Herbal hepatotoxicity: a critical review

This review deals with herbal hepatotoxicity, identical to herb induced liver injury (HILI), and critically summarizes the pitfalls associated with the evaluation of assumed HILI cases. Analysis of the relevant publications reveals that several dozens of different herbs and herbal products have been implicated to cause toxic liver disease, but major quality issues limit the validity of causality attribution. In most of these reports, discussions around quality specifications regarding herbal products, case data presentations and causality assessment methods prevail. Though the production of herbal drugs is under regulatory surveillance and quality aspects are normally not a matter of concern, low quality of the less regulated herbal supplements may be a critical issue considering product batch variability, impurities, adulterants and herb misidentifications. Regarding case data presentation, essential diagnostic information is often lacking, as is the use of valid and liver specific causality assessment methods that also consider alternative diseases. At present, causality is best assessed by using the Council for International Organizations of Medical Sciences scale ( CIOMS) in its original or updated form, which should primarily be applied prospectively by the treating physician when evaluating a patient rather than retrospectively by regulatory agencies. To cope with these problems, a common quality approach by manufacturers, physicians and regulatory agencies should strive for the best quality. We propose steps for improvements with impact on future cases of liver injury by herbs, herbal drugs and herbal supplements.     

Regulatory causality evaluation methods applied in kava hepatotoxicity: Are they appropriate?

Since 1998 liver injury has been assumed in some patients after the use of kava (Piper methysticum G. Forster) as an anxyolytic herbal extract, but the regulatory causality evaluation of these cases was a matter of international and scientific debate. This review critically analyzes the regulatory issues of causality assessments of patients with primarily suspected kava hepatotoxicity and suggests recommendations for minimizing regulatory risks when assessing causality in these and other related cases. The various regulatory causality approaches were based on liver unspecific assessments such as ad hoc evaluations, the WHO scale using the definitions of the WHO Collaborating Centre for International Drug Monitoring, and the Naranjo scale. Due to their liver unspecificity, however, these causality approaches are not suitable for assessing cases of primarily assumed liver related adverse reactions by drugs and herbs including kava. Major problems emerged trough the combination of regulatory inappropriate causality assessment methods with the poor data quality as presented by the regulatory agency when reassessment was done and the resulting data were heavily criticized worldwide within the scientific community. Conversely, causality of cases with primarily assumed kava hepatotoxicity is best assessed by structured, quantitative and liver specific causality algorithms such as the scale of the CIOMS (Council for International Organizations of Medical Sciences) or the main-test as its update. Future strategies should therefore focus on the implementation of structured, quantitative and liver specific causality assessment methods as regulatory standards to improve regulatory causality assessments for liver injury by drugs and herbs including kava.     

Herbal hepatotoxicity by Greater Celandine (Chelidonium majus): causality assessment of 22 spontaneous reports

Toxic liver injury due to the herb Greater Celandine (GC) (Chelidonium majus L.) has been assumed in patients originating from various European countries and created concern. Based on regulatory and liver unspecific ad hoc causality assessments in 22 spontaneous cases of Germany, causality levels for GC were considered probable in 16 and possible in 6 cases. We now analyzed the data of these 22 cases regarding their causality levels employing the liver specific, standardized, structured and quantitative assessment method of the updated scale of CIOMS (Council for International Organizations of Medical Sciences). Causality for GC was found highly probable (n = 2), probable (n = 6), possible (n = 10), unlikely (n = 1), and excluded (n = 3). Thus, causality could be upgraded in 2 cases to a highly probable causality level, but had to be down graded to excluded, unlikely, or possible causality levels in 3, 1, or 9 cases, respectively. GC hepatotoxicity shows a hepatocellular pattern of liver injury with female gender predominance. On average, age of the patients was 56.4 years, treatment 36.4 days, and latency period until first symptoms and jaundice 29.8 and 35.6 days, respectively. This analysis therefore provides further evidence for the existence of GC hepatotoxicity as a distinct form of herb induced liver injury, but due to poor data quality the causal association between GC use and liver injury is less strong than hitherto assumed. We propose replacement of the regulatory organ unspecific by a liver specific causality assessment method in cases of herb induced liver injury as well as stricter pharmacovigilance strategies towards improvements of data quality. Toxicological studies are now warranted to elucidate the mechanism(s) of human GC hepatotoxicity that represents a European issue.     

Hepatoprotective properties of extensively studied medicinal plant active constituents: Possible common mechanisms

Abstract

Context: We focused on certain plant active constituents considered to be the most promising/studied for liver disease and that were critically investigated from the basic science point of view and, to some extent, the clinical one. Due to insufficient pharmacological data, most of the herbal formulations containing these molecules cannot be recommended for the treatment of liver disease.

Objective: To present the most promising compounds tested experimentally and/or clinically and describe in brief popular models in experimental testing of potential hepatoprotective compounds.

Methods: A literature search using Web of Science (WOS), PubMed, and Google search was performed.

Results: Focusing on a few herbal hepatoprotective active constituents is useful to health professionals working in the field of therapeutics to develop evidence-based hepatoprotective agents by conducting research on pure chemical structures or on molecular modifications using computational chemistry. This review demonstrates that multi-pathways in the liver pathobiology can be interrupted at one or more levels by natural hepatoprotective studied, such as interference with the oxidative stress at multiple levels to reduce reactive oxygen/nitrogen species, resulting in ameliorating hepatotoxicity.

Conclusion: Hepatoprotective constituents of herbal medications are poorly absorbed after oral administration; methods that can improve their bioavailability are being developed. It is recommended that controlled prospective double-blind multicenter studies on isolated active plant constituents, or on related newly designed molecules after structural modifications, should be performed. This effort will lead to expanding the existing, limited drugs for the vast majority of liver diseases.     

Spontaneous reports of primarily suspected herbal hepatotoxicity by Pelargonium sidoides: Was causality adequately ascertained?

Spontaneous reports of primarily assumed hepatotoxicity in connection with the use of Pelargonium sidoides (PS) have been interpreted by the Drug Commission of the German Medical Association (DCGMA) as showing some hepatotoxic potential of PS used to treat common cold and other respiratory tract infections. Causality for PS was assessed using the liver specific, structured, quantitative, and updated scale of the Council for International Organizations of Medical Sciences (CIOMS). In none of the 15 cases was there a highly probable or probable causality for PS. Analysis revealed confounding factors such as numerous final diagnoses unrelated to PS and poor data quality in virtually all cases. In only a minority of the cases were data provided to consider even common other diseases of the liver. For instance, biliary tract imaging data were available in only 3 patients; data to exclude virus infections by hepatitis A–C were provided in 4 cases and by CMV and EBV in 1 case, whereas HSV and VZV virus infections remained unconsidered. Thus, convincing evidence is lacking that PS was a potential hepatotoxin in the analyzed cases.     

Herbal hepatotoxicity by Greater Celandine (Chelidonium majus): Causality assessment of 22 spontaneous reports

Toxic liver injury due to the herb Greater Celandine (GC) (Chelidonium majus L.) has been assumed in patients originating from various European countries and created concern. Based on regulatory and liver unspecific ad hoc causality assessments in 22 spontaneous cases of Germany, causality levels for GC were considered probable in 16 and possible in 6 cases. We now analyzed the data of these 22 cases regarding their causality levels employing the liver specific, standardized, structured and quantitative assessment method of the updated scale of CIOMS (Council for International Organizations of Medical Sciences). Causality for GC was found highly probable (n = 2), probable (n = 6), possible (n = 10), unlikely (n = 1), and excluded (n = 3). Thus, causality could be upgraded in 2 cases to a highly probable causality level, but had to be down graded to excluded, unlikely, or possible causality levels in 3, 1, or 9 cases, respectively. GC hepatotoxicity shows a hepatocellular pattern of liver injury with female gender predominance. On average, age of the patients was 56.4 years, treatment 36.4 days, and latency period until first symptoms and jaundice 29.8 and 35.6 days, respectively. This analysis therefore provides further evidence for the existence of GC hepatotoxicity as a distinct form of herb induced liver injury, but due to poor data quality the causal association between GC use and liver injury is less strong than hitherto assumed. We propose replacement of the regulatory organ unspecific by a liver specific causality assessment method in cases of herb induced liver injury as well as stricter pharmacovigilance strategies towards improvements of data quality. Toxicological studies are now warranted to elucidate the mechanism(s) of human GC hepatotoxicity that represents a European issue.     

Peroxisome proliferator-activated receptor alpha-mediated drug toxicity in the liver

Introduction: Drug-induced hepatic injury is the most common cause of acute liver failure in the United States. Peroxisome proliferator-activated receptor alpha (PPARα)-mediated drugs are included among the approximately 900 natural and synthetic substances, which have shown hepatotoxicity.

Areas covered: This review will focus on fibrates – PPARα agonists and their implication in causing liver injury.

Expert opinion: Compelling evidence for fibrate-induced hepatotoxicity is not available. Results have been varying because several large randomized clinical trials have reported similar elevations of plasma transaminase levels in fibrate or placebo treated groups. On the other hand, one meta-analysis has reported an increased risk of hepatotoxicity when fibrates are combined with statins. Fibrate induced clinically apparent liver damage has been demonstrated in case reports. However, there is a wide spectrum of clinical phenotypic presentations of these cases (onset of injury, pattern of enzyme elevation and resolution of the symptoms), which reduces the ability to identify specific cause and effect of any putative fibrate-induced hepatotoxicity. Thus, the current recommendations for using fibrates include monitoring of aminotransferase levels especially if combined with statins and discontinuation of the treatment only if the levels persist above three times the upper limit of normal.     

Is N-acetyl cysteine protective against monocrotaline-induced toxicity?

Abstract

Monocrotaline (MCT) is a pyrrolizidine alkaloid which induces cardio-pulmonary toxicity and hepatotoxicity in animals and humans. MCT is frequently ingested because of food grain contamination accidentally or in the form of herbal medicine preparations. The aim of this study was to observe the protective effect of N-acetyl cysteine (NAC) on MCT-induced pulmonary toxicity and hepatotoxicity. According to our results (right ventricular pressures [RVPs], ratios of right ventricle (RV)/heart weight (HW), plasma AST levels, liver glutathione levels, liver MDA levels and liver histopathological examinations of groups), protective effects were observed with NAC treatment in both MCT-induced pulmonary toxicity and hepatotoxicity.     

Highlights of drug - and herb- induced liver injury in the literature from 2016: how best to translate new information into clinical practice?

Introduction: Over 1500 papers on drug-induced liver injury (DILI) and herb-induced liver injury (HILI) were published in 2016, many of which have the potential to impact clinical practice.

Areas covered: Clinical studies and case series that lent themselves to new concepts in diagnosing, and treating DILI were selected for inclusion. Epidemiology of DILI in large prospective registries was highlighted. Causality assessment of drug hepatotoxicity remains challenging, as seen with cases of OxyELITE Pro (OEP). In 2016 updates to the Roussel Uclaf Causality Assessment Method (RUCAM) were published to aid in the accuracy of diagnosing DILI/HILI. New reports of established hepatotoxins were again discussed in 2016, including genetic risk factors for DILI with respect to antituberculous agents.

Expert opinion: 2016 marked a turning point in how much credence should be placed in the current causality assessment for DILI/HILI cases. Many recognized hepatotoxins are backed by a relatively few number of literature reports. Danan and Teschke make a strong case that an updated RUCAM should remain the gold standard for diagnosing DILI/HILI going forward, although the role of expert opinion is often still needed in cases where RUCAM falls short. The field of chemoinformatics continues to evolve while we await a truly predictive and diagnostic DILI biomarker.     

Hepatotoxicity of targeted therapy for cancer

Introduction: Understanding the mechanism of DILI with MTA, and how to avoid and manage these toxicities is essential for minimising inferior cancer treatment outcomes. An organised and comprehensive overview of MTA-associated hepatotoxicity is lacking; this review aims to fill the gap.

Areas covered: A literature review was performed based on published case reports and relevant studies or articles pertaining to the topics on PubMed. Food and Drug Administration drug information documents and search on the US National Library of Medicine LiverTox database was performed for all relevant MTA.

Expert opinion: MTA-associated hepatotoxicity is common but rarely fatal. The pattern of hepatotoxicity is predominantly idiosyncratic. Pharmacogenomics show potential in predicting patients at risk of poorly metabolising or developing immunoallergic responses to MTA, but prospective data is scant. Preventing reactivation of viral hepatitis using anti-viral drugs, and avoidance of drug combinations at high risk of negative interactions are the most readily preventable measures for DILI.     

Drug-induced hepatotoxicity in cancer patients - implication for treatment

ABSTRACT

Introduction: All anticancer drugs can cause idiosyncratic liver injury. Therefore, hepatoprotective agents assume particular importance to preserve liver function. Hepatic injury represents 10% of cases of acute hepatitis in adults; drug-related damage is still misjudged because of relative clinical underestimation and difficult differential diagnosis. Chemotherapeutic agents can produce liver toxicity through different pathways, resulting in different categories of liver injuries, but these drugs are not homogeneously hepatotoxic. Frequently, anticancer-induced hepatotoxicity is idiosyncratic and influenced by multiple factors.

Areas covered: The aim of this paper is to perform a review of the literature regarding anticancer-induced liver toxicity. We described hepatotoxicity mechanisms of principal anticancer agents and respective dose reductions. Furthermore, we reviewed studies on hepatoprotectors and their optimal use. Tiopronin, magnesium isoglycyrrhizinate and S-Adenosylmethionine (AdoMet) demonstrated, in some small studies, a potential hepatoprotective activity.

Expert Opinion: Actually, in the literature only small experiences are reported. Even though hepatoprotective agents seem to be useful in the oncologic setting, the lack of well-designed prospective Phase III randomized controlled trials is a major limit in the introduction of hepatoprotectors in cancer patients and these kind of studies are warranted to support their use and to give further recommendations for the clinical practice.     

The hepatotoxicity of Polygonum multiflorum: The emerging role of the immune-mediated liver injury

Herbal and dietary supplements(HDS)-induced liver injury has been a great concern all over the world.Polygonum multiflorum Thunb.,a well-known Chinese herbal medicine,is recently drawn increasing attention because of its hepatotoxicity.According to the clinical and experimental studies,P.multiflorum-induced liver injury(PM-DILI)is considered to be immune-mediated idiosyncratic liver injury,but the role of immune response and the underlying mechanisms are not completely elucidated.Previous studies focused on the direct toxicity of PM-DILI by using animal models with intrinsic drug-induced liver injury(DILI).However,most epidemiological and clinical evidence demonstrate that PM-DILI is immune-mediated idiosyncratic liver injury.The aim of this review is to assess current epidemiological,clinical and experimental evidence about the possible role of innate and adaptive immunity in the idiosyncratic hepatotoxicity of P.multiflorum.The potential effects of factors associated with immune tolerance,including immune checkpoint molecules and regulatory immune cells on the individual’s susceptibility to PM-DILI are also discussed.We conclude by giving our hypothesis of possible immune mechanisms of PM-DILI and providing suggestions for future studies on valuable biomarkers identification and proper immune models establishment.     

Propylthiouracil,and methimazole,and carbimazole-related hepatotoxicity

Introduction: Propylthiouracil (PTU) has been used for the treatment of hyperthyroidism since the 1940s, but over the years reports of significant hepatotoxicity have come forth, particularly in children. This led to a black box warning being issued by the US FDA in 2009, followed by a similar warning by the European Medicines Agency and the United Kingdom Medicines and Healthcare Regulatory Agency later that year.

Areas covered: This article provides a concise review of the data on hepatotoxicity associated with the currently available antithyroid drugs: PTU, methimazole (MMI) and carbimazole. The differences in mechanism are examined in detail, as well as clinical presentation, management and monitoring. Use in special populations and trends in use of antithyroid medication are also discussed.

Expert opinion: PTU is known to cause severe hepatic failure, particularly in children. Its use in children should be avoided. In adults, it is beneficial to use in the first trimester of pregnancy and thyroid storm. In the rest of the adult population, it should be used with caution. Carbimazole and MMI are associated with less severe hepatic injury and should be preferred when choosing thionamides as a treatment option.     

Immunoregulatory actions of polysaccharides from Chinese herbal medicine

Importance of the field: Polysaccharides, one of main classes of bioactive substances from Chinese herbal medicine (CHM), have been indicated to have wide pharmacological activities, especially broad immunomodulatory and antitumour effects. However, their immunoregulatory mechanisms are still not fully understood yet.

Areas covered in this review: Polysaccharides from CHM (CHMPS) are reviewed with focus on their immunoregulatory function, describing their immunoregulatory actions on immune organs, immune cells and immune molecules, and discussing their effects on cell surface receptors and cell signaling pathways.

What the reader will gain: A better understanding of the immunoregulatory effects of CHMPS and their structure–function relationship.

Take home message: CHMPS can active or regulate the immune system including innate and adaptive responses, and have profound effects on different diseases. Through examining the molecular mechanisms of the immunomodulating effects of CHMPS, it can be shown that CHMPS have the potential to be an adjuvant in cancer therapies.     

Systematic review on herb-induced liver injury in Korea

Herbal drugs are generally regarded as safe due to their extensive clinical use especially in East Asian countries. However, the potential toxicity of herbal drugs has become an important medical issue recently, resulting in numerous reports of drug-induced liver injury (DILI). Here, we performed a systematic review of herbal medicines with the potential to cause hepatotoxicity in Korea. A literature search of six databases, including PubMed and five Korean electronic databases, was performed to identify cases of herb-induced liver injury (HILI) in Korea, yielding 31 unique reports, including 21 single herb and 10 multi-herb preparations. From these reports, we identified 97 cases of HILI (47 males, 49 females, and 1 unknown sex) consisting of 74.7% hepatocellular-type injury, 10.8% cholestatic-type injury, and 14.5% mixed-type injury. Causative agents included 21 unique herbal preparations, including 11 single species and 10 multispecies, with Polygoni Multiflori (39.2%) and Dictamnus dasycarpus (37.1%) as the most frequent agents. These analyses presented a feature of HILI, and produced a comprehensive list of herbs with a higher risk of hepatotoxicity in Korea. Further studies will be necessary to ascertain the mechanisms by which these herbs induce HILI and to determine whether these effects are specific to the Korean population.     

Duloxetine hepatotoxicity: a case‐series from the drug‐induced liver injury network

Aliment Pharmacol Ther 2010; 32: 1174–1183

Summary

Background Case reports suggest that duloxetine hepatotoxicity may arise, but risk factors, presenting features and clinical course are not well‐described. Aim To describe the presenting features and outcomes of seven well‐characterized patients with suspected duloxetine hepatotoxicity. Methods Patients enrolled in the Drug‐Induced Liver Injury Network Prospective Study underwent an extensive laboratory and clinical evaluation to exclude competing aetiologies of liver injury as well as a standardized assessment for causality and disease severity. Results Between 1/2006 and 9/2009, six of the seven cases of DILI attributed to duloxetine were assessed as definite or very likely. Median patient age was 49 years, six (86%) were women and the median latency from drug initiation to DILI onset was 50 days. Six patients developed jaundice and the median peak alanine aminotransferase in the five patients with acute hepatocellular injury was 1633 IU/L. Ascites developed in one patient and acute renal dysfunction in two others (29%). All patients recovered without liver transplantation even though three had pre‐existing chronic liver disease. Liver histology in four cases demonstrated varying patterns of liver injury. Conclusions Duloxetine hepatotoxicity developed within 2 months of drug intake and led to clinically significant liver injury. A spectrum of laboratory, histological and extra‐hepatic features were noted at presentation.     

Targeting HMGB1 in the treatment of sepsis

Introduction: Sepsis refers to the host's deleterious and non-resolving systemic inflammatory response to microbial infections and represents the leading cause of death in the intensive care unit. The pathogenesis of sepsis is complex, but partly mediated by a newly identified alarmin molecule, the high mobility group box 1 (HMGB1).

Areas covered: Here we review the evidence that support extracellular HMGB1 as a late mediator of experimental sepsis with a wider therapeutic window and discuss the therapeutic potential of HMGB1-neutralizing antibodies and small molecule inhibitors (herbal components) in experimental sepsis.

Expert opinion: It will be important to evaluate the efficacy of HMGB1-targeting strategies for the clinical management of human sepsis in the future.     

Varenicline for tobacco dependence: panacea or plight?

Introduction: This review examines the postmarketing experience with varenicline, including case reports, newer clinical trials and secondary analyses of large clinical datasets.

Areas covered: Varenicline has been shown to be an effective treatment in a broad range of tobacco users with medical, behavioral and diverse demographic characteristics. Recent studies finding excellent safety and efficacy in groups of smokers with diseases including chronic obstructive pulmonary disease are particularly encouraging and call for increased use of this medication for smoking cessation. Despite case reports of serious neuropsychiatric symptoms in patients taking varenicline, including changes in behavior and mood, causality has not been established. Recent analyses of large datasets from clinical trials have not demonstrated that varenicline is associated with more depression or suicidality than other treatments for smoking cessation.

Expert opinion: Now that additional clinical trials in specific populations and observational studies on treatment-seeking smokers outside of clinical trials have been published, we can be confident that varenicline remains the most efficacious monotherapy for smoking cessation and that its side-effect profile remains good. The risk-to-benefit ratio of receiving varenicline to quit smoking must include the increased chances of quitting smoking and avoiding the sizeable risks of smoked-caused disease and death that remain if tobacco addiction is not properly treated.