Herb-induced liver injury: Systematic review and meta-analysis

Table 1 The prevalence of herbs or herbal compounds found in the systematic review

Variable	Patients, n = 936 (%)
Number of herbs per case
One	823 (87.9)
Two	87 (9.2)
Three	17 (1.8)
Four	9 (0.9)
Herbs	1084 (100)
He-Shou-Wu	91 (8.3)
Green tea extract	90 (8.3)
Herbalife	64 (5.9)
Kava kava	62 (5.7)
Greater celandine	48 (4.4)
Multiple herbs	38 (3.5)
Germander	35 (3.2)
Hydroxycut	35 (3.2)
Skullcap	35 (3.2)
Kratom	33 (3.0)
Gynura segetum	29 (2.6)
Garcinia cambogia	29 (2.6)
Ma huang	27 (2.4)
Chaparral	26 (2.4)
Senna	25 (2.3)
Aloe vera	22 (2.0)
Jin Bu Huan	19 (1.7)
Oxyelite	17 (1.5)
Valerian	16 (1.4)
Red Yeast Rice	16 (1.4)
Black Cohosh	15 (1.3)
Noni	14 (1.2)
Senecio	14 (1.2)
Turmeric	13 (1.2)
Dictamnus dasycarpus	12 (1.1)
No-xplode	12 (1.1)
St. John’s Wort	12 (1.1)
Black catechu	11 (1)
LipoKinetix	11 (1)
Others	159 (14.6)
Ginseng	10 (6.2)
Pennyroyal oil	9 (5.6)
Cascara-Sagrada	9 (5.6)
Ashwagandha	9 (5.6)
Atractylis gummifera	8 (5)
Comfrey	8 (5)
Psoralea corylifolia	8 (5)
Field Horsetail	7 (4.4)
Citrus aurantium	7 (4.4)
Equinácea	6 (3.7)
Heliotropium	5 (3.1)
Saw palmetto	5 (3.1)
Syo-saiko-to	5 (3.1)
Ba Jiao Lian	4 (2.5)
Crotalaria	3 (1.8)
Impila	3 (1.8)
Mistletoe	3 (1.8)
Erva-mate	3 (1.8)
Kombucha tea	3 (1.8)
Soy isoflavones	3 (1.8)
Centella asiática	3 (1.8)
Red Bush tea	3 (1.8)
Milk thistle	3 (1.8)
Mentha piperita	2 (1.2)
Tussilago farfara	2 (1.2)
Aesculus hippocastanum	2 (1.2)
Tinospora crispa	2 (1.2)
Malva	2 (1.2)
Margosa oil	2 (1.2)
Nerium oleander	1 (0.6)
Chinese Herbal Medicine	1 (0.6)
Maya nut	1 (0.6)
Eucalyptus globulus	1 (0.6)
Pelargonium sidoides	1 (0.6)
Lesser celandine	1 (0.6)
Kudzu root extract	1 (0.6)
Grifola frondosa	1 (0.6)
Adenostyles alliariae	1 (0.6)
Argemone Mexicana	1 (0.6)
Willow bark tea	1 (0.6)
Pioscoreae rhizome	1 (0.6)
Green coffee	1 (0.6)
Chamomile	1 (0.6)
Chaga tea	1 (0.6)
Yang ti cao	1 (0.6)
Orthosiphon aristatus	1 (0.6)
Solanum nigrum	1 (0.6)
Mango	1 (0.6)
Isabgol	1 (0.6)
Unknown	54 (4.9)

Table 2 Baseline features of herb-induced liver injury in 936 patients

Variable	Patients, n = 936 (%)
Mean age (yr)	42.67
Sex (female)	611 (65.2)
Race
White	82 (8.7)
Black	9 (0.9)
Other	53 (5.6)
Country
United States	253 (27)
Germany	103 (11)
China	78 (8.3)
Spain	58 (6.2)
Italy	50 (5.3)
South Corea	40 (4.2)
Others	354 (37.8)
Application
Weight loss	145 (15.4)
Psychiatry disorders	52 (5.5)
Pain control	46 (4.8)
Gastrointestinal disorders	41 (4.3)
Skin problems	37 (3.7)
Health improvement	34 (3.6)
Physical improvement	34 (3.6)
Sleep disorders	24 (2.5)
Symptoms
Jaundice	437 (46.3)
Abdominal pain	212 (22.4)
Nausea	163 (17.2)
Hepatomegaly	131 (13.8)
Fatigue	131 (13.8)
Urine alteration	127 (13.4)
Coluria	120 (12.7)
Hematuria	7 (0.7)
Vomiting	117 (12.4)
Ascites	104 (11)
Pruritus	84 (8.9)
Stools alteration	57 (6)
Clay colored	53 (5.6)
Melena	4 (0.4)
Anorexia	49 (5.1)
Encephalopathy	39 (4.1)
Asthenia	34 (3.6)
Malaise	33 (3.5)
Diarrhea	33 (3.5)
Abdominal distension	30 (3.1)
Weakness	27 (2.8)
Fever	22 (2.3)
Lethargy	19 (2)
Hyporexia	19 (2)
Splenomegaly	17 (1.8)
Myalgia	14 (1.4)
Altered mental status	14 (1.4)
Weight loss	13 (1.3)
Antibodies
ANA	48 (5)
ASMA	25 (2.6)
AMA	7 (0.7)
Anti-dsDNA	2 (0.2)
cANCA	2 (0.2)
Actin	1 (0.1)
Anti-LKM	1 (0.1)
AMA-M2	1 (0.1)
pANCA	1 (0.1)
Rheumatoid factor	1 (0.1)
AST (U/L)	1324
ALT (U/L)	1462
ALP (U/L)	283
GGT (U/L)	260
Total bilirubin (mg/dL)	28.37
Direct bilirubin (mg/dL)	7.71
HILI pattern
Hepatocellular	660 (70)
Sinusoidal obstruction syndrome	92 (9.7)
Cholestatic	80 (8.5)
Mix	78 (8.3)
Granulomatous hepatitis	6 (0.6)
Steatosis	5 (0.5)
Ductopenia	3 (0.3)
Nontippable	2 (0.2)
Other	10 (1)
Use duration (d)	125
Latency (d)	121
Stop and manifestation (d)	1
Normalization liver function (d)	77
Comorbidities
Dyslipidemia	40 (4.2)
Obesity	37 (3.9)
Hypertension	36 (3.8)
Alcohol use	26 (2.7)
Hypothyroidism	26 (2.7)
Osteoarthritis	13 (1.3)
Psoriasis	10 (1)
Anxiety	9 (0.9)
Asthma	9 (0.9)
Depression	9 (0.9)
Smoking	7 (0.7)
None	350 (37.1)
Other medications
Vitamins and minerals	63 (6.6)
Antihypertensive	53 (5.6)
NSAIDs	45 (4.7)
Estrogen/progesterone	40 (4.2)
Diuretics	23 (2.4)
Paracetamol	23 (2.4)
Statins	23 (2.4)
SSRI	17 (1.8)
Antibiotics	15 (1.6)
Corticoid	15 (1.6)
Benzodiazepine	14 (1.5)
Diabetes mellitus drugs	14 (1.5)
Proton pump inhibitor	12 (1.3)
None	452 (47.9)
Temporal relation	26 (15.6)
Biopsy	383 (40.5)
Viral hepatitis
Hep A	3 (0.4)
Hep B	5 (0.6)
Hep C	8 (0.9)
CMV	2 (0.2)
HSV	2 (0.2)
Alcoholic liver disease	2 (0.2)
Bile duct obstruction	2 (0.2)
Other causes
Pregnancy	3 (0.3)
Acute hypotension	2 (0.2)
Rechallenge	79 (8.3)
Previous report hepatotoxicity	855 (88.5)
Causality
Definitive	22 (2.3)
Highly probable	8 (0.8)
Probable	122 (12.9)
Possible	49 (5.1)
Improbable	2 (0.2)
Excluded	7 (0.8)
Maria and Victorino
Treatment	8.69 ± 3.93
Supportive care	699 (66.1)
Liver transplantation	70 (6.6)
Corticoid	39 (3.6)
Acetylcysteine	29 (2.7)
Ursodeoxycholic acid	28 (2.6)
Adenosylmethionine	21 (1.9)
Glutathione	20 (1.8)
Vitamin K	18 (1.6)
Glycyrrhizin	18 (1.6)
Polyene phosphatidylcholine	18 (1.6)
Antibiotics	17 (1.5)
Cholestyramine	4 (1.1)
Outcome
Recovery	782 (82.8)
Chronicity	14 (1.5)
Death	98 (10.4)

ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; GGT: Gamma-glutamyl transferase; Hep: Hepatitis; CMV: Cytomegalovirus; HSV: Herpes simplex virus.

Table 3 Characteristics of the 14 main herbs that induced-liver injury

Generic or trade names	Latin name	n	Age (mean)	Sex (male) (%)	Country/territory (%)	Symptoms (%)	AST (mean)	ALT (mean)	ALP (mean)	GGT (mean)	BT (mean)	BD (mean)	Biopsy (%)	HILI patterns (%)	Maira and Victorino score (mean)	Treatment (%)	Clinical outcome (%)
He-Shou-Wu; Fo-ti; Shou Wu Pian	Polygonum multiflorum	91	46	47 (51.6)	China (54.9), South Korea (28.5)	Jaundice (80), choluria (17.7), fatigue (15.5), hepatomegaly (13.3)	1279	1511	222	264	10.8	6.3	20 (31.7)	Hepatocellular (72.5), cholestatic (18.6), mixed (8.7)	8	Adenosylmethionine (12.3), glutathione (12.3), glycyrrhizin (12.3), polyene phosphatidylcholine (12.3), supportive care (45.8)	Recovery (93.4), chronification (3.3), died (3.3)
Green tea extract	Camellia sinensis	90	44	22 (24.4)	Usa (32.5), Spain (19.1), Japan (14.6)	Jaundice (61.4), fatigue (30.4), nausea (27.5), abdominal pain (26)	1715	1870	330	271	12.8	9.2	36 (60)	Hepatocellular (78.8), cholestatic (8.8), mixed (11.1)	9	Liver transplantation (10.5), corticoid (9.4), acetylcysteine (3.1), supportive care (45.8), udca (3.1), supportive care (69.4)	Recovery (91.7), chronification (1.1), died (7)
Kava kava	Piper methysticum	62	43	15 (24.1)	Germany (65), United States (21.6), Spain (3.3)	Jaundice (86.8), nausea (47.8), fatigue (34.7)	1206	1605	310	284	19	10	36 (69.2)	Hepatocellular (77.4), cholestatic (9.6), mixed (8)	8	Liver transplantation (23.9), corticoid (4.2), suportive care (57.7)	Recovery (91.9), died (8)
Greater celandine	Chelidonium majus	48	49	8 (17)	Germany (81.2), Italy (8.3)	Jaundice (34.2), choluria (31.4), pruritus (28.5), nausea (27.7)	631	1109	321	236	11.5	6.9	34 (79)	Hepatocellular (72.9), cholestatic (6.2), mixed (20.8)	10	Udca (6.1), corticoid (4), glutathione (2), supportive care (87.7)	Recovery (97.9), died (2)
Germander	Teucriumchamaedrys	35	49	11 (31.4)	France (28.5), Greece (22.8), United States (14.2)	Jaundice (77.1), nausea (17.1), choluria (17.1), abdominal pain (17.1)	1091	1127	251	183	13.7	9.1	13 (40.6)	Hepatocellular (94.2), mixed (5.7)	12	Udca (15.7), vit K (13.1), liver transplantation (5.2), supportive care (65.7)	Recovery (97.1), died (2.8)
Skullcap	Scutellaria spp.	35	54	9 (25.7)	United States (45.7), Australia (14.2), Scotland (11.4)	Jaundice (68), nausea (15.3), choluria (20)	859	1234	227	359	14	NA	12 (67.7)	Hepatocellular (74.2), CHOLESTATIC (5.7), MIxed (14.2)	9	Liver transplantation (11.1), corticoid (2.7), udca (2.7), supportive care (77.7)	Recovery (85.7), died (14.2)
Kratom	Mitragyna speciosa	33	36	20 (62)	United States (75), Canada (6.2), Sweden (6.2)	Jaundice (70), choluria (53.3), abdominal pain (43.5), nausea (23.3), fatigue (23.3)	1125	957	304	258	11.7	11.3	11 (39.2)	Hepatocellular (45.4), cholestatic (27.2), mixed (21.2)	11	Acetylcysteine (12.7), udca (7.6), corticoid (5.1), liver transplantation (5.1), supportive care (48.7)	Recovery (90.6), died (9.3)
Tusanqi or Jusanqi	Gynura segetum	29	54	14 (48.2)	China (75.8), Hong Kong (20.6), New Zeeland (3.4)	Ascites (100), hepatomegaly (86.9), jaundice (26)	469	460	NA	NA	1	0.5	1 (50)	Sinusoidal obstruction syndrome (100)	4	Glutathione (6.6), antibiotics (6.6), furosemide (6.6), supportative care (80)	Recovery (50), chronification (22.2), died (27.7)
Garcinia cambogia; Malabar tamarind	Garcinia gummi-gutta	29	45	3 (10.3)	United States (39.2), Italy (35.7)	Abdominal pain (56), jaundice (44), nausea (40), vomiting (24), fatigue (16)	1918	1927	243	249	10.9	7.5	12 (50)	Hepatocellular (86.2), cholestatic (10.3), mixed (3.4)	10	Liver transplantation (20.6), acetylcysteine (10.3), corticoid (3.5), supportive care (65.5)	Recovery (96.6), died (3.4)
Ma huang	Ephedra sinica	27	44	8 (32)	United States (68), South Korea (12), United Kingdom (8)	Abdominal Pain (72.7), nausea (63.6), jaundice (54.5), fatigue (45.4), hepatomegaly (36.3)	3173	2092	188	161	12.5	NA	10 (55.5)	Hepatocellular (96), mixed (4)	9	Liver transplantation (19.2), corticoid (3.8), urine alkalization (3.8), hemodialysis (3.8), diuretics (3.8), suportive care (65.3)	Recovery (92), died (8)
Chaparral	Larrea tridentata	26	44	9 (34.6)	United States (80.7), Australia (7.6), Canada (7.6)	Jaundice (84), abdominal pain (40), fatigue (36), nausea (28), pruritus (24)	1300	1081	189	317	17.7	9.6	10 (43.4)	Hepatocellular (84.6), steatosis (15.3)	11	Corticoid (7.6), liver transplantation (7.6), vit K (3.8), supportive care (80.7)	Recovery (92.3), died (7.6)
Senna; Sene	Senna spp.	25	33	5 (21.7)	India (24), Italy (16), Yemen (16)	Jaundice (43.4), abdominal pain (34.7), encephalopathy (20), asthenia (20), choluria (13)	1637	1688	477	128	7.4	5.1	7 (50))	Hepatocellular (84), cholestatic (4), mixed (12)	10	Antibiotics (9.6), vit K (12.9), lactulose (6.4), liver transplantation (3.2), acerylcysteine (3.2), supportive care (58)	Recovery (81.8), died (18.1)
Aloe Vera	Aloe vera	22	50	5 (22.7)	South Korea (18.1), Spain (9), Usa (9)	Abdominal pain (50), jaundice (40.9), fatigue (31.8), nausea (27.2)	1762	1300	414	167	10.1	8.7	11 (52.3)	Hepatocellular (86.3), cholestatic (4), mixed (9)	11	Antibiotics (4.1), liver transplantation (4.1), vit K (4.1), hemodialysis (4.1), supportive care (75)	Recovery (85.7), chronification (4.7), died (9.5)
Jin Bu Huan	Lycopodium serratum	19	46	2 (10.5)	United States (73.6), Canada (10.5), Italy (10.7)	Fatigue (52.6), hepatomegaly (42.1), pruritus (36.8), jaundice (31.)	596	1057	231	185	7.5	NA	6 (40)	Hepatocellular (84.2), cholestatic (5.2), mixed (10.5)	13	Cholestyramine (15.7), supportive care (84.2)	Recovery (100)

ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; GGT: Gamma-glutamyl transferase; BT: Total bilirubin; BD: Direct bilirubin; NA: Not available; UDCA: Ursodeoxycholic acid.