Victor J. Navarro, MD, FAASLD Herbal and Dietary Supplements Doc, is it good for my liver? Postgraduate Course: Challenges in Management of Common Liver Diseases 188 1
o Chief Complaint A 45 year old male referred for elevated liver enzymes No symptoms of advanced liver disease o History Obesity, diabetes, hypertension Reported meds: Metformin, Lisinopril o Exam BMI 30, no stigmata of chronic liver disease Centripetal obesity, hepatomegaly o Clinical Data Case Presentation ALT 125, AST 100, AlkPhos 135, Tbili 0.9, albumin 4.0, INR 1.0 US showed fatty liver with heterogeneous echotexture 2016 AMERICAN ASSOCIATION 189 FOR THE STUDY OF LIVER DISEASES 2 WWW.AASLD.ORG
Clinical Questions o Is there any evidence that Herbal and Dietary Supplements (HDS) improve liver health? o What is the risk of Drug Induced Liver Injury (DILI) from HDS? o How can liver injury from HDS be diagnosed? 2016 AMERICAN ASSOCIATION FOR THE 190 STUDY OF LIVER DISEASES WWW.AASLD.ORG 3
Background Information on Dietary Supplements o Herbal and Dietary Supplement (HDS) is a commonly used phrase o Dietary Supplement is the correct regulatory term in the U.S. DSHEA (1994) defined dietary ingredients as vitamins, minerals, herbs, amino acids (and any concentrate, metabolite, or extract thereof) Manufacturer attests to safety and has no responsibility to prove it Structure/function claims allowed calcium builds strong bones Standards exist for purity, strength, and composition o Regulation varies across the globe, mostly founded upon a history of safe use 2016 AMERICAN ASSOCIATION FOR THE 191 STUDY OF LIVER DISEASES WWW.AASLD.ORG 4
Regulation of Drugs and DS in the U.S. U.S. Food and Drug Administration CFSAN Center for Food Safety and Applied Nutrition CDER Center for Drug Evaluation and Research 2016 AMERICAN ASSOCIATION FOR THE 192 STUDY OF LIVER DISEASES WWW.AASLD.ORG 5
Prevalence of Supplement Use, NHANES 1999-2008 55 56 51 51 47 45 30 33 59 59 53 53 47 46 All Adults Adult-Males Adult-Females Children 31 31 55 48 42 29 99-00 01-02 03-04 05-06 07-08 Am J Epidemiol 2004;160:339; J. Nutr.2011 141: 261; Ecol Food Nutr 2013;52:76 2016 AMERICAN ASSOCIATION FOR THE 193 STUDY OF LIVER DISEASES WWW.AASLD.ORG 6
U.S. Supplement Sales ($ Billions) $8.6 $11.2 $15.1 $16.7 $18.8 $20.4 $22.5 $25.2 $28.1 $32.5 2014: $36.7; $6.4B, herbals* 1994 1996 1998 2000 2002 2004 2006 2008 2010 2012 *American Botanical Council 2016 AMERICAN ASSOCIATION FOR THE 194 STUDY OF LIVER DISEASES WWW.AASLD.ORG 7
Dietary Supplement Use in the U.S. o Most products are multi-ingredient mixtures o The use of multiple HDS concurrently is common o Consumers use HDS for many reasons: Self empowerment, disease self management, prevention Health promotion, physical enhancement Dissatisfaction with conventional treatments o Providers may not be aware of a patient s use 2016 AMERICAN ASSOCIATION FOR THE 195 STUDY OF LIVER DISEASES WWW.AASLD.ORG 8
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Is there any evidence that HDS improve liver health? o Animal models of liver injury Reduce liver enzymes Reduce hepatic inflammation or fibrosis o Human studies ClinicalTrials.gov (search Herbal + Liver) as of August 2016 50 studies 14 for liver disease indication Silymarin commonly studied o Many plant extracts have biological activity 2016 AMERICAN ASSOCIATION FOR THE 197 STUDY OF LIVER DISEASES WWW.AASLD.ORG 10
Doc, is it good for my liver? ois there proof of clinical benefit? ois there any evidence they can do harm? owhat is the patient forgoing in order to take the supplement? 2016 AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES WWW.AASLD.ORG 198 11
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Milk Thistle Silybum marianum 2016 AMERICAN ASSOCIATION FOR THE 200 STUDY OF LIVER DISEASES WWW.AASLD.ORG 13
Silymarin o Used in treatment and prevention of liver diseases for over 2000 years o Commonly used by HCV patients as shown in HALT-C (Seeff 2008) o Silybum marianum Flavonolignans Silybinin Isosilybin Silydianin Silychristin Silybinin is the most active 2016 AMERICAN ASSOCIATION FOR THE 201 STUDY OF LIVER DISEASES WWW.AASLD.ORG 14
Silymarin Proposed mechanisms of action o Antioxidant o Anti-fibrotic o Anti-inflammatory o Anti-cancer effects 2016 AMERICAN ASSOCIATION FOR THE 202 STUDY OF LIVER DISEASES WWW.AASLD.ORG 15
Silymarin for NASH & HCV SyNCH Trials A cooperative agreement with the NIDDK (completed) o Phase I Safety Tolerability o Phase II Efficacy assessment Longer term safety 203 2016 AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES WWW.AASLD.ORG 16
Silymarin for HCV ALT Endpoint o Phase I Safety Tolerability o Phase II Efficacy assessment Longer term safety Silymarin (Legalon) for Interferon Refractory HCV: a RCT Fried et al. JAMA 2012;308:274 p = 0.75 204 2016 AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES WWW.AASLD.ORG 17
Silymarin for NASH NAS Endpoint o Phase I Safety Tolerability o Phase II Efficacy assessment Longer term safety Silymarin (Legalon) for NASH Sponsor, Rottapharm - Unpublished 400 mg 116 Screened 78 Randomized 700 mg PBO 14% 19% 205 2016 AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES WWW.AASLD.ORG 12% NAS Endpoint p = 0.79 18
Proposed Mechanism Target Disease Betaine Methyl donor NASH No improvement in LFTs, histology Carnitine Glycyrrhizin Is there any evidence that HDS improve liver health? Fatty acid transport/oxidation Stimulates INF-a production Outcomes Best Evidence References NASH Improved LFTs Reduced NAS HCV, HCC Improved LFTs No effect on HCV RNA RCT, fair quality Abdelmalek 2009 RCT, fair quality Malaguarnera 2010 Somi 2014 RCT, good quality Van Rossum 1999 Kumada, 2002 Omega-3 Fatty acid oxidation NASH Improved LFTs Meta-analysis Parker, 2012 Resveratrol Improved insulin sensitivity NASH Improved LFTs Improved steatosis Conflicting data RCT, fair quality Poulsen, 2013 Chachay, 2014 Faghihzadeh, 2015 Vitamin E Antioxidant NASH in nondiabetics Improved NAS Conflicting data RCT, good quality Meta-analysis Sanyal, 2010 Lavine, 2011 Sato, 2015 2016 AMERICAN ASSOCIATION FOR THE 206 STUDY OF LIVER DISEASES WWW.AASLD.ORG Suggested reading: (1) Seeff et al. Gastro 2015;148:517 (2) Del Ben et al. Br J Clin Pharm 2016 19
What is the risk of DILI from HDS? o Population based studies Iceland (Bjornnsen Gastro 2015) 19 DILI cases per 100,000 HDS second most common cause Kaiser Health System (Goldberg Gastro 2015) 1.6 non-acetaminophen ALF events/1million person years HDS second most common cause Delaware (Navarro, Unpublished) 3 DILI cases per 100,000 in 2014 HDS second most common cause 2016 AMERICAN ASSOCIATION FOR THE 207 STUDY OF LIVER DISEASES WWW.AASLD.ORG 20
U.S. Drug Induced Liver Injury Network - 2014 U Michigan Fontana USC/ UCLA Stolz/ Durazo Indiana U Chalasani Mt Sinai Odin Einstein Navarro Duke CRI Barnhart U N Carolina Watkins 208
DILIN Study Cohort September 2004 to May 2013 1257 subjects 1091 subjects Completed Causality Assessment 899 definite, highly likely, or probable 142 possible and 50 unlikely 209 Chalasani et. al. Gastroenterology 2015;148:1340 1352
Top 10 therapeutic classes and individual agents to cause DILI in the USA (N=899) Therapeutic Class n 1 Antimicrobials 408 2 Herbal and dietary 145 3 CVS agent 88 4 CNS agents 82 5 Anti-neoplastics 49 6 Analgesics 33 7 Immunomodulatory 27 8 Endocrine 20 9 Rheumatologic 13 10 Gastrointestinal 12 210 Individual agent n 1 Amox-Clavulanate 91 2 INH 48 3 Nitrofurantoin 42 4 TMP/SMX (Bactrim) 31 5 Minocycline 28 6 Cefazolin 20 7 Azithromycin 18 8 Ciprofloxacin 16 9 Levofloxacin 13 10 Diclofenac 12
100% Temporal Trends in DILIN Navarro V, et al. Hepatology 2014;60:1399-1408 Data based on 136 patients with HDS Associated liver injury, enrolled 2003-2012 80% 60% 40% Drugs Bodybuilding Other HDS 20% 0% n 2004-2005 2006-2007 2008-2009 2010-2012 115 191 219 303 Trend for Bodybuilding HDS: p=0.01 211 Trend for Other HDS: p=0.05 24
DILIN Experience 2013 262 HDS Consumed by 136 Patients 33% 30% 2% 2% 3% 3% 4% 4% 19% 212
Outcomes of HDS Associated Liver Injury Navarro V, et al. Hepatology 2014;60:1399-1408 Data based on 136 patients with HDS Associated liver injury, enrolled 2003-2012 32 58 414 Percent 30 181 0 11 24 0 3 50 6 * 213 *p <.05, representing difference among groups
Why is there risk of DILI from HDS? o Inappropriate use o Inherent toxicity o Adulteration and contamination o Herb-drug interactions o Individual susceptibility 2016 AMERICAN ASSOCIATION FOR THE 214 STUDY OF LIVER DISEASES WWW.AASLD.ORG 27
The Ubiquity of Green Tea (Extract) 215
Green Tea Extract: Catechin and its Derivatives 216
The Risk of Polyphenols 217
Evidence for EGCG Toxicity o Toxic at high doses to rodents and dogs (Galati, 2006, Isbrucker, 2006) o Increases interleukins, monocyte chemoattractants o Single dose 1500mg/kg in mice led to 85% mortality (Lambert 2009) o EGCG induces oxidative stress (Hou 2005, Frei 2003, Higdon 2005) o Time-dependent increase in cytotoxicity and ROS formation (Galati, 2006) 218
Liver Injury due to Green Tea Extract o Over 50 reported clinical cases of liver injury o No clear relationship between GTE dose and severity of liver injury (Navarro, 2009) o Mechanism of injury conjectural o Typical picture Viral hepatitis like picture Very high ALT elevations Hepatocellular jaundice 2016 AMERICAN ASSOCIATION FOR THE 219 STUDY OF LIVER DISEASES WWW.AASLD.ORG 32
Does chronic liver disease predispose to DILI? Characteristic of Chronic Liver Disease Shunting, reduced hepatic inflow Reduced hepatocyte mass, CYP P450 Ascites Jaundice, Diminished bile flow Low albumin Cachexia Reduced glutathione Pharmacokinetic/ Pharmacodynamic Effect Increased drug exposure, increased half life Reduced metabolism, clearance Altered volume of distribution Impaired absorption or increased exposure Impaired protein binding Limited reserve Impaired antioxidant/reparative capacity 220
Diagnostic Approach to Liver Injury from HDS Liver injury Differential Diagnosis Viral Hepatitis, A,B,C,E Concomitant Drugs Autoimmune Liver Disease Hemodynamic Events Metabolic, Inherited Disorders Anatomical Abnormalities HDS Implicated Diagnostic Considerations Adulterants Unlabeled Ingredients Contaminants Sildenafil Anabolic steroids 221 Botanicals Microbes Heavy Metals
Causality Assessment Tools for HDS-DILI o RUCAM, most widely used Time to onset Course of injury Risk factors Concomitant agents Non-drug causes Known history of injury Rechallenge o Expert opinion Structured Takes into account all clinical nuances Draws on judgment and personal/group experience 2016 AMERICAN ASSOCIATION FOR THE 222 STUDY OF LIVER DISEASES WWW.AASLD.ORG 35
Questions and Answers o Is there any evidence that HDS improve liver health? Evidence for effectiveness of most products is scanty. livertox.nih.gov o What is the risk of DILI from HDS? DILI from HDS is rare, but may be on the rise. Injury can be severe, particularly when resulting from non-bodybuilding products. livertox.nih.gov o How can liver injury from HDS be diagnosed? Diagnosis requires suspicion and careful exclusions. Multiple and unlabeled ingredients, adulteration, contamination, product variability confound causality assessment. 2016 AMERICAN ASSOCIATION 223 FOR THE STUDY OF LIVER DISEASES 36 WWW.AASLD.ORG