[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.

Capecitabine and Hand-foot Syndrome: A Case Report.

Capecitabine, a prodrug of 5-fluorouracil, is an FDA-approved drug for adjuvant treatment of colon, metastatic colorectal, and breast cancer. A variety of mucocutaneous adverse effects has been recognized with capecitabine. The pathogenesis of such manifestations still remains an enigma though various theories have been proposed. Here, we report two such cases. A 59-year-old female with carcinoma of the sigmoid colon on palliative therapy developed localized cutaneous hyperpigmentation of the palms and soles secondary to capecitabine in her 2nd cycle. Another case was of a 42-year-old female with stomach adenocarcinoma, who developed similar adverse effects after administration of capecitabine in her 4th cycle. Since these drugs have been widely used in recent years due to their relative ease in administration, the relative unawareness of Hand-foot syndrome (HFS) caused due to this drug makes it a prudent topic to be reported.

Interpretation on Consensus on drug-induced liver injury by CIOMS Working Group:liver injury attributed to herbal and dietary supplements / 中国中药杂志

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.

Herb-Induced Liver Injury-A Challenging Diagnosis.

Herb-induced liver injury (HILI) can be caused by supplements containing herbs, natural products, and products used in traditional medicine. Herbal products' most common adverse reaction is hepatotoxicity. Almost every plant part can be used to make herbal products, and these products can come in many different forms, such as teas, powders, oils, creams, capsules, and injectables. HILI incidence and prevalence are hard to estimate and vary from study to study because of insufficient large-scale prospective studies. The diagnosis of HILI is a challenging process that requires not only insight but also a high degree of suspicion by the clinician. HILI presents with unspecific symptoms and is a diagnosis of exclusion. For diagnosis, it is necessary to make a causality assessment; the Council for International Organizations of Medical Sciences assessment is the preferred method worldwide. The most effective treatment is the suspension of the use of the suspected herbal product and close monitoring of liver function. The objective of this review is to highlight the necessary steps for the clinician to follow to reach a correct diagnosis of herb-induced liver injury. Further studies of HILI are needed to better understand its complexity and prevent increased morbidity and mortality.

Sports nutrition supplements and adverse events - a meta-epidemiological study of case reports specifically addressing causality assessment.

PURPOSE: This meta-epidemiological study aimed to systematically review case reports regarding sports nutrition supplements and adverse events (AEs), specifically addressing the issue of causality assessments. METHODS: Through a systematic literature search we identified all published case reports of AEs associated with sports nutrition supplements between 1 January 2008 and 1 March 2019. Data regarding AEs, suspected supplements, relevant causality assessment factors and the reporting of clinical reasoning and/or systematic causality assessment methods were extracted. RESULTS: In all, 72 publications were included, reporting 134 supplements and 37 different AEs in 97 patients (85% males; median age: 30 years [range: 14-60]). Information regarding previous health and regular prescription drugs was not presented in 30% (29/97) and 46% (45/97) of cases, respectively. In 23% (22/97) of the cases, no alternative cause was mentioned. Clinical reasoning was identified in 63% (61/97), and in 13% (8/61) of these, a systematic causality assessment method was applied. In cases with clinical reasoning, a theoretic rationale (92% vs 78%, P = 0.05), a description of previous cases (90% vs 72%, P = 0.021) and body fluid analysis (18% vs 3%, P = 0.027) were reported to a greater extent. Among cases with clinical reasoning, the application of a systematic causality assessment method captured additional important aspects: use of medication (100% vs 55%, P = 0.015), alcohol use (88% vs 43%, P = 0.020) and illicit drug use (88% vs 40%, P = 0.011). CONCLUSIONS: In published case reports where sports nutrition supplements were suspected to have caused AEs, essential factors for causality assessment were left out in a non-negligible proportion. Clinical reasoning was identified in most cases whereas a systematic causality assessment method was applied in a minority. Factors of importance for causality assessment were reported to a greater extent in cases including clinical reasoning, and the application of a systematic causality assessment method captured additional aspects of importance.

Herbal and dietary supplement induced liver injury: Highlights from the recent literature.

Herbal-induced liver injury (HILI) is an important and increasingly concerning cause of liver toxicity, and this study presents recent updates to the literature. An extensive literature review was conducted encompassing September 2019 through March 2021. Studies with clinically significant findings were analyzed and included in this review. We emphasized those studies that provided a causality assessment methodology, such as Roussel Uclaf Causality Assessment Method scores. Our review includes reports of individual herbals, including Garcinia cambogia, green tea extract, kratom as well as classes such as performance enhancing supplements, Traditional Chinese medicine, Ayurvedic medicine and herbal contamination. Newly described herbals include ashwagandha, boldo, skyfruit, and 'Thermo gun'. Several studies discussing data from national registries, including the United States Drug-Induced Liver Injury (DILI) Network, Spanish DILI Registry, and Latin American DILI Network were incorporated. There has also been a continued interest in hepatoprotection, with promising use of herbals to counter hepatotoxicity from anti-tubercular medications. We also elucidated the current legal conversation surrounding use of herbals by presenting updates from the Federal Drug Administration. The highlights of the literature over the past year indicate interest in HILI that will continue as the supplement industry in the United States grows.

Multi-Omics Integration to Reveal the Mechanism of Hepatotoxicity Induced by Dictamnine.

Herb-induced liver injury (HILI) has become a great concern worldwide due to the widespread usage of herbal products. Among these products is Dictamni Cortex (DC), a well-known Traditional Chinese Medicine (TCM), widely used to treat chronic dermatosis. Dictamni Cortex has drawn increasing attention because of its hepatotoxicity caused by the hepatotoxic component, dictamnine. However, the potential hepatotoxicity mechanism of dictamnine remains unclear. Therefore, this study aimed to use the multi-omics approach (transcriptomic, metabolomic, and proteomic analyses) to identify genes, metabolites, and proteins expressions associated with dictamnine-induced hepatotoxicity. A study on mice revealed that a high dose of dictamnine significantly increases serum aspartate aminotransferase (AST) activity, total bilirubin (TBIL), and direct bilirubin (DBIL) levels, the relative liver weight and liver/brain weight ratio in female mice (P < 0.05 and P < 0.01), compared to the normal control group. Liver histologic analysis further revealed a high dose of dictamnine on female mice caused hepatocyte vesicular steatosis characterized by hepatocyte microvesicles around the liver lobules. The expressed genes, proteins, and metabolites exhibited strong associations with lipid metabolism disorder and oxidative stress. Dictamnine caused increased oxidative stress and early hepatic apoptosis via up-regulation of glutathione S transferase a1 (GSTA1) and Bax/Bcl-2 ratio and down-regulation of the antioxidative enzymes superoxide dismutase (SOD), catalase, and glutathione peroxidase 1 (GPx-1). Besides, the up-regulation of Acyl-CoA synthetase long-chain family member 4 (ACSL4) and down-regulation of acetyl-coa acetyltransferase 1 (ACAT1) and fatty acid binding protein 1 (FABP-1) proteins were linked to lipid metabolism disorder. In summary, dictamnine induces dose-dependent hepatotoxicity in mice, which impairs lipid metabolism and aggravates oxidative stress.

Herbal Immune Booster-Induced Liver Injury in the COVID-19 Pandemic - A Case Series.

The COVID-19 pandemic has resulted in widespread use of complementary and alternative medicines. Tinospora cordifolia is a widely grown shrub which has been commonly used in India's traditional system of Ayurveda for its immune booster properties and has been extensively used as prophylaxis against COVID-19. Six patients (4 women, 2 men) with a median (IQR) age of 55 years (45-56) and with an history of Tinospora cordifolia consumption presented with symptoms of acute hepatitis during the study period of 4 months in the COVID-19 pandemic. The median (IQR) duration of Tinospora cordifolia consumption was 90 days (21-210). The median (IQR) peak bilirubin and AST were 17.5 mg/dl (12.2-24.9) and 1350 IU/ml (1099-1773), respectively. The patients had either a definite (n = 4) or probable (n = 2) revised autoimmune hepatitis score with an autoimmune pattern of drug-induced liver injury on biopsy. Four of these patients (all women) had underlying silent chronic liver disease of possible autoimmune etiology associated with other autoimmune diseases - hypothyroidism and type 2 diabetes mellitus. One of the three patients treated with steroids decompensated on steroid tapering. The other five patients had resolution of symptoms, liver profile, and autoimmune serological markers on drug withdrawal/continuing steroid treatment. The median (IQR) time to resolution from discontinuing the herb was 86.5 days (53-111). Tinospora cordifolia consumption seems to induce an autoimmune-like hepatitis or unmask an underlying autoimmune chronic liver disease, which may support its immune stimulant mechanism. However, the same mechanism can cause significant liver toxicity, and we recommend that caution be exercised in the use of this herb, especially in those predisposed to autoimmune disorders. Besides, in patients presenting with acute hepatitis, even in the presence of autoimmune markers, a detailed complementary and alternative medicine history needs to be elicited.

The Indian Network of Drug-Induced Liver Injury: Etiology, Clinical Features, Outcome and Prognostic Markers in 1288 Patients.

BACKGROUND: Etiology of and outcomes following idiosyncratic drug-induced liver injury (DILI) vary geographically. We conducted a prospective study of DILI in India, from 2013 to 2018 and summarize the causes, clinical features, outcomes and predictors of mortality. METHODS: We enrolled patients with DILI using international DILI expert working group criteria and Roussel Uclaf causality assessment method. Follow-up was up to 3 months from onset of DILI or until death. Multivariate logistics regression was carried out to determine predictors of non-survival. RESULTS: Among 1288 patients with idiosyncratic DILI, 51.4% were male, 68% developed jaundice, 68% required hospitalization and 8.2% had co-existing HIV infection. Concomitant features of skin reaction, ascites, and encephalopathy (HE) were seen in 19.5%, 16.4%, and 10% respectively. 32.4% had severe disease. Mean MELD score at presentation was 18.8 ± 8.8. Overall mortality was 12.3%; 65% in those with HE, 17.6% in patients who fulfilled Hy's law, and 16.6% in those that developed jaundice. Combination anti-TB drugs (ATD) 46.4%, complementary and alternative medicines (CAM) 13.9%, anti-epileptic drugs (AED) 8.1%, non-ATD antimicrobials 6.5%, anti-metabolites 3.8%, anti-retroviral drugs (ART)3.5%, NSAID2.6%, hormones 2.5%, and statins 1.4% were the top 9 causes. Univariate analysis identified, ascites, HE, serum albumin, bilirubin, creatinine, INR, MELD score (p < 0.001), transaminases (p < 0.04), and anti-TB drugs (p = 0.02) as predictors of non-survival. Only serum creatinine (p = 0.017), INR (p < 0.001), HE (p < 0.001), and ascites (p = 0.008), were significantly associated with mortality on multivariate analysis. ROC yielded a C-statistic of 0.811 for MELD and 0.892 for combination of serum creatinine, INR, ascites and HE. More than 50 different agents were associated with DILI. Mortality varied by drug class: 15% with ATD, 13.6% with CAM, 15.5% with AED, 5.8% with antibiotics. CONCLUSION: In India, ATD, CAM, AED, anti-metabolites and ART account for the majority of cases of DILI. The 3-month mortality was approximately 12%. Hy's law, presence of jaundice or MELD were predictors of mortality.

Outcomes and Predictors of Mortality in Patients With Drug-Induced Liver Injury at a Tertiary Hospital in South India: A Single-Centre Experience.

INTRODUCTION: Drug-induced liver injury (DILI) is an important cause of acute liver failure with significant morbidity and mortality. The outcome of DILI varies widely according to the drug implicated and the type of liver injury. Owing to the heterogeneous nature of liver injury, knowledge on clinical course and prognosis of DILI is limited. We had undertaken this study to determine the clinical characteristics, outcomes, and predictors of mortality in patients with DILI. MATERIALS AND METHODS: This prospective study was conducted from January 2015 through December 2018. We analyzed the drugs implicated, clinical course, and the outcome. Causality assessment was performed by using Roussel Uclaf Causality Assessment Method scoring. Patients were followed for 6 months until recovery/death or liver transplantation. RESULTS: There were 133 cases with DILI. The mean age was 47.6 years, and 51.9% of them were men. Drugs causing DILI were antitubercular drugs (37.5%) followed by neuropsychiatric drugs (16.5%), antibiotics/antifungals (12%), complementary and alternative medicine (10.5%), immunomodulatory/chemotherapeutic drugs (10.5%), and nonsteroidal antiinflammatory drugs (7.5%). Eighty-two (61.6%) patients were classified as hepatocellular, 30 (22.5%) as mixed and 21 (15.7%) as cholestatic type of injury. There was no significant difference in the mortality and morbidity between the three types of liver injury. There were 18 deaths (13.5%), of which antitubercular drugs constituted the majority (55.5%) followed by neuropsychiatric drugs (27.7%) and complementary and alternative medicine (16.6%). Based on receiver operating characteristic curve analysis, model for end-stage liver disease (MELD) score >28, mean international normalized ratio (INR) >1.97, mean bilirubin level >15.6 mg/dl, and creatinine level >1.35 mg/dl were associated with mortality. CONCLUSION: Although DILI is uncommon, it has significant morbidity and mortality. Antitubercular drugs were the most common cause for DILI and DILI-related mortality in our study. Variables such as MELD, INR, bilirubin, albumin, and creatinine help in predicting severity of liver injury and may help in triaging the patient for referral for liver transplantation.

Case series and review of Ayurvedic medication induced liver injury.

BACKGROUND: Complementary and alternative medicine use among Americans is prevalent. Originating in India, Ayurvedic medicine use in the United States has grown 57% since 2002. CAM accounts for a significant proportion of drug induced liver injury in India and China, but there have been only three reports of drug induced liver injury from Ayurvedic medications in the U.S. We report three cases of suspected Ayurvedic medication associated liver injury seen at a Southern California community hospital and review literature of Ayurvedic medication induced liver injury. CASE PRESENTATIONS: Three patients presented with acute hepatocellular injury and jaundice after taking Ayurvedic supplements for 90-120 days. First patient took Giloy Kwath consisting solely of Tinospora cordifolia. Second patient took Manjishthadi Kwatham and Aragwadhi Kwatham, which contained 52 and 10 individual plant extracts, respectively. Third patient took Kanchnar Guggulu, containing 10 individual plant extracts. Aminotransferase activities decreased 50% in < 30 days and all 3 patients made a full recovery. Roussel Uclaf Causality Assessment Method (RUCAM) scores were 7-8, indicating probable causality. These products all contained ingredients in other Ayurvedic and traditional Chinese medicines with previously reported associations with drug induced liver injury. CONCLUSIONS: These patients highlight the risk of drug induced liver injury from Ayurvedic medications and the complexity of determining causality. There is a need for a platform like LiverTox.gov to catalog Ayurvedic ingredients causing liver damage.

Drug induced liver injury: an update.

Drug induced liver injury (DILI) is a relatively rare hepatic condition in response to the use of medications, illegal drugs, herbal products or dietary supplements. It occurs in susceptible individuals through a combination of genetic and environmental risk factors believed to modify drug metabolism and/or excretion leading to a cascade of cellular events, including oxidative stress formation, apoptosis/necrosis, haptenization, immune response activation and a failure to adapt. The resultant liver damage can present with an array of phenotypes, which mimic almost every other liver disorder, and varies in severity from asymptomatic elevation of liver tests to fulminant hepatic failure. Despite recent research efforts specific biomarkers are not still available for routine use in clinical practice, which makes the diagnosis of DILI uncertain and relying on a high degree of awareness of this condition and the exclusion of other causes of liver disease. Diagnostic scales such as the CIOMS/RUCAM can support the causality assessment of a DILI suspicion, but need refinement as some criteria are not evidence-based. Prospective collection of well-vetted DILI cases in established DILI registries has allowed the identification and validation of a number of clinical variables, and to predict a more severe DILI outcome. DILI is also in need of properly designed clinical trials to evaluate the efficacy of new DILI treatments as well as older drugs such as ursodeoxycholic acid traditionally used to ameliorate cholestasis or corticosteroids now widely tried in the oncology field to manage the emergent type of hepatotoxicity related to immune checkpoint inhibitors.

Development and preliminary validation of an instrument to enable laypersons to assess suspected side effects from medicines.

PURPOSE: Research into causality assessment tools enabling patients to assess suspected adverse drug reactions (ADRs) is limited. Supporting patients with tools could improve their confidence in discussions with health professionals and encourage reporting of suspected ADRs to regulators. This study describes development and preliminary validation of an instrument: Side Effect Patient ASsessment Tool (SE-PAST). METHODS: SE-PAST was developed from survey and interview data involving patients experiencing suspected ADRs. It included 10 statements enabling causality assessment, covering timing, additional information sources, and experiences, with four options: yes/no/don't know/not applicable. Scoring and weighting resulted in four categories of causal association: highly probable, probable, possible, unlikely. Validation involved obtaining feedback from 31 individuals experiencing an ADR. Further validation involved online distribution through patient support groups and comparison of reported symptoms to known ADRs. RESULTS: Validators found SE-PAST easy to read (31), to understand (27), and to complete (29). A total of 294 respondents completed SE-PAST online, with 98% completing eight or more causality assessment statements. Symptoms were categorised as highly probable (46; 16%), probable (80; 62%), possible (44; 15%), and unlikely (21; 7%). A total of 221 respondents identified one suspected medicine, with 95% of these reporting at least one symptom known to be an ADR. Of 227 providing feedback, 139 (61%) found SE-PAST useful, 160 (71%) felt motivated to discuss their experience with a health professional, and 136 (60%) were encouraged to report to the regulator. CONCLUSION: SE-PAST was easily completed and understood by people experiencing suspected ADRs and could be useful in encouraging patient reporting to health professionals and agencies.

Chemical Analysis of Weight Loss Herbal Supplement Safe Lean™ Associated With Acute Liver Injury - A Concern for Spurious Drug, Misbranding and Adulteration.

Liver injury due to herbal and dietary supplements are well described in literature and its incidence has been on the rise in the past decade. Labelling an herbal product as non-medicinal and as a supplement precludes protocols needed for testing, trials and marketing criteria. This has led to rampant use of clinically unproven multi-herb-based drugs use for a myriad of lifestyle diseases. In this report, we discuss a new dietary weight loss supplement, Safe Lean™ that was found to be the cause of liver injury in a young obese woman, that resolved after discontinuation, and discuss current literature on component, toxicology and chemical analysis of the offending drug.

Traditional Chinese Medicine and Herb-induced Liver Injury: Comparison with Drug-induced Liver Injury.

Cases of suspected herb-induced liver injury (HILI) caused by herbal Traditional Chinese Medicines (TCMs) and of drug-induced liver injury (DILI) are commonly published in the scientific literature worldwide. As opposed to the multiplicity of botanical chemicals in herbal TCM products, which are often mixtures of several herbs, conventional Western drugs contain only a single synthetic chemical. It is therefore of interest to study how HILI by TCM and DILI compare with each other, and to what extent results from each liver injury type can be transferred to the other. China is among the few countries with a large population using synthetic Western drugs as well as herbal TCM. Therefore, China is well suited to studies of liver injury comparing drugs with TCM herbs. Despite some concordance, recent analyses of liver injury cases with verified causality, using the Roussel Uclaf Causality Assessment Method, revealed major differences in HILI caused by TCMs as compared to DILI with respect to the following features: HILI cases are less frequently observed as compared to DILI, have a smaller proportion of females and less unintentional rechallenge events, and present a higher rate of hepatocellular injury features. Since many results were obtained among Chinese residents who had access to and had used Western drugs and TCM herbs, such ethnic homogeneity supports the contention that the observed differences of HILI and DILI in the assessed population are well founded.

Clinical characteristics and outcomes of traditional Chinese medicine-induced liver injury: a systematic review.

BACKGROUNDS: Traditional Chinese medicine (TCM) is becoming increasingly popular and related adverse events are often ignored or underestimated. AIMS: This systematic review aimed to evaluate the clinical characteristics and outcomes of TCM-induced liver injury (TCM-ILI) and to estimate the proportion of TCM-ILI in all drug-induced liver injuries (DILI). METHODS: China National Knowledge Infrastructure, Wanfang, VIP, PubMed, and Embase databases were searched. Demographic, clinical, and survival data were extracted and pooled. Factors associated with worse outcomes were calculated. For the proportion meta-analyses, the data were pooled by using a random-effects model. RESULTS: Overall, 21,027 articles were retrieved, of which 625 were finally included. There was a predominance of female and older patients. The proportion of liver transplantation was 2.18% (7/321). The mortality was 4.67% (15/321). Male, higher aspartate aminotransferase and direct bilirubin, and lower albumin were significantly associated with an increased risk of death/liver transplantation in TCM-ILI patients. The proportion of TCM-ILI in all DILI was 25.71%. The proportion was gradually increased with year. CONCLUSIONS: Our work summarises current knowledge regarding clinical presentation, disease course, and prognosis of TCM-ILI. TCM can result in hepatotoxicity, even death or necessitate life-saving liver transplantation. Governmental regulation of TCM products should be strictly established.

Critical evaluation of causality assessment of herb-drug interactions in patients.

The aim of this review was to assess the severity of adverse drug reactions (ADRs) due to herb-drug interactions (HDI) in patients taking herbs and prescribed medications based on published evidence. Electronic databases of PubMed, the Cochrane Library, Medline and Scopus were searched for randomized or nonrandomized clinical studies, case-control and case reports of HDI. The data were extracted and the causal relationship of ADRs as consequences of HDI assessed using Horn's drug interaction probability scale or Roussel Uclaf Causality Assessment Method scoring systems. The mechanism of interaction was ascertained using Stockley's herbal medicine interaction companion. Forty-nine case reports and two observational studies with 15 cases of ADRs were recorded. The majority of the patients were diagnosed with cardiovascular diseases (30.60%), cancer (22.45%) and renal transplants (16.32%) receiving mostly warfarin, alkylating agents and cyclosporine, respectively. HDI occurred in patients resulting in clinical ADRs with different severity. Patients may poorly respond to therapeutic agents or develop toxicity due to severe HDI, which in either scenario may increase the cost of treatment and/or lead to or prolong patient hospitalization. It is warranted to increase patient awareness of the potential interaction between herbs and prescribed medicines and their consequences to curb HDI as a potential health problem.