Dietary Supplement-Induced Hepatotoxicity: A Clinical Perspective.

The consumption of dietary supplements (DS) has resulted in a significant and escalating number of cases involving liver injury. It is crucial for clinicians and consumers to be well informed about the adverse effects of such products, leading to their discontinuation and timely reporting of any harmful cases. This article delves into the clinical perspective of DS-related hepatotoxicity, highlighting key concepts such as a systematic diagnostic approach. The discussion extends to notable examples of both currently popular and potential future dietary supplements, such as garcinia cambogia, turmeric, and ashwagandha, accompanied by an overview of recent findings. Causality assessment tools play a crucial role in establishing a connection between these products and instances of liver injury, with consideration of the advantages and disadvantages associated with their use. Fostering a comprehensive understanding of regulatory standards, coupled with a solid foundation of knowledge of DS, will prove instrumental in preventing DS-related hepatotoxicity. Achieving this goal requires collaborative efforts from both consumers and clinicians.

Amiodarone and Dronedarone Causes Liver Injury with Distinctly Different Clinical Presentations.

OBJECTIVE: To describe hepatotoxicity due to amiodarone and dronedarone from the DILIN and the US FDA's surveillance database. METHODS: Hepatotoxicity due to amiodarone and dronedarone enrolled in the U.S. Drug Induced Liver Injury Network (DILIN) from 2004 to 2020 are described. Dronedarone hepatotoxicity cases associated with liver biopsy results were obtained from the FDA Adverse Event Reporting System (FAERS) from 2009 to 2020. RESULTS: Among DILIN's 10 amiodarone and 3 dronedarone DILIN cases, the latency for amiodarone was longer than with dronedarone (388 vs 119 days, p = 0.50) and the median ALT at DILI onset was significantly lower with amiodarone (118 vs 1191 U/L, p = 0.05). Liver biopsies in five amiodarone cases showed fibrosis, steatosis, and numerous Mallory-Denk bodies. Five patients died although only one from liver failure. One patient with dronedarone induced liver injury died of a non-liver related cause. Nine additional cases of DILI due to dronedarone requiring hospitalization were identified in the FAERS database. Three patients developed liver injury within a month of starting the medication. Two developed acute liver failure and underwent urgent liver transplant, one was evaluated for liver transplant but then recovered spontaneously, while one patient with cirrhosis died of liver related causes. CONCLUSION: Amiodarone hepatotoxicity resembles that seen in alcohol related liver injury, with fatty infiltration and inflammation. Dronedarone is less predictable, typically without fat and with a shorter latency of use before presentation. These differences may be explained, in part, by the differing pharmacokinetics of the two drugs leading to different mechanisms of hepatotoxicity.

Vancomycin-Induced Liver Injury, DRESS, and HLA-A∗32:01.

BACKGROUND: Intravenous vancomycin therapy can cause liver injury as well as "drug reaction with eosinophilia and systemic symptoms" (DRESS) syndrome. This study aimed to better define the clinical features and HLA associations of vancomycin-induced liver injury. OBJECTIVE: To describe clinical, biochemical, and temporal characteristics of vancomycin-induced liver injury. METHODS: Cases of liver injury with recent exposure to vancomycin who were enrolled in the US Drug-induced Liver Injury Network between 2004 and 2020 were assessed. Sequencing of HLA alleles was performed on stored blood samples. RESULTS: Among 1697 cases of drug-induced liver injury identified between 2004 and 2021, 9 (0.5%) were attributed to intravenous vancomycin. The 9 cases included 6 men, median age 60 years (range, 23-85 days), and treatment for 26 days (range, 1-34 days). The clinical presentation was DRESS syndrome in 8 patients, of whom 6 received corticosteroids. Liver injury varied from hepatocellular to cholestatic and from mild (n = 5) to fatal (n = 1). In survivors, liver injury and DRESS syndrome ultimately resolved. HLA typing demonstrated the HLA-A∗32:01 allele in 7 vancomycin cases (78%, all with DRESS syndrome), versus 1 of 81 cases (1.2%) exposed but not attributed to vancomycin, and 113 of 1708 cases (6.6%) without vancomycin exposure. The allele frequency in vancomycin cases was 0.44 compared with less than 0.04 in US populations. CONCLUSIONS: Vancomycin-induced liver injury is commonly associated with DRESS syndrome and linked to HLA-A∗32:01. HLA-A∗32:01 testing could be considered early to risk-stratify patients using long-term intravenous vancomycin therapy.

Garcinia cambogia, Either Alone or in Combination With Green Tea, Causes Moderate to Severe Liver Injury.

BACKGROUND & AIMS: Garcinia cambogia, either alone or with green tea, is commonly promoted for weight loss. Sporadic cases of liver failure from G cambogia have been reported, but its role in liver injury is controversial. METHODS: Among 1418 patients enrolled in the Drug-Induced Liver Injury Network (DILIN) from 2004 to 2018, we identified 22 cases (adjudicated with high confidence) of liver injury from G cambogia either alone (n = 5) or in combination with green tea (n = 16) or Ashwagandha (n = 1). Control groups consisted of 57 patients with liver injury from herbal and dietary supplements (HDS) containing green tea without G cambogia and 103 patients from other HDS. RESULTS: Patients who took G cambogia were between 17 and 54 years, with liver injury arising 13-223 days (median = 51) after the start. One patient died, one required liver transplantation, and 91% were hospitalized. The liver injury was hepatocellular with jaundice. Although the peak values of aminotransferases were significantly higher (2001 ± 1386 U/L) in G cambogia group (P < .018), the median time for improvement in total bilirubin was significantly lower compared with the control groups (10 vs 17 and 13 days; P = .03). The presence of HLA-B∗35:01 allele was significantly higher in the G cambogia containing HDS (55%) compared with patients because of other HDS (19%) (P = .002) and those with acute liver injury from conventional drugs (12%) (P = 2.55 × 10-6). CONCLUSIONS: The liver injury caused by G cambogia and green tea is clinically indistinguishable. The possible association with HLA-B∗35:01 allele suggests an immune-mediated mechanism of injury. CLINICAL TRIALS: gov number: NCT00345930.

Liver injury associated with kratom, a popular opioid-like product: Experience from the U.S. drug induced liver injury network and a review of the literature.

BACKGROUND: Kratom is a botanical product used as an opium substitute with abuse potential. METHODS: Assessment of suspected cases of kratom-induced liver injury in a prospective US cohort. RESULTS: Eleven cases of liver injury attributed to kratom were identified with a recent increase. The majority were male with median age 40 years. All were symptomatic and developed jaundice with a median latency of 14 days. The liver injury pattern was variable, most required hospitalization and all eventually recovered. Biochemical analysis revealed active kratom ingredients. CONCLUSION: Kratom can cause severe liver injury with jaundice.

HLA-B*35:01 and Green Tea-Induced Liver Injury.

BACKGROUND AND AIMS: Herbal supplements, and particularly multi-ingredient products, have become increasingly common causes of acute liver injury. Green tea is a frequent component in implicated products, but its role in liver injury is controversial. The aim of this study was to better characterize the clinical features, outcomes, and pathogenesis of green tea-associated liver injury. APPROACH AND RESULTS: Among 1,414 patients enrolled in the U.S. Drug-Induced Liver Injury Network who underwent formal causality assessment, 40 cases (3%) were attributed to green tea, 202 to dietary supplements without green tea, and 1,142 to conventional drugs. The clinical features of green tea cases and representation of human leukocyte antigen (HLA) class I and II alleles in cases and control were analyzed in detail. Patients with green tea-associated liver injury ranged in age from 17 to 69 years (median = 40) and developed symptoms 15-448 days (median = 72) after starting the implicated agent. The liver injury was typically hepatocellular (95%) with marked serum aminotransferase elevations and only modest increases in alkaline phosphatase. Most patients were jaundiced (83%) and symptomatic (88%). The course was judged as severe in 14 patients (35%), necessitating liver transplantation in 3 (8%), but rarely resulting in chronic injury (3%). In three instances, injury recurred upon re-exposure to green tea with similar clinical features, but shorter time to onset. HLA typing revealed a high prevalence of HLA-B*35:01, found in 72% (95% confidence interval [CI], 58-87) of green tea cases, but only 15% (95% CI, 10-20) caused by other supplements and 12% (95% CI, 10-14) attributed to drugs, the latter rate being similar to population controls (11%; 95% CI, 10.5-11.5). CONCLUSIONS: Green tea-related liver injury has distinctive clinical features and close association with HLA-B*35:01, suggesting that it is idiosyncratic and immune mediated.

Potential Modulation of Human NAD[P]H-Quinone Oxidoreductase 1 (NQO1) by EGCG and Its Metabolites-A Systematic Computational Study.

At high doses, green tea extracts and green tea's major active constituent, (-)-epigallocatechin gallate (EGCG), despite their generally perceived health benefits, have been suspected to cause hepatotoxicity in certain human populations. It has been reported that o-quinone metabolites of gallic acid or EGCG are causative agents for this hepatotoxicity. However, no experimental information is available at the molecular level on the possible role of NQO1 in the detoxification of EGCG and its metabolites, including reactive intermediates. In the present study, we investigated the possibility of NQO1 inhibition by EGCG and its metabolites by studying their interaction profiles and binding mechanism at the active site of NQO1 using molecular docking, binding free energy calculations, and molecular dynamics (MD) simulations. The binding free energy calculations showed that some metabolites exhibited strong predicted binding affinity and found that the binding orientation of the EGCG metabolites overlapped with that of dicoumarol found in an NQO1 X-ray crystal structure. The results suggest that these metabolites may act as strong NQO1 inhibitors, highlighting the need for experimental validation of this with appropriate biological methods. The Prime MM-GBSA computed average binding free energies after MD simulations of compounds 1, 2, 24, 31, and 33 revealed that these compounds highly favored van der Waals (VdW) and Coulombic interactions with NQO1. In addition, the MD results revealed that selected EGCG metabolites formed a stable and strong complex with NQO1, with amino acids W105, Y126, Y128, H161, F178, H194, F232, and F236 being critical for potential NQO1 binding. The current results together with experimental data as well as studies of the polymorphisms of NQO1 (especially C609T) may explain the observed idiosyncratic hepatotoxicity caused by the consumption of green tea and its constituents.

Correction: Silymarin in non-cirrhotics with non-alcoholic steatohepatitis: A randomized, double-blind, placebo controlled trial.

[This corrects the article DOI: 10.1371/journal.pone.0221683.].

Silymarin in non-cirrhotics with non-alcoholic steatohepatitis: A randomized, double-blind, placebo controlled trial.

The botanical product silymarin, an extract of milk thistle, is commonly used by patients to treat chronic liver disease and may be a treatment for NASH due to its antioxidant properties. We aimed to assess the safety and efficacy of higher than customary doses of silymarin in non-cirrhotic patients with NASH. This exploratory randomized double-blind placebo controlled multicenter Phase II trial tested a proprietary standardized silymarin preparation (Legalon®, Rottapharm|Madaus, Mylan) and was conducted at 5 medical centers in the United States. Eligible adult patients had liver biopsy within 12 months showing NASH without cirrhosis with NAFLD Activity Score (NAS) ≥4 per site pathologist's assessment. Participants were randomized to Legalon® 420 mg, 700 mg, or placebo t.i.d. for 48 weeks. The primary endpoint was histological improvement ≥2 points in NAS. Of 116 patients screened, 78 were randomized. There were no significant differences in adverse events among the treatment groups. After 48-50 weeks, 4/27 (15%) in the 700 mg dose, 5/26 (19%) participants randomized to 420 mg, and 3/25 (12%) of placebo recipients reached the primary endpoint (p = 0.79) among all randomized participants, indicating no benefit from silymarin in the intention to treat analysis Review by a central pathologist demonstrated that a substantial number of participants (49, 63%) did not meet histological entry criteria and that fibrosis stage improved most in the placebo treated group, although not significantly different from other groups. Silymarin (Legalon®) at the higher than customary doses tested in this study is safe and well tolerated. The effect of silymarin in patients with NASH remains inconclusive due to the substantial number of patients who entered the study but did not meet entry histological criteria, the lack of a statistically significant improvement in NAS of silymarin treated patients, and the unanticipated effect of placebo on fibrosis indicate the need for additional clinical trials. Trial Registration: clinicaltrials.gov, Identifier: NCT00680407.

Importance of Hepatitis C Virus RNA Testing in Patients with Suspected Drug-Induced Liver Injury.

BACKGROUND AND AIMS: The aims were to review the diagnosis, testing and presentation of acute hepatitis C (HCV) in patients initially diagnosed to have drug-induced liver injury (DILI) enrolled in the US DILI Network. METHODS: All patients with suspected DILI underwent testing for competing causes of liver injury and returned for 6-month follow-up. Causality was adjudicated by consensus expert opinion. RESULTS: Between 2004 and 2016, 1518 patients were enrolled and adjudicated and underwent 6 months of follow-up. Initial locally acquired anti-HCV results were available in 1457 (96%), but HCV RNA in only 795 (52%). Stored sera were available for repeat testing, so that results were available on all 1518 patients (1457 for anti-HCV and 1482 for HCV RNA). A total of 104 subjects (6.9%) had evidence of HCV infection-10 positive for HCV RNA alone, 16 for anti-HCV alone and 78 for both. All 104 HCV-positive cases were reviewed, and 23 cases were adjudicated as acute HCV. All presented with acute hepatocellular injury with median ALT 1448 U/L, alkaline phosphatase 232 U/L and total bilirubin 10.8 mg/dL. Twenty-two (96%) patients were jaundiced. While all 23 cases initially had been suspected of having DILI, 19 were adjudicated as acute HCV and not DILI at the 6-month follow-up; while 4 were still considered DILI. CONCLUSIONS: Twenty-three of 1518 (1.5%) cases of suspected DILI were due to acute HCV infection. We recommend that initial and follow-up HCV RNA testing should be performed to exclude HCV in patients with acute hepatocellular injury and suspected DILI.

Liver injury from herbal and dietary supplements.

Herbal and dietary supplements (HDS) are used increasingly both in the United States and worldwide, and HDS-induced liver injury in the United States has increased proportionally. Current challenges in the diagnosis and management of HDS-induced liver injury were the focus of a 2-day research symposium sponsored by the American Association for the Study of Liver Disease and the National Institutes of Health. HDS-induced liver injury now accounts for 20% of cases of hepatotoxicity in the United States based on research data. The major implicated agents include anabolic steroids, green tea extract, and multi-ingredient nutritional supplements. Anabolic steroids marketed as bodybuilding supplements typically induce a prolonged cholestatic but ultimately self-limiting liver injury that has a distinctive serum biochemical as well as histological phenotype. Green tea extract and many other products, in contrast, tend to cause an acute hepatitis-like injury. Currently, however, the majority of cases of HDS-associated liver injury are due to multi-ingredient nutritional supplements, and the component responsible for the toxicity is usually unknown or can only be suspected. HDS-induced liver injury presents many clinical and research challenges in diagnosis, identification of the responsible constituents, treatment, and prevention. Also important are improvements in regulatory oversight of nonprescription products to guarantee their constituents and ensure purity and safety. The confident identification of injurious ingredients within HDS will require strategic alignments among clinicians, chemists, and toxicologists. The ultimate goal should be to prohibit or more closely regulate potentially injurious ingredients and thus promote public safety. (Hepatology 2017;65:363-373).

Severe Acute Hepatocellular Injury Attributed to OxyELITE Pro: A Case Series.

BACKGROUND/AIM: Herbal and dietary supplement (HDS) hepatotoxicity is increasingly being reported in the USA. This case series describes the presenting clinical features and outcomes of seven patients with liver injury attributed to OxyELITE Pro enrolled in the Drug-Induced Liver Injury Network (DILIN) study. METHODS: The 6-month outcomes of patients with hepatotoxicity attributed to OxyELITE Pro enrolled in the DILIN prospective registry between 2004 and 2015 are presented. RESULTS: Six of the seven patients (86 %) presented in 2013 with symptoms of hepatitis and acute hepatocellular injury. The median duration of OxyELITE Pro use was 18 weeks (range 5-102 weeks). Median age was 36 years (range 28-62), 86 % were female, and 43 % were Asian. One patient had rash, none had eosinophilia, and three had antinuclear antibody reactivity. The median peak ALT was 2242 U/L, alkaline phosphatase 284 U/L and bilirubin 15.0 mg/dL. Six patients (86 %) were hospitalized, three developed acute liver failure and two underwent liver transplantation. DILIN causality scores for OxyELITE Pro were definite in 1, highly likely in 3, probable in 2, and possible in 1. Four of the five patients without liver transplant recovered completely within 6 months, while one patient had mild residual ALT elevations. CONCLUSIONS: Seven cases of severe acute hepatocellular injury attributed to OxyELITE Pro are reported. These results reinforce the need to assess for HDS supplement use in patients presenting with unexplained acute hepatitis and point to the need for additional regulatory oversight of HDS products.

Risk of Liver Injury Associated with Green Tea Extract in SLIMQUICK(®) Weight Loss Products: Results from the DILIN Prospective Study.

INTRODUCTION: Herbal and dietary supplements (HDS) have been increasingly recognized as a cause for acute liver injury (Navarro et al. Hepatology 60(4):1399-1408, 2014; Bailey et al. J Nutr 141:261-266, 2011). HDS products frequently contain numerous ingredients, and are marketed under various product names. A perusal of marketed weight loss products indicates that green tea extract (GTE) is a common ingredient in many. We aimed to describe the course and outcome of six patients who developed liver injury attributed to SLIMQUICK(®) weight loss products. METHODS: Patients with suspected drug-induced liver injury were enrolled in a prospective study of the Drug-Induced Liver Injury Network (DILIN) and causality was assessed by a panel of hepatologists. During the period under study, 6 of 1091 cases of liver injury were attributed to a SLIMQUICK(®) product and were assigned causality scores of probable, highly likely, or definite. RESULTS: Six cases of acute liver injury attributed to SLIMQUICK(®) products were enrolled in the DILIN prospective study between 2007 and 2011. All were women aged 22 to 58 years. Two had a normal body weight and four were mildly obese (body mass index 22.9-32.2 kg/m(2)). All were taking SLIMQUICK(®) products for weight loss and no patient reported prior use. Laboratory tests revealed a hepatocellular pattern of injury, with initial alanine aminotransferase (ALT) levels above 1000 U/L in all but one patient. Three patients were hospitalized and one underwent successful liver transplantation. No patients died of liver injury. GTE and/or its component catechins were listed among the ingredients for five of the six products. CONCLUSIONS: SLIMQUICK(®) products can lead to severe acute hepatocellular liver injury, which may result in transplantation. Given the frequency of GTE as a component in weight loss products, this ingredient should be studied further as a possible cause for liver injury.

Liver Injury from Herbal, Dietary, and Weight Loss Supplements: a Review.

Herbal and dietary supplement usage has increased steadily over the past several years in the United States. Among the non-bodybuilding herbal and dietary supplements, weight loss supplements were among the most common type of HDS implicated in liver injury. While drug induced liver injury is rare, its consequences are significant and on the rise. The purpose of this review is to highlight case reports of weight loss products such as Hydroxycut and OxyElite Pro as one form of HDS that have hepatotoxic potential and to characterize its clinical effects as well as pattern of liver injury. We also propose future strategies in the identification and study of potentially hepatotoxic compounds in an effort to outline a diagnostic approach for identifying any drug induced liver injury.