Comprehensive review of hepatotoxicity associated with traditional Indian Ayurvedic herbs

Table 1 A summary of all Ayurvedic herbs implicated in liver injury with potential mechanisms of toxicity, liver injury pattern, histopathology patterns and clinical outcomes

Ayurvedic herb	Author/study /country	Pattern of liver injury (hepatocellular, cholestatic or mixed type)	Liver biopsy features	Suspected potential toxic component (s)	Clinical outcomes and comments
Withania somnifera (Ashwagandha)	Inagaki et al[10]/report/Japan	Cholestatic type	Intrahepatic cholestasis, canalicular bile plugs	Unclassified triterpenoids	Resolved, survived
	Björnsson et al[11]/series (n = 5)/Iceland and United States	Cholestatic and mixed type	Cholestatic hepatitis		Resolved, survived
Bacopa monnieri, Centella asiatica (Brahmi or Gotu-kola)	Teschke et al[14]/report/Germany	Hepatocellular type	Not performed	Saponin triterpenoids. phytoglycosides, autoantibody or immune-mediated	Resolved, survived. However, multiple other associated herbals used
	Jorge et al[17]/series (n = 3)/Argentina	Mixed type	Granulomatous cholestatic hepatitis		One patient progressed to cirrhosis and acute decompensation on repeat herb intake; in another, complete resolution noted
	Dantuluri et al[18]/report/United Kingdom	Hepatocellular type	Not performed		Acute liver failure, spontaneous resolution, survived
Curcuma longa (Turmeric)	Lukefahr et al[22]/ report/United States	Hepatocellular type	Autoimmune hepatitis	Immunomodulatory polyphenolic compounds, drug triggered autoantibodies related liver injury	Complete resolution
	Suhail et al[23]/report/United States	Hepatocellular type	Acute panlobular hepatitis with early parenchymal collapse		Complete resolution in 3 wk
	Lee et al[24]/report/United States	Hepatocellular type	Autoimmune hepatitis with additional eosinophilic and neutrophilic interface hepatitis		Complete resolution
	Imam et al[25]/report/United States	Hepatocellular type	Not performed		Complete resolution
	Luber et al[26]/two patient report/Australia	Mixed type in first case and hepatocellular type in second patient	Biopsy performed in first case showed mixed lobular inflammation and severe interface hepatitis; biopsy not performed in case two		Complete resolution in both patients, autoantibodies positive in second patient
	Chand et al[27]/report/Australia	Hepatocellular type	Acute hepatitis with mixed inflammatory infiltrate of lobules and interface hepatitis with focal necrosis and mild cholestasis		Complete resolution, no autoantibodies noted, but high immunoglobulin G was remarkable
Guggul / Guggulipids (as part of polyherbal formulations and weight loss supplements)	Grieco et al[29]/report/Italy	Hepatocellular type	Necroinflammation with lobular eosinophilic inflammation	Guggul sterols associated herb-herb and herb-drug interaction; no direct hepatotoxicity described	Complete resolution
	Yellapu et al[30]/report/United States	Hepatocellular type	Massive hepatic necrosis		Acute liver failure necessitating cadaveric liver transplantation
	Polavarappu et al[31]/report/United States	Hepatocellular type	Not performed		Spontaneous resolution on drug withdrawal
	Dalal et al[32]/report/United States	Hepatocellular type	Mixed portal inflammation, interface hepatitis, eosinophilic lobular inflammation with ceroid laden macrophages		Spontaneous resolution on drug withdrawal
Psoralea corylifolia (Bakuchi, Babchi seeds)	Nam et al[34]/report/South Korea	Mixed type	Zone 3 necrosis, cholestasis and severe mixed inflammatory infiltration of lobules	Terpenoids like bakuchiol and coumarinoids	Complete clinical resolution
	Cheung et al[35]/series (n = 3)/	Hepatocellular type	Not performed		All three patients had uneventful recovery after drug withdrawal
	Smith et al[36]/report/United Kingdom	Hepatocellular type	Cholestatic acute hepatitis		Clinical resolution on drug withdrawal
Cassia angustifolio (Indian Senna)	Beuers et al[41]/report/Germany	Mixed type	Perivenular necrosis, lymphohistiocytic portal and lobular inflammation	Anthracoid sennoside and rhein anthron metabolites	Complete resolution, recurrence on rechallenge
	Sonmez et al[42]/report/Turkey	Mixed type	Bridging hepatocellular necrosis and canalicular cholestasis		Complete resolution
	Seybold et al[43]/report/Germany	Hepatocellular type	Not performed		Complete resolution
	Vanderperren et al[44]/Belgium	Hepatocellular type	Not performed	High amounts of cadmium on toxicology evaluation	Acute liver failure with renal failure, resolved on aggressive supportive care
Aloe vera	Rabe et al[52]/report/Germany	Cholestatic type	Portal and lobular lymphoplasmacytic inflammation, eosinophilic granulomas, bridging necrosis and bilirubinostasis	Aloe alkaloids, anthraquinones	Complete resolution on herbal drug withdrawal
	Parlati et al[53]/report and review series (n = 9)/France	Hepatocellular type	All patients had portal and lobular inflammation with neutrophils and lymphoplasmacytes along with granulomas, acidophil bodies, ballooning of hepatocytes, extensive bridging necrosis and bilirubinostasis		All cases had clinical resolution of symptoms, no acute liver failure and no chronicity noted on follow up
	Manso et al[56]/series on Herbalife® products/Spain	Hepatocellular type	Cholestatic hepatitis		Complete resolution after supplement withdrawal
	Vázquez-Fernández et al[57]/report/Spain	Cholestatic type	Cholestatic hepatitis with lymphocyte predominant portal inflammation		Acute decompensation of cirrhosis (underlying HCV related infection); outcome not reported
Morinda citrifolia (Noni juice)	Millonig et al[59]/report/Austria	Hepatocellular type	Severe mixed inflammatory infiltration of portal tracts with lobular eosinophilic inflammation and hepatocellular cholestasis in zone 3	Suspected noni anthraquinones	Complete resolution on herbal medicine withdrawal
	Stadlbauer et al[60] / two cases report/Austria	Both cases hepatocellular type	First case, confluent necrosis, second case centrilobular necrosis and mild inflammatory infiltration in both		First patient progressed to acute liver failure and underwent successful liver transplantation; second patient had complete clinical recovery on conservative care
	Yu et al[61]/report/United States	Hepatocellular type	Acute hepatitis with portal inflammation and periportal necrosis, hepatocellular cholestasis and numerous eosinophils in lobules		Paediatric case (14-year-old boy) with complete recovery on supportive care
Heliotropium sp., Trichodesma sp., Eupatorium sp., Senecia sp., Crotalaria sp. Chelidonium majus sp., Castilleja sp. Holarrhena antidysenterica	Neuman et al[66]/review series > 30 cases/Canada	Hepatocellular and mixed type	Early pathologic changes include the deposition of fibrinogen and factor VIII within the venular walls and liver sinusoids. In acute stage, haemorrhage into markedly dilated sinusoids with hepatocyte atrophy is noted, the sinusoids become denuded, parenchymal collapse is evident followed by the constriction and obliteration of small central veins by subendothelial swelling or fibrosis. The sinusoidal fibrosis and nodular regeneration may occur leading to cirrhosis and portal hypertension at later stages	Pyrrolizidine alkaloids	The acute form is rapidly fatal in 20% to 40% of patients. Adults have worse prognosis that the paediatric age group. Approximately 15% with acute disease will progress to subacute or chronic injury, and develop end-stage liver disease in a few years.
Garcinia cambogia (Malabar Tamarind)	Crescoli et al[71] and Kothadia et al[72]/case series review, n = 66/	Hepatocellular type	Acute hepatitis with necroinflammation and parenchymal collapse is commonly noted on histopathology	Hydroxycitric acid and adulteration with heavy metals and other toxic ingredients	Commonly self-limiting even after a prolonged course; acute liver failure and acute on chronic liver failure leading to death described; in liver failure, transplantation has been performed to increase survival; chronic and prolonged DILI has been described leading to cirrhosis and portal hypertension
Gymnema sylvestre (Gurmar or sugar destroyer)	Shiyovich et al[74] and Dara et al[75]/series of patients including those consuming herbal and dietary supplements such as Hydroxycut® containing Gymnema	Mixed type	Necroinflammation of the lobules and portal regions with marked ductular proliferation and neutrophilic infiltration of the portal areas	Triterpene saponins, gymnemic acids and polyalkaloids	Usually self-limiting with complete resolution after herbal drug withdrawal
Tribulus Terrestis (Gokshura or Puncture vine)	Talasaz et al[77] and Ryan et al[78] /reports / Iran and United States respectively	Hepatocellular type	Not performed	Phylloerythrin and beta-carboline alkaloids are suspected toxins	Associated with seizures and acute kidney injury (mostly bile cast nephropathy); usually self-limiting and responsive to conservative care
Valeriana officinalis (Valerian)	MacGregor et al[81] series (n = 4) /Edinburgh	Hepatocellular type	Not performed	Suspected toxins include valerian alkaloids and sesquiterpenes	All patients had uneventful recovery after drug withdrawal and supportive care
	Cohen et al[82]/report/United States	Cholestatic type	Not performed
	Vassiliadis et al[83] /report/Greece	Hepatocellular type	Lymphocytic and eosinophilic portal inflammation with perivenular necrosis and small bile duct damage
	Duoros et al[84]/series (n = 5)/Berlin	Hepatocellular and mixed type	Extensive necrosis, lobular and portal severe necroinflammation with neutrophils, lymphocytes and eosinophils

HCV: Hepatitis C virus; DILI: Drug-induced liver injury.