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

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

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.

Hugan tablets for the treatment of RUCAM based drug-induced liver injury: a propensity score matching analysis using a nationwide database.

BACKGROUND: Drug-induced liver injury (DILI) is a major clinical challenge with no specific therapeutic drugs available. It is crucial to develop new agents to improve the clinical outcome of patients with DILI. This study evaluated the efficacy and safety of Hugan tablets in DILI patients using a nationwide database. RESEARCH DESIGN AND METHODS: We analyzed the clinical data of DILI patients from a nationwide DILI database (www.hepatox.org). Patients who received oral Hugan tablets for DILI were defined as the Hugan group, and those who received no treatment for DILI were defined as the control group. RESULTS: There were 111 cases in the Hugan group and 512 cases in the control group. One-to-one propensity score matching created 111 matched pairs. The normalization rates of alanine aminotransferase and aspartate aminotransferase in the Hugan group were significantly higher than those in the control group (50.45% vs. 26.13%, p ≤ .0002 and 67.57% vs. 41.75%, p ≤ .0001). There were no differences in the incidence of renal function impairment or blood abnormality between the two groups. CONCLUSIONS: Hugan tablets are safe and effective in DILI treatment. Large-scale randomized controlled studies are needed to explore the effects of Hugan tablets on DILI induced by different offending drugs. TRIAL REGISTRATION: The study protocol was posted on ClinicalTrials.gov with NCT number: NCT02407964.

Vitamin A and retinoic acid accelerate the attenuation of intestinal adaptability upon feeding induced by high-fat diet in mice.

With its unique cellular plasticity, the small intestinal mucosa exhibits efficient adaptability upon feeding. However, little is known about the effect of high-fat diet (HFD) feeding on this adaption and its underlying mechanism. Herein, we demonstrated that the cell proliferation ability, mitochondrial morphology, and global transcriptomic profile of the small intestine exhibited a prominent discrepancy between the fasted and refed state in mice, which were markedly attenuated by long-term HFD feeding. The retinol (Vitamin A, VA) metabolism pathway was dramatically affected by HFD feeding in the small intestine. Both VA and its active metabolite retinoic acid (RA), with the administration of lipid micelles, promoted the expression of genes involved in lipid absorption and suppressed the expression of genes involved in the cell proliferation of intestinal organoids. Via chip-qPCR and RT-qPCR, genes involved in lipid metabolism and cell proliferation were target genes of RARα/RXRα in small intestinal organoids treated with RA and lipid micelles. The role of VA in the in vivo attenuation of intestinal adaptability, in response to HFD, was evaluated. Mice were fed a normal chow diet, HFD, or HFD diet supplemented with additional 1.5-fold VA for 12 weeks. VA supplementation in HFD accelerated the attenuation of intestinal adaptability upon feeding induced by HFD, promoted lipid absorption gene expression, and increased body weight and serum cholesterol levels. In conclusion, the discrepancy of the small intestine between the fasted and refed state was dramatically attenuated by HFD feeding, in which VA and RA might play important roles.

The Characteristics, Prevalence, and Risk Factors of Drug-Induced Liver Injury Among Brucellosis Inpatients in Xinjiang, China.

Background: We investigated the prevalence, demographic and clinical features, and risk factors associated with drug-induced liver injury (DILI) during the treatment of brucellosis inpatients in a retrospective study. Methods: We collected the clinical data of 782 brucellosis inpatients admitted at the Shawan County People's Hospital, Xinjiang, from 2015-2019. All cases were re-evaluated using the international consensus of DILI criteria and RUCAM rating scale. 71 patients were confirmed as DILI cases and compared with 523 other patients with normal liver function. Results: It was indicated that DILI occurred with a prevalence of about 9.08% among brucellosis inpatients receiving drug therapy. Hepatocellular injury was the most common type of DILI (61.97%, 95% confidence interval [CI] 50.34-72.37), followed by mixed (23.94%, 95% CI 15.52-35.04) and cholestatic types (14.08%, 95% CI 7.83-24.02). In addition, 13.64% of the hepatocellular DILI cases fulfilled Hy's law criteria and only two cases (2.82%) progressed to severe DILI. Most patients adopted the combination of rifampicin, antipyretic analgesics, anti-infective agents, and traditional Chinese medicine for the treatment of brucellosis, with all the 71 patients taking rifampicin as the drug of choice. Multivariable logistic regression analyses indicated that obesity, regular alcohol intake, and decreased serum albumin were the independent risk factors of DILI in patients with brucellosis after adjusting for gender, age, and ethnicity. Conclusion: DILI occurred in a minority of inpatients diagnosed with brucellosis receiving rifampicin-based therapeutic regimen. In addition, obesity, alcohol abuse, and decreased serum albumin were valuable predictors of the risk of DILI in patients with brucellosis.

Drug-induced liver injury: Asia Pacific Association of Study of Liver consensus guidelines.

Idiosyncratic drug-induced liver injury mimics acute and chronic liver disease. It is under recognized and underrecognised because of the lack of pathognomonic diagnostic serological markers. Its consequences may vary from being asymptomatic to self-limiting illness to severe liver injury leading to acute liver failure. Its incidence is likely to be more common in Asia than other parts of the world, mainly because of hepatotoxicity resulting from the treatment of tuberculosis disease and the ubiquitous use of traditional and complimentary medicines in Asian countries. This APASL consensus guidelines on DILI is a concise account of the various aspects including current evidence-based information on DILI with special emphasis on DILI due to antituberculosis agents and traditional and complementary medicine use in Asia.

Efficacy and safety of magnesium isoglycyrrhizinate injection in patients with acute drug-induced liver injury: A phase II trial.

BACKGROUND: Drug-induced liver injury (DILI) is the most common reason for a drug to be withdrawn from the market. Apart from stopping the offending drug, no regimens are available for treating idiosyncratic DILI in clinical practice. METHODS: We carried out a randomized, double-blind, multidoses, active drug controlled, multicentre phase II trial to assess the safety and efficacy of the study drug, magnesium isoglycyrrhizinate (MgIG), as compared to tiopronin, a standard therapy for DILI in China. The primary outcome was the proportion of alanine aminotransferase (ALT) normalization at week 4 after study drug administration. Logistic regression was used to examine the odds of ALT normalization between low dose (Group A) and high dose (Group B) vs active control (Group C). RESULTS: One hundred and seventy-four eligible subjects were randomized and enrolled into three groups: 59 in group A, 56 in group B and 59 in group C. It was shown that group A and group B lowered ALT level even at early stage of study drug administration; when compared with Group C (61.02%), the proportions of ALT normalization at week 4 were significantly greater in Group A (84.75%, P = .0029) and Group B (85.71%, P = .0037) respectively. The results from the univariate logistic model showed that the odds of ALT normalized among subjects in Group A were about 3.6 times greater (OR = 3.55, 95% CI: 1.47-8.57, P = .0049) than subjects in Group C. Similar effect was observed among subjects in Group B (OR = 3.83, 95% CI: 1.54-9.55, P = .0039). CONCLUSIONS: This trial provided preliminary evidence that MgIG is an effective and safe treatment for patients with acute DILI.

Incidence and Etiology of Drug-Induced Liver Injury in Mainland China.

BACKGROUND & AIMS: We performed a nationwide, retrospective study to determine the incidence and causes of drug-induced liver injury (DILI) in mainland China. METHODS: We collected data on a total of 25,927 confirmed DILI cases, hospitalized from 2012 through 2014 at 308 medical centers in mainland China. We collected demographic, medical history, treatment, laboratory, disease severity, and mortality data from all patients. Investigators at each site were asked to complete causality assessments for each case whose diagnosis at discharge was DILI (n = 29,478) according to the Roussel Uclaf Causality Assessment Method. RESULTS: Most cases of DILI presented with hepatocellular injury (51.39%; 95% confidence interval [CI] 50.76-52.03), followed by mixed injury (28.30%; 95% CI 27.73-28.87) and cholestatic injury (20.31%; 95% CI 19.80-20.82). The leading single classes of implicated drugs were traditional Chinese medicines or herbal and dietary supplements (26.81%) and antituberculosis medications (21.99%). Chronic DILI occurred in 13.00% of the cases and, although 44.40% of the hepatocellular DILI cases fulfilled Hy's Law criteria, only 280 cases (1.08%) progressed to hepatic failure, 2 cases underwent liver transplantation (0.01%), and 102 patients died (0.39%). Among deaths, DILI was judged to have a primary role in 72 (70.59%), a contributory role in 21 (20.59%), and no role in 9 (8.82%). Assuming the proportion of DILI in the entire hospitalized population of China was represented by that observed in the 66 centers where DILI capture was complete, we estimated the annual incidence in the general population to be 23.80 per 100,000 persons (95% CI 20.86-26.74). Only hospitalized patients were included in this analysis, so the true incidence is likely to be higher. CONCLUSIONS: In a retrospective study to determine the incidence and causes of DILI in mainland China, the annual incidence in the general population was estimated to be 23.80 per 100,000 persons; higher than that reported from Western countries. Traditional Chinese medicines, herbal and dietary supplements, and antituberculosis drugs were the leading causes of DILI in mainland China.

CSH guidelines for the diagnosis and treatment of drug-induced liver injury.

Drug-induced liver injury (DILI) is an important clinical problem, which has received more attention in recent decades. It can be induced by small chemical molecules, biological agents, traditional Chinese medicines (TCM), natural medicines (NM), health products (HP), and dietary supplements (DS). Idiosyncratic DILI is far more common than intrinsic DILI clinically and can be classified into hepatocellular injury, cholestatic injury, hepatocellular-cholestatic mixed injury, and vascular injury based on the types of injured target cells. The CSH guidelines summarized the epidemiology, pathogenesis, pathology, and clinical manifestation and gives 16 evidence-based recommendations on diagnosis, differential diagnosis, treatment, and prevention of DILI.

Causes, clinical features and outcomes of drug-induced liver injury in hospitalized patients in a Chinese tertiary care hospital.

Drug-induced liver injury (DILI) is an important liver disease in China, owing to the country's huge population and the availability of a multitude of drugs. Consequently, DILI is becoming an increasingly serious health problem. However, there is not enough relevant epidemiological data, and the clinical features of these patients are not clear. We conducted this study to report the causes and clinical features of DILI in hospitalized patients, and identify the mortality and predictive factors. We retrospectively collected and analyzed the data of all hospitalized patients whose discharge diagnosis was DILI at the Second Xiangya Hospital between January 2011 and December 2014. The data analyses were performed using SAS version 9.2. Among the 469 patients who were diagnosed with DILI at discharge, 361 met the criteria for DILI on re-evaluation. The crude annual incidence rate of DILI was 92.95 cases per 100,000 patients. Chinese herbal medicine was identified as the primary cause of DILI in 36.01 % of the patients. The overall mortality was 8.59 %. Alcohol consumption, use of antituberculosis drugs, serum total bilirubin, direct bilirubin, total protein, albumin, thrombinogen time, international normalized ratio, and the model for end-stage liver disease (MELD) score were significantly correlated with DILI-associated mortality. Among them, the MELD score and albumin were found to be independent predictors of outcome in patients with DILI. Chinese herbal medicine was the primary cause of DILI in the identified patients. The MELD score and albumin were independent predictors of outcome in patients with DILI.