Herbal Hepatotoxicity Research Articles

Hidden Dangers: Herbal and Dietary Supplement Induced Hepatotoxicity

Herbal and dietary supplements represent a multi-billion-dollar industry reportedly used by over half of American adults. However, these products are not regulated by the Federal Drug Agency and contain a wide range of contaminants, leading to over 50,000 adverse events each year. This review aims to highlight the widespread use and current regulatory status of herbal and dietary supplements, identify the presentation and diagnostic dilemmas faced with liver injury, and discuss the most common agents implicated in herbal and dietary supplement hepatotoxicity.

Green Tea Consumption Is Increasing but There Are Significant Hepatic Side Effects

Herbal medicines including teas and plant extracts have been in use for thousands of years. There are reports of the use of herbal preparations in Egypt, China, India, and Samaria. Many patients consider “natural” herbal teas to be completely free of unwanted side effects. Many herbal products, however, have biological activities that can result in severe hepatic cell toxicity or interact with other herbal products or prescription medications. Their use is increased dramatically. The most common herbal teas and nonmineral natural products are used as self-medication, principally for health improvement. However, these products are potentially dangerous to some individuals. Monitoring for liver injury is an important aspect of drug and herbal safety assessment. When present, herbal-induced liver injury (HILI) may limit the use or result in the discontinuation of these agents. HILI can exhibit with a wide spectrum of clinical and laboratory manifestations, ranging from asymptomatic elevations in aminotransferases to acute liver failure. Most cases of HILI resolve within several weeks after herbal remedy discontinuation. However, some cases can persist as low-level aminotransferase elevations. Our review aims to (1) describe the possible significant discrepancies between the ingredients listed on the label and the actual contents of the preparation; (2) evaluate teas containing multiple plants or herbs which may be adulterated by more toxic herbs, heavy metals, microbials, pharmaceuticals, and medicines; (3) describe pathophysiologic events in herbal tea-induced hepatotoxicity; and (4) discuss the key elements required for attributing the consumption of tea to the induction of liver injury. The widespread use of mixed heterogeneous remedies and the lack of randomized trials are an obstacle to providing safe use of plant-derived teas.

S2981 Drug-Induced Autoimmune-Like Hepatitis Due to HemoHIM in a 28-Year Old Pregnant Woman

Introduction: Drug-induced autoimmune-like hepatitis (DIAIH) is a pathologic immune response against proteins in the liver that can be triggered in susceptible individuals by drugs or herbal remedies. While any supplement can cause idiosyncratic hepatotoxicity, up to 16% of drug-induced liver injuries are attributable to herbal supplements. To date, there are still limited data on herbal medicine-related hepatotoxicity. This topic is particularly understudied in pregnant patients, with most current clinical information coming from case reports. While use of supplements is common during pregnancy, there is still limited information regarding their safety. Case Description/Methods: A previously healthy G4P2A1 28-year-old presented at 5 weeks of pregnancy with right upper quadrant pain and fevers, and was presumed to have acute cholecystitis resulting in a laparoscopic cholecystectomy. Despite this, her liver enzymes continued to worsen (AST 2893, ALT 2664, TBili 2.6, Alk Phos 460, INR 1.3). The patient also had laboratory evidence of AIH including Anti-Mi+ 34.5, U1-RNP/RNA-A68 2.4, Chromatin Abs 1.6. She underwent liver biopsy showing drug-induced liver injury and autoimmune hepatitis (AIH). Given that AIH often presents during pregnancy, it was unclear if this presentation represented DIAIH or AIH. Notably, the patient had recently started taking an herbal supplement with purported immune support called HemoHIM that was thought to be a possible driver of DIAIH, The supplement was discontinued and she was started on a 60mg prednisolone with subsequent clinical and laboratory improvement. Despite improvement, the patient suffered spontaneous abortion early in the treatment course and in retrospect underwent unnecessary cholecystectomy. Given concern for possible AIH and slow normalization of LFTs, she was started on azathioprine, but self-discontinued after 7 months. Her liver enzymes remained stable 6 months later; supporting a diagnosis of DIAIH due to HemoHIM rather than AIH which would have likely rebounded with such early treatment withdrawal. Discussion: While DIAILH is an underreported disease in pregnant women this case demonstrates the importance of early diagnosis and treatment. Additionally, it illustrates he challenges in distinguishing between DAILH and AIH especially in patients taking herbal supplements.

Incidence and risk factors of drug-induced liver injury.

The epidemiology and aetiology of drug-induced liver injury (DILI) vary across different countries and populations. Overall, DILI is rare in the general population but has become more prevalent in hospitalized patients, especially among patients with unexplained liver conditions. In addition, drugs implicated in DILI differ between Western and Eastern countries. Antibiotics are the leading drugs implicated in DILI in the West, whereas traditional Chinese medicine is the primary cause implicated in DILI in the East. The incidence of herbal and dietary supplements-induced hepatotoxicity is increasing globally. Several genetic and nongenetic risk factors associated with DILI have been described in the literature; however, there are no confirmed risk factors for all-cause DILI. Some factors may contribute to the risk of DILI in a drug-specific manner.

Real-time screening of hepatotoxins in natural medicine by peroxynitrite responsive lanthanide-based NIR-II luminescent probes

• An NIR-II nanoprobe was designed to monitor the ONOO ¯ in the liver of living mice. • The paracetamol-induced liver injury can be monitored in situ by the nanoprobe. • The probe enabled early diagnosis of liver injury prior to physiological disorder. • The probe successfully screened the hepatotoxic components from natural medicines. Herbal medicines and dietary supplements are widely used worldwide. However, reports have revealed that a large number of herbal medicines are implicated in the hepatic damage, which is referred to as Herbal medicines-induced liver injury (HILI). Traditional diagnostic methods for HILI include histological and serological assessments, which fail to offer real-time and unambiguous visualization of hepatotoxicity in vivo . Herein, we constructed a second near-infrared (NIR-II) luminescent nanoprobes to achieve accurate, high-efficiency, and non-invasive detection of HILI by the assembly of lanthanide-based NIR-II luminescence nanoparticles with a chromophore with absorption band in the NIR-II region. Specifically, the NIR-II luminescence of the lanthanide nanoparticles can be effectively quenched by the chromophores on the surface of nanoparticles via an absorption competition-induced quenching effect, and subsequently recovered by the pathophysiological biomarker peroxynitrite (ONOO − ) generated in early HILI. It is demonstrated that the nanoprobes are capable for the screening of liver toxins in a noninvasive pattern, which is more convenient than the conventional diagnostic approaches. Finally, our luminescence detection approach offers an immediate testing technique for the identification of hepatotoxic components of herbal medicine such as colchicine, monocrotaline and stibene glucoside, providing a high-throughput screening strategy for herbal medicine-induced hepatotoxicity.

2419 Fatal Outcome Associated With Herbal Supplements

INTRODUCTION: Herbal and dietary supplements are widely used without prescription and used by the public as harmless remedies for a variety of ailments. It is difficult to determine causal relationships between herbal preparations and hepatotoxicity. We present a case of fulminant hepatic failure from over-the-counter hair regrowth supplements containing Polygonum multiflorum. CASE DESCRIPTION/METHODS: A 71-year-old male presented to the ER with complaints of abdominal discomfort and jaundice, associated with nausea and vomiting. He went to the ER ten days prior for abdominal discomfort and nausea, labs showed total bilirubin 1.8, ALP 141, AST 267, ALT 85, platelet 70, BUN 31 and Creatinine 1.2. CT abdomen showed duodenitis and was discharged with Metoclopramide. His symptoms continued to worsen. 12 weeks prior, he started a hair regrowth supplement which contained Polygonum multiflorum. Pertinent labs were-Total Bilirubin 9.8, AP 280, AST 445, ALT 156, platelet 49, BUN 85, creatinine 3.4 and INR 1.82. CT abdomen showed mild hepatic steatosis, mild peripancreatic and periduodenal inflammatory changes. Ultrasound of the gallbladder showed no gallstones or cholecystitis. Normal CBD and common hepatic duct. Hepatitis A, B, C, Anti-smooth muscle antibodies, anti-mitochondrial antibodies, smear for parasites and tick borne were negative, IgG, IgM, IgA – normal, Ceruloplasmin 45. Acetaminophen level <10. He was getting supportive treatment. Day 3 labs showed AST 556, ALT 151, AP 278, total bilirubin 15.1, direct bilirubin 14.6, PT 23.7, INR 2.03. platelets 24, BUN 97, creatinine 2.5. He was started on Acetylcysteine and Lactulose, then transferred to a hospital with a liver transplant facility, where toxicology screening was positive for P multiflorum. He was not a candidate for liver transplant and labs continued to worsen. Shortly thereafter he coded while getting an HD catheter for dialysis and expired. Liver biopsy after autopsy showed diffuse necrosis of hepatic cells. DISCUSSION: The mechanism of hepatotoxicity of P multiflorum is unknown but it is known to have anthraquinones including chrysophanol, emodin, and rhein which can induce hepatotoxicity. The pattern of enzyme elevations is typically hepatocellular or mixed and the clinically resembles acute viral hepatitis. The latency to onset ranges from a few days to as long as 6 months. Liver biopsies show changes typical of acute hepatitis. The course is usually self-limited but there are also a small number of patients with liver failure and even death.

Drug-induced liver injury.

Drug-induced liver injury (DILI), including herbal and dietary supplement hepatotoxicity, is often passed lightly; however, it can lead to the requirement of a liver transplant or may even cause death because of liver failure. Recently, the American College of Gastroenterology, Chinese Society of Hepatology and European Association for the Study of the Liver guidelines for the diagnosis and treatment of DILI have been established, and they will be helpful for guiding clinical treatment decisions. Roussel Uclaf Causality Assessment Method scoring is the most commonly used method to diagnose DILI; however, it has some limitations, such as poor validity and reproducibility. Recently, studies on new biomarkers have been actively carried out, which will help diagnose DILI and predict the prognosis of DILI. It is expected that the development of new therapies such as autophagy inducers and various other technologies of the fourth industrial revolution will be applicable to DILI research.

Herb-Drug Interactions and Hepatotoxicity.

In recent times, herbals or phytomedicines have become very popular due to their global acceptance as a complementary and alternative remedy. While modern drugs are commercially available only after laboratory validations, clinical trials, as well as approval from drug regulatory authorities, majority of the marketed herbal products lack such scientific evidence of efficacy and safety. This results in herb or herb-drug interaction induced unfavorable clinical outcomes without crucial documentation on their temporal relations and concomitant use. An online literature search for peer-reviewed articles was conducted on the PubMed, Europe PMC, Medline and Google Scholar portals, using the phrases: complementary & alternative medicine, traditional Chinese medicine, herb-drug interaction, mechanisms of herb-drug interaction, herb-induced toxicity, herbal hepatotoxicity and causality, traditional medicine, viral hepatitis, etc. The retrieved data showed that globally, patients are attracted to herbal remedies with the misconception that these are completely safe and therefore, use them simultaneously with prescription drugs. Notably, there exists a potential risk of herb-drug interactions leading to some adverse side effects, including hepatotoxicity. The toxicological effect of a drug or herb is due to the inhibition of drug metabolizing enzymes (e.g., cytochrome P450), including interactions with certain prescription drugs through various mechanisms. Several cases of hepatotoxicity due to use of herbals in viral hepatitis-related liver diseases have been recently reported. However, limited experimental data and clinical evidence on herbal pharmacokinetics hamper the evaluation and reporting of adverse reactions and the underlying mechanisms. Herb-drug interaction related morbidity is thus an emerging serious public health issue with broad implications for clinicians, pharmaceutical industries and health authorities. Nonetheless, despite increasing recognition of herb-drug interaction, a standard system for interaction prediction and evaluation is still nonexistent. This review article discusses the herb-drug interactions related hepatotoxicity and underlying mechanisms, including drug metabolizing enzymes and their regulation.

A sub-chronic Xysmalobium undulatum hepatotoxicity investigation in HepG2/C3A spheroid cultures compared to an in vivo model

Ethnopharmacology relevanceTraditional herbal medicines are utilized by 27 million South Africans. Xysmalobium undulatum (Uzara) is one of the most widely used traditional medicinal plants in Southern Africa. A false belief in the safety of herbal medicine may result in liver injury. Herb-induced liver injury (HILI) range from asymptomatic elevation of liver enzymes, to cirrhosis and in certain instances even acute liver failure. Various in vitro and in vivo models are available for the pre-clinical assessment of drug and herbal hepatotoxicity. However, more reliable and readily available in vitro models are needed, which are capable of bridging the gap between existing models and real human exposure. Three-dimensional (3D) spheroid cultures offer higher physiological relevance, overcoming many of the shortcomings of traditional two-dimensional cell cultures. Aims of this studyThis study investigated the hepatotoxic and anti-prolific effects of the crude X. undulatum aqueous extract during a sub-chronic study (21 days), in both a 3D HepG2/C3A spheroid model and the Sprague Dawley rat model. MethodsHepG2/C3A spheroids were treated with a known hepatotoxin, valproic acid, and crude X. undulatum aqueous extract for 21 days with continuous evaluation of cell viability and proliferation. This was done by evaluating cell spheroid growth, intracellular adenosine triphosphate (ATP) levels and extracellular adenylate kinase (AK). Sprague Dawley rats were treated with the same compounds over 21 days, with evaluation of in vivo toxicity effects on serum chemistry. ResultsThe results from the in vitro study clearly indicated hepatotoxic effects and possible liver damage following treatment with valproic acid, with associated growth inhibition, loss of cell viability and increased cytotoxicity as indicated by reduced intracellular ATP levels and increased AK levels. These results were supported by the increased in vivo levels of AST, ALT and LDH following treatment of the Sprague Dawley rats with valproic acid, indicative of hepatic cellular damage that may result in hepatotoxicity. The in vitro 3D spheroid model was also able to predict the potential concentration dependant hepatotoxicity of the crude X. undulatum aqueous extract. Similarly, the results obtained from the in vivo Sprague Dawley model indicated moderate hepatotoxic potential. ConclusionThe data from both the 3D spheroid model and the Sprague Dawley model were able to indicate the potential concentration dependant hepatotoxicity of the crude X. undulatum aqueous extract. The results obtained from this study also confirmed the ability of the 3D spheroid model to effectively and reliably predict the long-term outcomes of possible hepatotoxicity.

Three-Level Hepatotoxicity Prediction System Based on Adverse Hepatic Effects.

Hepatotoxicity is a major cause of drug withdrawal from the market. To reduce the drug attrition induced by hepatotoxicity, an accurate and efficient hepatotoxicity prediction system must be constructed. In the present study, we constructed a three-level hepatotoxicity prediction system based on different levels of adverse hepatic effects (AHEs) combined with machine learning, using (1) an end point, hepatotoxicity; (2) four hepatotoxicity severity degrees; and (3) specific AHEs. After collecting and curing 15 873 compound-AHE pairs associated with 2017 compounds and 403 AHEs, we constructed 27 models with three end point levels with the random forest algorithm, and obtained accuracies ranging from 67.0 to 78.2% and the area under receiver operating characteristic curves (AUCs) of 0.715-0.875. The 27 models were fully integrated into a tiered hepatotoxicity prediction system. The existence of hepatotoxicity existence, severity degree, and potential AHEs for a given compound could be inferred simultaneously and systematically. Thus, the tiered hepatotoxicity prediction system allows researchers to have significant confidence in confirming compound hepatotoxicity, analyzing hepatotoxicity from multiple perspectives, obtaining warnings for the potential hepatotoxicity severity, and even rapidly selecting the proper in vitro experiments for hepatotoxicity verification. We also applied three external sets (11 drugs or candidates that failed in clinical trials or were withdrawn from the market, the PharmGKB (offsides) database, and an herbal hepatotoxicity data set) to test and validate the prediction ability of our system. Furthermore, the hepatotoxicity prediction system was adapted into a flow framework based on the Konstanz Information Miner, which was made available for researchers.

Herb-Induced Liver Injuries in Developing Nations: An Update.

The last few decades have seen a rise in the use of herbal supplements, natural products, and traditional medicines. However, there are growing concerns related to the safety and toxicities of these medicines. These herbal medicines are associated with complications such as liver damage with a high incidence of mortalities and morbidities. Clinical manifestations range from asymptomatic cases with abnormal liver functions tests to sudden and severe liver failure necessitating liver transplantation. This work aimed to review the etiology, risk factors, diagnosis, clinical manifestations and selected clinical case reports of herbal hepatotoxicity in developing nations. PubMed and Google Scholar searches were undertaken to identify relevant literature. Furthermore, we scanned the reference lists of the primary and review articles to identify publications not retrieved by electronic searches. Little data exists on clinical cases of herb-induced liver injury in some developing countries such as Nigeria, as most incidences are either not reported to health care providers or reports from hospitals go unpublished. Studies in Nigeria have highlighted a possible correlation between use of herbs and liver disease. In Uganda, and association between the use of traditional herbal medicine with liver fibrosis in HIV-infected and non-HIV patients was demonstrated. Reports from China have revealed incidences of acute liver failure as a result of herbal medicine use. The actual incidence and prevalence of HILI in developing nations remain largely unknown due to both poor pharmacovigilance programs and non-application of emerging technologies. Improving education and public awareness of the potential risks of herbals and herbal products is desirable to ensure that suspected adverse effects are formally reported. There is need for stricter regulations and pre-clinical studies necessary for efficacy and safety.

Hepatic Damage by Natural Remedies

The rising burden of herbal and dietary supplement hepatotoxicity (HILI) is a growing concern in Western countries. The estimated incidence of HILI in well-designed prospective studies ranges from less than 1 to 3 individuals per 100,000 inhabitants/year. Herbal hepatotoxicity has a particular signature encompassing female predominance, hepatocellular type of damage with markedly elevated transaminases on presentation, more common unintentional rechallenge, and a greater risk of death/liver transplantation. Herbal hepatotoxicity recognition is particularly challenging for hepatologists because of the often hidden herbal consumption, difficulties in identifying the causative herbal component, and the possibility of contamination, adulteration, and misidentification, which preclude a proper adjudication and lead to inaccurate reporting of cases in scientific journals. Collaborative efforts to retrieve detailed phenotypic data and biological samples of patients with HILI would facilitate genomic and other molecular approaches for a better understanding of host risk factors and, hopefully, for biomarker identification.

Aloe Vera-Induced Hepatotoxicity

Introduction: Herbal supplementation has been widely used by the general population as a safe and natural alternative to medications. Aloe Vera has been used as a sunburn reliever, laxative and in anti-aging products. Many herbal supplements have been linked to cause acute liver injury. Case presentation: We present a 52 year old male with history of hypertriglyceridemia who presented to our emergency department with complains of epigastric pain for 2 weeks duration. The patient described the pain as an intermittent sharp pain, 8/10 intensity, worse with food intake and no radiation. The Patient denied fever, chills, nausea, vomiting, diarrhea, constipation, melena or dysuria. The patient denied alcohol intake, acetaminophen or NSAIDS use. On further questioning patient revealed taking Aloe Vera extract to help with his abdominal pain. On arrival at the emergency room, his vitals were stable and he was afebrile. Laboratory workup was significant for an ALT of 837, an AST of 928, an a ALP of 175, a total bilirubin 1.6. an INR of 1.0. and a Lipase 473. CT of the abdomen showed fatty infiltration without focal lesion in the liver, cholelithiasis, with normal sized common bile duct. No evidence of pancreatitis seen. Workup for liver disease including viral hepatitis, acetaminophen level, iron studies, ceruloplasmin, ANA, AMA, ASMA, LKM AB, immunoglobulins were all normal. The patient was advised to stop taking Aloe Vera and was monitored in the hospital for 2 days with resolution of his symptoms. On two months follow up, the patient was asymptomatic and his LFTs are back to normal limits. Discussion: Patients usually take herbal supplementation with assumption that it is safe. Without careful history taking, many patients won't admit to using herbal supplementation. Establishing a definitive causative relationship between herbal supplement and hepatotoxicity is very challenging as a re-challenge may be unethical. Using the Roussel Uclaf Causality Assessment Method for determining drug hepatotoxicity (RUCAM) scale our patient scored 8 points which placed Aloe-vera as a “probable” cause of hepatotoxicity in our patient\ Conclusion: Herbal supplementation should be considered and investigated in patients presenting with hepatotoxicity. Careful history taking may reveal otherwise hidden causes of acute hepatis.

Mechanism-based biomarkers and the transformation of diagnosis and risk assessment of herbal hepatotoxicity

Mechanism-based biomarkers and the transformation of diagnosis and risk assessment of herbal hepatotoxicity

Mechanism-Based Inhibitors from Phytomedicine: Risks of Hepatotoxicity and their Potential Hepatotoxic Substructures.

The adverse drug reactions and poisoning events associated with the use of herbal medicines, especially the potential damaging effects of them on the liver organs, have increasingly been reported worldwide. Some herbal ingredients in medicinal plants carry the risk of herb-induced liver injury with a severe or potentially lethal clinical course, but the hepatotoxicity mechanisms and risk factors of them are not well characterized until now. Xenobiotics are converted by cytochrome P450 enzymes into highly reactive metabolites that covalently bind to the catalytic site of the enzyme itself, subsequently causing mechanism-based inhibition (MBI). Compared to reversible inhibition, MBI more frequently results in unfavorable acute and/or immune system-mediated idiosyncratic toxicities and drug/herb-drug interactions (DDI/HDIs). We searched PubMed databases (1980-2015) for articles published in the English language to identify publications on mechanism-based inhibitors from phytomedicine and herbal ingredients hepatotoxicity. 43 mechanism-based inhibitors from phytomedicine were summarized. Twelve of these inhibitors could cause hepatotoxicity, whereas the rest have no related reports. Among them, six hepatotoxic mechanism-based inhibitors are proven to induce hepatotoxicity via their reactive metabolites (RMs). The possible mechanism for this hepatotoxicity is that RMs react with cellular components such as proteins, DNA, and membranes, resulting in ROS overproduction, respiratory chain dysfunction, and cell stress. Moreover, the amine and furan heterocycle groups might be the most potential substructures in mechanism-based inhibitors which can cause hepatotoxicity. These results suggest that when mechanism-based inhibitors from phytomedicine containing amine or furan heterocycle substructures are used alone or with other drugs, in vivo hepatotoxicity screening or its clinical implications for herb-drug interactions are needed to attention.

Traditional Chinese Medicine (TCM) and Herbal Hepatotoxicity: RUCAM and the Role of Novel Diagnostic Biomarkers Such as MicroRNAs.

Background: Traditional Chinese Medicine (TCM) with its focus on herbal use is popular and appreciated worldwide with increased tendency, although its therapeutic efficacy is poorly established for most herbal TCM products. Treatment was perceived as fairly safe but discussions emerged more recently as to whether herb induced liver injury (HILI) from herbal TCM is a major issue; Methods: To analyze clinical and case characteristics of HILI caused by herbal TCM, we undertook a selective literature search in the PubMed database with the search items Traditional Chinese Medicine, TCM, alone and combined with the terms herbal hepatotoxicity or herb induced liver injury; Results: HILI caused by herbal TCM is rare and similarly to drugs can be caused by an unpredictable idiosyncratic or a predictable intrinsic reaction. Clinical features of liver injury from herbal TCM products are variable, and specific diagnostic biomarkers such as microsomal epoxide hydrolase, pyrrole-protein adducts, metabolomics, and microRNAs are available for only a few TCM herbs. The diagnosis is ascertained if alternative causes are validly excluded and causality levels of probable or highly probable are achieved applying the liver specific RUCAM (Roussel Uclaf Causality Assessment Method) as the most commonly used diagnostic tool worldwide. Case evaluation may be confounded by inappropriate or lacking causality assessment, poor herbal product quality, insufficiently documented cases, and failing to exclude alternative causes such as infections by hepatotropic viruses including hepatitis E virus infections; Conclusion: Suspected cases of liver injury from herbal TCM represent major challenges that deserve special clinical and regulatory attention to improve the quality of case evaluations and ascertain patients’ safety and benefit.

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

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. The 6-month outcomes of patients with hepatotoxicity attributed to OxyELITE Pro enrolled in the DILIN prospective registry between 2004 and 2015 are presented. 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 18weeks (range 5-102weeks). Median age was 36years (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 2242U/L, alkaline phosphatase 284U/L and bilirubin 15.0mg/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 6months, while one patient had mild residual ALT elevations. 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.

Drug-Induced Liver Injury: Highlights from a Review of the 2015 Literature.

Numerous publications contributed to the expanding knowledge base about drug-induced liver injury (DILI) in 2015. New findings from the US Drug Induced Liver Injury Network (DILIN) in their most recently updated registry include a 1- to 3-week delay in the appearance of acute DILI from short-course antibiotics such as cefazolin. They corroborated the finding that acute DILI in patients with underlying liver disease was far more severe and potentially fatal than in patients without liver disease. The only drug that seemed to have an increased risk of hepatotoxicity in these patients was azithromycin. While nearly one in six patients with acute DILI had persistently elevated liver tests at 6months, and results for 75% of these patients continued to be abnormal at 12months, most of these "chronic" injury cases were relatively minor and the result of cholestatic hepatotoxins. Newly described DILI agents include tolvaptan, as well as some new direct-acting antiviral protease inhibitors for chronic hepatitis C. The latter have been associated with serious acute hepatitis, hyperbilirubinemia, and decompensation. Herbal hepatotoxicity continues to be increasingly reported, although applying causality assessment to these cases can, in fact, be more challenging than with prescription drugs. As important as cases with DILI, the class of PCSK9 inhibitors used to lower low-density lipoprotein (LDL) cholesterol have not been associated with significant liver injury, in contrast with other lipid-lowering agents. With respect to pharmacologic DILI risk factors, new data show that drugs metabolized by cytochrome P450 enzymes had a nearly four times higher likelihood of causing DILI. Interestingly, high lipophilicity, which was previously felt to be a risk factor for DILI, was not found to be associated, although more study is needed to confirm this observation. While human leukocyte antigen (HLA) genotypes have been linked to several specific agents, the role of such testing in the general population remains undefined due to the currently low positive and negative predictive values of the available tests. New DILI biomarkers, specifically microRNA-122 and keratin-18, among others, appear to have the necessary predictive value to determine the prognosis and outcome of patients with paracetamol (acetaminophen [AAP])-induced acute liver failure (ALF), and may be of great benefit in deciding who requires N-acetylcysteine (NAC), and for what duration. Treatment options for other forms of DILI remain limited; no firm conclusions can currently be drawn for the use of NAC in non-AAP ALF.

Herbal Hepatotoxicity: Clinical Characteristics and Listing Compilation.

Herb induced liver injury (HILI) and drug induced liver injury (DILI) share the common characteristic of chemical compounds as their causative agents, which were either produced by the plant or synthetic processes. Both, natural and synthetic chemicals are foreign products to the body and need metabolic degradation to be eliminated. During this process, hepatotoxic metabolites may be generated causing liver injury in susceptible patients. There is uncertainty, whether risk factors such as high lipophilicity or high daily and cumulative doses play a pathogenetic role for HILI, as these are under discussion for DILI. It is also often unclear, whether a HILI case has an idiosyncratic or an intrinsic background. Treatment with herbs of Western medicine or traditional Chinese medicine (TCM) rarely causes elevated liver tests (LT). However, HILI can develop to acute liver failure requiring liver transplantation in single cases. HILI is a diagnosis of exclusion, because clinical features of HILI are not specific as they are also found in many other liver diseases unrelated to herbal use. In strikingly increased liver tests signifying severe liver injury, herbal use has to be stopped. To establish HILI as the cause of liver damage, RUCAM (Roussel Uclaf Causality Assessment Method) is a useful tool. Diagnostic problems may emerge when alternative causes were not carefully excluded and the correct therapy is withheld. Future strategies should focus on RUCAM based causality assessment in suspected HILI cases and more regulatory efforts to provide all herbal medicines and herbal dietary supplements used as medicine with strict regulatory surveillance, considering them as herbal drugs and ascertaining an appropriate risk benefit balance.

Integrated evidence chain-based identification of Chinese herbal medicine-induced hepatotoxicity and rational usage: Exemplification by <italic>Polygonum Multiflorum</italic> (He shou wu)

Toxicity and adverse drug reactions (events) related to Chinese herbal medicines (CHMs) have been reported increasingly and stirred discussion within the public, media, government and academia, of which hepatotoxicity has become prominent problems in recent years, especially for those CHMs not conventionally considered of toxicity, for instance, Polygonum Multiflorum Thunb. (He shou wu in Chinese). Nowadays, clinical diagnosis for drug-induced liver injury (DILI) mainly adopts the Roussel Uclaf Causality Assessment Method (RUCAM) and the structured expert opinion process (SEOP). However, the accurate diagnosis of DILI is still the international challenge due to a lack of specific diagnosis indicators. Herb-induced liver injury (HILI), nevertheless, is more difficult to diagnosis and sometimes exists misdiagnosis, by reason of the complexity of both the composition of CHMs and combinational prescription of CHMs and western medicines in clinic.