patients in the two groups

	DILI (n = 89)	DILI + NAFL (n = 110)	P value
Age (year)	51 (42, 58.5)	55 (43.75, 59.25)	0.224
Females (number)	70 (78.7)	85 (77.3)	0.816
BMI (kg/cm²)	23.55 (21.15, 25.83)	25.4 (23.25, 28)	0.019
Liver stiffness (kPa)	9.8 (7.8, 12.95)	10.4 (6.65, 14.8)	0.541
CAP (Db/m)	192 (171.5, 235.5)	237 (195.5, 282)	0
Smoking history (number)	12 (13.5)	17 (15.1)	0.485

DILI: Drug-induced liver injury; NAFL: Nonalcoholic fatty liver; BMI: body mass index; CAP: Controlled Attenuation Parameter.

Table 2 Analysis of clinical symptoms at onset in the two groups

	DILI (n = 89)	DILI + NAFL (n = 110)	P value
Urine color deepens	51 (57.3)	61 (55.45)	0.794
Fatigue	43 (48.31)	48 (43.64)	0.51
Poor appetite	47 (52.81)	42 (38.18)	0.039
Nausea	14 (15.73)	6 (5.45)	0.017
Bloating	6 (6.74)	11 (10)	0.414
Abdominal pain	7 (7.87)	6 (5.45)	0.494
Fever	4 (4.49)	5 (4.55)	0.986
Pruritic	1 (1.12)	1 (0.91)	1

DILI: Drug-induced liver injury; NAFL: Nonalcoholic fatty liver.

Table 3 Possible hepatotoxic drugs in the study cohort

Medication history	DILI	DILI + NAFL
Chinese medicine, proprietary Chinese medicine	Lianhua Qingdian (Mianma Guanzhong)	Gynostemma Total Glycosides Tablets
	Warm Stomach Shule (Astragalus, Yanhusuo)	Gastrointestinal An
	Danlu Tongdu Tablet (Salvia miltiorrhiza, Astragalus membranaceus, Yanhuosuo)	Kun Bao Wan (Prepared He Shou Wu, Astragalus)
	Xian Ling Bone Fructus Capsule (Radix et Rhizoma Polygoni Multiflori, Salviae Miltiorrhizae)	Uterine Blood Ning
	Milk fetish elimination (Poria cocos)	Shen Xiang Shu Yu (Yan Hu Suo, Chai Hu)
	Lingbao Heart Protecting Tablets (Salvia miltiorrhiza)	Gentiana Macrophyllae Capsules
	Nourishing Heart Tablets (Astragalus, Yanhusuo, Salvia Miltiorrhiza)	Panax ginseng powder
	Golden Chamber Kidney Qi Pills (Zelda)	Bailemian (Containing Shouwu Teng)
	Rejuvenation (Zedoary, Shouwu Teng)	Dan Hong (Salvia miltiorrhiza)
	Bailomian (Shouwu Teng)	Moistening Dryness and Relieving Itching Capsule (He Shouwu, Prepared He Shouwu)
	Zidan Blood Capsules (Panax ginseng saponin, Radix et Rhizoma Ginseng)	Salvia divinorum Drops (Salvia divinorum)
	Bai Cao Yishou Tea (Astragalus)	Exquisite Yin Qiao Tablets
	Ganoderma Lucidum Spore Powder	Tongxin Nourishing Heart (Prepared He Shouwu)
	Brain Heart (Astragalus, Salvia Miltiorrhiza, Scorpion, Leech)	Di Ao Heart Blood Kang
	Jia Wei Yi Puan (Mentha piperita, Chai Hu)	Mudan Granules (Huang's, Yanhuisuo, Panax ginseng, Paeonia lactiflora, Paeonia lactiflora, Salvia miltiorrhiza, Chuan Gong, Safflower, Sumac, Chickweed)
	Antelope Clear Lung Capsule (Smallpox Powder, Mint)	Xintong Oral Liquid (Astragalus, He Shouwu, Salvia Miltiorrhiza)
	Jumbo Pills (Clove)	Lipitor (Zedoary)
	Osteoporosis (Astragalus, Danshen)	Niu Huang Blood Pressure Reducing Pill (Astragalus, Mentha piperita)
	Deer Chuan Activating Capsule (Scorpion, Yanhuisuo)	Dendrobium Nightshade Pill
	Stomach-clearing Huanglian Pill (Smallpox Powder, Astragalus)	Gynostemma Capsules (Radix et Rhizoma Ginseng, Radix et Rhizoma Serpentae, Radix et Rhizoma Pinelliae, Radix et Rhizoma Bitterwood, Pericarpium Laminariae, Icicle, Menthol)
	Pu Shen Capsule (He Shou Wu, Pu Huang)	Sanwu Capsule (Shouwu Teng)
	Huo Xiang Zheng Qi Capsule (Semen Armeniacae)	Lianhua Qingdian (Mianma Guanzhong)
	Nourishing Blood and Nourishing Kidney Pill (Prepared He Shouwu)	Wind-dispersing and pain-relieving granules (Chai Hu)
	Nourishing the Heart by Nourishing the Veins (Prepared He Shouwu)	Blue Scutellaria Oral Liquid (Astragalus)
	Compound Danshen Drop Pills (Salvia divinorum)	Shu Shen Ling (Shou Wu Teng)
	Tangerine Red Phlegm and Cough Liquid (Semen Huperzia)	Nourishing Blood and Clearing Brain (Yanhuosuo)
	Gui Zhi Fu Ling Capsules	Compound Rheumatism Ning
	Betel Nut Si-Xie Tablet	Inibi Tablets
	Shuanghuanglian (Astragalus)	Inibalance Pills (Roasted Astragalus, Chai Hu)
	Hematoxylin (Chai Hu)	Qingdianxie Tablet (Smallpox Powder, Astragalus, Chai Hu)
	Pu Shen Capsule (He Shou Wu, Ze Xie)	Dong Ling Cao Tablet
	Ginkgo Biloba Ketone Ester Dispersible Tablets	Tongxuanliang Pill (Semixia, Astragalus)
	Muxiang Shunqi	Tiger Balm Tablets
	Liu Wei Di Huang Pill	Gui Long Tendon & Bone Ning (Salvia miltiorrhiza)
	Yanshou Tablets	Golden Throat Pills (Acacia Pi)
	Heze	Zachong Thirteen Flavor Pills (Clove)
	Shouwu Teng	Shu Brain Xin Drops
	Lei Gong Teng	Xihuang Pills
	Saffron	Zijin Long Tablets (Astragalus and Salvia Miltiorrhiza)
	Zedoary	Bornin (Roasted Astragalus)
	He Shou Wu	Zhen's Fu Zheng (Astragalus)
		Pingxiao Capsules
		Yin Qiao Tablet
		Pientzehuang Tablet
		Formula: (1) Fried Sophora japonica, Fried Bitter Almond, Pueraria Mirifica, Paeoniae Alba, Cortex Pseudostellariae, Peony Peel, Roasted Licorice, Ascorbic Acid, Gypsum, Ephedra, Cinnamon Branches, Cicada Shell
		(2) Forsythia, Rhizoma Atractylodis Macrocephalae, Roasted Epimedium, Cinnamon Branches, Folium Artemisiae, Hei Shun Piece, Jujubes, Ginger, Sequelae, Wine Huang Cen, Zingiber officinale, Burnt Hawthorn, Taraxacum officinale
		(3) Lycium barbarum, licorice, Radix Fructus Fructus, Fructus Chrysanthemi, Semen Coicis, Mulberry Leaf, Gardenia Jasminoides, Oyster, Cassia Seed, Lotus Seed
		(4) Gypsum, Zhi Mu, Radix et Rhizoma Ginseng, Pollen, Poria cocos, Morus alba, Zhe Bei, Xuan Shen, Ophiopogon, Chrysanthemum, Radix et Rhizoma Sheng Di
		Salvia miltiorrhiza
		Radix Bupleurum Chinense
		He Shou Wu
		Psoralea rubra
		Senna
		Xiaku Cao Cao Cream
		Deer Whip Cream
		Ginseng
		Lei Gong Teng
		Scorpion
		Leech
		Zezhi diarrhea (used in TCM)
		Acanthopanax Senticosus
		Dragon's blood exhaust
		Dandelion
Western medicine
Anti-infective drugs	Cefoperazone sodium sulbactam sodium, furotoxin, levofloxacin, azithromycin, amoxicillin, clindamycin, isoniazid, rifampicin, streptomycin, bispyrazinamide	Levofloxacin, furotoxin, amoxicillin, itraconazole, roxithromycin
Nonsteroidal anti-inflammatory drug	Loxoprofen, Lovenox Extended-Release Tablets, Acetaminophen	Saxifrage, aminopyrine, aminocaprofen tablets, cotrimoxazole, nimesulide
Cardiovascular drugs	Fluvastatin, Rosuvastatin, Propafenone	Amlodipine benzenesulfonate, aliskatam, nifedipine, irbesartan hydrochlorothiazide, valsartan, felodipine, trandolazine, atorvastatin, simvastatin, acyclovir, atorvastatin, simvastatin, acyclovir, propafenone
Antitumor drugs
Antiulcer drug	Omeprazole (antifungal agent)	Lansoprazole, Rabeprazole
Psychotropic drugs		Flunarizine hydrochloride, betahistine mesylate, clonazepam, trazodone
Hormone antagonists		Letrozole, exemestane, tamoxifen citrate
Other	Mothballs (naphthalene or p-dichlorobenzene), toluene	Glucosamine, analgesic injections (ketorolac tromethamine, resorcinol), eteplirisone hydrochloride tablets, methimazole
Dietary supplement	Amway Health Care, Herbalife, Jens United States	Bovine Vitamin Tablets, Enzymes, Glutamine

TCM: Traditional Chinese medicine; DILI: Drug-induced liver injury; NAFL: Nonalcoholic fatty liver.

Table 4 Comparison of biochemical indices in the two groups

	DILI (n = 89)	DILI + NAFL (n = 110)	P value
ALT (U/L)	765.7 (360.25, 1016.35)	523.35 (169.5, 1078.5)	0.069
AST (U/L)	471.4 (259.9, 658.2)	438.5 (127.5, 920.2)	0.715
γ-GT (U/L)	169 (101.3, 246.1)	202 (97.5, 391.73)	0.071
ALP (U/L)	155.8 (111, 189.85)	129.3 (93, 168.15)	0.509
LDH (IU/L)	259 (220.5, 309)	228 (179, 306)	0.511
TBA (μmol/L)	33 (7, 136)	36.75 (4.85, 142.03)	0.243
TBiL (μmol/L)	59.5 (21.95, 136.3)	74.1 (19.4, 202.63)	0.265
DBIL (μmol/L)	19.6 (6.6, 88.6)	43.4 (4.7, 122.35)	0.965
IBIL (μmol/L)	20.4 (11.65, 29.9)	17.7 (10.43, 35.15)	0.651
TP (g/L)	68.55 ± 7.78	69.45 ± 6.86	0.342
ALB (g/L)	40.29 ± 4.46	40.00 ± 5.07	0.674
TG (mmol/L)	1.57 (1, 2.195)	1.805 (1.435, 2.55)	0.006
CHO (mmol/L)	4.15 (3.51, 4.96)	4.58 (3.9, 5.43)	0.003
LDL (mmol/L)	2.29 (1.87, 2.82)	2.78 (2.03, 3.4)	0.008
HDL (mmol/L)	1.1 (0.87,1.46)	1.14 (0.8,1.39)	0.292
GLU (mmol/L)	5.34 (4.95, 5.79)	5.59 (4.94, 6.38)	0.113
HbA1C (%)	5.7 (5.3, 7.9)	6.5 (5.83, 7.08)	0.291
Insulin (μIU/mL)	9.62 (6.18, 13.14)	12.87 (9.96, 19.4)	0.022

DILI: Drug-induced liver injury; NAFL: Nonalcoholic fatty liver; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase. γ-GT: γ-glutamyl transpeptidase; ALP: Alkaline phosphatase; LDH: Lactate dehydrogenase; TBA: Total bile acids; TBiL: Total bilirubin; DBiL: Direct bilirubin; IBiL: Indirect bilirubin; TP: Total protein; ALB: Albumin; TG: Triglycerides; CHO: Cholesterol; LDL: Low-density lipoprotein; HDL: High-density lipoprotein; GLU: Glucose; HbA1C: Hemoglobin A1C.

Table 5 Classification of liver injury in the two groups

Drug-induced liver injury types	DILI (n = 89)	DILI + NAFL (n = 110)	P value
Hepatocellular	79 (88.8)	77 (70)	0.001
Cholestatic types	4 (4.5)	18 (16.4)	0.008
Mixed	6 (6.7)	15 (13.6)	0.115

DILI: Drug-induced liver injury; NAFL: Nonalcoholic fatty liver.

Table 6 Classification of severity of liver injury in the two groups

Grade	DILI (n = 89)	DILI + NAFL (n = 110)	P value
≤ grade 2	53 (59.55)	57 (51.82)	0.023
> grade 2 or above	36 (40.45)	53 (48.18)

DILI: Drug-induced liver injury; NAFL: Nonalcoholic fatty liver.

Table 7 Comparison of liver pathological findings in the two groups

	DILI (n = 89)	DILI + NAFL (n = 110)	P value
Hepatocellular carcinoma nodule	6 (6.7)	3 (2.7)	0.312
Lipoatrophy	39 (43.8)	77 (70)	0
Brownish-yellow granular deposits	10 (11.2)	13 (11.8)	0.898
Hepatocellular cholestasis	23 (25.8)	45 (40.9)	0.026
Vacuolar degeneration	7 (7.9)	22 (20)	0.016
Spotty necrosis	88 (98.9)	105 (95.5)	0.16
Apoptotic body	61 (68.5)	72 (65.5)	0.646
Inflammatory cell infiltration in the hepatic sinusoids	22 (24.7)	29 (26.4)	0.792
Hepatic sinusoidal dilatation and stasis	1 (1.1)	3 (2.7)	0.769
Pericarditis of the central vein	64 (72.7)	75 (68.2)	0.487
Epithelioid granuloma	2 (2.3)	5 (4.5)	0.636
Bridging necrosis	15 (17)	12 (10.9)	0.211
Phagocytic wax-like deposits	39 (44.3)	34 (30.9)	0.052
Lobular fusion necrosis	1 (1.1)	3 (2.7)	0.778
Expansion of the catchment area	87 (97.8)	107 (97.3)	0.83
Inflammatory cell infiltration in the confluent area	88 (98.9)	107 (97.3)	0.423
Microcystic bile ducts	76 (85.4)	88 (80)	0.32
Interlobular bile duct lesions	4 (4.5)	9 (8.2)	0.461
Boundary board damage	80 (89.9)	91 (82.7)	0.149
Fibrous tissue proliferation	79 (88.8)	105 (95.5)	0.075
Fiber gap formation	1 (1.1)	3 (2.7)	0.769
Lobular structural disorder	1 (1.1)	4 (3.6)	0.502
Iron staining is positive	10 (11.2)	12 (10.9)	0.942
Accompanied by an immune response	26 (29.2)	23 (24.6)	0.176

DILI: Drug-induced liver injury; NAFL: Nonalcoholic fatty liver.

Table 8 Comparison of autoantibody spectrum in the two groups

Autoantibody	DILI (n = 54)	DILI + NAFL (n = 78)	P value
Antinuclear antibody ANA	33 (61.1)	50 (64.1)	0.727
Anti-mitochondrial Antibodies AMA	2 (3.7)	2 (2.6)	0.707
Anti-smooth muscle antibodies ASMA	1 (1.9)	3 (3.8)	0.888
Anti-dsDNA antibody	0 (0)	1 (1.3)	1
Anti-dsDNA antibody	3 (3.2)	1 (2.3)	0.372
Anti-U1-snRNP antibody	2 (3.7)	0 (0)	0.166
Anti-SSA/Ro60 antibody	5 (9.3)	5 (6.4)	0.543
Anti-SSB/Ro52 antibody	5 (9.3)	3 (3.8)	0.363
Anti-SSB/la antibody	2 (3.7)	2 (2.6)	0.707
Anti-Scl-70 antibody	1 (1.9)	0 (0)	0.409
Anti-matrix antibody	0 (0)	0 (0)
Anti-Jo-1 antibody	0 (0)	0 (0)
Anti-Ribosomal P0 Antibody	0 (0)	0 (0)
P-ANCA	0 (0)	0 (0)
Atypical P-ANCA	0 (0)	0 (0)
Antiproteinase 3, PR3	0 (0)	0 (0)
Antiperoxidase, MPO	0 (0)	0 (0)
Anti-histone antibody	0 (0)	0 (0)
Anti-mitochondrial M2 antibody	0 (0)	2 (2.6)	0.513
Anti-nucleotide protein anti-Sp100	0 (0)	2 (2.6)	0.513
Anti-liver and kidney microparticle antibody LKM1	0 (0)	1 (1.3)	1
Anti-nuclear envelope antibody gp210	1 (1.9)	0 (0)	0.409
Anti-hepatocyte lysate antibody LC1	0 (0)	0 (0)
Anti-soluble liver antigen SLA	0 (0)	0 (0)
Serum perinuclear factor APF	0 (0)	0 (0)
Antikeratin antibody AKA	0 (0)	0 (0)
Anticyclic citrullinated peptide ACCP	1 (1.9)	1 (1.3)	1

DILI: Drug-induced liver injury; NAFL: Nonalcoholic fatty liver.

Table 9 Analysis of cytokine results in the two groups

Immunity	DILI (n = 31)	DILI + NAFL (n = 39)	P value
Interferon (pg/mL)	1.46 (0.67, 3.43)	2.29 (1.58, 3.14)	0.149
Tumor necrosis factor (pg/mL)	0.86 (0.48, 1.48)	1.09 (0.62, 2.27)	0.163
IL-2 (pg/mL)	0 (0, 0.93)	0.4 (0, 2.56)	0.092
IL-4 (pg/mL)	0.56 (0.28, 1.69)	1.6 (0.82, 2.69)	0.007
IL-6 (pg/mL)	4.65 (1.82, 6.39)	5.11 (2.79, 9.54)	0.144
IL-10 (pg/mL)	4.16 (2.85, 11.95)	4.28 (2.22, 9.91)	0.92
IL-17 (pg/mL)	0.91 (0.38, 1.95)	1.1 (0.6, 2.35)	0.274

DILI: Drug-induced liver injury; NAFL: Nonalcoholic fatty liver; IL: Interleukin.

Table 10 Analysis of immunological function results in the two groups

	DILI (n = 76)	DILI + NAFL (n = 98)	P value
C3 (g/L)	1.165 (0.99, 1.38)	1.27 (1.15, 1.4)	0.02
IgG (g/L)	13.3 (11.21, 16.09)	13.44 (10.84, 15.53)	0.714
C4 (g/L)	0.25 (0.19, 0.31)	0.26 (0.22, 0.31)	0.244
IgM (g/L)	1.01 (0.83, 1.48)	0.94 (0.72, 1.30)	0.047
IgA (g/L)	2.22 (1.89, 2.79)	2.43 (2.01, 3.35)	0.369

C3: Complement c3; IgG: Immunoglobulin G; C4: Complement c4; IgM: Immunoglobulin M; IgA: Immunoglobulin G; DILI: Drug-induced liver injury; NAFL: Nonalcoholic fatty liver.

Table 11 Analysis of steroid usage in the two groups

	DILI (n = 89)	DILI + NAFL (n = 110)	P value
Hormone use (number)	13 (14.6)	12 (10.9)	0.434

DILI: Drug-induced liver injury; NAFL: Nonalcoholic fatty liver.

Table 12 Liver function recovery time periods in the two groups

Normalized liver function	DILI (n = 58)	DILI + NAFL (n = 62)	P value
D ≤ 7	4 (6.9)	2 (3.2)	0.615
7 < D ≤ 14	2 (3.4)	1 (1.6)	0.953
14 < D ≤ 30	5 (8.6)	1 (1.6)	0.18
30 < D ≤ 90	17 (29.3)	11 (17.7)	0.134
90 < D ≤ 180	9 (15.5)	19 (30.6)	0.05

"D" represents the time for liver function recovery. DILI: Drug-induced liver injury; NAFL: Nonalcoholic fatty liver.

Table 13 Follow-up progression to chronic drug-induced liver injury in the two groups

Normalized liver function	DILI (n = 58)	DILI + NAFL (n = 62)	P value
> 180/chronicization	21 (36.2)	28 (45.2)	0.319

DILI: Drug-induced liver injury; NAFL: Nonalcoholic fatty liver.

Table 14 Follow-up progression to autoimmune hepatitis in the two groups

	DILI (n = 58)	DILI + NAFL (n = 62)	P value
Development of autoimmune hepatitis (number)	6 (10.3)	7 (11.3)	0.868

DILI: Drug-induced liver injury; NAFL: Nonalcoholic fatty liver.