Development and validation of a novel model to predict liver-related mortality in patients with idiosyncratic drug-induced liver injury.

BACKGROUND: Early identification of patients with high mortality risk is critical for optimizing the clinical management of drug-induced liver injury (DILI). We aimed to develop and validate a new prognostic model to predict death within 6 months in DILI patients. METHODS: This multicenter study retrospectively reviewed the medical records of DILI patients admitted to three hospitals. A DILI mortality predictive score was developed using multivariate logistic regression and was validated with area under the receiver operating characteristic curve (AUC). A high-mortality-risk subgroup was identified according to the score. RESULTS: Three independent DILI cohorts, including one derivation cohort (n = 741) and two validation cohorts (n = 650, n = 617) were recruited. The DILI mortality predictive (DMP) score was calculated using parameters at disease onset as follows: 1.913 × international normalized ratio + 0.060 × total bilirubin (mg/dL) + 0.439 × aspartate aminotransferase/alanine aminotransferase - 1.579 × albumin (g/dL) - 0.006 × platelet count (109/L) + 9.662. The predictive performance for 6-month mortality of DMP score was desirable, with an AUC of 0.941 (95% CI: 0.922-0.957), 0.931 (0.908-0.949) and 0.960 (0.942-0.974) in the derivation, validation cohorts 1 and 2, respectively. DILI patients with a DMP score ≥ 8.5 were stratified into high-risk group, whose mortality rates were 23-, 36-, and 45-fold higher than those of other patients in the three cohorts. CONCLUSIONS: The novel model based on common laboratory findings can accurately predict mortality within 6 months in DILI patients, which should serve as an effective guidance for management of DILI in clinical practice.

Stages of psychological change among patients with non-alcoholic fatty liver disease in China: a national cross-sectional study.

OBJECTIVES: Non-alcoholic fatty liver disease (NAFLD) is becoming the leading cause of chronic liver disease worldwide. However, treatment of NAFLD is potentially influenced by psychological conditions. Using the simplified version of the University of Rhode Island Change Assessment (URICA-SV) scale, this study aimed to evaluate the stage of psychological change as a prerequisite to refining implementation strategies for psychological change. DESIGN: A multicentre cross-sectional survey. SETTING: Ninety hospitals in China. PARTICIPANTS: 5181 patients with NAFLD were included in this study. OUTCOME MEASURES: All patients completed the URICA-SV questionnaire and were assigned to one of the three stages of change (precontemplation, contemplation or action) according to their readiness scores. A stepwise multivariate logistic regression analysis was used to identify independent factors associated with the stage of psychological change. RESULTS: A total of 4832 (93.3%) patients were included in the precontemplation stage and only 349 (6.7%) considered making a change or preparing to make one. There were significant differences in gender (Cohen's d=0.039, p=0.005), age (Cohen's d=-0.327, p<0.001), waist circumference (Cohen's d=0.143, p=0.003), alanine transaminase (Cohen's d=0.347, p=0.001), triglyceride (Cohen's d=0.351, p=0.002), body mass index (BMI; Cohen's d=0.056, p<0.001), proportion of hyperlipidaemia (Cohen's d=0.068, p<0.001) and cardiovascular disease (Cohen's d=0.032, p=0.029), therapeutic regimen (Cohen's d=0.136, p<0.001), and Chronic Liver Disease Questionnaire-Non-Alcoholic Fatty Liver Disease overall score (Cohen's d=-0.420, p<0.001) between patients with NAFLD in the precontemplation stage and those in the contemplation/action stage. Logistic regression identified BMI (HR 0.659, 95% CI 0.469 to 0.928, p=0.017), cardiovascular disease (HR 2.161, 95% CI 1.089 to 4.287, p=0.027) and triglyceride (HR 0.751, 95% CI 0.591 to 0.955, p=0.020) as independent factors predicting psychological change. CONCLUSIONS: The results demonstrated that very few patients with NAFLD presented psychological condition in the stage of action. Psychological condition was found to be significantly related to BMI, cardiovascular disease and triglyceride factors. Integrated diversity considerations for evaluating psychological change are necessary.

Pyroptotic MAITs link microbial translocation with severity of alcohol-associated liver disease.

BACKGROUND: Mucosal-associated invariant T cells (MAITs) are markedly reduced in patients with alcohol-associated liver disease (ALD); however, the potential mechanism underlying MAITs' loss remains elusive. Hence, we aimed to explore what induced MAITs' loss and its clinical significance. METHODS: The characteristics of pyroptotic MAITs were evaluated in a cohort of patients with ALD, including 41 patients with alcohol-associated liver cirrhosis (ALC) and 21 patients with ALC complicated with severe alcoholic hepatitis (ALC + SAH). RESULTS: In patients with ALD, blood MAITs were significantly decreased, hyperactivated, and displayed enhanced cell death through pyroptosis. The frequencies of pyroptotic MAITs increased with disease severity in patients with ALC and patients with ALC + SAH. These frequencies were negatively associated with the frequencies of MAITs and positively correlated with the levels of MAITs' activation, plasma levels of intestinal fatty acid-binding protein (a marker of intestinal enterocyte damage), soluble CD14, lipopolysaccharide-binding protein, and peptidoglycan recognition proteins (surrogate markers of microbial translocation). Pyroptotic MAITs were also found in the liver of patients with ALD. Interestingly, MAITs underwent further activation and pyroptosis in vitro under stimulation by Escherichia coli or direct bilirubin. Notably, blocking IL-18 signaling reduced the activation and frequencies of pyroptotic MAITs. CONCLUSIONS: The loss of MAITs in patients with ALD is, at least in part, due to cell death from pyroptosis and is associated with the severity of ALD. Such increased pyroptosis may be affected by dysregulated inflammatory responses to intestinal microbial translocation or direct bilirubin.

Reliability and validity of the Chinese version of chronic liver disease questionnaire-nonalcoholic fatty liver disease in patients with nonalcoholic fatty liver disease: a multicenter cross-sectional survey in China.

PURPOSE: The Chronic Liver Disease Questionnaire (CLDQ)-Nonalcoholic Fatty Liver Disease (NAFLD) is a disease-specific instrument to assess the health-related quality of life (HRQL) of patients with NAFLD. In order to provide further evidence for the cross-cultural utility of this instrument in the Chinese population, we translated the CLDQ-NAFLD into Chinese and examined its reliability and validity. METHODS: Patients with NAFLD in 90 hospitals across China were enrolled in this multicenter cross-sectional survey. Eligible patients completed the Chinese version of CLDQ-NAFLD at enrollment to assess HRQL. Internal consistency of the questionnaire was assessed using Cronbach's alpha coefficient and split-half reliability. Convergent and discriminant validity were assessed using Spearman correlation coefficient. Factor analysis was used to test the construct validity. RESULTS: Between March and August 2019, 5181 patients with a mean age of 43.8 ± 13.3 years were enrolled. All domains exhibited good internal consistency, with Cronbach's alpha and split-half reliability greater than 0.70. The scaling success rate of all domains was 100% for convergent validity and 99.4% (179/180) for discriminant validity. The inter-scale correlations indicated a significant correlation between all CLDQ-NAFLD domains (r = 0.608 to 0.832, all p < 0.001). Factor analysis of 36 items extracted 6 factors, which explained 69.14% of the total variance. CONCLUSION: The Chinese version of CLDQ-NAFLD is a reliable and valid instrument for assessing the HRQL of Chinese patients with NAFLD.

Metabolomic Profiling for Histologically Fibrotic Stage in Chronic Drug-Induced Liver Injury.

Background and aims: Chronic drug-induced liver injury (DILI) is a rare but under-researched adverse drug reaction-related disease, which is highly likely to progress into liver fibrosis and even cirrhosis. In this study, metabolomics was used to screen out characteristic metabolites related to the histological progression of fibrosis in chronic DILI and analyze the metabolic changes during the development of fibrosis to explain the underlying mechanism. Methods: Chronic DILI patients who underwent liver biopsy were divided into different fibrosis grades. Serum was analyzed by untargeted metabolomics to find serological characteristic metabolite fingerprints. The screened fingerprints were validated by the validation group patients, and the identification ability of fingerprints was compared using FibroScan. Results: A total of 31 metabolites associated with fibrosis and 11 metabolites associated with advanced fibrosis were identified. The validation group confirmed the accuracy of the two metabolite fingerprints [area under the curve (AUC) value 0.753 and 0.944]. In addition, the fingerprints showed the ability to distinguish the grades of fibrosis by comparing using FibroScan. The metabolite fingerprint pathway showed that bile acid synthesis is disturbed while lipid metabolism is extremely active, resulting in an overload of lipid metabolites in the occurrence and development of chronic DILI-associated fibrosis. Conclusions: Our metabolomic analysis reveals the unique metabolomic fingerprints associated with chronic DILI fibrosis, which have potential clinical diagnostic and prognostic significances. The metabolomic fingerprints suggest the disturbance of the lipid metabolites as the most important factor in the development of DILI fibrosis.

Metabolic Disorders Combined with Noninvasive Tests to Screen Advanced Fibrosis in Nonalcoholic Fatty Liver Disease.

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) is associated with metabolic disorders. This study aimed to explore the role of metabolic disorders in screening advanced fibrosis in NAFLD patients. METHODS: A total of 246 histologically-proven NAFLD patients were enrolled across 14 centers. We compared the severity of fibrosis in patients with different components of metabolic disorders. Based on standard noninvasive tests and metabolic disorders, we developed new algorithms to identify advanced fibrosis. RESULTS: Metabolic syndrome (MetS) was frequent in NAFLD patients (133/246, 54%). Patients with MetS had a higher proportion of significant fibrosis (p=0.014) and higher LSM values (9.2 kPa, vs. 7.4 kPa, p=0.002) than those without MetS. Patients with more metabolic disorders had higher fibrosis stages (p=0.017). Reduced high-density lipoprotein cholesterol (odds ratio [OR]: 2.241, 95% confidence interval [CI]: 1.004-5.002, p=0.049) and raised fasting glucose (OR: 4.500, 95% CI: 2.083-9.725, p<0.001) were significantly associated with advanced fibrosis. Using these two metabolic disorders as a screening tool, a sensitivity, specificity and accuracy of 92%, 81% and 83% was achieved, respectively. With the new algorithms combining metabolic disorders with noninvasive measurements, the number of patients requiring liver biopsy was reduced, especially in combination with the Fibrosis-4 score and metabolic disorders (36% to 17%, p<0.001). In addition, this stepwise algorithm could achieve a high accuracy (85%) and high negative predictive value (93%). CONCLUSIONS: Metabolic disorders should be taken into consideration in the diagnosis of advanced fibrosis. With further validation and investigation, new algorithms could be recommended in primary care units to spare patients from unnecessary referral and liver biopsies.

Herb-Induced Liver Injury Related to Reynoutria multiflora (Thunb.) Moldenke: Risk Factors, Molecular and Mechanistic Specifics.

Herbal medicine is widely used in Asia as well as the west. Hepatotoxicity is one of the most severe side effects of herbal medicine which is an increasing concern around the world. Reynoutria multiflora (Thunb.) Moldenke (Polygonum multiflorum Thunb., PM) is the most common herb that can cause herb-induced liver injury (HILI). The recent scientific and technological advancements in clinical and basic research are paving the way for a better understanding of the molecular aspects of PM-related HILI (PM-HILI). This review provides an updated overview of the clinical characteristics, predisposing factors, hepatotoxic components, and molecular mechanisms of PM-HILI. It can also aid in a better understanding of HILI and help in further research on the same.

The pathologic relevance of metabolic criteria in patients with biopsy-proven nonalcoholic fatty liver disease and metabolic dysfunction associated fatty liver disease: A multicenter cross-sectional study in China.

BACKGROUND: This study aimed to assess the association between metabolic syndrome (MetS) and severity of nonalcoholic fatty liver disease (NAFLD), and to discuss the pathological relevance of the diagnostic criteria in metabolic (dysfunction) associated fatty liver disease (MAFLD). METHODS: This was a multicenter, cross-sectional study. Patients with NAFLD confirmed by liver biopsy were enrolled between July 2016 and December 2018 from 14 centers across the mainland of China. Anthropometric and metabolic parameters were collected to assess the pathological relevance. RESULTS: Of 246 enrolled patients with NAFLD, 150 (61.0%) had the comorbidity of MetS. With the increase of metabolic components, the proportions of nonalcoholic steatohepatitis (NASH) and significant fibrosis were notably increased. The comorbid three metabolic components significantly increased the proportion of NASH, and further increase of metabolic components did not increase the proportion of NASH. However, the increase of metabolic components was parallel to the increase of the proportion of liver fibrosis. Among the 246 patients, 239 (97.2%) met the diagnostic criteria of MAFLD. Although non-MAFLD patients had less NASH, they present with similar proportion of significant fibrosis and cirrhosis. In the diagnostic criteria of MAFLD, BMI ≥ 23 kg/m2 was related to NASH (Mantel-Haenszel Common Estimate OR: 2.975; 95% CI: 1.037-8.538; P = 0.043), and T2DM was related to significant fibrosis (Mantel-Haenszel Common Estimate OR: 2.531; 95% CI: 1.388-4.613; P = 0.002). The homeostasis model assessment of insulin resistance (HOMA-IR) ≥ 2.5 was the most significant factor for NASH (OR: 4.100; 95% CI: 1.772-9.487; P = 0.001) and significant factor for liver fibrosis (OR: 2.947; 95% CI: 1.398-6.210; P = 0.004) after the adjustments of the BMI and diabetes. CONCLUSIONS: Metabolic dysregulations are important risk factors in NAFLD progression. The insulin resistance status may play a predominant role in the progression in MAFLD patients.

Metabolomic Analysis Uncovers Energy Supply Disturbance as an Underlying Mechanism of the Development of Alcohol-Associated Liver Cirrhosis.

Alcohol-associated liver disease (ALD) is caused by alcohol metabolism's effects on the liver. The underlying mechanisms from a metabolic view in the development of alcohol-associated liver cirrhosis (ALC) are still elusive. We performed an untargeted serum metabolomic analysis in 14 controls, 16 patients with ALD without cirrhosis (NC), 27 patients with compensated cirrhosis, and 79 patients with decompensated ALC. We identified two metabolic fingerprints associated with ALC development (38 metabolites) and those associated with hepatic decompensation (64 metabolites) in ALC. The cirrhosis-associated fingerprint (eigenmetabolite) showed a better capability to differentiate ALC from NC than the aspartate aminotransferase-to-platelet ratio index score. The eigenmetabolite associated with hepatic decompensation showed an increasing trend during the disease progression and was positively correlated with the Model for End-Stage Liver Disease score. These metabolic fingerprints belong to the metabolites in lipid metabolism, amino acid pathway, and intermediary metabolites in the tricarboxylic acid cycle. Conclusion: The metabolomic fingerprints suggest the disturbance of the metabolites associated with cellular energy supply as an underlying mechanism in the development and progression of alcoholic cirrhosis.

Health-related quality of life in Chinese population with non-alcoholic fatty liver disease: a national multicenter survey.

BACKGROUND: Health Related Quality of Life (HRQL) is a multi-dimensional construct that can comprehensively evaluate the patient's health status, including physical, emotional, mental and social well-being. In this study, we aimed to evaluate the impact of non-alcoholic fatty liver disease (NAFLD) on HRQL in a Chinese population. METHODS: In this national multicenter cross-sectional survey, patients with NAFLD were enrolled. Chronic Liver Disease Questionnaire (CLDQ)-NAFLD was used to qualify HRQL. Univariate and multivariate analysis were used to identify independent risk factors of HRQL. RESULTS: A total of 5181 patients with NAFLD from 90 centers were enrolled in this study (mean age, 43.8 ± 13.3 years; male, 65.8%). The overall CLDQ score was 5.66 ± 0.89. Multivariate logistic regression analysis showed that body mass index (BMI: HR, 1.642; 95% CI, 1.330-2.026), alanine transaminase (ALT: HR, 1.006; 95% CI, 1.001-1.011), triglyceride (HR, 1.184; 95% CI, 1.074-1.305), disease severity (HR, 3.203; 95% CI, 1.418-7.232) and cardiovascular disease (HR, 4.305; 95% CI, 2.074-8.939) were independent risk factors for overall CLDQ score. In the logistic analyses of individual domain, BMI and triglyceride were independent risk factors of all domains. ALT, disease severity, diabetes, depression and cardiovascular disease were influencing factors for the CLDQ score of several domains. CONCLUSIONS: This national multicenter cross-sectional survey in China indicated that the HRQL in patients with NAFLD was impaired. HRQL was found to be significantly associated with sociodemographic and clinical factors. Attention should be paid to the optimally managing care of patients with NAFLD to improve their HRQL.

Serum Metabolomic Analysis of Chronic Drug-Induced Liver Injury With or Without Cirrhosis.

Background: Chronic drug-induced liver injury (DILI) occurs in up to 20% of all DILI patients. It presents a chronic pattern with persistent or relapsed episodes and may even progress to cirrhosis. However, its underlying development mechanism is poorly understood. Aims: To find serum metabolite signatures of chronic DILI with or without cirrhosis, and to elucidate the underlying mechanism. Methods: Untargeted metabolomics coupled with pattern recognition approaches were used to profile and extract metabolite signatures from 83 chronic DILI patients, including 58 non-cirrhosis (NC) cases, 14 compensated cirrhosis (CC) cases, and 11 decompensated cirrhosis (DC) cases. Results: Of the 269 annotated metabolites associated with chronic DILI, metabolic fingerprints associated with cirrhosis (including 30 metabolites) and decompensation (including 25 metabolites), were identified. There was a significantly positive correlation between cirrhosis-associated fingerprint (eigenmetabolite) and the aspartate aminotransferase-to-platelet ratio index (APRI) (r = 0.315, P = 0.003). The efficacy of cirrhosis-associated eigenmetabolite coupled with APRI to identify cirrhosis from non-cirrhosis patients was significantly better than APRI alone [area under the curve (AUC) value 0.914 vs. 0.573]. The decompensation-associated fingerprint (eigenmetabolite) can effectively identify the compensation and decompensation periods (AUC value 0.954). The results of the metabolic fingerprint pathway analysis suggest that the blocked tricarboxylic acid cycle (TCA cycle) and intermediary metabolism, excessive accumulation of bile acids, and perturbed amino acid metabolism are potential mechanisms in the occurrence and development of chronic DILI-associated cirrhosis. Conclusions: The metabolomic fingerprints characterize different stages of chronic DILI progression and deepen the understanding of the metabolic reprogramming mechanism of chronic DILI progression to cirrhosis.

Metabolomic Signatures of Autoimmune Hepatitis in the Development of Cirrhosis.

Objectives: Autoimmune hepatitis (AIH) can progress into severe outcomes, i.e., decompensated cirrhosis, from remarkable and persistent inflammation in the liver. Considering the energy-expending nature of inflammation, we tried to define the metabolomics signatures of AIH to uncover the underlying mechanisms of cirrhosis development and its metabolic biomarkers. Methods: Untargeted metabolomics analysis was performed on sera samples from 79 AIH patients at the stages (phenotypes) of non-cirrhosis (n = 27), compensated cirrhosis (n = 22), and decompensated cirrhosis (n = 30). Pattern recognition was used to find unique metabolite fingerprints of cirrhosis with or without decompensation. Results: Out of the 294 annotated metabolites identified, 2 metabolic fingerprints were found associated with the development of cirrhosis (independent of the decompensated state, 42 metabolites) and the evolution of decompensated cirrhosis (out of 47 metabolites), respectively. The cirrhosis-associated fingerprints (eigenmetabolite) showed better capability to differentiate cirrhosis from non-cirrhosis patients than the aminotransferase-to-platelet ratio index. From the metabolic fingerprints, we found two pairs of metabolites (Mesobilirubinogen/6-Hydroxynicotinic acid and LysoPA(8:0/0:0)/7alpha-Hydroxycholesterol) calculated as ratio of intensities, which revealed robust abilities to identify cirrhosis or predict decompensated patients, respectively. These phenotype-related fingerprint metabolites featured fundamental energy supply disturbance along with the development of AIH cirrhosis and progression to decompensation, which was characterized as increased lipolysis, enhanced proteolysis, and increased glycolysis. Conclusions: Remodeling of metabolism to meet the liver inflammation-related energy supply is one of the key signatures of AIH in the development of cirrhosis and decompensation. Therefore, drug regulation metabolism has great potential in the treatment of AIH.

Metabolomics Profiling and Diagnosis Biomarkers Searching for Drug-Induced Liver Injury Implicated to Polygonum multiflorum: A Cross-Sectional Cohort Study.

Aim: The diagnosis of drug-induced liver injury (DILI) remains a challenge and the cases of Polygonum multiflorum Thunb. (PM) induced DILI (PM-DILI) have received much attention This study aimed to identify a simple and high-efficiency approach to PM-DILI diagnosis via metabolomics analysis. Methods: Plasma metabolites in 13 PM-DILI patients were profiled by liquid chromatography along with high-resolution mass spectrometry. Meanwhile, the metabolic characteristics of the PM-DILI were compared with that of autoimmune hepatitis (AIH), hepatitis B (HBV), and healthy volunteers. Results: Twenty-four metabolites were identified to present significantly different levels in PM-DILI patients compared with HBV and AIH groups. These metabolites were enriched into glucose, amino acids, and sphingolipids metabolisms. Among these essential metabolites, the ratios of P-cresol sulfate vs. phenylalanine and inosine vs. bilirubin were further selected using a stepwise decision tree to construct a classification model in order to differentiate PM-DILI from HBV and AIH. The model was highly effective with sensitivity of 92.3% and specificity of 88.9%. Conclusions: This study presents an integrated view of the metabolic features of PM-DILI induced by herbal medicine, and the four-metabolite decision tree technique imparts a potent tool in clinical diagnosis.

Risk profiling using metabolomic characteristics for susceptible individuals of drug-induced liver injury caused by Polygonum multiflorum.

Idiosyncratic drug-induced liver injury (IDILI) is a rare but potentially severe adverse drug reaction. To date, identifying individuals at risk for IDILI remains challenging. This is a prospective study, where a nested case-control (1:5) design was adopted. For six patients who had abnormalities in liver function test after Polygonum multiflorum Thunb. (PM) ingestion (susceptible group), 30 patients with normal liver function were matched (tolerant group). Based on liquid chromatography-mass spectrometry, metabolomics analysis was done on serum samples prior to PM ingestion, to screen the differential metabolites and characterize metabolomic profiles of patient serum in the two groups. Multivariate analysis showed that there were remarkable separations between susceptible and tolerant groups. A total of 25 major differential metabolites were screened out, involving glycerophospholipid metabolism, sphingolipid metabolism, fatty acid metabolism, histidine metabolism and aromatic amino acid metabolism. Wherein, the area under the curve of the receiver operating characteristic curves of metabolites PE 22:6, crotonoyl-CoA, 2E-tetradecenoyl-CoA, phenyllactic acid, indole-5,6-quinone, phosphoribosyl-ATP were all greater than 0.9. The overall serum metabolic profile comprising of 25 metabolites could clearly distinguish susceptible and tolerant groups. This proof-of-concept study used metabolomics to characterize the metabolic profile of IDILI risk individuals before drug ingestion for the first time. The metabolome characteristics in patient serum before PM ingestion may predict the risk of liver injury after PM ingestion.

Granulocytic myeloid-derived suppressor cell population increases with the severity of alcoholic liver disease.

Alcoholic liver disease (ALD) is a progressive liver disease that can cause a series of complications, including cirrhosis, liver failure and hepatocellular carcinoma. Granulocytic myeloid-derived suppressor cell (gMDSC) populations have been observed to expand in various liver diseases and to inhibit innate and adaptive immunity in patients with liver disease. However, the characteristics of gMDSCs in patients with ALD have not been studied. We studied 24 healthy controls (HCs) and 107 patients with ALD and found an accumulation of gMDSCs in the peripheral blood of patients with alcoholic liver cirrhosis (ALC). Furthermore, ALC patients with a poor prognosis displayed a significant increase in peripheral gMDSCs and showed an increased capacity for arginase I production compared to HCs. In contrast, plasma arginase I levels in ALC patients were negatively correlated with total bilirubin and international normalized ratio, two key parameters of liver damage. Importantly, gMDSCs accumulated in the livers of ALC patients, and the frequency of liver gMDSCs significantly correlated with that of peripheral gMDSCs. In addition, gMDSC enrichment in vitro significantly inhibited the function of natural killer (NK) cells, perhaps preventing the NK-induced apoptosis of hepatic stellate cells. In summary, increased peripheral and intrahepatic gMDSC populations are present in patients with ALC and may contribute to enhancing the severity of liver cirrhosis.

Disease spectrum of alcoholic liver disease in Beijing 302 Hospital from 2002 to 2013: A large tertiary referral hospital experience from 7422 patients.

Alcohol consumption in China has substantially increased over the last 3 decades and the number of patients with alcoholic liver disease (ALD) is rising at an alarming rate. However, accurate and representative data on time trends in its hospitalization rates are not available. The aim of this study is to assess the current status and burden of ALD in China by analyzing the data from a large tertiary referral hospital, Beijing 302 Hospital.Data were retrospectively recorded from patients diagnosed as ALD in Beijing 302 Hospital from 2002 to 2013. The disease spectrum and biochemical parameters of each patient were collected.The patients with ALD accounted for 3.93% (7422) of all patients (188,902) with liver diseases between 2002 and 2013. The number of patients hospitalized with ALD increased from 110 in 2002 to 1672 in 2013. The ratio of patients hospitalized with ALD to all patients hospitalized with liver diseases was rising almost continuously and increased from 1.68% in 2002 to 4.59% in 2013. Most patients with ALD were male. Age distribution of ALD hospitalization showed that the highest rate was in 40- to 49-year-old group in subjects. Notably, the annual proportion of severe alcoholic hepatitis (SAH) increased 2.43 times from 2002 to 2013. We found the highest levels of mean corpuscular volume, the aspartate aminotransferase/alanine aminotransferase ratio, total bilirubin, international normalized ratio, and alkaline phosphatase in SAH patients, while serum levels of hemoglobin, albumin, and cholinesterase were significantly decreased in SAH group. Among these ALD, the SAH patient population has the worst prognosis. Alcoholic cirrhosis (ALC) is the most common ALD, and annual admissions for ALC increased significantly during the analyzed period.The number of hospitalized patients with ALD and the annual hospitalization rate of ALD were increasing continuously in Beijing 302 Hospital from 2002 to 2013. More attention should be paid to develop population-based effective strategy to control ALD.

Urine metabolomics study on the liver injury in rats induced by raw and processed Polygonum multiflorum integrated with pattern recognition and pathways analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Polygonum multiflorum L. is a famous traditional Chinese medicine that has always been perceived to be safe. Recently, the increasing case reports on hepatotoxicity induced by Raw P. multiflorum (RP) have attracted particular attention. However, the diagnosis and identification of RP-induced hepatotoxicity are still very difficult for its unknown mechanism and the lack of specific biomarkers. AIM OF THE STUDY: To further explore the toxicity and metabolic mechanisms involved in the hepatotoxicity induced by RP. MATERIALS AND METHODS: The hepatotoxicity induced by RP and its processed products (PP) (dosed at 20g/kg for 4 weeks) on rats were investigated using conventional approaches including the biochemical analysis and histopathological observations. Further, a urinary metabolomic approach was developed to study the metabolic disturbances caused by RP and PP, followed by the pattern recognition approach and pathways analysis. RESULTS: RP showed obvious hepatotoxity whereas PP did not. 16 potential biomarkers (pyridoxamine, 4-pyridoxic acid, citrate et al.) differentially expressed in RP group were identified compared with the control and PP-treated groups. The pathways analysis showed that vitamin B6 metabolism, tryptophan metabolism and citrate cycle might be the major enriched pathways involved in the hepatotoxicity of the herb. CONCLUSION: 16 differentially expressed metabolites were identified to be involved in the RP-induced hepatotoxicity. Vitamin B6 metabolism might be mostly related to the hepatotoxicity induced by RP. This finding may provide a potential therapeutic target or option to treat hepatotoxicity induced by RP.

Hepatobiliary and pancreatic: Comparison between Chinese herbal medicine and Western medicine-induced liver injury of 1985 patients.

BACKGROUND AND AIM: Chinese herbal medicine (CHM), as well as Western medicine (WM), is an important cause of drug-induced liver injury (DILI). However, the differences between CHM and WM as agents implicated in liver injury have rarely been reported. METHODS: Overall, 1985 (2.05%) DILI cases were retrospectively collected from the 96 857 patients hospitalized because of liver dysfunction in the 302 Military Hospital between January 2009 and January 2014. RESULTS: In all the enrolled patients with DILI, CHM was implicated in 563 cases (28.4%), while 870 cases (43.8%) were caused by WM and the remaining patients (27.8%) by the combination of WM and CHM. Polygonum multiflorum was the major implicated CHM. Compared with WM, the cases caused by CHM showed more female (51 vs 71%, P < 0.001) and positive rechallenge (6.1 vs 8.9%, P = 0.046), a much greater proportion of hepatocellular injury (62.2 vs 88.5%, P < 0.001), and a higher mortality (2.8 vs 4.8%, P = 0.042); however, no differences in the rates of chronic DILI and ALF were found (12.9 vs 12.4%, P = 0.807; 7.6 vs 7.6%, P = 0.971). Based on Roussel Uclaf Causality Assessment Method, 75.6% of cases caused by CHM were classified as probable and only 16.6% as highly probable, significantly different from WM (38.4 and 60.3%, all P < 0.001). CONCLUSIONS: The causal relationship between CHM and liver injury is much complex, and the clinical characteristics of DILI caused by CHM differ from those caused by WM.

Proposed therapies in primary biliary cholangitis.

Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, is a model autoimmune disease with chronic cholestasis characterized by the hallmark of anti-mitochondrial antibodies and treated with ursodeoxycholic acid (UDCA). However, approximately 20-40% of patients incompletely respond to UDCA and have an increased risk of disease progression. Although there have been significant advances in the immunobiology of PBC, these have yet to be translated into newer therapeutic modalities. Current approaches to controlling the immune response include broad immunosuppression with corticosteroids as well as targeted therapies directed against T and B cells. In contrast, ameliorating cholestasis is the focus of other therapies in development, including obeticholic acid. In this article the authors will discuss ongoing clinical trials and, in particular, the rationale for choosing agents that may effectively target the aberrant immune response.

[Clinical Analysis of Drug-induced Liver Injury Caused by Polygonum multiflorum and its Preparations].

OBJECTIVE: To analyze hepatotoxicity of Polygonum multiflorum and clinical character- istics of drug-induced liver injury (DILI) caused by Polygonum multiflorum and its preparations. METHODS: A retrospective study was performed in 158 patients treated at 302 Military Hospital between January 2009 and January 2014. All of them had used Polygonum multiflorum and its preparations before the onset of DILI, and their clinical characteristics and prognoses were analyzed. RESULTS: Of the 158 DILI patients who used Polygonum multiflorum or its preparations, 92 (58.2%) combined with Western medicine or Chinese herbal preparations without Polygonum multiflorum; 66 patients (41.8%) used Polygonum mult florum and its preparations alone. In 66 DILI patients induced by Polygonum multiflorum or its preparations alone, 51 cases (77.3%) were induced by Polygonum multiflorum compounds and 22.7% by single Po- lygonum multiflorum; 4 cases (6.1%) were caused by crude Polygonum multiflorum and 62 (93.9%) by processed Polygonum multiflorum and its preparations. Clinical injury patterns were hepatocellular 92.4% (61 cases), cholestatic 1.5% (1 case), and mixed 6.1% (4 cases). Pathological examination was per- formed by liver biopsy in 32 cases (48.15%), manifested as hepatocellular degeneration and necrosis, fibroplasia, Kupffer cells with pigment granule, and a large number of eosinophil infiltration, were ob- served. Four patients were developed into liver failure, 4 into cirrhosis, and 1 died. CONCLUSION: Polygo- num multiflorum and its preparations could induce DILI, but clinical diagnosis of Polygonum multiflorum induced hepatotoxicity should be cautious.