Clinical Manifestations Of Liver Injury Research Articles

Theragnostic Efficacy of K18 Response in Alcohol Use Disorder with Clinically Significant Fibrosis Using Gut-Liver Axis.

(1) Background: Fibrosis in early-stage alcohol-associated liver disease (ALD) is commonly under-diagnosed in routine clinical practice. This study characterized the liver-injury and cell death response in alcohol use disorder (AUD) patients with ALD who also exhibited fibrosis and assessed the efficacy of standard of care (SOC) treatment in the improvement in liver injury. (2) Methods: Forty-eight heavy-drinking AUD patients aged 21–65 yrs. without clinical manifestations of liver injury were grouped by Fibrosis-4 (FIB-4) score, as negative (Gr.1 < 1.45, n = 21) or positive (Gr.2 ≥ 1.45, n = 27). Patients received 2-weeks (2 w) inpatient SOC. Data on demographics, drinking patterns, liver-injury, immune markers, and liver cell death (K18s) markers were analyzed at baseline (BL) and after 2 w SOC. (3) Results: Lifetime drinking (LTDH, yrs.) and acute heavy drinking (Heavy Drinking Days Past 90 Days [HDD90]) markers were significantly higher in Gr.2 vs. Gr.1. BL ALT, AST, AST:ALT and K18M65 were considerably higher in Gr.2. Dysregulated gut dysfunction and elevated immune activity were evident in Gr.2 characterized by TNF-α, IL-8 and LPS levels. After SOC, Gr.2 showed improvement in AST, ALT, AST/ALT ratio; and in the K18M65, K18M30 and K18M65/M30 ratio vs. Gr.1. The true positivity of BL IL-8 response to predict the improvement in K18M65 to normal levels among Gr.2 patients against those who did not have improvement after 2 w SOC was very high (AUROC = 0.830, p = 0.042). (4) Conclusions: Gut dysfunction, elevated cytokine response and necrotic liver cell death were elevated in AUD patients with early-stage ALD. K18 showed promise as a predictive theragnostic factor to differentiate among the AUD patients with early-stage ALD and baseline fibrosis who had improvement in liver injury against those who did not, by the levels of baseline IL-8.

Idiosyncratic Drug-Induced Liver Injury: Mechanistic and Clinical Challenges.

Idiosyncratic drug-induced liver injury (IDILI) remains a significant problem for patients and drug development. The idiosyncratic nature of IDILI makes mechanistic studies difficult, and little is known of its pathogenesis for certain. Circumstantial evidence suggests that most, but not all, IDILI is caused by reactive metabolites of drugs that are bioactivated by cytochromes P450 and other enzymes in the liver. Additionally, there is overwhelming evidence that most IDILI is mediated by the adaptive immune system; one example being the association of IDILI caused by specific drugs with specific human leukocyte antigen (HLA) haplotypes, and this may in part explain the idiosyncratic nature of these reactions. The T cell receptor repertoire likely also contributes to the idiosyncratic nature. Although most of the liver injury is likely mediated by the adaptive immune system, specifically cytotoxic CD8+ T cells, adaptive immune activation first requires an innate immune response to activate antigen presenting cells and produce cytokines required for T cell proliferation. This innate response is likely caused by either a reactive metabolite or some form of cell stress that is clinically silent but not idiosyncratic. If this is true it would make it possible to study the early steps in the immune response that in some patients can lead to IDILI. Other hypotheses have been proposed, such as mitochondrial injury, inhibition of the bile salt export pump, unfolded protein response, and oxidative stress although, in most cases, it is likely that they are also involved in the initiation of an immune response rather than representing a completely separate mechanism. Using the clinical manifestations of liver injury from a number of examples of IDILI-associated drugs, this review aims to summarize and illustrate these mechanistic hypotheses.

Characterization of Early-Stage Alcoholic Liver Disease with Hyperhomocysteinemia and Gut Dysfunction and Associated Immune Response in Alcohol Use Disorder Patients.

Heavy alcohol consumption can cause hyperhomocysteinemia, which could be consequential in the proinflammatory response and worsening of the neurobehavioral domains of alcohol use disorder (AUD), such as alcohol withdrawal. We examined the role of heavy drinking, hyperhomocysteinemia, gut dysfunction and inflammation in early-stage alcoholic liver disease (ALD) in AUD patients. A total of 110 AUD patients without clinical manifestations of liver injury were grouped by the serum homocysteine levels (SHL): normal ≤ 13 µmol/L (Group 1 (Gr.1); n = 80), and elevated > 13 µmol/L (Group 2 (Gr.2), n = 30). A comprehensive metabolic panel, SHL, a nutritional assessment, and drinking history assessed by the timeline followback questionnaire were evaluated. A subset analysis was performed on 47 subjects (Gr.1 n = 27; Gr.2 n = 20) for additional measures: Clinical Institute Withdrawal Assessment for Alcohol (CIWA) score, plasma cytokines (interleukin-1β (IL-1β)), gut dysfunction markers (lipopolysaccharide (LPS), and LPS-binding protein (LBP)); 27% of the AUD patients exhibited hyperhomocysteinemia. SHL was significantly associated (p = 0.034) with heavy drinking days (HDD90). Subset analyses showed that the withdrawal ratings were both clinically and statistically (p = 0.033) elevated and significantly associated with hyperhomocysteinemia (p = 0.016) in Gr.2. LBP, IL1-β, SHL, and HDD90 showed significant cumulative effects (adjusted R2 = 0.627) on withdrawal ratings in Gr.2 subset. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were significantly higher in all Gr.2 patients; AUROC showed a fair level of true positivity for ALT (0.676), and AST (0.686). Il1-β, LBP, SHL, and HDD90 showed significant cumulative effects (adjusted R2 = 0.554) on the elevated ALT in Gr.2 subset as well. The gut-brain derived proinflammatory response, patterns of heavy drinking, and hyperhomocysteinemia were closely associated with clinically elevated alcohol withdrawal and elevated liver injury. Hyperhomocysteinemia could have a potential phenotypic marker response indicative of early-stage ALD along with AUD.

Research progress of liver injury induced by Polygoni Mulitiflori Radix

Polygoni Mulitiflori Radix, or dried root tuber of Polygonum multiflorum(PM), is a traditional Chinese tonic medicine, with the effect in nourishing liver and kidney, and benefiting blood essence and hair. It is widely used in clinical and healthcare products. In recent years, more and more reports about adverse reactions of root tuber of P.multiflorum and its preparations have been reported. Fortunately, there is also substantial progress in the experimental study on liver injury induced by PM. According to the literature review, the possible causes of liver injury were found to be the mixture of raw and processed PM and long-term high-dose administration. In addition, the liver injury induced by PM is idiosyncratic liver injury, and individual factors are also the important cause. At the same time, according to the literature reports, the effects of chemical components in different pathological animal models were summarized, finding that 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside was the main component for liver injury; based on the clinical manifestations of liver injury induced by PM, the effects of some chemical components on bilirubin and bile acid metabolism were analyzed. This paper reviews the study progress of liver injury induced by PM.

Lower Serum Magnesium Concentrations are associated With Specific Heavy Drinking Markers, Pro-Inflammatory Response and Early-Stage Alcohol-associated Liver Injury§.

Chronic heavy alcohol intake frequently causes liver inflammation/injury, and altered mineral metabolism may be involved in this liver pathology. In this study, we evaluated the association of heavy drinking, changes in serum magnesium levels and biochemical evidence of liver injury in alcohol-use-disorder (AUD) patients who had no clinical signs or symptoms of liver injury. We also aimed to identify any sex-based differences in patients with mild or no biochemical evidence of liver injury induced by heavy drinking. 114 heavy drinking alcohol-dependent (AD) female and male patients aged 21-65years without clinical manifestations of liver injury, who were admitted to an alcohol treatment program, were grouped by alanine aminotransaminase (ALT) levels: ≤ 40IU/L, as no liver injury (GR.1), and ALT>40IU/L as mild liver injury (GR.2). Patients were actively drinking until the day of admission. Comprehensive metabolic biochemistry results, fatty acid panel, serum magnesium and drinking history data were collected at admission; and study-specific measures were evaluated. In all AD patients, lower magnesium was significantly associated with the heavy drinking marker and heavy drinking days past 90days (HDD90). A lower serum magnesium concentration was observed in AD patients with mild liver injury. Females of both groups had mean levels of magnesium in the deficient range. A clinically significant drop in magnesium levels was observed only in the GR.2 (mild liver injury) male AD patients. Females showed a significant association between low magnesium levels and the ω6:ω3 polyunsaturated fatty acids (PUFAs) ratio. Specific heavy drinking markers showed an association with lower magnesium levels. Low serum magnesium levels are common in subjects with AUD and appear to be associated with the onset of liver injury.

Analysis of chemotherapy drug-induced liver injury in children with acute lymphoblastic leukemia based on RUCAM scale

Objective To analyze the characteristics of drug-induced liver injury (DILI) in children with acute lymphoblastic leukemia (ALL), so as to improve the physician′s understanding of chemotherapy DILI, and to guide clinical rational drug use. Methods One hundred and forty-three cases with ALL diagnosed in the Department of Hematology and Oncology in the First Affiliated Hospital of Zhengzhou University from January 2012 to December 2016 were analyzed retrospectively.Based on DILI diagnostic criteria and the RUCAM scale, the cases with a score of ≥3 points were considered to have chemotherapy DILI.Grouped by gender, age, immunotyping, risk and stage of chemo-therapy, the incidence of DILI was compared.The situation after DILI prevention was compared between two groups which was grouped according to whether the application of hepatoprotective drugs. Results One hundred and eight cases (75.52%) had DILI, 66 cases (61.11%) showed clinical manifestations of liver injury, and 42 cases (38.89%) had no clinical symptoms.Among all the cases 57.41%(62 cases) were mild liver damage, 25%(27 cases) were moderate liver injury and 17.59%(19 cases) were severe liver damage.The clinical types which were hepatocellular accounting for 79.63%(86 cases), cholestatic 7.41%(8 cases) and mixed 12.96%(14 cases). Male were 80 cases (79.21%) and female 28 cases(66.67%), but the incidence of DILI between different gender group had no statistical difference (χ2=2.524, P=0.112). Seventy-five cases(77.32%) were 8 points accounted for 21 cases(19.45%), 6-8 points accounted for 59 cases(54.63%)and 3-5 points accounted for 28 cases(25.92%). Eighty-nine patients (92.71%) were effective in the hepatoprotective group and 8 patients (66.67%) in the no hepatoprotective therapy group.The difference between the 2 groups was statistically significant (χ2=5.317, P=0.021). Conclusions The clinical symptoms of drug-induced liver injury in children with ALL chemotherapy are lack of specificity.They are mainly characterized by mild liver injury.The clinical type of hepatic injury is common in hepatocellular.The RUCAM score was mostly 6 to 8.There is no relationship between the incidence in ALL and gender, age, type of leukemia.The incidence with moderate risk type is higher than that of the standard and high-risk type.The incidence in induction remission stage is highest.Application of hepatoprotective drugs is beneficial to DILI prognosis. Key words: Child; Acute lymphoblastic leukemia; RUCAM scale; Chemotherapy; Drug-induced liver injury

Carbimazole Drug-Induced Hepatitis during Treatment of Graves’ Disease: About Four Cases at Dakar Teaching Hospital

Introduction: Mostly reported common side effects of carbimazole are cutaneous allergies and severe agranulocytosis. However, hepatotoxicity is rarely described. Thus, we report four observations of carbimazole drug-induced hepatitis during the treatment of Graves’ disease, which imputability is likely and probably an immuno-allergic mechanism. Observations: They were four women whose average age was 43 years, with extreme ages of 32 and 54. Patients were monitored and treated with carbimazole in doses contained between 40 mg and 60 mg per day. Clinical manifestations of liver injury were mainly dominated by cholestatic jaundice, found in 100% of our patients. A painful sensitivity of the right hypochondrium was concomitant with jaundice for two patients. The jaundice time to onset after the beginning of treatment with carbimazole varies between 1 month and 6 months. They all had acute hepatitis. The biological assays used to determine the type of liver injury showed, in all cases, a mixed, cholestatic and cytolytic hepatitis. Therapeutically, in all patients, carbimazole was stopped as soon as the suspicion of its incrimination in the occurrence of liver damage was set up. They all had a substitution of carbimazole with benzylthiouracil. Evolution was favorable for all patients, after therapeutic substitution. It was marked by disappearance of jaundice and normalization of the liver biological parameters within a maximum delay of two months after stopping carbimazole use. Conclusion: Treatment with synthetic antithyroid drugs, particularly carbimazole that is most widely used in our regions, requires clinical and biological monitoring. This surveillance, which is often difficult in Africa because of the limited economic resources, can lead to the occurrence of side effects such as potentially serious drug-induced hepatitis, but which has been favorable in our observations.

Effects of Sex, Drinking History, and Omega-3 and Omega-6 Fatty Acids Dysregulation on the Onset of Liver Injury in Very Heavy Drinking Alcohol-Dependent Patients.

Heavy alcohol consumption frequently causes liver inflammation/injury, and certain fatty acids (FAs) may be involved in this liver pathology. In this study, we evaluated the association of heavy drinking and the changes in the FA levels involved in the ω-6 (pro-inflammatory) and ω-3 (anti-inflammatory) state in alcohol-dependent (AD) patients who had no clinical manifestations of liver injury. We aimed to identify sex-based differences in patients with mild or no biochemical evidence of liver injury induced by heavy drinking. A total of 114 heavy drinking AD female and male patients aged 21 to 65years without clinical manifestations of liver injury, who were admitted to an alcohol dependence treatment program, were grouped by the alanine aminotransferase (ALT) levels: ≤40 IU/l, as no liver injury (GR.1), and >40 IU/l, as mild liver injury (GR.2). Patients were actively drinking until the day of admission. Comprehensive metabolic panel, comprehensive FA panel, and drinking history data were evaluated. Elevated ALT and aspartate aminotransferase (AST) showed close association with markers of heavy alcohol intake. In the patients with mild biochemical liver injury (GR.2), females showed significantly higher AST level than males. Significant association of AST and total drinks in past 90 days (TD90) in females, and AST and heavy drinking days in past 90 days (HDD90) in males was observed. The ω-6:ω-3 ratio showed a significant pro-inflammatory response only in females with mild liver injury (GR.2) when adjusted by drinking history marker, TD90. Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) were increased in males with liver injury, while females did not show any comparable rise in EPA; and DHA levels were lower. Measures of heavy drinking, TD90 and HDD90, predicted changes in liver injury. Changes in the ω-3 and ω-6 FA levels and the ω-6:ω-3 ratio showed a pro-inflammatory shift in patients with biochemical liver injury with a significant effect in females. Changes in FAs involved in the inflammatory state may represent one mechanism for liver inflammation/injury in response to heavy alcohol drinking.

Clinical manifestations of liver injury in patients with anorexia nervosa

The number of Japanese patients with anorexia nervosa (AN) is increasing as society changes. Mild liver injury is a complication of AN in around 30% of cases. In some rare instances, patients present with severe liver injury similar to acute liver failure. However, there are numerous uncertainties over the clinical characteristics of this condition. The objective of the present study was to clarify the clinical characteristics of AN complicated by liver injury and to investigate the factors related to hepatic complications. Thirty-seven patients hospitalized at our institution with a diagnosis of AN were enrolled as the study subjects. The study used clinical data obtained at the time of hospitalization. The enrolled patients underwent subgroup analysis and were categorized into three groups: (i) normal alanine aminotransferase (ALT), (ii) moderately elevated ALT, and (iii) highly elevated ALT. All of the study subjects were female with a median age of 24 years and presenting with marked weight loss (mean body mass index, 13 kg/m(2) ). Thirteen of the subjects had liver injury. We found that patients in the highly elevated ALT group had a significantly high blood urea nitrogen (BUN)/creatinine ratio, and a low blood sugar level. Our present findings indicate that AN patients with highly elevated ALT have a severe dehydration. This suggests that dysfunction of hepatic circulation accompanying severe dehydration due to malnutrition may be an important factor in the development of liver injury in AN patients.