herbal and dietary supplement (hds) hepatotoxicity hds... · herbal and dietary supplement (hds)...

Herbal and Dietary Supplement (HDS) Hepatotoxicity

ผศ.นพ. เฉลมิรฐั บญัชรเทวกลุ Division of Gastroenterology and Hepatology

Rajavithi Hospital, Bangkok, Thailand

Scope of My Talk • Overview of HDS from around the world • Epidemiology of HDS hepatotoxicity • Diagnosis and causality assessment of

HDS hepatotoxicity • Clinical features of each particular HDS

hepatotoxicity (both from the Western and Eastern Countries)

• Herb-drug interactions

Acknowledgement

Professor Rajender K. Reddy, MD. – Professor of Medicine – Professor of Medicine in Surgery – Director of Hepatology – Director, Center for Viral Hepatitis – University of Pennsylvania, Philadelphia, USA

รศ.ดร. นพมาศ สนุทรเจรญินนท ์

– ผูเ้ชี�ยวชาญดา้นสมนุไพร

– ภาควชิาเภสชัวนิจิฉยั

– คณะเภสชัศาสตร ์มหาวทิยาลยัมหดิล

Types of Herbal and Dietary Supplements

Herbs Vitamins, minerals, antioxidants, nutrients, immune modulators

Single ingredient

Mixtures

Examples • Chinese herbal medicine • Indian ayurvedic medicine • Thai herbal medicine • Herbalife®

• Crude (e.g. roots, leaves, seeds, Crude (e.g. roots, leaves, seeds, Crude (e.g. roots, leaves, seeds, Crude (e.g. roots, leaves, seeds,

tea, tea, tea, tea, ยาหมอยาหมอยาหมอยาหมอ, , , , น้ําหมักน้ําหมักน้ําหมักน้ําหมัก) ) ) )

• Extracts/commercial products Extracts/commercial products Extracts/commercial products Extracts/commercial products

(e.g. tablets, capsules, defined (e.g. tablets, capsules, defined (e.g. tablets, capsules, defined (e.g. tablets, capsules, defined

formulations)formulations)formulations)formulations)

Examples • Silymarin • Senna

Use of HDS in the USA • ~19% of US adults used HDS during previous

12 months (NHIS CAM survey in 2002) • Represent a $180 billion market in US • Americans spend more than $6 billion

annually on nutritional supplements, and $1 billion on herbs and teas

• Increasing use by US public has been document by many surveys

• 20-40% did not disclose the use of HDS to their Physicians

Verma S. Thuluvath PJ. Clin Gastroenterol Hepatol 2007;5:408-416 Kenedy J. Clin Ther 2005;27:1847-58

Use of Complementary and Alternative Medicine (CAM) in Patients with Liver Disease

Strader DB, et al. Am J Gastroenterol 2002;97:2391-7

21%

13%

39% Used CAM in the preceding month (26% did not inform their physician)

Used herbal preparations (milk thistle = most common 12%)

Used herbs to treat their liver disease

0

10

20

30

40

50

%

989 patients from 6 geographically diverse Liver Cl inics in the US

CAM Herbs

Why Patients Use HDS ?

• Limitation of conventional therapies • Paradigm shift to natural products • Perception that HDS is safer and cheaper

form of therapy • Embracing a more holistic and spiritual

orientation to life • Had transformation experience • False/overstate advertising claims • Marketing (online, direct selling)

Astin JA. JAMA 1998;279:1548-53 Verma S, Thuluvath PJ. Clin Gastroenterol Hepatol 2007;5:408-16

http://morsengrich.blogspot.com

Health Risks of Herbal Remedies • Self treatment and diagnosis • Hepatotoxicity and/or toxicity to other organ

systems – Dose-dependent, idiosyncrasy, immunoallergic

• Herb-drug interactions • Contaminations: preparation, storage

– Infectious agents: e.g. bacteria, fungus – Toxins: e.g. aflatoxin – Heavy metals: e.g. arsenic, mercury, lead – Synthetic drugs: steroids, NSAIDs, antivirals

Epidemiology: HDS Hepatotoxicity • The true prevalence is unknown

– No strict regulations and surveillance – Data taken from anecdotal case reports, case

series, and prospective DILI registries – Seems to be high, but is underreported

• The incidence is variable – Overall seems to be low – Few RCT and prospective studies – Chinese traditional medicine

• Prospective study of 1,507 patient*: ~1% developed Prospective study of 1,507 patient*: ~1% developed Prospective study of 1,507 patient*: ~1% developed Prospective study of 1,507 patient*: ~1% developed ↑ALT >2 ↑ALT >2 ↑ALT >2 ↑ALT >2 xULNxULNxULNxULN; only 2 patients were symptomatic; only 2 patients were symptomatic; only 2 patients were symptomatic; only 2 patients were symptomatic

Bunchorntavakul C. Reddy KR. Aliment Pharmacol Ther 2013;37:3-17 *Melchart D, et al. JAMA 1999;282:28-9

ReportsReportsReportsReports Country / Patient characteristicsCountry / Patient characteristicsCountry / Patient characteristicsCountry / Patient characteristics Prevalence Prevalence Prevalence Prevalence Features and prognosis of Features and prognosis of Features and prognosis of Features and prognosis of

HDS HepatotoxicityHDS HepatotoxicityHDS HepatotoxicityHDS Hepatotoxicity

Ibunez

et al.

Spain (1993–1998)

N = 103; DILI

Population-based, prospective

11%

64% hepatocellular injury

18% mixed injury

18% cholestasis injury

Andrade

et al.

Spain (1994–2004)

N = 446; DILI

Multi-centre, prospective

2%

89% hepatocellular

11% cholestasis

56% hospitalized; 11% death

Chalasani

et al.

USA (2003–2008)

N = 300; DILI


9%

63% hepatocellular

17% cholestasis; 21% mixed

41% hospitalized

6% ALF; 9% chronic DILI

Suk

et al.

Korea (2005–2007)

N = 371; DILI


73%

78% hepatocellular

10% cholestasis; 12% mixed

1.5% death or LT

Wai

et al.

Singapore (2004–2006)

N = 31; DILI


71%

74% hepatocellular

19% cholestasis

7% mixed injury

Prevalence of HDS Hepatotoxicity in DILI Registry

Adapted from Bunchorntavakul C. Reddy KR. Aliment Pharmacol Ther 2013;37:3-17

ReportsReportsReportsReports Countries / Countries / Countries / Countries / ptptptpt characteristicscharacteristicscharacteristicscharacteristics Prevalence of HDS Prevalence of HDS Prevalence of HDS Prevalence of HDS

hepatotoxicityhepatotoxicityhepatotoxicityhepatotoxicity OutcomesOutcomesOutcomesOutcomes

Russo

et al.

USA (1990–2002)

N = 270; ALF from drug

Retrospective, UNOS data

5.1% All underwent LT

Reuben

et al.

USA (1998–2007)

N = 133; ALF from drug


10%

21% spontaneous

recovery

50% underwent LT

29% death

Estes

et al.

USA (2001-2002)

N=20, ALF

Single-center, retrospective

50% 60% underwent LT

Prevalence of HDS Hepatotoxicity in ALF Registry

Bunchorntavakul C. Reddy KR. Aliment Pharmacol Ther 2013;37:3-17

Difficulties in the Diagnosis and Causality Difficulties in the Diagnosis and Causality Difficulties in the Diagnosis and Causality Difficulties in the Diagnosis and Causality

Assessment of HDS HepatotoxicityAssessment of HDS HepatotoxicityAssessment of HDS HepatotoxicityAssessment of HDS Hepatotoxicity

• Lack of scientific testing and data • Numerous combinations • Unknown active ingredient(s) and other

non -standardized ingredient(s) • Production/manufacturing variability • Contaminations • Mislabeling • Unqualified practitioners • Concomitant medications and liver disease

Diagnosis and Causality Assessment of Diagnosis and Causality Assessment of Diagnosis and Causality Assessment of Diagnosis and Causality Assessment of

HDS HepatotoxicityHDS HepatotoxicityHDS HepatotoxicityHDS Hepatotoxicity

• High index of suspicion • Detailed history on all HDS used and timing • Examination of HDS and its label • Prompt recognition of known common

culprit HDS and their hepatotoxicity patterns • Liver biopsy – not specific • Exclusion of other cause(s) of liver disease • DILI scoring system: CIOMS/RUCAM,

Maria & Victorino, HDS -CAT (HDS-specific)*

Bunchorntavakul C. Reddy KR. Aliment Pharmacol Ther 2013;37:3-17 * Proposed by Navarro VJ, et al. in the EASL Meeting 2012

Pyrrolizidine Alkaloids (PA)Pyrrolizidine Alkaloids (PA)Pyrrolizidine Alkaloids (PA)Pyrrolizidine Alkaloids (PA)

• One of the most important and common One of the most important and common One of the most important and common One of the most important and common plant toxin associated with liver injuryplant toxin associated with liver injuryplant toxin associated with liver injuryplant toxin associated with liver injury

• Found in >350 plant species worldwideFound in >350 plant species worldwideFound in >350 plant species worldwideFound in >350 plant species worldwide – Jamaica bush tea, robage, coltsfoot, Jamaica bush tea, robage, coltsfoot, Jamaica bush tea, robage, coltsfoot, Jamaica bush tea, robage, coltsfoot,

Senecio, Comfrey, Senecio, Comfrey, Senecio, Comfrey, Senecio, Comfrey, Crotalaria spp. Crotalaria spp. Crotalaria spp. Crotalaria spp.

Heliotrope and some Chinese herbsHeliotrope and some Chinese herbsHeliotrope and some Chinese herbsHeliotrope and some Chinese herbs • Used: various conditionsUsed: various conditionsUsed: various conditionsUsed: various conditions • Metabolized by CYP450, forming pyrrole Metabolized by CYP450, forming pyrrole Metabolized by CYP450, forming pyrrole Metabolized by CYP450, forming pyrrole

derivatives (dosederivatives (dosederivatives (dosederivatives (dose----dependent hepatotoxin)dependent hepatotoxin)dependent hepatotoxin)dependent hepatotoxin) • Types of liver injuryTypes of liver injuryTypes of liver injuryTypes of liver injury

– VenoVenoVenoVeno----occlusive disease (VOD)occlusive disease (VOD)occlusive disease (VOD)occlusive disease (VOD) – Carcinogenesis Carcinogenesis Carcinogenesis Carcinogenesis –––– HCC ?HCC ?HCC ?HCC ?

Bunchorntavakul C. Reddy KR. Aliment Pharmacol Ther 2013;37:3-17 Stickel F, et al. J Hepatol 2005;43:901-910; Schiano TD. Clin Liver Dis 2003;7:453-473

หญางวงชาง หญางวงชาง หญางวงชาง หญางวงชาง ((((Heliotropium indicum) Heliotropium indicum) Heliotropium indicum) Heliotropium indicum)

ตนหิ่งหายตนหิ่งหายตนหิ่งหายตนหิ่งหาย (Crotalaria verrucosa) (Crotalaria verrucosa) (Crotalaria verrucosa) (Crotalaria verrucosa)

ปอเทือง ปอเทือง ปอเทือง ปอเทือง ((((Crotalaria juncea) Crotalaria juncea) Crotalaria juncea) Crotalaria juncea)

PAPAPAPA----Containing Plants in ThailandContaining Plants in ThailandContaining Plants in ThailandContaining Plants in Thailand

Clinical Features of PAClinical Features of PAClinical Features of PAClinical Features of PA----related VODrelated VODrelated VODrelated VOD

• Clinical onset (acute, Clinical onset (acute, Clinical onset (acute, Clinical onset (acute,

subacute or chronic) and subacute or chronic) and subacute or chronic) and subacute or chronic) and

severity are variableseverity are variableseverity are variableseverity are variable

• Ascites, hepatomegaly, Ascites, hepatomegaly, Ascites, hepatomegaly, Ascites, hepatomegaly,

edema, liver dysfunctionedema, liver dysfunctionedema, liver dysfunctionedema, liver dysfunction

• Liver histology: nonLiver histology: nonLiver histology: nonLiver histology: non----

thrombotic occlusion of small thrombotic occlusion of small thrombotic occlusion of small thrombotic occlusion of small

terminal hepatic venules, terminal hepatic venules, terminal hepatic venules, terminal hepatic venules,

leading to sinusoidal leading to sinusoidal leading to sinusoidal leading to sinusoidal

dilatation and centrilobular dilatation and centrilobular dilatation and centrilobular dilatation and centrilobular

necrosisnecrosisnecrosisnecrosis


PA: Mechanism of HepatotoxicityPA: Mechanism of HepatotoxicityPA: Mechanism of HepatotoxicityPA: Mechanism of Hepatotoxicity

Stickel F, et al. J Hepatol 2005;43:901-910

• Enzymatic transformation of pyrrolizidine alkaloids into nontoxic alkaloid NEnzymatic transformation of pyrrolizidine alkaloids into nontoxic alkaloid NEnzymatic transformation of pyrrolizidine alkaloids into nontoxic alkaloid NEnzymatic transformation of pyrrolizidine alkaloids into nontoxic alkaloid N----oxidesoxidesoxidesoxides

• Comedication with microsomal enzyme inducers (e.g. phenobarbital) favors the Comedication with microsomal enzyme inducers (e.g. phenobarbital) favors the Comedication with microsomal enzyme inducers (e.g. phenobarbital) favors the Comedication with microsomal enzyme inducers (e.g. phenobarbital) favors the

formation of toxic pyrroles by several microsomal CYP450 enzymesformation of toxic pyrroles by several microsomal CYP450 enzymesformation of toxic pyrroles by several microsomal CYP450 enzymesformation of toxic pyrroles by several microsomal CYP450 enzymes

CYP 3A4CYP 3A4CYP 3A4CYP 3A4

CYP 2B6CYP 2B6CYP 2B6CYP 2B6

CYP 2CCYP 2CCYP 2CCYP 2C

• Acute form Acute form Acute form Acute form

– 20202020----40404040% Death% Death% Death% Death

– 50505050% Complete recovery % Complete recovery % Complete recovery % Complete recovery

– 15151515----20202020% Protracted disease % Protracted disease % Protracted disease % Protracted disease –––– progressive progressive progressive progressive

perivenular and bridging fibrosis, and some may perivenular and bridging fibrosis, and some may perivenular and bridging fibrosis, and some may perivenular and bridging fibrosis, and some may

die from ESLD several years laterdie from ESLD several years laterdie from ESLD several years laterdie from ESLD several years later

• Subacute or chronic onset: smaller proportion Subacute or chronic onset: smaller proportion Subacute or chronic onset: smaller proportion Subacute or chronic onset: smaller proportion

• ManagementManagementManagementManagement

– Mainly supportive; consider OLT for ALF or ESLDMainly supportive; consider OLT for ALF or ESLDMainly supportive; consider OLT for ALF or ESLDMainly supportive; consider OLT for ALF or ESLD

– ? Defibrotide ? Defibrotide ? Defibrotide ? Defibrotide –––– no data in PAno data in PAno data in PAno data in PA----related VODrelated VODrelated VODrelated VOD

Prognosis and Rx of PAPrognosis and Rx of PAPrognosis and Rx of PAPrognosis and Rx of PA----related VODrelated VODrelated VODrelated VOD


Germander Germander Germander Germander (Teucrium chamaedrys)(Teucrium chamaedrys)(Teucrium chamaedrys)(Teucrium chamaedrys)

• Europe and Middle EastEurope and Middle EastEurope and Middle EastEurope and Middle East

• Used: fever, dyspepsia, etc.Used: fever, dyspepsia, etc.Used: fever, dyspepsia, etc.Used: fever, dyspepsia, etc.

• FuranFuranFuranFuran----containing diterpenoids containing diterpenoids containing diterpenoids containing diterpenoids

–––– cytotoxic and carcinogeniccytotoxic and carcinogeniccytotoxic and carcinogeniccytotoxic and carcinogenic

• Types of liver injuryTypes of liver injuryTypes of liver injuryTypes of liver injury

– Acute hepatitis Acute hepatitis Acute hepatitis Acute hepatitis

(occur few months after use)(occur few months after use)(occur few months after use)(occur few months after use)

– Massive centrilobular Massive centrilobular Massive centrilobular Massive centrilobular

necrosis necrosis necrosis necrosis –––– ALFALFALFALF

– Cirrhosis Cirrhosis Cirrhosis Cirrhosis

Bunchorntavakul C. Reddy KR. Aliment Pharmacol Ther 2013;37:3-17 Larrey D, et al. Ann Intern Med 1992;117:129-32; Laliberte L, et al. CMAJ 1996;154:1689-92

Germander: Mechanism of HepatotoxicityGermander: Mechanism of HepatotoxicityGermander: Mechanism of HepatotoxicityGermander: Mechanism of Hepatotoxicity

Stickel F, et al. J Hepatol 2005;43:901-910

• CYP450 3A activates furane CYP450 3A activates furane CYP450 3A activates furane CYP450 3A activates furane

neoneoneoneo----clerodane diterpenoids clerodane diterpenoids clerodane diterpenoids clerodane diterpenoids

contained in germander into contained in germander into contained in germander into contained in germander into

toxic epoxides, which may toxic epoxides, which may toxic epoxides, which may toxic epoxides, which may

be neutralized by be neutralized by be neutralized by be neutralized by

conjugation with glutathioneconjugation with glutathioneconjugation with glutathioneconjugation with glutathione

• In conditions of glutathione In conditions of glutathione In conditions of glutathione In conditions of glutathione

deficiency (as in starvation), deficiency (as in starvation), deficiency (as in starvation), deficiency (as in starvation),

epoxides may react with epoxides may react with epoxides may react with epoxides may react with

hepatic proteins and lead to hepatic proteins and lead to hepatic proteins and lead to hepatic proteins and lead to

liver cell death through the liver cell death through the liver cell death through the liver cell death through the

induction of apoptosisinduction of apoptosisinduction of apoptosisinduction of apoptosis

Greater Celandine Greater Celandine Greater Celandine Greater Celandine ((((Chelidonium majusChelidonium majusChelidonium majusChelidonium majus))))

• Found mainly in EuropeFound mainly in EuropeFound mainly in EuropeFound mainly in Europe

• Used: biliary disease, IBSUsed: biliary disease, IBSUsed: biliary disease, IBSUsed: biliary disease, IBS

• Contains several alkaloidsContains several alkaloidsContains several alkaloidsContains several alkaloids


– Acute hepatitis (within Acute hepatitis (within Acute hepatitis (within Acute hepatitis (within 3 3 3 3 mo)mo)mo)mo)

• ImmuneImmuneImmuneImmune----mediated (AIHmediated (AIHmediated (AIHmediated (AIH----like ?)like ?)like ?)like ?) • Histology Histology Histology Histology –––– portal inflammation portal inflammation portal inflammation portal inflammation

and eosinophilic infiltratesand eosinophilic infiltratesand eosinophilic infiltratesand eosinophilic infiltrates – Chronic hepatitis, cirrhosisChronic hepatitis, cirrhosisChronic hepatitis, cirrhosisChronic hepatitis, cirrhosis

– CholestasisCholestasisCholestasisCholestasis


Chaparral Chaparral Chaparral Chaparral (Larrea tridentata)(Larrea tridentata)(Larrea tridentata)(Larrea tridentata)

• Leaves of desert bush: Leaves of desert bush: Leaves of desert bush: Leaves of desert bush:

Greasewood (found in Greasewood (found in Greasewood (found in Greasewood (found in

California and Mexico)California and Mexico)California and Mexico)California and Mexico)

• Used: various conditions e.g. Used: various conditions e.g. Used: various conditions e.g. Used: various conditions e.g.

pain, cancer, wt. reduction pain, cancer, wt. reduction pain, cancer, wt. reduction pain, cancer, wt. reduction


– Hepatitis (zone 3 necrosis): Hepatitis (zone 3 necrosis): Hepatitis (zone 3 necrosis): Hepatitis (zone 3 necrosis): 3333----52 wk after ingestion 52 wk after ingestion 52 wk after ingestion 52 wk after ingestion

– ALFALFALFALF – CirrhosisCirrhosisCirrhosisCirrhosis


Black Cohosh Black Cohosh Black Cohosh Black Cohosh

• Actaea racemosa Actaea racemosa Actaea racemosa Actaea racemosa andandandandCimicifuga Cimicifuga Cimicifuga Cimicifuga

racemosaracemosaracemosaracemosa (found in the Eastern (found in the Eastern (found in the Eastern (found in the Eastern

US and Canada)US and Canada)US and Canada)US and Canada)

• Used: postUsed: postUsed: postUsed: post----menopausal symptoms menopausal symptoms menopausal symptoms menopausal symptoms

• Contains triterpene glycerides, Contains triterpene glycerides, Contains triterpene glycerides, Contains triterpene glycerides,

phenolic acids, flavonoids, phenolic acids, flavonoids, phenolic acids, flavonoids, phenolic acids, flavonoids,

volatile oils, and taninsvolatile oils, and taninsvolatile oils, and taninsvolatile oils, and tanins


– Acute hepatitis and ALFAcute hepatitis and ALFAcute hepatitis and ALFAcute hepatitis and ALF

– AIHAIHAIHAIH----like hepatitislike hepatitislike hepatitislike hepatitis


Pennyroyal OilPennyroyal OilPennyroyal OilPennyroyal Oil

• Squawmint orSquawmint orSquawmint orSquawmint or mosquito plant mosquito plant mosquito plant mosquito plant ((((พืชวงศกะเพรา หรือ วงศมิ้นตพืชวงศกะเพรา หรือ วงศมิ้นตพืชวงศกะเพรา หรือ วงศมิ้นตพืชวงศกะเพรา หรือ วงศมิ้นต))))

• Used: abortifacient, pesticideUsed: abortifacient, pesticideUsed: abortifacient, pesticideUsed: abortifacient, pesticide

• Centrilobular necrosis Centrilobular necrosis Centrilobular necrosis Centrilobular necrosis

– CYPCYPCYPCYP450450450450----induced toxic metabolite of induced toxic metabolite of induced toxic metabolite of induced toxic metabolite of menthofuran → induces reactive menthofuran → induces reactive menthofuran → induces reactive menthofuran → induces reactive metabolites and GSH depletionmetabolites and GSH depletionmetabolites and GSH depletionmetabolites and GSH depletion

– ALF, multiorgan failure can occurALF, multiorgan failure can occurALF, multiorgan failure can occurALF, multiorgan failure can occur

• Theoretically, replacement of GSH Theoretically, replacement of GSH Theoretically, replacement of GSH Theoretically, replacement of GSH

by NAC may helpby NAC may helpby NAC may helpby NAC may help


Chinese Herbal MedicinesChinese Herbal MedicinesChinese Herbal MedicinesChinese Herbal Medicines

• Widely used by Asia and Widely used by Asia and Widely used by Asia and Widely used by Asia and

Asian communities Asian communities Asian communities Asian communities

throughout the worldthroughout the worldthroughout the worldthroughout the world

• Usually in combination formUsually in combination formUsually in combination formUsually in combination form

– 3333----6 6 6 6 different herbs with a different herbs with a different herbs with a different herbs with a

primary active component primary active component primary active component primary active component

(King herbs)(King herbs)(King herbs)(King herbs)

• Contaminations with Contaminations with Contaminations with Contaminations with

synthetic drugs and heavy synthetic drugs and heavy synthetic drugs and heavy synthetic drugs and heavy

metals have been reportedmetals have been reportedmetals have been reportedmetals have been reported


Jin Bu Huan (Jin Bu Huan (Jin Bu Huan (Jin Bu Huan (Lycodium serratumLycodium serratumLycodium serratumLycodium serratum)))) สมุนไพรวงศสามรอยยอดหรือกูดขนสมุนไพรวงศสามรอยยอดหรือกูดขนสมุนไพรวงศสามรอยยอดหรือกูดขนสมุนไพรวงศสามรอยยอดหรือกูดขน

• Contains neuroactive substanceContains neuroactive substanceContains neuroactive substanceContains neuroactive substance • Used: sedative and analgesic Used: sedative and analgesic Used: sedative and analgesic Used: sedative and analgesic • Types of liver injuryTypes of liver injuryTypes of liver injuryTypes of liver injury

– Acute hepatitis Acute hepatitis Acute hepatitis Acute hepatitis • Duration Duration Duration Duration 7777----52 52 52 52 wk (mean wk (mean wk (mean wk (mean 20202020) after taking) after taking) after taking) after taking

• Eosinophilia and serum autoantibodies Eosinophilia and serum autoantibodies Eosinophilia and serum autoantibodies Eosinophilia and serum autoantibodies

may observe (immunemay observe (immunemay observe (immunemay observe (immune----mediated ?) mediated ?) mediated ?) mediated ?)

• Histology Histology Histology Histology –––– hepatitis, periportal necrosis hepatitis, periportal necrosis hepatitis, periportal necrosis hepatitis, periportal necrosis

and fibrosis, and microvesicular steatosisand fibrosis, and microvesicular steatosisand fibrosis, and microvesicular steatosisand fibrosis, and microvesicular steatosis

– Chronic hepatitisChronic hepatitisChronic hepatitisChronic hepatitis – Cholestasis or cholestatic hepatitisCholestasis or cholestatic hepatitisCholestasis or cholestatic hepatitisCholestasis or cholestatic hepatitis


MaMaMaMa----Haung (Haung (Haung (Haung (EphredaEphredaEphredaEphreda))))

• Sympathomimetic effectsSympathomimetic effectsSympathomimetic effectsSympathomimetic effects

• Used: nasal and sinus Used: nasal and sinus Used: nasal and sinus Used: nasal and sinus

congestion, bronchodilator, congestion, bronchodilator, congestion, bronchodilator, congestion, bronchodilator,

weight reduction, increased weight reduction, increased weight reduction, increased weight reduction, increased

athletic performance athletic performance athletic performance athletic performance


– Acute hepatitis (Acute hepatitis (Acute hepatitis (Acute hepatitis (3333----16 16 16 16 wk)wk)wk)wk)


– ALFALFALFALF

(1) Borum ML. AJG 2001;96:1654-5; (2) Nadir A. et al. AJG 1996;91:1436-8 (3) Schiano TD. Clin Liver Dis 2003;7:453-473; Skoulidis F, et al. EJGH 2005;17:581-4

DaiDaiDaiDai----SaikoSaikoSaikoSaiko----To, ShoTo, ShoTo, ShoTo, Sho----SaikoSaikoSaikoSaiko----To or TJTo or TJTo or TJTo or TJ----9999

• Consists of Consists of Consists of Consists of 7 7 7 7 herb components: herb components: herb components: herb components:

bupleurum root, pinellia tuber, bupleurum root, pinellia tuber, bupleurum root, pinellia tuber, bupleurum root, pinellia tuber,

scutellaria root, jujube fruit, scutellaria root, jujube fruit, scutellaria root, jujube fruit, scutellaria root, jujube fruit,

ginger rhizome, ginseng root, ginger rhizome, ginseng root, ginger rhizome, ginseng root, ginger rhizome, ginseng root,

and glycyrrhiza rootand glycyrrhiza rootand glycyrrhiza rootand glycyrrhiza root

• Used in China and Japan to Used in China and Japan to Used in China and Japan to Used in China and Japan to

treat liver disease treat liver disease treat liver disease treat liver disease


– Acute hepatitis (Acute hepatitis (Acute hepatitis (Acute hepatitis (1.51.51.51.5----3 3 3 3 mo)mo)mo)mo)



Lingzhi Mushroom, Lingzhi Mushroom, Lingzhi Mushroom, Lingzhi Mushroom, เห็ดหลนิจือเห็ดหลนิจือเห็ดหลนิจือเห็ดหลนิจือ((((Ganoderma lucidum )Ganoderma lucidum )Ganoderma lucidum )Ganoderma lucidum )

• One of the oldest medicinal mushroomOne of the oldest medicinal mushroomOne of the oldest medicinal mushroomOne of the oldest medicinal mushroom

• Used: cytoprotective, antiUsed: cytoprotective, antiUsed: cytoprotective, antiUsed: cytoprotective, anti----tumor, and tumor, and tumor, and tumor, and

antioxidantantioxidantantioxidantantioxidant

• Contains triterpenes (ganoderic acids) Contains triterpenes (ganoderic acids) Contains triterpenes (ganoderic acids) Contains triterpenes (ganoderic acids)

• 2 2 2 2 cases of severe hepatotoxicitycases of severe hepatotoxicitycases of severe hepatotoxicitycases of severe hepatotoxicity

– Both had taken powder formBoth had taken powder formBoth had taken powder formBoth had taken powder form

– Onset Onset Onset Onset 1111----2 2 2 2 mo after use mo after use mo after use mo after use

– LFT: severe hepatitis LFT: severe hepatitis LFT: severe hepatitis LFT: severe hepatitis ±±±± cholestasischolestasischolestasischolestasis

– One died / one recovered in One died / one recovered in One died / one recovered in One died / one recovered in 5 5 5 5 momomomo

Yeun MF, et al. J Hepatol 2004;41:686-7

Wanmuang H, et al. J Med Assoc Thai 2007;90:179-81

Lingzhi Mushroom HepatotoxicityLingzhi Mushroom HepatotoxicityLingzhi Mushroom HepatotoxicityLingzhi Mushroom Hepatotoxicity

• Liver histology: Liver histology: Liver histology: Liver histology: portal and lobular portal and lobular portal and lobular portal and lobular changes including changes including changes including changes including cholestasis [C], cholestasis [C], cholestasis [C], cholestasis [C], macrovesicular fatty macrovesicular fatty macrovesicular fatty macrovesicular fatty change [F], acidphilic change [F], acidphilic change [F], acidphilic change [F], acidphilic bodies [A] and bodies [A] and bodies [A] and bodies [A] and polymorphs [P]polymorphs [P]polymorphs [P]polymorphs [P]

• The presence of esoinophil infiltrations in the portal tracts The presence of esoinophil infiltrations in the portal tracts The presence of esoinophil infiltrations in the portal tracts The presence of esoinophil infiltrations in the portal tracts suggests that the mechanism of the hepatotoxicity is suggests that the mechanism of the hepatotoxicity is suggests that the mechanism of the hepatotoxicity is suggests that the mechanism of the hepatotoxicity is mediated through an immunoallergic reactionmediated through an immunoallergic reactionmediated through an immunoallergic reactionmediated through an immunoallergic reaction

Yeun MF, et al. J Hepatol 2004;41:686-7

Ayurvedic Herbal MedicineAyurvedic Herbal MedicineAyurvedic Herbal MedicineAyurvedic Herbal Medicine

• Generally consists of numerous plants; may Generally consists of numerous plants; may Generally consists of numerous plants; may Generally consists of numerous plants; may

combination with metals, minerals and gemscombination with metals, minerals and gemscombination with metals, minerals and gemscombination with metals, minerals and gems


– Acute and chronic hepatitisAcute and chronic hepatitisAcute and chronic hepatitisAcute and chronic hepatitis

– Worsening of cirrhosis (Liv.Worsening of cirrhosis (Liv.Worsening of cirrhosis (Liv.Worsening of cirrhosis (Liv.52525252)*)*)*)*

• Extrahepatic symptoms are commonExtrahepatic symptoms are commonExtrahepatic symptoms are commonExtrahepatic symptoms are common

Bunchorntavakul C. Reddy KR. Aliment Pharmacol Ther 2013;37:3-17 *Fleig WW, et al. J Hepatol 1997;126(Suppl 1):127

บอระเพ็ดบอระเพ็ดบอระเพ็ดบอระเพ็ด ((((Tinospora cordifolia,Tinospora cordifolia,Tinospora cordifolia,Tinospora cordifolia, T. crispaT. crispaT. crispaT. crispa))))

• ไมเถาเลือ้ยมีรสขมไมเถาเลือ้ยมีรสขมไมเถาเลือ้ยมีรสขมไมเถาเลือ้ยมีรสขม

• Used: various conditions, esp. DM Used: various conditions, esp. DM Used: various conditions, esp. DM Used: various conditions, esp. DM

• Contains alkaloids (berberine)Contains alkaloids (berberine)Contains alkaloids (berberine)Contains alkaloids (berberine)

• Data from RCTs*Data from RCTs*Data from RCTs*Data from RCTs*

• 10101010----12121212% developed hepatitis% developed hepatitis% developed hepatitis% developed hepatitis • Often occurs during Often occurs during Often occurs during Often occurs during 3333----6 6 6 6 mo mo mo mo • Most asymptomaticMost asymptomaticMost asymptomaticMost asymptomatic • Severe hepatitis in some casesSevere hepatitis in some casesSevere hepatitis in some casesSevere hepatitis in some cases

• สมุนไพรแฮมสมุนไพรแฮมสมุนไพรแฮมสมุนไพรแฮม////แหม แหม แหม แหม ((((Coscinium Coscinium Coscinium Coscinium

fenestratumfenestratumfenestratumfenestratum )))) also contains berberinealso contains berberinealso contains berberinealso contains berberine

*Chopra A, et al. Rheumatology (Oxford) 2013 [Epub ahead of print] *Sangsuwan C, et al. J Med Assoc Thai 2004;87:543-6

ตนขี้เหล็ก ตนขี้เหล็ก ตนขี้เหล็ก ตนขี้เหล็ก or Cassod tree or Cassod tree or Cassod tree or Cassod tree

((((Senna siameaSenna siameaSenna siameaSenna siamea))))

• Used: food or medicinal herbUsed: food or medicinal herbUsed: food or medicinal herbUsed: food or medicinal herb

• สวนใบออน ดอกสวนใบออน ดอกสวนใบออน ดอกสวนใบออน ดอก และ ยอด และ ยอด และ ยอด และ ยอด • Contain: anhydrobarakolContain: anhydrobarakolContain: anhydrobarakolContain: anhydrobarakol

• Effect: anxiolyticEffect: anxiolyticEffect: anxiolyticEffect: anxiolytic

• Acute hepatitis, ALFAcute hepatitis, ALFAcute hepatitis, ALFAcute hepatitis, ALF

• สวนใบสวนใบสวนใบสวนใบ

• Contain: anthraquinonesContain: anthraquinonesContain: anthraquinonesContain: anthraquinones

• Effect: laxativeEffect: laxativeEffect: laxativeEffect: laxative

• Acute hepatitisAcute hepatitisAcute hepatitisAcute hepatitis

Herbal LaxativesHerbal LaxativesHerbal LaxativesHerbal Laxatives

• มะขามแขก มะขามแขก มะขามแขก มะขามแขก ((((Senna alexandrinaSenna alexandrinaSenna alexandrinaSenna alexandrina), ), ), ),

คูน คูน คูน คูน ((((Cassia fistula Cassia fistula Cassia fistula Cassia fistula หรือ หรือ หรือ หรือ Golden Golden Golden Golden

shower), shower), shower), shower), ชุมเห็ดเทศ ชุมเห็ดเทศ ชุมเห็ดเทศ ชุมเห็ดเทศ ((((Senna alata Senna alata Senna alata Senna alata

หรือ หรือ หรือ หรือ Ring worm cassia) Ring worm cassia) Ring worm cassia) Ring worm cassia) และ และ และ และ

ใบขี้เหล็ก ใบขี้เหล็ก ใบขี้เหล็ก ใบขี้เหล็ก ((((Senna siamea )Senna siamea )Senna siamea )Senna siamea ) • Anthraquinones: doseAnthraquinones: doseAnthraquinones: doseAnthraquinones: dose----dependent dependent dependent dependent

hepatotoxin hepatotoxin hepatotoxin hepatotoxin


• Acute hepatitis and ALF (esp. Acute hepatitis and ALF (esp. Acute hepatitis and ALF (esp. Acute hepatitis and ALF (esp. with proximal tubular acidosis)with proximal tubular acidosis)with proximal tubular acidosis)with proximal tubular acidosis)

• Acute PVTAcute PVTAcute PVTAcute PVT

Soyuncu S, et al. Clin Toxicol 2008;46:774-7; Vanderperren B, et al. Ann Pharmacother 2005;39:1353-7 Beuers U, et al. Lancet 1991;337:372-3

Phytoestrogen Phytoestrogen Phytoestrogen Phytoestrogen

• กวาวเครอืขาว กวาวเครอืขาว กวาวเครอืขาว กวาวเครอืขาว ((((Pueraria candollei) Pueraria candollei) Pueraria candollei) Pueraria candollei)

และและและและ วานชกัมดลูกตวัเมยี วานชกัมดลูกตวัเมยี วานชกัมดลูกตวัเมยี วานชกัมดลูกตวัเมยี

((((Curcuma comosa)Curcuma comosa)Curcuma comosa)Curcuma comosa)

• Used: postUsed: postUsed: postUsed: post----menopausal menopausal menopausal menopausal

symptoms, promote symptoms, promote symptoms, promote symptoms, promote

women’s health women’s health women’s health women’s health

• Increased risk of breast CAIncreased risk of breast CAIncreased risk of breast CAIncreased risk of breast CA

• ? Increased risk for estrogen? Increased risk for estrogen? Increased risk for estrogen? Increased risk for estrogen----

related liver disease e.g. related liver disease e.g. related liver disease e.g. related liver disease e.g.

hepatic adenoma, cholestasis, hepatic adenoma, cholestasis, hepatic adenoma, cholestasis, hepatic adenoma, cholestasis,

peliosis hepatis peliosis hepatis peliosis hepatis peliosis hepatis

วานชักมดลูกวานชักมดลูกวานชักมดลูกวานชักมดลูก

• กานชอดอกสั้นกานชอดอกสั้นกานชอดอกสั้นกานชอดอกสั้น • Phytoestrogen +Phytoestrogen +Phytoestrogen +Phytoestrogen +

ตัวเมีย ตัวเมีย ตัวเมีย ตัวเมีย ((((Curcuma comosa)Curcuma comosa)Curcuma comosa)Curcuma comosa) ตัวผู ตัวผู ตัวผู ตัวผู ((((Curcuma zanthorrhiza) Curcuma zanthorrhiza) Curcuma zanthorrhiza) Curcuma zanthorrhiza)

• No phytoestrogenNo phytoestrogenNo phytoestrogenNo phytoestrogen • Induces platelet Induces platelet Induces platelet Induces platelet

dysfunction dysfunction dysfunction dysfunction –––– causing causing causing causing spontaneous bleeding in spontaneous bleeding in spontaneous bleeding in spontaneous bleeding in animal modelanimal modelanimal modelanimal model

Herbalife® ProductsHerbalife® ProductsHerbalife® ProductsHerbalife® Products

• HDS in the form of drinks, tablets, capsules and HDS in the form of drinks, tablets, capsules and HDS in the form of drinks, tablets, capsules and HDS in the form of drinks, tablets, capsules and

energy bars for weight control, nutritional support energy bars for weight control, nutritional support energy bars for weight control, nutritional support energy bars for weight control, nutritional support

and improvement in welland improvement in welland improvement in welland improvement in well----beingbeingbeingbeing

• Each product often has several ingredientsEach product often has several ingredientsEach product often has several ingredientsEach product often has several ingredients

• Distributed in over Distributed in over Distributed in over Distributed in over 60 60 60 60 countries countries countries countries

with the possibility of with the possibility of with the possibility of with the possibility of

regional variations in regional variations in regional variations in regional variations in

product qualityproduct qualityproduct qualityproduct quality

Navarro VJ. Semin Liver Dis 2009;29:373-82 Reddy KR. Bunchorntavakul C. Aliment Pharmacol Ther 2013;37:754-5

Herbalife® HepatotoxicityHerbalife® HepatotoxicityHerbalife® HepatotoxicityHerbalife® Hepatotoxicity

• Series of HerbalifeSeries of HerbalifeSeries of HerbalifeSeries of Herbalife----associated hepatotoxicity associated hepatotoxicity associated hepatotoxicity associated hepatotoxicity

– Major case series: from Isarel (14 cases)Major case series: from Isarel (14 cases)Major case series: from Isarel (14 cases)Major case series: from Isarel (14 cases)1111, Spain , Spain , Spain , Spain (20 cases)(20 cases)(20 cases)(20 cases)2222, and Switzerland (10 cases), and Switzerland (10 cases), and Switzerland (10 cases), and Switzerland (10 cases)3333

– Causality assessment was ‘probable’ in most cases, Causality assessment was ‘probable’ in most cases, Causality assessment was ‘probable’ in most cases, Causality assessment was ‘probable’ in most cases, although ‘certain’ cases were also reported (total of 6)although ‘certain’ cases were also reported (total of 6)although ‘certain’ cases were also reported (total of 6)although ‘certain’ cases were also reported (total of 6)


– Acute hepatitis in most cases (AIHAcute hepatitis in most cases (AIHAcute hepatitis in most cases (AIHAcute hepatitis in most cases (AIH----like features may be like features may be like features may be like features may be seen), but cholestasis and mixed were also observedseen), but cholestasis and mixed were also observedseen), but cholestasis and mixed were also observedseen), but cholestasis and mixed were also observed

– ALF requiring OLTALF requiring OLTALF requiring OLTALF requiring OLT

• Contamination with Contamination with Contamination with Contamination with Bacillus subtilis Bacillus subtilis Bacillus subtilis Bacillus subtilis (producing (producing (producing (producing

dosedosedosedose----dependent hepatotoxins) also reported dependent hepatotoxins) also reported dependent hepatotoxins) also reported dependent hepatotoxins) also reported 4444

(1) Elinav E, et al. J Hepatol 2007;47:514-20; (2) Manso G, et al. Pharmacoepidemiol Drug Saf 2011;20:1080-7

(3) Schoepfer AM, et al. J Hepatol 2007;47:521-6; (4) Stickel F, et al. J Hepatol 2009;50:111-117

AflatoxinsAflatoxinsAflatoxinsAflatoxins

• Naturally occurring mycotoxins that Naturally occurring mycotoxins that Naturally occurring mycotoxins that Naturally occurring mycotoxins that

are produced by many species of Aspergillusare produced by many species of Aspergillusare produced by many species of Aspergillusare produced by many species of Aspergillus

• พบในธญัพืชพบในธญัพืชพบในธญัพืชพบในธญัพืช, , , , มันสําปะหลังมันสําปะหลังมันสําปะหลังมันสําปะหลัง, , , , ผลิตภัณฑจากแปงผลิตภัณฑจากแปงผลิตภัณฑจากแปงผลิตภัณฑจากแปง, , , , ถั่วลิสงถั่วลิสงถั่วลิสงถั่วลิสง, , , , ผลไมอบแหงผลไมอบแหงผลไมอบแหงผลไมอบแหง, , , , ปลาแหงปลาแหงปลาแหงปลาแหง, , , , กุงแหงกุงแหงกุงแหงกุงแหง, , , , พริกแหงพริกแหงพริกแหงพริกแหง////พรกิปนพรกิปนพรกิปนพรกิปน

• Heat resistant (up to Heat resistant (up to Heat resistant (up to Heat resistant (up to 260 260 260 260 ooooC)C)C)C)

• Chronic exposure Chronic exposure Chronic exposure Chronic exposure –––– intercalate into DNA causing intercalate into DNA causing intercalate into DNA causing intercalate into DNA causing

mutation mutation mutation mutation –––– increased risk for HCCincreased risk for HCCincreased risk for HCCincreased risk for HCC

Hypervitaminosis A and LiverHypervitaminosis A and LiverHypervitaminosis A and LiverHypervitaminosis A and Liver

• Liver is the major storage site for vitamin ALiver is the major storage site for vitamin ALiver is the major storage site for vitamin ALiver is the major storage site for vitamin A

• In the liver, In the liver, In the liver, In the liver, 90909090% of vitamin A is stored within the % of vitamin A is stored within the % of vitamin A is stored within the % of vitamin A is stored within the

stellate cells (↑↑ amount stellate cells (↑↑ amount stellate cells (↑↑ amount stellate cells (↑↑ amount –––– stellate cell activation) stellate cell activation) stellate cell activation) stellate cell activation)

• Chronic toxicity doseChronic toxicity doseChronic toxicity doseChronic toxicity dose

– >>>>100100100100,,,,000 000 000 000 IU/day for IU/day for IU/day for IU/day for 6 6 6 6 mo mo mo mo – >>>>25252525,,,,000 000 000 000 IU/day for IU/day for IU/day for IU/day for 6 6 6 6 yryryryr – Lower threshold in children and elderlyLower threshold in children and elderlyLower threshold in children and elderlyLower threshold in children and elderly


– NonNonNonNon----cirrhotic portal hypertensioncirrhotic portal hypertensioncirrhotic portal hypertensioncirrhotic portal hypertension – Chronic hepatitis and cirrhosis Chronic hepatitis and cirrhosis Chronic hepatitis and cirrhosis Chronic hepatitis and cirrhosis

Geubel AP, et al. Gastroenterology 1991;100:1701-1709 Penniston KL. Tanumihardjo SA. Am J Clin Nutr 2006;83:191-201

Hypervitaminosis A and LiverHypervitaminosis A and LiverHypervitaminosis A and LiverHypervitaminosis A and Liver

• Liver biopsy: Stellate cell hyperplasia (located within Liver biopsy: Stellate cell hyperplasia (located within Liver biopsy: Stellate cell hyperplasia (located within Liver biopsy: Stellate cell hyperplasia (located within sinusoids) and vacuolated Kupffer cells sinusoids) and vacuolated Kupffer cells sinusoids) and vacuolated Kupffer cells sinusoids) and vacuolated Kupffer cells

• Other features: Hair loss, dystrophic nail changesOther features: Hair loss, dystrophic nail changesOther features: Hair loss, dystrophic nail changesOther features: Hair loss, dystrophic nail changes Cheruvattath R, et al. Liver Transplant 2006;12:1888-1891

Glucosamine Glucosamine Glucosamine Glucosamine

• Precursor for glycosaminoglycans Precursor for glycosaminoglycans Precursor for glycosaminoglycans Precursor for glycosaminoglycans

(major component of joint cartilage) (major component of joint cartilage) (major component of joint cartilage) (major component of joint cartilage)

• Used: osteoarthritis, joint painUsed: osteoarthritis, joint painUsed: osteoarthritis, joint painUsed: osteoarthritis, joint pain

• Often sold in combination with others Often sold in combination with others Often sold in combination with others Often sold in combination with others

e.g. chondroitin sulfate and MSM e.g. chondroitin sulfate and MSM e.g. chondroitin sulfate and MSM e.g. chondroitin sulfate and MSM

• No hepatotoxicity reported in RCTsNo hepatotoxicity reported in RCTsNo hepatotoxicity reported in RCTsNo hepatotoxicity reported in RCTs

• Types of liver injury reportedTypes of liver injury reportedTypes of liver injury reportedTypes of liver injury reported

– Acute hepatitis, mixed and ALFAcute hepatitis, mixed and ALFAcute hepatitis, mixed and ALFAcute hepatitis, mixed and ALF

– Causality assessment ~ probableCausality assessment ~ probableCausality assessment ~ probableCausality assessment ~ probable

– Move Free Advanced® contains Move Free Advanced® contains Move Free Advanced® contains Move Free Advanced® contains

Chinese skullcapChinese skullcapChinese skullcapChinese skullcap

Ebrahim V, et al. BMJ Case Rep 2012; Smith A, Dillon J. BMJ Case Rep 2009 Linnebur SA, et al. Pharmacotherapy. 2010;30:750, 258e-262e

Other HDS Associated with Hepatotoxicity

• Green tea (Green tea (Green tea (Green tea (ชาเขยีวจีนชาเขยีวจีนชาเขยีวจีนชาเขยีวจีน)))) • KavaKavaKavaKava • Camphor oil (Camphor oil (Camphor oil (Camphor oil (น้ํามันน้ํามันน้ํามันน้ํามันหอมการบูรหอมการบูรหอมการบูรหอมการบูร)))) • Gardenia fruit (Gardenia fruit (Gardenia fruit (Gardenia fruit (พุดพุดพุดพุดซอนซอนซอนซอน, , , , จืจืจืจือจื่ออจื่ออจื่ออจื่อ)))) • AtractylisAtractylisAtractylisAtractylis gummiferagummiferagummiferagummifera

• CallilepsisCallilepsisCallilepsisCallilepsis laureolalaureolalaureolalaureola

• PaeoniaPaeoniaPaeoniaPaeonia ((((สมุนไพรตระกูลโบตัน๋สมุนไพรตระกูลโบตัน๋สมุนไพรตระกูลโบตัน๋สมุนไพรตระกูลโบตัน๋)))) • ShouShouShouShou----wuwuwuwu----pianpianpianpian • Aloe Aloe Aloe Aloe veraveraveravera ((((สวนยางสวนยางสวนยางสวนยาง)))) • Saw palmetto Saw palmetto Saw palmetto Saw palmetto ((((ตนตนตนตนปาลมแคระปาลมแคระปาลมแคระปาลมแคระ)))) • CentellaCentellaCentellaCentella asiaticaasiaticaasiaticaasiatica ((((ใบบัวบกใบบัวบกใบบัวบกใบบัวบก))))

• Noni juiceNoni juiceNoni juiceNoni juice ((((น้ําลูกยอน้ําลูกยอน้ําลูกยอน้ําลูกยอ)))) • Cascara sagradaCascara sagradaCascara sagradaCascara sagrada

• Mistletoe Mistletoe Mistletoe Mistletoe • Skullcap Skullcap Skullcap Skullcap • Valerian Valerian Valerian Valerian • Margosa oil Margosa oil Margosa oil Margosa oil • Pennyroyal oilPennyroyal oilPennyroyal oilPennyroyal oil • Usnic acid Usnic acid Usnic acid Usnic acid • Hydroxycut® Hydroxycut® Hydroxycut® Hydroxycut® • ChaparralChaparralChaparralChaparral • Psyllium huskPsyllium huskPsyllium huskPsyllium husk


Management of HDS Hepatotoxicity Management of HDS Hepatotoxicity Management of HDS Hepatotoxicity Management of HDS Hepatotoxicity

• Discontinuation of useDiscontinuation of useDiscontinuation of useDiscontinuation of use

• Supportive treatmentSupportive treatmentSupportive treatmentSupportive treatment

• Consider OLT for ALF Consider OLT for ALF Consider OLT for ALF Consider OLT for ALF

• Potential antidote ?Potential antidote ?Potential antidote ?Potential antidote ?

– Pyrrolizidine alkaloids Pyrrolizidine alkaloids Pyrrolizidine alkaloids Pyrrolizidine alkaloids –––– defibrotide defibrotide defibrotide defibrotide

– Germander Germander Germander Germander –––– NAC NAC NAC NAC

– Pennyroyal oil Pennyroyal oil Pennyroyal oil Pennyroyal oil –––– NAC NAC NAC NAC

– Amanita mushroom Amanita mushroom Amanita mushroom Amanita mushroom –––– NAC, silibinin, penicillinNAC, silibinin, penicillinNAC, silibinin, penicillinNAC, silibinin, penicillin

– HDSHDSHDSHDS----induced AIH induced AIH induced AIH induced AIH –––– corticosteroids corticosteroids corticosteroids corticosteroids


HerbHerbHerbHerb----Drug InteractionsDrug InteractionsDrug InteractionsDrug Interactions

• Some herbs may have interactions with Some herbs may have interactions with Some herbs may have interactions with Some herbs may have interactions with

certain prescription medications by various certain prescription medications by various certain prescription medications by various certain prescription medications by various

mechanisms leading to adverse eventsmechanisms leading to adverse eventsmechanisms leading to adverse eventsmechanisms leading to adverse events

• Many herbs have been identified as Many herbs have been identified as Many herbs have been identified as Many herbs have been identified as

substrates, inhibitors, and/or inducers of substrates, inhibitors, and/or inducers of substrates, inhibitors, and/or inducers of substrates, inhibitors, and/or inducers of

various CYPvarious CYPvarious CYPvarious CYP450450450450, such as St. John’s Wort, , such as St. John’s Wort, , such as St. John’s Wort, , such as St. John’s Wort,

garlic, pepper, licorice, flavonoids, garlic, pepper, licorice, flavonoids, garlic, pepper, licorice, flavonoids, garlic, pepper, licorice, flavonoids,

triterpenoids and anthraquinonestriterpenoids and anthraquinonestriterpenoids and anthraquinonestriterpenoids and anthraquinones

Posadzki P, Watson L, Ernst E. Br J Clin Pharmacol 2013;75:603-18 Bunchorntavakul C. Reddy KR. Aliment Pharmacol Ther 2013;37:3-17

St. John’s WortSt. John’s WortSt. John’s WortSt. John’s Wort

• Hypericum perforatum Hypericum perforatum Hypericum perforatum Hypericum perforatum extractextractextractextract

• Used: variety of indications Used: variety of indications Used: variety of indications Used: variety of indications

especially depressive disordersespecially depressive disordersespecially depressive disordersespecially depressive disorders

• Inhibits synaptosomal uptake of Inhibits synaptosomal uptake of Inhibits synaptosomal uptake of Inhibits synaptosomal uptake of

5555----HT, NE, DA, and GABA HT, NE, DA, and GABA HT, NE, DA, and GABA HT, NE, DA, and GABA

• Potent inducer of CYPPotent inducer of CYPPotent inducer of CYPPotent inducer of CYP3333AAAA4444

– ↑ Acetaminophen toxicity↑ Acetaminophen toxicity↑ Acetaminophen toxicity↑ Acetaminophen toxicity

– ↓ Levels of warfarin, ↓ Levels of warfarin, ↓ Levels of warfarin, ↓ Levels of warfarin,

cyclosporine and protease cyclosporine and protease cyclosporine and protease cyclosporine and protease

inhibitors inhibitors inhibitors inhibitors (HIV, HCV)(HIV, HCV)(HIV, HCV)(HIV, HCV)

Linde K, et al. BMJ 1996;313:253-58 Bunchorntavakul C. Reddy KR. Aliment Pharmacol Ther 2013;37:3-17

HerbsHerbsHerbsHerbs Interactions and potential consequencesInteractions and potential consequencesInteractions and potential consequencesInteractions and potential consequences

Danshen (S. miltiorrhiza) Increased INR → bleeding risk

Lingzhi mushroom (เห็ดหลินจือ) Increased INR → bleeding risk

Garlic (กระเทียม) Increased INR → bleeding risk

Papaya (มะละกอ) Increased INR → bleeding risk

Tamarind (มะขาม) Increased aspirin level → bleeding risk

Feverfew (T. parthenium) Platelet dysfunction → bleeding risk

Gingko biloba (แปะกวย) Platelet dysfunction → bleeding risk

วานชักมดลูกตัวผู (C. zanthorrhiza) Platelet dysfunction → bleeding risk

Ginseng (โสม) Decreased INR → clotting risk

St. John’s Wort Decreased INR → clotting risk

Devil’s claw (H. cumbens) Purpura

HerbHerbHerbHerb----drug Interactions: Warfarin and Aspirindrug Interactions: Warfarin and Aspirindrug Interactions: Warfarin and Aspirindrug Interactions: Warfarin and Aspirin

Bunchorntavakul C. Reddy KR. Aliment Pharmacol Ther 2013;37:3-17 Strader DB, Navarro VJ, Seeff LB. Zakim and Boyer’s Hepatology. 6th edition (2012)

MedicationsMedicationsMedicationsMedications HerbsHerbsHerbsHerbs Interactions and potential consequencesInteractions and potential consequencesInteractions and potential consequencesInteractions and potential consequences

CYP3A4 drugs Pyrrolizidine alkaloids Germander

CYP3A4 induction → increased hepatotoxicity

Cyclosporine St. John’s Wort Grape fruit juice

CYP3A4 induction → increased rejection risk

MTX St. John’s Wort Echinacea (ดอกโคน)

Increased methotrexate toxicity

Prednisolone

Ginseng (โสม) Possible additive effect

Licorice (ชะเอม) Reduced clearance → hypokalemia

Sho-saiko-to Altered clearance → low pred level

Protease inhibitors

St. John’s Wort Garlic (กระเทียม)

CYP3A4 induction → suboptimal antiviral activity

Spironolactone Licorice (ชะเอม) Mineralocorticoid → Reduced spironolactone effect

HerbHerbHerbHerb----drug Interactions: Other Medicationsdrug Interactions: Other Medicationsdrug Interactions: Other Medicationsdrug Interactions: Other Medications

Bunchorntavakul C. Reddy KR. Aliment Pharmacol Ther 2013;37:3-17 Strader DB, Navarro VJ, Seeff LB. Zakim and Boyer’s Hepatology. 6th edition (2012)

Thank You for Your Kind Attention

You’re eating too many herbs !

herbal and dietary supplement (hds) hepatotoxicity hds... · herbal and dietary supplement (hds)...

Documents