Herbal Supplements and the Liver Lauren Myers PA-C, MMsc
The Planner Lauren Myers, MMSc, PA-C - have no relevant financial relationships to disclose.
Herbal Dietary Supplements in the US 42% of Americans use some form of alternative therapy Approximately 19% use herbal dietary supplements (HDS) Reasons for use of HDS remedies Muscle building Weight loss Insomnia Well-being Cold prevention Menopausal symptoms Strader et al Am J Gastro 2002, Seeff et al. Hepatology 2008, Gardiner Arch Intern Med 2006, Nahin, RL etal National Health Statistics/NIH 2016
Herbal Dietary Supplements in the US 21% of adult prescription drug users also use HDS concurrently 69% do not disclose HDS use to their conventional provider Americans spent $12.8 billion out-of-pocket on natural product supplements 20-40% of liver patients use herbal supplements
Milk Thistle (Silymarin) Milk Thistle (Silybum marianum) most commonly used HDS in liver patients Herb native to Mediterranean region Used by ancient Greeks and Romans for liver and biliary complaints and to promote lactation Complex mixture of flavonolingans extracted from milk thistle seeds- known collectively as silymarin In vitro and animal studies demonstrating antioxidant, anti-inflammatory and anti-fibrotic properties Silymarin inhibits Hep C virus entry/fusion, RNA and protein synthesis Dosing 250-750mg capsules or tablets typically taken 2-3x daily Wagoner et al, Hepatology 2010, Wah-Kheong et al. Clin Gastro Hepatol 2017
Milk Thistle (Silymarin) and HCV HALT-C Trial Observational Data Trial designed to assess efficacy of long-term PEG-IFN those who failed prior standard treatment, advanced fibrosis Collected data on use of herbal supplements before/during trial Study data included serologic, biopsy and clinical outcomes (CTP score, death, cirrhosis complications) No difference in ALT or HCV levels in those who used silymarin vs. nonusers No association with clinical outcomes in crude or adjusted models Use was associated with fewer liver-related symptoms, improved quality of life than never users (adjusted for lifestyle factors and demographics) Seef et al, Hepatology 2008
Milk Thistle (Silymarin) and HCV Silymarin use in patients with untreated Hepatitis C Randomized, double-blind, placebo-controlled multicenter trial (N=154) 2 doses of silymarin (420mg or 700mg silymarin) vs placebo TID x 24 weeks Non-responders to PEG-IFN (note excluded cirrhotics, HIV co-infected) Outcomes measured: ALT levels/change, change in HCV RNA, quality of life (general and liver-related) and depression No change in ALT vs Placebo No changes in mental or physical health, liver related quality of life or depression No difference in adverse events between groups Fried, et al. JAMA 2012
Milk Thistle (Silymarin) and NASH Silymarin use in biopsy-proven NASH Randomized, double-blind, placebo-controlled trial with biopsy-proven NASH and a NAFLD activity score (NAS) 4 (NAS):sum of scores (0-3) on biopsy for steatosis, hepatocellular ballooning, lobular inflammation Silymarin 700mg vs placebo TID x 48 weeks in 99 patients Primary outcome was decrease 30% NAS score NAS changes similar between groups (33% silymarin and 26% placebo) Improvement in Fibrosis ( 1-point reduction) more frequently in silymarin vs placebo (22% vs 6%) No adverse events related to study drug Wah-Kheong et al. Clin Gastro Hepatol 2017
Milk Thistle (Silymarin) Milk thistle is very popular among patients with liver disease Side effects similar to placebo Silymarin lacks high quality evidence in improvement in clinical outcomes for HCV but may have a role yet in NASH
Turmeric (Curcumin) Turmeric (Curcuma longa) with yellow-colored active principle curcumin Perennial herb extensively used as spice, food preservative, coloring in India, China and South East Asia Used in traditional Indian medicine for treatment of biliary and hepatic disorders Curcumin is an antioxidant and has been shown to regulate pro-inflammatory and pro-fibrotic cytokines present in liver diseases Curcumin was shown to affect HCV viral envelope fluidity resulting in impairment of viral binding and fusion More studies needed FAO and WHO Expert Committee on Food additives report acceptable daily intake of curcumin up to 3mg/kg body weight Chattopadhyay et al. Cur Science 2004, Anggakusuma et al. Gut 2014, Nabavi et al Comprehensive Review in Food Science Food Safety 2014
The Dark Side of Herbal Dietary Supplements Regulatory framework established by Dietary Supplement Health and Education Act (DSHEA) of 1994 Manufacturer is responsible for safety, new dietary ingredients require pre-market review of safety data FDA approval is not required before marketing and can only take action if proven adulteration of HDS or injury due to HDS Incidence of clinically significant Drug Induced Liver Injury (DILI) is increasing along with the use of HDS in America (7%-20% within 10 year study period) DILI related to HDS is more likely to result in liver transplantation than injury related to conventional medications Navarro et al. Hepatology 2014
Herbal Dietary Supplements and DILI Drug Induced Liver Injury Network (DILIN) prospective study 33/300 patients took HDS either alone or in combination prescription drug DILI due to HDS associated with higher trends of bilirubin and longer duration Chalasani et al. Gastro 2008
Herbal Dietary Supplements associated with DILI Androstenedione Mistletoe Atractylis gummifera Pennyroyal Black cohosh Pyrrolizidine alkaloids Callilepis laureola Senna Chaparral Usnic acid Germander Valerian Greater celandine Herbalife (some products) Green tea extract Hydroxycut (some products) Kava Lipokinetix Licorice OxyELITE Pro
Herbal Dietary Supplements and DILI While HDS related cases of DILI are increasing, no reliable population-based statistics for incidence of toxicity Complicated by many HDS comprise mixtures of ingredients Vulnerable to variations in quality and strength Reports exist of contaminants of heavy metals, pharmaceuticals, microbial products and pesticides Analytical phytochemistry of HDS products implicated in DILI often reveal adulteration of the product, mislabeling or absence of botanical listed Mechanism of hepatotoxicity many cases is unknown but based on DILIN- most patients have a hepatocellular pattern of injury
https://livertox.nih.gov