Challenges in herbal-induced liver injury identification and prevention.

Herbal and dietary supplements (HDS) are being used worldwide at an increasing rate. Mirroring this trend, HDS-induced liver injury, also known as HDS-induced liver injury (HILI), has increased significantly over the past three decades in the Drug-Induced Liver Injury Network (DILIN), now accounting for 20% of cases of drug-induced liver injury (DILI). There are significant challenges in the identification and prevention of HILI due to varying presentations, ability to make clear diagnosis, identification of the responsible ingredient, lack of treatment, and lack of regulatory oversight of HDS products to confirm their ingredients and ensure safety. The major implicated agents include anabolic steroids, green tea extract, garcinia cambogia, kratom, ashwagandha, turmeric and multi-ingredient nutritional supplements. Fortunately, with the formation of major DILI consortiums across the world, the last decade has seen advances in the identification of at-risk genetic phenotypes, the use of chemical analysis on multi-ingredient nutritional supplements, and the publication of data/injury patterns of potentially risky HDS.

[Interpretation on Consensus on drug-induced liver injury by CIOMS Working Group:liver injury attributed to herbal and dietary supplements].

With the increase in the medical level, the improvement of adverse drug reaction(ADR) monitoring systems, and the enhancement of public awareness of safe medication, drug safety incidents have been frequently reported. Drug-induced liver injury(DILI), especially liver injury attributed to herbal and dietary supplements(HDS), has globally attracted high attention, bringing great threats and severe challenges to the people for drug safety management such as clinical medication and medical supervision. Consensus on drug-induced liver injury had been published by the Council for International Organizations of Medical Sciences(CIOMS) in 2020. In this consensus, liver injury attributed to HDS was included in a special chapter for the first time. The hot topics, including the definition of HDS-induced liver injury, epidemiological history, potential risk factors, collection of related risk signals, causality assessment, risk prevention, control and management were discussed from a global perspective. Based on the previous works, some experts from China were invited by CIOMS to undertake the compilation of this chapter. Meanwhile, a new causality assessment in DILI based on the integrated evidence chain(iEC) method was widely recognized by experts in China and abroad, and was recommended by this consensus. This paper briefly introduced the main contents, background, and characteristics of the Consensus on drug-induced liver injury. Significantly, a brief interpretation was illustrated to analyze the special highlights of Chapter 8, "Liver injury attributed to HDS", so as to provide practical references for the medical staff and the researchers who worked on either Chinese or Western medicine in China.

Herbal and Dietary Supplements-Induced Liver Injury in Latin America: Experience From the LATINDILI Network.

BACKGROUND: Herbal and dietary supplements (HDS) consumption, a growing cause of hepatotoxicity, is a common practice among Latin-American populations. OBJECTIVES: To evaluate clinical, laboratory features and outcome in HDS-hepatotoxicity included in the Latin America-Drug Induced Liver Injury (LATINDILI) Network. METHODS: A total of 29 adjudicated cases of HDS hepatotoxicity reported to the LATINDILI Network from October 2011 through December 2019 were compared with 322 DILI cases due to conventional drugs and 16 due to anabolic steroids as well as with other series of HDS-hepatotoxicity. RESULTS: From 367 DILI cases, 8% were attributed to HDS. An increasing trend in HDS-hepatotoxicity was noted over time (p = .04). Camellia sinensis, Herbalife® products, and Garcinia cambogia, mostly used for weight loss, were the most frequently adjudicated causative agents. Mean age was 45 years (66% female). Median time to onset was 31 days. Patients presented typically with hepatocellular injury (83%) and jaundice (66%). Five cases (17%) developed acute liver failure. Compared to conventional medications and anabolic steroids, HDS hepatotoxicity cases had the highest levels of aspartate and alanine transaminase (p = .008 and p = .021, respectively), had more re-exposure events to the culprit HDS (14% vs 3% vs 0%; p = .026), and had more severe and fatal/liver transplantation outcomes (21% vs 12% vs 13%; p = .005). Compared to other DILI cohorts, less HDS hepatotoxicity cases in Latin America were hospitalized (41%). CONCLUSIONS: HDS-hepatotoxicity in Latin-America affects mainly young women, manifests mostly with hepatocellular injury and is associated with higher frequency of accidental re-exposure. HDS hepatotoxicity is more serious with a higher chance of death/liver transplantation than DILI related to conventional drugs.

Monocyte-Derived Hepatocyte-Like Cell Test: A Novel Tool for in vitro Identification of Drug-Induced Liver Injury in Patients with Herbal or Dietary Supplements.

BACKGROUND: Drug-induced liver injury caused by herbal and dietary supplements (HDS) has been an increasingly important phenomenon in recent years. Diagnosis is the major challenge. Definite causality assessment, especially in patients with concomitant prescription medicine or other potential causes of liver injury, can be impossible. OBJECTIVES: We investigated the usefulness of an in vitro test on the basis of peripheral monocytes of the individual patients in patients with acute liver injury consuming HDS. METHOD: Patients with acute liver injury who had been prospectively recruited by the University Hospital Munich (LMU, Munich) and the Chinese University of Hong Kong (CUHK) and who took at least 1 HDS were selected for this analysis. Diagnosis of drug-induced liver injury (DILI) was based on local expert adjudication, Roussel Uclaf Causality Assessment Method (RUCAM) score, and course of the disease and was supported by the monocyte-derived hepatocyte-like (MH) cell test. RESULTS: We identified 47 patients with liver injury and intake of at least 1 HDS: 32 (68%) were diagnosed with DILI. HDS was determined as the causative agent in 28 out of those 32 patients. The MH cell test could correctly identify 29 out of those 32 DILI cases and showed false positive results in only 2 out of the 15 non-DILI patients. The MH cell test therefore reached a sensitivity and specificity of 90.6 and 86.7%, respectively, in patients with acute liver injury and HDS intake. CONCLUSIONS: Our data provide evidence that the MH cell test can be a useful tool to identify the role of HDS in causing DILI and therefore support causality assessment in patients consuming HDS.

Screening of hepatotoxic compounds in Psoralea corylifolia L., a traditional Chinese herbal and dietary supplement, using high-resolution mass spectrometry and high-content imaging.

Owing to the complexity of the composition of herbal and dietary supplements, it is a challenging problem to efficiently screen and identify active or toxic compounds. Psoralea corylifolia L. (PCL) was selected as the subbject to establish a methodology for rapid screening and identification of hepatotoxic compounds. High-content imaging, ultra-performance liquid chromatography and high-resolution mass spectrometry were used in this study to detect the hepatotoxicity and identify unknown compounds in PCL samples. Then, putative toxic compounds which are highly related to hepatotoxicity were screened by spectrum-toxicity correlation analysis, and the toxicity intensity verified by high-content imaging. The maximum nontoxic dose of processed samples with good detoxification effect reduced more than 9 times compared with unprocessed raw medicinal materials. Spectrum-toxicity correlation analysis showed that bavachinin A, bavachin, isobavachalcone and neobavaisoflavone had high correlation with the hepatotoxicity of PCL, and psoralen and isopsoralen had low correlation with hepatotoxicity. This study verified the hepatotoxicity of these six putative compound monomers, proving the results of spectrum-toxicity correlation analysis. Based on the correlation analysis of high-resolution mass spectrometry of detection compounds and high-content imaging of hepatocyte toxicity data, the potential toxic compound of herbal and dietary supplement products can be quickly and accurately screened.

Profile of herbal and dietary supplements induced liver injury in Latin America: A systematic review of published reports.

Hepatotoxicity related to HDS is a growing global health issue. We have undertaken a systematic review of published case reports and case series from LA from 1976 to 2020 to describe the clinical features of HDS related hepatotoxicity in this region. We search in PubMed, Web of Science, Scopus and specific LA databases according to PRISMA guidelines. Only HILI cases published in LA that met criteria for DILI definition were included. Duplicate records or reports that lacked relevant data that precluded establishing causality were excluded. Finally, 17 records (23 cases) were included in this review. Centella asiatica, Carthamus tinctorius, and Herbalife® were the most reported HDS culprit products, the main reason for HDS consumption was weight loss. The clinical characteristics of HDS hepatotoxicity in our study were compared to those of other studies in the USA, Europe and China showing a similar signature with predominance of young females, hepatocellular damage, a high rate of ALF and mortality, more frequent inadvertent re-challenge and chronic damage. This study underscores the challenge in causality assessment when multi-ingredients HDS are taken and the need for consistent publication practice when reporting hepatotoxicity cases due to HDS, to foster HDS liver safety particularly in LA.

The landscape of hepatobiliary adverse reactions across 53 herbal and dietary supplements reveals immune-mediated injury as a common cause of hepatitis.

Recent evidence suggests herbal-induced liver injury (HILI) to account for 20% of cases among the U.S. Drug-Induced-Liver-Injury-Network. To define injury patterns of HILI, we reviewed the clinical data of 413 patients exposed to 53 HDS products by considering the evidence for HILI and its grades of severity. Outstandingly, females developed HILI more rapidly (p = 0.018) and the time to recovery was significantly increased (p = 0.0153). > 90% of reported cases were severe and half of HDS products caused acute liver failure (ALF) requiring liver transplantation or resulted in fatal outcomes. Liver biopsies of 243 patients defined 13 histological features; two-thirds of products elicited immune-mediated hepatitis and included 154 Hy's law positive cases. The histological injury patterns were confirmed among unrelated patients, while accidental re-challenges evidenced culprits as causative. Furthermore, one-fifth of patients presented elevated autoantibody titres indicative of autoimmune-like HILI, and one-third of the products were linked to chronic hepatitis and cholestatic injuries not resolving within 6 months. Lastly, INR and TBL are critical laboratory parameters to predict progression of severe HILI to ALF. Our study highlights the need for a regulatory framework to minimize the risk for HILI. Better education of the public and a physician-supervised self-medication plan will be important measures to abate risk of HILI.

The Development of a Database for Herbal and Dietary Supplement Induced Liver Toxicity.

The growing use of herbal dietary supplements (HDS) in the United States provides compelling evidence for risk of herbal-induced liver injury (HILI). Information on HDS products was retrieved from MedlinePlus of the U.S. National Library of Medicine and the herbal monograph of the European Medicines Agency. The hepatotoxic potential of HDS was ascertained by considering published case reports. Other relevant data were collected from governmental documents, public databases, web sources, and the literature. We collected information for 296 unique HDS products. Evidence of hepatotoxicity was reported for 67, that is 1 in 5, of these HDS products. The database revealed an apparent gender preponderance with women representing 61% of HILI cases. Culprit hepatotoxic HDS were mostly used for weight control, followed by pain and inflammation, mental stress, and mood disorders. Commonly discussed mechanistic events associated with HILI are reactive metabolites and oxidative stress, mitochondrial injury, as well as inhibition of transporters. HDS⁻drug interactions, causing both synergistic and antagonizing effects of drugs, were also reported for certain HDS. The database contains information for nearly 300 commonly used HDS products to provide a single-entry point for better comprehension of their impact on public health.

"Autoimmune(-Like)" Drug and Herb Induced Liver Injury: New Insights into Molecular Pathogenesis.

Idiosyncratic drug-induced liver injury (DILI) and hepatic injury due to herbal and dietary supplements (HDS) can adapt clinical characteristics of autoimmune hepatitis (AIH), such as the appearance of autoantibodies and infiltration of the liver by immune competent cells. To describe these cases of DILI/HDS, the poorly-defined term "autoimmune(-like)" DILI/HDS came up. It is uncertain if these cases represent a subgroup of DILI/HDS with distinct pathomechanistic and prognostic features different from "classical" DILI/HDS. Besides, due to the overlap of clinical characteristics of "immune-mediated" DILI/HDS and AIH, both entities are not easy to differentiate. However, the demarcation is important, especially with regard to treatment: AIH requires long-term, mostly lifelong immunosuppression, whereas DILI/HDS does not. Only through exact diagnostic evaluation, exclusion of differential diagnoses and prolonged follow-up can the correct diagnosis reliably be made. Molecular mechanisms have not been analysed for the subgroup of "autoimmune(-like)" DILI/HDS yet. However, several pathogenetic checkpoints of DILI/HDS in general and AIH are shared. An analysis of these shared mechanisms might hint at relevant molecular processes of "autoimmune(-like)" DILI/HDS.

Hepatocellular Jaundice due to Hydroxycut in Monozygotic Twins.

Liver injury associated with the use of a number of different of herbal and dietary supplements are increasingly recognized. It is though often unclear which of the sometimes multiple ingredients are responsible for the liver injury. Several case reports have been published on suspected liver injury due to Hydroxycut, which is a multi-ingredient supplement often used to induce weight loss. However, the hepatotoxic potential of Hydroxycut has though been disputed, and steatotic liver disease has also been implicated in patients who are found to have elevated liver enzymes while on Hydroxycut. We report clinically apparent liver injury with jaundice associated with the use of Hydroxycut in monozygotic twins with remarkably similar type of liver injury. Both had the genotype HLA-B 35:01 allele, a risk factor for green-tea extract induced liver injury, which is included in Hydroxycut.

Herbal and dietary supplement induced liver injury leading to hepatitis-associated severe aplastic anemia: A case report.

Herbal and dietary supplements (HDS) are a common etiology of drug induced liver injury and, specifically, Herbalife® supplements have been implicated. Hepatitis associated aplastic anemia (HAAA) is a rare and potentially fatal complication after acute hepatitis characterized by pancytopenia. While there have been rare cases of HDS leading to HAAA, no cases of Herbalife® induced liver injury leading to HAAA have been reported from this specific HDS. We report a unique case of severe aplastic anemia developing after sub-fulminant liver failure associated with chronic HDS use. This case illustrates the importance of warning the public about HDS as their use continues to increase. It is not only important to recognize HDS as etiology, but also for healthcare providers to carefully monitor these patients after resolution of liver injury for the development of HAAA.

Chinese guideline for the diagnosis and treatment of drug-induced liver injury: an update.

Drug-induced liver injury (DILI) is an important adverse drug reaction that can lead to acute liver failure or even death in severe cases. Currently, the diagnosis of DILI still follows the strategy of exclusion. Therefore, a detailed history taking and a thorough and careful exclusion of other potential causes of liver injury is the key to correct diagnosis. This guideline was developed based on evidence-based medicine provided by the latest research advances and aims to provide professional guidance to clinicians on how to identify suspected DILI timely and standardize the diagnosis and management in clinical practice. Based on the clinical settings in China, the guideline also specifically focused on DILI in chronic liver disease, drug-induced viral hepatitis reactivation, common causing agents of DILI (herbal and dietary supplements, anti-tuberculosis drugs, and antineoplastic drugs), and signal of DILI in clinical trials and its assessment.

A Yellow Flower With Jaundice Power: Liver Injury Attributed to Greater Celandine.

Greater celandine (Chelidonium majus) leaf extracts have been used for centuries as a natural remedy for various gastrointestinal symptoms. Greater celandine is associated with several case reports of hepatotoxicity, mainly from Europe. No cases from the United States have been identified. We present a case of acute hepatitis from greater celandine in the United States in a 72-year-old man taking this herbal supplement for nausea. In patients presenting with acute liver injury, gastroenterologists should be aware of this herb and reminded to assess for herbal and dietary supplement hepatotoxicity, especially in those remedies used to treat common gastrointestinal symptoms.

Acute Liver Failure Induced by Provitalize: A Menopause Supplement Concocted From Herbs & Probiotics.

Drug-induced liver injury is one of the most common causes of acute liver failure in the Western world. Despite discontinuation of the offending agent, it can still tax a grim prognosis. We describe a case of a menopausal woman taking a herbal supplement called "Provitalize" to relieve hot flashes and bloating. This is the first case report of liver injury from this supplement. She initially presented with mild jaundice and elevated transaminases. Unfortunately, she rapidly progressed to encephalopathy, experienced multiorgan failure, and then died.

Ashwagandha-induced acute liver injury: A case report.

Drug-induced liver injury became one of the most important liver disorders and diagnostic challenge for clinicians and pathologists. Here, we report a rare case of ashwagandha-induced acute liver injury. The patient developed jaundice 2 weeks after starting ashwagandha intake and recovered within 5 months after withdrawal without any specific treatment.

The use of herbal and dietary supplements for COVID-19 prevention: A survey among the public in a Malaysian suburban town.

Introduction: The spread of the novel coronavirus disease (COVID-19) may lead people to seek preventative measures. The use of herbal and dietary supplements (HDS) may have become prevalent during the COVID-19 pandemic. This study aims to identify the prevalence, predictors, and patterns of HDS use for COVID-19 prevention in a sample of the general public in a suburban town in Malaysia. Methods: An online cross-sectional survey was conducted between May and June 2021 involving adults ≥ 18 years old. Data on the self-reported use of HDS for COVID-19 prevention were collected. Logistic regression analysis was conducted to determine the predictors of HDS use. Results: Overall, 41.9 % (168/401) reported using HDS to prevent COVID-19. Multivariate analysis showed that HDS users were more likely to be individuals ≥ 40 years old (adjusted odds ratio [aOR] = 1.774, 95 % confidence interval [CI] = 1.016 - 3.098), and to have had a history of HDS use prior to the pandemic (aOR = 19.378, 95 % CI = 5.901 - 63.639). Most HDS users referred to social media or websites (66.7 %, 112/168) for HDS information. Approximately half of them had consulted either pharmacists or doctors about their HDS use. Conclusion: HDS use to prevent COVID-19 was common among the respondents. Several issues - such as the concurrent use of HDS with conventional medications, the use of unreliable sources of information, and the lack of consultation with healthcare providers (HCPs) - indicate that HCPs should be more proactive in their consultative and information-providing roles regarding HDS use.

Drug-Induced Liver Injury from Herbal Liver Detoxification Tea.

The increasing consumption of unregulated herbal and dietary supplements has presented clinicians with new challenges in assessing and managing acute liver injury. Patients may present in various ways ranging from asymptomatic transaminitis to acute liver failure. Several natural products have been found to mitigate drug-induced liver injury, which has led to the creation of numerous registries to outline all its aspects further. We describe the case of a 36-year-old female who developed a clinically significant acute liver injury with a cholestatic pattern due to an over-the-counter herbal liver detox tea. This is the first case reported of a hepatotoxic effect from any of these compounds or ingredients in the detox tea: burdock root, stinging nettle leaf, cleavers herb, dandelion root, lemon peel, and lemon myrtle leaf (Backhousia citriodora). Idiosyncratic drug-induced liver injury (DILI) remains poorly understood; however, recognizing potential toxins is imperative to understanding toxicogenomics and identifying those at risk.

Why Did I Consult My Pharmacist about Herbal and Dietary Supplements? An Online Survey Amid the COVID-19 Pandemic in Malaysia.

Herbal and dietary supplements (HDSs) are frequently obtained from community pharmacies, but community pharmacists (CPs) have been underutilized for information regarding them. This study aimed to determine the prevalence of, factors behind, and reasons for consultation with CPs among HDS consumers in Malaysia. A cross-sectional study using an online survey was conducted among conveniently sampled individuals in Malaysia. Reasons for consultation or non-consultation with CPs about HDSs were sought from the respondents. A logistic regression analysis was conducted to determine the predictors of consultation with CPs. Overall, 40.3% (239/593) of participants consulted CPs about the HDSs that they purchased. The participants were predominantly unmarried (362/588, 61.6%) and belonged to the 18-29 age group (332/593, 56%). The multivariate analysis showed that a suburban residential setting was the only significant predictor for consultation with CPs (adjusted odds ratio = 0.390, 95% CI = 0.260-0.583). Respondents who consulted CPs generally agreed that the CPs were the right people to consult on HDSs (mean = 4.37, SD = 0.73). However, their discussion with CPs regarding HDSs mostly revolved around the benefits and directions for use, but little on the potential risks. Meanwhile, most respondents who did not consult CPs agreed that they had never thought of consulting CPs about their HDS use (mean = 3.45, SD = 1.02). The majority of them referred to the Internet (61.3%, 217/354) and social media (59.9%, 212/354) for information about HDSs. The findings from this study show that more efforts are warranted in encouraging consumers to consult CPs about their HDS use and to enhance their awareness of the roles of CPs in ensuring the safe use of HDSs.

Self-Learning about Herbal and Dietary Supplements: Perspectives Using the Theoretical Domains Framework.

Background: Self-learning (SL) is a process in which individuals take the initiative to acquire knowledge with or without the help of others. Knowledge about herbal and dietary supplements (HDS) is important for pharmacists. Unfortunately, there is limited coverage of topics relating to HDS in the pharmacy curricula. The present focus group study applies the Theoretical Domains Framework (TDF) to explore pharmacy students' practices and beliefs regarding SL about HDS (SL-HDS). Methods: Focus group interviews (FGIs) were conducted between April and May 2019 among a sample of undergraduate pharmacy students at a public university (n = 20). Four FGI sessions were conducted, each lasting about 60 to 75 min, and all the sessions were audio-recorded. The interviews were transcribed verbatim and analysed using thematic content analysis. Results: Beliefs about SL-HDS were categorised into 12 domains based on the TDF. Students showed positive attitudes towards SL-HDS and agreed that their involvement in SL-HDS was instrumental in improving their knowledge about various aspects of HDS including indications, adverse effects, and HDS-drug interactions. Various facilitators and barriers influencing students' participation in SL-HDS were uncovered (e.g., access to the internet, time, availability of reference resources). The students demanded to be equipped with critical appraisal skills, as they had limited confidence in assessing literature or information about HDS. Conclusion: This study revealed that the students saw the benefits of SL-HDS. They also perceived that engaging in SL-HDS is compatible with the role of pharmacy students. The findings showed students' readiness and willingness to conduct SL-HDS.

Integrative medicine smart phrase pilot study: Evaluating an EHR tool to improve providers' attitudes, knowledge and use of herbal and dietary supplements.

CONTEXT: While many patients use herbal and dietary supplements (H/DS) for wellness, disease prevention and treatment, providers still cite a lack of resources and formal training as barriers to responding to patients' inquiries about H/DS. Although the federal government, academic institutions and the private sector now offer more opportunities for education and research on H/DS, greater support in real time is needed to facilitate providers during the clinical encounter. OBJECTIVE: This small, pilot study evaluates the effects of implementation of smart phrases in the electronic health record (EHR) and an educational intervention on providers' knowledge, attitude and use of H/DS in the clinical encounter. DESIGN, SETTING AND PARTICIPANTS: The study was conducted at The Institute for Family Health (IFH), a Federally Qualified Health Center and academic health center which operates the Department of Family Medicine and Community Health in affiliation with the Icahn School of Medicine at Mount Sinai. Baseline and post-intervention surveys were conducted to explore providers' attitudes, knowledge and use of integrative medicine (IM) smart phrases on H/DS. MAIN OUTCOME MEASURES: Providers' awareness of smart phrases of H/DS, knowledge of the content, confidence in using smart phrases to discuss H/DS, self-reported use of smart phrases were measured. RESULTS: A total of 32 subjects participated in the intervention and completed the baseline survey. Only half of the participants were familiar with the IM smart phrases in our system and 12.5% felt they were aware of the information covered in these smart phrases. Eighteen of 32 participants completed the post-intervention assessment. The intervention was successful in statistically increasing participants' self-reported awareness of the information covered in the IM smart phrases (p<0.01). Increased confidence in using IM smart phrases to initiate patients on a new supplement showed statistical significance (p=0.03). There were no clear patterns in reported behavior changes following the training with the exception of a significant increase in the self-reported frequency of past month use of IM smart phrases during a patient visit (p=0.01). Lastly, there were no changes in the frequency of smart phrase use in the EHR. CONCLUSION: The implementation and adoption of evidence-based use of H/DS in the clinical encounter requires a sustained educational component to make the availability of smart phrases via technology (EHR) an effective strategy.