Complementary and alternative medicines and liver disease.

Complementary and alternative medicines (CAM) include conventional medical treatments. Patients worldwide use CAM at alarming rates; thus, reports of CAM-related DILI have been on the rise. The clinical presentations include asymptomatic liver test abnormalities, acute hepatitis with or without jaundice, acute cholestatic liver disease (bland or with hepatitis), acute liver failure, severe hepatitis with features of portal hypertension, and acute decompensation of known or unknown cirrhosis that can lead to acute-on-chronic liver failure. Acute hepatitis with or without necrosis, hepatocellular and canalicular cholestasis, herb-induced or CAM-triggered autoimmune hepatitis, granulomatous hepatitis, severe steatohepatitis, and vanishing bile duct syndrome are common liver biopsy findings in CAM-DILI. The presence of preexisting liver disease predicts severe liver injury, risk of progression to liver failure, and decreased transplant-free survival in patients with CAM-DILI. This review discusses global epidemiology and trends in CAM-DILI, clinical presentation, assessment and outcomes, commonly emerging threats in the context of hepatotoxic herbs, pragmatic assessment of "liver beneficial" herbs and health care myths, patient communication, regulatory framework, and future directions on research in CAM.

Association between potential supplement-drug interactions and liver diseases in patients with cancer: A large prospective cohort study.

BACKGROUND & AIMS: The concurrent use of herbal and dietary supplements and conventional drugs can lead to interactions in patients with cancer, of which hepatotoxicity is one of the most concerning sequelae. This study examined the potential supplement-drug interactions involving the hepatic system, and their associations with documented liver diseases, among patients with cancer in a large population-based cohort in the UK Biobank. METHODS: Participants diagnosed with cancer and had completed supplement-use assessment after diagnosis were included. Potentially interacting supplement-drug combinations that involved CYP enzymes or increased the risk of hepatotoxicity were identified from four tertiary databases. Liver diseases were identified using ICD-codes K70-77. Log-binomial regression was used to investigate the associations between potentially-interacting supplement-drug combinations and liver diseases documented (1) at any time, and (2) confined to only after the time of supplement-use assessment, adjusting for age, sex and pre-existing comorbidities. RESULTS: This analysis included 30,239 participants (mean age = 60.0 years; 61.9% female). Over half (n = 17,698, 58.5%) reported the use of supplements after cancer diagnoses. Among supplements users, 36.9% (n = 6537/17,698) were on supplement-drug combinations with interacting potential involving the hepatic system. Patients taking supplements and drugs who had hepatic comorbidities were more likely to take potentially interacting pairs (adjusted risk ratio = 1.14, 95% CI = 1.06-1.23, p < 0.001). However, no significant association was observed between the use of these combinations and subsequent liver diseases (all p > 0.05). CONCLUSION: Approximately one-third of the participants who had cancer and were supplement users had a risk of potential supplement-drug interactions that contribute to adverse liver effect. Healthcare professionals should communicate with patients with cancer, especially those with pre-existing liver diseases, about supplement use and proactively assess the clinical significance of potential interactions.

[Drug-induced liver injury: diagnosis of exclusion].

Drug-induced liver injury (DILI) is a relevant issue in clinical practice and is still a diagnosis of exclusion. Despite the low incidence in the general population, DILI is the cause of most cases of acute hepatic injury and has a mortality rate of up to 50%. Despite many reports in the medical literature about the DILI mechanisms, a clear causal relationship between them, drugs, and risk factors has not been established. Current clinical practice is based on a combination of a thorough study of a history of risk factors, the timing of drug and dietary supplements' administration, and the analysis of laboratory and instrumental tests. It aligns with the international criteria of the Rousell Uclaf Causality Assessment Method (RUCAM), which is considered one of the main diagnostic algorithms for DILI. The article addresses current DILI classification, risk factors, diagnostic algorithms, causalities, clinical evaluation, promising liver function biomarkers, and specific treatment.

[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.

Acute liver failure secondary to the use of unmonitored drugs and herbal supplements: an underreported and serious issue.

Acute liver failure (ALF) is a potentially fatal illness marked by the abrupt development of jaundice, coagulopathy, and hepatic encephalopathy (HE) in persons having no previous history of hepatic disease. It is a relatively uncommon illness, having an incidence of 1 to 8 per million people. Hepatitis A, B, and E viruses have been documented as the most prevalent etiologies of acute liver failure in Pakistan and other developing nations. However, ALF may also occur secondary to toxicity caused by the unmonitored overdosing and toxicity of traditional medicines, herbal supplements, and alcohol. Similarly, in some instances, the etiology remains unknown. Herbal products, alternative, and complementary therapies are frequently practiced across the globe for treating various illnesses. In recent times, their use has gained much popularity. Indications and the use of these supplementary drugs vary significantly. The majority of these products have not gained approval from Food and Drug Administration (FDA). Unfortunately, the incidence of documented adverse effects linked to the usage of herbal products has increased recently, but still, these events are underreported, and the condition is known as drug-induced liver injury (DILI) and herb-induced liver injury (HILI). The estimated total herbal retail sales increased from $4230 million in 2000 to $6032 million in 2013, representing a total of 42 and 3.3% per annum increase. To reduce the occurrence of HILI and DILI, physicians in general practice settings should inquire about patients' understanding of potential toxicity with the consumption of hepatotoxic and herbal medicines.

Drug-induced liver injury in COVID-19 patients during hospitalization.

Since coronavirus disease 2019 (COVID-19) outbreaks in December 2019 in Wuhan, almost no studies have systematically described drug-induced liver injury (DILI) in COVID-19 patients. This study aimed to assess the characteristics of liver test abnormality or liver injury in patients with COVID-19, and further to explore DILI in COVID-19 patients during hospitalization. It was a single-center retrospective analysis of confirmed severe acute respiratory syndrome coronavirus 2 infected patients in the hospital from January 2020 to March 2020. Univariate and multivariate logistic regression analysis were used to assess the risk factors associated with liver test abnormality or liver injury. At admission, 148 (48.8%, 148/303) patients had abnormal liver test results and 7 (2.4%, 7/303) had liver injury, while 195 (64.4%, 195/303) had abnormal liver test results and 17 (5.6%, 17/303) had liver injury during hospitalization. After excluding these patients with liver disease and liver function abnormalities or liver injury at admission, 15 (11.1%, 15/135) patients developed DILI during hospitalization. Further regression analysis indicated that methylprednisolone (odds ratio = 4.177, 95% confidence interval [1.106-15.771], P = .035), but not Chinese herbal medicine or other used drug, was associated with DILI in patients during hospitalization. Abnormal liver function results were in more than half of patients with COVID-19, and the incidence of DILI in COVID-19 patients was 11.1% during hospitalization. Liver test abnormality or liver injury in patients might be directly caused by the viral infection at admission, but the detrimental effects on liver injury mainly related to certain medications used during hospitalization, particularly methylprednisolone. Severe COVID-19 could increase the occurrence of liver injury (P = .007) during hospitalization, but not a risk factor of liver injury. However, Chinese herbal medicine was a protective factor for liver injury.

A series of homeopathic remedies-related severe drug-induced liver injury from South India.

INTRODUCTION: Homeopathic remedies are highly diluted formulations without proven clinical benefits, traditionally believed not to cause adverse events. Nonetheless, published literature reveals severe local and non-liver-related systemic side effects. We present the first series on homeopathy-related severe drug-induced liver injury (DILI) from a single center. METHODS: A retrospective review of records from January 2019 to February 2022 identified 9 patients with liver injury attributed to homeopathic formulations. Competing causes were comprehensively excluded. Chemical analysis was performed on retrieved formulations using triple quadrupole gas chromatography-mass spectrometry and inductively coupled plasma atomic emission spectroscopy. RESULTS: Males predominated with a median age of 54 years. The most typical clinical presentation was acute hepatitis, followed by acute on chronic liver failure. All patients developed jaundice, and ascites were notable in one-third of the patients. Five patients had underlying chronic liver disease. COVID-19 prevention was the most common indication for homeopathic use. Probable DILI was seen in 77.8%, and hepatocellular injury predominated (66.7%). Four (44.4%) patients died (3 with chronic liver disease) at a median follow-up of 194 days. Liver histopathology showed necrosis, portal and lobular neutrophilic inflammation, and eosinophilic infiltration with cholestasis. A total of 29 remedies were consumed between 9 patients, and 15 formulations were analyzed. Toxicology revealed industrial solvents, corticosteroids, antibiotics, sedatives, synthetic opioids, heavy metals, and toxic phyto-compounds, even in 'supposed' ultra-dilute formulations. CONCLUSION: Homeopathic remedies potentially result in severe liver injury, leading to death in those with underlying liver disease. The use of mother tinctures, insufficient dilution, poor manufacturing practices, adulteration and contamination, and the presence of direct hepatotoxic herbals were the reasons for toxicity. Physicians, the public, and patients must realize that Homeopathic drugs are not 'gentle placebos.'

A new framework for advancing in drug-induced liver injury research. The Prospective European DILI Registry.

BACKGROUND & AIMS: No multi-national prospective study of drug-induced liver injury (DILI) has originated in Europe. The design of a prospective European DILI registry, clinical features and short-term outcomes of the cases and controls is reported. METHODS: Patients with suspected DILI were prospectively enrolled in the United Kingdom, Spain, Germany, Switzerland, Portugal and Iceland, 2016-2021. DILI cases or non-DILI acute liver injury controls following causality assessment were enrolled. RESULTS: Of 446 adjudicated patients, 246 DILI patients and 100 had acute liver injury due to other aetiologies, mostly autoimmune hepatitis (n = 42) and viral hepatitis (n = 34). DILI patients (mean age 56 years), 57% women, 60% with jaundice and 3.6% had pre-existing liver disease. DILI cases and non-DILI acute liver injury controls had similar demographics, clinical features and outcomes. A single agent was implicated in 199 (81%) DILI cases. Amoxicillin-clavulanate, flucloxacillin, atorvastatin, nivolumab/ipilimumab, infliximab and nitrofurantoin were the most commonly implicated drugs. Multiple conventional medications were implicated in 37 (15%) and 18 cases were caused by herbal and dietary supplements. The most common single causative drug classes were antibacterials (40%) and antineoplastic/immunomodulating agents (27%). Overall, 13 (5.3%) had drug-induced autoimmune-like hepatitis due to nitrofurantoin, methyldopa, infliximab, methylprednisolone and minocycline. Only six (2.4%) DILI patients died (50% had liver-related death), and another six received liver transplantation. CONCLUSIONS: In this first multi-national European prospective DILI Registry study, antibacterials were the most commonly implicated medications, whereas antineoplastic and immunomodulating agents accounted for higher proportion of DILI than previously described. This European initiative provides an important opportunity to advance the study on DILI.

Sex disparity and drug-induced liver injury.

Drug-induced liver injury (DILI) is a potentially serious clinical condition that remains a major problem for patients, physicians and those involved in the development of new drugs. Population and hospital-based studies have reported incidences of DILI varying from 1.4 to 19.1/100.000. Overall, females have a 1.5- to 1.7-fold greater risk of developing adverse drug reactions and the female/male ratio increases after the age of 49 years, suggesting a clear susceptibility of DILI after menopause. Sex differences in pharmacokinetics and pharmacodynamic, sex-specific hormonal effects or interaction with signalling molecules that can influence drug efficacy and safety and differences in abnormal immune response following drug exposure are the main probable causes of the higher vulnerability observed among female patients. A novel phenotype of autoimmune-mediated DILI following the use of check-point inhibitors in oncology and haematology has been recently described. Finally, there have been increasing reports of DILI associated with use of herbal and dietary supplements that is more frequently reported in women.

Spectrum of drug-induced liver injury in a tertiary hospital in southern India.

Background Anti-tuberculosis drugs are thought to account for about 50% of drugs that cause liver injury in India. We show that the spectrum of drugs is much wider than previously reported. Methods We evaluated all patients with unexplained acute liver injury presenting during 2006-2016 using a structured proforma for drug-induced liver injury (DILI). The Roussel Uclaf Causality Assessment Method was used to assess causality. Results DILI was found in 143 of 2534 patients with acute liver injury. Nineteen patients had probable ayurvedic DILI. The other common causes of DILI were statins (16 patients) and anti-tuberculosis drugs (11 patients). Eight patients had DILI post-liver transplant. Fluconazole was the most common cause of post-liver transplant DILI. Chronic DILI (abnormal liver function test after 12 months of stopping the suspected drug) was found in 2 patients. Conclusion In otherwise unexplained acute liver injury, DILI due to ayurvedic drugs should be sought. DILI should be considered in post-liver transplant patients. Patients with DILI should be monitored for at least 12 months to exclude progression to chronic DILI.

Differences in clinical characteristics among 726 patients with Chinese herbal medicine- or Western medicine-induced liver injury.

The differences between Chinese herbal medicine (CHM)- and Western medicine (WM)-induced liver injury have rarely been reported. Our aim was to investigate the clinical features of patients with drug-induced liver injury (DILI) caused by CHM or WM. The medical records of 726 DILI patients were retrospectively collected at Peking University First Hospital from January 1995 through August 2019. The number of inpatients with DILI in our hospital showed an increasing trend over time. The incidence of DILI caused by CHM exhibited a linear trend toward an increase with time (P = .0012). Of the 726 DILI patients, females accounted for 65.8%. There were 353 cases (48.6%) caused by CHM and 225 cases (40.0%) caused by WM. The 3 most common causative CHMs were Polygonum multiflorum (38 cases), Fructus Psoraleae (35 cases), and Epimedium (26 cases). The proportions of female patients, alanine aminotransferase (ALT) levels, aspartate aminotransferase (AST) levels, total bilirubin (TBIL) levels and antinuclear antibody (ANA) positivity rates among cases caused by CHM were higher than those of cases caused by WM (P < .05). There were more patients with severe cases caused by CHM than with severe cases caused by WM (P < .05). The clinical characteristics of DILI caused by CHM differ from those caused by WM. The incidence of DILI caused by CHM is increasing yearly. The medication time of DILI caused by CHM is longer than that of DILI caused by WM, and the severity is greater. Therefore, it is necessary to scientifically and rationally use traditional CHM and monitor liver function. For DILI caused by CHM, the CHM prescription should be recorded in detail to provide detailed clinical data for scientific research on the liver toxicity of CHM.

[Clinical characteristics and prognosis analysis of 498 cases with drug-induced liver injury].

Objective: To determine the risk factors, clinical characteristics and treatment prognosis, so as to provide reference for clinicians to diagnose, treat and prevent drug-induced liver injury (DILI). Methods: Data of 712 confirmed DILI cases were collected from the Second Affiliated Hospital of Kunming Medical University between 2013 to 2019. Among them, 498 cases were included in the study. All patients medical history, clinical manifestations and classification, laboratory parameters, disease severity, and mortality rate were collected. Statistical analysis was performed using t-test, Mann-Whitney U test/Pearson χ2 test/Fisher's exact test or Spearman's rank test. Results: Among the suspicious drugs causing DILI, single medication accounted for 89.56%, mainly including traditional Chinese medicine (56.43%), anti-tumor and immunomodulatory agents (8.03%), anti-infective drugs (4.42%), antipyretic and analgesic drugs (4.22%) %), etc., while combination medication accounted for 10.44%. The clinical classification was dominated with hepatocyte injury (63.05%), and there was a statistically significant difference in clinical classification among age groups (P<0.001). Age, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL) and total bile acid (TBA) had statistically significant difference among different suspicious drugs in DILI caused by different drug (P<0.001, 0.003, 0.001, <0.001 and <0.001). Laboratory test results showed that there were statistically significant differences in ALT, AST, ALP, γ-glutamyltransferase (GGT), TBA, international normalized ratio (INR), and eosinophils (P<0.001, <0.001, <0.001, 0.018, 0.003 and 0.019, respectively). Chronic hepatitis was more common in the 54 cases who completed histopathological examination of the liver biopsy. Fibrosis degree was higher in the Western medicine group than Chinese herbal medicine group (P<0.05), and the difference was statistically significant (P<0.05). 96.99% of DILI patients were cured or improved, and 3.01% of patients were uncured. Ordinal logistic regression analysis showed that GGT and INR were independent predictors of poor prognosis. Conclusions: Suspicious drugs for DILI are herbal/dietary supplements, anti-tumor and immunomodulatory, anti-infective, and antipyretic and analgesic. The most common clinical classification is hepatocyte injury. Most patients with DILI have a good prognosis after drug withdrawal and GGT and INR are independent predictors of poor prognosis.

Analysis of Drug-Induced Liver Injury from Bofutsushosan Administration Using Japanese Adverse Drug Event Report (JADER) Database.

Bofutsushosan is a traditional Japanese Kampo medicine. In recent years, it has been reported to be effective in the treatment of lifestyle-related diseases, and its use is increasing. However, side effects from bofutsushosan administration are common, with drug-induced liver injury being the most frequently reported complication. In this study, we analyzed the Japanese Adverse Drug Event Report (JADER) database regarding the occurrence of liver injury after bofutsushosan administration. The results showed that bofutsushosan presented a significant reporting odds ratio (ROR) signal [crude ROR 14, 95% confidence interval (CI) 12-17; p < 0.001], indicating liver injury. Furthermore, the incidents of adverse events following bofutsushosan administration, as recorded in the JADER database, were higher in women aged between 30 and 59 years. The results of logistic regression analysis in patients taking this agent showed that females in the aforementioned age range had higher odds of developing drug-induced liver injury (adjusted ROR 5.5, 95% CI 2.8-11; p < 0.001). Therefore, although bofutsushosan is a useful drug for lifestyle-related diseases, it may be necessary to refrain from its overuse, and caution should be taken during its occasional use to avoid severe adverse events.

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.

Impact of Prior Drug Allergies on the Risk, Clinical Features, and Outcomes of Idiosyncratic Drug-Induced Liver Injury in Adults.

BACKGROUND: Prior drug allergies are common and may increase susceptibility to adverse medication effects. The aim of this study was to compare the frequency, clinical features, and outcomes of DILI among patients with and without a history of prior drug allergy. METHODS: The EMR at a large liver referral center was searched for all DILI encounters using ICD-10 T-codes for drug poisoning/toxicity and K-71 codes for toxic liver injury between 10/1/2015 and 9/30/2019. Clinically significant liver injury was identified using predefined laboratory criteria, and cases were adjudicated using a 5-point expert opinion scale: 1/2/3 = probable DILI and 4/5 = non-DILI. Drug allergy was defined as a history of anaphylaxis, hives, rash, or pruritus after drug exposure. RESULTS: Among 766,930 patient encounters, 127 unique patients met inclusion criteria with 72 (56.7%) cases adjudicated as probable DILI and 55 (43.3%) as non-DILI. In the probable DILI group, the most frequent suspect drug classes were: antimicrobials (41.9%), herbal and dietary supplements (9.5%), and antineoplastics (8.1%). Twenty-three of the 72 DILI patients (31.9%) had a history of drug allergy before the DILI episode compared to 16 (29.1%) of the 55 non-DILI cases (p = 0.89). However, none of the allergy drugs and suspect DILI drugs were the same although many were in the same drug class. DILI patients with a prior drug allergy were more likely to be female (73.9% vs. 44.9%, p = 0.04) and have lower serum bilirubin (4.0 vs. 7.8, p = 0.08) and INR (1.1 vs. 1.6, p = 0.043) levels at presentation. The likelihood of death or liver transplantation among probable DILI cases with prior drug allergy was lower than those without prior drug allergy (0% vs. 8.2%, p = 0.35). The suspect drug was subsequently documented in the "Drug Allergy" section of the EMR in only 23 (31.9%) of the 72 probable DILI patients, and these patients were more likely to present with a rash (7% vs. 2%, p = 0.006) and higher serum bilirubin levels (10.5 vs. 4.7, p = 0.008) compared to those in whom the suspect drug was not listed as "drug allergy." CONCLUSION: A prior drug allergy history was not associated with a greater likelihood of developing DILI compared to other causes of acute liver injury. However, the probable DILI patients with a history of prior drug allergy tended to have less severe liver injury and clinical outcomes. The low rate of suspect drug documentation in the "Drug Allergy" section of EMR after a DILI episode is of concern and could lead to avoidable harm from inadvertent suspect drug re-challenge.

Risk Factors for Hepatic Toxicity of High-dose Methotrexate in Patients With Osteosarcoma.

BACKGROUND/AIM: High-dose methotrexate (HD-MTX) is widely used to treat osteosarcoma. However, some patients develop hepatic toxicity, leading to dose modification and delays in the scheduled chemotherapy. The present study aimed to identify the risk factors of hepatotoxicity in patients with osteosarcoma. PATIENTS AND METHODS: We conducted a retrospective study of patients with osteosarcoma treated with HD-MTX between January 2014 and June 2020 at the National Cancer Center Hospital, Japan. The risk factors for MTX-induced hepatotoxicity (≥grade 3) were identified using multivariate logistic regression analysis. RESULTS: The final analysis included 88 courses of 36 patients. Hepatotoxicity occurred in 51 (58.0%) of the 88 courses. Female sex, MTX dose (>10.2 g/m2), and serum calcium concentration (>9.3 mg/dl) were identified as risk factors for HD-MTX-induced hepatotoxicity. CONCLUSION: Identifying the risk factors of HD-MTX-induced hepatotoxicity may contribute to improvements in the safety and management of HD-MTX therapy.

Secular Trends in Severe Idiosyncratic Drug-Induced Liver Injury in North America: An Update From the Acute Liver Failure Study Group Registry.

INTRODUCTION: Idiosyncratic drug-induced liver injury (DILI) is the second leading cause of acute liver failure (ALF) in the United States. Our study aims were to characterize secular trends in the implicated agents, clinical features, and outcomes of adults with DILI ALF over a 20-year period. METHODS: Among 2,332 patients with ALF enrolled in the ALF Study Group registry, 277 (11.9%) were adjudicated as idiosyncratic DILI ALF (INR ≥ 1.5 and hepatic encephalopathy) through expert opinion. The 155 cases in era 1 (January 20, 1998-January 20, 2008) were compared with the 122 cases in era 2 (January 21, 2008-January 20, 2018). RESULTS: Among 277 cases of DILI ALF, 97 different agents, alone or in combination, were implicated: antimicrobials, n = 118 (43%); herbal/dietary supplements (HDS), n = 42 (15%); central nervous system agents/illicit substances, n = 37 (13%); oncologic/biologic agents, n = 29 (10%); and other, n = 51 (18%). Significant trends over time included (i) an increase in HDS DILI ALF (9.7% vs 22%, P < 0.01) and decrease in antimicrobial-induced DILI ALF (45.8% vs. 38.5%, P = 0.03) and (ii) improved overall transplant-free survival (23.5%-38.7%, P < 0.01) while the number of patients transplanted declined (46.4% vs 33.6%, P < 0.03). DISCUSSION: DILI ALF in North America is evolving, with HDS cases rising and other categories of suspect drugs declining. The reasons for a significant increase in transplant-free survival and reduced need for liver transplantation over time remain unclear but may be due to improvements in critical care, increased NAC utilization, and improved patient prognostication.

Drug-induced liver injury: Pathogenesis, epidemiology, clinical features, and practical management.

Drug-induced liver injury (DILI) is an important but rare adverse event which can range from mild liver enzyme elevations to liver failure, transplantation or death. A large proportion of commonly used medications, in addition to herbal and dietary supplements, can cause liver injury. DILI has been categorized as direct or idiosyncratic but indirect liver injury has emerged as a third type of drug-induced liver injury. These types of liver injury may warrant different clinical approach and treatment. Associations of HLA genotypes and risk of DILI have highlighted the importance of the immune system in the pathogenesis of DILI. Furthermore, novel agents affecting the immune response can lead to liver injury, often associated with autoimmune features in serologic tests and liver biopsies. Overall, the diagnosis of DILI remains a challenge as it is requires detailed case evaluation in addition to reviewing the hepatotoxic potentials and clinical signatures of the implicated agents. Biochemical profiles vary between agents and although individual drugs tend to portray a consistent clinicopathologic signature, many drugs have multiple signatures. Thanks to multicenter prospective studies on DILI and websites in the public domain such as LiverTox, physicians are provided with tools to investigate suspected DILI cases to increase the likelihood of establishing adiagnosis. The pathogenesis of DILI, epidemiology and current challenges in the diagnosis and management of the disease are reviewed in the paper.

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.

Evidence of drug-induced hepatotoxicity in the Maghrebian population.

Drug-induced hepatotoxicity is one of the most challenging hepatic diseases faced nowadays due to a large number of drugs currently used in clinical practice, the enormous dietary supplements which are potentially hepatotoxic, as well as the ability to appear with different clinical symptoms and the absence of specific markers. The current research survey was conducted to investigate drug-induced hepatotoxicity and demographic characteristics of patients with liver damage in the general Maghrebian population between 1992 and 2018. To achieve this goal a questionnaire was adopted to report details on the undesirable effects of drugs and demographic characteristics of affected patients. The results obtained in the current survey showed that 1001 in 25 093 cases of drug-induced toxicity were registered with drug-induced liver damage between 1992 and 2018. Regarding demographic characteristics of affected patients, the most affected age group was 18 to 44-years-old with a percentage of 45.70% followed by the age group 45 to 64-year-old with a percentage of 27.20%. Females were the most frequently affected by the hepatic side effects of drugs vs. males. Paracetamol, isoniazid, rifampicin, and pyrazinamide were the main responsible drugs for liver damage in the study population. Alteration of biological parameters and subclinical phenomena were used as clinical manifestations of liver damage in the study population. The outcome of the present study suggests paying more attention to drugs used for medication and the involvement of rigorous clinical monitoring to prevent or to minimize the side effects of drugs.