Increased Alanine Aminotransferase Levels Research Articles

Proton beam radiotherapy vs. radiofrequency ablation for recurrent hepatocellular carcinoma: A randomized phase III trial

Proton beam radiotherapy (PBT) has recently been applied to treat hepatocellular carcinoma (HCC); however, there is no randomized controlled trial-based evidence on its safety and efficacy. We compared the outcomes of PBT and radiofrequency ablation (RFA) in patients with recurrent/residual HCC (rHCC) in a phase III non-inferiority trial. Patients with rHCC (size <3 cm, number ≤2) were randomly assigned to receive PBT or RFA according to Child-Pugh score and tumor stage. After randomization, if the assigned treatment was technically infeasible, crossover was allowed. The primary endpoint was 2-year local progression-free survival (LPFS), with a non-inferiority margin of 15% in the per-protocol (PP) population; a complementary analysis was performed in the intention-to-treat (ITT) population (NCT01963429). The ITT population comprised 144 patients receiving either PBT (n= 72) or RFA (n= 72). Six patients switched from the PBT arm to the RFA arm and 19 patients switched from the RFA arm to the PBT arm. In the PP population, the 2-year LPFS rate with PBT (n= 80) vs. RFA (n= 56) was 94.8% vs. 83.9%, a difference of 10.9 percentage points (90% CI 1.8-20.0; p <0.001); in the ITT population, the 2-year LPFS rate with PBT vs. RFA was 92.8% vs. 83.2%, a difference of 9.6 percentage points (90% CI 0.7-18.4; p <0.001), meeting the criteria for non-inferiority. The 3- and 4-year LPFS rates for PBT were also non-inferior to those for RFA. The most common adverse events were radiation pneumonitis (32.5%) and decreased leukocyte counts (23.8%) for PBT and increased alanine aminotransferase levels (96.4%) and abdominal pain (30.4%) for RFA. No Grade 4 adverse events or mortality were noted. PBT showed LPFS values that were non-inferior to those for RFA; in addition, PBT was tolerable and safe. CLINICAL TRIAL NUMBER: #NCT01963429 (ClinicalTrials.gov). Radiofrequency ablation is the standard of care for patients with small hepatocellular carcinoma in whom surgery is not feasible. This study is the first phase III randomized controlled trial to evaluate the clinical outcomes of proton beam radiotherapy vs. radiofrequency ablation in patients with recurrent small HCC. Our findings show that this new technique is not inferior and can be applied safely in patients with small recurrent hepatocellular carcinoma.

The Association of 3-Hydroxy-3-Methylglutaryl-CoA Reductase, Apolipoprotein E, and Solute Carrier Organic Anion Genetic Variants with Atorvastatin Response among Jordanian Patients with Type 2 Diabetes.

Atorvastatin is commonly used among type 2 diabetic (DM2) patients at the University of Jordan Hospital to prevent cardiovascular complication. However, we noticed that there is a wide inter-individual variation in the efficacy and toxicity of atorvastatin. This study aimed to find out the effects of major genetic variants in 3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMGCR), Apolipoprotein E (APOE), and Solute Carrier Organic Anion (SLCO1B1) genes on atorvastatin response among DM2 patients. A sample of 139 DM2 patients on 20 mg of atorvastatin was included in this study. The lipid and glycemic profile and the levels of hepatic enzymes alanine aminotransferase (ALT) and aspartate transaminase were recorded before and after 3 months of atorvastatin treatment. Additionally, the genetic variants HMGCR rs17244841, APOE rs7412 and rs429357, and SLCO1B1 rs2306283 and rs11045818 were genotyped using an Applied Biosystems DNA sequencing method (ABI3730×1). We found that atorvastatin reduced total cholesterol and low-density lipoprotein (LDL) more significantly (p-value < 0.05) in patients with wild genotype than variant alleles APOE rs7412C > T and SLCO1B1 rs2306283A > G. Furthermore, the ALT level was elevated significantly (p-value < 0.05) by 27% in patients with heterozygous SLCO1B1 rs11045818 G/A genotype, while it was not elevated among wild genotype carriers. Additionally, atorvastatin reduced total cholesterol more significantly (p-value < 0.05) in patients with SLCO1B1 rs2306283A and rs11045818G haplotypes and increased ALT levels by 27% (p-value < 0.05) in patients with SLCO1B1 rs2306283G and rs11045818A haplotypes. In conclusion, it was found in this study that APOE rs7412, SLCO1B1 rs2306283, and rs11045818 genotypes can be considered as potential genetic biomarkers of atorvastatin response among DM2 patients of Jordanian Arabic origin. Further clinical studies with larger sample numbers are needed to confirm these findings.

ApoE deficiency promotes hepatic pathology by aggravating Th17/Treg imbalance in murine schistosomiasis japonica.

The Schistosoma japonicum (Sjaponicum)-infected ApoE gene deficiency (ApoE-/- ) mice were used to determine effect of ApoE on hepatic immunopathology. Murine activities and appetite, body weight, and ratio of liver weight to its body weight (Hepatic mass index, HMI) were observed. Worm load and liver egg burden were evaluated as the infection intensity. Number and size of liver egg granulomas and serum levels of alanine aminotransferase (ALT) were investigated. We analysed hepatic fibrosis by markers of fibrosis in tissue, detected hepatic Th17 and Treg frequency by flow cytometry, and measured hepatic expressions of RORγt, Foxp3, IL-17A and TGF-β1 via qPCR. Lipid metabolism was determined by serum levels of cholesterol (TC) and triglyceride (TG) as well as hepatic Oil red O staining. In the infected ApoE-/- mice, the increased infection intensity aggravated the hepatic immunopathology (evidenced by increased HMI, elevated egg granulomas and increased ALT levels) and fibrosis (increased hepatic collagen deposition). ApoE deficiency resulted in significantly elevated ratio of hepatic Th17/Treg and higher serum levels of TC and TG, along with higher level of hepatic Oil red O staining. ApoE deficiency promotes hepatic pathology and fibrosis by exacerbating Th17/Treg imbalance and altering lipid metabolism in murine schistosomiasis japonica.

The Safety and Side Effects of Amide-Based Local Anesthetics in Rats with Acetaminophen-Induced Hepatic Injury.

Background: The use of amide-based local anesthetics is generally considered to be safe. However, the literature on their safety in patients with hepatic injury is scarce. For the first time, the present study aimed to evaluate the effect and safety of five commonly used amide-based local anesthetics in the setting of hepatic failure.Methods: A total of 96 Sprague-Dawley rats were studied from September 2015 to September 2016 in the Animal Laboratory Center, Shiraz University of Medical Sciences, Shiraz, Iran. They divided into three groups, namely a control, induced liver failure (LF), and non-LF groups. The rats were administered local anesthetic agents (lidocaine, prilocaine with felypressin, lidocaine with epinephrine, mepivacaine, articaine, and prilocaine). The effect of these drugs was evaluated by comparing the liver enzyme levels of the rats. The data were analyzed using SPSS software. The independent t test, one-way ANOVA, and the post hoc tests were used to compare groups. A P<0.05 was considered statistically significant.Results: In non-LF rats, mepivacaine, lidocaine, and lidocaine with epinephrine caused a significant increase in aspartate aminotransferase (AST) level compared with the effect of prilocaine with felypressin and articaine. In non-LF rats, only mepivacaine resulted in a significant increase in AST level compared with lidocaine (P=0.007) and prilocaine with felypressin (P=0.044). In this group, only mepivacaine caused a significant increase in alanine transaminase (ALT) level compared with lidocaine (P=0.016). Whereas in the LF group, mepivacaine caused an increase in ALT level compared with the effect of both prilocaine with felypressin (P=0.009) and articaine (P<0.001). The use of mepivacaine in the LF group caused a significant increase in gamma-glutamyl transpeptidase level compared prilocaine with felypressin (P=0.039). Conclusion: Articaine and prilocaine with felypressin local anesthetics induced the least change in hepatic enzyme levels in rats with abnormal hepatic function.

Efficacy of Selpercatinib in RET-Altered Thyroid Cancers

BackgroundRET mutations occur in 70% of medullary thyroid cancers, and RET fusions occur rarely in other thyroid cancers. In patients with RET-altered thyroid cancers, the efficacy and safety of selective RET inhibition are unknown.MethodsWe enrolled patients with RET-mutant medullary thyroid cancer with or without previous vandetanib or cabozantinib treatment, as well as those with previously treated RET fusion–positive thyroid cancer, in a phase 1–2 trial of selpercatinib. The primary end point was an objective response (a complete or partial response), as determined by an independent review committee. Secondary end points included the duration of response, progression-free survival, and safety.ResultsIn the first 55 consecutively enrolled patients with RET-mutant medullary thyroid cancer who had previously received vandetanib, cabozantinib, or both, the percentage who had a response was 69% (95% confidence interval [CI], 55 to 81), and 1-year progression-free survival was 82% (95% CI, 69 to 90). In 88 patients with RET-mutant medullary thyroid cancer who had not previously received vandetanib or cabozantinib, the percentage who had a response was 73% (95% CI, 62 to 82), and 1-year progression-free survival was 92% (95% CI, 82 to 97). In 19 patients with previously treated RET fusion–positive thyroid cancer, the percentage who had a response was 79% (95% CI, 54 to 94), and 1-year progression-free survival was 64% (95% CI, 37 to 82). The most common adverse events of grade 3 or higher were hypertension (in 21% of the patients), increased alanine aminotransferase level (in 11%), increased aspartate aminotransferase level (in 9%), hyponatremia (in 8%), and diarrhea (in 6%). Of all 531 patients treated, 12 (2%) discontinued selpercatinib owing to drug-related adverse events.ConclusionsIn this phase 1–2 trial, selpercatinib showed durable efficacy with mainly low-grade toxic effects in patients with medullary thyroid cancer with and without previous vandetanib or cabozantinib treatment. (Funded by Loxo Oncology and others; LIBRETTO-001 ClinicalTrials.gov number, NCT03157128.)

Efficacy of Selpercatinib in RET Fusion–Positive Non–Small-Cell Lung Cancer

BackgroundRET fusions are oncogenic drivers in 1 to 2% of non–small-cell lung cancers (NSCLCs). In patients with RET fusion–positive NSCLC, the efficacy and safety of selective RET inhibition are unknown.MethodsWe enrolled patients with advanced RET fusion–positive NSCLC who had previously received platinum-based chemotherapy and those who were previously untreated separately in a phase 1–2 trial of selpercatinib. The primary end point was an objective response (a complete or partial response) as determined by an independent review committee. Secondary end points included the duration of response, progression-free survival, and safety.ResultsIn the first 105 consecutively enrolled patients with RET fusion–positive NSCLC who had previously received at least platinum-based chemotherapy, the percentage with an objective response was 64% (95% confidence interval [CI], 54 to 73). The median duration of response was 17.5 months (95% CI, 12.0 to could not be evaluated), and 63% of the responses were ongoing at a median follow-up of 12.1 months. Among 39 previously untreated patients, the percentage with an objective response was 85% (95% CI, 70 to 94), and 90% of the responses were ongoing at 6 months. Among 11 patients with measurable central nervous system metastasis at enrollment, the percentage with an objective intracranial response was 91% (95% CI, 59 to 100). The most common adverse events of grade 3 or higher were hypertension (in 14% of the patients), an increased alanine aminotransferase level (in 12%), an increased aspartate aminotransferase level (in 10%), hyponatremia (in 6%), and lymphopenia (in 6%). A total of 12 of 531 patients (2%) discontinued selpercatinib because of a drug-related adverse event.ConclusionsSelpercatinib had durable efficacy, including intracranial activity, with mainly low-grade toxic effects in patients with RET fusion–positive NSCLC who had previously received platinum-based chemotherapy and those who were previously untreated. (Funded by Loxo Oncology and others; LIBRETTO-001 ClinicalTrials.gov number, NCT03157128.)

Synthetic Peptides Containing Three Neutralizing Epitopes of Genotype 4 Swine Hepatitis E Virus ORF2 induced Protection against Swine HEV Infection in Rabbit.

Genotype 4 hepatitis E virus (HEV) is a zoonotic pathogen transmitted to humans through food and water. Previously, three genotype 4 swine HEV ORF2 peptides (407EPTV410, 410VKLYTS415, and 458PSRPF462) were identified as epitopes of virus-neutralizing monoclonal antibodies that partially blocked rabbit infection with swine HEV. Here, individual and tandem fused peptides were synthesized, conjugated to keyhole limpet hemocyanin (KLH), then evaluated for immunoprotection of rabbits against swine HEV infection. Forty New Zealand White rabbits were randomly assigned to eight groups; groups 1 thru 5 received three immunizations with EPTV-KLH, VKLYTS-KLH, PSRPF-KLH, EPTVKLYTS-KLH, or EPTVKLYTSPSRPF-KLH, respectively; group 6 received truncated swine HEV ORF2 protein (sp239), and group 7 received phosphate-buffered saline. After an intravenous swine HEV challenge, all group 7 rabbits exhibited viremia and fecal virus shedding by 2–4 weeks post challenge (wpc), seroconversion by 4–9 wpc, elevated alanine aminotransferase (ALT) at 2 wpc, and severe liver lymphocytic venous periphlebitis. Only 1–2 rabbits/group in groups 1–4 exhibited delayed viremia, fecal shedding, seroconversion, increased ALT levels, and slight liver lymphocytic venous periphlebitis; groups 5–6 showed no pathogenic effects. Collectively, these results demonstrate that immunization with a polypeptide containing three genotype 4 HEV ORF2 neutralizing epitopes completely protected rabbits against swine HEV infection.

Manifestations of liver injury in 333 hospitalized patients with coronavirus disease 2019

Objective To investigate the manifestations of liver injury in hospitalized patients with coronavirus disease 2019 (COVID-19), to investigate the prognosis indicators of the disease, and to provide the reference for clinical diagnosis and treatment. Methods From January 10 to February 14, 2020, at Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, the data of 333 hospitalized patients with COVID-19 were collected. The changes of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBil), direct bilirubin (DBil), indirect bilirubin (IBil) and albumin of the first liver function test after admission and the reexaminations of liver function test during hospitalization period in patients with liver injury were retrospectively analyzed. Student t test and Chi-square test were used for statistical analysis. Results Liver injury occurred in 39.6% (132/333) of COVID-19 patients. There was no statistically significant difference in the rate of liver injury between patients in intensive care unit (ICU) and in general ward (45.6%, 26/57 vs. 38.4%, 106/276; χ2=1.026, P>0.05). 67.4% (89/132) of COVID-19 patients with liver injury presented with increased ALT or AST level on admission. During hospitalization, the level of ALT was higher than that of the first examination after admission ((60.28±50.44) U/L vs. (42.25±32.21) U/L), and the difference was statistically significant (t=-3.230, P<0.05). The levels of ALT and AST of 71.2% (94/132) patients were both <80 U/L, which indicated that most of the patients showed mild liver injury. The patients with elevated level of TBil, DBil and IBil accounted for 3.9% (13/333), 5.4% (18/333) and 2.4% (8/333) of the COVID-19 patients, respectively. The albumin level of COVID-19 patients with liver injury during hospitalization was lower than that of the first examination after admission ((31.8±5.1) g/L vs. (33.7±5.4) g/L), and the difference was statistically significant (t=2.712, P<0.05). The albumin levels at first examination on admission and reexamination during hospitalization of patients in ICU were both significantly lower than those of patients in general ward ((29.3±3.7) g/L vs. (34.8±5.1) g/L and (27.6±2.8) g/L vs. (32.9±5.1) g/L), and the differences were statistically significant (t=4.928 and 4.783, both P<0.05). Conclusions The incidence of liver injury in COVID-19 patients is high. A slight increase in aminotransferase levels is particularly common. Bilirubin abnormality is relatively rare and mild. The level of albumin may be one of the indicators for the severity and prognosis of COVID-19. Key words: 2019-nCoV; COVID-19; Liver injury; Albumin

Hepatoprotective Impact Of TLR9 Antagonist ODN 2088 Against Carbon Tetrachloride (CCl4)-Induced Hepatic Injury

The main objective of this study is to evaluate the hepatoprotective impact of TLR9 antagonist ODN 2088 against carbon tetrachloride (CCl4)-induced acute liver injury. In this study, 24 mice were grouped into four groups. CCl4 was introduced in all groups except for the control group intraperitoneally after pretreatment with ODN 2088 and silymarin for seven days. To assess the liver injury, serum alanine Aminotransferase (ALT) and aspartate Aminotransferase (AST) were estimated and histopathological changes in the liver tissue were investigated. Expression of pro-inflammatory cytokines including TNF-α and IL-6 were measured. It was observed that the serum levels of biochemical parameters such as ALT and AST were remarkably elevated in mice treated only with CCl4 compared with the control mice (treated with corn oil). This increase in levels of ALT and AST was remarkably diminished by pretreatment with ODN 2088. The hepatoprotective impact of ODN 2088 on CCl4-intoxicated mice was verified by histopathological studies. ODN2088 pretreatment inhibited liver inflammation by diminishing the liver expression of CCl4-induced activity of TNF-α and IL-6. In conclusion, TLR9 antagonist, ODN 2088, protected the mice against CCl4-induced liver damage and inflammation by down-regulating the expression of pro-inflammatory cytokines.

Usefulness of serum Mac-2 binding protein glycosylation isomer in patients undergoing hepatectomy: A case controlled study.

BackgroundTo evaluate the clinical significance of Mac-2 binding protein glycosylation isomer (M2BPGi), we investigated the relationship between M2BPGi and clinicopathological and surgical parameters and posthepatectomy complications.Materials and methodsWe examined M2BPGi in 115 patients with hepatic malignancies undergoing hepatectomy. Significance as an independent prognostic marker was determined with multivariate logistic regression analysis.ResultsThe mean serum M2BPGi level was 1.14 ± 1.03 C.O.I. (range 0.2–5.79). M2BPGi in the chronic viral hepatitis group (1.42 ± 1.25) was significantly higher than that in the other disease groups (p < 0.05). The M2BPGi level correlated negatively with platelet count, LHL15 and GSA-Rmax (r = −0.36, −0.69 and −0.56, respectively; p < 0.01) but correlated positively with serum hyaluronate level (fibrotic marker), ICGR15 and HH15 (r = 0.52, 0.63 and 0.57, respectively; p < 0.01). In 53 patients examined for histological hepatic fibrosis, the M2BPGi level was highest for hepatic fibrosis stage 4, indicating cirrhosis (2.15 ± 1.56), and was significantly higher than that for stages 0–2 (p < 0.05). M2BPGi level did not correlate significantly with any surgical parameters. The preoperative level correlated significantly only with increased alanine aminotransferase level (r = −0.21, p < 0.05) and was significantly higher in patients with (1.35 ± 0.78) than without (1.11 ± 1.07) hepatectomy-related complications (p < 0.05). Area under the ROC curve analysis for prediction of hepatic fibrosis score 4 showed a cut-off value of 0.78 for M2BPGi to have high sensitivity (90%) and specificity (58%). For postoperative hepatectomy-related complications, only the M2BPGi level (at a cut-off value 0.90) tended to show significance (p = 0.06).ConclusionsThe non-invasively measured serum level of M2BPGi reflected impaired liver function or cirrhosis and hepatectomy-related complications after surgery, making it potentially useful as a complementary parameter accompanying other liver function parameters.

Dipeptidyl peptidase-4 inhibitors and aerobic exercise synergistically protect against liver injury in ovariectomized rats.

Menopause increases the risk of non‐alcoholic fatty liver disease (NAFLD). We investigated the effect of incretin and/ or exercise on the hepatic fat accumulation in ovariectomized rats. Rats were divided into five groups: Group 1: Control rats, Group 2: Ovariectomized rats, Group 3: Ovariectomized rats + Dipeptidyl peptidase‐4 inhibitor (DPPi) (30 mg/kg/day, orally), Group 4: Ovariectomized rats + swimming, and Group 5: Ovariectomized rats + swimming + DPPi. After 6 weeks, Alanine aminotransferase (ALT), glucose, insulin, HOMA IR (Homeostatic Model Assessment for Insulin Resistance), FFA (free fatty acids), Tumor necrosis factor alpha (TNF α), IL6, IL1B levels were measured in blood. The livers were collected for Hematoxylin and eosin (H&E) examination and evaluation of hepatic gene expression of SREBP (sterol regulatory element‐binding protein1c), PPAR α (peroxisome proliferator‐activated receptor alpha), ACC 1 (acetyl‐CoA carboxylase), LC3 (microtubule‐associated protein 1 light chain 3), SIRT (sirtuin), hepatic triglycerides, IL6, IL10, caspase 3 and AMPK (adenosine monophosphate‐activated protein kinase). A significant increase in ALT level and area of liver tissue defects with a significant increase in glucose HOMA IR, serum FFA, IL6, IL1B, TNF α, liver TGs (triglycerides), inflammation, apoptosis, SREBP1c, ACC1 were found in ovariectomized rats as compared to control group with a significant decrease in PPAR α, LC3, AMPK and SIRT1. DPPi treated rats with and without exercise showed a significant improvement in ALT and area of liver tissue defects, inflammation and apoptosis and serum IL6, IL1B, TNF α, FFA, liver LC3, SIRT1, AMPK, TGs, PPAR α, ACC1 and SREBP1c as compared to the ovariectomized group. Findings from the study confirm the derangement of fat metabolism in the ovariectomized rats and showed that incretin‐based therapy and exercise synergistically improved liver fat metabolism, achieved significant beneficial metabolic effects and offer full protection against NAFLD.

Mortality risk factors in children with severe influenza virus infection admitted to the pediatric intensive care unit.

Some children hospitalized for severe influenza virus infection require intensive care or die because of disease progression, which may be combined with other complications. The objective of this study was to identify the mortality risk factors in the patients with severe influenza virus infection admitted to the pediatric intensive care unit (PICU).Seventy-seven pediatric patients with severe influenza virus infection who were admitted in the PICU at Guangzhou Women and Children's Medical Center between 2013 and 2017 were evaluated. Data were transcribed and analyzed.The patients’ median age was 3.0 years (interquartile range, 1.0–4.0 years), with 59.7% of the patients aged <3 years. The mortality was 16.9%, and patients aged >3 years accounted for 69.2% of the cases. Influenza A virus infection was found in 83.1% of the patients. Coinfection was detected in 58.7% of the patients. Haemophilus influenzae (11.7%) and adenovirus (9.1%) were the predominant bacterial and viral pathogens isolated, respectively. Older age, oxygen saturation level of <90% at admission, acute respiratory distress syndrome, pneumorrhagia, influenza-associated encephalopathy (IEA), septic shock, low ratio of partial pressure of oxygen in arterial blood (PaO2, <60 mm Hg) to the fraction concentration of oxygen in inspired air (FiO2; P/F), higher oxygenation index, increased alanine aminotransferase level (>100 IU/L), increased aspartate aminotransferase level (>100 IU/L), increased lactate dehydrogenase level (>500 IU/L), high fraction concentration of oxygen in inspired air (FiO2 > 60%), and positive end-expiratory pressure (>8 cmH2O) were associated with poor outcome. The deceased patients were more likely to have oxygen saturation levels of <90% at admission and IEA than those who survived. Higher P/F ratio was a protective factor against death in patients.The children with severe influenza virus infection who were admitted in the PICU were mainly aged <3 years. The presence of an oxygen saturation level of <90% at admission and IEA were the prognostic variables independently associated with mortality. Higher P/F ratio was a protective factor against death in patients.

Effect of Bile Duct Ligation-induced Liver Dysfunction on Methamphetamine Pharmacokinetics and Locomotor Activity in Rats.

Methamphetamine (METH) abuse is associated with hepatic dysfunction related comorbidities such as HIV, hepatitis C, and polysubstance abuse with acetaminophen-containing opioid formulations. We aimed to develop a bile duct ligation (BDL)-induced hepatic dysfunction model for studying both METH and experimental treatments for METH abuse in this comorbidity. Sham or BDL surgery was performed in male Wistar rats on day 0. Liver function was measured throughout the study. On days 7 and 19, serum pharmacokinetics studies were performed with 1 mg/kg subcutaneous (sc) METH. On day 21, this dose was repeated to determine 2 h post-METH brain concentrations. METH-induced open field behaviors were measured every other day (days 12 - 16) with ascending sc doses (0.3 - 3 mg/kg). BDL transiently increased alanine aminotransferase levels and altered liver structure, which resulted in significantly greater METH serum and brain exposure. In the BDL compared to sham group, there was a longer duration of METH-induced locomotor activity (after 1 and 3 mg/kg) and stereotypy (after 3 mg/kg). In rats, liver dysfunction reduced METH clearance, increased brain METH concentrations, and enhanced METH effects on locomotor activity in a dose dependent manner. In addition, this model could be further developed to simulate the associated hepatic dysfunction of key METH abuse comorbidities for preclinical testing of novel pharmacotherapies for effectiveness and/or toxicity in vulnerable populations.

Evaluation of a logistic regression model for predicting liver necroinflammation in hepatitis B e antigen‐negative chronic hepatitis B patients with normal and minimally increased alanine aminotransferase levels

Liver necroinflammation is the indicator for treating patients with chronic hepatitis B (CHB) infection. However, there is no suitable non-invasive index for diagnosing liver necroinflammation. This study aimed to create a non-invasive index to predict liver necroinflammation in patients who lack clear-cut clinical inflammation parameters. Patients who were hepatitis B e antigen (HBeAg)-negative and underwent liver histological diagnosis, had a normal or minimally increased alanine aminotransferase (ALT) level were enrolled. Liver necroinflammation was defined as histological active index ≥4. A logistic regression model (LRM) was established based on the parameters independently associated with liver necroinflammation. Of all 550 patients, 36.73% had necroinflammation. In patients with an abnormal ALT level, the rate of necroinflammation was 52.49%. The area under the curve (AUC) of the ALT level for predicting necroinflammation was 0.655 (95% confidence interval [CI], 0.609-0.702), and that of the HBV DNA level ≥2000IU/mL combined with an abnormal ALT level was 0.618. By using the LRM, the AUC improved to 0.769 (95% CI, 0.723-0.815) with a Youden index of 0.519 and diagnostic accuracy of 75.3%. The cutoff value ≥0.7 in the LRM had a specificity of 97.4% and positive predictive value of 85.0% for predicting necroinflammation. By using the cutoff value <0.15 in the LRM, the presence of necroinflammation could be excluded with a negative predictive value of 90.8%. This study indicated that the LRM can be used to effectively diagnose liver necroinflammation in HBeAg-negative patients with CHB who have normal or minimally elevated ALT levels.

Changes in the Levels of Some Biochemical Parameters in the Serum of Children in Response to the Giardiasis Infection

Giardiasis is one of the most common intestinal protozoan infections worldwide. The study aimed to determine the levels of a number of biochemical parameters in the sera of children with giardiasis without receiving any medication for the treatment of giardiasis or intestinal helminthic infections in the previous 7 days. The study conducted 34 (19 females and 15 males) children and 34 (18 females and 16 males) healthy children as a control group. The mean ages of infected children and control groups were 8 ± 2 and 7 ± 2 years, respectively. Serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatinine, urea, sodium, potassium, uric acid, and albumin were determined. AST level in males was significantly higher than healthy children control (14.20 ± 1.896 and 10.06 ± 0.699), respectively (P &lt; 0.05), and no significant difference in females was noticed whereas the significant increases in ALT level were found when compared to control (12.43 ± 0.806 and 8.666 ± 0.449), for female, respectively, whereas no significant change in males was observed. Creatinine levels showed significant decrease in females when compared to control (57.72 ± 1.170 and 73.37 ± 1.635) (P ≤ 0.001), respectively.

A toll-like receptor 9 agonist sensitizes mice to mitochondrial dysfunction-induced hepatic apoptosis via the Fas/FasL pathway.

Early hepatocyte death occurs in most liver injury cases and triggers liver inflammation, which in combination with other risk factors leads to the development of liver disease. However, the pathogenesis of early phase hepatocyte death remains poorly understood. Here, C57BL/6J mice were treated with the hepatotoxic drug flucloxacillin (FLUX) and the toll-like receptor 9 agonist CpG oligodeoxynucleotide (ODN) to reproduce the early phase of drug-induced hepatotoxicity and investigate its pathogenesis. C57BL/6J mice were treated with FLUX (100mg/kg, gavage) alone or in combination with ODN (40μg/mouse, intraperitoneally). Plasma alanine aminotransferase (ALT) level was measured as a marker of hepatotoxicity. FLUX or ODN alone was insufficient to induce ALT elevation, whereas combination treatment with FLUX and ODN increased ALT levels 24h after FLUX treatment and upregulated Fas ligand in natural killer T (NKT) cells and Fas in hepatocytes. FLUX induced mitochondrial permeability transition (MPT), and pretreatment with ODN sensitized mitochondria to FLUX-induced MPT. The increase in ALT levels induced by ODN and FLUX co-treatment was suppressed in Fas ligand (gld/gld)-deficient mice and in mice deficient in a component of MPT pore opening (cyclophilin D-knockout mice). These results suggested that ODN activated the Fas/Fas ligand-mediated pathway in NKT cells and hepatocytes, which may predispose to FLUX-induced mitochondrial dysfunction and lead to early phase hepatocyte apoptosis. Taken together, these findings elucidate a potentially novel mechanism underlying drug-induced early phase hepatocyte death related to the Fas/Fas ligand death receptor pathway and mitochondrial dysfunction.

Development and Validation of a Novel Model to Predict Liver Histopathology in Patients with Chronic Hepatitis B.

It is still vague for chronic hepatitis B (CHB) patients with normal or mildly increasing alanine aminotransferase (ALT) level to undergo antiviral treatment or not. The purpose of our study was to establish a noninvasive model based on routine blood test to predict liver histopathology for antiviral therapy. This retrospective study enrolled 258 CHB patients with liver biopsy from the First Hospital of Quanzhou (training cohort, n=126) and Huashan Hospital (validation cohort, n=132). Histologic grading of necroinflammation (G) and liver fibrosis (S) was performed according to the Scheuer scoring system. A novel model, ATPI, including aspartate aminotransferase (AST), total bilirubin (TBil), and platelets (PLT), was developed in training cohort. The area under ROC curves (AUC) of ATPI for predicting antiviral therapy indication was 0.83 in training cohort and was 0.88 in the validation cohort, respectively. Similarly, ATPI also displayed the highest AUC in predicting antiviral therapy indication in CHB patients with normal or mildly increasing ALT level. In conclusion, ATPI is a novel independent model to predict liver histopathology for antiviral therapy in CHB patients with normal and mildly increased ALT levels.

Changes of Th17/Treg ratio in the transition of chronic hepatitis B to liver cirrhosis and correlations with liver function and inflammation.

The changes in ratio of T helper 17 cells (Th17) to Treg cells in the transition of chronic hepatitis B (CHB) to liver cirrhosis, and the correlations with liver function and inflammation were investigated. A total of 20 normal subjects (control group), 35 CHB patients (CHB group) and 40 post-hepatitis liver cirrhosis patients (liver cirrhosis group) were enrolled into this study. Liver function was measured through the levels of alanine aminotransferase (ALT) and aspartic transaminase (AST), and the hematoxylin and eosin (H&E) staining method was used to detect the histopathological features. mRNA expression of inflammation-associated factors was detected using RT-PCR. The protein expression of nuclear factor κB (NF-κB) was measured in liver tissues using the immunofluorescent method and western blot assay. In the CHB and liver cirrhosis groups, the increases in Th17 cells were more evident than those in Treg cells. Moreover, an evident increase in levels of ALT and AST was identified in the two groups. Structures of liver tissues in the CHB and liver cirrhosis groups were destroyed with damage to the cell nuclei. The expression of inflammation-associated factors were significantly elevated compared to those in the control group. NF-κB expressed in the CHB and liver cirrhosis groups was significantly higher than that in control group. The results of analysis of variance indicated that differences in the expression of interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α and NF-κB in the three groups had statistical significance (P<0.01). In conclusion, transition from CHB to liver cirrhosis comes with significant changes in Th17/Treg ratio, which is correlated with a decrease in liver function, and also closely associated with the development and progression of inflammation.

Hepatitis E virus in Spanish donors and the necessity for screening.

Hepatitis E virus (HEV) represents a major health problem worldwide. As the course of HEV cases is often subclinical, asymptomatic infections could represent an important source of viral spread and infection via routes such as blood donations. Before universal screening for HEV in blood donations can be implemented, studies evaluating the incidence of infection are needed to establish the potential risk of viral transmission. This is a prospective longitudinal study that included blood donors recruited at the Hospital de Ciudad Real Transfusion Service between October 2017 and January 2018. Pools of eight donations were tested for HEV viremia by PCR. Positive pools were individually evaluated following the same procedure. Positive samples were tested for anti-HEV IgG and IgM. Recipients of blood transfusions obtained from HEV-positive donors were retrospectively evaluated. The prevalence of HEV was calculated. A total of 11313 healthy donors were analysed during the study period. Four blood donations from four different donors were HEV RNA-reactive. The prevalence of HEV infection was 0.035% (95% CI: 0.01%-0.09%), which meant a ratio of one positive donation per 2828 donations. All donors were negative for anti-HEV IgM at the time of the donation. Five patients received transfusions from HEV-positive blood donations, none of them showed an increase in alanine aminotransferase levels after transfusion. In conclusion, our study found a high prevalence of HEV infection in blood donors from south-central Spain. In view of the prevalence, Spanish blood banks should carefully consider including screening for HEV.

Liver function biomarkers disorder is associated with exposure to perfluoroalkyl acids in adults: Isomers of C8 Health Project in China

Exposure to chemicals may affect liver enzyme to increase the risk of liver diseases. Perfluoroalkyl acids (PFAAs) are one kind of persistent organic pollutants with hepatotoxic effect in organism. However, data is scarce to characterize the hepatotoxic effects of specific structural PFAA isomers in general population. To address this data gap, we evaluated the association between serum PFAAs concentration and liver function biomarkers in the Isomers of C8 Health Project in China. High performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was used to measure 18 serum PFAAs, except for linear and branched isomers of PFOA/PFOS, nine perfluorinated carboxylic acids (PFCAs) and two perfluorinated sulfonic acids (PFSAs) were also included, in 1605 adult residents of Shenyang, China. Values for nine serum liver function biomarkers were determined by full-automatic blood biochemical analyzer. Linear regression was used to evaluate associations between PFAAs and continuous liver function biomarkers and logistic regression to assess markers dichotomized per clinical reference intervals. Results indicated that serum PFAAs concentrations were associated with liver biomarker levels suggestive of hepatotoxicity, especially for liver cell injury. For example, a 1 ln-unit increase in total- perfluorooctanoic acid (PFOA) exposure was associated with a 7.4% [95% confidence interval (CI): 3.9%, 11.0%] higher alanine aminotransferase (ALT) level in serum. Interestingly, we observed association between branched PFAA isomers and liver biomarkers. For example, one ln-unit increase in branched perfluorooctane sulfonate (PFOS) isomers exposure was associated with a 4.3% increase in ALT level (95% CI: 1.2%, 7.4%) and a 33.0% increased odds of having abnormal ALT (95% CI: 5.0%, 67.0%). Also, we found that PFNA had positive association with ALT [(6.2%, 95% CI: 3.1%, 9.4%) and AST levels (2.5%, 95% CI: 0.5%, 4.5%)]. Logistic regression results showed that PFPeA, PFHxA, PFNA, PFDoDA, PFTrDA and PFTeDA had statistically association with abnormal prealbumin. Conclusively, our results support previous studies showing association between PFAAs exposure and liver function biomarkers. We found new evidence that branched PFAAs isomer exposure is associated with the risk of clinically relevant hepatocellular dysfunction.